Oral PCLX-001 in the Treatment of Human Cancer

Abstract

In one aspect, a method is provided for treating cancer in a subject in need thereof, comprising administering an oral dosage form of PCLX-001, wherein the oral dosage comprises 20 mg of PCLX-001 per day, 40 mg of PCLX-001 per day, 70 mg of PCLX-001 per day, 100 mg of PCLX-001 per day, 140 mg of PCLX-001 per day, 210 mg of PCLX-001 per day, 280 mg of PCLX-001 per day, 350 mg of PCLX-001 per day, or 420 mg of PCLX-001 per day.

Description

[Technical field]

[0001] Field The present disclosure relates generally to oral PCLX-001 in the treatment of human cancers. [Background technology]

[0002] background Myristoylation, the N-terminal modification of proteins with the fatty acid myristate, is essential for membrane targeting of hundreds of human proteins[1], including some essential for intracellular signaling. Cancer cells often have increased expression of N-myristoyltransferase (NMT) proteins, and NMT has been proposed as an anticancer target[2] but has not previously been studied in human clinical trials. [Prior art documents] [Patent documents]

[0003] [Patent Document 1] WO2010 / 026365 Summary of the Invention

[0004] overview In one aspect, a method is provided for treating cancer in a subject in need thereof, comprising administering an oral dosage form of PCLX-001, wherein the oral dosage comprises 20 mg of PCLX-001 per day, 40 mg of PCLX-001 per day, 70 mg of PCLX-001 per day, 100 mg of PCLX-001 per day, 140 mg of PCLX-001 per day, 210 mg of PCLX-001 per day, 280 mg of PCLX-001 per day, 350 mg of PCLX-001 per day, or 420 mg of PCLX-001 per day.

[0005] In one example, the oral dosage provides an effect comprising a T1 / 2 of about 5 hours to about 18 hours.

[0006] In one example, the oral dosage provides an effect comprising a T1 / 2 of about 5.5 hours to about 14 hours.

[0007] In one aspect, a method for treating cancer in a subject in need thereof is provided, comprising administering an oral dosage form of PCLX-001, wherein the oral dosage comprises 20 mg of PCLX-001 per day.

[0008] In one example, the oral dosage provides an effect comprising a T1 / 2 of about 6 hours to about 9 hours.

[0009] In one example, the oral dosage provides an effect comprising a T1 / 2 of about 6.9 hours to about 8.9 hours.

[0010] In one aspect, a method for treating cancer in a subject in need thereof is provided, comprising administering an oral dosage form of PCLX-001, wherein the oral dosage comprises 40 mg of PCLX-001 per day.

[0011] In one example, the oral dosage provides an effect comprising a T1 / 2 of about 5 hours to about 11 hours.

[0012] In one example, the oral dosage provides an effect comprising a T1 / 2 of about 5.5 hours to about 10.5 hours.

[0013] In one aspect, a method for treating cancer in a subject in need thereof is provided, comprising administering an oral dosage form of PCLX-001, wherein the oral dosage comprises 70 mg of PCLX-001 per day.

[0014] In one example, the oral dosage provides an effect including a T1 / 2 of about 9 hours.

[0015] In one example, the oral dose provides an effect with a T1 / 2 of about 9.4 hours.

[0016] In one aspect, a method for treating cancer in a subject in need thereof is provided, comprising administering an oral dosage form of PCLX-001, wherein the oral dosage comprises 100 mg of PCLX-001 per day.

[0017] In one example, the oral dosage provides an effect comprising a T1 / 2 of about 7 hours to about 8 hours.

[0018] In one example, the oral dosage provides an effect comprising a T1 / 2 of about 7.2 hours to about 7.5 hours.

[0019] In one aspect, a method for treating cancer in a subject in need thereof is provided, comprising administering an oral dosage form of PCLX-001, wherein the oral dosage comprises 140 mg of PCLX-001 per day.

[0020] In one example, the oral dosage provides an effect comprising a T1 / 2 of about 6 hours to about 14 hours.

[0021] In one example, the oral dosage provides an effect comprising a T1 / 2 of about 6.7 hours to about 13.8 hours.

[0022] In one example, the cancer is diffuse large B-cell lymphoma (DLBCL).

[0023] In one example, the DLBC is refractory DLBC.

[0024] In one example, the cancer is lymphoma, leukemia, myeloma, breast cancer, small cell lung cancer, non-small cell lung cancer; melanoma, adenocarcinoma, pancreatic cancer, bladder cancer, ovarian cancer, brain cancer, colon cancer, neuroblastoma, carcinoma, endometrial cancer, sarcoma, thyroid cancer, fibrosarcoma, oral cancer, tongue cancer, nasopharyngeal cancer, laryngeal cancer, esophageal cancer, germ cell cancer, gastric cancer, hepatocellular carcinoma, biliary tract cancer, small intestine cancer, testicular cancer, epidermoid carcinoma, cervical cancer, renal cancer, prostate cancer, or pharyngeal cancer.

[0025] In one example, the subject is a human.

[0026] In one aspect, there is provided a use of an oral dosage form of PCLX-001 for treating cancer in a subject in need thereof, wherein said oral dosage comprises 20 mg of PCLX-001 per day, 40 mg of PCLX-001 per day, 70 mg of PCLX-001 per day, 100 mg of PCLX-001 per day, 140 mg of PCLX-001 per day, 210 mg of PCLX-001 per day, 280 mg of PCLX-001 per day, 350 mg of PCLX-001 per day, or 420 mg of PCLX-001 per day.

[0027] In one aspect, there is provided a use of an oral dosage form of PCLX-001 in the manufacture of a medicament for treating cancer in a subject in need thereof, wherein said oral dosage comprises 20 mg of PCLX-001 per day, 40 mg of PCLX-001 per day, 70 mg of PCLX-001 per day, 100 mg of PCLX-001 per day, 140 mg of PCLX-001 per day, 210 mg of PCLX-001 per day, 280 mg of PCLX-001 per day, 350 mg of PCLX-001 per day, or 420 mg of PCLX-001 per day.

[0028] In one example, the oral dosage provides an effect comprising a T1 / 2 of about 5 hours to about 18 hours.

[0029] In one example, the oral dosage provides an effect comprising a T1 / 2 of about 5.5 hours to about 14 hours.

[0030] In one aspect, there is provided a use of an oral dosage form of PCLX-001 for treating cancer in a subject in need thereof, wherein said oral dosage comprises 20 mg of PCLX-001 per day.

[0031] In one aspect, there is provided the use of an oral dosage form of PCLX-001 in the manufacture of a medicament for treating cancer in a subject in need thereof, wherein the oral dosage comprises 20 mg of PCLX-001 per day.

[0032] In one example, the oral dosage provides an effect comprising a T1 / 2 of about 6 hours to about 9 hours.

[0033] In one example, the oral dosage provides an effect comprising a T1 / 2 of about 6.9 hours to about 8.9 hours.

[0034] In one aspect, there is provided a use of an oral dosage form of PCLX-001 for treating cancer in a subject in need thereof, wherein said oral dosage comprises 40 mg of PCLX-001 per day.

[0035] In one aspect, there is provided the use of an oral dosage form of PCLX-001 in the manufacture of a medicament for treating cancer in a subject in need thereof, wherein the oral dosage comprises 40 mg of PCLX-001 per day.

[0036] In one example, the oral dosage provides an effect comprising a T1 / 2 of about 5 hours to about 11 hours.

[0037] In one example, the oral dosage provides an effect comprising a T1 / 2 of about 5.5 hours to about 10.5 hours.

[0038] In one aspect, there is provided a use of an oral dosage form of PCLX-001 for treating cancer in a subject in need thereof, wherein said oral dosage comprises 70 mg of PCLX-001 per day.

[0039] In one aspect, there is provided the use of an oral dosage form of PCLX-001 in the manufacture of a medicament for treating cancer in a subject in need thereof, wherein the oral dosage comprises 70 mg of PCLX-001 per day.

[0040] In one example, the oral dosage provides an effect including a T1 / 2 of about 9 hours.

[0041] In one example, the oral dose provides an effect with a T1 / 2 of about 9.4 hours.

[0042] In one aspect, there is provided a use of an oral dosage form of PCLX-001 for treating cancer in a subject in need thereof, wherein said oral dosage comprises 100 mg of PCLX-001 per day.

[0043] In one aspect, there is provided the use of an oral dosage form of PCLX-001 in the manufacture of a medicament for treating cancer in a subject in need thereof, wherein the oral dosage comprises 100 mg of PCLX-001 per day.

[0044] In one example, the oral dosage provides an effect comprising a T1 / 2 of about 7 hours to about 8 hours.

[0045] In one example, the oral dosage provides an effect comprising a T1 / 2 of about 7.2 hours to about 7.5 hours.

[0046] In one aspect, there is provided a use of an oral dosage form of PCLX-001 for treating cancer in a subject in need thereof, wherein said oral dosage comprises 140 mg of PCLX-001 per day.

[0047] In one aspect, there is provided the use of an oral dosage form of PCLX-001 in the manufacture of a medicament for treating cancer in a subject in need thereof, wherein the oral dosage comprises 140 mg of PCLX-001 per day.

[0048] In one example, the oral dosage provides an effect comprising a T1 / 2 of about 6 hours to about 14 hours.

[0049] In one example, the oral dosage provides an effect comprising a T1 / 2 of about 6.7 hours to about 13.8 hours.

[0050] In one example, the cancer is diffuse large B-cell lymphoma (DLBCL).

[0051] In one example, the DLBC is refractory DLBC.

[0052] In one example, the cancer is lymphoma, leukemia, myeloma, breast cancer, small cell lung cancer, non-small cell lung cancer; melanoma, adenocarcinoma, pancreatic cancer, bladder cancer, ovarian cancer, brain cancer, colon cancer, neuroblastoma, carcinoma, endometrial cancer, sarcoma, thyroid cancer, fibrosarcoma, oral cancer, tongue cancer, nasopharyngeal cancer, laryngeal cancer, esophageal cancer, germ cell cancer, gastric cancer, hepatocellular carcinoma, biliary tract cancer, small intestine cancer, testicular cancer, epidermoid carcinoma, cervical cancer, renal cancer, prostate cancer, or pharyngeal cancer.

