Combination therapies with hafnium oxide nanoparticles and PD-l1 antibodies for use in the treatment of non small cell lung cancer

Abstract

Provide herein are methods of treating non-small cell lung cancer (NSCLC) in an individual in need thereof by administering a combination of a nanoparticle composition comprising HfO2, radiation therapy, chemotherapy, and a PD-L1 antibody to the individual. Also provided are methods of selecting an individual for treatment of NSCLC according to the methods provided herein.

Description

Docket No.: 242272002940COMBINATION THERAPIES WITH HAFNIUM OXIDE NANOPARTICLES AND PD-L1 ANTIBODIESCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to and the benefit of U.S. Provisional Application No. 63 / 702,404, filed October 2, 2024; U.S. Provisional Application No. 63 / 774,567, filed March 19, 2025; and U.S. Provisional Application No. 63 / 872,714, filed August 29, 2025, the contents of each of which are incorporated herein by reference in their entirety.FIELD OF THE INVENTION

[0002] The present disclosure relates to methods of treating non-small cell lung cancer (NSCLC) by administering a combination of a nanoparticle composition comprising HfC , radiation therapy, chemotherapy, and a PD-L1 antibody to an individual in need thereof.Also provided are methods of selecting an individual for treatment of NSCLC according to the methods provided herein.REFERENCE TO AN ELECTRONIC SEQUENCE LISTING

[0003] The content of the electronic sequence listing (242272002940seqlist.xml; Size: 10,550 bytes; and Date of Creation: September 30, 2025) is herein incorporated by reference in its entirety.BACKGROUND

[0004] The World Health Organization (WHO) estimates 2.1 million people are diagnosed with lung cancer globally each year. Almost 1.76 million deaths occur annually from this disease, making it the leading cause of cancer-related deaths (see, e.g., WHO 2022). In the United States, it is estimated that 127,000 deaths may have occurred in 2023 (see, e.g., Siegel 2023).

[0005] Most lung cancers are non-small cell lung cancers (NSCLC) with about 20% having locally advanced disease (AJCC Stage III), of which approximately 80% are unresectable at presentation (see, e.g., SEER 2023). Furthermore, about 10% to 20% of patients with early- stage lung cancer initially treated with definitive therapy recur as locally advanced and often unresectable disease (see, e.g., Timmerman 2018a, Timmerman 2018b, Spratt 2016, Marwaha 2014, Robinson 2013, and Inagaki 2023).

[0006] For the past several decades, the first line SOC treatment for patients with locally advanced and unresectable Stage III NSCLC has been concurrent platinum-based doublet ChT with RT (cCRT). While this treatment paradigm potentially benefited a small subset,1MF-361301351Docket No.: 242272002940 overall, this was associated with very poor outcomes (5-year progression free survival [PFS] of 19%; 5-year overall survival [OS] of 33%) (see, e.g., Paz-Ares 2017). Furthermore, despite the addition of concurrent ChT to RT, there continues to be high rates of local failure ranging from 28% to 43% (see, e.g., Auperin 2010, and Kishi 2023).

[0007] In recent years, there have been significant improvements in outcomes with the addition of consolidation immunotherapy (cIT), highlighted by the results of the PACIFIC study (i.e., NCT02125461). With the addition of consolidation durvalumab, the PACIFIC study noted improvements in outcomes, with an increase in 5-year PFS to 33% and 5-year OS to 43% (see, e.g., Spigel 2022). These data were the basis of approval in 2017 of IMFINZI (durvalumab) for the treatment of adult patients with unresectable, Stage III NSCLC whose disease has not progressed following cCRT. As a result, the SOC has shifted to cCRT followed by 12 months of durvalumab consolidation therapy.

[0008] While this new treatment paradigm has improved patient outcomes, there remains a continued significant unmet need in patients with locally advanced and unresectable Stage III NSCLC. Of note, only participants who did not have progressive disease (PD) after cCRT were eligible for durvalumab consolidation, suggesting that the PACIFIC study was enriched with patients with a relatively favorable prognosis (see, e.g., Paz-Ares 2017). It is estimated that 10% to 20% of patients with locally advanced and unresectable Stage III disease are not eligible for durvalumab after cCRT, presumably due to progression of disease (see, e.g., Desilets 2021, Offin 2020, Bruni 2021, and Herbst 2022). The prognosis of this population is expected to be worse compared with those who go on to receive durvalumab and is likely similar to the poor PFS and OS outcomes seen prior to the PACIFIC study. Furthermore, 10% to 30% of patients with unresectable Stage III NSCLC who are eligible for durvalumab consolidation have programmed death-ligand 1 (PD-L1) expression of <1%, for which population subset analyses have suggested decreased efficacy of immunotherapy (see, e.g., Zhang 2023, and Spigel 2022). Taken together, a significant portion of the locally advanced and unresectable Stage III NSCLC patient population are either not eligible for durvalumab or will not derive a benefit from it, thus representing a large percentage with an unmet need. Furthermore, even for those patients who are eligible and responsive to durvalumab, many have poor survival outcomes and are in search of additional therapeutic opportunities.Therefore, while the PACIFIC regimen represents a relatively recent improvement in outcomes, there continues to be a clinically significant unmet need for patients with locally advanced and unresectable Stage III NSCLC.2MF-361301351Docket No.: 242272002940BRIEF SUMMARY

[0009] In one aspect, the present application relates to a method of treating locally advanced and unresectable Stage III non-small cell lung cancer (NSCLC) in an individual comprising:(i) administering a nanoparticle composition comprising nanoparticles comprising HIO2 with a biocompatible coating to the individual; (ii) administering radiation therapy to the individual; (iii) administering chemotherapy to the individual; and (iv) administering a PD- L1 antibody to the individual. In another aspect, the present application relates to a method of treating locally advanced and unresectable Stage IIIA or Stage IIIB non-small cell lung cancer (NSCLC) in an individual comprising: (i) administering a nanoparticle composition comprising nanoparticles comprising HfCL with a biocompatible coating to the individual;(ii) administering radiation therapy to the individual; (iii) administering chemotherapy to the individual; and (iv) administering a PD-L1 antibody to the individual. In another aspect, the present application relates to a method of treating locally advanced and unresectable Stage IIIC non-small cell lung cancer (NSCLC) in an individual comprising: (i) administering a nanoparticle composition comprising nanoparticles comprising HfCL with a biocompatible coating to the individual; (ii) administering radiation therapy to the individual; (iii) administering chemotherapy to the individual; and (iv) administering a PD-L1 antibody to the individual. In some embodiments, the method further comprises administering a corticosteroid to the individual prior to administering the nanoparticle composition. In some embodiments, the corticosteroid is selected from the group consisting of prednisone and dexamethasone.

[0010] In some embodiments according to any of the methods provided herein, the corticosteroid is prednisone, wherein the prednisone is administered at a dose of about 30 mg, and wherein the prednisone is administered less than 24 hours before the nanoparticle composition is administered. In some embodiments, about 30 mg prednisone is administered to the individual about 12+2 hours or about 2+2 hours before the nanoparticle composition is administered. In some embodiments, the prednisone is administered orally.

[0011] In some embodiments according to any of the methods provided herein, the corticosteroid is dexamethasone, wherein the dexamethasone is administered less than three hours before the nanoparticle composition is administered. In some embodiments, the dexamethasone is administered about an hour before the nanoparticle composition is administered. In some embodiments, the dexamethasone is administered intravenously.3MF-361301351Docket No.: 242272002940

[0012] In some embodiments according to any of the methods provided herein, the average size of the nanoparticles in the nanoparticle composition is between about 10 nm and about 200 nm. In some embodiments, the hydrodynamic diameter of the nanoparticles in the nanoparticle composition is about 50 nm. In some embodiments, the biocompatible coating of the of the nanoparticles in the nanoparticle composition is sodium trimetaphosphate (STMP) or sodium hexametaphosphate (HMP). In some embodiments, the nanoparticles in the nanoparticle composition act as a radio-enhancer. In some embodiments, the nanoparticles in the nanoparticle composition amplify energy deposition at the site of a tumor. In some embodiments, the nanoparticle composition comprises: (a) about 5 mL of a concentrated aqueous solution comprising the nanoparticles at a density of about 64 g / L and at a pH of about 6.0 to about 8.0; and (b) about 1 mL of a 30% glucose solution; wherein the nanoparticle composition has a density of about 54.2 g / L and a pH of about 6.0 to about 8.0. In some embodiments, the nanoparticle composition comprises: (a) about 5 mL of a concentrated aqueous solution comprising the nanoparticles at a density of about 64 g / L and at a pH of about 6.0 to about 8.0; and (b) about 1 mL of a 30% glucose solution; wherein the nanoparticle composition has a density of about 54 mg / mL and a pH of about 6.0 to about 8.0. In some embodiments, the nanoparticle composition is administered intratumorally and / or intranodally. In some embodiments, the nanoparticle composition is administered in a fractionated dose to an individual with a tumor comprising a dimension of > 3 cm, wherein the dimension is the longest dimension. In some embodiments, the nanoparticle is administered via bronchoscopic and / or percutaneous approach. In some embodiments, the nanoparticle composition is administered once. In some embodiments, the nanoparticle composition is administered intratumorally and / or intranodally at a dose of between about 15% gross tumor volume (GTV) to about 40% GTV of a tumor. In some embodiments, the nanoparticle composition is administered intratumorally and / or intranodally at a dose of about 22% GTV or a dose of about 33% GTV. In some embodiments, the nanoparticle composition comprises nanoparticles at a concentration of about 50 g / L to about 60 g / L.

[0013] In some embodiments according to any of the methods provided herein, the radiation therapy is administered two days or more after administration of the nanoparticle composition. In some embodiments according to any of the methods provided herein, the radiation therapy is first administered two days or more after administration of the nanoparticle composition. In some embodiments, the radiation therapy comprises administering more than one fraction of ionizing radiation over more than one day. In some4MF-361301351Docket No.: 242272002940 embodiments, the radiation therapy comprises administering at least 10 fractions of ionizing radiation. In some embodiments, the ionizing radiation is selected from the group consisting of X-Rays, y-Rays, electron beams and radioisotope emissions. In some embodiments, the ionizing radiation is administered by intensity modulated radiation therapy (IMRT). In some embodiments, the IMRT is selected from the group consisting of static field IMRT, helical IMRT, and volumetric modulated arc therapy (VMAT) using megavoltage therapy. In some embodiments, the ionizing radiation is administered by external beam intensity modulated radiation therapy (IMRT). In some embodiments, the external beam IMRT is selected from the group consisting of static field IMRT, helical IMRT, and volumetric modulated arc therapy (VMAT) using megavoltage therapy. In some embodiments, the radiation therapy comprises administering a total of about 40 Gy to about 80 Gy of radiation to the individual. In some embodiments, administering radiation therapy comprises administering about 1 Gy to about 3 Gy per fraction to the individual. In some embodiments, the radiation therapy comprises administering radiation therapy to the individual four times per week to six times per week. In some embodiments, the radiation therapy comprises administering radiation therapy five times per week. In some embodiments, the radiation therapy comprises administering about 2 Gy radiation five times per week for six weeks, wherein the first dose is administered two or more days after administration of the nanoparticle composition.

[0014] In some embodiments according to any of the methods provided herein, the chemotherapy comprises carboplatin and paclitaxel. In some embodiments, the chemotherapy comprises administering carboplatin intravenously at a dose of AUC2 and administering paclitaxel at a dose of 45-50 mg / m2. In some embodiments, the chemotherapy comprises administering carboplatin intravenously at a dose of AUC2 and administering paclitaxel at a dose of 45 mg / m2. In some embodiments, the chemotherapy administration is started between three days before and three days after starting the radiation therapy (e.g., the first dose of the chemotherapy treatment is administered between about three days before and about three days after the first dose of the radiation therapy is administered). In some embodiments, the chemotherapy administration is started on the same day as starting the radiation therapy (e.g., the first dose of the chemotherapy treatment is administered on the same day as the first dose of the radiation therapy is administered). In some embodiments, the chemotherapy is administered once per week ± 3 days. In some embodiments, the carboplatin and the paclitaxel are administered on Day One of a seven-day chemotherapy cycle. In some embodiments, six chemotherapy cycles are administered to the individual.5MF-361301351Docket No.: 242272002940

[0015] In some embodiments according to any of the methods provided herein, the PD-L1 antibody is durvalumab. In some embodiments, the PD-L1 antibody is administered to the individual within 10 weeks after administration of a last fraction of the radiation therapy. In some embodiments, the PD-L1 antibody is first administered to the individual within 10 weeks after administration of a last fraction of the radiation therapy. In some embodiments, the PD-L1 antibody is administered to the individual within 10 weeks after a last dose of the chemotherapy. In some embodiments, the PD-L1 antibody is first administered to the individual within 10 weeks after a last dose of the chemotherapy. In some embodiments, the PD-L1 antibody is administered the later of: (a) within six weeks of administration of a last fraction of the radiation therapy, or (b) within six weeks of administration of a last dose of the chemotherapy. In some embodiments, the PD-L1 antibody is first administered the later of: (a) within six weeks of administration of a last fraction of the radiation therapy, or (b) within six weeks of administration of a last dose of the chemotherapy. In some embodiments, the durvalumab is administered at a dose of about 1500 mg. In some embodiments, the durvalumab is administered in an immunotherapy cycle of every four weeks (Q4W) ± 3 days. In some embodiments, the durvalumab is administered in an immunotherapy cycle of every four weeks (Q4W). In some embodiments, the immunotherapy cycle is continued for up to 13 cycles over 52 weeks. In some embodiments, the durvalumab is administered at a dose of about 10 mg / kg. In some embodiments, the durvalumab is administered in an immunotherapy cycle of every two weeks (Q2W) ± 3 days. In some embodiments, the durvalumab is administered in an immunotherapy cycle of every two weeks (Q2W). In some embodiments, the immunotherapy cycle is continued for up to 26 cycles over 52 weeks.

[0016] In another aspect provided herein is a method of treating locally advanced and unresectable Stage III non-small cell lung cancer in an individual comprising a dosing schedule of at least 52 weeks comprising: (i) administering a nanoparticle composition comprising nanoparticles comprising HfC with a biocompatible coating to the individual on day 0; (ii) administering radiation therapy to the individual at a dose of 2 Gy per fraction, wherein one fraction is delivered daily for five days per week for a total of six weeks, wherein the radiation therapy is started two or more days after the nanoparticle composition is administered; (iii) administering chemotherapy to the individual, wherein the chemotherapy comprises: (a) carboplatin administered at a dose of AUC2, and (b) paclitaxel administered at a dose of about 45-50 mg / m2on day one of a seven day chemotherapy cycle, wherein six chemotherapy cycles are administered to the individual, and wherein the6MF-361301351Docket No.: 242272002940 chemotherapy is started up to three days before or three days after the radiation therapy is started; and (iv) administering durvalumab to the individual, wherein durvalumab administration is started within six weeks of administration of a last dose of the chemotherapy or a last dose of radiation therapy, wherein the durvalumab is administered to the individual: (a) at a dose of about 1500 mg, Q4W up to 13 times over 52 weeks; or (b) at a dose of about 10 mg / kg Q2W for up to 26 times over 52 weeks.

[0017] In another aspect provided herein is a method of treating locally advanced and unresectable Stage IIIA or Stage IIIB non-small cell lung cancer in an individual comprising a dosing schedule of at least 52 weeks comprising: (i) administering a nanoparticle composition comprising nanoparticles comprising HfC with a biocompatible coating to the individual on day 0; (ii) administering radiation therapy to the individual at a dose of 2 Gy per fraction, wherein one fraction is delivered daily for five days per week for a total of six weeks, wherein the radiation therapy is started two or more days after the nanoparticle composition is administered; (iii) administering chemotherapy to the individual, wherein the chemotherapy comprises: (a) carboplatin administered at a dose of AUC2, and (b) paclitaxel administered at a dose of about 45 mg / m2on day one of a seven day chemotherapy cycle, wherein six chemotherapy cycles are administered to the individual, and wherein the chemotherapy is started up to three days before or three days after the radiation therapy is started; and (iv) administering durvalumab to the individual within six weeks of administration of a last dose of the chemotherapy or a last dose of radiation therapy, wherein the durvalumab is administered to the individual: (a) at a dose of about 1500 mg, Q4W up to 13 times over 52 weeks; or (b) at a dose of about 10 mg / kg Q2W for up to 26 times over 52 weeks.

[0018] In another aspect provided herein is a method of treating locally advanced and unresectable Stage IIIC non-small cell lung cancer in an individual comprising a dosing schedule of at least 52 weeks comprising: (i) administering a nanoparticle composition comprising nanoparticles comprising HfC with a biocompatible coating to the individual on day 0; (ii) administering radiation therapy to the individual at a dose of 2 Gy per fraction, wherein one fraction is delivered daily for five days per week for a total of six weeks, wherein the radiation therapy is started two or more days after the nanoparticle composition is administered; (iii) administering chemotherapy to the individual, wherein the chemotherapy comprises: (a) carboplatin administered at a dose of AUC2, and (b) paclitaxel administered at a dose of about 45-50 mg / m2on day one of a seven day chemotherapy cycle,7MF-361301351Docket No.: 242272002940 wherein six chemotherapy cycles are administered to the individual, and wherein the chemotherapy is started up to three days before or three days after the radiation therapy is started; and (iv) administering durvalumab to the individual, wherein durvalumab administration is started within six weeks of administration of a last dose of the chemotherapy or a last dose of radiation therapy, wherein the durvalumab is administered to the individual: (a) at a dose of about 1500 mg, Q4W up to 13 times over 52 weeks; or (b) at a dose of about 10 mg / kg Q2W for up to 26 times over 52 weeks.

[0019] In some embodiments according to any of the methods provided herein, the size of a tumor in the individual is decreased following treatment. In some embodiments, the size of the tumor before treatment and following treatment is assessed by CT of the chest and upper abdomen including liver and adrenal glands, and optionally by PET-CT scan and / or contrast MRI-brain scan.

[0020] In some embodiments according to any of the methods provided herein, the individual has an objective response. In some embodiments, the objective response rate in a population of patients receiving such therapy is improved (e.g., by about any of 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, or more) compared to the standard of care. In some embodiments, the disease control rate in a population of patients receiving such therapy is improved compared to the standard of care. In some embodiments, the objective response rate is based upon an independent central review assessment according to RECIST b 1.1. In some embodiments, the objective response rate is determined after administration of the chemotherapy and before administration of the PD-L1 antibody. In some embodiments, the progression free survival in a population of patients receiving such therapy is improved compared to the standard of care.

[0021] In some embodiments according to any of the methods provided herein, the time to event and landmark at 6, 12, and 24 months in a population of patients receiving such therapy is improved compared to the standard of care.

[0022] In some embodiments according to any of the methods provided herein, the time to locoregional failure and time to distant failure in a population of patients receiving such therapy is improved compared to the standard of care.

[0023] In some embodiments according to any of the methods provided herein, the individual does not experience a treatment emergent adverse event.8MF-361301351Docket No.: 242272002940

[0024] In another aspect provided herein is a method of selecting an individual for treatment of NSCLC, comprising: (a) identifying an individual with Stage III NSCLC, and (b) administering to the individual the treatment according to any the methods described herein.

[0025] In another aspect provided herein is a method of selecting an individual for treatment of NSCLC, comprising: (a) identifying an individual with Stage IIIA or Stage IIIB NSCLC, and (b) administering to the individual the treatment according to any the methods described herein.

[0026] In another aspect provided herein is a method of selecting an individual for treatment of NSCLC, comprising: (a) identifying an individual with Stage IIIC NSCLC, and (b) administering to the individual the treatment according to any the methods described herein.

[0027] In some embodiments according to any of the methods provided herein, the individual has a life expectancy of at least 6 months at the start of treatment.

[0028] In some embodiments according to any of the methods provided herein, the individual has locally advanced Stage III NSCLC according to the Eighth Edition Lung Cancer Stage Classification that is unresectable.

[0029] In some embodiments according to any of the methods provided herein, the individual has locally advanced Stage IIIA or IIIB NSCLC according to the Eighth Edition Lung Cancer Stage Classification that is unresectable.

[0030] In some embodiments according to any of the methods provided herein, the individual has locally advanced Stage IIIC NSCLC according to the Eighth Edition Lung Cancer Stage Classification that is unresectable.

[0031] In some embodiments according to any of the methods provided herein, the individual has a tumor proportion score of PD-L1. In some embodiments, the Stage III NSCLC expresses PD-L1. In some embodiments, the Stage IIIA or Stage IIIB NSCLC expresses PD- Ll. In some embodiments, the Stage IIIC NSCLC expresses PD-L1.

[0032] In some embodiments according to any of the methods provided herein, the individual does not have metastatic disease.

[0033] In some embodiments according to any of the methods provided herein, the individual has unresectable Stage III NSCLC. In some embodiments according to any of the methods provided herein, the individual has unresectable Stage IIIA or unresectable Stage IIIB NSCLC. In some embodiments according to any of the methods provided herein, the individual has unresectable Stage IIIC NSCLC.9MF-361301351Docket No.: 242272002940

[0034] In some embodiments according to any of the methods provided herein, the individual has a calculated total gross tumor volume < 909 mL. In some embodiments, the individual does not have a tumor with invasion and / or encasement of great vessels or esophagus, baseline presence of fistula, and / or malignant airway obstruction requiring endoscopic intervention.

[0035] In some embodiments according to any of the methods provided herein, the individual does not have ipsilateral or contralateral scalene or supraclavicular lymph node involvement.

[0036] In some embodiments according to any of the methods provided herein, the individual does not have a corrected QT interval by Fredericia (QTcF interval) greater than 480 msec.

[0037] In some embodiments according to any of the methods provided herein, the individual has: (a) a serum total bilirubin level of < 1.5x upper limit of normal (ULN), or wherein the individual has been diagnosed with or is suspected to have congenital nonhemolytic hyperbilirubinemia and has a total bilirubin level of < 6 mg / dL and has a conjugated bilirubin level of < 20% of total bilirubin; (b) an AST level and / or an ALT level of < 3 x ULN; (c) a hemoglobin level of > 9.0 g / dL; (d) a serum creatinine clearance rate of > 50 mL / min by the Cockcroft- Gault formula; (e) a platelet count of > 100 xl09 / L; and / or (f) an absolute neutrophil count of > 1.5 xl09 / L, wherein the individual has not been administered a growth factor within about 10 days before the start of treatment.

[0038] In some embodiments according to any of the methods provided herein, the individual has: (a) an AST level and / or an ALT level of < 3 x ULN; (b) a hemoglobin level of > 9.0 g / dL; (c) a platelet count of > 100 xl09 / L; and / or (d) an absolute neutrophil count of > 1.5 X109 / L, wherein the individual has not been administered a growth factor within about 10 days before the start of treatment.BRIEF DESCRIPTION OF THE DRAWINGS

[0039] FIGs. 1A-1B show an overview of the clinical trial protocol for the run-in Part 1 (FIG. 1A) and the dose optimization in Part 2 (FIG. IB).1indicates that all participants are scheduled to start consolidation durvalumab treatment within 6 weeks of last fraction of radiation therapy (RT) or last dose of platinum-based doublet chemotherapy (ChT) (whichever is later) if no evidence of PD at post-cCRT CT assessment by the investigator, including participants who are clinically stable but whose disease assessment is a suspicious PD, and per investigator’s determination, a confirmation CT is planned for which results are pending (no less than 4 weeks after the initial assessment of PD).2indicates that tumor assessments are performed at screening and after completion of cCRT, q8w during cIT10MF-361301351Docket No.: 242272002940 treatment, at the end of treatment (EOT), and ql2w post-cIT treatment until confirmed PD per RECIST vl.l.3indicates that the post-cCRT CT scan occurs within 4 weeks after the last fraction of RT or the last dose of ChT administered, whichever is later.4indicates that EOT is defined as completing the planned study treatment, confirmed PD on CT as assessed by investigator per RECIST vl.l, or premature termination of study treatment for any reason, whichever occurs first.5indicates that all participants will be followed up until 24 months after last treatment of cCRT. After the clinical cutoff for the primary clinical study report (CSR), participants are enrolled under a separate protocol to be followed for up to 5 years for late radiation adverse event of special interest (AESI) on a long-term safety follow-up extension study. R=randomization; HfCh nano. = hafnium oxide (HfCh) nanoparticles; cCRT = concurrent platinum-based doublet chemotherapy with radiation therapy; cIT = consolidation immunotherapy; PD = progressive disease; RECIST vl.l = Response Evaluation Criteria in Solid Tumors version 1.1; q8w = every 8 weeks; EOT = end of treatment; ql2w = every 12 weeks; CT = computed tomography.

[0040] FIG. 2 provides a schematic overview of a Phase I clinical trial protocol that evaluated the safety of the HfOi nanoparticles.

[0041] FIG. 3A provides a Kaplan-Meier curve that demonstrates local progression-free survival up to 24 months following administration of the HfCh nanoparticles in combination with reirradiation (reRT). FIG. 3B provides a Kaplan-Meier plot for Overall Survival.

[0042] FIGs. 4A-4B show an overview of the clinical trial protocol for the run-in Part 1 (FIG. 4A) and the dose optimization in Part 2 (FIG. 4B).1indicates that all participants are scheduled to start consolidation durvalumab treatment within 6 weeks of last fraction of radiation therapy (RT) or last dose of platinum-based doublet chemotherapy (ChT) (whichever is later) if no evidence of PD at post-cCRT CT assessment by the investigator, including participants who are clinically stable but whose disease assessment is a suspicious PD, and per investigator’s determination, a confirmation CT is planned for which results are pending (no less than 4 weeks after the initial assessment of PD).2indicates that tumor assessments are performed at screening and after completion of cCRT, and subsequently at a fixed schedule, q8w (±7 days) for 12 months and then ql2w (±14 days) until 24 months after last dose of cCRT, radiographic PD or participant withdrawal, whichever occurs first.3indicates that the post-cCRT CT scan occurs within 2 weeks (±14 days) after the last fraction of RT or the last dose of ChT administered, whichever is later.4indicates that all participants will be followed up until 24 months after last treatment of cCRT, unless participant11MF-361301351Docket No.: 242272002940 discontinues from study, or sponsor decision, whichever occurs first. After the clinical cutoff for the primary clinical study report (CSR), participants are enrolled under a separate protocol to be followed for up to 5 years for late radiation adverse event of special interest (AESI) on a long-term safety follow-up extension study. R=randomization; HIO2 nano. = hafnium oxide (HfCh) nanoparticles; cCRT = concurrent platinum-based doublet chemotherapy with radiation therapy; cIT = consolidation immunotherapy; PD = progressive disease; RECIST vl.l = Response Evaluation Criteria in Solid Tumors version 1.1; q8w = every 8 weeks; EOT = end of treatment; ql2w = every 12 weeks; CT = computed tomography.DETAILED DESCRIPTION

[0043] Unless defined otherwise, technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Singleton et al., Dictionary of Microbiology and Molecular Biology 2nd ed., J. Wiley & Sons (New York, N.Y. 1994), and March, Advanced Organic Chemistry Reactions, Mechanisms and Structure 4th ed., John Wiley & Sons (New York, N.Y. 1992), provide one skilled in the art with a general guide to many of the terms used in the present application.

[0044] All references referred to in this application are hereby incorporated by reference in their entireties.I. Definitions

[0045] Before describing the invention in detail, it is to be understood that this invention is not limited to particular compositions or biological systems, which can, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting.

[0046] For purposes of interpreting this specification, the following definitions will apply and whenever appropriate, terms used in the singular will also include the plural and vice versa. In the event that any definition set forth below conflicts with any document incorporated herein by reference, the definition set forth below shall control.

[0047] As used in this specification and the appended claims, the singular forms “a,” “an” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “a protein” or an “antibody” includes a plurality of proteins or antibodies, respectively; reference to “a nanoparticle” includes mixtures of nanoparticles; reference to “a cell” includes mixtures of cells; and the like.12MF-361301351Docket No.: 242272002940

[0048] The term “about” as used herein refers to the usual error range for the respective value readily known to the skilled person in this technical field. Reference to “about” a value or parameter herein includes (and describes) embodiments that are directed to that value or parameter per se.

[0049] Ranges provided in the specification and appended claims include both end points and all points between the end points. Thus, for example, a range of 2.0 to 3.0 includes 2.0, 3.0, and all points between 2.0 and 3.0.

[0050] It is understood that aspects and embodiments of the invention described herein include “comprising,” “consisting,” and “consisting essentially of’ aspects and embodiments.

[0051] The term “pharmaceutical formulation” refers to a preparation which is in such form as to permit the biological activity of the active ingredient to be effective, and which contains no additional components which are unacceptably toxic to a subject to which the formulation would be administered. Such formulations are sterile. “Pharmaceutically acceptable” excipients (vehicles, additives) are those which can reasonably be administered to a subject mammal to provide an effective dose of the active ingredient employed.

[0052] A “pharmaceutically acceptable carrier” refers to an ingredient in a pharmaceutical formulation, other than an active ingredient, which is nontoxic to a subject. A pharmaceutically acceptable carrier includes, but is not limited to, a buffer, excipient, stabilizer, or preservative.

[0053] A “reference level”, or “reference number”, as used herein, refers to a number, an amount, etc. with a predetermined value. The reference level or number can be a value determined from the same prior to onset of treatment, a value from a healthy patient, or a value from a control patient, as indicated herein. In this context, “level” encompasses the absolute number or amount, the relative number or amount, the proportion, the percentage, etc. as well as any value or parameter which correlates thereto or can be derived therefrom. The reference level, reference number, or reference frequency can be determined in reference samples obtained from patients prior to treatment administration or obtained from healthy individuals.

[0054] In one embodiment, a sample is obtained from a subject or patient prior to the onset of treatment (e.g., before administration of the HfOi nanoparticle composition), wherein said sample is hereafter referred to as a “baseline” or “reference” sample. In another embodiment, a sample is obtained from a subject or patient following the onset of treatment (e.g., after administration of the HfOi nanoparticle composition), for example as a “test” sample.13MF-361301351Docket No.: 242272002940

[0055] The term “therapeutic agent” refers to any agent that is used to treat a disease, including but not limited to an agent that treats a symptom of the disease.

[0056] As used herein, the term “treatment” refers to clinical intervention designed to alter the natural course of the individual or cell being treated during the course of clinical pathology. Desirable effects of treatment include decreasing the rate of disease progression, ameliorating or palliating the disease state, and remission or improved prognosis. For example, an individual is successfully “treated” if one or more symptoms associated with cancer are mitigated or eliminated, including, but are not limited to, reducing the proliferation of (or destroying) cancerous cells, decreasing symptoms resulting from the disease, increasing the quality of life of those suffering from the disease, decreasing the dose of other medications required to treat the disease, and / or prolonging survival of individuals..

[0057] The term “treatment emergent” as used herein refers to an event that occurs after a first dose of a therapeutic agent is administered. For example, a “treatment emergent adverse event” is an event that is identified upon or after the first dose of a treatment in a clinical study.

[0058] “Treatment regimen” refers to a combination of dosage, frequency of administration, or duration of treatment, with or without addition of a second medication.

[0059] “Effective treatment regimen” refers to a treatment regimen that will offer beneficial response to a patient receiving the treatment.

[0060] An “effective amount” or “effective dose” of an agent refers to an amount or dose effective, for periods of time necessary, to achieve the desired result. For example, a “therapeutically effective amount” is an amount effective, for periods of time necessary, to treat the indicated disease, condition, clinical pathology, or symptom, such as a cancer. In some embodiments, a therapeutically effective amount reduces or slows progression of the cancer, treats and / or cures the cancer, and / or to alleviates one or more symptoms of the cancer.

