Methods for treating cancer

Abstract

Methods of treating an advanced solid cancer tumor in a human in need thereof are provided. The methods comprise a treatment regimen comprising orally administering to the human 50-800 mg / day of a compound that is Compound A, Compound B, or a salt thereof. Also provided are oral formulations containing Compound A and their use for treating advanced solid cancer tumors in humans in need thereof.

Description

106265.000233METHODS FOR TREATING CANCERCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This applications claims the benefit of the priority of U.S. Provisional Patent Application No. 63 / 696,426, filed September 19, 2024, the contents of which are incorporated herein by reference.TECHNICAL FIELD

[0002] The disclosure is related to methods for treating cancer.BACKGROUND

[0003] Ataxia tel engi ectasia and rad3 -related (ATR) protein kinase is integral to the replication stress response. ATR belongs to a family of kinases, i.e., phosphatidyl inositol 3' kinase-related kinases (PIKKs), that are involved in the signaling scheme and repair of DNA damage. While other members of this family (ataxia-telangiectasia mutated (ATM) and DNA-dependent protein kinase catalytic subunit (DNA-PKcs)) are required for the repair of double strand breaks (DSBs), ATR is recruited to, and activated by, single strand DNA (ssDNA) generated at stalled replication forks or as an intermediate in the repair of DSBs. However, significant suppression of ATR activity (by more than 90%) by mutations in ATR is well tolerated by bone marrow and intestinal epithelium, the tissues that are most sensitive to traditional chemotherapeutics.

[0004] ATR inhibition is synthetically lethal in cancers with mutations that cause oncogenic stress or disruption of the DNA damage response (DDR). Genetic changes associated with cancer promote the activation of the replicative stress response and other DNA damage response (DDR) pathways. Activation of the DDR by oncogenic stress has been proposed to contribute to selection for mutation, and loss of, p53 and ATM. Mutations in the tumor suppressor p53 are found in -50% of all human cancers. Similar mutation frequencies are observed in the oncogene Myc, while significant numbers of cancers also harbor mutations in the Ras family of genes (-16%) and to a lesser degree the DDR protein ATM. Studies have found that ATR inhibition elicits synthetic lethality under each of these cancer associated conditions.

[0005] Methods for treating cancer are needed.106265.000233\4929-0640-0602.1106265.000233\4907-1676-0170.1106265.000233SUMMARY

[0006] In certain aspects, the disclosure provides methods of treating an advanced solid cancer tumor in a human in need thereof. The methods comprise a treatment regimen comprising orally administering to the human 50-800 mg / day of a compound that is Compound A, Compound B, or a salt thereof:The methods may also comprise a treatment regimen comprising orally administering to the human 50-1500 mg / day of a compound that is Compound A, Compound B, or a salt thereof:

[0007] In other aspects, the disclosure provides Compound B:106265.000233

[0008] In yet further aspects, the disclosure provides oral formulations, comprising:(i) about 45 to about 65 wt%, based on the weight of the oral formulation, of Compound A, or a salt thereof:(ii) one or more intragranular excipients; and(iii) one or more extragranular excipients.

[0009] In other aspects, the disclosure provides tablets comprising the oral formulation described herein.

[0010] In further aspects, the disclosure provides methods of treating an advanced solid cancer tumor, comprising administering the oral formulation or tablet described herein to a human in need thereof.

[0011] In still other aspects, the disclosure provides processes for preparing the oral formulation described herein.DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS

[0012] The disclosure may be more fully appreciated by reference to the following description, including the following glossary of terms and the concluding examples. It is to be appreciated that certain features of the disclosed methods which are, for clarity, described herein in the context of separate aspects, may also be provided in combination in a single aspect. Conversely, various features of the disclosed methods that are, for brevity, described in the context of a single aspect, may also be provided separately or in any subcombination.

[0013] In the following descriptions of exemplary embodiments of the present invention, all references, including publications, patent applications, and patents, cited herein are incorporated by reference into this application to the same extent as if each reference were individually and specifically indicated to be incorporated by reference and were set forth in its entirety herein.106265.000233

[0014] It will be appreciated by those skilled in the art that changes could be made to the exemplary embodiments shown and described above without departing from the broad inventive concept thereof. It is understood, therefore, that this invention is not limited to the exemplary embodiments shown and described, but it is intended to cover modifications within the spirit and scope of the present invention as defined by the claims. For example, specific features of the exemplary embodiments may or may not be part of the claimed invention and features of the disclosed embodiments may be combined. Unless specifically set forth herein, the terms “a”, “an” and “the” are not limited to one element but instead should be read as meaning “at least one”.

[0015] “Pharmaceutically acceptable” means approved or approvable by a regulatory agency of the Federal or a state government or the corresponding agency in countries other than the United States, or that is listed in the U.S. Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, and more particularly, in humans.

[0016] “Subject” as used herein refers to a mammalian animal. In some embodiments, the patient or subject is a human. In certain embodiments, the human is an adult. In other embodiments, the human is an adult of 18 years of age or older. In further embodiments, the human is a child. In yet other embodiments, the human is a child of 12 to 17 years of age. In still further embodiments, the human is 16 years of age or older and has an Eastern Cooperative Oncology Group (ECOG) performance status of 1 or less before the treatment regimen. In other embodiments, the human is 16 years of age or older and has a Karnofsky Performance Status (KPS) of 70% or greater, e.g., 70%, 80%, 90%, or 100%, before the treatment regimen. In further embodiments, the human is less than 16 years of age and has a Lansky Play -Performance Scale (LPPS) of 70% or greater, e.g., 70%, 80%, 90%, or 100%, before the treatment regimen.

[0017] As known in the art, the ECOG performance scale is the following:106265.000233See, e.g., Oken, “Toxicology and response criteria of the Eastern Cooperative Oncology Group.” Am. J. Clin. Oncol. 1982;5:649-655, which is incorporated by reference herein.

[0018] As known in the art, the KPS is an assessment tool for classification of patients as to functional impairment and is the following:106265.000233See, e.g., Crooks, “The use of the Karnofsky Performance Scale in determining outcomes and risk in geriatric outpatients,” J Gerontol. 1991, 46: M139-M144; de Haan, “Measuring quality of life in stroke,” Stroke. 1993, 24:320-327; Hollen, “Measurement of quality of life in patients with lung cancer in multicenter trials of new therapies,” Cancer, 1994, 73:2087- 2098; O'Toole, “Evaluating cancer patients for rehabilitation potential,” West J Med. 1991, 155:384-387; Oxford Textbook of Palliative Medicine, Oxford University Press, 1993;109; and Schag, “Karnofsky performance status revisited: Reliability, validity, and guidelines,” J Clin Oncology, 1984, 2: 187-193, which are incorporated by reference herein.

[0019] As known in the art, the LPPS is an assessment tool for classification of pediatric patients as to functional impairment and is the following:106265.000233See, e.g., Lansky, “The measurement of performance in childhood cancer patients,” Cancer, 1987, 60(7): 1651-6; and Klaasen, “Evaluating the Ability to Detect Change of Health- Related Quality of Life in Children With Hodgkin Disease,” Cancer, 2010, 116: 1608-14, which are incorporated by reference herein.

[0020] “Treating” or “treatment” of any disease or disorder refers, in one embodiment, to ameliorating the disease or disorder (i.e., arresting or reducing the development of the disease or at least one of the clinical symptoms thereof). In another embodiment “treating” or “treatment” refers to ameliorating at least one physical parameter, which may not be discernible by the subject. In yet another embodiment, “treating” or “treatment” refers to modulating the disease or disorder, either physically, (e.g., stabilization of a discernible symptom), physiologically, (e.g., stabilization of a physical parameter), or both. In yet another embodiment, “treating” or “treatment” refers to delaying the onset of the disease or disorder.Methods

[0021] According to the disclosure, methods of treating an advanced solid cancer tumor in a human in need thereof are provided. The methods comprise a treatment regimen comprising orally administering to the human a compound that is Compound A, Compound B, or a salt thereof:

[0022] In some embodiments, the compound is Compound A. In other embodiments, the compound is a salt of Compound A. In further embodiments, the106265.000233 compound iyet other embodiments, the compound is Compound B. In still further embodiments, the compound is a salt of Compound B. Compounds A and B may be prepared as described in, e.g., U.S. Patent No. 9,663,535, which is hereby incorporated by reference, and using skill in the art.

[0023] Salts of Compound A and Compound B also are contemplated. In some embodiments, the salt is a pharmaceutically acceptable salt. “Pharmaceutically acceptable salt” refers to a salt of a compound of the disclosure that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound. In particular, such salts are non-toxic may be inorganic or organic acid addition salts and base addition salts. Specifically, such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3 -(4- hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2 -hydroxy ethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4- toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]-oct-2-ene-l -carboxylic acid, glucoheptonic acid, 3 -phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like; or (2) salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine and the like. Salts further include, e.g., sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; and when the compound contains a basic functionality, salts of nontoxic organic or inorganic106265.000233 acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate and the like. In some embodiments, the compounds are hydrochloride (HC1) salts.