[0053] In one example, the subject is a human.

[0054] BRIEF DESCRIPTION OF THE DRAWINGS Embodiments of the present disclosure will now be described, by way of example only, with reference to the accompanying figures. [Brief description of the drawings]

[0055] [Figure 1] FIG. 1 depicts the chemical structure of PCLX-001 (2,6-dichloro-N-(3-isobutyl-1,5-dimethyl-1H-pyrazol-4-yl)-4-(2-(piperazin-1-yl)pyridin-4-yl)benzenesulfonamide) C24H30Cl2N6O2S. [Diagram 2] Figure 2 depicts computed tomography images of Patient 2: (A) October 29, 2021 - TL#2 segment 5 of liver, (B) October 29, 2021 - TL#2 segment 5 of liver (no measurements) image 27 / 4, (C) December 30, 2021 - TL#2 segment 5 of liver image 24 / 4 with measurements, (D) December 30, 2021 - TL#2 segment 5 of liver (no measurements) image 24 / 4, (E) October 29, 2021 - TL#2 segment 5 of liver image 27 / 4 (liver photo), (F) December 30, 2021 - TL#2 segment 5 of liver image 24 / 4 (liver photo). [Diagram 3] Figures 3A and 3B depict non-compartmental analysis for PCLX-001 in patient 1 (patient 115-002-001) on (A) day 1 and (B) day 15. [Figure 4] Figure 4 (A) depicts non-compartmental analysis for PCLX-001 in patient 2 (patient 115-002-002) on day 1, (B) on day 15, and (C) depicts non-compartmental analysis for PCLX-001 in patient 3 (patient 115-002-004) on day 1, (D) on day 15. [Diagram 5] FIG. 5 depicts the nonparametric superposition simulation to steady state in patient 1 (patient 115-002-001). [Figure 6] FIG. 6 depicts the non-parametric superposition simulation to steady state in patient 2 (patient 115-002-002). [Figure 7] FIG. 7 depicts the non-parametric superposition simulation to steady state in patient 3 (patient 115-002-004). [Figure 8] Figures 8A and 8B depict dose proportionality analysis on Day 1. Figure 8A depicts Cmax / dose vs. dose on Day 1. Figure 8B depicts AUClast / dose vs. dose on Day 1. [Figure 9] Figures 9A and 9B depict the dose proportionality analysis on day 14. Figure 9A depicts Cmax / dose vs. dose on day 14. Figure 9B depicts AUClast / dose vs. dose on day 14. [Figure 10] FIG. 10 depicts steady state assessment-pre-dose PCLX-001 concentrations for subjects not taking Pantoprozole. [Figure 11] FIG. 11A, FIG. 11B, and FIG. 11C depict plasma concentrations of PCLX-001 following oral administration of 20 mg QD of PCLX-001 to cancer patients. [Figure 12]FIG. 12A, FIG. 12B, and FIG. 12C depict plasma concentrations of PCLX-001 following oral administration of 40 mg QD of PCLX-001 to cancer patients. [Figure 13] FIG. 13A, FIG. 13B, FIG. 13C depict plasma concentrations of PCLX-001 following oral administration of 70 mg QD of PCLX-001 to cancer patients. [Figure 14] FIG. 14A, FIG. 14B, FIG. 14C, FIG. 14D depict plasma concentrations of PCLX-001 following oral administration of 100 mg QD of PCLX-001 to cancer patients. [Figure 15] FIG. 15A, FIG. 15B, FIG. 15C depict plasma concentrations of PCLX-001 following oral administration of 140 mg QD of PCLX-001 to cancer patients. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0056] Detailed Description In one aspect, a method of treating cancer in a subject is provided, comprising administering an oral dosage form of PCLX-001.

[0057] PCLX-001 is also known as DDD86418 (WO2010 / 026365).

[0058] In one aspect, a method of treating cancer in a subject is provided, comprising administering an oral dosage form of PCLX-001, wherein the oral dosage comprises 20 mg of PCLX-001 per day.

[0059] In one aspect, a method of treating cancer in a subject is provided, comprising administering an oral dosage form of PCLX-001, wherein the oral dosage comprises 40 mg of PCLX-001 per day, 70 mg of PCLX-001 per day, 100 mg of PCLX-001 per day, 140 mg of PCLX-001 per day, 210 mg of PCLX-001 per day, 280 mg of PCLX-001 per day, 350 mg of PCLX-001 per day, or 420 mg of PCLXX-001 per day.

[0060] In one aspect, a method of treating cancer in a subject is provided, comprising administering an oral dosage form of PCLX-001, wherein the oral dosage comprises 20 mg of PCLX-001 per day to 420 mg of PCLX-001 per day.

[0061] In one aspect, a method of treating cancer in a subject is provided, comprising administering an oral dosage form of PCLX-001, wherein the oral dosage comprises 15 mg of PCLX-001 to 500 mg of PCLX-001 per day.

[0062] The term "cancer" as used herein refers to various conditions caused by the abnormal and uncontrollable growth of cells.Cells capable of causing cancer, referred to as "cancer cells", possess characteristic properties, such as uncontrollable growth, immortality, metastatic potential, rapid growth and proliferation rate, and / or certain typical morphological features.Cancer cells can be in the form of tumors, but such cells can be present alone in a subject or can be non-tumorigenic cancer cells.

[0063] Cancer may be detected in any of a number of ways, including, but not limited to, detecting the presence of a tumor(s) (e.g., by clinical or radiological means), examining cells in the tumor or from another biological sample (e.g., from a tissue biopsy), measuring blood markers indicative of cancer, and detecting genotypes indicative of cancer. However, a negative result in one or more of the above detection methods does not necessarily indicate the absence of cancer; for example, a patient who has had a complete response to cancer treatment may still have cancer, as evidenced by a subsequent relapse.

[0064] It will be appreciated that generally, determining the severity of the disease requires identification of certain disease characteristics, such as whether the cancer is pre-metastatic or metastatic, the stage and / or grade of the cancer, etc.

[0065] Staging is a process used to describe how advanced a cancer is in a subject. Staging can be important in determining prognosis, planning treatment, and assessing the results of such treatment. Different cancer staging systems may need to be used for different types of cancer, but most staging systems generally involve describing how far the cancer has spread anatomically and attempt to place subjects with similar prognosis and treatment into the same staging group.

[0066] Examples of common staging systems used for most solid tumors, some leukemias and lymphomas are the Overall Stage Grouping system and the TMN system. The Overall Stage Grouping system uses Roman numerals I to IV to indicate four stages of cancer. Generally, if a cancer has not spread to any lymph nodes and is only detectable in the area of ​​the primary lesion, it is called stage I. Stage II and III cancers are generally locally advanced and / or have spread to regional lymph nodes. For example, if a cancer is locally advanced and has spread only to the nearest lymph nodes, it is called stage II. In stage III, the cancer is locally advanced and has generally spread to lymph nodes that are close to the site of the primary lesion. Cancers that have metastasized from the primary tumor to distant parts of the body, such as the liver, bone, brain, or another site, are called stage IV, which is the most advanced stage. Thus, stage I cancers are generally small, localized cancers that are curable, while stage IV cancers usually represent inoperable or metastatic cancers. As with other staging systems, the prognosis for a given stage and treatment often depends on the type of cancer. For some cancers, classification into four prognostic groups is insufficient, and the overall stage classification is further divided into subgroups. In contrast, some cancers may have fewer than four stage groupings.

[0067] Cancer that recurs after all visible tumor has been eradicated is called recurrent disease, with local recurrence occurring at the site of the primary tumor and distant recurrence representing distant metastasis.

[0068] Variations in staging systems may depend on the type of cancer. Moreover, for a particular type of cancer, the staging system for an individual cancer may be revised with new information, and the resulting stage may then alter the prognosis and treatment for the specific cancer.

[0069] Cancer "grade" can be used to describe how closely a tumor resembles normal tissue of the same type. Based on the microscopic appearance of a tumor, pathologists identify the grade of the tumor based on parameters such as cell morphology, cell organization, and other differentiation markers. In principle, the grade of a tumor corresponds to its growth rate or aggressiveness, and tumors are typically graded from least aggressive (grade I) to most aggressive (grade IV).

[0070] Thus, the higher the grade, the more aggressive and faster growing the cancer is. Information about tumor grade is useful in planning treatment and predicting prognosis.

[0071] In some cases, in the case of lymphoma, stage 1 refers to lymphoma in only one group of lymph nodes. Stage II refers to two or more groups of lymph nodes being affected, but either all above or below the diaphragm, or all within the chest or all within the abdomen. Stage III refers to two or more groups of lymph nodes being affected both within the chest and within the abdomen. Stage IV refers to lymphoma in at least one organ (e.g., bone marrow, liver, or lungs) and lymph nodes. Additional designations may be added to the above stages. For example, "A" means that the patient is generally not experiencing bothersome symptoms. "B" means that the patient is experiencing B symptoms (e.g., fever, night sweats, weight loss). X means that the patient has bulky disease (e.g., large tumors greater than 10 cm in size). E means that the patient has extranodal disease (e.g., disease outside the lymph nodes).

[0072] In a particular example, the cancer is lymphoma.