[0061] The term “progression” as used herein refers to the worsening or advancement of a disease or condition over time. For example, progression may refer to an individual, patient, or subject as having an NSCLC tumor that is growing larger over time. The “progression rate” or “rate of progression” of a disease refers to how fast or slow a disease develops over time in a patient diagnosed with the disease. The progression rate of a disease can be represented by measurable changes over time of particular characteristics of the disease. On the other hand, an individual, subject, or patient responding to a therapy is said to have, or14MF-361301351Docket No.: 242272002940 more likely to have, “decreased progression rate” if their disease progression slows down after the therapy, when compared to their disease state prior to the treatment or compared to the disease state of other patients not receiving the treatment.

[0062] An “effective response” of a patient or a patient’s “responsiveness” to treatment with a medicament and similar wording refers to the clinical or therapeutic benefit imparted to a patient at risk for, or suffering from, a disease or disorder, such as cancer. In one embodiment, such benefit includes any one or more of: extending survival (including overall survival and progression free survival); resulting in an objective response (including a complete response or a partial response); or improving signs or symptoms of cancer.

[0063] A patient who “does not have an effective response” to treatment refers to a patient who does not have any one of extending survival (including overall survival and progression free survival); resulting in an objective response (including a complete response or a partial response); or improving signs or symptoms of cancer.

[0064] A patient who is “likely to respond” to a therapy refers to a patient who has been identified based on one or more specific biological features or traits relative to the disease, disorder, or condition (such as cancer) that are correlated with treatment responsiveness (or effective response to treatment). This correlation can be identified statistically such that a patient identified as “likely to respond” can refer to a patient with a calculable statistical probability of likelihood to show an effective response to treatment.

[0065] The phrase “responsive to” or “improve” or “improvement” in the context of the present invention indicates that a patient suffering from, being suspected to suffer or being prone to suffer from, or diagnosed with a disorder as described herein, shows a positive response to a treatment, for example an HfCh nanoparticle composition treatment described herein. Treatment response can be defined based on progression free survival (PFS), overall survival (OS), and objective response rate (ORR), including partial response or complete response to treatment. The term “improvement” may further refer to a result indicative of a beneficial response as compared to a control treatment regimen.

[0066] The phrase “standard of care” refers to the standard medical treatment and accompanying regimen that a patient diagnosed with a disease will receive. For example, the standard of care (SOC) treatment for patients with locally advanced and unresectable Stage III NSCLC is concurrent platinum-based doublet chemotherapy (ChT) with radiation therapy (RT) (“cCRT”), followed by 12 months of consolidation immunotherapy (cIT, e.g.,15MF-361301351Docket No.: 242272002940 consolidation durvalumab). In some embodiments, control participants as described herein are administered the SOC treatment for locally advanced and unresectable Stage III NSCLC.

[0067] As used herein, the term “patient” refers to any single subject for which treatment is desired.

[0068] A “subject” or “individual” or “patient” or “participant” as described herein is a human. Typically, the subject is eligible for treatment, e.g., has non-small cell lung cancer (NSCLC), for example, has locally advanced and unresectable Stage III NSCLS, such as Stage IIIA, Stage IIIB, or Stage IIIC NSCLC. An eligible individual, subject, or patient is one that has been diagnosed with NSCLC (e.g., locally advanced and unresectable Stage III NSCLS, such as Stage IIIA, Stage IIIB, or Stage IIIC NSCLC). Intended to be included as an individual or subject are any individuals or subjects involved in clinical research trials, or individuals or subjects involved in epidemiological studies, or individuals or subjects once used as controls. Each of a “subject” or “individual” or “patient” or “participant” may be used interchangeably herein.

[0069] As used herein, “lifetime” of a subject refers to the remainder of the life of the subject after starting treatment.

[0070] The phrase “selecting a patient” or “identifying a patient” as used herein refers to using the information or data generated relating to the diagnosis of Stage III NSCLS, such as Stage IIIA, Stage IIIB, or Stage IIIC NSCLC, in an individual or select a patient that has already been diagnosed with Stage III NSCLS, such as Stage IIIA, Stage IIIB, or Stage IIIC NSCLC, as more likely to benefit from a treatment comprising an HfOi nanoparticle composition. The information or data used or generated may be in any form, written, oral or electronic. In some embodiments, using the information or data generated includes communicating, presenting, reporting, storing, sending, transferring, supplying, transmitting, dispensing, or combinations thereof. In some embodiments, communicating, presenting, reporting, storing, sending, transferring, supplying, transmitting, dispensing, or combinations thereof are performed by a computing device, analyzer unit or combination thereof. In some further embodiments, communicating, presenting, reporting, storing, sending, transferring, supplying, transmitting, dispensing, or combinations thereof are performed by a laboratory or medical professional. In some embodiments, the information or data includes an indication that a specific cancer or cancer-associated biomarker is present or absent in the sample. In some embodiments, the information or data includes an indication that the patient is more likely to respond to a therapy comprising an HfCh nanoparticle composition.16MF-361301351Docket No.: 242272002940

[0071] The term “monoclonal antibody” as used herein refers to an antibody obtained from a population of substantially homogeneous antibodies, i.e., the individual antibodies comprising the population are identical except for possible naturally occurring mutations that may be present in minor amounts. Monoclonal antibodies are highly specific, being directed against a single antigen. Furthermore, in contrast to polyclonal antibody preparations that typically include different antibodies directed against different determinants (epitopes), each monoclonal antibody is directed against a single determinant on the antigen.

[0072] The monoclonal antibodies herein specifically include “chimeric” antibodies in which a portion of the heavy and / or light chain is identical with or homologous to corresponding sequences in antibodies derived from a particular species or belonging to a particular antibody class or subclass, while the remainder of the chain(s) is identical with or homologous to corresponding sequences in antibodies derived from another species or belonging to another antibody class or subclass, as well as fragments of such antibodies, so long as they exhibit the desired biological activity (U.S. Patent No. 4,816,567; and Morrison etal., Proc. Natl. Acad. Sci. USA, 1984; 81:6851-6855).

[0073] The “class” of an antibody refers to the type of constant domain or constant region possessed by its heavy chain. There are five major classes of antibodies: IgA, IgD, IgE, IgG, and IgM, and several of these may be further divided into subclasses (or “isotypes”), e.g., IgGl, IgG2, IgG3, IgG4, IgAl, and IgA2. The heavy chain constant domains that correspond to the different classes of immunoglobulins are called oc, 8, £, y, and |1, respectively.

[0074] “Humanized” forms of non-human (e.g., murine) antibodies are chimeric antibodies that contain minimal sequence derived from non-human immunoglobulin. For the most part, humanized antibodies are human immunoglobulins (recipient antibody) in which residues from a hypervariable region of the recipient are replaced by residues from a hypervariable region of a non-human species (donor antibody) such as mouse, rat, rabbit or nonhuman primate having the desired specificity, affinity, and capacity. In some instances, framework region (FR) residues of the human immunoglobulin are replaced by corresponding non- human residues. Furthermore, humanized antibodies may comprise residues that are not found in the recipient antibody or in the donor antibody. These modifications are made to further refine antibody performance. In general, the humanized antibody will comprise substantially all of at least one, and typically two, variable domains, in which all or substantially all of the hypervariable loops correspond to those of a non-human immunoglobulin and all or substantially all of the FRs are those of a human immunoglobulin17MF-361301351Docket No.: 242272002940Io sequence. The humanized antibody optionally will also comprise at least a portion of an immunoglobulin constant region (Fc), typically that of a human immunoglobulin. For further details, see Jones et al., Nature, 1986; 321:522-525; Riechmann et al., Nature, 1988; 332:323-329; and Presta, Curr. Op. Struct. Biol. 1992; 2:593-596. See also the following review articles and references cited therein: Vaswani and Hamilton, Ann. Allergy, Asthma & Immunol., 1998; 1: 105-115; Harris, Biochem. Soc. Transactions, 1995; 23: 1035-1038; Hurle and Gross, Curr. Op. Biotech., 1994; 5:428-433.

[0075] A “human antibody” is one which comprises an amino acid sequence corresponding to that of an antibody produced by a human or a human cell and / or has been derived from a non-human source that utilizes human antibody repertoires or other human antibodyencoding sequences, for example made using any of the techniques for making human antibodies as disclosed herein. Such techniques include, but are not limited to, screening human-derived combinatorial libraries, such as phage display libraries (see, e.g., Marks et al., J. Mol. Biol., 1991; 222: 581-597 and Hoogenboom et al., Nucl. Acids Res., 1991; 19: 4133- 4137); using human myeloma and mouse-human heteromyeloma cell lines for the production of human monoclonal antibodies (see, e.g., Kozbor J. Immunol., 1984; 133: 3001; Brodeur et al., Monoclonal Antibody Production Techniques and Applications, pp. 55-93 (Marcel Dekker, Inc., New York, 1987); and Boemer et al., J. Immunol., 1991; 147: 86); and generating monoclonal antibodies in transgenic animals (e.g., mice) that are capable of producing a full repertoire of human antibodies in the absence of endogenous immunoglobulin production (see, e.g., Jakobovits et al., Proc. Natl. Acad. Sci USA, 1993; 90: 2551; Jakobovits et al., Nature, 1993; 362: 255; Bruggermann et al., Year in Immunol., 1993; 7: 33). This definition of a human antibody specifically excludes a humanized antibody comprising antigen-binding residues from a non-human animal.

[0076] An “isolated” antibody is one which has been identified and separated and / or recovered from a component of its natural environment. Contaminant components of its natural environment are materials which would interfere with diagnostic or therapeutic uses for the antibody, and may include enzymes, hormones, and other proteinaceous or nonproteinaceous solutes. In some embodiments, an antibody is purified to greater than 95% or 99% purity as determined by, for example, electrophoretic (e.g., SDS-PAGE, isoelectric focusing (IEF), capillary electrophoresis) or chromatographic (e.g., ion exchange or reverse phase HPLC). For review of methods for assessment of antibody purity, see, e.g., Flatman et al., J. Chromatogr. B, 2007; 848:79-87.18MF-361301351Docket No.: 242272002940

[0077] The term “variable region” or “variable domain” refers to the domain of an antibody heavy or light chain that is involved in binding the antibody to antigen. The variable domains of the heavy chain and light chain (VH and VL, respectively) of a native antibody generally have similar structures, with each domain comprising four conserved framework regions (FRs) and three hypervariable regions (HVRs). (See, e.g., Kindt et al. Kuby Immunology, 6th ed., W.H. Freeman and Co., page 91 (2007).) A single VH or VL domain may be sufficient to confer antigen-binding specificity. Furthermore, antibodies that bind a particular antigen may be isolated using a VH or VL domain from an antibody that binds the antigen to screen a library of complementary VL or VH domains, respectively. See, e.g., Portolano et al., J. Immunol., 1993; 150:880-887; Clarkson et al., Nature, 1991; 352:624-628.

[0078] The term “hypervariable region,” “HVR,” or “HV,” when used herein refers to the regions of an antibody variable domain which are hypervariable in sequence and / or form structurally defined loops. Generally, antibodies comprise six hypervariable regions; three in the VH (Hl, H2, H3), and three in the VL (LI, L2, L3). A number of hypervariable region delineations are in use and are encompassed herein. The Kabat Complementarity Determining Regions (CDRs) are based on sequence variability and are the most commonly used (Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md. (1991)). Chothia refers instead to the location of the structural loops (Chothia and Lesk J. Mol. Biol., 1987; 196:901-917). The AbM hypervariable regions represent a compromise between the Kabat CDRs and Chothia structural loops, and are used by Oxford Molecular's AbM antibody modeling software. The “contact” hypervariable regions are based on an analysis of the available complex crystal structures. The residues from each of these HVRs are noted below.Loop Kabat AbM Chothia Contact LI L24-L34 L24-L34 L26-L32 L30-L36L2 L50-L56 L50-L56 L50-L52 L46-L55L3 L89-L97 L89-L97 L91-L96 L89-L96Hl H31-H35B H26-H35B H26-H32 H30-H35B (Kabat Numbering) Hl H31-H35 H26-H35 H26-H32 H30-H35 (Chothia Numbering)H2 H50-H65 H50-H58 H53-H55 H47-H58H3 H95-H102 H95-H102 H96-H101 H93-H101

[0079] Hypervariable regions may comprise “extended hypervariable regions” as follows: 24-36 or 24-34 (LI), 46-56 or 49-56 or 50-56 or 52-56 (L2) and 89-97 (L3) in the VL and 26-19MF-361301351Docket No.: 24227200294035 (Hl), 50-65 or 49-65 (H2) and 93-102, 94-102 or 95-102 (H3) in the VH. The variable domain residues are numbered according to Kabat et al., supra for each of these definitions.

[0080] “Framework” or “FR” residues are those variable domain residues other than the hypervariable region residues as herein defined. The FR of a variable domain generally consists of four FR domains: FR1, FR2, FR3, and FR4. Accordingly, the HVR and FR sequences generally appear in the following sequence in VH (or VL): FR1-H1(L1)-FR2- H2(L2)-FR3-H3(L3)-FR4.

[0081] “Percent (%) amino acid sequence identity” with respect to a reference polypeptide sequence is defined as the percentage of amino acid residues in a candidate sequence that are identical with the amino acid residues in the reference polypeptide sequence, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity, and not considering any conservative substitutions as part of the sequence identity. Alignment for purposes of determining percent amino acid sequence identity can be achieved in various ways that are within the skill in the art, for instance, using publicly available computer software such as BLAST, BLAST-2, ALIGN or Megalign (DNASTAR) software. Those skilled in the art can determine appropriate parameters for aligning sequences, including any algorithms needed to achieve maximal alignment over the full length of the sequences being compared. For purposes herein, however, % amino acid sequence identity values are generated using the sequence comparison computer program ALIGN-2. The ALIGN-2 sequence comparison computer program was authored by Genentech, Inc., and the source code has been filed with user documentation in the U.S. Copyright Office, Washington D.C., 20559, where it is registered under U.S. Copyright Registration No.TXU5 10087. The ALIGN-2 program is publicly available from Genentech, Inc., South San Francisco, California, or may be compiled from the source code. The ALIGN-2 program should be compiled for use on a UNIX operating system, including digital UNIX V4.0D. All sequence comparison parameters are set by the ALIGN-2 program and do not vary.

[0082] In situations where ALIGN-2 is employed for amino acid sequence comparisons, the % amino acid sequence identity of a given amino acid sequence A to, with, or against a given amino acid sequence B (which can alternatively be phrased as a given amino acid sequence A that has or comprises a certain % amino acid sequence identity to, with, or against a given amino acid sequence B) is calculated as follows: 100 times the fraction (X / Y); where X is the number of amino acid residues scored as identical matches by the sequence alignment program ALIGN-2 in that program’s alignment of A and B, and where Y is the total number20MF-361301351Docket No.: 242272002940 of amino acid residues in B. It will be appreciated that where the length of amino acid sequence A is not equal to the length of amino acid sequence B, the % amino acid sequence identity of A to B will not equal the % amino acid sequence identity of B to A. Unless specifically stated otherwise, all % amino acid sequence identity values used herein are obtained as described in the immediately preceding paragraph using the ALIGN-2 computer program.

[0083] The term “package insert” is used to refer to instructions customarily included in commercial packages of therapeutic products, that contain information about the indications, usage, dosage, administration, combination therapy, contraindications and / or warnings concerning the use of such therapeutic products. The term “package insert” is also used to refer to instructions customarily included in commercial packages of diagnostic products that contain information about the intended use, test principle, preparation and handling of reagents, specimen collection and preparation, calibration of the assay and the assay procedure, performance and precision data such as sensitivity and specificity of the assay.

[0084] An “imaging agent” is a compound that has one or more properties that permit its presence and / or location to be detected directly or indirectly. Examples of such imaging agents include proteins and small molecule compounds incorporating a labeled moiety that permits detection.

[0085] A “label” is a marker coupled with a molecule to be used for detection or imaging. Examples of such labels include: a radiolabel, a fluorophore, a chromophore, or an affinity tag. In one embodiment, the label is a radiolabel used for medical imaging, for example tc99m or 1123, or a spin label for nuclear magnetic resonance (NMR) imaging (also known as magnetic resonance imaging, MRI), such as iodine-123 again, iodine-131, indium-i l l, fluorine-19, carbon-13, nitrogen-15, oxygen-17, gadolinium, manganese, iron, etc.IL Methods of Treating NSCLC

[0086] Certain aspects of the present disclosure relate to methods for treating non-small cell lung cancer (NSCLC) in an individual in need thereof, by administering to the individual an effective amount of a hafnium oxide (HfCh) nanoparticle composition, a chemotherapy treatment, a radiation therapy, and an anti-PD-Ll antibody (such as durvalumab). In some embodiments, the hafnium oxide (HfCE) nanoparticle composition comprises a biocompatible coating and is injected directly into the tumor and / or lymph node, e.g., as described in greater detail below. Specifically described herein are methods of treating locally advanced and21MF-361301351Docket No.: 242272002940 unresectable Stage III NSCLC. Also specifically described herein are methods of treating locally advanced and unresectable Stage IIIA, Stage IIIB, or Stage IIIC NSCLC.

[0087] Any of the HfCL nanoparticle compositions, chemotherapy treatments, radiation therapies, and anti-PD-Ll antibodies described herein may be used in the methods of the disclosure.

[0088] The HfCL nanoparticle composition according to the present disclosure is designed to enhance the radiation therapy responses, e.g., to amplify energy deposition at the site of injection (such as a tumor or lymph node), in the individual. The amplified energy may cause tumor cell death and may augment the magnitude and quality of additional therapeutic agents that are administered in the methods described herein. For example, administering concurrent platinum-based doublet chemotherapy (ChT) with radiation therapy (RT) (cCRT) and HIO2 nanoparticle composition followed by consolidation immunotherapy (cIT) to block the PD- Ll / PD-1 pathway in the individual, e.g., by administration of an anti-PD-Ll antibody such as durvalumab, may enhance reactivation of T-cells, and / or improve the activity of dysfunctional T-cells for example by reducing the degree of functional T-cell exhaustion, thereby enhancing immune responses. The HfCL nanoparticle composition is to be administered prior to the onset of radiation therapy and concurrent chemotherapy (cCRT). Administration of the anti-PD-Ll antibody occurs after the individual has no demonstrated disease progression following the six weeks of cCRT (e.g., as cIT), and may further reduce the tumor burden of the individual.

[0089] The HfCL nanoparticle composition according to the present disclosure is designed to enhance the radiation therapy responses, e.g., to amplify energy deposition at the site of injection (such as a tumor or lymph node), in the patient. The amplified energy may cause tumor cell death and may augment the magnitude and quality of additional therapeutic agents that are administered in the methods described herein. For example, administering concurrent platinum-based doublet chemotherapy (ChT) with radiation therapy (RT) (cCRT) and HfCL nanoparticle composition followed by consolidation immunotherapy (cIT) to block the PD- Ll / PD-1 pathway in the patient, e.g., by administration of an anti-PD-Ll antibody such as durvalumab, may enhance reactivation of T-cells, and / or improve the activity of dysfunctional T-cells for example by reducing the degree of functional T-cell exhaustion, thereby enhancing immune responses. The HfCL nanoparticle composition is to be administered prior to the onset of radiation therapy and concurrent chemotherapy (cCRT). Administration of the anti-PD-Ll antibody occurs after the individual has no demonstrated22MF-361301351Docket No.: 242272002940 disease progression following the six weeks of cCRT (e.g., as cIT), and may further reduce the tumor burden of the individual.

[0090] Accordingly, in some embodiments, the methods of treating locally advanced and unresectable Stage III non-small cell lung cancer (NSCLC) in an individual comprise: (i) administering a nanoparticle composition comprising nanoparticles comprising HIO2 with a biocompatible coating to the individual; (ii) administering radiation therapy to the individual; (iii) administering chemotherapy to the individual; and (iv) administering a PD-L1 antibody to the individual. In some embodiments, the method further comprises administering a corticosteroid to the individual prior to administering the HfCh nanoparticle composition. In some embodiments, the methods of treating locally advanced and unresectable Stage IIIA or Stage IIIB non-small cell lung cancer (NSCLC) in an individual comprise: (i) administering a nanoparticle composition comprising nanoparticles comprising HfCh with a biocompatible coating to the individual; (ii) administering radiation therapy to the individual; (iii) administering chemotherapy to the individual; and (iv) administering a PD-L1 antibody to the individual. In some embodiments, the method further comprises administering a corticosteroid to the individual prior to administering the HfCh nanoparticle composition. In some embodiments, the methods of treating locally advanced and unresectable Stage IIIC non-small cell lung cancer (NSCLC) in an individual comprise: (i) administering a nanoparticle composition comprising nanoparticles comprising HfCh with a biocompatible coating to the individual; (ii) administering radiation therapy to the individual; (iii) administering chemotherapy to the individual; and (iv) administering a PD-L1 antibody to the individual. In some embodiments, the method further comprises administering a corticosteroid to the individual prior to administering the HfCh nanoparticle composition.

[0091] In some embodiments, the methods of treating locally advanced and unresectable Stage III non-small cell lung cancer (NSCLC) in an individual comprise a dosing schedule of at least 52 weeks comprising: (i) administering a nanoparticle composition comprising nanoparticles comprising HfCh with a biocompatible coating to the individual on day 0; (ii) administering radiation therapy to the individual at a dose of 2 Gy per fraction, wherein one fraction is delivered daily for five days per week for a total of six weeks, wherein the first dose of radiation therapy is administered two or more days after the nanoparticle composition is administered; (iii) administering chemotherapy to the individual, wherein the chemotherapy comprises: (a) carboplatin administered at a dose of AUC2, and (b) paclitaxel administered at a dose of about 45-50 mg / m2on Day 1 of a seven day chemotherapy cycle,23MF-361301351Docket No.: 242272002940 wherein six chemotherapy cycles are administered to the individual, and wherein the chemotherapy is started (i.e., the first dose is administered) up to three days before or three days after the first dose of radiation therapy is administered; and (iv) administering durvalumab to the individual, wherein durvalumab administration is started within six weeks of administration of a last dose of the chemotherapy or a last dose of radiation therapy, wherein the durvalumab is administered to the individual: (a) at a dose of about 1500 mg, q4w up to 13 times over 52 weeks; or (b) at a dose of about 10 mg / kg q2w for up to 26 times over 52 weeks.

[0092] In some embodiments, the methods of treating locally advanced and unresectable Stage IIIA or Stage IIIB non-small cell lung cancer (NSCLC) in an individual comprise a dosing schedule of at least 52 weeks comprising: (i) administering a nanoparticle composition comprising nanoparticles comprising HfC with a biocompatible coating to the individual on day 0; (ii) administering radiation therapy to the individual at a dose of 2 Gy per fraction, wherein one fraction is delivered daily for five days per week for a total of six weeks, wherein the first dose of radiation therapy is administered two or more days after the nanoparticle composition is administered; (iii) administering chemotherapy to the individual, wherein the chemotherapy comprises: (a) carboplatin administered at a dose of AUC2, and (b) paclitaxel administered at a dose of about 45 mg / m2on Day 1 of a seven day chemotherapy cycle, wherein six chemotherapy cycles are administered to the individual, and wherein the chemotherapy is started (i.e., the first dose is administered) up to three days before or three days after the first dose of radiation therapy is administered; and (iv) administering durvalumab to the individual within six weeks of administration of a last dose of the chemotherapy or a last dose of radiation therapy, wherein the durvalumab is administered to the individual: (a) at a dose of about 1500 mg, q4w up to 13 times over 52 weeks; or (b) at a dose of about 10 mg / kg q2w for up to 26 times over 52 weeks.

[0093] In some embodiments, the methods of treating locally advanced and unresectable Stage IIIC non-small cell lung cancer (NSCLC) in an individual comprise a dosing schedule of at least 52 weeks comprising: (i) administering a nanoparticle composition comprising nanoparticles comprising HfCh with a biocompatible coating to the individual on day 0; (ii) administering radiation therapy to the individual at a dose of 2 Gy per fraction, wherein one fraction is delivered daily for five days per week for a total of six weeks, wherein the first dose of radiation therapy is administered two or more days after the nanoparticle composition is administered; (iii) administering chemotherapy to the individual, wherein the24MF-361301351Docket No.: 242272002940 chemotherapy comprises: (a) carboplatin administered at a dose of AUC2, and (b) paclitaxel administered at a dose of about 45-50 mg / m2on Day 1 of a seven day chemotherapy cycle, wherein six chemotherapy cycles are administered to the individual, and wherein the chemotherapy is started (i.e., the first dose is administered) up to three days before or three days after the first dose of radiation therapy is administered; and (iv) administering durvalumab to the individual, wherein durvalumab administration is started within six weeks of administration of a last dose of the chemotherapy or a last dose of radiation therapy, wherein the durvalumab is administered to the individual: (a) at a dose of about 1500 mg, q4w up to 13 times over 52 weeks; or (b) at a dose of about 10 mg / kg q2w for up to 26 times over 52 weeks.

[0094] In some embodiments, there is provided a method of treating locally advanced and unresectable Stage III non-small cell lung cancer (NSCLC) in an individual, comprising: (i) administering a nanoparticle composition comprising nanoparticles comprising HfCh with a biocompatible coating to the individual; (ii) administering radiation therapy to the individual; (iii) administering chemotherapy to the individual; and (iv) administering a PD-L1 antibody to the individual; wherein the nanoparticle composition is administered on Day 1; wherein the nanoparticle composition is administered once, optionally wherein the nanoparticle composition is administered in a fractionated dose to an individual with a tumor comprising a dimension of > 3 cm, wherein the dimension is the longest dimension; and wherein the radiation therapy is first administered two days or more after administration of the nanoparticle composition. In some embodiments, there is provided a method of treating locally advanced and unresectable Stage IIIA or Stage IIIB non-small cell lung cancer (NSCLC) in an individual, comprising: (i) administering a nanoparticle composition comprising nanoparticles comprising HfCL with a biocompatible coating to the individual; (ii) administering radiation therapy to the individual; (iii) administering chemotherapy to the individual; and (iv) administering a PD-L1 antibody to the individual; wherein the nanoparticle composition is administered on Day 1; wherein the nanoparticle composition is administered once, optionally wherein the nanoparticle composition is administered in a fractionated dose to an individual with a tumor comprising a dimension of > 3 cm, wherein the dimension is the longest dimension; and wherein the radiation therapy is administered two days or more after administration of the nanoparticle composition. In some embodiments, there is provided a method of treating locally advanced and unresectable Stage IIIC non- small cell lung cancer (NSCLC) in an individual, comprising: (i) administering a nanoparticle25MF-361301351Docket No.: 242272002940 composition comprising nanoparticles comprising HIO2 with a biocompatible coating to the individual; (ii) administering radiation therapy to the individual; (iii) administering chemotherapy to the individual; and (iv) administering a PD-L1 antibody to the individual; wherein the nanoparticle composition is administered on Day 1; wherein the nanoparticle composition is administered once, optionally wherein the nanoparticle composition is administered in a fractionated dose to an individual with a tumor comprising a dimension of > 3 cm, wherein the dimension is the longest dimension; and wherein the radiation therapy is first administered two days or more after administration of the nanoparticle composition. In some embodiments, the radiation therapy comprises administering more than one fraction of ionizing radiation over more than one day, for example at least 10 fractions of ionizing radiation. In some embodiments, the radiation therapy comprises administering a total of about 40 Gy to about 80 Gy of radiation to the individual, wherein each fractionated dose is administered at about 1 Gy to about 3 Gy per fraction (e.g., 2 Gy) to the individual. In some embodiments, the radiation therapy comprises administering radiation therapy to the individual four times per week to six times per week (e.g., five times per week). For example, in some embodiments, the radiation therapy comprises administering about 2 Gy radiation five times per week for six weeks, wherein the first dose is administered about two or more days after administration of the nanoparticle composition. In some embodiments, the chemotherapy comprises carboplatin and paclitaxel, wherein the chemotherapy comprises administering carboplatin intravenously at a dose of AUC2 and administering paclitaxel at a dose of 45-50 mg / m2and wherein the first dose of chemotherapy is administered between about three days before and about three days after the first dose of the radiation therapy is administered, for example wherein the first dose of chemotherapy is administered on the same day as the first dose of radiation therapy. In some embodiments, the chemotherapy comprises carboplatin and paclitaxel, wherein the chemotherapy comprises administering carboplatin intravenously at a dose of AUC2 and administering paclitaxel at a dose of 45 mg / m2and wherein the first dose of chemotherapy is administered between about three days before and about three days after the first dose of the radiation therapy is administered, for example wherein the first dose of chemotherapy is administered on the same day as the first dose of radiation therapy. In some embodiments, the chemotherapy is administered once per week ± 3 days (e.g., on Day 1 of a seven-day cycle), wherein six chemotherapy cycles are administered to the individual. In some embodiments, the PD-L1 antibody is first administered to the individual within 10 weeks after administration of a last fraction of the26MF-361301351Docket No.: 242272002940 radiation therapy. In some embodiments, the PD-L1 antibody is first administered to the individual within 10 weeks after a last dose of the chemotherapy. In some embodiments, the PD-L1 antibody is first administered the later of: (a) within six weeks of administration of a last fraction of the radiation therapy, or (b) within six weeks of administration of a last dose of the chemotherapy. In some embodiments, the size of the tumor before treatment and following treatment is assessed by CT of the chest and upper abdomen including liver and adrenal glands, and optionally by PET-CT scan and / or contrast MRI-brain scan. In some embodiments, the size of a tumor in the individual is decreased following treatment. In some embodiments, the individual has an objective response, including an improved objective response rate and an improved disease control rate as described herein. In some embodiments, the individual does not experience a treatment emergent adverse event. In some embodiments, the duration of concurrent platinum-based doublet ChT with RT (cCRT) treatment, with or without prior HfCh nanoparticle injection, followed by consolidation immunotherapy (cIT) is up to about 68 weeks from enrollment / randomization, or from about 65 weeks to about 70 weeks, such as about 68 weeks.

[0095] In some embodiments, the NSCLC to be treated is Stage IIIA. In some embodiments, the NSCLC to be treated is Stage IIIB. In some embodiments, the NSCLC to be treated is Stage IIIC. In some embodiments, the NSCLC to be treated is locally advanced Stage IIIA. In some embodiments, the NSCLC to be treated is locally advanced Stage IIIB. In some embodiments, the NSCLC to be treated is locally advanced Stage IIIC. In some embodiments, the NSCLC to be treated is locally advanced and unresectable Stage IIIA. In some embodiments, the NSCLC to be treated is locally advanced and unresectable Stage IIIB. In some embodiments, the NSCLC to be treated is locally advanced and unresectable Stage IIIC. In some embodiments, the locally advanced and unresectable Stage III NSCLC is not metastatic. In some embodiments, the locally advanced and unresectable Stage IIIA or Stage IIIB NSCLC is not metastatic. In some embodiments, the locally advanced and unresectable Stage IIIC NSCLC is not metastatic. In some embodiments, the locally advanced and unresectable Stage III NSCLC has a tumor proportion score of PD-L1 >1%. In some embodiments, the locally advanced and unresectable Stage IIIA or Stage IIIB NSCLC has a tumor proportion score of PD-L1 >1%. In some embodiments, the locally advanced and unresectable Stage IIIC NSCLC has a tumor proportion score of PD-L1 >1%. In some embodiments, the locally advanced and unresectable Stage III NSCLC has a tumor proportion score of PD-L1 <1%. In some embodiments, the locally advanced and27MF-361301351Docket No.: 242272002940 unresectable Stage IIIA or Stage IIIB NSCLC has a tumor proportion score of PD-L1 <1%. In some embodiments, the locally advanced and unresectable Stage IIIC NSCLC has a tumor proportion score of PD-L1 <1%. In some embodiments, the tumor is amenable to injection and irradiation. In some embodiments, the tumor is amenable to injection and external beam irradiation. In some embodiments, a tumor amenable to injection is a lung lesion having a longest diameter (LD) >10 mm. In some embodiments, a tumor amenable to injection is an involved lymph node having a short axial diameter (SAD) >10 mm. In some embodiments, the calculated and / or planned nanoparticle composition volume for injection is >0.2 mL.A. Therapeutic Agents

[0096] In one aspect, the methods of the present invention comprise administering an HfCh nanoparticle composition, a radiation therapy, a chemotherapy, and an anti-PD-Ll antibody to an individual. In some embodiments, the methods further comprise administering corticosteroid premedication prior to the administration of the HfCh nanoparticle composition. z. Hafnium Oxide Nanoparticles

[0097] In some embodiments, a hafnium oxide (HfCh) nanoparticle composition of the present disclosure is administered. In some embodiments, the HfCh nanoparticle composition comprises a crystalline solution of functionalized hafnium oxide (HfCL) nanoparticles.