[0024] The disclosure also provide methods of treating an advanced solid cancer tumor in a human in need thereof, comprising a treatment regimen comprising orally administering to the human an oral formulation described herein that is Compound A or a salt thereof:

[0025] The treatment regimen includes administering 50-800 mg / day or 50-1500 mg / day of the compound of the disclosure. In some embodiments, the treatment regimen comprises administering 50 mg / day of the compound. In other embodiments, the treatment regimen comprises administering 100 mg / day of the compound. In further embodiments, the treatment regimen comprises administering 200 mg / day of the compound. In yet other embodiments, the treatment regimen comprises administering 300 mg / day of the compound. In still further embodiments, the treatment regimen comprises administering 350 mg / day of the compound. In other embodiments, the treatment regimen comprises administering 500 mg / day of the compound. In further embodiments, the treatment regimen comprises administering 550 mg / day of the compound. In still other embodiments, the treatment regimen comprises administering 800 mg / day of the compound. In yet further embodiments, the treatment regimen comprises administering 1100 mg / day of the compound. In other embodiments, the treatment regimen comprises administering 1300 mg / day of the compound. In further embodiments, the treatment regimen comprises administering 1500 mg / day of the compound.

[0026] The compound may be administered at a frequency determined by the attending physician. In some embodiments, the total daily amount of the compound is administered at least once a day. In other embodiments, the total daily amount of the compound is administered once a day. In further embodiments, the total daily amount of the compound is administered in divided doses. In yet other embodiments, the total daily amount of the compound is administered in two doses. In still further embodiments, the total daily amount of the compound is administered in two doses and each of the two doses comprises about half of the total daily amount of the compound. In other embodiments, the total daily amount of the compound is administered in two doses and the doses of the compound are administered about twelve hours apart.106265.000233

[0027] In some embodiments, the treatment regimen comprises administering 400 mg of the compound twice daily. In other embodiments, the treatment regimen comprises administering 550 mg of the compound twice daily. In further embodiments, the treatment regimen comprises administering 1300 mg of the compound once daily. In yet other embodiments, the treatment regimen comprises administering 1100 mg of the compound once daily. In still further embodiments, the treatment regimen comprises administering 800 mg of the compound once daily. In other embodiments, the treatment regimen comprises administering 550 mg of the compound once daily. In further embodiments, the treatment regimen comprises administering 350 mg of the compound once daily. In still other embodiments, the treatment regimen comprises administering 200 mg of the compound once daily. In yet further embodiments, the treatment regimen comprises administering 100 mg of the compound once daily. In other embodiments, the treatment regimen comprises administering 50 mg of the compound once daily. The methods permit the treatment of advanced, solid cancer tumors. In some embodiments, the advanced solid cancer tumor has a mutation. In certain embodiments, the advanced solid cancer tumor has a DDR mutation. In other embodiments, the DDR mutation is an AT -rich interactive domain-containing protein 1 A (ARID1 A). In further embodiments, the DDR mutation is ataxia telangiectasia mutated (ATM). In yet other embodiments, the DDR mutation is ataxia telangiectasia and Rad3- related kinase (ATR). In still further embodiments, the DDR mutation is breast cancer 1 gene (BRCA1). In other embodiments, the DDR mutation is breast cancer 2 gene (BRCA2). In further embodiments, the DDR mutation is cyclin El (CCNE1). In still other embodiments, the DDR mutation is cyclin K (CCNK). In yet further embodiments, the DDR mutation is cyclin dependent kinase 12 (CDK12). In other embodiments, the DDR mutation is cyclin dependent kinase inhibitor 2A (CDKN2A). In other embodiments, the DDR mutation is checkpoint kinase 1 (CHEK1). In further embodiments, the DDR mutation is checkpoint kinase 2 (CHEK2). In yet other embodiments, the DDR mutation is DnaJ heat shock protein family member C9 (DNAJC9). In still further embodiments, the DDR mutation is FA complementation group A (FANCA). In other embodiments, the DDR mutation is FA complementation group M (FANCM). In further embodiments, the DDR mutation is heterochromatin protein 1 binding protein 3 (HP1BP3). In still other embodiments, the DDR mutation is HUS1 checkpoint clamp component (HUS1). In yet further embodiments, the DDR mutation is Kirsten rat sarcoma virus (KRAS), such as G12C, G12D, G12V, G13D, and106265.000233Q61H. In other embodiments, the DDR mutation is MutL homolog 1 (MLH1). In further embodiments, the DDR mutation is MRE11 homolog. In yet other embodiments, the DDR mutation is double strand break repair nuclease (MRE11 A). In still further embodiments, the DDR mutation is MutS homolog 2 (MSH2). In other embodiments, the DDR mutation is MutS homolog 6 (MSH6). In further embodiments, the DDR mutation is methylthioadenosine phosphorylase (MTAP). In still other embodiments, the DDR mutation is myelocytomatosis oncogene (MYC). In yet further embodiments, the DDR mutation is nibrin (NBN). In other embodiments, the DDR mutation is neuronal precursor cell -expressed developmentally downregulated 4 (NEDD4). In further embodiments, the DDR mutation is partner and localizer of BRCA2 (PALB2). In yet other embodiments, the DDR mutation is poly-ADP ribose polymerase 1 (PARP1). In still further embodiments, the DDR mutation is PMS1 homolog 2, mismatch repair system component (PMS2). In other embodiments, the DDR mutation is polymerase delta 1 (POLDI). In further embodiments, the DDR mutation is DNA polymerase epsilon, catalytic subunit (POLE). In still other embodiments, the DDR mutation is protein phosphatase 2 regulatory subunit Balpha (PPP2R2A). In yet further embodiments, the DDR mutation is RAD51 recombinase (RAD51), such as RAD51C and RAC51D. In other embodiments, the DDR mutation is RB transcriptional corepressor 1 (RBI). In further embodiments, the DDR mutation is ribonuclease H2 subunit B (RNASEH2B). In yet other embodiments, the DDR mutation is replication protein Al (RPA1). In still further embodiments, the DDR mutation is SET domain containing 2, histone lysine methyltransferase (SETD2). In other embodiments, the DDR mutation is Siah E3 ubiquitin protein ligase 1 (SIAH1). In further embodiments, the DDR mutation is SWI / SNF related, matrix associated, actin dependent regulator of chromatin, subfamily A (SMARCA), such as SWI / SNF related, matrix associated, actin dependent regulator of chromatin, subfamily A, member 4 (SMARCA4). In still other embodiments, the DDR mutation is DNA topoisomerase II binding protein 1 (TOPBP1). In yet further embodiments, the DDR mutation is tumor protein p53 (TP53). In other embodiments, the DDR mutation is tumor protein, translationally-controlled 1 (TPT1). In further embodiments, the DDR mutation is ubiquitin protein ligase E3 component N-recognin 5 (UBR5). In yet other embodiments, the DDR mutation is ubiquitin specific peptidase 9 X-linked (USP9X). In still further embodiments, the DDR mutation is WRN RecQ like helicase (WRN). In other embodiments, the DDR mutation is x-ray repair cross complementing 1 (XRCC1). In further106265.000233 embodiments, the DDR mutation is x-ray repair cross complementing 2 (XRCC2). In still other embodiments, the DDR mutation is x-ray repair cross complementing 5 (XRCC5) mutation.

[0028] In some embodiments, the mutation is an AT -rich interactive domaincontaining protein 1 A (ARID 1 A). Examples of ARID 1 A mutations include, without limitation, ARID1 A missense mutation, ARID1 A nonsense mutation, ARID1 A truncating mutation, ARID 1 A frameshift mutation, ARID 1 A splicing mutation, or ARID 1 A deep deletion.

[0029] In further embodiments, the mutation is a missense mutation in KRAS at Glyl2, missense mutation in KRAS at Gly 13, or missense mutation in KRAS at Glu 12 and Gly 13.

[0030] In yet other embodiments, the mutation is a loss of function mutation (e.g., nonsense mutation, truncating mutation frameshift mutation, splicing mutation, or deep deletion), such as ataxia telangiectasia mutated (ATM), ataxia telangiectasia and Rad3 -related kinase (ATR), alpha thalassemia / mental retardation syndrome X-linked (ATRX), breast cancer 1 gene (BRCA1), breast cancer 2 gene (BRCA2), BRCA1 interacting protein C- terminal helicase 1 (BRIP1), cyclin K (CCNK), cyclin dependent kinase 12 (CDK12), cyclin dependent kinase inhibitor 2 A (CDKN2A), checkpoint kinase 2 (CHEK1), FA complementation group A (FANCA), FA complementation group C (FANCC), FA complementation group M (FANCM), heterochromatin protein 1 binding protein 3 (HP1BP3), HUS1 checkpoint clamp component (HUS1), microdystrophin construct 2 (MDC2), MutL homolog 1 (MLH1), MRE11 homolog, double strand break repair nuclease (MRE11 A), MutS homolog 2 (MSH2), MutS homolog 6 (MSH6), methylthioadenosine phosphorylase (MTAP), nibrin (NBN), neuronal precursor cell -expressed developmentally downregulated 4 (NEDD4), partner and localizer of BRCA2 (PALB2), poly-ADP ribose polymerase 1 (PARP1), PMS1 homolog 2, mismatch repair system component (PMS2), polymerase delta 1 (POLDI), DNA polymerase epsilon, catalytic subunit (POLE), protein phosphatase 2 regulatory subunit Balpha (PPP2R2A), RAD50, RAD51 recombinase (RAD51), RB transcriptional corepressor 1 (RBI), ribonuclease H2 subunit B (RNASEH2B), replication protein Al (RPA1), SET domain containing 2, histone lysine methyltransferase (SETD2), Siah E3 ubiquitin protein ligase 1 (SIAH1), SWI / SNF related, matrix associated, actin dependent regulator of chromatin, subfamily A, member 4 (SMARCA4), DNA106265.000233 topoisomerase II binding protein 1 (TOPBP1), tumor protein, translationally-controlled 1 (TPT1), ubiquitin protein ligase E3 component N-recognin 5 (UBR5), ubiquitin specific peptidase 9 X-linked (USP9X), WRN RecQ like helicase (WRN), x-ray repair cross complementing 1 (XRCC1), x-ray repair cross complementing 2 (XRCC2), or x-ray repair cross complementing 5 (XRCC5) mutation.