[0073] The term "lymphoma" generally refers to malignant neoplasms of the lymphatic system, including cancers of the lymphatic system. The two main types of lymphoma are Hodgkin's disease (HD or HL) and non-Hodgkin's lymphoma (NHL). Abnormal cells appear as clusters that enlarge lymph nodes, form solid tumors in the body, or, more rarely, circulate in the blood, as in leukemia. Hodgkin's disease lymphomas include nodular lymphocyte-predominant Hodgkin's lymphoma; classical Hodgkin's lymphoma; nodular sclerosis Hodgkin's lymphoma; lymphocyte-rich classical Hodgkin's lymphoma; mixed cellularity Hodgkin's lymphoma; lymphocyte-depleted Hodgkin's lymphoma. Non-Hodgkin's lymphomas include small lymphocytic NHL, follicular NHL, mantle cell NHL, mucosa-associated lymphoid tissue (MALT) NHL, diffuse large B-cell NHL, mediastinal large B-cell NHL, precursor T-lymphoblastic NHL, cutaneous T-cell NHL, T-cell and natural killer cell NHL, mature (peripheral) T-cell NHL, Burkitt's lymphoma, mycosis fungoides, Sézary syndrome, precursor B-lymphoblastic lymphoma, B-cell small lymphocytic lymphoma, lymphoplasmacytic lymphoma, and splenic marginal zone lymphoma. Includes B-cell lymphoma; nodal marginal zone lymphoma; plasma cell myeloma / plasmacytoma; intravascular large B-cell NHL; primary effusion lymphoma; blastic natural killer cell lymphoma; enteropathic T-cell lymphoma; hepatosplenic gamma-delta T-cell lymphoma; subcutaneous panniculitis-like T-cell lymphoma; angioimmunoblastic T-cell lymphoma; primary systemic anaplastic large T / null cell lymphoma, diffuse large B-cell lymphoma (DLBCL), and refractory diffuse large B-cell lymphoma (DLBCL).

[0074] In a specific example, the lymphoma is a B-cell lymphoma.

[0075] In one example, the cancer is diffuse large B-cell lymphoma (DLBCL).

[0076] In one example, the cancer is refractory diffuse large B-cell lymphoma (DLBCL).

[0077] In some examples, the compositions and / or compositions described herein (e.g., PCLX-001) can be used to treat various stages and grades of cancer development and progression. In some examples, PCLX-001 can be used in the treatment of early cancers, including early neoplasias, which may be small, slow-growing, localized, and / or non-aggressive, with the intention of curing the disease or causing cancer regression, as well as in the treatment of intermediate stages, and in the treatment of advanced and / or metastatic and / or aggressive neoplasias, including late-stage cancers, for example, to slow down disease progression, reduce metastasis, or increase patient survival. Similarly, PCLX-001 can be used in the treatment of low-grade cancers, intermediate-grade cancers, and / or high-grade cancers.

[0078] In some examples, it is contemplated that PCLX-001 may be used in the treatment of recurrent cancer, including indolent cancer, locally recurrent, distantly recurrent and / or refractory cancer (i.e., cancer that has not responded to treatment), metastatic cancer, locally advanced cancer, and aggressive cancer.

[0079] In another example, the cancer is leukemia, myeloma, breast cancer, small cell lung cancer, non-small cell lung cancer; melanoma, adenocarcinoma, pancreatic cancer, bladder cancer, ovarian cancer, brain cancer, colon cancer, neuroblastoma, carcinoma, endometrial cancer, sarcoma, thyroid cancer, fibrosarcoma, oral cancer, tongue cancer, nasopharyngeal cancer, laryngeal cancer, esophageal cancer, germ cell cancer, gastric cancer, hepatocellular carcinoma, biliary tract cancer, small intestine cancer, testicular cancer, epidermoid carcinoma, cervical cancer, renal cancer, prostate cancer, or pharyngeal cancer.

[0080] In some examples, PCLX-001 may be used alone or in combination with one or more therapeutic agents as part of a primary or adjuvant therapy. "Primary therapy" or "first-line therapy" refers to treatment upon initial diagnosis of cancer in a subject. Exemplary primary therapies may involve surgery, broad-spectrum chemotherapy, immunotherapy, and / or radiation therapy. If the first-line or primary therapy is not a systemic chemotherapy or immunotherapy, the subsequent chemotherapy or immunotherapy may be considered a "first-line systemic therapy." In one example, PCLX-001 may be used for the first-line systemic therapy.

[0081] The term "adjuvant therapy" refers to therapy administered to a subject at risk of relapse following a primary therapy. Adjuvant systemic therapy is typically initiated immediately after the primary therapy to delay recurrence, extend survival, or cure the subject. Treatment of refractory cancers may be referred to as "second line therapy" and is a contemplated use of the present invention in addition to the first line therapy.

[0082] In some cases, the subject is also treated with a proton pump inhibitor (PPI), which is typically prescribed for the short-term treatment of active duodenal ulcers, gastrointestinal ulcers, gastroesophageal reflux disease (GERD), severe erosive esophagitis, and / or poorly responsive symptomatic GERD.

[0083] Examples of proton pump inhibitors include omeprazole (Prilosec®), lansoprazole (Prevacid®), esomeprazole (Nexium®), rabeprazole (Aciphex®), pantoprazole (Protonix®), pariprazole, tenatoprazole, and leminoprazole. This class of drugs suppresses gastrointestinal acid secretion by specific inhibition of the H+ / K+-ATPase enzyme system (proton pump) on the secretory surface of gastrointestinal parietal cells.

[0084] In a specific example, the PPI used is pantoprazole.

[0085] In one embodiment of the invention, the combination is used in the treatment of early stage cancer, hi another embodiment, the combination is used as a first line systemic therapy for early stage cancer.

[0086] In alternative examples, PCLX-001 may be used in the treatment of terminal and / or advanced and / or metastatic cancer. In further embodiments, PCLX-001 may be administered as a first-line systemic therapy for the treatment of terminal and / or advanced and / or metastatic cancer.

[0087] Refractory cancer refers to cancer that is not amenable to surgical intervention, where the cancer is initially unresponsive to either chemo- or radiotherapy, or where the cancer becomes unresponsive over time.

[0088] The term "relapse" refers to a patient who achieves a clinical response (CR) or partial response (PR) and then experiences disease progression.

[0089] The term "clinical response" refers to, among other things, inhibition of disease progression, inhibition of tumor growth, reduction of primary tumors, relief of tumor-related symptoms, inhibition of tumor-secreted factors (including tumor-secreted hormones, such as those that contribute to carcinoid syndrome), delay in onset of primary or secondary tumors, slowing of development of primary or secondary tumors, reduction in appearance of primary or secondary tumors, slowing or reducing the severity of secondary effects of disease, cessation of tumor growth and regression of tumors, increase in time to progression (TTP), increase in progression-free survival (PFS), increase in overall survival (OS).

[0090] The term "overall survival" or "OS" refers to the time from enrollment to death from any cause.

[0091] The term "duration of response" or "DOR" refers to the time from the first appearance of documented objective response to disease progression.

[0092] The term "progression free survival" or "PFS" refers to the time from enrollment to the date of the first recorded occurrence of disease progression.

[0093] The term "stable disease" or "SD" refers to neither sufficient shrinkage to qualify for CR or PR nor sufficient increase in tumor growth to qualify for PD.

[0094] The term "partial response" refers to the persistence of one or more non-target lesions and / or maintenance of tumor marker levels above normal limits (if applicable).

[0095] The term "subject," as used herein, refers to an animal and can include, for example, domesticated animals, such as cats, dogs, and the like, farm animals (e.g., cows, horses, pigs, sheep, goats, and the like), laboratory animals (e.g., mice, rabbits, rats, guinea pigs, and the like), mammals, non-human mammals, primates, non-human primates, rodents, birds, reptiles, amphibians, fish, and any other animals.

[0096] In a specific example, the subject is a human.

[0097] The term "treatment" or "treating" as used herein refers to obtaining beneficial or desired results, including clinical results. Beneficial or desired clinical results can include, but are not limited to, alleviation or remission of one or more symptoms or conditions, whether detectable or not, reduction in the extent of disease, stabilization (i.e., not worsening) of disease, preventing the spread of disease, delay or slowing of disease progression, remission or alleviation of symptoms, reduction in recurrence of disease, and remission (whether partial or total). "Treatment" and "treatment" can also mean a longer survival compared to the expected survival in the absence of treatment. "Treatment" and "treatment" as used herein also include preventative treatment. For example, a subject with early stage cancer, such as early stage lymphoma, can be treated with a compound or composition described herein to prevent progression, or alternatively, a subject in remission can be treated to prevent recurrence.

[0098] The term "pharmacologically acceptable" as used herein includes compounds, materials, compositions, and / or dosage forms (e.g., unit dosages) that are suitable for use in contact with the tissues of a subject without undue toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio. Each carrier, excipient, etc., also may be "acceptable" in the sense of being compatible with the other ingredients of the formulation.

[0099] The term "excipient" refers to a pharmacologically inactive ingredient, such as a diluent, lubricant, surfactant, carrier, etc. Excipients useful in preparing pharmaceutical compositions are generally safe, non-toxic, and acceptable for use in human pharmacy. Reference to an excipient includes both one and more than one such excipient.

[0100] As used herein, the term "pharmaceutically acceptable carrier" refers to any of the standard pharmaceutical carriers, including, but not limited to, phosphate buffered saline, water, emulsions (e.g., oil / water or water / oil emulsions), and various types of wetting agents, any and all solvents, dispersion media, coatings, sodium lauryl sulfate, isotonic and absorption delaying agents, disintegrants (e.g., potato starch or sodium starch glycolate), stabilizers and preservatives, and the like.

[0101] "Treatment or dosage regimen" as used herein refers to a combination of dosages, frequency of administration, or duration of treatment, with or without the addition of a second agent.

[0102] The term "diagnosis" as used herein refers to the identification of a molecular and / or pathological state, disease or condition, such as the identification of lymphoma or other types of cancer.

[0103] The term "ameliorate" as used herein refers to the decrease, reduction or elimination of a condition, disease, disorder or phenotype, including an abnormality or symptom.

[0104] In some aspects, a pharmaceutical composition is provided that comprises PCLX-001 in admixture with a pharma- ceutically acceptable adjuvant, diluent or carrier.

[0105] The pharmaceutical compositions of the present disclosure may also contain adjuvants, such as preservatives, wetting agents, emulsifying agents, and dispersing agents. Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, such as paraben, chlorobutanol, or phenol sorbic acid. It may also be desirable to include isotonic agents, such as sugars or sodium chloride.