[0098] Hafnium has a high atomic number, which is important for efficient interaction between nanoparticles and ionizing radiation. High electron density nanoparticles of hafnium oxide have an inert behavior in biological media: a low solubility, absence of redox phenomena or electron transfer, and no marked surface acidity, which indicate the absence of significant toxicity of an HfCh nanoparticle composition.

[0099] In some embodiments, the HI'CL nanoparticle composition acts as a radio-enhancer to amplify energy deposition and its associated biological effects. Activation of the HfCh nanoparticle composition with ionizing radiation results in an approximately 9-fold increase (per Monte Carlo simulation) in energy deposition locally at the subcellular level to enhance cancer cell death (see, e.g., Maggiorella 2012). The biological effect may include an increase of tumor cell killing, either directly or by preventing tumor cell proliferation.

[0100] Nonclinical data has identified significant immune and distant effects from the addition of an HI'CL nanoparticle composition with radiation therapy. In dual tumor murine models using anti-PD-1 resistant cell lines, the addition of an HfOi nanoparticle composition to radiation and anti-PD-1 therapy not only overcame PD-1 resistance, but also led to28MF-361301351Docket No.: 242272002940 abscopal responses in nonradiated tumors. The immune response was confirmed with genomic analyses revealing upregulation of immune pathways and pathologic analyses revealing increased cytotoxic cells (CD8+ T cells and natural killer cells), dendritic cells, and total tumor infiltrating lymphocytes when compared with controls. Furthermore, there was a dramatic reduction in the development of distant lung metastases in mice treated with the combination of an HfC nanoparticle composition, radiation therapy, and anti-PD-1 therapy (see, e.g., Hu 2021).

[0101] HfC nanoparticles have exhibited an optimal intratumor bioavailability, with a long permanence within the tumor mass. These HfCh nanoparticles were found both in the center and at the periphery of the tumor into which the HfCh nanoparticles were injected, forming clusters in the cytoplasm within the cancer cells. HfCh nanoparticles have also been demonstrated to avoid leakage from the tumor structure into the surrounding healthy tissues across multiple cancer models.

[0102] In some embodiments, the HfCh nanoparticles comprise a biocompatible coating. Organic coatings for nanoparticles can be classified according to various categories, e.g., the size of a single unit of the coating material, which is defined by the molecular weight (MW). This can vary from monomeric type (small molecules, MW < 1000 g / mol) to polymeric type (MW > 1000 g / mol) coatings. Monomeric coatings are usually comprised of either multivalently charged small molecules (e.g. succinic acid, citric acid), or of amphiphilic surfactant molecules consisting of a polar head group (e.g., thiolates, dithiolates, amines, ammoniums, carboxylates, cyanides, isothiocyanates, phosphines) and a hydrocarbon chain. The former stabilize nanoparticles electrostatically whereas the latter can self-assemble into monolayers (SAMs) or bilayers to allow the stable dispersion of particles in both organic and aqueous media, respectively. Exemplary amphiphilic coatings include, but are not limited to, cetrimonium bromide (CTAB), benzyl dimethyl ammonium chloride (BDAC), oleate, etc. Polymer coatings lead to a higher colloidal stability compared to that of small molecules and comprise steric and electrostatic stabilization, depending on whether the polymers are uncharged or charged, respectively. In the case of charged polymers, i.e., poly electrolytes, the stabilization of the nanoparticles arises from both steric and electrostatic interactions (i.e., electrosteric stabilization). See, e.g., Liu et al. (2018) Theranostics. lT. 1824-1849, and Schubert & Chanana (2019) Curr Med Chem. 25(35): 4556-4586, each hereby incorporated by reference in its entirety.29MF-361301351Docket No.: 242272002940

[0103] Another way of providing a high steric stabilization to colloids is to coat nanoparticles with a relatively thick layer of a crosslinked polymer gel. The most prominent example for such gel networks are hydrogels, which consist of hydrophilic, crosslinked polymer networks swollen with water. The high degree of hydration of the hydrogel coatings (>95%) does not only lead to high colloidal stability of nanoparticles, but also to low protein adsorption (stealth behavior) on the nanoparticles’ surface, and thus are useful for biomedical applications. Furthermore, the porous structure of the gel coating can be used to trap drug molecules for drug delivery applications. See, e.g., Liu et al. (2018), and Schubert & Chanana (2019).

[0104] Biopolymers have highly defined structures and functions, but with huge variety and complexity. The main advantage of a biopolymer is the intrinsic biocompatibility and biodegradability. Biopolymers can feature various physicochemical properties such as polar / nonpolar, charged / uncharged, positive / negative charges, and even stimuli-responsive behavior. Biopolymers also can feature more sophisticated properties and functions, catalytic activity, recognition, specific binding, and structure formation. See, e.g., Liu et al. (2018), and Schubert & Chanana (2019).

[0105] Examples of synthetic (artificial) and organic polymers or co-polymers usable in the context of the invention to prepare organic nanoparticles can be selected from polylactic acid (PLA), Poly (lactide-co-glycolic) acid (PLGA), Polyethyleneglycol (PEG), Polyglactin, Polylactide, Polyoxyethylene fatty acid esters, Polypropylene glycol, Polysorbate, Polyvinyl alcohol, Polyacrylamide, Polymethylmethacrylate, Polyalkylcyanoacrylate, Polylactate-co- glycolate, Poly(amido amine), Poly (ethyleneimine), alginate, cellulose and cellulose derivatives polymers, collagen, hyaluronic acid, polyglutamic acid (PGA), actin, polysaccharide, and gelatin. The organic nanoparticle may be a drug carrier nanoparticle. See, e.g., US 10,265,406, hereby incorporated by reference in its entirety.

[0106] The biocompatible hydrophilic coating can be made of one or more biocompatible hydrophilic polymer. These polymers can be positively or negatively charged as far as the surface charge value of each of the biocompatible nanoparticle is between -15 mV and +15 mV when measured in aqueous medium at pH 6.0-8.0. These biocompatible hydrophilic polymers can be selected from the group consisting of polyethylene glycol (PEG), polyglycerol, polyethylene oxide, polyvinyl alcohol such as polyvinylpyrrolidone, polymethylmethacrylate, polyacrylate, polyacrylamide such as poly(N-isopropylacrylamide), polyetheretherketone, polycarbamide, polysaccharides such as dextran, sulfate dextran,30MF-361301351Docket No.: 242272002940 chitosan, alginate, xylan, hyaluronic acid or P-Glucan, proteins such as collagen, polyglutamic acid, polylysine or albumin. These biocompatible hydrophilic polymers can also be selected from the group consisting of co-polymers such as poloxamers, poly(lactic- co-glycolic acid) or N-(2-Hydroxypropyl) methacrylamide or combination of the different polymers or co-polymers. See, e.g., US 10,265,406.

[0107] In some embodiments, the biocompatible coating is sodium trimetaphosphate (STMP) or sodium hexametaphosphate (HMP). In some embodiments, the HfCh nanoparticles bear a negative surface charge.

[0108] In some embodiments, the diameter of the HfCh nanoparticles is about 10 nm to about 200 nm, such as about any of 10 nm to 20 nm, 15 nm to 25 nm, 20 nm to 30 nm, 25 nm to 35 nm, 30 nm to 40 nm, 35 nm to 45 nm, 40 nm to 50 nm, 45 nm to 55 nm, 50 nm to 60 nm, 55 nm to 65 nm, 60 nm to 70 nm, 65 nm to 75 nm, 70 nm to 80 nm, 75 nm to 85 nm, 80 nm to 90 nm, 85 nm to 95 nm, 90 nm to 100 nm, 95 nm to 105 nm, 100 nm to 110 nm, 105 nm to 115 nm, 110 nm to 120 nm, 115 nm to 125 nm, 120 nm to 130 nm, 125 nm to 135 nm, 130 nm to 140 nm, 135 nm to 145 nm, 140 nm to 150 nm, 145 nm to 155 nm, 150 nm to 160 nm, 155 nm to 165 nm, 160 nm to 170 nm, 165 nm to 175 nm, 170 nm to 180 nm, 175 nm to 185 nm, 180 nm to 190 nm, 185 nm to 195 nm, 190 nm to 200 nm, or 195 nm to 205 nm in diameter. In some embodiments, the diameter of the HfCh nanoparticles is about any of 10 nm, 15 nm, 20 nm, 25 nm, 30 nm, 35 nm, 40 nm, 45 nm, 50 nm, 55 nm, 60 nm, 65 nm, 70 nm, 75 nm, 80 nm, 85 nm, 90 nm, 95 nm, 100 nm, 105 nm, 110 nm, 115 nm, 120 nm, 125 nm, 130 nm, 135 nm, 140 nm, 145 nm, 150 nm, 155 nm, 160 nm, 165 nm, 170 nm, 175 nm, 180 nm, 185 nm, 190 nm, 195 nm, or 200 nm. In some embodiments, the diameter of the HfCh nanoparticles is about 40 nm to about 60 nm. In some embodiments, the diameter of the HfCh nanoparticles is about 50 nm.

[0109] In some embodiments, the HfCh nanoparticle composition is administered to the individual (e.g., patient, participant, or subject) once. In some embodiments, the HfCh nanoparticle composition is administered to the individual as a fractionated dose. In some embodiments, the HfCh nanoparticle composition is administered intratumorally and / or intranodally. In some embodiments, the HfCh nanoparticle composition is administered intratumorally. In some embodiments, the HfCh nanoparticle composition is administered intratumorally and intranodally. In some embodiments, the HfCh nanoparticle composition is injected via bronchoscopic approach or via percutaneous approach.31MF-361301351Docket No.: 242272002940

[0110] In some embodiments, the HIO2 nanoparticle composition for administration has a density of about 45 g / L to about 60 g / L, e.g., about any of 45 g / L, 46 g / L, 47 g / L, 48 g / L, 49 g / L, 50 g / L, 51 g / L, 52 g / L, 53 g / L, 54 g / L, 55 g / L, 56 g / L, 57 g / L, 58 g / L, 59 g / L, or 60 g / L. In some embodiments, the HIO2 nanoparticle composition for administration has a density of about 54.2 g / L. In some embodiments, the HIO2 nanoparticle composition for administration has a density of about 54 mg / mL. In some embodiments, the HI O2 nanoparticle composition for administration is formulated at a pH of about 6.0 to about 8.0, for example a pH of about any of 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, or 8.0.

[0111] In some embodiments, the HIO2 nanoparticle composition is administered to the individual at a dose of about 2.5% to about 42% of the gross tumor volume (GTV) or estimated tumor volume (ETV), such as about any of 3%, 3.5%, 4%, 4.5%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 18%, 20%, 22%, 25%, 27%, 30%, 33%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, or 42% GTV or ETV. In some embodiments, the HfO2nanoparticle composition is administered to the individual at about 22% to about 33% GTV. In some embodiments, the HIO2 nanoparticle composition is administered to the individual at about 22% or at about 33% GTV. In some embodiments, the injection volume is determined as a percentage of total tumor volume. Utilization of the gross tumor volume (GTV) method by CT or MRI is consistent with common practice standards that radiation oncologists use to define tumor volumes for radiation therapy planning, such as CT simulation and contouring. The ETV is calculated as (length x width x depth), for example the baseline ETV. zz. Radiation Therapies

[0112] In some embodiments, an HI O2 nanoparticle composition of the present disclosure is administered in combination with a radiation therapy.

[0113] For example, the radiation therapy can be selected from the group consisting of external-beam radiation therapy, internal radiation therapy (brachytherapy), intraoperative radiation therapy (IORT), systemic radiation therapy, radioimmunotherapy, and administration of radiosensitizers and radioprotectors.

[0114] In some embodiments, the radiation therapy is external-beam radiation therapy, optionally comprising three-dimensional conformal radiation therapy (3D-RT), intensity modulated radiation therapy (IMRT), photon beam therapy, image-guided radiation therapy (IGRT), and stereotactic radiation therapy (SRT).32MF-361301351Docket No.: 242272002940

[0115] In some embodiments, the radiation therapy is brachytherapy, optionally comprising interstitial brachytherapy, intracavitary brachytherapy, intraluminal radiation therapy, and radioactively tagged molecules given intravenously.

[0116] In some embodiments, the radiation therapy comprises irradiation at a site of the cancer to be treated. In some embodiments, the radiation therapy comprises irradiation at a site that is different from the site of the cancer to be treated. In some embodiments, the radiation therapy comprises reirradiation at a site of the cancer to be treated. In some embodiments, the dose of the radiation therapy is insufficient to kill tumor cells. In some embodiments, the dose of the radiation therapy is sufficient to kill tumor cells.

[0117] In some embodiments, the dose of radiation therapy is fractionated. In some embodiments, the total dose of radiation therapy is about 50 to about 90 Gy, for example about any of 50 Gy, 55 Gy, 60 Gy, 65 Gy, 70 Gy, 75 Gy, 80 Gy, 85 Gy, or 90 Gy. In some embodiments the total dose of radiation therapy is about 60 Gy. In some embodiments, the total dose of 60 Gy radiation therapy is fractionated such that each fractionated dose is administered at about 1 Gy to about 5 Gy, such as about any of 1 Gy, 2 Gy, 3 Gy, 4 Gy, or 5 Gy. In some embodiments, the fractionated dose is administered at about 2 Gy, wherein the fractionated dose is administered 30 times until a total dose of 60 Gy has been administered. In some embodiments, the fractionated dose is administered at least about once a week, such as about any of lx, 2x, 3x, 4x, 5x, 6x, or 7x a week. In some embodiments, the fractionated dose is administered about five times a week (5x / wk) over the span of 6 weeks until a total dose of 60 Gy has been administered. In some embodiments, 60 Gy of radiation is administered at a dose of 2 Gy per fraction delivered daily for five days per week for six weeks.

[0118] In some embodiments, the radiation therapy comprises intensity modulated radiation therapy (IMRT). In some embodiments, the radiation therapy comprises is external-beam radiation therapy (EBRT), wherein the EBRT is intensity modulated radiation therapy (IMRT). In some embodiments, the radiation therapy comprises ionizing radiation. In some embodiments, the ionizing radiation is selected from the group consisting of X-Rays, y-Rays, electron beams, and radioisotope emissions. In some embodiments, the IMRT is selected from the group consisting of: static field IMRT, helical IMRT, and volumetric modulated arc therapy (VMAT) using megavoltage therapy. In some embodiments, the external beam IMRT is selected from the group consisting of: static field IMRT, helical IMRT, and volumetric modulated arc therapy (VMAT) using megavoltage therapy. In some embodiments, the33MF-361301351Docket No.: 242272002940 radiation therapy comprises irradiation at site of the cancer to be treated. In some embodiments, the injected HfC nanoparticle composition further enhances the radiation therapy. In some embodiments, the combination of HfC nanoparticle composition and IMRT is sufficient to kill tumor cells. In some embodiments, the combination of HfCh nanoparticle composition and IMRT with administration of paclitaxel and carboplatin is sufficient to kill tumor cells. In some embodiments, the radiation therapy is administered as fractionated doses at 2 Gy to a total dose of 60 Gy. In some embodiments, the radiation therapy is administered five times per week over the span of six weeks. In some embodiments, the radiation therapy is administered at least about two days after the administration of the HIO2 nanoparticle composition. In some embodiments, the radiation therapy is administered about two days to about two months after the administration of the HI O2 nanoparticle composition, for example about any of 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 1 month, or 2 months after the administration of the HI O2 nanoparticle composition. In some embodiments, the radiation therapy is administered about two days after the administration of the HIO2 nanoparticle composition. In some embodiments, the radiation therapy is first administered at least about two days after the administration of the HIO2 nanoparticle composition. In some embodiments, the radiation therapy is first administered about two days to about two months after the administration of the HI O2 nanoparticle composition, for example about any of 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 1 month, or 2 months after the administration of the HI O2 nanoparticle composition. In some embodiments, the radiation therapy is first administered about two days after the administration of the HIO2 nanoparticle composition.Hi. Chemotherapy Agents

[0119] In some embodiments, an HI O2 nanoparticle composition of the present disclosure is administered in combination with a radiation therapy and a chemotherapy agent. In some embodiments, the chemotherapy agent is carboplatin and / or paclitaxel. Carboplatin is also known as PARAPLATIN® and is an antineoplastic alkylating agent. Paclitaxel is also known as ABRAXANE® or TAXOL® and is an anti-microtubule agent that stalls mitosis, thereby preventing cancer cells from dividing and proliferating.34MF-361301351Docket No.: 242272002940

[0120] For the past several decades, the first line standard of care (SOC) treatment for patients with locally advanced and unresectable Stage III NSCLC has been concurrent platinum-based doublet chemotherapy (ChT) with radiation therapy (RT) (“cCRT”), e.g., combination chemotherapy using carboplatin and paclitaxel and concurrent radiation therapy. In recent years, there have been significant improvements in NSCLC patient outcomes with the addition of consolidation immunotherapy (cIT, e.g., consolidation durvalumab). These data were the basis of approval in 2017 of durvalumab for the treatment of adult patients with unresectable, Stage III NSCLC whose disease has not progressed following cCRT. As a result, the SOC has shifted to cCRT followed by 12 months of durvalumab consolidation therapy.

[0121] In some embodiments, the chemotherapy treatment comprises administration of concurrent platinum-based doublet chemotherapy (ChT) with radiation therapy (RT) (cCRT). In some embodiments, concurrent platinum-based doublet chemotherapy comprises administration of the chemotherapy agents, carboplatin and paclitaxel. In some embodiments, carboplatin is administered intravenously to the individual at about AUC2, and paclitaxel is administered intravenously to the individual at about 45-50 mg / m2on Day 1 of Cycles 1-6, wherein each Cycle is 7 days, for a total of 6 cycles. In some embodiments, carboplatin is administered intravenously to the individual at about AUC2, and paclitaxel is administered intravenously to the individual at about 45 mg / m2on Day 1 of Cycles 1-6, wherein each Cycle is 7 days, for a total of 6 cycles. In some embodiments, carboplatin is administered intravenously to the patient at about AUC2, and paclitaxel is administered intravenously to the patient at about 45-50 mg / m2on Day 1 of Cycles 1-6, wherein each Cycle is 7 days, for a total of 6 cycles. In some embodiments, carboplatin is administered intravenously to the patient at about AUC2, and paclitaxel is administered intravenously to the patient at about 45-50 mg / m2on Day 1 of Cycles 1-7, wherein each Cycle is 7 days, for a total of 7 cycles. In some embodiments, carboplatin is administered intravenously to the patient at about AUC2, and paclitaxel is administered intravenously to the patient at about 45 mg / m2on Day 1 of Cycles 1-6, wherein each Cycle is 7 days, for a total of 6 cycles. In some embodiments, carboplatin is administered intravenously to the patient at about AUC2, and paclitaxel is administered intravenously to the patient at about 45 mg / m2on Day 1 of Cycles 1-7, wherein each Cycle is 7 days, for a total of 7 cycles. In some embodiments, the duration of exposure to carboplatin and paclitaxel is about six weeks. In some embodiments, the chemotherapy treatment is administered intravenously to the individual. In some embodiments, the35MF-361301351Docket No.: 242272002940 chemotherapy treatment is administered intravenously to the patient. In some embodiments, the chemotherapy treatment is administered as described herein.

[0122] In some embodiments, the chemotherapy treatment is started between about three days before and about three days after (i.e., ± 3 days) starting the radiation therapy (e.g., the first dose of the chemotherapy treatment is administered between about three days before and about three days after (i.e., ± 3 days) the first dose of the radiation therapy is administered). In some embodiments, the chemotherapy treatment is started on the same day as starting the radiation therapy (e.g., the first dose of the chemotherapy treatment is administered on the same day as the first dose of the radiation therapy is administered). In some embodiments, the chemotherapy agent is administered once per week ± 3 days. In some embodiments, the chemotherapy agent is administered on Day 1 of a seven-day cycle. In some embodiments the chemotherapy agent is administered for 6 cycles. In some embodiments the chemotherapy agent is administered for 7 cycles. vi. Anti-PD-Ll Antibodies

[0123] In some embodiments, an HfC nanoparticle composition of the present disclosure is administered in combination with a chemotherapy agent, a radiation therapy, and an anti-PD- L1 antibody. In some embodiments, the anti-PD-Ll antibody (e.g., durvalumab) is administered as consolidation immunotherapy (“cIT”, e.g., consolidation durvalumab). In some embodiments, the cIT is administered over a duration of about 52 weeks or about 12 months.

[0124] A variety of anti-PD-Ll antibodies are contemplated and described herein. In any of the embodiments herein, the anti-PD-Ll antibody can bind to a human PD-L1, for example a human PD-L1 as shown in UniProtKB / Swiss-Prot Accession No. Q9NZQ7.1, or a variant thereof. In some embodiments, the anti-PD-Ll antibody is capable of inhibiting binding between PD-L1 and PD-1 and / or between PD-L1 and B7-1. In some embodiments, the anti- PD-Ll antibody is a monoclonal antibody. In some embodiments, the anti-PD-Ll antibody is an antibody fragment selected from the group consisting of Fab, Fab’-SH, Fv, scFv, and (Fab’ fragments. In some embodiments, the anti-PD-Ll antibody is a humanized antibody. In some embodiments, the anti-PD-Ll antibody is a human antibody. Examples of anti-PD- Ll antibodies useful for the methods of this invention, and methods for making thereof are described in PCT patent application WO 2010 / 077634 Al and US Patent No. 8,217,149, which are incorporated herein by reference.36MF-361301351Docket No.: 242272002940

[0125] In some embodiments, the anti-PD-Ll antibody is durvalumab (CAS Registry Number: 1428935-60-7). Durvalumab, also known as MEDI4736, is an Fc optimized human monoclonal IgGl kappa anti-PD-Ll antibody (Medlmmune, AstraZeneca) described in WO201 1 / 066389 and US2013 / 034559.

[0126] In some embodiments, the anti-PD-Ll antibody comprises a heavy chain variable region and a light chain variable region, wherein: (a) the heavy chain variable region comprises an HVR-H1, HVR-H2, and HVR-H3 sequence of RYWMS (SEQ ID NO: 1), NIKQDGSEKY (SEQ ID NO:2) and EGGWFGELAF (SEQ ID NOG), respectively, and (b) the light chain variable region comprises an HVR-L1, HVR-L2, and HVR-L3 sequence of RVSSSYLA (SEQ ID NOG), DASSRA (SEQ ID NOG) and QQYGSLPWT (SEQ ID NOG), respectively. In some embodiments, the anti-PD-Ll antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises the amino acid sequence:EVQLVESGGGLVQPGGSLRLSCAASGFTFSRYWMSWVRQAPGKGLEWVANIKQDG SEKYYVDSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCAREGGWFGELAFDY WGQGTLVTVSS (SEQ ID NO:9), or a variant thereof comprising about 90% (such as about any of 95%, 96%, 97%, 98%, 99%, or more) sequence identity to SEQ ID NO:9, and the VL comprises the amino acid sequence:EIVLTQSPGTLSLSPGERATLSCRASQRVSSSYLAWYQQKPGQAPRLLIYDASSRATGI PDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYGSLPWTFGQGTKVEIK (SEQ ID NO: 10), or a variant thereof comprising about 90% (such as about any of 95%, 96%, 97%, 98%, 99%, or more) sequence identity to SEQ ID NO: 10. In some embodiments, the anti-PD- Ll antibody comprises a heavy chain and a light chain sequence, wherein: (a) the heavy chain comprises the amino acid sequence:EVQLVESGGGLVQPGGSLRLSCAASGFTFSRYWMSWVRQAPGKGLEWVANIKQDG SEKYYVDSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCAREGGWFGELAFDY WGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGAL TSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCD KTHTCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYV DGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEK TISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNY KTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG (SEQ ID NO:4), and (b) the light chain comprises the amino acid sequence:37MF-361301351Docket No.: 242272002940EIVLTQSPGTLSLSPGERATLSCRASQRVSSSYLAWYQQKPGQAPRLLIYDASSRATGI PDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYGSLPWTFGQGTKVEIKRTVAAPSVF IFPPSDEQEKSGTASVVCEENNFYPREAKVQWKVDNAEQSGNSQESVTEQDSKDSTY SLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID N0:8).

[0127] In some embodiments, the anti-PD-Ll antibody is MPDL3280A, also known as atezolizumab and TECENTRIQ® (CAS Registry Number: 1422185-06-5), with a WHO Drug Information (International Nonproprietary Names for Pharmaceutical Substances), Proposed INN: List 112, Vol. 28, No. 4, published January 16, 2015 (see page 485) described therein.

[0128] In some embodiments, the anti-PD-Ll antibody is avelumab (CAS Registry Number: 1537032-82-8). Avelumab, also known as MSB0010718C, is a human monoclonal IgGl anti-PD-Ll antibody (Merck KGaA, Pfizer).

[0129] In some embodiments, the anti-PD-Ll antibody is MDX-1105 (Bristol Myers Squibb). MDX-1105, also known as BMS-936559, is an anti-PD-Ll antibody described in W02007 / 005874. In some embodiments, the anti-PD-Ll antibody is LY3300054 (Eli Lilly). In some embodiments, the anti-PD-Ll antibody is STLA1014 (Sorrento). STLA1014 is a human anti-PD-Ll antibody. In some embodiments, the anti-PD-Ll antibody is KN035 (Suzhou Alphamab). KN035 is single-domain antibody (dAB) generated from a camel phage display library.

[0130] In some embodiments, the anti-PD-Ll antibody comprises a cleavable moiety or linker that, when cleaved (e.g., by a protease in the tumor microenvironment), activates an antibody antigen binding domain to allow it to bind its antigen, e.g., by removing a nonbinding steric moiety. In some embodiments, the anti-PD-Ll antibody is CX-072 (CytomX Therapeutics).

[0131] In some embodiments, the anti-PD-Ll antibody comprises the six HVR sequences (e.g., the three heavy chain HVRs and the three light chain HVRs) and / or the heavy chain variable domain and light chain variable domain from an anti-PD-Ll antibody described in US20160108123 (Assigned to Novartis), W02016 / 000619 (Applicant: Beigene), WO2012 / 145493 (Applicant: Amplimmune), US9205148 (Assigned to Medlmmune), WO2013 / 181634 (Applicant: Sorrento), and W02016 / 061142 (Applicant: Novartis).

[0132] In some embodiments, the anti-PD-Ll antibody is administered intravenously to the individual. In some embodiments, the anti-PD-Ll antibody is administered to the individual at a dose of about 1300 mg to about 1600 mg, for example about any of 1300 mg, 1350 mg,38MF-361301351Docket No.: 2422720029401400 mg, 1450 mg, 1500 mg, 1550 mg, or 1600 mg, or more. In some embodiments, the anti- PD-L1 antibody is administered to the individual at a dose of about 5 mg / kg to about 20 mg / kg, for example about any of 5 mg / kg, 10 mg / kg, 15 mg / kg, or 20 mg / kg. In some embodiments, the anti-PD-Ll antibody is durvalumab, and the durvalumab is administered intravenously to the individual at a dose of about 1500 mg or about 10 mg / kg.

[0133] In some embodiments, the anti-PD-Ll antibody is administered intravenously to the patient. In some embodiments, the anti-PD-Ll antibody is administered to the patient at a dose of about 1300 mg to about 1600 mg, for example about any of 1300 mg, 1350 mg, 1400 mg, 1450 mg, 1500 mg, 1550 mg, or 1600 mg, or more. In some embodiments, the anti-PD- Ll antibody is administered to the patient at a dose of about 5 mg / kg to about 20 mg / kg, for example about any of 5 mg / kg, 10 mg / kg, 15 mg / kg, or 20 mg / kg. In some embodiments, the anti-PD-Ll antibody is durvalumab, and the durvalumab is administered intravenously to the patient at a dose of about 1500 mg or about 10 mg / kg.

[0134] In some embodiments, the durvalumab is administered intravenously to the individual at about 1500 mg once every four weeks (i.e., q4w) for up to 13 cycles over 52 weeks. In some embodiments, the durvalumab is administered intravenously to the individual at about 10 mg / kg once every two weeks (i.e., q2w) for up to 26 cycles over 52 weeks. In some embodiments, the durvalumab is administered to the individual within 10 weeks after administration of a last fraction of the radiation therapy. In some embodiments, the durvalumab is administered to the individual within 10 weeks after a last dose of the chemotherapy. In some embodiments, the durvalumab is administered intravenously to the individual within at least about 6 weeks after administration of the last fraction of radiation therapy or the last dose of chemotherapy, whichever is later.

[0135] In some embodiments, the durvalumab is administered intravenously to the patient at about 1500 mg once every four weeks (i.e., q4w) for up to 13 cycles over 52 weeks. In some embodiments, the durvalumab is administered intravenously to the patient at about 10 mg / kg once every two weeks (i.e., q2w) for up to 26 cycles over 52 weeks. In some embodiments, the durvalumab is administered to the individual within 10 weeks after administration of a last fraction of the radiation therapy. In some embodiments, the durvalumab is administered to the individual within 10 weeks after a last dose of the chemotherapy. In some embodiments, the durvalumab is administered intravenously to the patient within at least about 6 weeks after administration of the last fraction of radiation therapy or the last dose of chemotherapy, whichever is later.39MF-361301351Docket No.: 242272002940

[0136] In some embodiments, an HfC nanoparticle composition of the present disclosure is administered in combination with a chemotherapy agent, a radiation therapy, and one or more EGFR- targeted therapies. In some embodiments, the one or more EGFR- targeted therapies is an alternative to an anti-PD-Ll antibody. In some embodiments, the one or more EGFR- targeted therapies is an alternative to durvalumab. v. Corticosteroids

[0137] In some embodiments, an HI O2 nanoparticle composition of the present disclosure is administered in combination with a chemotherapy agent, a radiation therapy, and an anti-PD- Ll antibody, wherein a corticosteroid is administered as a premedication before the administration of the HI O2 nanoparticle composition.

[0138] Examples of corticosteroids may include but are not limited to any of bethamethasone, prednisone, prednisolone, triamcinolone, methylprednisolone, dexamethasone, hydrocortisone, cortisone, ethamethasoneb, fludrocortisone, etc.

[0139] In some embodiments, the corticosteroid premedication is prednisone. In some embodiments, the prednisone is administered orally. In some embodiments, the prednisone is administered at about 15 mg to about 50 mg, such as about any of 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, or 50 mg. In some embodiments, the prednisone is administered at approximately 12 hours and 2 hours before administration of the HIO2 nanoparticle composition. In some embodiments, the prednisone is administered at approximately 12+2 hours and 2+2 hours before administration of the HI O2 nanoparticle composition.

[0140] In some embodiments, the corticosteroid premedication is dexamethasone. In some embodiments, the dexamethasone is administered intravenously. In some embodiments, the dexamethasone is administered at about 1 mg to about 20 mg, such as about any of 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, or 20 mg dexamethasone. In some embodiments, the dexamethasone is administered at approximately 1+1 hours before administration of the HI O2 nanoparticle composition.B. Dosing and Administration z. Pharmaceutical Formulations

[0141] Also provided herein are pharmaceutical compositions and formulations, e.g., for the treatment of locally advanced and unresectable Stage III NSCLC, such as Stage IIIA, Stage40MF-361301351Docket No.: 242272002940IIIB, or Stage IIIC NSCLC. In some embodiments, the pharmaceutical compositions and formulations further comprise a pharmaceutically acceptable carrier.