[0031] In other embodiments, the advanced solid cancer tumor has an amplification of myelocytomatosis oncogene (MYC), cyclin El (CCNE1), or cyclin E2 (CCNE2), or such as more than four genomic copies in total.

[0032] The advanced solid cancer tumors may be the result of any number of cancers. In some embodiments, the advanced solid cancer tumor is merkel cell carcinoma (MCC). In other embodiments, the advanced solid cancer tumor is advanced MCC. In yet other embodiments, the advanced solid cancer tumor is MCC regardless of mutation status. In further embodiments, the advanced solid cancer tumor is metastatic castration-resistant prostate cancer (mCRPC). In yet other embodiments, the advanced solid cancer tumor is endometrial cancer, such as a clear cell endometrial carcinoma. In still further embodiments, the advanced solid cancer tumor is adrenal cancer, such as an adrenocortical carcinoma. In other embodiments, the advanced solid cancer tumor is colorectal cancer, such as a sigmoid colon adenocarcinoma. In further embodiments, the advanced solid cancer tumor is pancreatic cancer, such as a pancreatic adenocarcinoma. In still other embodiments, the advanced solid cancer tumor is appendiceal cancer. In yet further embodiments, the advanced solid cancer tumor is a fallopian tube cancer. In other embodiments, the advanced solid cancer tumor is duodenal cancer. In yet other embodiments, the advanced solid cancer tumor is rectal cancer. In still further embodiments, the advanced solid cancer tumor is breast cancer, such as triple negative breast cancer (TNBC). In other embodiments, the advanced solid cancer tumor is lung cancer, such as non-small cell lung cancer (NSCLC), or such as squamous cell NSCLC. In further embodiments, the advanced solid cancer tumor is prostate cancer. In still other embodiments, the advanced solid cancer tumor is lung cancer, such as lung neuroendocrine cancer. In yet further embodiments, the advanced solid cancer tumor is ovarian cancer, such as an ovarian adenocarcinoma. In other embodiments, the advanced solid cancer tumor is colon cancer, such as a colon adenocarcinoma. In yet other embodiments, the advanced solid cancer tumor is an esophageal cancer, such as a esophageal adenocarcinoma. In other embodiments, the advanced solid cancer tumor is rectal cancer,106265.000233 such as a rectal adenocarcinoma, or a rectosigmoid adenocarcinoma. In still other embodiments, the advanced solid cancer tumor is a leiomyosarcoma. In other embodiments, the advanced solid cancer tumor is renal cancer, such as a renal cell carcinoma, optionally with sarcomatoid and rhabdoid morphologies.

[0033] Prior to the treatment regimen, the advanced solid cancer tumor was treated with another cancer therapy. The term “another cancer therapy” includes a chemotherapeutic, radiotherapy, immunotherapy, immuno-oncology, or a combination thereof. The “another cancer therapy” may depend on the specific advanced solid tumor being treated. In some embodiments, the another cancer therapy is one or more of a chemotherapeutic. In other embodiments, the another cancer therapy is one or more of a radiotherapy. The radiotherapy may include radiation therapy or a radiotherapeutic. As used herein, a “radiotherapeutic” is a chemical compound that provides radiation when administered to the human in vivo. In further embodiments, the another cancer therapy is immunotherapy. In yet other embodiments, the another cancer therapy is immuno- oncotherapy.

[0034] In certain embodiments, the another cancer therapy failed prior to the treatment regimen. As used herein, the term “failed” means that the human did not respond to treatment (also known as refractory) or initially responded to treatment but later progressed (also known as relapse).

[0035] Prior to the treatment, the human has at least one solid tumor. In some embodiments, the tumor is at least 20 mm, e.g., 20 mm, 25 mm, 30 mm, 35 mm, 40 mm, 45 mm, or 50 mm, in at least one dimension as measured by chest x-ray. In other embodiments, the tumor is at least 10 mm in at least one dimension as measured by a computerized tomography (CT) scan. In further embodiments, the tumor is at least 10 mm, e.g., 10 mm, 15 mm, 20 mm, 25 mm, 30 mm, 35 mm, 40 mm, 45 mm, or 50 mm, in at least one dimension as measured by magnetic resonance imaging (MRI). In yet other embodiments, the tumor is at least 10 mm, e.g., 10 mm, 15 mm, 20 mm, 25 mm, 30 mm, 35 mm, 40 mm, 45 mm, or 50 mm, in at least one dimension as measured by calipers by clinical exam. The attending physician would be able to select suitable chest x-ray machines, CT machines, MRI devices, or calipers for measurement of the one or more solid tumors.

[0036] In certain aspects, the human has mCRPC and radiographic disease progression prior to the treatment session, as measured by prostate cancer working group 3106265.000233(PCWG3) criteria. In some embodiments, the cancer progressed to the pelvic and / or extrapelvic region of the human. In other embodiments, the human has up to five tumors in the pelvic and / or extrapelvic region. In further embodiments, the cancer progressed to the bone of the human. In yet other embodiments, the human has new lesions and the new lesions are in the bone. In still further embodiments, the cancer progressed to one or more lymph nodes of the human. In other embodiments, the lymph node grew by 5 mm or more, e.g., 5 mm, 10 mm, 15 mm, 20 mm, 25 mm, 30 mm, 35 mm, 40 mm, 45 mm, or 50 mm, in the short axis from baseline prior to the treatment session. In further embodiments, the lymph node is 1 cm or more, e.g., 1 mm, 2 mm, 5 mm, 10 mm, 15 mm, 20 mm, 25 mm, 30 mm, 35 mm, 40 mm, 45 mm, or 50 mm, in the short axis, when measured at an earlier timepoint prior to the treatment session. In further embodiments, the cancer progressed to the one or more soft tissues. In still other embodiments, the cancer progress to one or more visceral sites of the human. In yet further embodiments, the visceral site is one or both lungs, the adrenal system, or the central nervous system. In some aspects, the visceral site is one lung. In other aspects, the visceral site is both lungs. In further aspects, the visceral site is the adrenal system, such as the pituitary gland, pineal gland, thyroid, parathyroid, thymus, pancreas, and adrenal glands. In yet other aspects, the visceral site is the central nervous system, such as the brain and the spinal cord.

[0037] The treatment regimen is correlated with a decrease in the tumor size. As such, the tumor size decreases after the treatment regimen. In some embodiments, the treatment regimen is correlated with the tumor size being less than 20 mm, e.g., about 15 mm, about 10 mm, about 5 mm, or about 1 mm, in at least one dimension as measured by chest x-ray. In other embodiments, the tumor size is less than 20 mm, e.g., about 15 mm, about 10 mm, about 5 mm, or about 1 mm, in at least one dimension as measured by chest x- ray after the treatment regimen. In further embodiments, embodiments, the treatment regimen is correlated with the tumor size being less than 10 mm, e.g., about 9 mm, about 8 mm, about 7 mm, about 6 mm, about 5 mm, about 4 mm, about 3 mm, about 2 mm, or about 1 mm, in at least one dimension as measured by CT scan. In yet other embodiments, the tumor size is less than about 10 mm, e.g., about 9 mm, about 8 mm, about 7 mm, about 6 mm, about 5 mm, about 4 mm, about 3 mm, about 2 mm, or about 1 mm, in at least one dimension as measured by CT scan after the treatment regimen. In still further embodiments, the treatment regimen is correlated with the tumor size being less than 10 mm, e.g., about 9106265.000233 mm, about 8 mm, about 7 mm, about 6 mm, about 5 mm, about 4 mm, about 3 mm, about 2 mm, or about 1 mm, in at least one dimension as measured by MRI. In other embodiments, the tumor size is less than 10 mm, e.g., about 9 mm, about 8 mm, about 7 mm, about 6 mm, about 5 mm, about 4 mm, about 3 mm, about 2 mm, or about 1 mm, in at least one dimension as measured by MRI after the treatment regimen. In further embodiments, the treatment regimen is correlated with the tumor size being less than 10 mm, e.g., about 9 mm, about 8 mm, about 7 mm, about 6 mm, about 5 mm, about 4 mm, about 3 mm, about 2 mm, or about 1 mm, in at least one dimension as measured by calipers by clinical exam. In yet other embodiments, the tumor size is less than 10 mm, e.g., about 9 mm, about 8 mm, about 7 mm, about 6 mm, about 5 mm, about 4 mm, about 3 mm, about 2 mm, or about 1 mm, in at least one dimension as measured by calipers by clinical exam after the treatment regimen. In still further embodiments, the human has mCRPC and the treatment regimen is correlated with a reduction in radiographic disease progression, as measured by PCWG3 criteria. In other embodiments, the human has mCRPC and there is a reduction in radiographic disease progression, as measured by PCWG3 criteria, after the treatment regimen.