[0106] Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In such solid dosage forms, the active compound (e.g., PCLX-001) is typically mixed with at least one inert pharma- ceutically acceptable excipient or carrier, such as sodium citrate or dicalcium phosphate, and / or one or more of: a) fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol and silicic acid; b) binders, such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia; c) humectants, such as glycerol; d) disintegrants. agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate; e) solution retarders such as paraffin; f) absorption accelerators such as quaternary ammonium compounds; g) wetting agents such as cetyl alcohol and glycerol monostearate; h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also contain buffering agents. Solid compositions of a similar type may also be used as fillers in soft and hard-filled gelatin capsules using excipients such as lactose or milk sugar and high molecular weight polyethylene glycols.

[0107] The term "solid" as used herein refers to a material that is solid or semi-solid at room temperature. Thus, as used herein, a "solid" material may be liquid, for example, at body temperature.

[0108] Cmax is the maximum plasma concentration of PCLX-001.

[0109] Tmax is the time at which the peak plasma concentration of PCLX-001 is achieved.

[0110] The term "pharmacokinetics" (or PK) refers to the factors that determine achieving and maintaining an adequate concentration of a drug at a site of action.

[0111] The term "AUC" refers to the area under the concentration (or area under the curve) that represents the concentration of a compound or its metabolite in a patient's body fluid as a function of time following administration of the compound to the patient.

[0112] Pharmacokinetic analysis of PCLX-001 is presented herein. Table 1A summarizes the measured pharmacokinetic parameters for Patient 1, Patient 2, and Patient 3, respectively. Figure 3, Figures 4A-4B, and Figures 4C-4D show the single 20 mg oral dose pharmacokinetic profiles for Patient 1, Patient 2, and Patient 3, respectively.

[0113] Surprisingly, as shown herein, the trough concentrations (see Figures 5, 6 and 7) approached the levels we expected for treating cell lines ex vivo (Table 2). These findings were unexpected, in part because allometric scaling from non-human species suggested that much higher doses would be required for efficacy (Table 3).

[0114] In the case of patient 2, the efficacy and therapeutic utility of the dosing regimen was determined.

[0115] Patient 2 was a 56-year-old woman with heavily pretreated DLBCL and the second patient in a Phase 1 dose-escalation study of PCLX-001. Initial daily oral administration of 20 mg PCLX-001 tablets achieved a lower Cmax and a lower degree of exposure was evident compared to patient 1, whereas the terminal half-life could not be accurately estimated and significant drug exposure was observed. Furthermore, PK analysis on day 15 suggested a terminal half-life of approximately 10 hours. No significant drug accumulation was observed and nonparametric superposition suggested that steady-state concentrations were rapidly reached. These characteristics favor once-daily dosing and could also support more frequent dosing or a modified release formulation.

[0116] In a finding that was unexpected and not anticipated by the allometric scaling of PK results in mice, rats, and dogs, PCLX-001 dosing achieved higher through concentrations (measured immediately prior to dosing on days 2, 15, and 22) than expected in patients 1, 2, and 3, respectively. Peak plasma concentrations exceeded those required to inhibit cultured human cancer cell growth. Trough plasma concentrations were approximately equal to those required to inhibit cultured human cancer cell growth. Furthermore, the efficacy of PCLX-001 treatment in patient 2 was demonstrated by a significant reduction in the volume of liver metastatic disease in comparison of pre- and post-treatment computed tomography images.

[0117] Relative growth rates from mice predicted that approximately 180 mg po qd would be required to achieve a therapeutic result, however, as shown herein, indications of efficacy were seen at 20 mg.

[0118] Relative growth rates are based on toxicity, which establishes the maximum tolerated dose (MTD) in animal studies. In mice, one toxicity study established the MTD to be 35 mg / kg. In other studies using mice, doses of 35 mg / kg or higher had anti-cancer effects in mice implanted with human tumors (3). Dosing mice bearing human cancer at 10 mg / kg or lower generally had no appreciable anti-cancer activity. As shown herein, doses significantly lower than 180 mg per day in humans were not expected to have anti-cancer effects.

[0119] In one example, a method is provided for treating cancer in a subject in need thereof, comprising administering an oral dosage form of PCLX-001, wherein the oral dosage comprises 20 mg of PCLX-001 per day.

[0120] In another example, a method is provided for treating cancer in a subject in need thereof, comprising administering an oral dosage form of PCLX-001, wherein the oral dosage comprises 40 mg of PCLX-001 per day, 70 mg of PCLX-001 per day, 100 mg of PCLX-001 per day, 140 mg of PCLX-001 per day, 210 mg of PCLX-001 per day, 280 mg of PCLX-001 per day, 350 mg of PCLX-001 per day, or 420 mg of PCLX-001 per day.

[0121] In one example, the oral dosage provides an effect comprising a T1 / 2 of 8±3 hours when the oral dosage comprises 40 mg of PCLX-001 per day, 70 mg of PCLX-001 per day, 100 mg of PCLX-001 per day, 140 mg of PCLX-001 per day, 210 mg of PCLX-001 per day, 280 mg of PCLX-001 per day, 350 mg of PCLX-001 per day, or 420 mg of PCLX-001 per day. In another example, the oral dosage provides an effect comprising a T1 / 2 of 8 hours.

[0122] In one example, the oral dosage provides an effect including a Tmax of about 2.25±1.75 hours when the oral dosage includes 40 mg of PCLX-001 per day, 70 mg of PCLX-001 per day, 100 mg of PCLX-001 per day, 140 mg of PCLX-001 per day, 210 mg of PCLX-001 per day, 280 mg of PCLX-001 per day, 350 mg of PCLX-001 per day, or 420 mg of PCLX-001 per day. In another example, the oral dosage provides an effect including a Tmax of about 2.25 hours.

[0123] In vitro studies of PCLX-001 have demonstrated inhibition of cell growth in blood cancer cells, including lymphoma, leukemia, and myeloma; breast cancer cells; small cell lung cancer cells; non-small cell lung cancer cells; melanoma cells; adenocarcinoma cells; pancreatic cancer cells; bladder cancer cells; ovarian cancer cells; brain cancer cells; colon cancer cells; neuroblastoma; carcinoma cancer cells; endometrial cancer cells; sarcoma cancer cells; thyroid cancer cells; fibrosarcoma cancer cells; tongue cancer cells; testicular cancer cells; epidermoid cancer cells; cervical cancer cells; renal cancer cells; prostate cancer cells; and pharyngeal cancer cells.(3)

[0124] The term "bioavailability" refers to the rate and amount of drug that reaches the patient's systemic circulation after administration of the drug or its prodrug to the patient, and can be determined, for example, by assessing the plasma or blood concentration versus time profile for the drug. Parameters useful in characterizing the plasma or blood concentration versus time curve include the area under the concentration (AUC), the time to peak concentration (Tmax), and the maximum drug concentration (Cmax).

[0125] Absolute oral bioavailability is the bioavailability of a compound or its metabolites following oral administration compared to the bioavailability of an equivalent amount of the compound or its metabolites following intravenous administration. Relative oral bioavailability of a compound or its metabolites is the bioavailability of a compound or its metabolites following oral administration compared to the administration of an equivalent amount of the compound or its metabolites in another dosage form and / or route of administration.

[0126] The term "dosage form" refers to a form of formulation containing an amount of an active agent or a prodrug of an active agent, such as PCLX-001, that can be administered to a patient to achieve a therapeutic effect.

[0127] Oral dosage forms are intended to be administered to a patient via ingestion, e.g., via the mouth, and swallowed.

[0128] The terms "oral ingestion" and "oral administration" refer to the manner in which an active agent is provided to a subject or patient through the mouth via the gastrointestinal tract (digestive tract, digestive tract, GI tract, GIT, gut, or alimentary canal). The gastrointestinal tract is the organ system in humans and other animals that takes in food, digests it to extract and absorb energy and nutrients, and excretes remaining waste products as feces. The mouth, esophagus, stomach, and intestines are parts of the gastrointestinal tract.

[0129] Suitably, the oral formulation may contain a dissolution aid. The dissolution aid is not limited in terms of its properties, so long as it is pharma- ceutically acceptable. Examples include non-ionic surfactants, such as sucrose fatty acid esters, glycerol fatty acid esters, sorbitan fatty acid esters (e.g., sorbitan trioleate), polyethylene glycol, polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene alkyl ethers, methoxypolyoxyethylene alkyl ethers, polyoxyethylene alkylphenyl ethers, polyethylene glycol fatty acid esters, polyoxyethylene alkylamines, polyoxyethylene alkylthioethers, polyoxyethylene polyoxypropylene copolymers, polyoxyethylene glycerol fatty acid esters, pentaerythritol fatty acid esters, propylene glycol monohydrates, and the like. mono- and di-tert-butyl fatty acid esters, polyoxyethylene propylene glycol mono- and di-tert-butyl fatty acid esters, polyoxyethylene sorbitol fatty acid esters, fatty acid alkylolamides and alkylamine oxides; bile acids and their salts (e.g., chenodeoxycholic acid, cholic acid, deoxycholic acid, dehydrocholic acid and their salts, and glycine or its taurine conjugates); ionic surfactants such as sodium lauryl sulfate, fatty acid soaps, alkyl sulfonates, alkyl phosphates, phosphate ethers, fatty acid salts of basic amino acids; triethanolamine soaps and alkyl quaternary ammonium salts; and amphoteric surfactants such as betaine and aminocarboxylates.

[0130] Solid dosage forms such as tablets, dragees, capsules, pills and granules can be prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical formulation art. They may optionally contain opacifying agents and can be of a composition such that they release the active ingredient only, or preferentially, in a certain part of the intestinal tract, and / or in a delayed manner. Examples of embedding compositions include polymeric substances and waxes.

[0131] PCLX-001 can also be in microencapsulated form, if appropriate, with one or more of the above-mentioned excipients.

[0132] Liquid dosage forms for oral administration include pharma- ceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs. In addition to PCLX-001, liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (especially cottonseed, peanut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol, and fatty acid esters of sorbitan, and mixtures thereof. In addition to inert diluents, oral compositions may also contain adjuvants, such as wetting agents, emulsifying and suspending agents, sweeteners, flavoring agents, and perfuming agents. Suspensions may contain, in addition to the active compound, suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, and tragacanth, and mixtures thereof.