[0142] Pharmaceutical compositions and formulations as described herein can be prepared by mixing the active ingredients (such as a hafnium oxide nanoparticle, chemotherapy agent, and / or antibody) having the desired degree of purity with one or more optional pharmaceutically acceptable carriers (Remington’s Pharmaceutical Sciences 16th edition, Osol, A. Ed. (1980)), in the form of aqueous solutions.

[0143] HfC Nanoparticle Composition-. The therapeutically effective amount of the HfOi nanoparticle composition is determined by taking into account the desired dose volumes and mode(s) of administration, for example intratumoral or intranodal injection. In some embodiments, the intratumoral and / or intranodal injection is performed using a percutaneous and / or a bronchoscopic approach. In some embodiments, the HIO2 nanoparticle composition is formulated as a concentrated aqueous solution, wherein the HIO2 nanoparticles are at a density of about 60 g / L to about 75 g / L, e.g., about any of 60 g / L, 61 g / L, 62 g / L, 63 g / L, 64 g / L, 65 g / L, 66 g / L, 67 g / L, 68 g / L, 69 g / L, 70 g / L, 71 g / L, 72 g / L, 73 g / L, 74 g / L, or 75 g / L. In some embodiments, the HfCL nanoparticles are at a density of about 64 g / L. In some embodiments, the HI'CL nanoparticle composition is formulated at a pH of about 6.0 to about 8.0, for example a pH of about any of 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, or 8.0.

[0144] In some embodiments, the HfCL nanoparticle composition for administration is prepared by combining about 5 mL of the concentrated HI O2 nanoparticle aqueous solution and about 1 mL of a 20-40% glucose solution. In some embodiments, the glucose solution is about any of 20%, 25%, 30%, 35%, or 40% glucose. In some embodiments, the glucose solution is about 30% glucose. In some embodiments, the HfCL nanoparticle composition for administration has a density of about 45 g / L to about 60 g / L, e.g., about any of 45 g / L, 46 g / L, 47 g / L, 48 g / L, 49 g / L, 50 g / L, 51 g / L, 52 g / L, 53 g / L, 54 g / L, 55 g / L, 56 g / L, 57 g / L, 58 g / L, 59 g / L, or 60 g / L. In some embodiments, the HIO2 nanoparticle composition for administration has a density of about 54.2 g / L. In some embodiments, the HIO2 nanoparticle composition for administration has a density of about 54 mg / mL. In some embodiments, the HfCL nanoparticle composition for administration is formulated at a pH of about 6.0 to about 8.0, for example a pH of about any of 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, or 8.0.41MF-361301351Docket No.: 242272002940

[0145] Corticosteroid'. The therapeutically effective amount of the corticosteroid is determined by taking into account the desired dose volumes and mode(s) of administration, for example intravenous infusion or oral ingestion. In some embodiments, the corticosteroid is dexamethasone. In some embodiments, the formulation comprises about 1 mg to about 20 mg dexamethasone, for example about any of 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, or 20 mg dexamethasone. In some embodiments, the formulation comprises about 10 mg dexamethasone prepared for intravenous infusion. In some embodiments, the formulation comprises about 5 mg to about 50 mg prednisone in a tablet, for example about any of 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, or 60 mg prednisone in a tablet. In some embodiments, the formulation comprises about 30 mg prednisone in a tablet.

[0146] Chemotherapy Agent'. The therapeutically effective amount of the chemotherapy agent is determined by taking into account the desired dose volumes and mode(s) of administration, for example intravenous infusion. In some embodiments, the chemotherapy agent is carboplatin and / or paclitaxel. In some embodiments, the formulation comprises about 5 mg / mL to about 20 mg / mL carboplatin in a multi-dose vial, for example about any of 5 mg / mL, 6 mg / mL, 7 mg / mL, 8 mg / mL, 9 mg / mL, 10 mg / mL, 11 mg / mL, 12 mg / mL, 13 mg / mL, 14 mg / mL, 15 mg / mL, 16 mg / mL, 17 mg / mL, 18 mg / mL, 19 mg / mL, or 20 mg / mL carboplatin in a multi-dose vial. In some embodiments, the formulation comprises about 10 mg / mL carboplatin in a multi-dose vial. In some embodiments, the formulation comprises about 1 mg / mL to about 10 mg / mL paclitaxel in a multi-dose vial, for example about any of 2 mg / mL, 3 mg / mL, 4 mg / mL, 5 mg / mL, 6 mg / mL, 7 mg / mL, 8 mg / mL, 9 mg / mL, or 10 mg / mL paclitaxel in a multi-dose vial. In some embodiments, the formulation comprises about 6 mg / mL paclitaxel in a multi-dose vial. In some embodiments, the formulation comprises about 10 mg / mL carboplatin and about 6 mg / mL paclitaxel in a multi-dose vial.

[0147] Anti-PD-Ll Antibody. The therapeutically effective amount of the anti-PD-Ll antibody is determined by taking into account the desired dose volumes and mode(s) of administration, for example intravenous infusion. From about 25 mg / mL to about 150 mg / mL, or from about 30 mg / mL to about 140 mg / mL, or from about 35 mg / mL to about 130 mg / mL, or from about 40 mg / mL to about 120 mg / mL, or from about 50 mg / mL to about 130 mg / mL, or from about 50 mg / mL to about 125 mg / mL, or from about 50 mg / mL to about 120 mg / mL, or from about 50 mg / mL to about 110 mg / mL, or from about 50 mg / mL to about 10042MF-361301351Docket No.: 242272002940 mg / mL, or from about 50 mg / mL to about 90 mg / mL, or from about 50 mg / mL to about 80 mg / mL, or from about 54 mg / mL to about 66 mg / mL is an exemplary antibody concentration in a pharmaceutical formulation. In some embodiments, the formulation comprises about 25 mg / mL to about 75 mg / mL durvalumab in a single-dose vial. In some embodiments, the formulation comprises about 25 mg / mL, about 30 mg / mL, about 35 mg / mL, about 40 mg / mL, about 45 mg / mL, about 50 mg / mL, about 55 mg / mL, about 60 mg / mL, about 65 mg / mL, about 70 mg / mL, or about 75 mg / mL durvalumab in a single-dose vial. In some embodiments, the formulation comprises about 50 mg / mL durvalumab in a single-dose vial. In some embodiments, an anti-PD-Ll antibody described herein (such as durvalumab) is administered at a dose of about 1500 mg. In some embodiments, an anti-PD-Ll antibody described herein (such as durvalumab) is administered at a dose of about 10 mg / kg.

[0148] Exemplary lyophilized antibody formulations are described in US Patent No. 6,267,958. Aqueous antibody formulations include those described in US Patent No. 6,171,586 and W02006 / 044908, the latter formulations including a histidine-acetate buffer. In some embodiments, the anti-PD-Ll antibody is formulated as a liquid for subcutaneous (SC) or intravenous (IV) administration.

[0149] Pharmaceutical formulations of FDA-approved corticosteroids (e.g., dexamethasone and prednisone) are commercially available. For example, dexamethasone is known under the trade name (as described elsewhere herein) CORT AREN® or HEXADROL®. Prednisone is known under the trade name (as described elsewhere herein) DELTASONE® or PREDNICOT®. In some embodiments, dexamethasone or prednisone is used and / or prepared for administration to an individual as described in the prescribing information available with the commercially available product.

[0150] Pharmaceutical formulations of FDA-approved chemotherapy agents (e.g., carboplatin and paclitaxel) are commercially available. For example, carboplatin is known under the trade name (as described elsewhere herein) PARAPLATIN®. Paclitaxel is known under the trade name (as described elsewhere herein) ABRAXANE® or TAXOL®. In some embodiments, carboplatin and / or paclitaxel are used and / or prepared for administration to an individual as described in the prescribing information available with the commercially available product.

[0151] Pharmaceutical formulations of FDA-approved anti-PD-Ll antibody (e.g., durvalumab, atezolizumab, etc.) are commercially available. For example, durvalumab is known under the trade name (as described elsewhere herein) IMFINZI®. Atezolizumab is43MF-361301351Docket No.: 242272002940 known under the trade name (as described elsewhere herein) TECENTRIQ®. In some embodiments, durvalumab is used and / or prepared for administration to an individual as described in the prescribing information available with the commercially available product. ii. Routes of Administration

[0152] Dosing can be by any suitable route, e.g. by injections, such as intravenous or subcutaneous injections, depending in part on whether the administration is brief or chronic.

[0153] In some embodiments, the HfCh nanoparticle composition is administered by intratumoral injection. In some embodiments, the HfCh nanoparticle composition is administered by intranodal injection. In some embodiments, the HfCh nanoparticle composition is administered by both intratumoral and intranodal injection. In some embodiments, the intratumoral injection and / or intranodal injection is performed via percutaneous approach and / or bronchoscopic approach.

[0154] In some embodiments, the chemotherapy agent(s) is administered intravenously.

[0155] In some embodiments, the radiation therapy is an intensity modulated radiation therapy (IMRT). In some embodiments, the IMRT is administered by linear accelerator (LINAC).

[0156] In some embodiments, the corticosteroid is administered orally. In some embodiments, the corticosteroid is formulated for oral delivery as a tablet, a syrup, a solution, a spray, etc.

[0157] In some embodiments, the corticosteroid is administered by intravenous infusion.

[0158] In some embodiments, the anti-PD-Ll antibody is administered by intravenous infusion.Hi. Dosing

[0159] In some embodiments, the HfCh nanoparticle composition is administered directly into the tumor or the tumors. In some embodiments, the HfCh nanoparticle composition is administered as a fractionated dose within the tumor, such as for the improvement of HfCh nanoparticle diffusion within the tumor. In some embodiments, the HfCh nanoparticle composition is administered into affected lymph nodes. In some embodiments, the HfCh nanoparticle composition is administered to the individual at a dose of about 2.5% to about 42% of the gross tumor volume (GTV) or estimated tumor volume (ETV), such as about any of 3%, 3.5%, 4%, 4.5%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 18%, 20%, 22%, 25%, 27%, 30%, 33%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, or 42% GTV or ETV. In some embodiments, the HfCh nanoparticle composition is administered to the individual at 44MF-361301351Docket No.: 242272002940 about 22% to about 33% GTV. In some embodiments, the HfOi nanoparticle composition is administered to the individual at about 22% or at about 33% GTV. In some embodiments, the injection volume is determined as a percentage of total tumor volume. Utilization of the gross tumor volume (GTV) method by CT or MRI is consistent with common practice standards that radiation oncologists use to define tumor volumes for radiation therapy planning, such as CT simulation and contouring. The ETV is calculated as (length x width x depth), for example the baseline ETV. In some embodiments, <300 mL of the HfOi nanoparticle composition is injected into the tumor and / or lymph node, for example 300 mL, 290 mL, 280 mL, 270 mL, 260 mL, 250 mL, 240 mL, 230 mL, 220 mL, 210 mL, 200 mL, 190 mL, 180 mL, 170 mL, 160 mL, 150 mL, 140 mL, 130 mL, 120 mL, 110 mL, 100 mL, 90 mL, 80 mL, 70 mL, 60 mL, 50 mL or less of the HfOi nanoparticle composition is injected into the tumor and / or lymph node. In some embodiments, the HfOi nanoparticle composition is administered once (e.g., on Day 1).

[0160] In some embodiments, a corticosteroid is administered prior to the administration of the HfOi nanoparticle composition. In some embodiments, the corticosteroid is prednisone, and the prednisone is administered orally. In some embodiments, the prednisone is administered at about 15 mg to about 50 mg, such as about any of 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, or 50 mg. In some embodiments, the prednisone is administered twice prior to the administration of the HfOi nanoparticle composition. In some embodiments, the prednisone is administered orally at about 30 mg approximately 12+2 hours and approximately 2+2 hours before administration of the HfOi nanoparticle composition. In some embodiments, the corticosteroid is dexamethasone, and the dexamethasone is administered intravenously. In some embodiments, the dexamethasone is administered at about 1 mg to about 20 mg, such as about any of 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, or 20 mg dexamethasone. In some embodiments, the dexamethasone is administered once prior to the administration of the HfOi nanoparticle composition. In some embodiments, the dexamethasone is administered intravenously at about 10 mg approximately 1+1 hour before administration of the HfOi nanoparticle composition.

[0161] In some embodiments, the total dose of radiation therapy is about 50 to about 90 Gy, for example about any of 50 Gy, 55 Gy, 60 Gy, 65 Gy, 70 Gy, 75 Gy, 80 Gy, 85 Gy, or 90 Gy. In some embodiments the total dose of radiation therapy is about 60 Gy. In some embodiments, the total dose of 60 Gy radiation therapy is fractionated such that each45MF-361301351Docket No.: 242272002940 fractionated dose is administered at about 1 Gy to about 5 Gy, such as about any of 1 Gy, 2 Gy, 3 Gy, 4 Gy, or 5 Gy. In some embodiments, the radiation therapy comprises administering more than one fraction of ionizing radiation over more than one day. In some embodiments, the radiation therapy is fractionated such that the radiation therapy comprises at least 10 fractions of ionizing radiation. In some embodiments, the fractionated dose is administered at about 2 Gy. In some embodiments, the fractionated dose is administered 30 times until a total dose of 60 Gy has been administered. In some embodiments, the fractionated dose is administered at least about once a week, such as about any of lx, 2x, 3x, 4x, 5x, 6x, or 7x a week. In some embodiments, the fractionated dose is administered about five times a week (5x / wk) over the span of six weeks until a total dose of 60 Gy has been administered. In some embodiments, each 2 Gy fractionated dose of radiation therapy is administered Monday through Friday for about six consecutive weeks until a total dose of 60 Gy has been administered.

[0162] In some embodiments, the chemotherapy is platinum-based doublet chemotherapy (“ChT”). In some embodiments, the platinum-based doublet ChT comprises administration of carboplatin and paclitaxel. In some embodiments, the dose of carboplatin is calculated using the Calvert method to calculate the total carboplatin dose needed to achieve a given AUC (area under the free carboplatin plasma concentration versus time curve). This calculation method further adjusts for renal dysfunction by using the Cockcroft- Gault formula to estimate glomerular filtration rate (GFR). In some embodiments, carboplatin is administered intravenously at about AUC1 to about AUC6, such as about any of AUC1, AUC2, AUC3, AUC4, AUC5, or AUC6. In some embodiments, carboplatin is administered intravenously at about AUC2. In some embodiments, paclitaxel is administered intravenously at about 25 mg / m2to about 200 mg / m2, such as about any of 25 mg / m2, 30 mg / m2, 35 mg / m2, 40 mg / m2, 45 mg / m2, 50 mg / m2, 60 mg / m2, 70 mg / m2, 80 mg / m2, 90 mg / m2, 100 mg / m2, 110 mg / m2, 120 mg / m2, 130 mg / m2, 140 mg / m2, 150 mg / m2, 160 mg / m2, 170 mg / m2, 175 mg / m2, 180 mg / m2, 185 mg / m2, 190 mg / m2, 195 mg / m2, or 200 mg / m2. In some embodiments, paclitaxel is administered intravenously at about 45 mg / m2. In some embodiments, paclitaxel is administered intravenously at about 45 mg / m2to about 50 mg / m2. In some embodiments, the chemotherapy is administered on Day 1 of Cycles 1-6, wherein each Cycle is 7 days (i.e., 1 week), for a total of 6 cycles (e.g., about 6 weeks). In some embodiments, the chemotherapy is administered on Day 1 of Cycles 1-7, wherein each Cycle is 7 days (i.e., 1 week), for a total of 6 cycles (e.g., about 7 weeks). In some embodiments, the chemotherapy is started46MF-361301351Docket No.: 242272002940 between about three days before and about three days after (i.e., ± 3 days) starting the radiation therapy (e.g., the first dose of the chemotherapy treatment is administered between about three days before and about three days after (i.e., ± 3 days) the first dose of the radiation therapy is administered). In some embodiments, the chemotherapy treatment is started on the same day as starting the radiation therapy (e.g., the first dose of the chemotherapy treatment is administered on the same day as the first dose of the radiation therapy is administered). In some embodiments, the chemotherapy is administered once per week ± 3 days. In some embodiments, the chemotherapy is administered on Day 1 of a seven- day cycle. In some embodiments the chemotherapy is administered for about 6 cycles, i.e., for about 6 weeks. In some embodiments the chemotherapy is administered for about 7 cycles, i.e., for about 7 weeks. In some embodiments, the duration of exposure to carboplatin and paclitaxel is about six weeks.

[0163] In some embodiments, the anti-PD-Ll antibody is administered as consolidation immunotherapy (“cIT”). In some embodiments, the anti-PD-Ll antibody is administered intravenously. In some embodiments, the anti-PD-Ll antibody is administered at a dose of about 1300 mg to about 1600 mg, for example about any of 1300 mg, 1350 mg, 1400 mg, 1450 mg, 1500 mg, 1550 mg, or 1600 mg, or more. In some embodiments, the anti-PD-Ll antibody is administered at a dose of about 5 mg / kg to about 20 mg / kg, for example about any of 5 mg / kg, 10 mg / kg, 15 mg / kg, or 20 mg / kg. In some embodiments, the anti-PD-Ll antibody is durvalumab, and the durvalumab is administered intravenously at a dose of about 1500 mg or about 10 mg / kg. In some embodiments, the durvalumab is administered intravenously at about 1500 mg once every four weeks (i.e., q4w) for up to 13 cycles over 52 weeks. In other embodiments, the durvalumab is administered intravenously to the individual at about 10 mg / kg once every two weeks (i.e., q2w) for up to 26 cycles over 52 weeks. In other embodiments, the durvalumab is administered intravenously to the patient at about 10 mg / kg once every two weeks (i.e., q2w) for up to 26 cycles over 52 weeks. In some embodiments, the durvalumab is administered to the individual within 10 weeks after administration of a last fraction of the radiation therapy. In some embodiments, the durvalumab is administered to the individual within 10 weeks after a last dose of the chemotherapy. In some embodiments, the durvalumab is administered intravenously to the individual within at least about 6 weeks after administration of the later of: (a) the last fraction of radiation therapy, or (b) the last dose of chemotherapy. However, other dosage47MF-361301351Docket No.: 242272002940 regimens may be useful. The progress of this therapy and the above-described therapies each can be monitored by conventional techniques and assays.

[0164] In some embodiments, the individual’s weight is used to calculate the dose to be administered. If the individual’s weight changes by > 10% from the previous reference weight, the current weight becomes the new reference weight for subsequent dosing. Additional recalculations are performed if an individual’s weight further changes again > 10%.

[0165] In some embodiments, the patient’s weight is used to calculate the dose to be administered. If the patient’s weight changes by > 10% from the previous reference weight, the current weight becomes the new reference weight for subsequent dosing. Additional recalculations are performed if a patient’s weight further changes again > 10%.C. Therapeutic Responses and Assessments

[0166] In some embodiments, the methods provided herein result in one or more benefits to an individual with Stage III NSCLC. In some embodiments, the methods provided herein result in one or more benefits to an individual with Stage IIIA or Stage IIIB NSCLC. In some embodiments, the methods provided herein result in one or more benefits to an individual with Stage IIIC NSCLC. In some embodiments, the benefit (such as reduced tumor volume) is measured compared to a “reference” value. In some embodiments, a reference value is a measurement taken from one or more individuals with Stage III NSCLC that have not received the HfCL nanoparticle therapy. In some embodiments, a reference value is a measurement taken from one or more individuals with Stage IIIA or Stage IIIB NSCLC that have not received the HfCL nanoparticle therapy. In some embodiments, a reference value is a measurement taken from one or more individuals with Stage IIIC NSCLC that have not received the HfCL nanoparticle therapy. In some embodiments, the individuals that have not received the HfCL nanoparticle therapy receive a control therapy. In some embodiments, the reference value is a measurement taken from the individual prior to the onset of treatment, i.e., a baseline value.

[0167] In certain aspects, provided herein are methods of treating locally advanced and unresectable Stage III non-small cell lung cancer (NSCLC) in an individual comprising (i) administering a nanoparticle composition comprising nanoparticles comprising HfCh with a biocompatible coating to the individual; (ii) administering radiation therapy to the individual; (iii) administering chemotherapy to the individual; and (iv) administering a PD-L1 antibody to the individual; wherein the size of the tumor before treatment and following treatment is48MF-361301351Docket No.: 242272002940 assessed by CT of the chest and upper abdomen including liver and adrenal glands, and optionally by PET-CT scan and / or contrast MRI-brain scan.

[0168] In certain aspects, provided herein are methods of treating locally advanced and unresectable Stage IIIA or Stage IIIB non-small cell lung cancer (NSCLC) in an individual comprising (i) administering a nanoparticle composition comprising nanoparticles comprising HfC with a biocompatible coating to the individual; (ii) administering radiation therapy to the individual; (iii) administering chemotherapy to the individual; and (iv) administering a PD-L1 antibody to the individual; wherein the size of the tumor before treatment and following treatment is assessed by CT of the chest and upper abdomen including liver and adrenal glands, and optionally by PET-CT scan and / or contrast MRI-brain scan.

[0169] In certain aspects, provided herein are methods of treating locally advanced and unresectable Stage IIIC non-small cell lung cancer (NSCLC) in an individual comprising (i) administering a nanoparticle composition comprising nanoparticles comprising HIO2 with a biocompatible coating to the individual; (ii) administering radiation therapy to the individual; (iii) administering chemotherapy to the individual; and (iv) administering a PD-L1 antibody to the individual; wherein the size of the tumor before treatment and following treatment is assessed by CT of the chest and upper abdomen including liver and adrenal glands, and optionally by PET-CT scan and / or contrast MRI-brain scan.

[0170] In some embodiments, administering such treatment results in the size of the tumor in the individual decreasing following treatment, compared to the baseline tumor size. In some embodiments, administering such treatment results in an objective response (e.g., a complete response or a partial response). A complete response occurs when the tumor completely disappears. A partial response is so categorized when the total diameters (i.e., the longest dimension) of the tumor decrease by at least about 30% (e.g., at least about any of 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, or more). In some embodiments, administering such treatment results in the objective response rate in a population of patients receiving such therapy improving compared to a population of patients receiving the standard of care, for example by at least about 18% (e.g., at least about any of 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, or more) as compared to the reference population of patients receiving the standard of care.

[0171] In some embodiments, administering such treatment results in increased tumor cell killing in a population of patients receiving such therapy improving compared to a population49MF-361301351Docket No.: 242272002940 of patients receiving the standard of care. In the short term, increases in tumor cell killing manifests as increased rates of observed objective responses.

[0172] The objective response rate (“ORR”) is defined as the proportion of participants who have a best response of complete response (“CR”) or partial response (“PR”) according to RECIST vl.l. The ORR is assessed post-cCRT (i.e., after combination chemotherapy and radiation therapy) and pre-cIT (i.e., before anti-PD-Ll antibody therapy). In some embodiments, administering such treatment results in the objective response rate in a population of patients receiving such therapy improving compared to a population of patients receiving the standard of care.

[0173] In some embodiments, the objective response rate is determined after administration of the chemotherapy and before administration of the PD-L1 antibody. In some embodiments, the individual does not have disease progression after administration of the chemotherapy and before administration of the PD-L1 antibody.

[0174] The disease control rate (DCR) is defined as the proportion of participants who have a best response rate of CR, PR or stable disease (“SD”) according to RECIST vl.l. The DCR is assessed post-cCRT (i.e., after combination chemotherapy and radiation therapy) and pre-cIT (i.e., before anti-PD-Ll antibody therapy). In some embodiments, administering such treatment results in the disease control rate in a population of patients receiving such therapy improving compared to a population of patients receiving the standard of care.

[0175] Progression-free survival (“PFS”) is defined as the time from the enrollment or randomization until disease progression or death due to any cause. In some embodiments, the progression free survival in a population of patients receiving such therapy is improved compared to a population of patients receiving the standard of care. In some embodiments, the time to event and landmark at 6, 12, and 24 months in a population of patients receiving such therapy is improved compared to a population of patients receiving the standard of care.

[0176] The duration of response (“DoR”) is calculated among responders from the date of initial documentation of a response to the date of first documented evidence of relapse according to RECIST vl.l, or death due to any cause, whichever occurs first. In some embodiments, the duration of response in a population of patients receiving such therapy is improved compared to a population of patients receiving the standard of care.

[0177] Time to locoregional failure (LRF) and time to distant failure (DF) are defined as the time from enrollment or randomization to the first LRF failure or the first DF failure, respectively, using independent central review (“ICR”) assessments. In-field LRF (IF-LRF) is50MF-361301351Docket No.: 242272002940 defined as disease progression within the baseline radiation planning target volume (PTV). Out-of-field LRF (OF-LRF) is defined as any disease outside of PTV and involving the ipsilateral lung (involved lobe[s]) and / or lymph node(s) in the bilateral hilum, bilateral mediastinum, or bilateral supraclavicular regions without IF-LRF. Distant failure DF is defined as any other disease progression identified in the ipsilateral lung but in an uninvolved lobe, contralateral lung parenchyma, or outside the thorax without IF-LRF or OF-LRF. In some embodiments, the time to locoregional failure and time to distant failure in a population of patients receiving such therapy is improved compared to a population of patients receiving the standard of care.

[0178] In some embodiments, the individual does not experience a treatment emergent adverse event (TEAE). In some embodiments, the therapeutic safety and / or tolerability in a population of patients receiving such therapy is improved or unchanged compared to a population of patients receiving the standard of care. Safety and tolerability can be measured by analyzing the individual for each of: TEAEs, abnormal clinical laboratory tests, abnormal vital signs, abnormal physical examination findings, and ECOG score changes from baseline. A treatment-emergent adverse event (TEAE) is defined as: (1) any new or worsening adverse event (AE) occurring at or after the initial administration of study treatment through the day of last dose of study treatment received plus 30 days or prior to the start (i.e., administration of the first dose) of subsequent anticancer therapy (non-durvalumab), whichever is earlier; or (2) any follow-up AE (linked to an existing TEAE) with onset date and time beyond 30 days after the last dose of study treatment but prior to the start (i.e., administration of the first dose) of subsequent anticancer therapy; or (3) any AE that is considered treatment-related regardless of the start date of the event. Parameters with predefined NCLCTCAE v5.0 toxicity grades (e.g., number of participants with TEAEs; early onset TEAEs, defined as AEs occurring from the first study treatment up to 30 days post last dose / fraction of cCRT or first dose of cIT, whichever is earlier; late onset TEAEs, defined as AEs occurring after the early onset TEAE period; TEAEs related to HfCL nanoparticle injection procedure, HfOi nanoparticles, RT, ChT, or cIT) is evaluated for severity / intensity by using the standard grades provided in Table 1 below.Table 1. General guidelines for grading the severity of adverse events (NCLCTCAE v5.0).51MF-361301351Docket No.: 242272002940* Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the telephone, managing money, etc.** Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and not bedridden.

[0179] In some embodiments, the one or more assessments given to an individual and / or a study partner are administered by the same physician and / or the same evaluator at each visit. In some embodiments, the one or more assessments given to a patient and / or a study partner are administered by the same physician and / or the same evaluator at each visit.

[0180] In some embodiments, a diagnostic CT-chest scan without contrast or RT planning scan (e.g., CT simulation) will be collected at least 24 hours after the intratumoral and / or intranodal injection of the HI'CL nanoparticle composition. This assessment can be used to identify the presence, absence, leakage, and / or distribution of the HfCL nanoparticle composition. In some embodiments, baseline disease burden is assessed using contrast CT of chest and upper abdomen including liver and adrenal glands, PET-CT scan, and contrast MRI-brain scan prior to the onset of treatment. In some embodiments, subsequent efficacy evaluations include radiographic imaging (e.g., CT-chest scan, PET-CT scan, and MRI-brain scan) of all disease sites documented at baseline.

[0181] In some embodiments, patient reported outcomes (PROs) are assessed. In some embodiments, the PROs include any one or more of NSCLC-SAQ, EORTC QLQ-C30 (v3), and EORTC IL46 side effect bother.

[0182] The Non-Small Cell Lung Cancer - Symptom Assessment Questionnaire (NSCLC- SAQ) was developed in accordance with US FDA PRO guidance and scientific best practices for use in clinical trials of NSCLC (see, e.g., McCarrier 2016). It contains 7 items rated on a 5-point scale that assess cough, pain, dyspnea, fatigue, and poor appetite over a 7-day recall period.52MF-361301351Docket No.: 242272002940

[0183] The EORTC QLQ-C30, v3 is a self-administered, 30-item questionnaire measuring the HRQoL of participants with cancer. The recall period for most items is the past week. EORTC QLQ-C30 includes 5 functional scales (physical, role, cognitive, emotional, and social), 3 symptom scales (fatigue, pain, and nausea and vomiting), a global health status / QoL scale, and 6 single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties). Responses to items 1-28 are rated on a 4-point Likert response scale ranging from 1 “Not at all” to 4 “Very much.” Two global health status items are rated on a 7-point numeric rating scale from 1 “Very Poor” to 7 “Excellent.” Higher scores indicate greater functioning, better global health status, and more severe symptoms. The EORTC QLQ-C30 can generally be completed in 4 to 5 minutes.

[0184] The EORTC IL46 consists of a single question that measures global impression of burden due to treatment-related symptoms. The response options range from “Not at all” to “Very much” on a 4-point scale.

[0185] In some embodiments, vital signs are assessed, e.g., temperature, pulse / heart rate, respiratory rate, and blood pressure. In some embodiments, blood samples for serum chemistry, hematology, and thyroid function and a screening urine sample for urinalysis are collected. In some embodiments, blood and urine samples are analyzed for hafnium whole blood and urine concentration. In some embodiments, ECOG performance status scale is used to grade changes in the daily living activities of the individual on a 5-point scale. In some embodiments, signs or symptoms of disease progression that are of clinical significance, such as spinal cord compression, vena cava superior syndrome, major vessel rupture, efflux obstruction, or organ failure, are assessed.

[0186] In some embodiments, the methods herein further comprising assessing the level of one or more biomarkers associated with disease progression. For example, in some embodiments, an archival biopsy sample of lung tumor and / or associated lymph nodes is analyzed for tumor genomic profiling (e.g., mutations, insertions, deletions, fusions, etc.). In some embodiments, a matched whole blood sample is collected to identify any variants that are the result of clonal hematopoiesis. In some embodiments, a plasma sample is collected to analyze circulating tumor DNA (ctDNA). In some embodiments, the level of ctDNA is assessed prior to the onset of treatment (i.e., baseline reference level) as well as after the onset of treatment (i.e., experimental levels) in order to identify any changes in ctDNA levels in response to treatment.53MF-361301351Docket No.: 242272002940

[0187] In some embodiments, the biomarker includes protein immune markers, for example C-reactive protein (CRP), high- sensitivity C-reactive protein (hsCRP), lactate dehydrogenase (LDH), cytokines, chemokines, and / or inflammatory proteins that can be assessed in plasma samples. In some embodiments, the biomarker is an IFN-y level and / or a CXCL10 level. In some embodiments, IFN-y and / or CXCL10 are measured from plasma samples and compared to baseline plasma levels. In some embodiments, the biomarker is an hsCRP, a CRP, and / or an LDH level. In some embodiments, hsCRP, CRP, and / or LDH levels are measured from plasma samples and compared to baseline plasma levels. Additional serum immune biomarkers may also be assessed to characterize immunological responses to the HfCh nanoparticle therapy.

[0188] In some embodiments, the biomarker is an imaging biomarker, such as a biomarker that is assess using positron emission tomography (PET), computed tomography scan (CT scan), or magnetic resonance imaging (MRI). In some embodiments, the biomarker is assessed using ELISA (enzyme-linked immunosorbent assay).