[0038] Desirably after the treatment regimen, there is no evidence of the cancer in the humans’ pelvic region, extrapelvic region, bone, one or more lymph node, or one or more soft tissue, or any combination thereof. As used herein, the term “pelvic region” refers to the lower part of the human’s torso that is located between the abdomen and the legs. The pelvic region includes the bony pelvis, the pelvic cavity, the pelvic floor, below the pelvic cavity, and the perineum, together with the embedded skeleton. As such, the “extrapelvic region” refers to the buttock, hip (outside of the pelvic region), thigh, leg, and the extraperitoneal space of the abdomen. In some embodiments, there is no evidence of the cancer in the humans’ pelvic region after the treatment regimen. In other embodiments, there is no evidence of the cancer in the humans’ extrapelvic region after the treatment regimen. In further embodiments, there is no evidence of the cancer in the humans’ bone after the treatment regimen. In yet other embodiments, there is no evidence of the cancer in the humans’ one or more lymph node after the treatment regimen. In still further embodiments, there is no evidence of the cancer in the humans’ one or more soft tissue after the treatment regimen.

[0039] It also is desirable that the human has less than five tumors in the pelvic and / or extrapelvic region, the human less than two tumors in the bone, and / or the human’s106265.000233 lymph nodes are normal in size after the treatment regimen. In some embodiments, the human has less than five tumors, e.g., four, three, two, one, or zero, in the pelvic and / or extrapelvic region after the treatment regimen. In other embodiments, the human has less than two tumors, e.g., zero or 1, in the bone, after the treatment regimen. In further embodiments, the human’s lymph nodes are normal in size after the treatment regimen. A “normal lymph node” as described herein refers to a lymph node that is a size of about 1.5 cm or less. Thus, the treatment regimen results in lymph nodes that are about 1.5 cm or less, e.g., about 1.5 cm, about 1 cm, about 0.5 cm, or about 0.1 cm.

[0040] For humans 16 years of age or older, there is an improvement in the EGOG performance status, KPS, and / or LPPS after the treatment session. In some embodiments, humans 16 years of age or older having an Eastern Cooperative Oncology Group (ECOG) performance status of 1 or less before the treatment regimen, there is an improvement in the EGOG performance status after the treatment regimen. In other embodiments, humans 16 years of age or older having a Karnofsky Performance Status (KPS) of 70% or greater, e.g., 70%, 80%, 90%, or 100%, before the treatment regimen, there is an improvement in the KPS after the treatment regimen. In further embodiments, humans less than 16 years of age and having a Lansky Play -Performance Scale (LPPS) of 70% or greater, e.g., 70%, 80%, 90%, or 100% before the treatment regimen, there is an improvement in the LPPS after the treatment regimen.

[0041] Prior to or after the treatment regimen, the methods may further include measuring one or more serum biomarker for the cancer. In some embodiments, the cancer is prostate cancer and the serum biomarker is prostate specific antigen (PSA). In other embodiments, the cancer is ovarian cancer and the serum biomarker is cancer antigen 125 (CA-125). In further embodiments, the cancer is colorectal cancer and the serum biomarker is carcinoembryonic antigen (CEA).Compositions

[0042] Oral formulations comprising Compound A, or a salt thereof, also are provided. The oral forulations may be used in smethod of treating advanced solid cancer tumor, as described herein.

[0043] The oral formulation may about 45 to about 65 wt%, based on the weight of the oral formulation, of Compound A, or a salt thereof. In some embodiments, the oral formulation contains about 45, about 46, about 47, about 48, about 49, about 50, about 51,106265.000233 about 52, about 53, about 54, about 55, about 56, about 57, about 58, about 59, about 60, about 61, about 62, about 63, about 64, or about 65 wt%, based on the weight of the oral formulation, of Compound A, or a salt thereof. In other embodiments, the oral formulation contains about 45 to about 60 wt%, about 45 to about 55 wt%, about 45 to about 50 wt%, about 50 to about 65 wt%, about 50 to about 60 wt%, about 50 to about 55 wt%, about 55 to about 65 wt%, about 55 to about 60 wt%, or about 60 to about 65 wt%, based on the weight of the oral formulation, of Compound A, or a salt thereof.

[0044] According to the disclosure, the oral compositions comprise about 45 to about 55 mg of Compound A. In some embodiments, the oral compositions comprise about 45, about 46, about 47, about 48, about 49, about 50, about 51, about 52, about 53, about 54, or about 55 mg of Compound A. In some embodiments, the oral compositions comprise about 45 to about 50 or about 50 to about 55 of Compound A.

[0045] According to the disclosure, the oral formulations comprise one or more intragranular excipients. In some embodiments, the intragranular excipient comprises one or more of an intragranular diluent. The oral formulations comprise about 40 to about 45 wt%, based on the weight of the oral formulation, of the intragranular diluent. In some embodiments, the oral formulation contains about 40, about 41, about 42, about 43, about 44, or about 45 wt%, based on the weight of the oral formulation, of the intragranular diluent. In other embodiments, the oral formulations comprise about 40 to about 44, about 40 to about 43, about 40 to about 42, about 40 to about 41, about 41 to about 45, about 41 to about 44, about 41 to about 43, about 41 to about 42, about 42 to about 45, about 42 to about 44, about 42 to about 43, about 43 to about 45, about 43 to about 44, or about 44 to about 45 wt%, based on the weight of the oral formulation, of the intragranular diluent.

[0046] According to the disclosure, at least one intragranular diluent is microcrystalline cellulose. In some embodiments, the oral formulation contains about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, about 20, about 21, about 22, about 23, about 24, or about 25 wt%, based on the weight of the oral formulation, of the microcrystalline cellulose. In other embodiments, the oral formulation contains about 10 to about 25 wt%, based on the weight of the oral formulation, of the microcrystalline cellulose. In other embodiments, the oral formulations contain about 10 to about 23, about 10 to about 20, about 10 to about 17, about 10 to about 15, about 10 to about 13, about 13 to about 25, about 13 to about 23, about 13 to about 20, about 13 to about106265.00023317, about 13 to about 15, about 15 to about 25, about 15 to about 23, about 15 to about 20, about 15 to about 17, about 17 to about 25, about 17 to about 23, about 17 to about 20, about 20 to about 25, about 20 to about 23, about 21 to about 24, or about 22 to about 23, or about22.5 wt%, based on the weight of the oral formulation, of the microcrystalline cellulose. In further embodiments, the oral formulations contain about 22.5 wt%, based on the weight of the oral formulation, of the microcrystalline cellulose. In yet other embodiments, the oral formulations contain about 22.75 wt%, based on the weight of the oral formulation, of the microcrystalline cellulose.

[0047] According to the disclosure, at least one intragranular diluent is lactose. In some embodiments, the oral formulation contains about 10 to about 20 wt%, based on the weight of the oral formulation, of the lactose. In further embodiments, the oral formulations contains about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about18, about 19, about 20, about 21, about 22, about 23, about 24, or about 25 wt%, based on the weight of the oral formulation, of the lactose. In other embodiments, the oral formulation contains about 10 about 18, about 10 to about 17.5, about 10 to about 15, about 10 to about 13, about 10 to about 12.5, about 12.5 to about 20, about 12.5 to about 18, about 12.5 to about 17.5, about 12.5 to about 15, about 14 to about 16, about 15 to about 2, about 15 to about 18, about 15 to about 17.5, or about 17.5 to about 20 wt%, based on the weight of the oral formulation, of the lactose. In further embodiments, the oral formulation contains about 15 wt%, based on the weight of the oral formulation, of the lactose. In yet other embodiments, the lactose is spray dried.

[0048] According to the disclosure, the oral formulation contains at least one intragranular binder. In some embodiments the intragranular binder is starch. In other embodiments, the starch is pregelatinized starch. In further embodiments, the oral formulations comprise about 2.5 to about 7.5 wt%, based on the weight of the oral formulation, of the binder. In yet other embodiments, the oral formulation contains about 2.5, about 3, about 3.5, about 4, about 4.5, about 5, about 5.5, about 6, about 6.5, about 7, or about7.5 wt%, based on the weight of the oral formulation, of the binder. In still further embodiments, the oral formulations contains about 2.5 to about 7, about 2.5 to about 6, about2.5 to about 5, about 2.5 to about 4, about 2.5 to about 3, about 3 to about 7, about 3 to about 6, about 3 to about 5, about 3 to about 4, about 4 to about 7, about 4 to about 6, about 4 to about 5, about 5 to about 7, about 5 to about 6, or about 6 to about 7 wt%, based on the106265.000233 weight of the oral formulation, of the binder. In other embodiments, the oral formulations contains about 5 wt%, based on the weight of the oral formulation, of the binder.

[0049] According to the disclosure, the oral formulation contains at least one intragranular disintegrant. In some embodiments, the intragranular disintegrant is croscarmellose sodium. In other embodiments, the oral formulation contains about 1.5 to about 3.5 wt%, based on the weight of the oral formulation, of the intragranular disintegrant. In yet other embodiments, the oral composition contains about 1.5, about 1.75, about 2, about 2.25, about 2.5, about 2.75, about 3, about 3.25, or about 3.5 wt%, based on the weight of the oral formulation, of the intragranular disintegrant. In further embodiments, the oral formulation contains about 1.5 to about 3.25, about 1.5 to about 3, about 1.5 to about 2.75, about 1.5 to about 2.5, about 1.5 to about 2.25, about 1.5 to about 2, about 1.5 to about 1.75, about 1.75 to about 3.5, about 1.75 to about 3.25, about 1.75 to about 3, about 1.75 to about 2.75, about 1.75 to about 2.5, about 1.75 to about 2.25, about 1.75 to about 2, about 2 to about 3.5, about 2 to about 3, about 2 to about 2.75, about 2 to about 2.5, about 2 to about2.25, about 2.25 to about 3.5, about 2.25 to about 3.25, about 2.25 to about 3, about 2.25 to about 2.75, about 2.25 to about 2.5, about 2.5 to about 3.5, about 2.5 to about 3.25, about 2.5 to about 3, about 2.5 to about 2.75, about 2.75 to about 3.5, about 2.75 to about 3.25, about 2.75 to about 3, about 3 to about 3.5, about 3 to about 3.25, about 3.25 to about 35 wt%, based on the weight of the oral formulation, of the intragranular disintegrant . In yet other embodiments, the oral formulation contains about 2.5 wt%, based on the weight of the oral formulation, of the intragranular disintegrant.