[0133] In other examples, the pharmaceutical compositions of the present disclosure may be used for parenteral injection, and preferably include sterilized pharmaceutically acceptable aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions immediately before use. Examples of suitable aqueous and non-aqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (e.g., glycerol, propylene glycol, polyethylene glycol, etc.), and suitable mixtures thereof, vegetable oils (e.g., olive oil), and injectable organic esters, such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by maintaining the required particle size in the case of dispersions, and by the use of surfactants.

[0134] Prolonged absorption of the injectable pharmaceutical form can be brought about by the inclusion of agents which delay absorption, for example, aluminum monostearate and gelatin.

[0135] In some cases, in order to prolong the effect of the pharmaceutical compositions of the present disclosure, it is desirable to slow the absorption of the composition or PCLX-001 from subcutaneous or intramuscular injection. This can be accomplished by the use of a liquid suspension in which PCLX-001 is suspended. The rate of absorption of PCLX-001 then depends on its dissolution rate.

[0136] Alternatively, delayed absorption of a parenterally administered pharmaceutical composition of the present disclosure is accomplished by dissolving or suspending PCLX-001 in an oil vehicle. Injectable depot forms are conveniently made by forming microencapsulated matrices of PCLX-001 in biodegradable polymers, such as polylactide-polyglycolide. The rate of release can be controlled depending on the ratio of PCLX-001 to polymer and the nature of the particular polymer employed. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides).

[0137] Depot injectable formulations can also be prepared by encapsulating PCLX-001 in liposomes or microemulsions that are compatible with body tissues. The injectable formulations can be sterilized, for example, by filtration through a bacteria-retaining filter or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved or dispersed in sterile water or other sterile injectable medium immediately before use.

[0138] In other examples, pharmaceutical compositions of the present disclosure for rectal or vaginal administration are preferably suppositories, which may be prepared by mixing PCLX-001 with a suitable non-irritating excipient or carrier, such as cocoa butter, polyethylene glycol or a suppository wax, which is solid at room temperature but liquid at body temperature and thus will melt in the rectal or vaginal cavity and release PCLX-001.

[0139] PCLX-001 may be administered in the form of liposomes. As known in the art, liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed by mono- or multi-layered hydrated liquid crystals dispersed in an aqueous medium. Any non-toxic, physiologically acceptable and metabolizable lipid capable of forming liposomes may be used. The pharmaceutical composition of the present disclosure in liposomal form may contain, in addition to PCLX-001, stabilizers, preservatives, excipients, and the like. Preferred lipids are phospholipids and phosphatidylcholines (lecithins), both natural and synthetic. Methods for forming liposomes are known in the art.

[0140] Dosage forms for topical administration of PCLX-001 include powders, sprays, ointments and inhalants. PCLX-001 may be mixed under sterile conditions with a pharma- ceutically acceptable carrier and any necessary preservatives, buffers or propellants that may be required. PCLX-001 may be administered, for example, as part of a pharmaceutical composition, in ophthalmic formulations, or eye ointments, powders and solutions.

[0141] The methods of the present invention are conveniently practiced by providing the compounds and / or compositions used in such methods in the form of a kit. Such a kit preferably contains the composition. Such a kit preferably contains instructions for its use.

[0142] In order to obtain a better understanding of the invention described herein, the following examples are set forth. It should be understood that these examples are for illustrative purposes only. Thus, they should not be construed as limiting the scope of the present invention in any way. EXAMPLES

[0143] Working Example summary Many human cancers are inadequately treated with existing anticancer drugs. Among such cancers, relapsed and refractory diffuse large B-cell lymphoma (DLBCL) is in need of new therapeutic approaches, especially for transplant / CAR-T ineligible and elderly patients. We describe two patients with DLBCL treated with novel anticancer drugs, and a third patient with heavily pretreated soft tissue sarcoma. Patient 1 was an 86-year-old woman with heavily pretreated DLBCL who received a novel first-in-class small molecule inhibitor of N-myristoyltransferase (NMT) as the first patient in a Phase I dose-escalation study. Daily oral administration of 20 mg PCLX-001 tablets produced a pharmacokinetic profile suitable for single daily dosing: rapid oral absorption, followed by apparent elimination half-lives of 8.54 hours on day 1 and 10.3 hours on day 15, substantial trough concentrations of drug, and no systemic accumulation of drug by day 15. The patient did not experience any dose-limiting toxicity, but had disease progression after 28 days of study therapy. Patient 2 was a 56-year-old woman with heavily pretreated DLBCL and was the second patient in a Phase 1 dose-escalation study of PCLX-001. Daily oral administration of 20 mg PCLX-001 tablets achieved a lower Cmax and longer Tmax, with a lower degree of exposure evident compared to patient 1. In an unexpected and unexpected finding due to the allometric scaling of PK results in mice, rats and dogs, PCLX-001 dosing achieved higher through concentrations (measured immediately prior to dosing on days 2, 15 and 22) than expected in patients 1, 2 and 3, respectively. Peak plasma concentrations exceeded those required to inhibit cultured human cancer cell growth. Trough plasma concentrations were approximately equal to those required to inhibit cultured human cancer cell growth. Furthermore, the efficacy of treatment with PCLX-001 in patient 2 was demonstrated by a significant reduction in the volume of liver metastatic disease in comparison of pre- and post-treatment computed tomography images. Patient 3 was a 55-year-old female with heavily pre-treated soft tissue sarcoma and was the third patient in a Phase 1 dose-escalation study of PCLX-001. Daily oral administration of 20 mg PCLX-001 tablets had PK characteristics consistent with the requirement for daily oral dosing.The estimated half-lives were 5.61 hours on day 1 and 6.86 hours on day 15. Peak plasma concentrations exceeded those required to inhibit human cancer cell growth in culture. Trough plasma concentrations were approximately equal to those required to inhibit human cancer cell growth in culture.

[0144] Introduction PCLX-001 is a potent small molecule inhibitor of both human NMT proteins, NMT1 and NMT2. Preclinical studies have shown that PCLX-001 markedly inhibited hematologic and lymphoma cell lines in tissue culture and achieved complete remission in human cancers grown in immunodeficient mice [3] and tumor responses in solid tumors [4]. PCLX-001 has multiple potential mechanisms of action, but in B cell lymphoma models, it inhibits early B cell receptor (BCR) signaling events that are essential for survival. In addition to abrogating myristoylation of Src family kinases, PCLX-001 also promotes their degradation, as well as that of a number of non-myristoylated BCR effectors, including c-Myc, NFκB, and P-ERK, leading to cancer cell death in vitro and in xenograft models [3]. The molecule has been extensively investigated in preclinical safety studies [5] and was found to be suitable for formal drug development in humans.

[0145] Herein, we report the first three patients treated with an NMT inhibitor. Pharmacokinetic endpoints were explored in this first-in-human drug exposure, demonstrating that PCLX-001 has favorable pharmacokinetic properties for oral, once-daily cancer therapy.

[0146] 2. Materials and Methods 2.1. PCLX-001 - Investigational Drug PCLX-001 (Figure 1) is a potent small molecule inhibitor of human NMT1 and NMT2 proteins. In animal models, it has full oral bioavailability. There is no significant off-target kinase inhibition as demonstrated by KINOME scan (Fremont, CA, USA) [3]. Preclinical studies revealed no significant hERG interactions, and animal preclinical safety studies showed no cardiac conduction problems. In GLP preclinical safety studies, diarrhea was dose limiting [5]. Mechanism of action studies indicate that NMT inhibition can affect approximately 600 human proteoforms [1], while in models of human lymphoma, Bruton's tyrosine kinase (BTK) modification and downstream signaling were largely inhibited in the presence of PCLX-001 [3].

[0147] 2.2. Clinical Trials The clinical trial is titled "Phase I Study of PCLX-001 in B-cell Non-Hodgkin Lymphoma and Advanced Solid Malignancies" and is registered as NCT04836195 on clinicaltrials.gov. It is a Phase I dose escalation study of oral PCLX-001 with a multicenter, non-randomized, open-label, non-controlled design. The study consists of two parts: Part A (single-agent dose escalation) and Part B (single-agent expansion cohort)[6].

[0148] The primary endpoint of the study is to determine, during the dose escalation phase, the recommended dose of PCLX-001 for the dose expansion phase of the study.

[0149] Patients will receive daily oral PCLX-001 in 28-day cycles, beginning with a starting dose of 20 mg.

[0150] The study was performed in accordance with the guidelines of the Declaration of Helsinki and was approved by the Institutional Review Board of the Cross Cancer Institute (postcode T6G1Z2 and protocol code HREBA CC-21-0157, approved June 24, 2021). Informed consent was obtained from all subjects involved in the study.

[0151] 2.3.Pharmacokinetic analysis The primary pharmacokinetic analysis endpoints were as follows:

[0152] i) During Cycle 1: Pre-dose on Days 1, 2, 8 (±2), 15 (±2), and 22 (±2); Days 1 and 15 will also be measured at 0.5, 1, 2, 4, and 8 hours post-dose; To determine the time to maximum plasma levels (Tmax) of PCLX-001 measured pre-dose on Day 1 of Cycle 2.

[0153] Tmax is the time at which the peak plasma concentration of PCLX-001 is achieved.

[0154] ii) In Cycle 1: pre-dose on days 1, 2, 8 (±2), 15 (±2), and 22 (±2); days 1 and 15 will also be measured at 0.5, 1, 2, 4, and 8 hours post-dose; to determine the maximum plasma level (Cmax) of PCLX-001 measured pre-dose on day 1 of Cycle 2.

[0155] Cmax is the maximum plasma concentration of PCLX-001.

[0156] Patients were administered an oral dose of 20 mg of PCLX-001. After dosing, blood samples (3 mL volume) were collected serially into heparinized tubes from a butterfly cannula in the right forearm. All blood specimens were frozen and later assayed using a validated UHPLC-MS detection method.

[0157] Noncompartmental pharmacokinetic analysis was performed using Phoenix Winnonlin 8.3 using trapezoidal rule and linear up-down methodology. Winnonlin was allowed to select the optimal terminal phase. The results are shown in Table 1A.