[0189] Tumor burden can be analyzed using diagnostic imaging techniques and tools, for example using CT-chest scanning. Serial CT scans of an individual taken over time, e.g., before and after administration of a treatment (or at one or more intervals throughout the course of a treatment regimen), can permit detection of increased, decreased, or unchanged tumor burden in the lungs. Serial CT scans of a patient taken over time, e.g., before and after administration of a treatment (or at one or more intervals throughout the course of a treatment regimen), can permit detection of increased, decreased, or unchanged tumor burden in the lungs. This technique can further be used to determine whether these biomarkers are increasing or decreasing.III. Patient Populations

[0190] The present invention provides methods for treating non-small cell lung cancer (NSCLC) in an individual with locally advanced and unresectable Stage III non-small cell lung cancer (NSCLC). The present invention further provides methods for treating non-small cell lung cancer (NSCLC) in an individual with locally advanced and unresectable Stage IIIA or Stage IIIB non-small cell lung cancer (NSCLC). The present invention further provides methods for treating non-small cell lung cancer (NSCLC) in an individual with locally advanced and unresectable Stage IIIC non-small cell lung cancer (NSCLC). The present invention provides methods for treating non-small cell lung cancer (NSCLC) in a patient with locally advanced and unresectable Stage IIIA or Stage IIIB non-small cell lung cancer54MF-361301351Docket No.: 242272002940(NSCLC). The present invention provides methods for treating non-small cell lung cancer (NSCLC) in a patient with locally advanced and unresectable Stage IIIC non-small cell lung cancer (NSCLC). Also provided herein are methods of selecting an individual for treatment of NSCLC, comprising: (a) identifying an individual with Stage III NSCLC, and (b) administering to the individual the treatment according to the methods described herein. Also provided herein are methods of selecting an individual for treatment of NSCLC, comprising: (a) identifying an individual with Stage IIIA or Stage IIIB NSCLC, and (b) administering to the individual the treatment according to the methods described herein. Also provided herein are methods of selecting an individual for treatment of NSCLC, comprising: (a) identifying an individual with Stage IIIC NSCLC, and (b) administering to the individual the treatment according to the methods described herein. In some embodiments, the NSCLC is locally advanced and unresectable Stage IIIA NSCLC. In some embodiments, the NSCLC is locally advanced and unresectable Stage IIIB NSCLC. In some embodiments, the NSCLC is locally advanced and unresectable Stage IIIC NSCLC. In some embodiments, the individual has locally advanced Stage III NSCLC according to the Eighth Edition Lung Cancer Stage Classification that is unresectable. In some embodiments, the individual has locally advanced Stage IIIA or IIIB NSCLC according to the Eighth Edition Lung Cancer Stage Classification that is unresectable. In some embodiments, the individual has locally advanced Stage IIIC NSCLC according to the Eighth Edition Lung Cancer Stage Classification that is unresectable. In some embodiments, the individual has a medical history of pathologically (histologically or cytologically) proven diagnosis of NSCLC within about 3 months prior to enrollment / randomization. Diagnosis of NSCLC may be made based on clinical history, clinical examination, established imaging modalities, etc. The individual to be selected and / or the individual to be treated may display any of the described characteristics below.

[0191] In some embodiments, the individual has a life expectancy of at least 6 months at the start of treatment, for example at least about any of 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 1 year, 2 years, 3 years, 4 years, 5 years or more.

[0192] In some embodiments, the individual has a tumor proportion score of PD-L1. In some embodiments, the tumor proportion score is >1%, for example at least about any of 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, or higher. In some embodiments, the tumor proportion score is <1%, for example 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%,55MF-361301351Docket No.: 2422720029400.2%, 0.1%, or lower. In some embodiments, a tumor proportion score being >1% is indicative of the tumor expressing PD-L1.

[0193] In some embodiments, the individual has a tumor that is amenable to injection and irradiation. In some embodiments, the individual has a tumor that is amenable to injection and external beam irradiation. In some embodiments, the tumor amenable to injection is a lung lesion having a longest diameter (LD) >10 mm, such as at least about any of 10 mm, 11 mm, 12 mm, 13 mm, 14 mm, 15 mm, 16 mm, 17 mm, 18 mm, 19 mm, 20 mm, 21 mm, 22 mm, 23 mm, 24 mm, 25 mm, or longer. In some embodiments, a tumor amenable to injection is an involved lymph node having a short axial diameter (SAD) >10 mm, such as at least about any of 10 mm, 11 mm, 12 mm, 13 mm, 14 mm, 15 mm, 16 mm, 17 mm, 18 mm, 19 mm, 20 mm, 21 mm, 22 mm, 23 mm, 24 mm, 25 mm, or longer.

[0194] In some embodiments, the individual does not have metastatic disease. In some embodiments, the individual has unresectable Stage III NSCLC. In some embodiments, the individual has unresectable Stage IIIA or unresectable Stage IIIB NSCLC. In some embodiments, the individual has unresectable Stage IIIC NSCLC. In some embodiments, the individual has a calculated total gross tumor volume < 909 mL. In some embodiments, at least about 50% (such as at least about any of 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or more) of the gross tumor volume is accessible for intratumoral and / or intranodal injection of the HfCL nanoparticle composition.

[0195] In some embodiments, the individual does not have a tumor with invasion and / or encasement of great vessels or esophagus, baseline presence of fistula, and / or malignant airway obstruction requiring endoscopic intervention. In some embodiments, the individual does not have ipsilateral or contralateral scalene or supraclavicular lymph node involvement.

[0196] In some embodiments, the individual does not have a corrected QT interval by Fredericia (QTcF interval) greater than 480 msec.

[0197] In some embodiments, the individual does not have an EGFR mutation, an ALK mutation, or both.

[0198] In some embodiments, the individual has a serum total bilirubin level of < 1.5x upper limit of normal (ULN), or wherein the individual has been diagnosed with or is suspected to have congenital nonhemolytic hyperbilirubinemia and has a total bilirubin level of < 6 mg / dL and has a conjugated bilirubin level of < 20% of total bilirubin. In some embodiments, the individual has an AST level and / or an ALT level of < 3 x the upper limit of normal (ULN). In some embodiments, the individual has a hemoglobin level of > 9.0 g / dL. In some56MF-361301351Docket No.: 242272002940 embodiments, the individual has a serum creatinine clearance rate of > 50 mL / min by the Cockcroft- Gault formula. In some embodiments, the individual has a platelet count of > 100 X109 / L. In some embodiments, the individual has an absolute neutrophil count of > 1.5 X109 / L, wherein the individual has not been administered a growth factor within about 10 days before the start (i.e., before administration of the first dose) of the HfOi nanoparticle treatment.

[0199] In some embodiments, the individual is about 18 years of age or older, such as about any of 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28 29, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, or more years of age. In some embodiments, the individual is about 80 years of age or younger, such as about any of 79, 78, 77, 76, 75, 74, 73, 72, 71, 70, 65, 60, 55, 50, 45, 40, 35, 30, 25, 20, or less years of age. In some embodiments, the individual is between about 18 years and about 80 years in age.

[0200] In some embodiments, the patient is about 18 years of age or older, such as about any of 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28 29, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, or more years of age. In some embodiments, the patient is about 80 years of age or younger, such as about any of 79, 78, 77, 76, 75, 74, 73, 72, 71, 70, 65, 60, 55, 50, 45, 40, 35, 30, 25, 20, or less years of age. In some embodiments, the patient is between about 18 years and about 80 years in age.

[0201] In some embodiments, the individual has an Eastern Cooperative Oncology Group (ECOG) status of 0-2. In some embodiments, the individual has an Eastern Cooperative Oncology Group (ECOG) status of 0-1.

[0202] In some embodiments, the individual is willing and able to undergo diagnostic imaging. In some embodiments, the diagnostic imaging may include, but is not limited to, positron emission tomography (PET), magnetic resonance imaging (MRI), computed tomography (CT), ultrasound, [18F]-fluorodeoxyglucose PET, X-rays, etc. In some embodiments, the individual is willing and able to undergo contrast CT of the chest and upper abdomen (e.g., including liver and adrenal glands), PET-CT scan, and contrast MRI-brain scan. In some embodiments, the CT-chest scan covers the thoracic cavity and upper abdomen with IV contrast, including liver and adrenal glands, plus other areas of known disease involvement. In some embodiments, the diagnostic imaging comprises administration of a contrast to the individual. In some embodiments, contrast is administered intravenously unless the individual is not medically suitable to undergo CT scans with intravenous contrast due to allergy that is refractory to premedication or contraindicated due to renal insufficiency.57MF-361301351Docket No.: 242272002940In some embodiments, the individual receives appropriate premedication and then undergoes CT scans with intravenous contrast. In some embodiments, the individual is intolerant of intravenous contrast agents, wherein the individual undergoes CT scans performed with oral contrast. In some embodiments, PET-CT scan is used for body staging. In some embodiments, MRI brain scan with contrast is used for brain staging unless medically contraindicated, wherein a CT-brain scan with contrast is used instead. In some embodiments, the individual does not have brain metastases present at screening. In some embodiments, evaluation of disease response is not assessed solely by any one or combination of ultrasound, [18F]-fluorodeoxyglucose PET, and / or X-rays. Techniques in addition to CT or MRI may be used, based upon investigator judgment, local standard of care, and RECIST vl.l guidelines.

[0203] In some embodiments, the individual may have one or more co-morbidities. In some embodiments, the individual has no known co-morbidities that interfere with the methods described herein.

[0204] In some embodiments, the patient may have one or more co-morbidities. In some embodiments, the patient has no known co-morbidities that interfere with the methods described herein.

[0205] In some embodiments, the individual does not use any other medications that have the potential to significantly affect or interfere with the efficacy of any one or more of the therapeutic agents administered herein. In some embodiments, other medications include, but are not limited to, antiemetics, antidiarrheals, anticholinergics, antispasmodics, antipyretics, antihistamines, analgesics, H2 receptor antagonists or proton pump inhibitors, and other medications intended to treat symptoms or signs of disease. In some embodiments, the individual may use these medications short-term or intermittently as deemed medically necessary for the treatment of a non-excluded medical condition.

[0206] In some embodiments, the patient does not use any other medications that have the potential to significantly affect or interfere with the efficacy of any one or more of the therapeutic agents administered herein. In some embodiments, other medications include, but are not limited to, antiemetics, antidiarrheals, anticholinergics, antispasmodics, antipyretics, antihistamines, analgesics, H2 receptor antagonists or proton pump inhibitors, and other medications intended to treat symptoms or signs of disease. In some embodiments, the patient may use these medications short-term or intermittently as deemed medically necessary for the treatment of a non-excluded medical condition.58MF-361301351Docket No.: 242272002940

[0207] In some embodiments, the individual does not use other non-approved anti-cancer therapies, immunotherapy, targeted therapy, experimental, or investigational therapy, and hormonal anticancer therapies without receipt of sponsor approval. In some embodiments, the individual does not use anti-coagulant medication. In some embodiments, the individual may use routinely recommended vaccinations. In some embodiments, the individual does not use any investigational drug, device, or experimental medication within 60 days (or five halflives, whichever is longer) of the screening and / or initial treatment visit. In some embodiments, the individual does not have a history of severe allergic, anaphylactic, or other hypersensitivity reactions to nanoparticles with biocompatible coatings or to chimeric, human, or humanized antibodies or fusion proteins.

[0208] In some embodiments, the patient does not use other non-approved anti-cancer therapies, immunotherapy, targeted therapy, experimental, or investigational therapy, and hormonal anticancer therapies without receipt of sponsor approval. In some embodiments, the patient does not use anti-coagulant medication. In some embodiments, the patient may use routinely recommended vaccinations. In some embodiments, the patient does not use any investigational drug, device, or experimental medication within 60 days (or five half-lives, whichever is longer) of the screening and / or initial treatment visit. In some embodiments, the patient does not have a history of severe allergic, anaphylactic, or other hypersensitivity reactions to nanoparticles with biocompatible coatings or to chimeric, human, or humanized antibodies or fusion proteins.

[0209] In some embodiments, the individual has received prior definitive radiation therapy. In some embodiments, the individual has inoperable, locoregional recurrent NSCLC. In some embodiments, the individual displays overlap between the inoperable, locoregional recurrent NSCLC in need of treatment and prior radiation treatment (RT) field. In some embodiments, the individual is administered a reirradiation therapy (reRT). In some embodiments, the individual was administered the prior definitive radiation therapy more than 6 months prior to administration of the HfCh nanoparticles in combination with reRT. In some embodiments, the individual receiving reRT did not display a grade 4 radiation therapy toxicity upon administration of the prior definitive RT. In some embodiments, the individual receiving reRT did not display an interstitial lung disease upon administration of the prior definitive RT.

[0210] In some embodiments, the individual has unknown epidermal growth factor receptor (EGFR) mutation during screening. In some embodiments, the individual is EGFR mutation59MF-361301351Docket No.: 242272002940 positive post-enrollment and / or randomization. In some embodiments, the methods described herein further comprise treating the individual with one or more EGFR-targeted therapies. In some embodiments, the one or more EGFR-targeted therapies is an alternative to consolidation durvalumab.

[0211] In some embodiments, the methods comprise comparison to a reference, e.g. a baseline reference of symptoms or a baseline reference level of a biomarker measured prior to the onset of the therapeutic method described herein. In some embodiments, the reference is established by a plurality of patients receiving a control medication. In some embodiments, the plurality of patients receiving the control medication also have been diagnosed with locally advanced and unresectable Stage III NSCLC. In some embodiments, the plurality of patients receiving the control medication also have been diagnosed with locally advanced and unresectable Stage IIIA or Stage IIIB NSCLC. In some embodiments, the plurality of patients receiving the control medication also have been diagnosed with locally advanced and unresectable Stage IIIC NSCLC.IV. Kits and Articles of Manufacture

[0212] In another aspect of the invention, an article of manufacture or a kit is provided that comprises materials useful for the treatment of an individual having NSCLC (e.g., locally advanced and unresectable Stage III NSCLC, such as Stage IIIA, Stage IIIB, or Stage IIIC NSCLC). The article of manufacture comprises a container and a label or package insert on or associated with the container. Suitable containers include, for example, bottles, vials, syringes, IV solution bags, etc. The containers may be formed from a variety of materials such as glass, plastic (such as polyvinyl chloride or polyolefin), or metal alloy (such as stainless steel or hastelloy). The container holds a composition which is by itself or combined with another one or more composition(s) effective for treating NSCLC (e.g., locally advanced and unresectable Stage III NSCLC, such as Stage IIIA, Stage IIIB, or Stage IIIC NSCLC) and may have a sterile access port (for example the container may be an intravenous solution bag or a vial having a stopper pierceable by a hypodermic injection needle). At least one active agent in the composition is a nanoparticle composition comprising nanoparticles comprising HIO2 with a biocompatible coating. In some embodiments, the kit comprises a nanoparticle composition comprising HIO2 with a biocompatible coating, a chemotherapy agent (e.g., each of paclitaxel and carboplatin), and an anti-PD-Ll antibody (e.g., durvalumab). In some embodiments, the kit further comprises a corticosteroid composition comprising dexamethasone or prednisone. In some embodiments,60MF-361301351Docket No.: 242272002940 each composition or therapy is in its own container within the kit such that each composition or therapy can be administered independently from the other as per the methods described herein.

[0213] The label or package insert indicates that the composition is used for treating NSCLC (e.g., locally advanced and unresectable Stage III NSCLC, such as Stage IIIA, Stage IIIB, or Stage IIIC NSCLC). In some embodiments, the article of manufacture or kit further comprises a package insert comprising instructions for using the nanoparticle composition comprising nanoparticles comprising HfCL with a biocompatible coating in conjunction with radiation therapy, chemotherapy, and / or anti-PD-Ll antibody therapy, and optionally a corticosteroid, to treat NSCLC (e.g., locally advanced and unresectable Stage III NSCLC, such as Stage IIIA, Stage IIIB, or Stage IIIC NSCLC). The article of manufacture may further comprise a second (or third) container comprising a pharmaceutically-acceptable buffer, such as bacteriostatic water for injection (BWFI), phosphate-buffered saline, Ringer's solution, and dextrose solution. It may further include other materials desirable from a commercial and user standpoint, including other buffers, diluents, filters, needles, and syringes.EMBODIMENTS

[0214] The following embodiments are exemplary and are not intended to limit the scope of any invention described herein.

[0215] 1. A method of treating locally advanced and unresectable Stage IIIA or Stage IIIB non-small cell lung cancer (NSCLC) in an individual comprising i) administering a nanoparticle composition comprising nanoparticles comprising HfO2 with a biocompatible coating to the individual; ii) administering radiation therapy to the individual; iii) administering chemotherapy to the individual; and iv) administering a PD-L1 antibody to the individual.

[0216] 2. The method of embodiment 1, further comprising administering a corticosteroid to the individual prior to administering the nanoparticle composition.

[0217] 3. The method of embodiment 2, wherein the corticosteroid is selected from the group consisting of prednisone and dexamethasone.

[0218] 4. The method of any one of embodiments 2-3, wherein the corticosteroid is prednisone, wherein the prednisone is administered at a dose of about 30 mg, and wherein the prednisone is administered less than 24 hours before the nanoparticle composition is administered.61MF-361301351Docket No.: 242272002940

[0219] 5. The method of embodiment 4, wherein about 30 mg prednisone is administered to the individual about 12 hours or about 2 hours before the nanoparticle composition is administered.

[0220] 6. The method of any one of embodiments 3-5, wherein the prednisone is administered orally.

[0221] 7. The method of embodiment 3, wherein the corticosteroid is dexamethasone, wherein the dexamethasone is administered less than three hours before the nanoparticle composition is administered.

[0222] 8. The method of embodiment 3 or 7, wherein the dexamethasone is administered about an hour before the nanoparticle composition is administered.

[0223] 9. The method of any one of embodiments 3, 7, or 8, wherein the dexamethasone is administered intravenously.

[0224] 10. The method of any one of embodiments 1-9, wherein the nanoparticle composition is administered intratumorally and / or intranodally.

[0225] 11. The method of embodiment 10, wherein the nanoparticle composition is administered in a fractionated dose to an individual with a tumor comprising a dimension of > 3 cm and wherein the dimension is the longest dimension.

[0226] 12. The method of any one of embodiments 1-11, wherein the nanoparticle is administered via bronchoscopic and / or percutaneous approach.

[0227] 13. The method of any one of embodiments 1-12, wherein the radiation therapy is administered two days or more after administration of the nanoparticle composition.

[0228] 14. The method of any one of embodiments 1-13, wherein the nanoparticle composition is administered once.

[0229] 15. The method of any one of embodiments 1-14, wherein the nanoparticle composition is administered intratumorally and / or intranodally at a dose of between about 15% gross tumor volume (GTV) to about 40% GTV of a tumor.

[0230] 16. The method of any one of embodiments 1-15, wherein the nanoparticle composition is administered intratumorally and / or intranodally at a dose of about 22% GTV or a dose of about 33% GTV.

[0231] 17. The method of any one of embodiments 1-16, wherein the nanoparticle composition comprises nanoparticles at a concentration of about 50 g / L to about 60 g / L.

[0232] 18. The method of any one of embodiments 1-17, wherein the radiation therapy comprises administering more than one fraction of ionizing radiation over more than one day.62MF-361301351Docket No.: 242272002940

[0233] 19. The method of any one of embodiments 1-18, wherein the radiation therapy comprises administering at least 10 fractions of ionizing radiation.

[0234] 20. The method of any one of embodiments 1-19, wherein the radiation therapy comprises administering a total of about 40 Gy to about 80 Gy of radiation to the individual.

[0235] 21. The method of any one of embodiments 18-20, wherein administering radiation therapy comprises administering about 1 Gy to about 3 Gy per fraction to the individual.

[0236] 22. The method of any one of embodiments 1-21, wherein the radiation therapy comprises administering radiation therapy to the individual four times per week to six times per week.

[0237] 23. The method of any one of embodiments 1-22, wherein the radiation therapy comprises administering radiation therapy five times per week.

[0238] 24. The method of any one of embodiments 1-23, wherein the radiation therapy comprises administering about 2 Gy radiation five times per week for six weeks starting two or more days after administration of the nanoparticle composition.

[0239] 25. The method of any one of embodiments 1-24, wherein the chemotherapy comprises carboplatin and paclitaxel.

[0240] 26. The method of any one of embodiments 1-25, wherein the chemotherapy comprises administering carboplatin intravenously at a dose of AUC2 and administering paclitaxel at a dose of 45 mg / m2.

[0241] 27. The method of any one of embodiments 1-26, wherein the chemotherapy administration is started between three days before and three days after starting the radiation therapy.

[0242] 28. The method of any one of embodiments 1-27, wherein the chemotherapy administration is started on the same day as starting the radiation therapy.

[0243] 29. The method of any one of embodiments 1-28, wherein the chemotherapy is administered once per week ± 3 days.

[0244] 30. The method of any one of embodiments 26-29, wherein the carboplatin and the paclitaxel are administered on Day 1 of a seven-day chemotherapy cycle.

[0245] 31. The method of embodiment 30, wherein six chemotherapy cycles are administered to the individual.

[0246] 32. The method of any one of embodiment 1-31, wherein the PD-L1 antibody is durvalumab.63MF-361301351Docket No.: 242272002940

[0247] 33. The method of any one of embodiments 1-32, wherein the PD-L1 antibody is administered to the individual within 10 weeks after administration of a last fraction of the radiation therapy.

[0248] 34. The method of any one of embodiments 1-33, wherein the PD-L1 antibody is administered to the individual within 10 weeks after a last dose of the chemotherapy.

[0249] 35. The method of any one of embodiments 1-34, wherein the PD-L1 antibody is administered the later of: a. within six weeks of administration of a last fraction of the radiation therapy, or b. within six weeks of administration of a last dose of the chemotherapy.

[0250] 36. The method of any one of embodiments 32-35 wherein the durvalumab is administered at a dose of about 1500 mg.

[0251] 37. The method of embodiment 36, wherein the durvalumab is administered in an immunotherapy cycle of every four weeks (Q4W) ± 3 days.

[0252] 38. The method of embodiment 36 or 37, wherein the durvalumab is administered in an immunotherapy cycle of every four weeks (Q4W).

[0253] 39. The method of embodiment 37 or 38, wherein the immunotherapy cycle is continued for up to 13 cycles over 52 weeks.

[0254] 40. The method of any one of embodiments 32-35, wherein the durvalumab is administered at a dose of about 10 mg / kg.

[0255] 41. The method of embodiment 40, wherein the durvalumab is administered in an immunotherapy cycle of every two weeks (Q2W) ± 3 days.

[0256] 42. The method of embodiment 41, wherein the durvalumab is administered in an immunotherapy cycle of every two weeks (Q2W).

[0257] 43. The method of embodiment 41 or 42, wherein the immunotherapy cycle is continued for up to 26 cycles over 52 weeks.

[0258] 44. A method of treating locally advanced and unresectable Stage IIIA or Stage IIIB non-small cell lung cancer in an individual comprising a dosing schedule of at least 52 weeks comprising: i) administering a nanoparticle composition comprising nanoparticles comprising HfO2 with a biocompatible coating to the individual on Day 0; ii) administering radiation therapy to the individual at a dose of 2 Gy per fraction, wherein one fraction is delivered daily for five days per week for a total of six weeks, wherein the radiation therapy is started two or more days after the nanoparticle composition is administered; iii) administering chemotherapy to the individual, wherein the chemotherapy comprises: a. carboplatin administered at a dose of AUC2, and b. paclitaxel administered at a dose of about 45 mg / m264MF-361301351Docket No.: 242272002940 on Day 1 of a seven-day chemotherapy cycle, wherein six chemotherapy cycles are administered to the individual, and wherein the chemotherapy is started up to three days before or three days after the radiation therapy is started; and iv) administering durvalumab to the individual within six weeks of administration of a last dose of the chemotherapy or a last dose of radiation therapy, wherein the durvalumab is administered to the individual: a. at a dose of about 1500 mg, Q4W up to 13 times over 52 weeks; or b. at a dose of about 10 mg / kg Q2W for up to 26 times over 52 weeks.

[0259] 45. The method of any one of embodiments 1-44, wherein the size of a tumor in the individual is decreased following treatment.

[0260] 46. The method of embodiment 45, wherein the size of the tumor before treatment and following treatment is assessed by CT of the chest and upper abdomen including liver and adrenal glands, and optionally by PET-CT scan and / or contrast MRI-brain scan.

[0261] 47. The method of any one of embodiments 1-46, wherein the individual has an objective response.

[0262] 48. The method of any one of embodiments 1-47, wherein the objective response rate in a population of patients receiving such therapy is improved compared to the standard of care.

[0263] 49. The method of any one of embodiments 1-48, wherein the disease control rate in a population of patients receiving such therapy is improved compared to the standard of care.

[0264] 50. The method of embodiment 48 or 49, wherein the objective response rate is based upon an independent central review assessment according to RECIST bl.1.

[0265] 51. The method of any one of embodiments 48-50, wherein the objective response rate is determined after administration of the chemotherapy and before administration of the PD-L1 antibody.

[0266] 52. The method of any one of embodiments 1-51, wherein the progression free survival in a population of patients receiving such therapy is improved compared to the standard of care.

[0267] 53. The method of any one of embodiments 1-52, wherein the time to event and landmark at 6, 12, and 24 months in a population of patients receiving such therapy is improved compared to the standard of care.

[0268] 54. The method of any one of embodiments 1-53, wherein the time to locoregional failure and time to distant failure in a population of patients receiving such therapy is improved compared to the standard of care.65MF-361301351Docket No.: 242272002940

[0269] 55. The method of any one of embodiments 1-54, wherein the individual does not experience a treatment emergent adverse event.

[0270] 56. A method of selecting an individual for treatment of NSCLC, comprising: (a) identifying an individual with Stage IIIA or Stage IIIB NSCLC, and (b) administering to the individual the treatment according to the method of any one of embodiments 1-55.

[0271] 57. The method of any one of embodiments 1-56, wherein the individual has a life expectancy of at least 6 months at the start of treatment.

[0272] 58. The method of any one of embodiments 1-57, wherein the individual has locally advanced Stage IIIA or IIIB NSCLC according to the Eighth Edition Lung Cancer Stage Classification that is unresectable.

[0273] 59. The method of any one of embodiments 1-58, wherein the individual has a tumor proportion score of PD-L1 >1% or <1%.

[0274] 60. The method of any one of embodiments 1-59, wherein the Stage IIIA or Stage IIIB NSCLC expresses PD-L1.

[0275] 61. The method of any one of embodiments 1-60, wherein the individual does not have metastatic disease.

[0276] 62. The method of any one of embodiments 1-61, wherein the individual has unresectable Stage IIIA or unresectable Stage IIIB NSCLC.

[0277] 63. The method of any one of embodiments 1-62, wherein the individual has a calculated total gross tumor volume < 909 mL.

[0278] 64. The method of any one of embodiments 1-63, wherein the individual does not have a tumor with invasion and / or encasement of great vessels or esophagus, baseline presence of fistula, and / or malignant airway obstruction requiring endoscopic intervention.

[0279] 65. The method of any one of embodiments 1-64, wherein the individual does not have ipsilateral or contralateral scalene or supraclavicular lymph node involvement.

[0280] 66. The method of any one of embodiments 1-65, wherein the individual does not have a corrected QT interval by Fredericia (QTcF interval) greater than 480 msec.

[0281] 67. The method of any one of embodiments 1-66, wherein the individual has: a. a serum total bilirubin level of < 1.5x upper limit of normal (ULN), or wherein the individual has been diagnosed with or is suspected to have congenital nonhemolytic hyperbilirubinemia and has a total bilirubin level of < 6 mg / dL and has a conjugated bilirubin level of < 20% of total bilirubin; b. an AST level and / or an ALT level of < 3 x ULN; c. a hemoglobin level of > 9.0 g / dL; d. a serum creatinine clearance rate of > 50 mL / min by the Cockcroft- Gault66MF-361301351Docket No.: 242272002940 formula; e. a platelet count of > 100 xlO9 / L; and / or f. an absolute neutrophil count of > 1.5 xlO9 / L, wherein the individual has not been administered a growth factor within about 10 days before the start of treatment.

[0282] 68. The method of any one of embodiments 1-67, wherein the individual has an Eastern Cooperative Oncology Group (ECOG) status of 0-1.

[0283] 69. The method according to any one of embodiments 1-68, wherein said biocompatible coating is sodium trimetaphosphate (STMP) or sodium hexametaphosphate (HMP).

[0284] 70. The method according to any one of embodiments 1-69, wherein the average size of the nanoparticles in the nanoparticle composition is between about 10 nm and about 200 nm.

[0285] 71. The method according to any one of embodiments 1-70, wherein the ionizing radiation is selected from the group consisting of X-Rays, y-Rays, electron beams, and radioisotope emissions.

[0286] 72. The method according to embodiment 71, wherein the ionizing radiation is administered by external beam intensity modulated radiation therapy (IMRT).

[0287] 73. The method according to embodiment 72, wherein the external beam IMRT is selected from the group consisting of: static field IMRT, helical IMRT, and volumetric modulated arc therapy (VMAT) using megavoltage therapy.

[0288] 74. The method according to any one of embodiments 1-73, wherein the nanoparticles act as a radio-enhancer.

[0289] 75. The method according to any one of embodiments 1-74, wherein the nanoparticles amplify energy deposition at the site of a tumor.

[0290] 76. A method of treating locally advanced and unresectable Stage III non-small cell lung cancer (NSCLC) in an individual comprising i) administering a nanoparticle composition comprising nanoparticles comprising HfO2 with a biocompatible coating to the individual; ii) administering radiation therapy to the individual; iii) administering chemotherapy to the individual; and iv) administering a PD-L1 antibody to the individual.

[0291] 77. The method of embodiment 76, further comprising administering a corticosteroid to the individual prior to administering the nanoparticle composition.

[0292] 78. The method of embodiment 77, wherein the corticosteroid is selected from the group consisting of prednisone and dexamethasone.67MF-361301351Docket No.: 242272002940

[0293] 79. The method of any one of embodiments 77-78, wherein the corticosteroid is prednisone, wherein the prednisone is administered at a dose of about 30 mg, and wherein the prednisone is administered less than 24 hours before the nanoparticle composition is administered.

[0294] 80. The method of embodiment 79, wherein about 30 mg prednisone is administered to the individual 12+2 hours or 2+2 hours before the nanoparticle composition is administered.

[0295] 81. The method of any one of embodiments 78-80, wherein the prednisone is administered orally.

[0296] 82. The method of embodiment 78, wherein the corticosteroid is dexamethasone, wherein the dexamethasone is administered less than three hours before the nanoparticle composition is administered.

[0297] 83. The method of embodiment 78 or 82, wherein the dexamethasone is administered about an hour before the nanoparticle composition is administered.

[0298] 84. The method of any one of embodiments 78, 82, or 83, wherein the dexamethasone is administered intravenously.

[0299] 85. The method of any one of embodiments 76-84, wherein the nanoparticle composition is administered intratumorally and / or intranodally.

[0300] 86. The method of embodiment 85, wherein the nanoparticle composition is administered in a fractionated dose to an individual with a tumor comprising a dimension of > 3 cm and wherein the dimension is the longest dimension.

[0301] 87. The method of any one of embodiments 76-86, wherein the nanoparticle is administered via bronchoscopic and / or percutaneous approach.

[0302] 88. The method of any one of embodiments 76-87, wherein the radiation therapy is first administered two days or more after administration of the nanoparticle composition.

[0303] 89. The method of any one of embodiments 76-88, wherein the nanoparticle composition is administered once.

[0304] 90. The method of any one of embodiments 76-89, wherein the nanoparticle composition is administered intratumorally and / or intranodally at a dose of between about 15% gross tumor volume (GTV) to about 40% GTV of a tumor.

[0305] 91. The method of any one of embodiments 76-90, wherein the nanoparticle composition is administered intratumorally and / or intranodally at a dose of about 22% GTV or a dose of about 33% GTV.68MF-361301351Docket No.: 242272002940

[0306] 92. The method of any one of embodiments 76-91, wherein the nanoparticle composition comprises nanoparticles at a concentration of about 50 g / L to about 60 g / L.