[0050] According to the disclosure, the oral formulation contains at least one intragranular glidant. In some embodiments, the intragranular glidant is silicon dioxide. In other embodiments, the intragranular glidant is colloidal silicon dioxide. In some embodiments, the oral formulation contains about 0.25 to about 1.5 wt%, based on the weight of the oral formulation, of the intragranular glidant. In other embodiments, the oral formulation contains about 0.25, about 0.5, about 0.75, about 1, about 1.25, or about 1.5 wt%, based on the weight of the oral formulation, of the intragranular glidant. In yet other embodiments, the oral formulation contains about 0.25 to about 1.25, about 0.25 to about 1, about 0.25 to about 0.75, about 0.25 to about 0.5, or about 0.4 to about 0.6 wt%, about 0.5 to about 1.5, about 0.5 to about 1.25, about 0.5 to about 1, about 0.5 to about 0.75, about 0.75 to about 1.5, about 0.75 to about 1.25, about 0.75 to about 1, about 1 to about 1.5, about 1 to106265.000233 about 1.25, or about 1.25 to about 5 wt%, based on the weight of the oral formulation, of the intragranular glidant. In further embodiments, the oral formulation contains about 0.5%, based on the weight of the oral formulation, of the intragranular glidant.

[0051] According to the disclosure, the oral formulation contains at least one intragranular lubricant. In some embodiments, the intragranular lubricant is sodium stearyl fumarate. In some embodiments, the oral formulations contain about 0.5 to about 3 wt%, based on the weight of the oral formulation, of the intragranular lubricant. In other embodiments, the oral formulation contains 0.5, about 0.75, about 1, about 1.25, about 1.5, about 1.75, about 2, about 2.25, about 2.5, about 2.75, or about 3 wt%, based on the weight of the oral formulation, of the intragranular lubricant. In yet other embodiments, the oral formulation contains about 0.5 to about 2.5, about 0.5 to about 2, about 0.5 to about 1.5, about 0.5 to about 1, about 1 to about 3, about 1 to about 2.5, about 1 to about 2, about 1 to about 1.5, about 1.5 to about 3, about 1.5 to about 2.5, about 1.5 to about 2, about 2 to about 3, about 2 to about 2.5, or about 2.5 to about 3, based on the weight of the oral formulation, of the intragranular lubricant. In further embodiments, the oral formulation contains about 1.25 wt%, based on the weight of the oral formulation, of the intragranular lubricant. In yet other embodiments, the oral formulation contains about 1 wt%, based on the weight of the oral formulation, of the intragranular lubricant.

[0052] According to the disclosure, the oral formulation contains one or more extragranular excipients. In some embodiments, the extragranular excipient contain at least one extragranular disintegrant. In certain embodiments the extragranular disintegrant is croscarmellose sodium. In some embodiments, the oral formulation contains about 1.5 to about 3.5 wt%, based on the weight of the oral formulation, of the extragranular disintegrant. In other embodiments, the oral formulation contains about 1.5, about 1.75, about 2, about 2.25, about 2.5, about 2.75, about 3, or about 3.5 wt%, based on the weight of the oral formulation, of the extragranular disintegrant. In yet other embodiments, the oral formulation contains about 1.5 to about 3, about 1.5 to about 2.5, about 1 to about 2, about 2 to about 3.5, about 2 to about 3, about 2 to about 2.5, about 2.5 to about 3.5, about 2.5 to about 3, or about 3 to about 3.5 wt%, based on the weight of the oral formulation, of the extragranular disintegrant. In further embodiments, the oral formulation contains about 2.5 wt%, based on the weight of the oral formulation, of the extragranular disintegrant.106265.000233

[0053] According to the disclosure, the extragranular excipient contains at least one extragranular glidant. In some embodiments, the extragranular glidant is silicon dioxide. In other embodiments, the extragranular glidant is colloidal silicon dioxide. In some embodiments, the oral formulation contains about 0.05 to about 1 wt%, based on the weight of the oral formulation, of the extragranular glidant. In other embodiments, the oral formulation contains about 0.05, about 0.1, about 0.25, about 0.5, about 0.75, or about 1 wt%, based on the weight of the oral formulation, of the extragranular glidant. In yet other embodiments, the oral formulation contains about 0.05 to about 0.75, about 0.05 to about 0.5, about 0.05 to about 0.25, about 0.05 to about 0.1, about 0.1 to about 1, about 0.1 to about 0.75, about 0.1 to about 0.5, about 0.1 to about 0.25, about 0.25 to about 1, about 0.25 to about 0.5, about 0.5 to about 1, about 0.5 to about 0.75, or about 0.75 to about 1 wt%, based on the weight of the oral formulation, of the extragranular glidant. In further embodiments, the oral formulation contains about 0.25%, based on the weight of the oral formulation, of the extragranular glidant.

[0054] According to the disclosure, the extragranular excipient further comprises at least one extragranular lubricant. In some embodiments, the extragranular lubricant sodium stearyl fumarate. In other embodiments, the oral formulation contains about 0.1 to about 1 wt%, based on the weight of the oral formulation, of the extragranular lubricant. In yet other embodiments, the oral formulation contains 0.1, about 0.2, about 0.3, about 0.4, about 0.5, about 0.6, about 0.7, about 0.8, about 0.9 or about 1 wt%, based on the weight of the oral formulation, of the extragranular lubricant. In further embodiments, the oral formulation contains about 0.1 to about 0.7, about 0.1 to about 0.5, about 0.1 to about 0.25, about 0.25 to about 1, about 0.25 to about 0.75, about 0.25 to about 0.5, about 0.5 to about 1, about 0.5 to about 0.75, or about 0.75 to about 1 wt%, based on the weight of the oral formulation, of the extragranular lubricant. In yet other embodiments, the oral formulation contains about 0.5 wt%, based on the weight of the oral formulation, of the extragranular lubricant.

[0055] According to the disclosure, the oral formulation contains about 95 to about 98 wt%, based on the weight of the oral formulation, of the Compound A and intragranular excipients. In some embodiments, the oral formulation contains about 95, about 96, about 97, or about 98 wt%, based on the weight of the oral formulation, of the Compound A and intragranular excipients. In other embodiments, the oral formulation contains about 95 to about 97, about 95 to about 96, about 96 to about 98, about 96 to about 97 wt%, about 97 to106265.000233 about 98 wt%, based on the weight of the oral formulation, of the Compound A and intragranular excipients. In further embodiments, the oral formulation contains about 96.75 wt%, based on the weight of the oral formulation, of the Compound A and intragranular excipients.

[0056] According to the disclosure, the oral formulation contain about 2 to about 5 wt%, based on the weight of the oral formulation, of the extragranular excipients. In some embodiments, the oral formulation contains about 2, about 2.25, about 2.5, about 2.75, about 3, about 3.25, about 3.5, about 3.75, about 4, about 4.25, about 4.5, about 4.75, or about 5 wt%, based on the weight of the oral formulation, of the extragranular excipients. In other embodiments, the oral formulation contains about 2.5 to about 4.5, about 2.5 to about 4, about 2.5 to about 3.5, about 2.5 to about 3, about 3 to about 5, about 3 to about 4.5, about 4 to about 4, about 3 to about 3.5, about 3.5 to about 5, about 3.5 to about 4.5, about 3.5 to about 4, about 4 to about 5, about 4 to about 4.5, or about 4.5 to about 5 wt%, based on the weight of the oral formulation, of the extragranular excipients. In further embodiments, the oral formulation contains about 3.25 wt%, based on the weight of the oral formulation, of the extragranular excipients.

[0057] Tablets contain the oral formulation described herein also are provided. Suitable tablets for oral administration may be prepared using skill in the art including, without limitation, direct compression. Tablets of various sizes are contemplated.

[0058] The tablets may contain one or more coating layers. In some embodiments, the tablet contains one coating layer. Coating layers are known in the art and include enteric coatings, among others. In some embodiments, the one or more coating layers is an immediate release layer. In some embodiments, the immediate release coating is a talc / titanium dioxide-based powder that is dispersed in water or solvent. Examples of immediate release coating layers include coatings containing the Opadry® II product. In some embodiments, the tablets contain about 1 to about 5 wt%, based on the weight of the dry tablet, of the one or more coating layers. In other embodiments, the tablets contain about 1, about 1.5, about 2, about 2.5, about 3, about 3.5, about 4, about 4.5, or about 5 wt%, based on the weight of the dry tablet, of the one or more coating layers. In further embodiments, the tablets contain about 1 to about 4, about 1 to about 3, about 1 to about 2, about 2 to about 5, about 2 to about 4, about 2 to about 3, about 3 to about 5, about 3 to about 4, or about 4 to about 5 wt%, based on the weight of the dry tablet, of the one or more coating layers. In yet106265.000233 other embodiments, the tablets contain about 3 wt%, based on the weight of the dry tablet, of the one or more coating layers.