[0158] Non-parametric superposition was performed using Phoenix Winnonlin non-parametric superposition to predict steady state data for each patient based on day 1 data, which utilized 8 and 24 hour time points for terminal phase estimation for the purposes of this exercise. We simulated a daily oral dose of 20 mg and the simulation was run to steady state. The results are shown in Figures 5, 6 and 7.

[0159] 2.4. Toxicity assessment Subjects were assessed for toxicity using daily diary entries, clinical assessments at baseline, days 8, 15, 22, and 28. Dose-limiting toxicities were DLTs defined as the following cycle 1 CTCAE version 5.0 adverse events: Gr 4 platelets, Gr 3 or greater platelets with bleeding and / or transfusion, Gr 4 ANC for ≥7 days, Gr 3 or greater febrile neutropenia, and Gr 3 or greater non-hematological toxicity.

[0160] 2.5.Efficacy evaluation Patients 1 and 2 had baseline cross-sectional imaging and PET imaging, and patient 3 had baseline cross-sectional imaging. Protocol-defined imaging was CT every 2 cycles and PET every 6 cycles or as clinically indicated. Response was assessed by Lugano criteria for non-Hodgkin lymphoma and RECIST 2.0 for soft tissue tumors.

[0161] 3. Results – Patient 1 3.1. Patient demographics The patient (Patient 1) was an 86-year-old Caucasian female with refractory relapsed diffuse large B-cell lymphoma (DLBCL) with immunohistochemical subclassification consistent with germinal center B cell (GCB) as the cell of origin. Comorbidities included hypothyroidism, hypertension, osteoporosis, and endovascular repair of an abdominal aortic aneurysm in 2018. Her initial cancer diagnosis was stage IVA DLBCL, non-GCB cell of origin (CD10 negative, BCL2, BCL6, MUM1 positive) in September 2014, for which she received R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) chemotherapy. Relapse was diagnosed in July 2021 as stage IVA DLBCL, GCB cell of origin (CD10 negative, MUM1 negative, BCL2, BCL6 positive) for which she received ibrutinib. Immediately prior to study entry, baseline blood work showed normal hematopoiesis and biochemistry. Computed tomography demonstrated a tongue mass, cervical, hilar, and mediastinal nodal involvement, and T10 involvement. A bone marrow biopsy of the iliac crest was nondiagnostic.

[0162] 3.2. PCLX-001 Administration PCLX-001 was administered orally every morning as two tablets, each containing 10 mg of PCLX-001. PCLX-001 was initiated on September 14, 2021 and discontinued on day 29 due to symptomatic back pain and CT confirmed lymph node progression.

[0163] Pharmacokinetics Pharmacokinetic analysis was performed as described above. Figure 3 shows the plasma concentrations of PCLX-001 after the first oral dose and after dosing on day 15. Table 1A shows the pharmacokinetic parameters determined by this analysis. The results on day 1 show a rapid absorption rate, with a peak plasma concentration achieved 1 hour after oral dosing, a peak plasma concentration of 353 ng / ml, and an apparent terminal half-life of 8.54 hours. The results on day 15 show rapid absorption, with a peak plasma concentration of 479 ng / mL achieved 1 hour after dosing. A nonparametric superposition simulation (Figure 7) shows rapid achievement of steady-state kinetics. Both of these parameters support a single daily oral dosing schedule for PCLX-001, although they may support more frequent oral dosing or the use of a sustained release formulation.

[0164] [Table 1]

[0165] A different pharmacokinetic modeling program was used in the public PK Solver 2.0 freeware (https: / / www.boomer.org / boomer / software / pksolver.zip; accessed November 26, 2021) to determine single-dose pharmacokinetic parameters using a two-compartment model. This was used for patent applications that do not assume compartments and models, rather they do not let the data speak for itself without the constraints of a compartment model. As noted above, non-compartmental pharmacokinetic analysis was performed using Phoenix Winnonrin 8.3, using a trapezoidal rule and linear up-log-down methodology. Winnonrin was allowed to select the optimal terminal phase.

[0166] The results are shown in Table 1B.

[0167] Pharmacokinetic analysis was performed as described above. Table 1B shows the pharmacokinetic parameters determined from this analysis using two different software and compartmental versus non-compartmental methods. Both of these parameters support a single daily oral dosing schedule for PCLX-001.

[0168] [Table 2]

[0169] Longer half-life 16.42 hours vs. 8.84, slightly lower Cmax 278.23ng / mL vs. 353, slightly lower AUClast 1710 vs. 1701.33, and slightly higher AUCinf 2355.81 (ng×h / mL) vs. 2034, lower AUC on day 15 2635.63 (ng×h / mL) vs. 3498.

[0170] 3.4. PCLX-001 toxicity The patient's diary revealed perfect compliance with the drug delivery schedule. The patient experienced no protocol-defined dose-limiting toxicities. Her hematopoietic profile and biochemistry remained normal throughout the study.

[0171] 3.5.Efficacy The subject had baseline cross-sectional imaging and PET imaging. Repeat computed tomography imaging was performed on Day 28 due to the patient's increasing symptoms of back pain, revealing progression of lymphoma volume as defined by the Lugano classification criteria for the evaluation of non-Hodgkin's lymphoma. As a result, the patient discontinued PCLX-001 at that time.

[0172] 4. Results – Patient 2 4.1. Patient demographics This patient (Patient 2) is a 56-year-old woman with transformed stage IV DLBCL diagnosed in April 2018 and was initially treated with six cycles of R-CEOP immunochemotherapy, which was completed in September 2018 with a complete response. The lymphoma relapsed in May 2019 and she received R-DICEP salvage immunochemotherapy followed by BEAM high-dose conditioning chemotherapy with autologous stem cell transplant. The aggressive lymphoma was suppressed with an anti-CD19 CAR-T protocol in mid-2020. The aggressive lymphoma was diagnosed in May 2021. The patient received intermittent radiation therapy and corticosteroids. She agreed to be the second patient to receive PCLX-001 as part of the PCLX-001 clinical trial in October 2021.

[0173] 4.2. PCLX-001 Administration PCLX-001 was administered orally every morning as two tablets, each containing 10 mg of PCLX-001. PCLX-001 was initiated on November 9, 2021 and discontinued on January 3, 2022 due to a mixed disease response to therapy, as demonstrated by significant interval tumor responses in the liver metastases but progressive disease in the lymph nodes; discontinuation of study drug was recommended in the context of the mixed disease response with the treating clinician allowing other therapies.

[0174] Pharmacokinetics Pharmacokinetic analysis was performed as described above. Figure 4 shows the plasma concentration of PCLX-001 after the first oral dose. Table 1A and Table 1B show the pharmacokinetic parameters determined by this analysis, where she is described as patient 115-002-002. After her first dose of PCLX-001, peak plasma concentration was achieved at 4 hours with a peak plasma concentration of 127 ng / ml. By dosing on day 15, peak plasma concentration was achieved after 2 hours with a peak plasma concentration of 215 ng / ml with an estimated terminal half-life of 10.3 hours. Nonparametric superposition simulation (Figure 8) shows rapid attainment of steady-state kinetics.

[0175] In patient 2, we observed efficacy and therapeutic benefit of the dosing regimen. Daily oral administration of 20 mg PCLX-001 tablets achieved a lower Cmax and longer Tmax, with a lower degree of exposure evident compared to patient 1. All pharmacokinetic parameters supported a single daily oral dosing schedule for PCLX-001, but may be amenable to more frequent daily dosing or modified release formulations.

[0176] In a finding that was unexpected and not anticipated by the allometric scaling of PK results in mice, rats, and dogs, PCLX-001 dosing consistently achieved higher trough concentrations (measured immediately prior to dosing on days 2, 15, and 22) than expected in Patient 1, Patient 2, and Patient 3, respectively. Peak plasma concentrations exceeded those required to inhibit cultured human cancer cell growth. Trough plasma concentrations were approximately equal to those required to inhibit cultured human cancer cell growth.

[0177] 4.3.1 Computed tomography Computed tomography was performed on patient 2 on two occasions: immediately prior to treatment (pre-treatment scan acquired on October 29, 2021) and after two 28-day cycles of oral PCLX-001 at a daily dose of 20 mg by mouth (post-treatment scan acquired on December 30, 2021). Both scans were performed on the same scanner using the same technique, including the use of intravenous contrast. Three sets of pre- and post-treatment scans are of the same cross-section of the patient to identify the clinical trial target lesion of liver metastasis in the subcapsular region of segment 5 of the liver. These scans demonstrate a baseline discrete 2.9 x 2 cm liver metastasis at baseline. These scans demonstrate a vague and uncertain residual hypoattenuation after treatment measuring 1.7 x 1.2 cm. These radiological changes pointed to a significant tumor regression. Figures 2A-4F.

[0178] 4.5. PCLX-001 toxicity The patient's diary revealed perfect compliance with the drug delivery schedule. The patient experienced no protocol-defined dose-limiting toxicities. Her hematopoietic profile and biochemistry remained normal throughout the study.

[0179] 4.6 Efficacy As shown herein, unexpectedly, high drug exposure was achieved with PCLX-001, as evidenced by higher than expected trough concentrations (i.e., drug levels measured immediately prior to taking the next pill, Figures 5-7), a longer half-life than expected compared to animal studies, and evidence that patient number 2 had regression of malignant lesions in the liver (Figures 2A-F).

[0180] 4.7 Summary of demographics and outcomes of patient 3 The patient was a 55-year-old woman with heavily pretreated leiomyosarcoma with systemic metastases. She received PCLX-001 daily from November 24, 2021 to January 19, 2022. No drug-related toxicities were identified. Her medication records showed perfect adherence to her medication. Response assessment scans after two 28-day cycles of PCLX-001 showed progressive disease and study drug was discontinued. Her pharmacokinetic results are summarized in Table 1A and Table 1B (where she is represented as patient 115-002-004).