[0307] 93. The method of any one of embodiments 76-92, wherein the radiation therapy comprises administering more than one fraction of ionizing radiation over more than one day.

[0308] 94. The method of any one of embodiments 76-93, wherein the radiation therapy comprises administering at least 10 fractions of ionizing radiation.

[0309] 95. The method of any one of embodiments 76-94, wherein the radiation therapy comprises administering a total of about 40 Gy to about 80 Gy of radiation to the individual.

[0310] 96. The method of any one of embodiments 93-95, wherein administering radiation therapy comprises administering about 1 Gy to about 3 Gy per fraction to the individual.

[0311] 97. The method of any one of embodiments 76-96, wherein the radiation therapy comprises administering radiation therapy to the individual four times per week to six times per week.

[0312] 98. The method of any one of embodiments 76-97, wherein the radiation therapy comprises administering radiation therapy five times per week.

[0313] 99. The method of any one of embodiments 76-98, wherein the radiation therapy comprises administering about 2 Gy radiation five times per week for six weeks starting two or more days after administration of the nanoparticle composition.

[0314] 100. The method of any one of embodiments 76-99, wherein the chemotherapy comprises carboplatin and paclitaxel.

[0315] 101. The method of any one of embodiments 76-100, wherein the chemotherapy comprises administering carboplatin intravenously at a dose of AUC2 and administering paclitaxel at a dose of 45 mg / m2 to 50 mg / m2.

[0316] 102. The method of any one of embodiments 76-101, wherein the chemotherapy administration is started between three days before and three days after starting the radiation therapy.

[0317] 103. The method of any one of embodiments 76-102, wherein the chemotherapy administration is started on the same day as starting the radiation therapy.

[0318] 104. The method of any one of embodiments 76-103, wherein the chemotherapy is administered once per week ± 3 days.

[0319] 105. The method of any one of embodiments 101-104, wherein the carboplatin and the paclitaxel are administered on Day 1 of a seven-day chemotherapy cycle.69MF-361301351Docket No.: 242272002940

[0320] 106. The method of embodiment 105, wherein six or seven chemotherapy cycles are administered to the individual.

[0321] 107. The method of any one of embodiment 76-106, wherein the PD-L1 antibody is durvalumab.

[0322] 108. The method of any one of embodiments 76-107, wherein the PD-L1 antibody is first administered to the individual within 10 weeks after administration of a last fraction of the radiation therapy.

[0323] 109. The method of any one of embodiments 76-108, wherein the PD-L1 antibody is first administered to the individual within 10 weeks after a last dose of the chemotherapy.

[0324] 110. The method of any one of embodiments 76-109, wherein the PD-L1 antibody is first administered the later of: a. within six weeks of administration of a last fraction of the radiation therapy, or b. within six weeks of administration of a last dose of the chemotherapy.

[0325] 111. The method of any one of embodiments 107-110, wherein the durvalumab is administered at a dose of about 1500 mg.

[0326] 112. The method of embodiment 111, wherein the durvalumab is administered in an immunotherapy cycle of every four weeks (Q4W) ± 3 days.

[0327] 113. The method of embodiment 111 or 112, wherein the durvalumab is administered in an immunotherapy cycle of every four weeks (Q4W).

[0328] 114. The method of embodiment 112 or 113, wherein the immunotherapy cycle is continued for up to 13 cycles over 52 weeks.

[0329] 115. The method of any one of embodiments 107-110, wherein the durvalumab is administered at a dose of about 10 mg / kg.

[0330] 116. The method of embodiment 115, wherein the durvalumab is administered in an immunotherapy cycle of every two weeks (Q2W) ± 3 days.

[0331] 117. The method of embodiment 116, wherein the durvalumab is administered in an immunotherapy cycle of every two weeks (Q2W).

[0332] 118. The method of embodiment 116-117, wherein the immunotherapy cycle is continued for up to 26 cycles over 52 weeks.

[0333] 119. A method of treating locally advanced and unresectable Stage III non-small cell lung cancer in an individual comprising a dosing schedule of at least 52 weeks comprising: i) administering a nanoparticle composition comprising nanoparticles comprising HfO2 with a biocompatible coating to the individual on Day 0; ii) administering radiation therapy to the individual at a dose of 2 Gy per fraction, wherein one fraction is delivered daily for five days70MF-361301351Docket No.: 242272002940 per week for a total of six weeks, wherein the radiation therapy is started two or more days after the nanoparticle composition is administered; iii) administering chemotherapy to the individual, wherein the chemotherapy comprises: a. carboplatin administered at a dose of AUC2, and b. paclitaxel administered at a dose of about 45 mg / m2 to about 50 mg / m2 on Day 1 of a seven-day chemotherapy cycle, wherein six or seven chemotherapy cycles are administered to the individual, and wherein the chemotherapy is started up to three days before or three days after the radiation therapy is started; and iv) administering durvalumab to the individual, wherein durvalumab administration is started within six weeks of administration of a last dose of the chemotherapy or a last dose of radiation therapy, wherein the durvalumab is administered to the individual: a. at a dose of about 1500 mg, Q4W up to 13 times over 52 weeks; or b. at a dose of about 10 mg / kg Q2W for up to 26 times over 52 weeks.

[0334] 120. The method of any one of embodiments 76-119, wherein the size of a tumor in the individual is decreased following treatment.

[0335] 121. The method of embodiment 120, wherein the size of the tumor before treatment and following treatment is assessed by CT of the chest and upper abdomen including liver and adrenal glands, and optionally by PET-CT scan and / or contrast MRI-brain scan.

[0336] 122. The method of any one of embodiments 76-121, wherein the individual has an objective response.

[0337] 123. The method of any one of embodiments 76-122, wherein the objective response rate in a population of patients receiving such therapy is improved compared to the standard of care.

[0338] 124. The method of any one of embodiments 76-123, wherein the disease control rate in a population of patients receiving such therapy is improved compared to the standard of care.

[0339] 125. The method of embodiment 123 or 124, wherein the objective response rate is based upon an independent central review assessment according to RECIST vl.l.

[0340] 126. The method of any one of embodiments 123-125, wherein the objective response rate is determined after administration of the chemotherapy and before administration of the PD-L1 antibody.

[0341] 127. The method of any one of embodiments 76-126, wherein the progression free survival in a population of patients receiving such therapy is improved compared to the standard of care.71MF-361301351Docket No.: 242272002940

[0342] 128. The method of any one of embodiments 76-127, wherein the time to event and landmark at 6, 12, and 24 months in a population of patients receiving such therapy is improved compared to the standard of care.

[0343] 129. The method of any one of embodiments 76-128, wherein the time to locoregional failure and time to distant failure in a population of patients receiving such therapy is improved compared to the standard of care.

[0344] 130. The method of any one of embodiments 76-129, wherein the individual does not experience a treatment emergent adverse event.

[0345] 131. A method of selecting an individual for treatment of NSCLC, comprising: (a) identifying an individual with Stage III NSCLC, and (b) administering to the individual the treatment according to the method of any one of embodiments 76-130.

[0346] 132. The method of any one of embodiments 76-131, wherein the individual has a life expectancy of at least 6 months at the start of treatment.

[0347] 133. The method of any one of embodiments 76-132, wherein the individual has locally advanced Stage III NSCLC according to the Eighth Edition Lung Cancer Stage Classification that is unresectable.

[0348] 134. The method of any one of embodiments 76-133, wherein the individual has a tumor proportion score of PD-L1 >1% or <1%.

[0349] 135. The method of any one of embodiments 76-134, wherein the Stage III NSCLC expresses PD-L1.

[0350] 136. The method of any one of embodiments 76-135, wherein the individual does not have metastatic disease.

[0351] 137. The method of any one of embodiments 76-136, wherein the individual has unresectable Stage III NSCLC.

[0352] 138. The method of any one of embodiments 76-137, wherein the individual has a calculated total gross tumor volume < 909 mL.

[0353] 139. The method of any one of embodiments 76-138, wherein the individual does not have a tumor with invasion and / or encasement of great vessels or esophagus, baseline presence of fistula, and / or malignant airway obstruction requiring endoscopic intervention.

[0354] 140. The method of any one of embodiments 76-139, wherein the individual does not have ipsilateral or contralateral scalene or supraclavicular lymph node involvement.

[0355] 141. The method of any one of embodiments 76-140, wherein the individual does not have a corrected QT interval by Fredericia (QTcF interval) greater than 480 msec.72MF-361301351Docket No.: 242272002940

[0356] 142. The method of any one of embodiments 76-141, wherein the individual has: a. an AST level and / or an ALT level of < 3 x ULN; b. a hemoglobin level of > 9.0 g / dL; c. a platelet count of > 100 xlO9 / L; and / or d. an absolute neutrophil count of > 1.5 xlO9 / L, wherein the individual has not been administered a growth factor within about 10 days before the start of treatment.

[0357] 143. The method of any one of embodiments 76-142, wherein the individual has an Eastern Cooperative Oncology Group (ECOG) status of 0-1.

[0358] 144. The method according to any one of embodiments 76-143, wherein said biocompatible coating is sodium trimetaphosphate (STMP) or sodium hexametaphosphate (HMP).

[0359] 145. The method according to any one of embodiments 76-144, wherein the average size of the nanoparticles in the nanoparticle composition is between about 10 nm and about 200 nm.

[0360] 146. The method according to any one of embodiments 76-145, wherein the ionizing radiation is selected from the group consisting of X-Rays, y-Rays, electron beams, and radioisotope emissions.

[0361] 147. The method according to embodiment 146, wherein the ionizing radiation is administered by intensity modulated radiation therapy (IMRT).

[0362] 148. The method according to embodiment 147, wherein the IMRT is selected from the group consisting of: static field IMRT, helical IMRT, and volumetric modulated arc therapy (VMAT) using megavoltage therapy.

[0363] 149. The method according to any one of embodiments 76-148, wherein the nanoparticles act as a radio-enhancer.

[0364] 150. The method according to any one of embodiments 76-149, wherein the nanoparticles amplify energy deposition at the site of a tumor.EXAMPLESEXAMPLE 1 - Preclinical analyses of hafnium oxide (HfCh) nanoparticles.

[0365] This example describes the in vitro and in vivo preclinical analyses of the HfOi nanoparticles for cancer treatment.Radiation-Induced in vitro Cell Killing and Radiation Survival Studies:

[0366] The in vitro efficacy of HIO2 nanoparticles was assessed in multiple cancer and noncancer cell lines using a standard clonogenic survival assay. As the standard of care (SOC) of radiation therapy (RT) usually utilizes a linear accelerator to deliver high energy73MF-361301351Docket No.: 242272002940 radiation, the 60Co source and 6 MV accelerator were used as well as lower energy radiation such as 125, 200, or 320 keV. HfOi nanoparticle efficacy in vitro evaluation was based on the dose enhancement factor (DEF) and survival fraction (SF) parameters, testing the product against irradiation alone. DEF involves a comparator equal to 1, which is represented in this methodology by the RT efficacy. Values superior to 1 represent relative enhancement. Biological DEF values above 1.20 are considered meaningful radio-enhancement (see, e.g., Harrington 2011). DEF values increased with the increase of HIO2 nanoparticle concentration from 400 to 800 pM, and the radiation dose from 2 to 4 Gy. Data not shown.Pharmacokinetic, Immunogenicity, and Metabolism Studies:

[0367] Mammalian cell systems do not metabolize HfOi nanoparticles, which are hard crystals of high chemical stability. Hafnium oxide does not have dissolution properties. The excretion of HfOi nanoparticles after a single IV injection in rats was very slow (5% of the product 3 weeks after injection). The main excretion pathway was fecal (about 5% of the dose in males and females) and none was detected in urine. Tests with HfOi nanoparticles did not indicate any relevant interactions with components of the immune system, including macrophage-like THP-1 cells. Data not shown.Pharmacology and Efficacy Studies:

[0368] The proof-of-concept of performance, mechanism of action, general mechanistic profile, and antitumor properties of HfOi nanoparticles activated by ionizing radiation were established in an in vitro panel of cancer cell lines and in vivo panel of mice tumor xenografts. Results show an absence of negative impact of protein corona (derived from the phagocytic process) on radio-enhancement, with some increase of in vitro performance when HfOi nanoparticles are covered by protein layer as well as the stability of the biological effect of HfOi nanoparticles (in terms of uptake and radio-enhancement) for up to 2 months at 37°C. In radioresistant and radiosensitive human tumor xenograft models, as well as patient- derived xenograft model, HfOi nanoparticles injected intratumorally and activated by radiation therapy (RT) inhibited tumor growth and prolonged median survival time in mice models compared with RT alone. (Data not shown.)

[0369] Qualitative assessments of HfOi nanoparticle distribution and retention after a single intratumoral injection in xenograft models were performed by CT scans. The localization of HfOi nanoparticles inside the tumor showed largely homogenous diffusion throughout the tumor volume with only a small or negligible quantity localized in the injection puncture site, leading to adequate conditions for the RT activation of HfOi nanoparticles starting 24 hours74MF-361301351Docket No.: 242272002940 post-injection for up to 5 to 7 weeks. Long term experiments showed retention of JNJ 90301900 within injected tumor during a testing period of nearly 2 months. These experiments confirmed the relevance of using an HfCh nanoparticle product for fractionated RT delivered in 5 to 7 weeks, which is the current practice of radiation oncology. (Data not shown.)

[0370] HI'CL nanoparticles in combination with RT demonstrated significant improvements in tumor- specific growth delay, median survival time, and OS when compared with RT in 2 human head and neck squamous cell carcinoma (HNSCC) mouse models. In a patient- derived tumor xenograft model, the activation of HfOi nanoparticles by RT significantly increased the OS of LPS8OT3 tumor-bearing mice compared with RT alone. (Data not shown.)Toxicity Studies:

[0371] In rat studies, HfOi nanoparticles tested in a single dose 800 mg / kg IV (with a followup of up to 6 months), was well tolerated apart from transient hepatic enzymes elevation (AST, ALT). The HfOi nanoparticles did not affect mating performance, fertility, embryofetal or early postnatal development, or the immune system at an IV dose of 533.3 mg / kg in rats. Severe local toxicity and vascular / endothelial lesion, inflammation, and thrombus at the IV site were noted following continuous IV infusion. (Data not shown.)

[0372] A GLP toxicity study was conducted in cynomolgus monkeys after single IV administration of HfCh nanoparticles, and evaluations were performed after 6 and 9 months. This study was meant to mimic a worst-case scenario in which all of the administered HfOi nanoparticles were distributed to the circulatory system instead of into a tumor. In this experiment, a single IV 1-hour infusion of HIO2 nanoparticles at 533 mg / kg, 1066 mg / kg, and 1599 mg / kg induced severe adverse acute reactions, resulting in the premature sacrifice of 2 animals given 1599 mg / kg and 1 animal given 1066 mg / kg. In addition, lesions on extremities in several animals at all doses were observed, resulting in tail amputation. The moribund condition of these animals was due to vascular lesions (thrombosis), characterized by hemorrhagic and vascular inflammatory changes (including ischemic brain infarction), which correlated with changes on hematological parameters (decreased RBC parameters, platelet count and fibrinogen concentration, and increased coagulation time within 24 hours after dosing). These acute effects of the HfOi nanoparticles could be attributable to effects of the negatively charged nanoparticles in terms of dose / systemic exposure and contact time with endothelium, which can result in thrombosis and hemorrhage compatible with a process75MF-361301351Docket No.: 242272002940 of disseminated intravascular coagulation (DIC). DIC was observed at a 2.8-fold exposure multiple relative to the maximum dose that is administered in the clinical study described in Example 2 below, in the event that all of the HIO2 nanoparticles is injected IV. At 533 mg / kg, a 1.4-fold exposure, no DIC was observed. Clinical signs and clinical pathology changes did not persist over the 6- and 9-months observation periods, except for prolonged coagulation times and elevated AST values that persisted up to 9-months in some monkeys. Changes in serum chemistry parameters between 6-months and 9-months were limited to lower mean direct bilirubin concentration in males treated across all doses, and elevated AST activity in 1 female treated at 1599 mg / kg. Histopathological results of the individual monkeys did not show any sign of inflammation or hepatic lesion. In a nonclinical setting, no special risk could be identified of adverse exaggerated side effects in the HfCh nanoparticle storage in organs (liver and spleen) when exposed to ionizing radiation such as for diagnostic CT.Clinical Study 1

[0373] A phase I dose escalation / expansion trial [NCT03589339] evaluated administration of HfCh nanoparticles / Stereotactic Body RT (SBRT) followed by administration of either nivolumab or pembrolizumab in three cohorts of patients with advanced solid tumors, including treated lung metastases. Lung SBRT dose was 45 Gy administered in five fractions. The primary objective was the safety and the recommended Phase 2 dose (RP2D) of the combination therapy. The secondary objectives included efficacy. See FIG. 2 for schematic overview of the trial protocol.

[0374] As of April 2024, 25 patients received intratumoral HfCh nanoparticle injection in metastatic lung lesions (4 patients from NSCLC, 20 patients from HNSCC, and 1 patient from rectal primaries). Patients were primarily male (88%), and the median age was 64 years. Eight patients (32%) were immune checkpoint inhibitor (ICI) naive, 17 (68%) were ICI resistant. 17 patients (68%) had peripheral lesions, and 8 patients (32%) had central lesions injected. Grade >3 treatment related AEs (TEAEs) occurred in three patients (12%). 22 patients were evaluable for efficacy for which the injected lesion overall response rate (ORR) was 54.5% and disease control rate (DCR) was 100%. For all lesions, the ORR was 31.8% and DCR was 77.3%.

[0375] As of September 2024, 29 patients received intratumoral HI O2 nanoparticle injection in metastatic lung lesions (5 patients from NSCLC and 21 patients from HNSCC). Patients were primarily male (90%), and median age was 64 years. Eight patients (28%) were ICI naive, and 21 patients (72%) were ICI resistant. 21 patients (72%) had peripheral lesions, and76MF-361301351Docket No.: 2422720029408 patients (28%) had central lesions injected. Grade >3 TEAEs occurred in seven patients (24%). 27 patients were evaluable for efficacy. Objective response rate (ORR) for injected / irradiated lesions was 51.9%, and disease control rate (DCR) was 100%. For all lesions (target and nontarget, including injected / irradiated and noninjected / nonirradiated), ORR was 30.8% and DCR was 73.1%. In naive patients, injected / irradiated ORR was 62.5% and DCR was 100%. For all lesions in naive patients, ORR was 50% and DCR was 75%. In resistant patients, injected / irradiated ORR was 47.4% and DCR was 100%. For all lesions in resistant patients, ORR was 22.2% and DCR was 72.2%.

[0376] Among patients evaluable for efficacy, ORR was 51.9% in injected lesions, and 30.8% overall. Promising local control was observed, with DCR of 100% in injected lesions, and 73.1% overall. Progressive disease was due to new lesions or non target lesions, with no progression observed in injected lesions.

[0377] These results demonstrated that HfCh nanoparticle injection with radiation therapy in lung lesions was feasible and well-tolerated in combination with anti-PDl antibody therapy. Promising early signs of efficacy were observed. See Tables 2A-2B, 3A-3B, 4A-4B, and 5A- 5B below.Table 2A. Baseline participant characteristics.77MF-361301351Docket No.: 242272002940Table 2B. Updated baseline participant characteristics.78MF-361301351Docket No.: 24227200294079MF-361301351Docket No.: 242272002940(1) 10 naive subjects may have received 10 as an adjuvant therapy.Table 3A. Injection feasibility results.80MF-361301351Docket No.: 242272002940Table 3B. Updated injection feasibility results.81MF-361301351Docket No.: 242272002940Table 4 A. Safety results.82MF-361301351Docket No.: 242272002940Table 4B. Updated safety results.83MF-361301351Docket No.: 242272002940Table 5A. Efficacy results.all patients (PD above or equal to +20% / PR below or equal to -30% / SD in-between / CR if equal to -100%)(2) Best overall response have been derived as single best overall response observed for 6 patients still ongoing (0 CR, 3 PR, 2 SD and 1 PD)(3) Number of days from first to last RECIST assessment with CR or PR(4) Number of days from first to last RECIST assessment with CR, PR or SD(5) Number of days from first to last RECIST assessment with CR, PR, SD, or PDsubjects (PD above or equal to +20% / PR below or equal to -30% / SD in-between / CR if equal to -100%).Table 5B. Updated efficacy results.84MF-361301351Docket No.: 242272002940Clinical Study 2

[0378] A phase I dose escalation / expansion trial [NCT04505267] evaluated administration of HfC nanoparticles and reirradiation (reRT) in two cohorts of patients with Stage IA-IV biopsy-proven recurrent NSCLC within a prior field of radiotherapy (RT). Patients with a history of RT within the prior 6 months, grade 4 RT toxicity, or interstitial lung disease were excluded. HfCh nanoparticles were administered via intratumoral and / or intranodal lung injection at a dose of 22% or 33% of gross tumor volume (GTV) based on the RT planning CT scan. Up to four sites were allowed to be injected with the HfCh nanoparticles. ReRT85MF-361301351Docket No.: 242272002940 dose was 45 Gy administered in fifteen fractions. 30 Gy in ten fractions was permitted per physician discretion to meet protocol organ at risk constraints.

[0379] The primary objective was the safety, the feasibility, the recommended Phase 2 dose (RP2D) of intra-tumoral HfOi nanoparticle injection in combination with reRT, and the maximum tolerated dose of intra-tumoral HfOi nanoparticle injection. Dose limiting toxicities (DLTs) were defined as any CTCAE v5.0 Grade 3+ adverse events (AEs) related to HfOi nanoparticles or RT within 2 months of HfOi nanoparticle injection.

[0380] The secondary objectives included efficacy. Local progression free survival (LPFS) was estimated by the Kaplan Meier method.

[0381] From 2022 to 2023, 12 patients (median age 71 years, range 47-91) were enrolled. 14 sites were injected and treated (2 sites in 2 patients): 3 mediastinal lymph nodes and 11 lung lesions (10 central, 1 peripheral). HfOi nanoparticles were injected bronchoscopically (n=10) or by CT guidance (n=4). Median GTV was 16 mL (range 3-157). Median HfOi nanoparticle volume was 5 mL (range 1-51). 3 patients received a HfOi nanoparticle dose of 22%; 9 patients received a HfOi nanoparticle dose of 33%. All 12 patients completed treatment with HfOi nanoparticles plus reRT without dose limiting toxicities (DLTs). Maximum tolerated dose was not reached. HfOi nanoparticle RP2D was 33% of GTV. At 14.7 months median follow-up, RT -related AEs were:• Grade 5 respiratory failure (6 months after RT, possibly related); and• Grade 3: dyspnea (n=2), lymphopenia (n=l), hypotension (n=l), tachycardia (n=l). There were no Grade 3-5 HfOi nanoparticle / injection related AEs. 1-year local progression- free survival (LPFS) was 64%, and median LPFS was 18.6 months. See Kaplan-Meier LPFS curve provided in FIG. 3A. 83% overall survival (OS) was observed. A median overall survival (OS) of 30.2 months was also observed, as shown in FIG. 3B.

[0382] These results demonstrated that HfOi nanoparticle injection with radiation therapy in locally recurrent NSCLC lesions was feasible and well-tolerated in combination with reRT.EXAMPLE 2 - A Phase 2, randomized, open-label, active-controlled study of functionalized hafnium oxide (HfOi) nanoparticles in combination with chemoradiation followed by durvalumab in locally advanced and unresectable Stage III non-small cell lung cancer.

[0383] The first- in-class intratumoral crystalline solution of hafnium oxide (HfOi) nanoparticles acts as a radio-enhancer to amplify energy deposition and its associated radiobiological effects. When injected directly into the tumor, the HfOi nanoparticles have been shown to augment tumor cell death without increasing the radiation exposure of86MF-361301351Docket No.: 242272002940 noninjected healthy surrounding tissues (see, e.g., Maggiorella 2012). Activation of these HfCh nanoparticles with ionizing radiation was found to result in an approximately 9-fold increase (per Monte Carlo simulation) in energy deposition locally at the subcellular level to enhance cancer cell death (see, e.g., Maggiorella 2012). The effects of the HfCh nanoparticles have been demonstrated in a variety of cancer cell lines (including radioresistant models) following activation with different radiation therapy (RT) dose fractionations and schedules (see, e.g., Maggiorella 2012, and Marill 2014). In addition, nonclinical evidence has demonstrated that these HfCh nanoparticles can trigger systemic adaptive antitumor activity via immunogenic cell death (see, e.g., Damion 2022), which can overcome anti-programmed cell death protein 1 (PD-1) resistance (see, e.g., Hu 2021). Clinically, the HfCh nanoparticles are an effective radio-enhancer to RT in multiple solid tumor indications and have demonstrated a good tolerability and safety profile.

[0384] Nonclinical data suggested significant immune and distant effects from the addition of the HfCh nanoparticles with RT. In dual tumor murine models using anti-PD-1 resistant cell lines, the addition of the HfCh nanoparticles to radiation and anti-PD-1 therapy not only overcame PD-1 resistance, but also led to abscopal responses in nonradiated tumors. The immune response was confirmed with genomic analyses revealing upregulation of immune pathways and pathologic analyses revealing increased cytotoxic cells (CD8+ T cells and natural killer cells), dendritic cells, and total tumor infiltrating lymphocytes when compared with controls. Furthermore, there was a dramatic reduction in development of distant lung metastases in mice treated with the combination of the HfCh nanoparticles, RT, and anti-PD- 1 therapy (see, e.g., Hu 2021). For example, as described in Example 1 above, administration of the HfCh nanoparticles in combination with RT demonstrated significant improvements in tumor- specific growth delay, median survival time, and OS when compared with RT in 2 human HNSCC mouse models. In a patient-derived tumor xenograft model, the activation of the HfCh nanoparticles by RT significantly increased the OS of LPS8OT3 tumor-bearing mice compared with RT alone. In radioresistant and radiosensitive human tumor xenograft models, as well as patient-derived xenograft model, the HfCh nanoparticles injected intratumorally and activated by RT inhibited tumor growth and prolonged median survival time in mice models compared with RT alone. Activation of the HfCh nanoparticles with ionizing radiation may promote an antitumor immune response, as shown by the abscopal (i.e., distant) effect in nonclinical models with lung (see, e.g., Hu 2021, and Hu 2022) and colorectal cancer (see, e.g., Zhang 2020, and Marill 2019). Furthermore, these nonclinical87MF-361301351Docket No.: 242272002940 models demonstrated decreased development of lung metastases and immune memory when rechallenged with tumor after cure (see, e.g., Hu 2020).

[0385] This Example describes a randomized, open-label, active-controlled, parallel-group, multicenter study of functionalized hafnium oxide (HfOi) nanoparticles as a radio-enhancer in combination with chemoradiation followed by durvalumab for locally advanced and unresectable Stage IIIA and IIIB NSCLC (according to the Eighth Edition Lung Cancer Stage Classification) without evidence of ipsilateral or contralateral scalene or supraclavicular lymph node involvement.Study Design and Objectives

[0386] This clinical study is conducted in two parts: a sequential procedure optimization run- in part including two HfOi nanoparticle dose level cohorts (Part 1) and a 3-arm randomized dose optimization and proof-of-concept part (Part 2). The intratumoral dosing of the HfOi nanoparticles is based on a percentage of the gross tumor volume (GTV) for each lesion (primary lung lesion[s] and / or involved lymph node[s]) as measured / contoured on CT-based volumetric imaging.

[0387] Up to five participants with acceptable CT scan data are treated in Cohort A of Part 1 with HfOi nanoparticles at a dose level of 22% GTV. Cohort B of Part 1 enrolls up to five participants with acceptable CT scan data to be treated with HfOi nanoparticles at 33% GTV. During Part 2, 120 participants are randomized to the experimental Arms A and B and to control Arm C, wherein 40 evaluable participants with acceptable CT scan data are included in each arm. (See FIGs. 1A-1B.)

[0388] During the run-in Part 1, a total of up to five participants with acceptable CT scan data each are enrolled in two sequential cohorts to optimize the procedure and workflow of HfOi nanoparticle injection to the primary lung lesion(s) and involved pathologic lymph node(s), to train the investigational site study team, and to confirm the feasibility of the HfOi nanoparticle injection procedure. See FIG. 1A.

[0389] Cohort A of the run-in Part 1 is initially enrolling up to five participants with acceptable CT scan data to be treated with HfOi nanoparticles at a dose level of 22% GTV to evaluate the feasibility of injection (e.g., access, volume, duration) into all accessible lung lesions and involved lymph node(s) and assess technical aspects of the procedure, namely presence and extent of leakage / extravasation of HfOi nanoparticles by a confirmation CT at least 24 hours post-injection. Learnings from Cohort A are used to modify the injection procedure (if necessary) in Cohort B of the run-in Part 1 for up to five participants with HfOi88MF-361301351Docket No.: 242272002940 nanoparticles at a dose level of 33% GTV to further optimize the injection procedure for the randomized Part 2. Data collected in run-in Part 1, including a confirmation CT without contrast at least 24 hours post-injection, are reviewed and decision for the study entering the randomized Part 2 is then made. See FIG. 1A.

[0390] During the dose optimization and proof-of-concept Part 2, 120 participants are randomized to the experimental Arms A and B and to the control Arm C, with 40 participants with acceptable CT scan data randomized to each arm, to evaluate the efficacy and safety of two dose levels of HfCh nanoparticles (22% GTV in Arm A and 33% GTV in Arm B) as an intratumoral radio-enhancer added to cCRT followed by cIT in participants with locally advanced and unresectable Stage IIIA and IIIB NSCLC compared with participants receiving cCRT only followed by cIT. The intent of the study is to provide the magnitude and precision of the effect of two dose levels of HfOi nanoparticles added to cCRT followed by cIT as measured by ORR in this patient population when compared with cCRT only followed by cIT. Randomized Part 2 uses the following key stratification variables to minimize bias. See FIG. IB.• NSCLC staging: IIIA versus IIIB.• PD-L1 status: >1% versus <1%.

[0391] Participants in Part 2 are randomly assigned to one of three study arms based on a computer-generated randomization schedule prepared before the study by or under the supervision of the sponsor. The randomization will be balanced by using randomly permuted blocks at a 1: 1: 1 ratio (22% GTV dose of HfOi nanoparticle composition: 33% GTV dose of HfOi nanoparticle composition: control) and will be stratified by NSCLC staging (IIIA versus IIIB) and PD-L1 status (>1% versus <1%).

[0392] The duration of individual participation is up to 118 weeks (2 years plus 14 weeks). The duration of cCRT treatment with or without prior HfOi nanoparticle injection followed by cIT is up to 68 weeks from enrollment / randomization.

[0393] HfC Nanoparticles'. For participants in the run-in Part 1 and the experimental Arms A and B of the randomized Part 2, HfOi nanoparticles at a concentration of 54.2 g / L are injected intratumorally and / or intranodally (using either bronchoscopic and / or percutaneous approaches) into the majority of the lesions >2 days before start of RT at a dose of 22% (Cohort A and Arm A) or 33% (Cohort B and Arm B) of the computed GTV contour for each primary lesion and / or involved lymph node(s). To minimize disparities in efficacy due to tumor size variations, HfOi nanoparticle injection volume is determined as a percentage of89MF-361301351Docket No.: 242272002940 total tumor volume. Utilization of the gross tumor volume (GTV) method by CT or MRI is consistent with common practice standards that radiation oncologists use to contour and define tumor volumes for RT planning. In this study, the GTV contour method is used to determine tumor volume of each individual target lesion (both primary lesion[s] and involved lymph node[s]).