[0059] The oral formulation described herein may be preparing using well-known procedures including, without limitation, blending, compacting, milling, and / or coating steps. In some embodiments, the processes for preparing the oral formulation include (i) blending the Compound A and intragranular excipients, (ii) roller compacting the product of step (i), (iii) milling the product of step (ii) to provide granules; and (iv) blending the granules of step (iii) with the extragranular excipients. In some embodiments, the processes may include further comprising compacting the product of step (iv) to provide a tablet. In other embodiments, the processes may include coating the tablet. In further embodiments, the coating is performed by spraying a suspension comprising a polymer onto the tablet. The coating is then dried using conventional techniques. In some embodiments the polymer is hydroxypropyl methylcellulose (HPMC) or polyvinyl alcohol (PVA).Aspects

[0060] Aspect 1. A method of treating an advanced solid cancer tumor in a human in need thereof, comprising a treatment regimen comprising orally administering to the human 50-800 mg / day of a compound that is Compound A, Compound B, or a salt thereof:

[0061] Aspect 2. The method of Aspect 1, wherein the compound is compound A.

[0062] Aspect 3. The method of Aspect 1 or 2, wherein the compound is a salt of compound A.106265.000233

[0063] Aspect 4. The method of any one of Aspects 1-3, wherein the compound is

[0064] Aspect 5. The method of Aspect 1, wherein the compound is compound B.

[0065] Aspect 6. The method of any one of the preceding Aspects, comprising administering 50 mg / day of the compound

[0066] Aspect 7. The method of any one of Aspects 1-5, wherein the treatment regimen comprises administering 100 mg / day of the compound.

[0067] Aspect 8. The method of any one of Aspects 1-5, wherein the treatment regimen comprises administering 200 mg / day of the compound.

[0068] Aspect 9. The method of any one of Aspects 1-5, wherein the treatment regimen comprises administering 300 mg / day of the compound.

[0069] Aspect 10. The method of any one of Aspects 1-5, wherein the treatment regimen comprises administering 350 mg / day of the compound.

[0070] Aspect 11. The method of any one of Aspects 1-5, wherein the treatment regimen comprises administering 500 mg / day of the compound.

[0071] Aspect 12. The method of any one of Aspects 1-5, wherein the treatment regimen comprises administering 550 mg / day of the compound.

[0072] Aspect 13. The method of any one of Aspects 1-5, wherein the treatment regimen comprises administering 800 mg / day of the compound.

[0073] Aspect 14. The method of any one of the preceding Aspects, wherein the total daily amount of the compound is administered once a day.

[0074] Aspect 15. The method of any one of Aspects 1-14, wherein the total daily amount of the compound is administered in divided doses.

[0075] Aspect 16. The method of Aspect 15, wherein the total daily amount of the compound is administered in two doses.106265.000233

[0076] Aspect 17. The method of Aspect 16, wherein each of the two doses comprises about half of the total daily amount of the compound.

[0077] Aspect 18. The method of Aspect 16 or 17, wherein the doses of the compound are administered about twelve hours apart.

[0078] Aspect 19. The method of any one of the preceding Aspects, wherein the advanced solid cancer tumor has a DDR mutation.

[0079] Aspect 20. The method of Aspect 19, wherein the DDR mutation is an AT- rich interactive domain-containing protein 1 A (ARID 1 A), ataxia telangiectasia mutated (ATM), ataxia telangiectasia and Rad3-related kinase (ATR), breast cancer 1 gene (BRCA1), breast cancer 2 gene (BRCA2), cyclin El (CCNE1), cyclin K (CCNK), cyclin dependent kinase 12 (CDK12), cyclin dependent kinase inhibitor 2 A (CDKN2A), checkpoint kinase 2 (CHEK1), DnaJ heat shock protein family member C9 (DNAJC9), FA complementation group A (FANCA), FA complementation group M (FANCM), heterochromatin protein 1 binding protein 3 (HP1BP3), HUS1 checkpoint clamp component (HUS1), Kirsten rat sarcoma virus (KRAS), MutL homolog 1 (MLH1), MRE11 homolog, double strand break repair nuclease (MRE11 A), MutS homolog 2 (MSH2), MutS homolog 6 (MSH6), methylthioadenosine phosphorylase (MTAP), myelocytomatosis oncogene (MYC), nibrin (NBN), neuronal precursor cell -expressed developmentally downregulated 4 (NEDD4), partner and localizer of BRCA2 (PALB2), poly-ADP ribose polymerase 1 (PARP1), PMS1 homolog 2, mismatch repair system component (PMS2), polymerase delta 1 (POLDI), DNA polymerase epsilon, catalytic subunit (POLE), protein phosphatase 2 regulatory subunit Balpha (PPP2R2A), RAD51 recombinase (RAD51), RB transcriptional corepressor 1 (RBI), ribonuclease H2 subunit B (RNASEH2B), replication protein Al (RPA1), SET domain containing 2, histone lysine methyltransferase (SETD2), Siah E3 ubiquitin protein ligase 1 (SIAH1), SWI / SNF related, matrix associated, actin dependent regulator of chromatin, subfamily A, member 4 (SMARCA4), DNA topoisomerase II binding protein 1 (TOPBP1), tumor protein p53 (TP53), tumor protein, translationally -controlled 1 (TPT1), ubiquitin protein ligase E3 component N-recognin 5 (UBR5), ubiquitin specific peptidase 9 X-linked (USP9X), WRN RecQ like helicase (WRN), x-ray repair cross complementing 1 (XRCC1), x-ray repair cross complementing 2 (XRCC2), or x-ray repair cross complementing 5 (XRCC5) mutation.106265.000233

[0080] Aspect 21. The method of any one of the preceding Aspects, wherein the advanced solid cancer tumor is merkel cell carcinoma (MCC), such as advanced MCC.

[0081] Aspect 22. The method of any one of Aspects 1-20, wherein the advanced solid cancer tumor is metastatic castration-resistant prostate cancer (mCRPC).

[0082] Aspect 23. The method of any one of the preceding Aspects, wherein prior to the treatment regimen, the advanced solid cancer tumor was treated with another cancer therapy.

[0083] Aspect 24. The method of Aspect 23, wherein the another cancer therapy failed.

[0084] Aspect 25. The method of any one of the preceding Aspects, wherein the human has at least one solid tumor.

[0085] Aspect 26. The method of any one of the preceding Aspects, wherein, prior to the treatment regimen, the tumor is: at least 20 mm in at least one dimension as measured by chest x-ray, at least 10 mm in at least one dimension as measured by CT scan, at least 10 mm in at least one dimension as measured by MRI, and / or at least 10 mm in at least one dimension as measured by calipers by clinical exam.

[0086] Aspect 27. The method of any one of the preceding Aspects, wherein, prior to the treatment regimen, the human has mCRPC and radiographic disease progression, as measured by prostate cancer working group 3 (PCWG3) criteria.

[0087] Aspect 28. The method of Aspect 27, wherein:(a) the cancer progressed to the pelvic and / or extrapelvic region;(b) the cancer progressed to the bone;(c) the cancer progressed to one or more lymph nodes;(d) the cancer progressed to the one or more soft tissues;(e) the cancer progress to one or more visceral sites; or(f) any combination of (a)-(e).

[0088] Aspect 29. The method of Aspect 28, wherein:(a) the human has up to five tumors in the pelvic and / or extrapelvic region;(b) the human has new lesions and the new lesions are in the bone;106265.000233(c) the lymph node grew by 5 mm or more in the short axis, when compared to the size of the lymph node when measured at an earlier timepoint, and the lymph node is1 cm or more in the short axis;(d) the visceral site is one or both lungs, the adrenal system, or the central nervous system; or(e) any combination of (a)-(c).

[0089] Aspect 30. The method of any one of the preceding Aspects, wherein the human is an adult of 18 years of age or older.

[0090] Aspect 31. The method of any one of Aspects 1-29, wherein the human is a child of 12 to 17 years of age.

[0091] Aspect 32. The method of any one of Aspects 1-29, wherein the human is 16 years of age or older and has an Eastern Cooperative Oncology Group (ECOG) performance status of 1 or less before the treatment regimen.

[0092] Aspect 33. The method of Aspect 32, wherein the EGOG performance status improves after the treatment regimen.

[0093] Aspect 34. The method of any one of Aspects 1-29, wherein the human is 16 years of age or older and has a Karnofsky Performance Status (KPS) of 70% or greater before the treatment regimen.

[0094] Aspect 35. The method of Aspect 34, wherein the KPS improves after the treatment regimen.

[0095] Aspect 36. The method of any one of Aspects 1-29, wherein the human is less than 16 years of age and has a Lansky Play -Performance Scale (LPPS) of 70% or greater before the treatment regimen.

[0096] Aspect 37. The method of Aspect 32, wherein the LPPS improves after the treatment regimen.

[0097] Aspect 38. The method of any one of the preceding Aspects, further comprising measuring one or more serum biomarker for the cancer.

[0098] Aspect 39. The method of Aspect 38, wherein the cancer is prostate cancer and the serum biomarker is prostate specific antigen (PSA).

[0099] Aspect 40. The method of Aspect 38, wherein the cancer is ovarian cancer and the serum biomarker is cancer antigen 125 (CA-125).106265.000233

[0100] Aspect 41. The method of Aspect 38, wherein the cancer is colorectal cancer and the serum biomarker is carcinoembryonic antigen (CEA).

[0101] Aspect 42. The method of any one of the preceding Aspects, wherein the treatment regimen is correlated with a decrease in the tumor size.

[0102] Aspect 43. The method of Aspect 42, wherein the treatment regimen is correlated with the tumor size being less than 20 mm in at least one dimension as measured by chest x-ray, less than 10 mm in at least one dimension as measured by CT scan, less than 10 mm in at least one dimension as measured by MRI, or less than 10 mm in at least one dimension as measured by calipers by clinical exam.