[0181] 4.8 Expected Serum PCLX-001 Levels for Indications Preclinical data on ex vivo sensitivity of various cultured human cancer cells has been performed in three panels and reported previously (3). Table 2 summarizes the mean concentrations that inhibited cancer cell growth (defined as EC50<500nM or IC50<500nM) in sensitive cancer cell lines. As can be seen, mean effective concentrations of PCLX-001 were achieved at concentrations as low as 80.9nM. Peak plasma concentrations exceed these levels in patients 1, 2, and 3, respectively. Trough concentrations observed on days 2, 15, and 22 are also close to those required to inhibit cancer cell growth (Figures 5, 6, 7). The conversion factor from ng / ml to nM for PCLX-001 is approximately a multiplier of 1.86, where, for example, 100ng / ml converts to a concentration of 186nM.

[0182] [Table 3]

[0183] 4.9 PCLX-001 trough levels are higher than expected A summary of selected previous pharmacokinetic analyses performed on non-human species is shown in Table 3. These studies showed that PCLX-001 is rapidly cleared from plasma in non-human species. As a result, the consistent finding of substantial pre-dose PCLX-001 plasma levels on days 2, 8, 15, and 22 in all patients was an unexpected finding (Figures 5-7). Possible explanations for this finding include hysteresis loops (7) and flip-flop pharmacokinetics (7).

[0184] 4.10 Allometric data from animal studies suggest that oral doses of PCLX-001 required to achieve efficacy would have to be substantially higher than 20 mg daily Allometric scaling is a means by which PK results from animal studies can be used to predict human drug exposure for a range of drug doses. In this case, allometric scaling was performed using representative values ​​from a PK study using daily oral PCLX-001 administration over 14 or 28 days in a non-human species. These inputs were analyzed by www.truedose.app to predict the maximum tolerated dose we would see in this Phase 1 clinical trial (Figure 2). Anti-cancer efficacy data from mice bearing human tumors suggested that the effective dose of PCLX-001 was greater than 50% of the PCLX-001 dose that produced mouse toxicity in any given experiment.

[0185] [Table 4]

[0186] Overall, the animal PK data, animal efficacy data, and animal allometric data suggest that 20 mg of PCLX-001 administered orally daily would not be expected to achieve anticancer efficacy. As a result, the human clinical trial results are unexpected and novel.

[0187] FIG. 1 shows PCLX-001 (2,6-dichloro-N-(3-isobutyl-1,5-dimethyl-1H-pyrazol-4-yl)-4-(2-(piperazin-1-yl)pyridin-4-yl)benzenesulfonamide) C 24 H 30 Draw the chemical structure of Cl2N6O2S.

[0188] Figure 2 depicts computed tomography images of Patient 2: (A) October 29, 2021 - TL#2 segment 5 of liver, (B) October 29, 2021 - TL#2 segment 5 of liver (no measurements) image 27 / 4, (C) December 30, 2021 - TL#2 segment 5 of liver image 24 / 4 with measurements, (D) December 30, 2021 - TL#2 segment 5 of liver (no measurements) image 24 / 4, (E) October 29, 2021 - TL#2 segment 5 of liver image 27 / 4 (liver photo), (F) December 30, 2021 - TL#2 segment 5 of liver image 24 / 4 (liver photo).

[0189] FIG. 3 depicts non-compartmental analysis for PCLX-001 in patient 1 (patient 115-002-001) on (A) day 1 and (B) day 15.

[0190] Figure 4 (A) depicts non-compartmental analysis for PCLX-001 in patient 2 (patient 115-002-002) on day 1, (B) on day 15, and (C) depicts non-compartmental analysis for PCLX-001 in patient 3 (patient 115-002-004) on day 1, (D) on day 15.

[0191] FIG. 5 depicts the nonparametric superposition simulation to steady state in patient 1 (patient 115-002-001).

[0192] FIG. 6 depicts the non-parametric superposition simulation to steady state in patient 2 (patient 115-002-002).

[0193] FIG. 7 depicts the non-parametric superposition simulation to steady state in patient 3 (patient 115-002-004).

[0194] Figures 8A and 8B depict dose proportionality analysis on Day 1. Figure 8A depicts Cmax / dose vs. dose on Day 1. Figure 8B depicts AUClast / dose vs. dose on Day 1.

[0195] Figures 9A and 9B depict the dose proportionality analysis on day 14. Figure 9A depicts Cmax / dose vs. dose on day 14. Figure 9B depicts AUClast / dose vs. dose on day 14.

[0196] FIG. 10 depicts steady state assessment-pre-dose PCLX-001 concentrations for subjects not taking pantoprozole.

[0197] FIG. 11A, FIG. 11B, and FIG. 11C depict plasma concentrations of PCLX-001 following oral administration of 20 mg QD of PCLX-001 to cancer patients.

[0198] FIG. 12A, FIG. 12B, and FIG. 12C depict plasma concentrations of PCLX-001 following oral administration of 40 mg QD of PCLX-001 to cancer patients.

[0199] FIG. 13A, FIG. 13B, FIG. 13C depict plasma concentrations of PCLX-001 following oral administration of 70 mg QD of PCLX-001 to cancer patients.

[0200] FIG. 14A, FIG. 14B, FIG. 14C, FIG. 14D depict plasma concentrations of PCLX-001 following oral administration of 100 mg QD of PCLX-001 to cancer patients.

[0201] FIG. 15A, FIG. 15B, FIG. 15C depict plasma concentrations of PCLX-001 following oral administration of 140 mg QD of PCLX-001 to cancer patients.

[0202] For non-compartmental analysis, the Phoenix Winnonlin 8.3 trapezoidal rule was used with a linear up-log down methodology. This allowed Winnonlin to select the optimal terminal phase (Winnonlin would tolerate an adjusted Rsq of >0.7). Additional analysis to assess the appropriate fie included visual inspection of the data and AUC extrap should be less than 15%.

[0203] For non-parametric overlay, the Phoenix Winnonlin non-parametric overlay was used to predict steady state data based on day 1 data for each patient. For the purposes of this exercise, the 8 and 24 hour time points were used to estimate the terminal phase. 20 mg QD was simulated. The simulation was run to steady state.

[0204] 5. Discussion This is the first report of human exposure to an inhibitor of N-myristoyltransferase, a potential new class of anticancer drug. In this promising Phase I dose-escalation study, the first patient received 20 mg oral PCLX-001 daily for a complete 28-day cycle and experienced no dose-limiting toxicity. This patient had relapsed and pretreated aggressive non-Hodgkin's lymphoma, and she experienced disease progression despite PCLX-001, but without evidence of toxicity to hematopoietic, hepatic, or renal function.

[0205] In patient 1, pharmacokinetic analysis was performed as described above. Figure 3 shows the plasma concentrations of PCLX-001 after the first oral dose and after dosing on day 15. Table 1A and Table 1B show the pharmacokinetic parameters determined by this analysis. The results on day 1 show a rapid absorption kinetics, with a peak plasma concentration achieved 1 hour after oral dosing, a peak plasma concentration of 353 ng / ml, and an apparent terminal half-life of 8.5 hours. The results on day 15 show rapid absorption, with a peak plasma concentration of 479 ng / mL achieved 1 hour after dosing. A nonparametric superposition simulation (Figure 5) shows rapid achievement of steady-state kinetics. Both of these parameters support a single daily oral dosing schedule for PCLX-001.

[0206] Furthermore, plasma trough levels, measured immediately prior to daily dosing, achieve drug concentrations approximating the IC50 required to inhibit some PCLX-001-sensitive cultured cancer cell lines (Figures 5-7).

[0207] Patient 1 had prior exposure to the Bruton's tyrosine kinase (BTK) inhibitor ibrutinib. Some of the myristoylated substrates for NMT, including Lyn and HGAL, are upstream of BTK in the B cell receptor signaling cascade. [3] As additional patients are accrued to this ongoing study, it will be evaluated whether prior BTK inhibitor exposure is related to PCLX-001 efficacy.

[0208] For patient 2, pharmacokinetic analysis was performed as described above. Figure 5 shows the plasma concentration of PCLX-001 after the first oral dose. Table 1A (Table 1)Table 1B (Table 2) show the pharmacokinetic parameters determined by this analysis, where she is described as patient 115-002-002. After her PCLX-001 dose, the peak plasma concentration was achieved at 4 hours, with a peak plasma concentration of 127 ng / ml. By dosing on day 15, the peak plasma concentration was achieved after 2 hours, with a peak plasma concentration of 215 ng / ml, with an estimated terminal half-life of 10.3 hours. Nonparametric superposition simulations show rapid achievement of steady-state kinetics. We observed a lower degree of PCLX-001 exposure compared to patient 1. Nevertheless, the drug exposure and trough levels of PCLX-001 (Figure 6) were unexpectedly high when compared to expectations from preclinical studies in animals. After approximately two months of continued daily oral administration of PCLX-001, patient no. 2 had regression of malignant lesions in the liver (Figure 2).

[0209] 6. Conclusion This is the first report of any therapeutic human use of an N-myristoyltransferase inhibitor. PCLX-001, a potent small molecule inhibitor of human N-myristoyltransferase protein, has favorable pharmacokinetic parameters suitable for once-daily oral dosing, or more frequent oral dosing, or modified release formulations. Unexpectedly, low doses of the drug produced higher than expected drug exposure and radiological regression of malignant liver metastases in women with heavily pretreated DLBCL. References [Table 4-2]

[0210] Example 2 This example shows that PCLX-001 was readily absorbed with a median (range) Tmax value of 2.00 (0.50, 8.00). Tmax values ​​were similar on days 1 and 15 of dosing.

[0211] The t1 / 2 of PCLX-001 ranged from 5.02 to 17.4 hours across dose groups. The t1 / 2 of PCLX-001 was similar between patients taking pantoprazole and those not taking pantoprazole. The t1 / 2 tended to be higher in the highest dose group (140 mg).

[0212] Systemic exposure to PCLX-001 was dose-proportional over the dose range of 20 to 140 mg.

[0213] Systemic exposure to PCLX-001 was lower in patients taking pantoprazole.

[0214] [Table 5]

[0215] NC = not calculated because the elimination rate could not be adequately estimated.