[0394] Corticosteroid Premedication-. For participants who receive HIO2 nanoparticle injection, corticosteroid premedication is administered according to one of two regimens: (1) Oral route - Prednisone 30 mg at approximately 12 hours and 2 hours before HIO2 nanoparticle administration; or (2) intravenous (IV) route - Dexamethasone 10 mg IV at approximately 1 hour before HIO2 nanoparticle administration. Other corticosteroids with similar properties at an equivalent dose are allowed.

[0395] Radiation Therapy. For participants who receive HIO2 nanoparticle injection, the first dose of RT via external beam intensity modulated radiation therapy (“IMRT”) is administered at least 2 days after HIO2 nanoparticle injection and within 11+3 days of enrollment / randomization (Day 1). For participants in the control Arm C, the first dose of RT is administered within 11+3 days of randomization (Day 1). For all participants, RT dose will be 60 Gy at 2 Gy per fraction, delivered daily for five days per week (typically Monday through Friday) via IMRT for six weeks, for a total of 30 fractions. The duration of exposure to RT is up to six weeks.

[0396] Chemotherapy. For all participants, the first dose of ChT starts on the same day or +3 days of the first fraction of RT. Participants receive carboplatin AUC 2 IV and paclitaxel 45 mg / m2IV on Day 1 of Cycles 1-6 (each cycle is seven days) for a total of six cycles. The duration of exposure to carboplatin-paclitaxel treatment is six weeks.

[0397] Durvalumab'. After cCRT, participants without evidence of PD as assessed by investigator per Response Evaluation Criteria in Solid Tumors (RECIST) vl.l start cIT (durvalumab) via IV infusion within six weeks after administration of the last fraction of RT or the last dose of ChT, whichever is later. The duration of exposure to durvalumab treatment is 52 weeks. Participants receive one of two cIT regimen options, according to investigator’s judgment and per local guidelines. See Table 6 below for a description of the treatments by study arm.• Option 1: Durvalumab 1500 mg per cycle, once q4w (i.e., every 4 weeks) for up to 13 cycles over 52 weeks; or90MF-361301351Docket No.: 242272002940• Option 2: Durvalumab 10 mg / kg per cycle, once q2w (i.e., every 2 weeks) for up to 26 cycles over 52 weeks.

[0398] For this study, “study treatment” refers to HfCF nanoparticle injection and corticosteroid premedication followed by cCRT and subsequent consolidation durvalumab; the HfCF nanoparticle composition is considered an investigational medicinal product (IMP). All other study-specified medications are considered concomitant medications.

[0399] Furthermore, for this study, “baseline” is defined as the measurement recorded on, or prior to, enrollment / randomization. All tumor assessments are evaluated relative to this baseline. Sensitivity analysis is performed on selected endpoints (e.g., unconfirmed ORR by ICR or by the investigators’ assessments, and time to event endpoint considering an alternative baseline defined as when the first treatment is received).Table 6. Description of Treatments by Study Arm.MF-361301351Docket No.: 24227200294092MF-361301351Docket No.: 242272002940

[0400] For participants who receive HfOi nanoparticles, a diagnostic CT-chest scan without contrast or RT planning scan (aka CT simulation) is collected at least 24 hours after the HfOi nanoparticle intratumoral / intranodal injection and reviewed by the investigator to document the presence, absence, leakage, and / or distribution of HfOi nanoparticles (radiopaque visualization) in the injected lesion(s) prior to the start of cCRT. The post-cCRT follow-up occurs within four weeks after the last fraction of RT or the last dose of ChT administered, whichever is later. Following the post-cCRT follow-up and RECIST vl.l assessment by investigator, participants without evidence of PD receive cIT by durvalumab per local guidelines but within six weeks of the last dose of RT or ChT, whichever is later.

[0401] Patient Reported Outcomes'. Patient reported outcomes (PROs) include NSCLC-SAQ, EORTC QLQ-C30 (v3), and EORTC IL46.• The Non-Small Cell Lung Cancer - Symptom Assessment Questionnaire (NSCLC- SAQ) was developed in accordance with US FDA PRO guidance and scientific best practices for use in clinical trials of NSCLC (see, e.g., McCarrier 2016). It contains 7 items rated on a 5-point scale that assess cough, pain, dyspnea, fatigue, and poor appetite over a 7-day recall period.93MF-361301351Docket No.: 242272002940• The European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Cancer Module (EORTC QLQ-C30), v3 is a self-administered, 30-item questionnaire measuring the health-related quality of life (HRQoL) of participants with cancer. The recall period for most items is the past week. EORTC QLQ-C30 includes 5 functional scales (physical, role, cognitive, emotional, and social), 3 symptom scales (fatigue, pain, and nausea and vomiting), a global health status / QoL scale, and 6 single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties). Responses to items 1-28 are rated on a 4-point Likert response scale ranging from [1 “Not at all”] to [4 “Very much”]. Two global health status items are rated on a 7-point numeric rating scale from [1 “Very Poor”] to [7 “Excellent”]. Higher scores indicate greater functioning, better global health status, and more severe symptoms. The EORTC QLQ-C30 generally is completed in 4 to 5 minutes.• The European Organisation for Research and Treatment of Cancer (EORTC) IL46 consists of a single question that measures global impression of burden due to treatment-related symptoms. The response options range from “Not at all” to “Very much” on a 4-point scale.

[0402] Pharmacokinetic, Safety, and / or Efficacy Analyses: Blood samples for serum chemistry, hematology, and thyroid function and a screening urine sample for urinalysis are collected to assess safety and tolerability. The total blood volume collected from each participant is approximately 473 mL. Whole blood and urine samples from participants who receive HfOi nanoparticles are used to evaluate the concentrations of hafnium using a validated, specific, and sensitive ICP-MS / MS method to assess pharmacokinetics (PK), as well as to evaluate safety and / or efficacy. Urine and blood collections for PK assessments are kept as close to specified times as possible. All planned assessments, including clinical laboratory tests, are completed and the results reviewed at each site visit.

[0403] Diagnostic Imaging: Baseline disease burden is assessed using contrast CT of chest and upper abdomen including liver and adrenal glands (unless the local imaging protocol requires addition of a full abdomen and pelvis), PET-CT scan, and contrast MRLbrain scan. CT-chest must cover the thoracic cavity and upper abdomen with IV contrast, including liver and adrenal glands, plus other areas of known disease involvement as appropriate. Contrast via IV administration is required unless a participant is not medically suitable to undergo CT scans with IV contrast due to allergy that is refractory to premedication or contraindicated due to renal insufficiency. Participants who can receive appropriate premedication should94MF-361301351Docket No.: 242272002940 undergo CT scans with IV contrast. Participants who are intolerant of IV contrast agents may have CT scans performed with oral contrast and the reason for not using IV contrast is then documented in source documents. PET-CT scan is required for body staging. MRI brain with contrast is required for brain staging unless medically contraindicated, for which a CT-brain with contrast can then be used. If brain metastases are present at screening, the patient is not eligible for enrollment. Ultrasound, [18F]-fluorodeoxyglucose PET, and plain X-rays are not acceptable sole methods of evaluating disease response. Techniques in addition to CT or MRI may be used, based upon investigator judgment, local SOC, and RECIST vl.l guidelines.

[0404] Subsequent efficacy evaluations during the study include radiographic imaging of all disease sites documented at baseline. CT with and without contrast of the chest and upper abdomen (including liver and adrenal glands) is required unless the local imaging protocol requires the addition of a full abdomen and pelvis. CT images are used throughout the course of the study to characterize each identified and reported lesion to document disease status. Additional anatomy may be imaged, and additional image modalities may be used based on the signs and symptoms of individual participants. The same CT scanning modality and parameters are used at all visits for each participant.

[0405] Inclusion Criteria: The target population include participants with locally advanced and unresectable NSCLC Stage IIIA and IIIB as this population has an increased risk of locoregional failure (LRF). This Study enrolls nonmetastatic participants, thus optimizing locoregional control to target all accessible lesions in order to maximize the therapeutic benefit. Participants are males or females >18 years of age with locally advanced and unresectable Stage IIIA and IIIB NSCLC. This Study aims to enroll a participant population that is geographically reflective of the overall incidence / prevalence of this disease. Screening for eligible participants is performed within 42 days before enrollment / randomization. Patients with the following disease characteristics are considered for participant enrollment:• Patient is a candidate for SOC treatment of NSCLC by cCRT following by consolidation durvalumab treatment, as determined by the investigator and per local guidelines at screening;• Patient has a life expectancy >6 months at the time of informed consent;• Patient has a medical history of pathologically (histologically or cytologically) proven diagnosis of NSCLC within 3 months prior to enrollment / randomization;95MF-361301351Docket No.: 242272002940• Patient has locally advanced Stage IIIA or IIIB NSCLC according to the Eighth Edition Lung Cancer Stage Classification (see, e.g., Detterbeck 2017) that is unresectable as determined by the investigator at screening;• Patient has at least 1 target lesion (primary lung lesion or involved lymph node[s]) per RECIST vl.l that is amenable to intratumoral and / or intranodal injection and external beam radiation therapy (EBRT), as determined by the investigator at screening;• Patient has documented tumor proportion score (TPS) of PD-L1 by a local or central laboratory within 3 months prior to enrollment / randomization;• Patient has no known EGFR and ALK mutation at screening;• At least 50% of total gross tumor volume (sum of all lesions) is accessible for injection in the Patient;• Patient has an ECOG performance status of 0 to 1 (i.e., Eastern Cooperative Oncology Group (ECOG) Performance Status Score);• Patient has adequate organ and marrow function as measured by local laboratory at screening without history of RBC or platelet transfusion within 7 days prior to the date of the test;• Patient lab results show: o Absolute neutrophil count >1.5 x 109 / L (1500 per mm3) without the use of growth factors (eg, G-CSF, GM-CSF) within 10 days prior to the date of the test; o Platelets >100 x 109 / L (100,000 per mm3); o Hemoglobin >9.0 g / dL (5.59 mmol / L); o Serum creatinine clearance >50 mL / min by the Cockcroft- Gault formula; o aspartate transaminase (AST) level and / or an alanine transaminase (ALT) level <3 x ULN (i.e., upper limit of normal); and o Serum total bilirubin <1.5 x ULN. For participants with known or suspected congenital nonhemolytic hyperbilirubinemias such as Gilbert's Syndrome, total bilirubin must be <6 mg / dL and conjugated [direct] bilirubin is <20% of total bilirubin.

[0406] Exclusion Criteria-. The target population excludes anyone with the following characteristics:• Patient has active or prior documented autoimmune or inflammatory disorders (e.g., scleroderma, active systemic lupus erythematosus);96MF-361301351Docket No.: 242272002940• Patient has end-stage renal disease (i.e., Patient is on dialysis, or dialysis has been recommended);• Patient has acute bacterial or fungal infection requiring IV antibiotics at the time of enrollment / randomization ;• Patient has acute viral infection requiring hospitalization within two weeks prior to enrollment / randomization ;• Patient has chronic obstructive pulmonary disease exacerbation, any pneumonitis or radiation pneumonitis including acute interstitial pneumonitis, pneumonitis, or other respiratory illness requiring hospitalization or precluding study therapy within 30 days of enrollment / randomization;• Patient has interstitial lung disease or pulmonary fibrosis that precludes or is contraindicated for SOC RT;• Patient has severe hepatic disease, defined as a diagnosis of Child-Pugh class B or C hepatic disease;• Patient has uncontrolled neuropathy Grade >2, regardless of cause;• Patient has any of the following within 3 months prior to enrollment / randomization: severe or unstable angina, myocardial infarction, major thromboembolic events (eg, pulmonary embolism, cerebrovascular accident), clinically significant ventricular arrhythmias or heart failure New York Heart Association functional classification Class III to IV. Uncomplicated deep vein thrombosis is not considered exclusionary.• Patient has a QTcF interval >480 msec on screening ECG;• Patient has another concurrent or prior primary malignancy (other than NSCLC) within the last 36 months at informed consent;• Patient has a medical history of primary immunodeficiency and / or organ transplant that requires therapeutic immunosuppression;• Patient has known allergies, hypersensitivity, or intolerance to any ingredients of the HfOi nanoparticle crystalline solution, platinum-based doublet ChT, or durvalumab;• Patient has active bleeding diathesis or requirement for therapeutic anticoagulation or antiplatelet that cannot be interrupted or altered for procedures;• Patient has active hepatitis of infectious origin or any other clinically active liver disease of infectious origin;• Patient is known to be positive for HIV and meets at least one of the following criteria:97MF-361301351Docket No.: 242272002940 o Detectable viral load (ie, >50 copies / mL) at screening; o CD4+ count <350 cells / mm3at screening; o AIDS-defining opportunistic infection within 6 months of the start of screening; o A change in antiretroviral therapy within 6 months of the start of screening; o Not receiving HAART. Any changes in HAART due to resistance / progression should occur at least 3 months prior to screening. A change in HAART due to toxicity is allowed up to 4 weeks prior to screening; o Not agreeing to start HAART and be on HAART >4 weeks plus having HIV load <400 copies / mL at the end of a 4-week period to ensure HAART is tolerated and HIV is controlled; o HAART that could interfere with study treatment;• Patient has evidence of ipsilateral or contralateral scalene or supraclavicular lymph node involvement;• Patient has tumors with invasion / encasement of great vessels or esophagus, baseline presence of fistula, and / or malignant airway obstruction that requires endoscopic intervention;• Patient has mixed small cell and non-small cell lung cancer histology;• Patient has presence of metastatic disease (Ml);• Patient has a primary tumor status that is not able to be assessed (TX);• Patient has a calculated total gross tumor volume >909 mL;• Patient received prior systemic anticancer therapy within the prior 36 months at informed consent: o Prior systemic ChT for lung cancer within the prior 36 months at informed consent; o Concurrent treatment with any other nonstudy anticancer therapy, including chemotherapy, immunotherapy, targeted therapy, gene therapy, or participants planning to receive these treatments during the study;• Patient received prior intrathoracic RT that would overlap with the current study PTV for lung cancer, or recommended normal tissue constraints are exceeded when creating a summation of the prior and current radiation plans. Prior RT is allowable only if the treatment is >36 months at informed consent and does not interfere with98MF-361301351Docket No.: 242272002940 the study lesion assessment; RT to chest wall, such as for early- stage breast cancer or skin cancer, is allowable;• Patient has contraindications to the use of the HfC nanoparticles or platinum-based doublet ChT or durvalumab per local prescribing information;• Patient received an investigational treatment or used an invasive investigational medical device within 30 days before the enrollment / randomization or received an investigational biological product within 3 months or 5 half-lives, whichever is longer, before the enrollment / randomization, or is currently enrolled in an investigational study.Primary Objective(s)

[0407] The primary objective of this study is to determine whether the HfCh nanoparticles, as an intratumoral / intranodal radio-enhancer added to cCRT followed by cIT, can improve objective response rate (ORR) in participants with locally advanced and unresectable Stage IIIA and IIIB NSCLC. The objective measuring ORR was chosen because the impact of HIO2 nanoparticle administration may increase tumor cell killing, which manifests as increased rates of observed objective responses in the short-term.

[0408] Primary Endpoint'. ORR is defined as the proportion of participants who have a best response of CR or PR according to RECIST vl.l. The primary analysis is performed on confirmed ORR using ICR assessments at the first and second data cutoff. Since enrollment / randomization is at the start of the cCRT, patients progressing and not continuing with durvalumab treatment are counted as non-responders (not meeting CR / PR) for the primary endpoint ORR. Strata- adjusted ORRs and the corresponding confidence interval of the treatment difference are estimated.Secondary Objective(s)

[0409] The secondary objectives of this study are to: (1) assess additional measures of clinical benefit in participants treated with the H IO2 nanoparticles in combination with cCRT ; (2) assess the locoregional and distant effects of the HIO2 nanoparticles as a radio-enhancer to cCRT; and (3) assess the safety and tolerability profile of the HIO2 nanoparticles as a radio-enhancer to cCRT, with cCRT followed by cIT.

[0410] Secondary [Efficacy] Endpoints: Analysis is provided for the best ORR based on investigator’s assessment according to RECIST vl.l. After the completion of cCRT, the investigator evaluates the disease status prior to the start of the durvalumab. The disease response rate or ORR (CR+PR) and Disease Control Rate (DCR) (CR+PR+SD) are99MF-361301351Docket No.: 242272002940 summarized at this time point. CR = complete response; PR = partial response; SD = stable disease.

[0411] Progression-free survival (PFS) is defined as the time from the enrollment / randomization until disease progression or death due to any cause. Participants without such an event are censored at the last known date the participant is alive and progression-free. Time-to-event PFS is analyzed based on the programmatically derived progression from ICR assessments. In addition, progression-free event rates at 6-, 12-, and 24-months post-enrollment / randomization are estimated.

[0412] The duration of response (DoR) is summarized descriptively with Kaplan-Meier curves. DoR is calculated among responders from the date of initial documentation of a response to the date of first documented evidence of relapse according to RECIST v 1.1, or death due to any cause, whichever occurs first. For participants with disease that has not relapsed and who are alive, data are censored at the last disease assessment. In addition, the restricted mean duration of response (mDoR) based on the probability of being in response function (PBRF) is estimated and analyzed for treatment comparison.

[0413] The time to LRF and time to DF are defined as the time from enrollment / randomization to the first LRF and DF, respectively, using ICR assessments. Participants who do not have LRF or DF are censored at the last disease assessment. In addition, LRF rates and DF rates are presented at 6-, 12-, and 24-months post- enrollment / randomization. IF-LRF is defined as PD within the baseline radiation PTV. OF- LRF is defined as any disease outside of PTV and involving the ipsilateral lung (involved lobe[s]) and / or lymph node(s) in the bilateral hilum, bilateral mediastinum, or bilateral supraclavicular regions without IF-LRF. DF is defined as any other disease progression identified in the ipsilateral lung but in an uninvolved lobe, contralateral lung parenchyma, or outside the thorax without IF-LRF or OF-LRF.Safety Objective(s)

[0414] The assessment of the safety and tolerability profile of the HfCh nanoparticles as a radio-enhancer of cCRT is a safety objective that also is a secondary objective. Safety is monitored on a continuous basis. Safety is assessed by physical examinations, vital signs, clinical laboratory tests, monitoring for AEs and AESIs, and ECOG status. Concomitant medication usage and use of subsequent anticancer therapy are recorded. Adverse events are graded by the investigator using NCLCTCAE v5.0.100MF-361301351Docket No.: 242272002940

[0415] Safety Endpoints: All safety analyses are made on the Safety Analysis Set. Safety data are summarized descriptively overall and by study parts (i.e., run-in Part 1 and randomized Part 2). In addition, within Part 2, a summary is presented by study arm. Safety data can include TEAEs, abnormal clinical laboratory tests, abnormal vital signs, abnormal physical examination findings, and ECOG score changes from baseline.

[0416] A treatment-emergent adverse event (TEAE) is defined as: (1) any new or worsening adverse event (AE) occurring at or after the initial administration of study treatment through the day of last dose of study treatment received plus 30 days or prior to the start of subsequent anticancer therapy (non-durvalumab), whichever is earlier; or (2) any follow-up AE (linked to an existing TEAE) with onset date and time beyond 30 days after the last dose of study treatment but prior to the start of subsequent anticancer therapy; or (3) any AE that is considered treatment-related regardless of the start date of the event. All reported TEAEs are included in the analysis. For each AE, the percentage of participants who experience at least 1 occurrence of the given event is summarized by study treatment group. Parameters with predefined NCI-CTCAE v5.0 toxicity grades are summarized (e.g., number of participants with TEAEs; early onset TEAEs, defined as AEs occurring from the first study treatment up to 30 days post last dose / fraction of cCRT or first dose of cIT, whichever is earlier; late onset TEAEs, defined as AEs occurring after the early onset TEAE period;TEAEs related to HfCh nanoparticle injection procedure, HfOi nanoparticles, RT, ChT, or cIT).Exploratory Objective(s)

[0417] The exploratory objectives for this study are the following: (1) determine the effect of the HfCh nanoparticles as a radio-enhancer to cCRT on the number of participants eligible for durvalumab consolidation post-cCRT; (2) determine time-to-event effects of HIO2 nanoparticles as a radio-enhancer to cCRT; (3) assess the feasibility of retention and distribution of intratumoral and intranodal HIO2 nanoparticle injection; (4) assess the intraparticipant efficacy of intratumoral and intranodal Hl'C nanoparticle injection; (5) assess the systemic hafnium concentrations; (6) explore immunogenicity to protein corona formed around Hl'Ch nanoparticles if needed; (7) explore blood and tissue biomarkers that may be associated with the biology of NSCLC and influence the progression of the disease and / or response to treatment; and (8) explore the impact of study treatment on disease-related symptom experience, functional status, and side effect impact.101MF-361301351Docket No.: 242272002940

[0418] Exploratory Endpoints'. The following exploratory endpoints are analyzed using the same method as the primary endpoint(s): percentage of participants receiving cIT after cCRT treatment and percentage of participants completing planned cCRT. The following time-to- event exploratory endpoints are analyzed: (1) time to response (TTR) - time from enrollment / randomization to first documented CR or PR (participants who do not reach CR or PR will be censored at the last disease assessment while on treatment); and (2) overall survival (OS) - OS is defined as the time from enrollment / randomization until death due to any cause (participants who have no events are censored at the last known alive date; OS rate at 12- and 24-months post-enrollment / randomization is estimated).

[0419] HfOi nanoparticle treatment dose is summarized by lesion and by subject including the following: (1) HfOi nanoparticle volumes injected relative to lesion volumes; (2) HfOi nanoparticle volumes retained in the lesion relative to injected at least 24 hours after injection; (3) HfOi nanoparticle volumes retained relative to lesion volumes at least 24 hours after injection; (4) injected HfC nanoparticle distribution relative to lesion volume at least 24 hours after injection; and (5) tumor response in HfC nanoparticle-injected lesions compared with noninjected lesions in the same participant (when applicable).

[0420] Disease-related symptom experience, functional status, and side effect impact are summarized descriptively by visit and change from baseline as appropriate using the following PRO tools: NSCLC-SA; EORTC QLQ-C30, v3; and EORTC IL46 side effect bother.

[0421] Subgroup analyses on ORR and PFS are explored considering stratification factors and HfOi nanoparticle coverage (e.g., injection volume, injection distribution, nodal coverage, number of injected lesions). In addition, ORR is evaluated by examining both injected and non-injected lesions.

[0422] Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, the descriptions and examples should not be construed as limiting the scope of the invention. The disclosures of all patent applications and publications and scientific literature cited herein are expressly incorporated in their entirety by reference for any purpose.102MF-361301351Docket No.: 242272002940EXAMPLE 3 - Update to a Phase 2, randomized, open-label, active-controlled study of functionalized hafnium oxide (HfOi) nanoparticles in combination with chemoradiation followed by durvalumab in locally advanced and unresectable Stage III non-small cell lung cancer.

[0423] This Example describes an update to the study described by Example 2. Described below a randomized, open-label, active-controlled, parallel-group, multicenter study of functionalized hafnium oxide (HfOi) nanoparticles as a radio-enhancer in combination with chemoradiation followed by durvalumab for locally advanced and unresectable Stage III NSCLC (according to the Eighth Edition Lung Cancer Stage Classification) without evidence of ipsilateral or contralateral scalene or supraclavicular lymph node involvement.Study Design and Objectives

[0424] This clinical study is conducted in two parts: a sequential procedure optimization run- in part including two HfOi nanoparticle dose level cohorts (Part 1) and a 3-arm randomized dose optimization and proof-of-concept part (Part 2). The intratumoral dosing of the HfOi nanoparticles is based on a percentage of the gross tumor volume (GTV) for each lesion (primary lung lesion[s] and / or involved lymph node[s]) as measured / contoured on CT-based volumetric imaging.

[0425] Approximately five participants are treated in Cohort A of Part 1 with HfOi nanoparticles at a dose level of 22% GTV. Cohort B of Part 1 enrolls approximately five participants to be treated with HfOi nanoparticles at 33% GTV. During Part 2, 120 participants are randomized to experimental Arms A and B and to control Arm C, wherein 40 evaluable participants with acceptable CT scan data are included in each arm. (See FIGs. 4A- 4B.)

[0426] During the run-in Part 1, a total of approximately five participants with acceptable CT scan data each are enrolled in two sequential cohorts to optimize the procedure and workflow of HfOi nanoparticle injection to the primary lung lesion(s) and involved pathologic lymph node(s), to train the investigational site study team, and to confirm the feasibility of the HfOi nanoparticle injection procedure. See FIG. 4A.

[0427] Cohort A of the run-in Part 1 is initially enrolling approximately five participants to be treated with HfOi nanoparticles at a dose level of 22% GTV to evaluate the feasibility of injection (e.g., access, volume, duration) into all accessible lung lesions and involved lymph node(s) and assess technical aspects of the procedure, namely presence and distribution of HfOi nanoparticles by a confirmation CT at least 24 hours post-injection. Learnings from Cohort A are used to modify the injection procedure (if necessary) in Cohort B of the run-in103MF-361301351Docket No.: 242272002940Part 1 for approximately five participants with HfOi nanoparticles at a dose level of 33% GTV to further optimize the injection procedure for the randomized Part 2. Data collected in run-in Part 1, including a confirmation CT without contrast at least 24 hours post- injection, are reviewed and decision for the study entering the randomized Part 2 is then made. See FIG. 4A.

[0428] During the dose optimization and proof-of-concept Part 2, 120 participants are randomized to the experimental Arms A and B and to the control Arm C, with 40 participants with acceptable CT scan data randomized to each arm, to evaluate the efficacy and safety of two dose levels of HfCh nanoparticles (22% GTV in Arm A and 33% GTV in Arm B) as an intratumoral radio-enhancer added to cCRT followed by cIT in participants with locally advanced and unresectable Stage III NSCLC compared with participants receiving cCRT only followed by cIT. The intent of the study is to provide the magnitude and precision of the effect of two dose levels of HfOi nanoparticles added to cCRT followed by cIT as measured by ORR in this patient population when compared with cCRT only followed by cIT.Randomized Part 2 uses the following key stratification variables to minimize bias. See FIG. 4B.• NSCLC staging: IIIA versus IIIB / IIIC.• PD-L1 status: >1% versus <1%.

[0429] Participants in Part 2 are randomly assigned to one of three study arms based on a computer-generated randomization schedule prepared before the study by or under the supervision of the sponsor. The randomization will be balanced by using randomly permuted blocks at a 1: 1: 1 ratio (22% GTV dose of HfOi nanoparticle composition: 33% GTV dose of HfOi nanoparticle composition: control) and will be stratified by NSCLC staging (IIIA versus IIIB / IIIC) and PD-L1 status (>1% versus <1%).

[0430] The duration of individual participation is up to 118 weeks (2 years plus 14 weeks). The duration of cCRT treatment with or without prior HfOi nanoparticle injection followed by cIT is up to 68 weeks from enrollment / randomization.

[0431] HfC Nanoparticles'. For participants in the run-in Part 1 and the experimental Arms A and B of the randomized Part 2, HfOi nanoparticles at a concentration of 54 mg / mL are injected intratumorally and / or intranodally (using either bronchoscopic and / or percutaneous approaches) into the majority of the lesions >2 days before start of RT at a dose of 22% (Cohort A and Arm A) or 33% (Cohort B and Arm B) of the computed GTV contour for each primary lesion and / or involved lymph node(s). To minimize disparities in efficacy due to104MF-361301351Docket No.: 242272002940 tumor size variations, HIO2 nanoparticle injection volume is determined as a percentage of total tumor volume. Utilization of the gross tumor volume (GTV) method by CT or MRI is consistent with common practice standards that radiation oncologists use to contour and define tumor volumes for RT planning. In this study, the GTV contour method is used to determine tumor volume of each individual target lesion (both primary lesion[s] and involved lymph node[s]).

[0432] Corticosteroid Premedication-. For participants who receive HIO2 nanoparticle injection, corticosteroid premedication is administered according to one of two regimens: (1) Oral route - Prednisone 30 mg at approximately 12+2 hours and 2+2 hours before HIO2 nanoparticle administration; or (2) intravenous (IV) route - Dexamethasone 10 mg IV at approximately 1+1 hour before HI O2 nanoparticle administration. Other corticosteroids with similar properties at an equivalent dose are allowed.

[0433] Radiation Therapy. For participants who receive HIO2 nanoparticle injection, the first dose of RT via intensity modulated radiation therapy (“IMRT”) is administered at least 2 days after HIO2 nanoparticle injection and within 14 days of enrollment / randomization (Day 1) and within 3 days (the same day preferred) of the first IMRT treatment. For participants in the control Arm C, the first dose of RT is administered within 14 days of randomization (Day 1). For all participants, RT dose will be 60 Gy at 2 Gy per fraction, delivered daily for five days per week (typically Monday through Friday) via IMRT for six weeks, for a total of 30 fractions. The duration of exposure to RT is up to six weeks.

[0434] Chemotherapy. For all participants, the first dose of ChT starts on the same day or +3 days of the first fraction of RT. Participants receive carboplatin AUC 2 IV and paclitaxel 45-50 mg / m2IV per local guidelines on Day 1 of Cycles 1-6 (each cycle is seven days) for a total of six cycles. The duration of exposure to carboplatin-paclitaxel treatment is six weeks. If RT is interrupted and not completed within 6 weeks, an optional 7th cycle of ChT may be given per local guidelines due to the delay of RT completion.

[0435] Durvalumab'. After cCRT, participants without evidence of PD as assessed by investigator per Response Evaluation Criteria in Solid Tumors (RECIST) vl.l start cIT (durvalumab) via IV infusion within six weeks after administration of the last fraction of RT or the last dose of ChT, whichever is later. The duration of exposure to durvalumab treatment is 52 weeks. Participants receive one of two cIT regimen options per local guidelines. See Table 7 below for a description of the treatments by study arm.105MF-361301351Docket No.: 242272002940• Option 1: Durvalumab 1500 mg per cycle, once q4w (i.e., every 4 weeks) for up to 13 cycles over 52 weeks; or• Option 2: Durvalumab 10 mg / kg per cycle, once q2w (i.e., every 2 weeks) for up to 26 cycles over 52 weeks.

[0436] For participants within unknown epidermal growth factor receptor (EGFR) mutation during screening but tested to be EGFR mutation positive post-enrollment / randomization, participants can be treated with EGFR-targeted therapies per local guidelines as an alternative to consolidation durvalumab upon sponsor approval. The medication and dosing of this alternative consolidation therapy will be recorded in electronic case report form (eCRF). These participants will be followed up for all study assessments as specified in the schedule of activities.

[0437] For this study, “study treatment” refers to HfCF nanoparticle injection and corticosteroid premedication followed by cCRT and subsequent consolidation durvalumab; the HfCF nanoparticle composition is considered an investigational medicinal product (IMP). All other study-specified medications are considered concomitant medications.

[0438] Furthermore, for this study, “baseline” is defined as the measurement recorded on, or prior to, enrollment / randomization. All tumor assessments are evaluated relative to this baseline. Sensitivity analysis is performed on selected endpoints (e.g., unconfirmed ORR by ICR or by the investigators’ assessments, and time to event endpoint considering an alternative baseline defined as when the first treatment is received).Table 7. Description of Treatments by Study Arm.106MF-361301351Docket No.: 242272002940107MF-361301351Docket No.: 242272002940

[0439] For participants who receive HfOi nanoparticles, a diagnostic CT-chest scan without contrast or RT planning scan (aka CT simulation) is collected at least 24 hours after the HfOi nanoparticle intratumoral / intranodal injection and reviewed by the investigator to document the presence, absence, leakage, and / or distribution of HfOi nanoparticles (radiopaque visualization) in the injected lesion(s) prior to the start of cCRT. The post-cCRT follow-up occurs within two weeks ±14 days after the last fraction of RT or the last dose of ChT administered, whichever is later. Following the post-cCRT follow-up and RECIST vl.l assessment by investigator, participants without evidence of PD receive cIT by durvalumab per local guidelines but within six weeks of the last dose of RT or ChT, whichever is later.