[0103] Aspect 44. The method of any one of Aspects 1-12, 14-28, 33, or 34, wherein the human has mCRPC and the treatment regimen is correlated with a reduction in radiographic disease progression, as measured by PCWG3 criteria.

[0104] Aspect 45. The method of Aspect 44, wherein, after the treatment regimen, there is no evidence of the cancer in the humans’ pelvic region, extrapelvic region, bone, one or more lymph node, or one or more soft tissue, or any combination thereof.

[0105] Aspect 46. The method of Aspect 44 or 45, wherein:(a) the human has less than five tumors in the pelvic and / or extrapelvic region;(b) the human less than two tumors in the bone;(c) the lymph nodes are normal in size; or(d) any combination of (a)-(c).

[0106] Aspect 47. A compound that ia salt thereof.Aspects II106265.000233

[0107] Aspect II- 1. A method of treating an advanced solid cancer tumor in a human in need thereof, comprising a treatment regimen comprising orally administering to the human 50-1500 mg / day of a compound that is Compound A, Compound B, or a salt thereof:

[0108] Aspect II-2. The method of Aspect II- 1, wherein the compound is compound A.

[0109] Aspect II-3. The method of Aspect II-l or II-2, wherein the compound is a salt of compound A.

[0110] Aspect II-4. The method of any one of Aspects II- 1 to II-3, wherein the

[0111] Aspect II-5. The method of Aspect II-l, wherein the compound is compound B.

[0112] Aspect II-6. The method of any one of the preceding Aspects II, wherein the treatment regimen comprises administering 50 mg / day of the compound

[0113] Aspect II-7. The method of any one of Aspects II-l to II-5, wherein the treatment regimen comprises administering 100 mg / day of the compound.

[0114] Aspect II-8. The method of any one of Aspects II-l to II-5, wherein the treatment regimen comprises administering 200 mg / day of the compound.106265.000233

[0115] Aspect II-9. The method of any one of Aspects II- 1 to II-5, wherein the treatment regimen comprises administering 300 mg / day of the compound.

[0116] Aspect II- 10. The method of any one of Aspects II- 1 to II-5, wherein the treatment regimen comprises administering 350 mg / day of the compound.

[0117] Aspect II-l 1. The method of any one of Aspects II-l to II-5, wherein the treatment regimen comprises administering 500 mg / day of the compound.

[0118] Aspect 11-12. The method of any one of Aspects II-l to II-5, wherein the treatment regimen comprises administering 550 mg / day of the compound.

[0119] Aspect 11-13. The method of any one of Aspects II-l to II-5, wherein the treatment regimen comprises administering 800 mg / day of the compound.

[0120] Aspect 11-14. The method of any one of Aspects II-l to II-5, wherein the treatment regimen comprises administering 1100 mg / day of the compound.

[0121] Aspect 11-15. The method of any one of Aspects II-l to II-5, wherein the treatment regimen comprises administering 1300 mg / day of the compound.

[0122] Aspect 11-16. The method of any one of Aspects II-l to II-5, wherein the treatment regimen comprises administering 1500 mg / day of the compound.

[0123] Aspect 11-17. The method of any one of the preceding Aspects II, wherein the total daily amount of the compound is administered once a day.

[0124] Aspect 11-18. The method of any one of Aspects II-l to 11-17, wherein the total daily amount of the compound is administered in divided doses.

[0125] Aspect 11-19. The method of Aspect 11-18, wherein the total daily amount of the compound is administered in two doses.

[0126] Aspect 11-20. The method of Aspect 11-19, wherein each of the two doses comprises about half of the total daily amount of the compound.

[0127] Aspect 11-21. The method of Aspect 11-19 or 11-20, wherein the doses of the compound are administered about twelve hours apart.

[0128] Aspect 11-22. The method of any one of the preceding Aspects II, wherein the advanced solid cancer tumor has a mutation.

[0129] Aspect 11-23. The method of Aspect 11-22, wherein the mutation is an AT- rich interactive domain-containing protein 1A (ARID1A), such as a ARID1A missense mutation, ARID 1 A nonsense mutation, ARID 1 A truncating mutation, ARID 1 A frameshift mutation, ARID 1 A splicing mutation, or ARID 1 A deep deletion.106265.000233

[0130] Aspect 11-24. The method of Aspect 11-22, wherein the mutation is a missense mutation in KRAS at Glyl2, missense mutation in KRAS at Gly 13, or missense mutation in KRAS at Glu 12 and Gly 13.

[0131] Aspect 11-25. The method of Aspect 11-22, wherein the mutation is a loss of function mutation (e.g., nonsense mutation, truncating mutation frameshift mutation, splicing mutation, or deep deletion), such as ataxia telangiectasia mutated (ATM), ataxia telangiectasia and Rad3-related kinase (ATR), alpha thalassemia / mental retardation syndrome X-linked (ATRX), breast cancer 1 gene (BRCA1), breast cancer 2 gene (BRCA2), BRCA1 interacting protein C-terminal helicase 1 (BRIP1), cyclin K (CCNK), cyclin dependent kinase 12 (CDK12), cyclin dependent kinase inhibitor 2 A (CDKN2A), checkpoint kinase 2 (CHEK1), FA complementation group A (FANCA), FA complementation group C (FANCC), FA complementation group M (FANCM), heterochromatin protein 1 binding protein 3 (HP1BP3), HUS1 checkpoint clamp component (HUS1), microdystrophin construct 2 (MDC2), MutL homolog 1 (MLH1), MRE11 homolog, double strand break repair nuclease (MRE11 A), MutS homolog 2 (MSH2), MutS homolog 6 (MSH6), methylthioadenosine phosphorylase (MTAP), nibrin (NBN), neuronal precursor cell -expressed developmentally downregulated 4 (NEDD4), partner and localizer of BRCA2 (PALB2), poly-ADP ribose polymerase 1 (PARP1), PMS1 homolog 2, mismatch repair system component (PMS2), polymerase delta 1 (POLDI), DNA polymerase epsilon, catalytic subunit (POLE), protein phosphatase 2 regulatory subunit Balpha (PPP2R2A), RAD50, RAD51 recombinase (RAD51), RB transcriptional corepressor 1 (RBI), ribonuclease H2 subunit B (RNASEH2B), replication protein Al (RPA1), SET domain containing 2, histone lysine methyltransferase (SETD2), Siah E3 ubiquitin protein ligase 1 (SIAH1), SWI / SNF related, matrix associated, actin dependent regulator of chromatin, subfamily A, member 4 (SMARCA4), DNA topoisomerase II binding protein 1 (TOPBP1), tumor protein, translationally-controlled 1 (TPT1), ubiquitin protein ligase E3 component N-recognin 5 (UBR5), ubiquitin specific peptidase 9 X-linked (USP9X), WRN RecQ like helicase (WRN), x-ray repair cross complementing 1 (XRCC1), x-ray repair cross complementing 2 (XRCC2), or x-ray repair cross complementing 5 (XRCC5) mutation.

[0132] Aspect 11-26. The method of any one of Aspects 11-1 to 11-21, wherein the advanced solid cancer tumor has an amplification of myelocytomatosis oncogene (MYC),106265.000233 cyclin El (CCNE1), or cyclin E2 (CCNE2), or such as more than four genomic copies in total.

[0133] Aspect 11-27. The method of any one of the preceding Aspects II, wherein the advanced solid cancer tumor is merkel cell carcinoma (MCC), such as advanced MCC, or such as MCC regardless of mutation status.

[0134] Aspect 11-28. The method of any one of Aspects II- 1 to 11-25, wherein the advanced solid cancer tumor is metastatic castration-resistant prostate cancer (mCRPC).

[0135] Aspect 11-29. The method of any one of the preceding Aspects II, wherein prior to the treatment regimen, the advanced solid cancer tumor was treated with another cancer therapy.

[0136] Aspect 11-30. The method of Aspect 11-29, wherein the another cancer therapy failed.

[0137] Aspect II-31. The method of any one of the preceding Aspects II, wherein the human has at least one solid tumor.

[0138] Aspect 11-32. The method of any one of the preceding Aspects II, wherein, prior to the treatment regimen, the tumor is: at least 20 mm in at least one dimension as measured by chest x-ray, at least 10 mm in at least one dimension as measured by CT scan, at least 10 mm in at least one dimension as measured by MRI, and / or at least 10 mm in at least one dimension as measured by calipers by clinical exam.

[0139] Aspect 11-33. The method of any one of the preceding Aspects II, wherein, prior to the treatment regimen, the human has mCRPC and radiographic disease progression, as measured by prostate cancer working group 3 (PCWG3) criteria.

[0140] Aspect 11-34. The method of Aspect 11-33, wherein: the cancer progressed to the pelvic and / or extrapelvic region; the cancer progressed to the bone; the cancer progressed to one or more lymph nodes; the cancer progressed to the one or more soft tissues; the cancer progress to one or more visceral sites; or any combination of (a)-(e).

[0141] Aspect 11-35. The method of Aspect 11-34, wherein:(a) the human has up to five tumors in the pelvic and / or extrapelvic region;106265.000233(b) the human has new lesions and the new lesions are in the bone;(c) the lymph node grew by 5 mm or more in the short axis, when compared to the size of the lymph node when measured at an earlier timepoint, and the lymph node is 1 cm or more in the short axis;(d) the visceral site is one or both lungs, the adrenal system, or the central nervous system; or(e) any combination of (a)-(c).

[0142] Aspect 11-36. The method of any one of the preceding Aspects II, wherein the human is an adult of 18 years of age or older.