[0216] Tmax is expressed as median (min, max).

[0217] * represents values ​​from N=1 patient.

[0218] [Table 6]

[0219] NC = not calculated because the elimination rate could not be adequately estimated.

[0220] T max is expressed as median(min, max).

[0221] In one example, T1 / 2 is from about 5 hours to about 18 hours. In another example, T1 / 2 is from about 5.5 hours to about 14 hours.

[0222] In one example, when an oral dose contains 20 mg of PCLX-001 per day, T1 / 2 is about 6 to about 9 hours. In another example, T1 / 2 is about 6.9 to about 8.9 hours.

[0223] In one example, when an oral dose contains 40 mg of PCLX-001 per day, T1 / 2 is about 5 hours to about 11 hours. In another example, T1 / 2 is about 5.5 hours to about 10.8 hours.

[0224] In one example, when an oral dose contains 70 mg of PCLX-001 per day, the T1 / 2 is about 9 hours. In another example, the T1 / 2 is about 9.4 hours.

[0225] In one example, when an oral dose contains 100 mg of PCLX-001 per day, T1 / 2 is about 7 to about 8 hours. In another example, T1 / 2 is about 7.2 to about 7.5 hours.

[0226] In one example, when an oral dose includes 140 mg of PCLX-001 per day, T1 / 2 is about 6 hours to about 14 hours. In another example, T1 / 2 is about 6.7 hours to about 13.8 hours.

[0227] Figures 8A and 8B depict dose proportionality analysis on Day 1. Figure 8A depicts Cmax / dose vs. dose on Day 1. Figure 8B depicts AUClast / dose vs. dose on Day 1. Patients taking pantoprazole had lower PCLX-001 Cmax and AUClast values ​​than patients not taking pantoprazole. Consistent AUCtau / dose or Cmax / dose values ​​across the dose range of 20 mg to 140 mg QD suggest dose proportionality.

[0228] Figures 9A and 9B depict dose proportionality analysis on day 14. Figure 9A depicts Cmax / dose vs. dose on day 14. Figure 9B depicts AUClast / dose vs. dose on day 14. Patients taking pantoprazole had lower PCLX-001 Cmax and AUClast values ​​than patients not taking pantoprazole. Consistent AUCtau / dose or Cmax / dose values ​​across the dose range of 20 mg to 140 mg QD suggest dose proportionality.

[0229] Figure 10 depicts steady state assessment-pre-dose PCLX-001 concentrations for patients not taking pantoprozole. Data is limited to assessing time to achieve steady state for 20 mg (N=3), 40 mg (N=1), 70 mg (N=1), 100 mg (N=2) and 140 mg (N=1) due to small subject numbers.

[0230] Supporting individual data slides Non-compartmental analysis Phoenix Winnonlin 8.3 trapezoidal rule. Linear up-log down method was used. Let Winnonlin choose the optimal terminal phase (Winnonlin will tolerate an adjusted Rsq of over 0.7).

[0231] Further analyses to assess adequate fit. Visual inspection of data. AUCextrap should be less than 15%.

[0232] Plots. For all plots, values ​​were not collected on Day 15 as no 24 hour sample was collected, so the Day 22 pre-dose value was used for the Day 15 24 hour value.

[0233] FIG. 11A, FIG. 11B, and FIG. 11C depict plasma concentrations of PCLX-001 following oral administration of 20 mg QD of PCLX-001 to cancer patients.

[0234] [Table 7]

[0235] *Terminal half-life and AUCinf could not be adequately characterized.

[0236] Note: AUCextrap is underlined and highlighted in red, and extrapolated if >15% of the AUC.

[0237] Figures 12A, 12B, and 12C depict plasma concentrations of PCLX-001 following oral administration of 40 mg QD of PCLX-001 to cancer patients. Note: Pre-dose values ​​on day 22 were plotted for visualization purposes since 24-hour samples on day 15 were not collected.

[0238] [Table 8]

[0239] *Terminal half-life and AUCinf could not be adequately characterized.

[0240] Note: AUCextrap is underlined and highlighted in red, and extrapolated if >15% of the AUC.

[0241] FIG. 13A, FIG. 13B, FIG. 13C depict plasma concentrations of PCLX-001 following oral administration of 70 mg QD of PCLX-001 to cancer patients.

[0242] [Table 9]

[0243] *Terminal half-life and AUCinf could not be adequately characterized.

[0244] Note: AUCextrap is underlined and highlighted in red, and extrapolated if >15% of the AUC.

[0245] FIG. 14A, FIG. 14B, FIG. 14C, FIG. 14D depict plasma concentrations of PCLX-001 following oral administration of 100 mg QD of PCLX-001 to cancer patients.

[0246] [Table 10]

[0247] *Terminal half-life and AUCinf could not be adequately characterized.

[0248] Note: AUCextrap is underlined and highlighted in red, and extrapolated if >15% of the AUC.

[0249] FIG. 15A, FIG. 15B, FIG. 15C depict plasma concentrations of PCLX-001 following oral administration of 140 mg QD of PCLX-001 to cancer patients.

[0250] [Table 11]

[0251] Note: AUCextrap is extrapolated if it is >15% of AUCinf, as highlighted in red and underlined.

[0252] It is shown herein that there is greater exposure of PCLX-001 (driven in large part by the longer half-life) and rapid oral absorption of PCLX-001 than expected from the animal data.

[0253] Malabsorption / small bowel resection has also been shown to delay absorption and reduce exposure.

[0254] Interactions with proton pump inhibitors, such as pantoprazole (low gastric acidity), have also been shown to reduce oral absorption.

[0255] It has also been shown that trough drug levels (i.e., pre-dose levels) significantly exceeding the IC50 and IC90 of cultured cancer cell lines treated with PCLX-001 in tissue culture can be achieved, suggesting that therapeutic drug levels and exposures can be achieved in humans.

[0256] The embodiments described herein are intended to be examples only. Alterations, modifications, and variations may be realized in the specific embodiments by those skilled in the art. The claims should not be limited by the specific embodiments set forth herein, but should be construed in a manner consistent with the specification as a whole.

[0257] All publications, patents, and patent applications mentioned in this specification are indicative of the level of those skilled in the art to which this invention pertains, and are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.

[0258] The invention being thus described, it will be obvious that the same may be varied in many respects. Such variations are not to be regarded as departures from the spirit and scope of the invention, and all such modifications which would be obvious to those skilled in the art are intended to be included within the scope of the following claims.

Claims

1. 1. An oral dosage form of PCLX-001 for use in treating cancer in a subject in need thereof, wherein the oral dosage comprises 20 mg of PCLX-001 per day, 40 mg of PCLX-001 per day, 70 mg of PCLX-001 per day, 100 mg of PCLX-001 per day, 140 mg of PCLX-001 per day, 210 mg of PCLX-001 per day, 280 mg of PCLX-001 per day, 350 mg of PCLX-001 per day, or 420 mg of PCLX-001 per day.

2. 2. The oral dosage form of PCLX-001 for use according to claim 1, wherein the oral dosing provides an effect comprising a T1 / 2 of about 5 hours to about 18 hours, or about 5.5 hours to about 14 hours.

3. 1. An oral dosage form of PCLX-001 for use in treating cancer in a subject in need thereof, wherein said oral dosage comprises 20 mg of PCLX-001 per day.

4. 4. The oral dosage form of PCLX-001 for use according to claim 3, wherein the oral dosing provides an effect comprising a T1 / 2 of about 6 hours to about 9 hours, or about 6.9 hours to about 8.9 hours.

5. 1. An oral dosage form of PCLX-001 for use in treating cancer in a subject in need thereof, wherein said oral dosage comprises 40 mg of PCLX-001 per day.

6. 6. The oral dosage form of PCLX-001 for use according to claim 5, wherein the oral dosing provides an effect comprising a T1 / 2 of about 5 hours to about 11 hours, or about 5.5 hours to about 10.5 hours.

7. 1. An oral dosage form of PCLX-001 for use in treating cancer in a subject in need thereof, wherein said oral dosage comprises 70 mg of PCLX-001 per day.

8. 8. The oral dosage form of PCLX-001 for use according to claim 7, wherein the oral dosing provides an effect comprising a T1 / 2 of about 9 hours, or about 9.4 hours.

9. 1. An oral dosage form of PCLX-001 for use in treating cancer in a subject in need thereof, wherein said oral dosage comprises 100 mg of PCLX-001 per day.

10. 10. The oral dosage form of PCLX-001 for use according to claim 9, wherein the oral dosing provides an effect comprising a T1 / 2 of about 7 hours to about 8 hours, or about 7.5 hours.

11. 1. An oral dosage form of PCLX-001 for use in treating cancer in a subject in need thereof, wherein said oral dosage comprises 140 mg of PCLX-001 per day.

12. 12. The oral dosage form of PCLX-001 for use according to claim 11, wherein the oral dosing provides an effect comprising a T1 / 2 of about 6 hours to about 14 hours, or about 6.7 hours to about 13.8 hours.

13. 13. The oral dosage form of PCLX-001 for use according to any one of claims 1 to 12, wherein the cancer is diffuse large B-cell lymphoma (DLBCL), and optionally the DLBCL is refractory DLBCL.

14. 14. The oral dosage form of PCLX-001 for use according to any one of claims 1 to 13, wherein the cancer is lymphoma, leukemia, myeloma, breast cancer, small cell lung cancer, non-small cell lung cancer; melanoma, adenocarcinoma, pancreatic cancer, bladder cancer, ovarian cancer, brain cancer, colon cancer, neuroblastoma, carcinoma, endometrial cancer, sarcoma, thyroid cancer, fibrosarcoma, mouth cancer, tongue cancer, nasopharyngeal cancer, laryngeal cancer, esophageal cancer, germ cell cancer, gastric cancer, hepatocellular carcinoma, biliary tract cancer, small intestine cancer, testicular cancer, epidermoid carcinoma, cervical cancer, kidney cancer, prostate cancer or pharyngeal cancer.

15. 15. The oral dosage form of PCLX-001 for use according to any one of claims 1 to 14, wherein the subject is a human.

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