[0440] Patient Reported Outcomes'. Patient reported outcomes (PROs) include NSCLC-SAQ, EORTC QLQ-C30 (v3), and EORTC IL46.• The Non-Small Cell Lung Cancer - Symptom Assessment Questionnaire (NSCLC- SAQ) was developed in accordance with US FDA PRO guidance and scientific best 108MF-361301351Docket No.: 242272002940 practices for use in clinical trials of NSCLC (see, e.g., McCarrier 2016). It contains 7 items rated on a 5-point scale that assess cough, pain, dyspnea, fatigue, and poor appetite over a 7-day recall period.• The European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Cancer Module (EORTC QLQ-C30), v3 is a self-administered, 30-item questionnaire measuring the health-related quality of life (HRQoL) of participants with cancer. The recall period for most items is the past week. EORTC QLQ-C30 includes 5 functional scales (physical, role, cognitive, emotional, and social), 3 symptom scales (fatigue, pain, and nausea and vomiting), a global health status / QoL scale, and 6 single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties). Responses to items 1-28 are rated on a 4-point Likert response scale ranging from [1 “Not at all”] to [4 “Very much”]. Two global health status items are rated on a 7-point numeric rating scale from [1 “Very Poor”] to [7 “Excellent”]. Higher scores indicate greater functioning, better global health status, and more severe symptoms. The EORTC QLQ-C30 generally is completed in 4 to 5 minutes.• The European Organisation for Research and Treatment of Cancer (EORTC) IL46 consists of a single question that measures global impression of burden due to treatment-related symptoms. The response options range from “Not at all” to “Very much” on a 4-point scale.

[0441] Pharmacokinetic, Safety, and / or Efficacy Analyses: Blood samples for serum chemistry, hematology, and thyroid function are collected to assess safety and tolerability. The total blood volume collected from each participant is approximately 473 mL. Whole blood and urine samples from participants who receive HfOi nanoparticles are used to evaluate the concentrations of hafnium using a validated, specific, and sensitive ICP-MS / MS method to assess pharmacokinetics (PK), as well as to evaluate safety and / or efficacy. Urine and blood collections for PK assessments are kept as close to specified times as possible. All planned assessments, including clinical laboratory tests, are completed and the results reviewed at each site visit.

[0442] Diagnostic Imaging: Baseline disease burden is assessed using contrast CT of chest and upper abdomen including liver and adrenal glands (unless the local imaging protocol requires addition of a full abdomen and pelvis), [18F]-fluorodeoxyglucose (FDG) PET-CT whole body scan, and contrast MRI brain scan. CT-chest must cover the thoracic cavity and upper abdomen with IV contrast, including liver and adrenal glands, plus other areas of109MF-361301351Docket No.: 242272002940 known disease involvement as appropriate. Contrast via IV administration is required unless a participant is not medically suitable to undergo CT scans with IV contrast due to allergy that is refractory to premedication or contraindicated due to renal insufficiency. Participants who can receive appropriate premedication should undergo CT scans with IV contrast. Participants who are intolerant of IV contrast agents may have CT scans performed with oral contrast and the reason for not using IV contrast is then documented in source documents. Contrast MRI is an acceptable alternative for liver imaging. If multiple diagnostic CT with contrast scans were performed within 6 weeks of enrollment / randomization, the one closest to the enrollment / randomization should be used for baseline lesion assessment. Whole body FDG PET-CT scan (base of skull to mid-thigh, or site standard) is required for body staging. MRI brain with contrast is required for brain staging unless medically contraindicated, for which a CT-brain with contrast can then be used. If brain metastases are present at screening, the patient is not eligible for enrollment. Ultrasound, FDG-PET, and plain X-rays are not acceptable sole methods of evaluating disease response. Techniques in addition to CT or MRI may be used, based upon investigator judgment, local SOC, and RECIST vl.l guidelines.

[0443] Subsequent efficacy evaluations during the study include radiographic imaging of all disease sites documented at baseline. CT with and without contrast of the chest and upper abdomen (including liver and adrenal glands) is required unless the local imaging protocol requires the addition of a full abdomen and pelvis. CT images are used throughout the course of the study to characterize each identified and reported lesion to document disease status. FDG PET-CT will be performed at week 25 of cIT. Additional anatomy may be imaged, and additional image modalities may be used based on the signs and symptoms of individual participants. The same CT scanning modality and parameters are used at all visits for each participant.

[0444] The first disease response evaluation will occur 2 weeks (±14 days) after last study treatment of cCRT (ie, post-cCRT CT). From the post-cCRT CT scan, at a fixed schedule, CT assessment will occur q8w (±7 days) for 12 months, then ql2w (±14 days) until 24 months after last dose of cCRT, radiographic progression or participant withdrawal, whichever occurs first. After completion of cCRT, the imaging schedule should follow calendar days and should not be delayed due to interruptions or delays in study treatment.

[0445] Inclusion Criteria: The target population include participants with locally advanced and unresectable NSCLC Stage III as this population has an increased risk of locoregional failure (LRF). This Study enrolls nonmetastatic participants, thus optimizing locoregional110MF-361301351Docket No.: 242272002940 control to target all accessible lesions in order to maximize the therapeutic benefit. Participants are males or females >18 years of age with locally advanced and unresectable Stage III NSCLC. This Study aims to enroll a participant population that is geographically reflective of the overall incidence / prevalence of this disease. Screening for eligible participants is performed within 42 days before enrollment / randomization. Patients with the following disease characteristics are considered for participant enrollment:• Patient is a candidate for SOC treatment of NSCLC by cCRT following by consolidation durvalumab treatment, as determined by the investigator and per local guidelines at screening;• Patient has a life expectancy >6 months at the time of informed consent;• Patient has a medical history of pathologically (histologically or cytologically) proven diagnosis of NSCLC within 3 months prior to enrollment / randomization; o Pathologic mediastinal staging with mediastinoscopy, mediastinotomy, endobronchial ultrasound (EBUS), endoscopic ultrasound (EUS), and / or CT guided biopsy is required when deemed technically feasible and clinically appropriate• Patient has locally advanced Stage III NSCLC according to the Eighth Edition Lung Cancer Stage Classification (see, e.g., Detterbeck 2017) that is unresectable as determined by the investigator at screening;• Patient has at least 1 target lesion (primary lung lesion or involved lymph node[s] planned to receive the full dose of prescribed RT [60 Gy]) per RECIST vl.l that is amenable to intratumoral and / or intranodal injection and intensity modulated radiation therapy (IMRT), as determined by the investigator at screening; o All primary tumor lesions and involved lymph nodes that will be radiated with the full dose of planned RT (ie, 60 Gy) should be considered for HfOi nanoparticle injection if a lesion meets the minimum size requirement and deemed accessible for HfOi nanoparticle injection per investigator’s assessment• Patient has documented tumor proportion score (TPS) of PD-L1 by a local or central laboratory within 3 months prior to enrollment / randomization;• Patient has no known EGFR and ALK mutation at screening;• At least 50% of total gross tumor volume (sum of all lesions) is accessible for injection in the Patient;111MF-361301351Docket No.: 242272002940 o All primary tumor lesions and involved lymph nodes that will be radiated with the full dose of planned RT (ie, 60 Gy) should be considered for HfC nanoparticle injection if a lesion meets the minimum size requirement (see Section 6.1.1) and deemed accessible for HfC nanoparticle injection per investigator’s assessment.• Patient has an ECOG performance status of 0 to 1 (i.e., Eastern Cooperative Oncology Group (ECOG) Performance Status Score);• Patient has adequate organ and marrow function as measured by local laboratory at screening without history of RBC or platelet transfusion within 7 days prior to the date of the test;• Patient lab results show: o Absolute neutrophil count >1.5 x 109 / L (1500 per mm3) without the use of growth factors (eg, G-CSF, GM-CSF) within 10 days prior to the date of the test; o Platelets >100 x 109 / L (100,000 per mm3); o Hemoglobin >9.0 g / dL (5.59 mmol / L); and o aspartate transaminase (AST) level and / or an alanine transaminase (ALT) level <3 x ULN (i.e., upper limit of normal).

[0446] Exclusion Criteria-. The target population excludes anyone with the following characteristics:• Patient has active or prior documented autoimmune or inflammatory disorders (e.g., scleroderma, active systemic lupus erythematosus);• Patient has end-stage renal disease (i.e., Patient is on dialysis, or dialysis has been recommended);• Patient has acute bacterial or fungal infection requiring IV antibiotics at the time of enrollment / randomization ;• Patient has acute viral infection requiring hospitalization within two weeks prior to enrollment / randomization ;• Patient has chronic obstructive pulmonary disease exacerbation, any pneumonitis or radiation pneumonitis including acute interstitial pneumonitis, pneumonitis, or other respiratory illness requiring hospitalization or precluding study therapy within 30 days of enrollment / randomization;112MF-361301351Docket No.: 242272002940• Patient has interstitial lung disease or pulmonary fibrosis that precludes or is contraindicated for SOC RT;• Patient has severe hepatic disease, defined as a diagnosis of Child-Pugh class B or C hepatic disease;• Patient has uncontrolled neuropathy Grade >2, regardless of cause;• Patient has any of the following within 3 months prior to enrollment / randomization: severe or unstable angina, myocardial infarction, clinically significant ventricular arrhythmias or heart failure New York Heart Association functional classification Class III to IV.• Patient has a QTcF interval >480 msec on screening ECG;• Patient has another concurrent or prior primary malignancy within the last 36 months at informed consent;• Patient has a medical history of primary immunodeficiency and / or organ transplant that requires therapeutic immunosuppression;• Patient has known allergies, hypersensitivity, or intolerance to any ingredients of the HfOi nanoparticle crystalline solution, platinum-based doublet ChT, or durvalumab;• Patient has history of coagulation disorders, including o active bleeding diathesis or requirement for therapeutic anticoagulation or antiplatelet that cannot be interrupted or altered for procedures o Major thromboembolic events (eg, pulmonary embolism, cerebrovascular accident) within 3 months of enrollment / randomization. Uncomplicated deep vein thrombosis is not considered exclusionary;• Patient has active hepatitis of infectious origin or any other clinically active liver disease of infectious origin;• Patient is positive for HIV antibody testing and meets at least one of the following criteria: o Detectable viral load (ie, >50 copies / mL) at screening; o CD4+ count <350 cells / mm3at screening; o AIDS-defining opportunistic infection within 6 months of the start of screening; o A change in antiretroviral therapy within 6 months of the start of screening;113MF-361301351Docket No.: 242272002940 o Any changes in HAART due to resistance / progression should occur at least 3 months prior to screening. A change in HAART due to toxicity is allowed up to 4 weeks prior to screening; o Not receiving HAART o Not agreeing to start HAART and be on HAART >4 weeks plus having HIV load <400 copies / mL at the end of a 4-week period to ensure HAART is tolerated and HIV is controlled; o HAART that could interfere with study treatment;• Patient has evidence of ipsilateral or contralateral scalene or supraclavicular lymph node involvement;• Patient has tumors with invasion / encasement of great vessels or esophagus, baseline presence of fistula, and / or malignant airway obstruction that requires endoscopic intervention;• Patient has mixed small cell and non-small cell lung cancer histology;• Patient has presence of metastatic disease (Ml);• Patient has a primary tumor status that is not able to be assessed (TX);• Patient has a calculated total gross tumor volume >909 mL;• Patient received prior systemic anticancer therapy within the prior 36 months at informed consent: o Prior systemic ChT for lung cancer within the prior 36 months at informed consent; o Concurrent treatment with any other nonstudy anticancer therapy, including chemotherapy, immunotherapy, targeted therapy, gene therapy, or participants planning to receive these treatments during the study;• Patient received prior intrathoracic RT that would overlap with the current study PTV for lung cancer, or recommended normal tissue constraints are exceeded when creating a summation of the prior and current radiation plans. Prior RT is allowable only if the treatment is >36 months at informed consent and does not interfere with the study lesion assessment; RT to chest wall, such as for early- stage breast cancer or skin cancer, is allowable;• Patient has contraindications to the use of the HfCh nanoparticles or platinum-based doublet ChT or durvalumab per local prescribing information;114MF-361301351Docket No.: 242272002940• Patient received an investigational treatment or used an invasive investigational medical device within 30 days before the enrollment / randomization or received an investigational biological product within 3 months or 5 half-lives, whichever is longer, before the enrollment / randomization, or is currently enrolled in an investigational study.Primary Objective(s)

[0447] The primary objective of this study is to determine whether the HfCh nanoparticles, as an intratumoral / intranodal radio-enhancer added to cCRT followed by cIT, can improve objective response rate (ORR) in participants with locally advanced and unresectable Stage III NSCLC. The objective measuring ORR was chosen because the impact of HfOi nanoparticle administration may increase tumor cell killing, which manifests as increased rates of observed objective responses in the short-term.

[0448] Primary Endpoint'. ORR is defined as the proportion of participants who have a best response of CR or PR according to RECIST vl.l. The primary analysis is performed on ORR using ICR assessments at the first and second data cutoff. Since enrollment / randomization is at the start of the cCRT, patients progressing and not continuing with durvalumab treatment are counted as non-responders (not meeting CR / PR) for the primary endpoint ORR. Strata- adjusted ORRs and the corresponding confidence interval are estimated.Secondary Objective(s)

[0449] The secondary objectives of this study are to: (1) assess additional measures of clinical benefit in participants treated with the HfOi nanoparticles in combination with standard of care cCRT followed by cIT; (2) assess the locoregional and distant effects of the HfOi nanoparticles as a radio-enhancer to cCRT; and (3) assess the safety and tolerability profile of the HfOi nanoparticles as a radio-enhancer to cCRT, with cCRT followed by cIT.

[0450] Secondary [Efficacy] Endpoints'. Analysis is provided for the best ORR based on investigator’s assessment according to RECIST vl.l. After the completion of cCRT, the investigator evaluates the disease status prior to the start of the durvalumab. The disease response rate or ORR (CR+PR) and Disease Control Rate (DCR) (CR+PR+SD) are summarized at this time point. CR = complete response; PR = partial response; SD = stable disease.

[0451] Progression-free survival (PFS) is defined as the time from the enrollment / randomization until disease progression or death due to any cause. Participants without such an event are censored at the last known date the participant is alive and115MF-361301351Docket No.: 242272002940 progression-free. Time-to-event PFS is analyzed based on the programmatically derived progression from ICR assessments. In addition, progression-free event rates at 6-, 12-, and 24-months post-enrollment / randomization are estimated.

[0452] The duration of response (DoR) is summarized descriptively with Kaplan-Meier curves. DoR is calculated among responders from the date of initial documentation of a response to the date of first documented evidence of relapse according to RECIST v 1.1, or death due to any cause, whichever occurs first. For participants with disease that has not relapsed and who are alive, data are censored at the last disease assessment. In addition, the restricted mean duration of response (mDoR) based on the probability of being in response function (PBRF) is estimated and analyzed for treatment effect.

[0453] The time to ERF and time to DF are defined as the time from enrollment / randomization to the first ERF and DF, respectively, using ICR assessments. Participants who do not have LRF or DF are censored at the last disease assessment. In addition, LRF rates and DF rates are presented at 6-, 12-, and 24-months post- enrollment / randomization. IF-LRF is defined as PD within the baseline radiation PTV. OF- LRF is defined as any disease outside of PTV and involving the ipsilateral lung (involved lobe[s]) and / or lymph node(s) in the bilateral hilum, bilateral mediastinum, or bilateral supraclavicular regions without IF-LRF. DF is defined as any other disease progression identified in the ipsilateral lung but in an uninvolved lobe, contralateral lung parenchyma, or outside the thorax without IF-LRF or OF-LRF.Safety Objective(s)

[0454] The assessment of the safety and tolerability profile of the HfCh nanoparticles as a radio-enhancer of cCRT is a safety objective that also is a secondary objective. Safety is monitored on a continuous basis. Safety is assessed by physical examinations, vital signs, clinical laboratory tests, monitoring for AEs and AESIs, and ECOG status. Concomitant medication usage and use of subsequent anticancer therapy are recorded. Adverse events are graded by the investigator using NCLCTCAE v5.0.

[0455] Safety Endpoints'. All safety analyses are made on the Safety Analysis Set. Safety data are summarized descriptively overall and by study parts (i.e., run-in Part 1 and randomized Part 2). In addition, within Part 2, a summary is presented by study arm. Safety data can include TEAEs, abnormal clinical laboratory tests, abnormal vital signs, abnormal physical examination findings, and ECOG score changes from baseline.116MF-361301351Docket No.: 242272002940

[0456] A treatment-emergent adverse event (TEAE) is defined as: (1) any new or worsening adverse event (AE) occurring at or after the initial administration of study treatment through the day of last dose of study treatment received plus 30 days or prior to the start of subsequent anticancer therapy (non-durvalumab), whichever is earlier; or (2) any follow-up AE (linked to an existing TEAE) with onset date and time beyond 30 days after the last dose of study treatment but prior to the start of subsequent anticancer therapy; or (3) any AE that is considered treatment-related regardless of the start date of the event. All reported TEAEs are included in the analysis. For each AE, the percentage of participants who experience at least 1 occurrence of the given event is summarized by study treatment group. Parameters with predefined NCI-CTCAE v5.0 toxicity grades are summarized (e.g., number of participants with TEAEs; early onset TEAEs, defined as AEs occurring from the first study treatment up to 30 days post last dose / fraction of cCRT or first dose of cIT, whichever is earlier; late onset TEAEs, defined as AEs occurring after the early onset TEAE period; TEAEs related to HfCh nanoparticle injection procedure, HfOi nanoparticles, RT, ChT, or cIT).Exploratory Objective(s)

[0457] The exploratory objectives for this study are the following: (1) determine the effect of the HfCh nanoparticles as a radio-enhancer to cCRT on the number of participants eligible for durvalumab consolidation post-cCRT; (2) determine time-to-event effects of HIO2 nanoparticles as a radio-enhancer to cCRT; (3) assess the feasibility to evaluate distribution of injected HIO2 nanoparticles; (4) assess the intraparticipant efficacy of intratumoral and intranodal Hl'Ch nanoparticle injection; (5) assess the systemic hafnium concentrations; (6) explore immunogenicity to protein corona formed around HfOi nanoparticles if needed; (7) explore blood and tissue biomarkers that may be associated with the biology of NSCLC and influence the progression of the disease and / or response to treatment; (8) explore the impact of study treatment on disease-related symptom experience, functional status, and side effect impact; and (9) explore radiographic tissue characterization and impact on lesion evaluability.

[0458] Exploratory Endpoints'. The following exploratory endpoints are analyzed using the same method as the primary endpoint(s): percentage of participants receiving cIT after cCRT treatment and percentage of participants completing planned cCRT. The following time-to- event exploratory endpoints are analyzed: (1) time to response (TTR) - time from enrollment / randomization to first documented CR or PR (participants who do not reach CR or PR will be censored at the last disease assessment while on treatment); and (2) overall117MF-361301351Docket No.: 242272002940 survival (OS) - OS is defined as the time from enrollment / randomization until death due to any cause (participants who have no events are censored at the last known alive date; OS rate at 12- and 24-months post-enrollment / randomization is estimated).

[0459] HIO2 nanoparticle treatment dose is summarized by lesion and by subject including the following: (1) HIO2 nanoparticle volumes injected relative to lesion volumes; (2) HIO2 nanoparticle volumes retained in the lesion relative to injected at least 24 hours after injection; (3) HIO2 nanoparticle volumes retained relative to lesion volumes at least 24 hours after injection; (4) injected HIO2 nanoparticle distribution relative to lesion volume at least 24 hours after injection; and (5) tumor response in HI O2 nanoparticle-injected lesions compared with noninjected lesions in the same participant (when applicable).

[0460] Disease-related symptom experience, functional status, and side effect impact are summarized descriptively by visit and change from baseline as appropriate using the following PRO tools: NSCLC-SA; EORTC QLQ-C30, v3; and EORTC IL46 side effect bother.

[0461] Subgroup analyses on ORR and PFS are explored considering stratification factors and HfOi nanoparticle coverage (e.g., injection volume, injection distribution, nodal coverage, number of injected lesions). In addition, ORR is evaluated by examining both injected and non-injected lesions.

[0462] Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, the descriptions and examples should not be construed as limiting the scope of the invention. The disclosures of all patent applications and publications and scientific literature cited herein are expressly incorporated in their entirety by reference for any purpose.118MF-361301351Docket No.: 242272002940SEQUENCE LISTING KEYMF-361301351

Claims

Docket No.: 242272002940CLAIMS1. A method of treating locally advanced and unresectable Stage III non-small cell lung cancer (NSCLC) in an individual comprising i) administering a nanoparticle composition comprising nanoparticles comprising HfC with a biocompatible coating to the individual; ii) administering radiation therapy to the individual; iii) administering chemotherapy to the individual; and iv) administering a PD-L1 antibody to the individual.

2. The method of claim 1, further comprising administering a corticosteroid to the individual prior to administering the nanoparticle composition.

3. The method of claim 2, wherein the corticosteroid is selected from the group consisting of prednisone and dexamethasone.

4. The method of any one of claims 2-3, wherein the corticosteroid is prednisone, wherein the prednisone is administered at a dose of about 30 mg, and wherein the prednisone is administered less than 24 hours before the nanoparticle composition is administered.

5. The method of claim 4, wherein about 30 mg prednisone is administered to the individual 12+2 hours or 2+2 hours before the nanoparticle composition is administered.

6. The method of any one of claims 3-5, wherein the prednisone is administered orally.

7. The method of claim 3, wherein the corticosteroid is dexamethasone, wherein the dexamethasone is administered less than three hours before the nanoparticle composition is administered.

8. The method of claim 3 or 7, wherein the dexamethasone is administered about an hour before the nanoparticle composition is administered.

9. The method of any one of claims 3, 7, or 8, wherein the dexamethasone is administered intravenously.

10. The method of any one of claims 1-9, wherein the nanoparticle composition is administered intratumorally and / or intranodally.120MF-361301351Docket No.: 24227200294011. The method of claim 10, wherein the nanoparticle composition is administered in a fractionated dose to an individual with a tumor comprising a dimension of > 3 cm and wherein the dimension is the longest dimension.

12. The method of any one of claims 1-11, wherein the nanoparticle is administered via bronchoscopic and / or percutaneous approach.

13. The method of any one of claims 1-12, wherein the radiation therapy is first administered two days or more after administration of the nanoparticle composition.

14. The method of any one of claims 1-13, wherein the nanoparticle composition is administered once.

15. The method of any one of claims 1-14, wherein the nanoparticle composition is administered intratumorally and / or intranodally at a dose of between about 15% gross tumor volume (GTV) to about 40% GTV of a tumor.

16. The method of any one of claims 1-15, wherein the nanoparticle composition is administered intratumorally and / or intranodally at a dose of about 22% GTV or a dose of about 33% GTV.

17. The method of any one of claims 1-16, wherein the nanoparticle composition comprises nanoparticles at a concentration of about 50 g / L to about 60 g / L.

18. The method of any one of claims 1-17, wherein the radiation therapy comprises administering more than one fraction of ionizing radiation over more than one day.

19. The method of any one of claims 1-18, wherein the radiation therapy comprises administering at least 10 fractions of ionizing radiation.

20. The method of any one of claims 1-19, wherein the radiation therapy comprises administering a total of about 40 Gy to about 80 Gy of radiation to the individual.

21. The method of any one of claims 18-20, wherein administering radiation therapy comprises administering about 1 Gy to about 3 Gy per fraction to the individual.

22. The method of any one of claims 1-21, wherein the radiation therapy comprises administering radiation therapy to the individual four times per week to six times per week.121MF-361301351Docket No.: 24227200294023. The method of any one of claims 1-22, wherein the radiation therapy comprises administering radiation therapy five times per week.

24. The method of any one of claims 1-23, wherein the radiation therapy comprises administering about 2 Gy radiation five times per week for six weeks starting two or more days after administration of the nanoparticle composition.

25. The method of any one of claims 1-24, wherein the chemotherapy comprises carboplatin and paclitaxel.

26. The method of any one of claims 1-25, wherein the chemotherapy comprises administering carboplatin intravenously at a dose of AUC2 and administering paclitaxel at a dose of 45 mg / m2to 50 mg / m2.

27. The method of any one of claims 1-26, wherein the chemotherapy administration is started between three days before and three days after starting the radiation therapy.

28. The method of any one of claims 1-27, wherein the chemotherapy administration is started on the same day as starting the radiation therapy.

29. The method of any one of claims 1-28, wherein the chemotherapy is administered once per week ± 3 days.

30. The method of any one of claims 26-29, wherein the carboplatin and the paclitaxel are administered on Day 1 of a seven-day chemotherapy cycle.

31. The method of claim 30, wherein six or seven chemotherapy cycles are administered to the individual.

32. The method of any one of claim 1-31, wherein the PD-L1 antibody is durvalumab.

33. The method of any one of claims 1-32, wherein the PD-L1 antibody is first administered to the individual within 10 weeks after administration of a last fraction of the radiation therapy.

34. The method of any one of claims 1-33, wherein the PD-L1 antibody is first administered to the individual within 10 weeks after a last dose of the chemotherapy.122MF-361301351Docket No.: 24227200294035. The method of any one of claims 1-34, wherein the PD-L1 antibody is first administered the later of: a. within six weeks of administration of a last fraction of the radiation therapy, or b. within six weeks of administration of a last dose of the chemotherapy.

36. The method of any one of claims 32-35, wherein the durvalumab is administered at a dose of about 1500 mg.

37. The method of claim 36, wherein the durvalumab is administered in an immunotherapy cycle of every four weeks (Q4W) ± 3 days.

38. The method of claim 36 or 37, wherein the durvalumab is administered in an immunotherapy cycle of every four weeks (Q4W).

39. The method of claim 37 or 38, wherein the immunotherapy cycle is continued for up to 13 cycles over 52 weeks.

40. The method of any one of claims 32-35, wherein the durvalumab is administered at a dose of about 10 mg / kg.

41. The method of claim 40, wherein the durvalumab is administered in an immunotherapy cycle of every two weeks (Q2W) ± 3 days.

42. The method of claim 41, wherein the durvalumab is administered in an immunotherapy cycle of every two weeks (Q2W).

43. The method of claim 41 or 42, wherein the immunotherapy cycle is continued for up to 26 cycles over 52 weeks.

44. A method of treating locally advanced and unresectable Stage III non-small cell lung cancer in an individual comprising a dosing schedule of at least 52 weeks comprising: i) administering a nanoparticle composition comprising nanoparticles comprising HfCh with a biocompatible coating to the individual on Day 0; ii) administering radiation therapy to the individual at a dose of 2 Gy per fraction, wherein one fraction is delivered daily for five days per week for a total of six weeks, wherein the radiation therapy is started two or more days after the nanoparticle composition is administered;123MF-361301351Docket No.: 242272002940 iii) administering chemotherapy to the individual, wherein the chemotherapy comprises: a. carboplatin administered at a dose of AUC2, and b. paclitaxel administered at a dose of about 45 mg / m2to about 50 mg / m2on Day 1 of a seven-day chemotherapy cycle, wherein six or seven chemotherapy cycles are administered to the individual, and wherein the chemotherapy is started up to three days before or three days after the radiation therapy is started; and iv) administering durvalumab to the individual, wherein durvalumab administration is started within six weeks of administration of a last dose of the chemotherapy or a last dose of radiation therapy, wherein the durvalumab is administered to the individual: a. at a dose of about 1500 mg, Q4W up to 13 times over 52 weeks; or b. at a dose of about 10 mg / kg Q2W for up to 26 times over 52 weeks.

45. The method of any one of claims 1-44, wherein the size of a tumor in the individual is decreased following treatment.

46. The method of claim 45, wherein the size of the tumor before treatment and following treatment is assessed by CT of the chest and upper abdomen including liver and adrenal glands, and optionally by PET-CT scan and / or contrast MRI-brain scan.

47. The method of any one of claims 1-46, wherein the individual has an objective response.

48. The method of any one of claims 1-47, wherein the objective response rate in a population of patients receiving such therapy is improved compared to the standard of care.

49. The method of any one of claims 1-48, wherein the disease control rate in a population of patients receiving such therapy is improved compared to the standard of care.

50. The method of claim 48 or 49, wherein the objective response rate is based upon an independent central review assessment according to RECIST vl.l.124MF-361301351Docket No.: 24227200294051. The method of any one of claims 48-50, wherein the objective response rate is determined after administration of the chemotherapy and before administration of the PD-L1 antibody.

52. The method of any one of claims 1-51, wherein the progression free survival in a population of patients receiving such therapy is improved compared to the standard of care.

53. The method of any one of claims 1-52, wherein the time to event and landmark at 6, 12, and 24 months in a population of patients receiving such therapy is improved compared to the standard of care.

54. The method of any one of claims 1-53, wherein the time to locoregional failure and time to distant failure in a population of patients receiving such therapy is improved compared to the standard of care.

55. The method of any one of claims 1-54, wherein the individual does not experience a treatment emergent adverse event.

56. A method of selecting an individual for treatment of NSCLC, comprising: (a) identifying an individual with Stage III NSCLC, and (b) administering to the individual the treatment according to the method of any one of claims 1-55.

57. The method of any one of claims 1-56, wherein the individual has a life expectancy of at least 6 months at the start of treatment.

58. The method of any one of claims 1-57, wherein the individual has locally advanced Stage III NSCLC according to the Eighth Edition Lung Cancer Stage Classification that is unresectable.

59. The method of any one of claims 1-58, wherein the individual has a tumor proportion score of PD-L1 >1% or <1%.

60. The method of any one of claims 1-59, wherein the Stage III NSCLC expresses PD- Ll.

61. The method of any one of claims 1-60, wherein the individual does not have metastatic disease.125MF-361301351Docket No.: 24227200294062. The method of any one of claims 1-61, wherein the individual has unresectable Stage III NSCLC.

63. The method of any one of claims 1-62, wherein the individual has a calculated total gross tumor volume < 909 mL.

64. The method of any one of claims 1-63, wherein the individual does not have a tumor with invasion and / or encasement of great vessels or esophagus, baseline presence of fistula, and / or malignant airway obstruction requiring endoscopic intervention.

65. The method of any one of claims 1-64, wherein the individual does not have ipsilateral or contralateral scalene or supraclavicular lymph node involvement.

66. The method of any one of claims 1-65, wherein the individual does not have a corrected QT interval by Fredericia (QTcF interval) greater than 480 msec.

67. The method of any one of claims 1-66, wherein the individual has: a. an AST level and / or an ALT level of < 3 x ULN; b. a hemoglobin level of > 9.0 g / dL; c. a platelet count of > 100 xl09 / L; and / or d. an absolute neutrophil count of > 1.5 xl09 / L, wherein the individual has not been administered a growth factor within about 10 days before the start of treatment.

68. The method of any one of claims 1-67, wherein the individual has an Eastern Cooperative Oncology Group (ECOG) status of 0-1.

69. The method according to any one of claims 1-68, wherein said biocompatible coating is sodium trimetaphosphate (STMP) or sodium hexametaphosphate (HMP).

70. The method according to any one of claims 1-69, wherein the average size of the nanoparticles in the nanoparticle composition is between about 10 nm and about 200 nm.

71. The method according to any one of claims 1-70, wherein the ionizing radiation is selected from the group consisting of X-Rays, y-Rays, electron beams, and radioisotope emissions.126MF-361301351Docket No.: 24227200294072. The method according to claim 71, wherein the ionizing radiation is administered by intensity modulated radiation therapy (IMRT).

73. The method according to claim 72, wherein the IMRT is selected from the group consisting of: static field IMRT, helical IMRT, and volumetric modulated arc therapy (VMAT) using megavoltage therapy.

74. The method according to any one of claims 1-73, wherein the nanoparticles act as a radio-enhancer.

75. The method according to any one of claims 1-74, wherein the nanoparticles amplify energy deposition at the site of a tumor.127MF-361301351

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