[0143] Aspect 11-37. The method of any one of Aspects II- 1 to 11-35, wherein the human is a child of 12 to 17 years of age.

[0144] Aspect 11-38. The method of any one of Aspects II- 1 to 11-35, wherein the human is 16 years of age or older and has an Eastern Cooperative Oncology Group (ECOG) performance status of 1 or less before the treatment regimen.

[0145] Aspect 11-39. The method of Aspect 11-38, wherein the EGOG performance status improves after the treatment regimen.

[0146] Aspect 11-40 The method of any one of Aspects II- 1 to 11-35, wherein the human is 16 years of age or older and has a Karnofsky Performance Status (KPS) of 70% or greater before the treatment regimen.

[0147] Aspect 11-41. The method of Aspect 11-40, wherein the KPS improves after the treatment regimen.

[0148] Aspect 11-42. The method of any one of Aspects II- 1 to 11-35, wherein the human is less than 16 years of age and has a Lansky Play -Performance Scale (LPPS) of 70% or greater before the treatment regimen.

[0149] Aspect 11-43. The method of Aspect 11-42, wherein the LPPS improves after the treatment regimen.

[0150] Aspect 11-44. The method of any one of the preceding Aspects II, further comprising measuring one or more serum biomarker for the cancer.

[0151] Aspect 11-45. The method of Aspect 11-44, wherein the cancer is prostate cancer and the serum biomarker is prostate specific antigen (PSA).

[0152] Aspect 11-46. The method of Aspect 11-44, wherein the cancer is ovarian cancer and the serum biomarker is cancer antigen 125 (CA-125).106265.000233

[0153] Aspect 11-47. The method of Aspect 11-44, wherein the cancer is colorectal cancer and the serum biomarker is carcinoembryonic antigen (CEA).

[0154] Aspect 11-48. The method of any one of the preceding Aspects II, wherein the treatment regimen is correlated with a decrease in the tumor size.

[0155] Aspect 11-49. The method of Aspect 11-48, wherein the treatment regimen is correlated with the tumor size being less than 20 mm in at least one dimension as measured by chest x-ray, less than 10 mm in at least one dimension as measured by CT scan, less than 10 mm in at least one dimension as measured by MRI, or less than 10 mm in at least one dimension as measured by calipers by clinical exam.

[0156] Aspect 11-50. The method of any one of Aspects II- 1 to 11-12, 11-17 to 11-34, 11-39, or 11-40, wherein the human has mCRPC and the treatment regimen is correlated with a reduction in radiographic disease progression, as measured by PCWG3 criteria.

[0157] Aspect II-51. The method of Aspect 11-50, wherein, after the treatment regimen, there is no evidence of the cancer in the humans’ pelvic region, extrapelvic region, bone, one or more lymph node, or one or more soft tissue, or any combination thereof.

[0158] Aspect 11-52. The method of Aspect 11-50 or 11-51, wherein:(a) the human has less than five tumors in the pelvic and / or extrapelvic region;(b) the human less than two tumors in the bone;(c) the lymph nodes are normal in size; or any combination of (a)-(c).

[0159] Aspect 11-53. A compound that ior a salt thereof.106265.000233106265.000233106265.000233106265.000233

[0160] Example 1

[0161] A. Purpose and Study Objectives

[0162] (i) Purpose

[0163] The purpose of this study is to assess the safety and efficacy of Compound A through the performance of a Phase l / 2a, open-label, safety, PK, and preliminary efficacy study of oral Compound A in patients with advanced solid tumors.

[0164] (ii) Study Objectives

[0165] Primary Objectives

[0166] The primary objectives of this study are to evaluate the safety profile of escalating doses of daily oral Compound A and to determine the maximum tolerated dose106265.000233(MTD) and recommended Phase 2 dose (RP2D) as well as to characterize the PK profile of oral Compound A and Compound B.

[0167] Secondary Objective

[0168] The secondary objective is to evaluate antitumor activity of oral Compound A in various solid tumors.

[0169] Exploratory Objective

[0170] The exploratory objective is to explore the association between mutations identified in tumor tissue and clinical outcome.

[0171] B. Investigational Plan

[0172] (i) Study Design

[0173] This Phase l / 2a study will include two Parts. Part 1 will be a dose escalation to evaluate the general safety, dose limiting toxicity (DLT), MTD, and PK of two dosing schedules of Compound A: once-daily and BID. It will include a sequential evaluation of 3-6 patients per dose level in a standard 3+3 design for 6 dose levels in the once-daily arm and for 4 dose levels in the BID arm. One treatment cycle is 28 days. The BID arm will include a daily Compound A schedule administered once in the morning and once in the evening with the total daily dose not to exceed the corresponding once-daily total daily dose. After determination of the once-daily MTD and the BID MTD in Part 1 (maximum feasible dose [MFD] is 800 mg), dose expansion (Part 2) will enroll up to an additional 30 patients in each arm (total 60 patients) at the respective R2PD.

[0174] The once-daily and BID arms will be studied independently and concurrently. Within each arm, increasing dose levels will be studied after the immediately preceding dose level has been cleared. Enrollment into the once-daily arm and BID arm will proceed as follows: After Compound A 200 mg once-daily (Level 3), enrollment of 3 patients in the Compound A 350 mg once-daily level may proceed. Then, the next 3 patients can be enrolled in the Compound A 100 mg BID level (total 200 mg daily dose). Similarly, when the 350 mg once-daily level has been approved, the next 3 patients can be enrolled in the Compound A 550 once-daily followed by 3 patients into the 150 mg BID level. When the 550 mg once-daily level has been approved, the next 3 patients can be enrolled in the Compound A 800 once-daily followed by 3 patients into the 250 mg BID level. When the 800 mg once-daily level has been approved, the once-daily arm can proceed directly to dose expansion without waiting for the BID level to be completed. When the 800 mg once-daily106265.000233 level has been approved, 3 patients can be enrolled in the Compound A 400 mg BID level (Table 1).

[0175] Given that a BID dose level cannot be started until the corresponding once- daily level has been cleared, the once-daily arm will finish dose escalation (Part 1) ahead of the BID arm. With approval, the once-daily arm can proceed to dose expansion (Part 2) without waiting for the BID arm dose escalation to be completed.

[0176] Adverse event monitoring should be continued for at least 30 days following the last dose of Compound A. In addition, all serious adverse events (SAEs), regardless of suspected causality, must be reported up until at least 30 days after the patient has stopped Compound A. Any SAEs experienced after this 30-day period should only be reported if a causal relationship to Compound A is suspected.

[0177] If a patient discontinues Compound A at any time, an end-of-treatment visit at 7 (± 7) days after the last dose of Compound A and a follow-up visit at 30 (± 14) days after the last dose of Compound A are required. For the follow-up visit, not all laboratory and AE assessments may be needed, e.g., affected by concomitant therapies. Follow-up phone calls106265.000233 will be performed approximately every 3 months after the last dose of Compound A up to 1 year.

[0178] Patients receiving clinical benefit from Compound A may continue on treatment while the study remains opens. The duration of study will depend on recruitment rates, the number of dose levels required, and the timing of patients’ participation in the study (withdrawal rates due to toxicity or progression). The end of the study will be when each patient has been followed for up to one year from his / her start of treatment, or all patients have died, been lost to follow-up or withdrawn consent; whichever occurs first.

[0179] (a) Part 1 (dose escalation)

[0180] The once-daily arm will begin with Dose level 1 and the BID arm will begin with Dose level 3. Each dose level will start with 3 patients receiving Compound A in the morning on Day 1 under fasted condition. Fasted condition is nothing by mouth for one hour before dosing and one hour after dosing; water is allowed during fasting. Patients will remain in the clinic to obtain blood samples for PK evaluation (over 8 hours) and for safety monitoring. Patients in the BID arm will go home with a single dose of Compound A to take in the evening on Day 1.

[0181] Patients will return to the clinic site on Day 2 in the morning. A predose blood sample for PK evaluation will be obtained (fasted condition) before Compound A is administered. There will be no postdose evaluation. After a 1-hour observation period and no significant side effects are observed, patients will return home with Compound A with sufficient quantity (once-daily or BID) until Day 7. Patients will take Compound A at home on Days 3 through 6, with a safety evaluation conducted by phone on Day 5. Patients will return to the clinic site on Day 7 and be administered Compound A in the morning and have predose and postdose PK evaluation (similar to Day 1). If the patient is tolerating Compound A with an acceptable level of toxicity, they will receive a sufficient quantity of Compound A to take on an outpatient basis until the next in-clinic visit. Patients will return to clinic on Days 14 and 28 (both predose PK evaluation under fasted condition) and have safety evaluation conducted by phone on Day 21.

[0182] After the DLT evaluation period (Cycle 1), patients will continue to take Compound A on an outpatient basis. For Cycle 2, patients will have in-clinic visits on Days 7 and 14 and have safety evaluation by phone on Day 21. Patients will return to clinic on Day 28 for PK evaluation (predose, fasted condition). For Cycles 3 and 4, patients will return to106265.000233 clinic on Days 14 and 28 for study assessments. Cycle 5 and onward will include a safety evaluation by phone on Day 14 and in-clinic visit on Day 28. Efficacy assessments, including SOC tumor biomarkers and Response Evaluation Criteria in Solid Tumors (RECIST] imaging or Prostate Cancer Working Group 3 (PCWG3] criteria for metastatic castrationresistant prostate cancer (mCRPC), will be obtained on Day 28 of every even-numbered cycle.

[0183] Each dose of Compound A should be taken with 240 mL (8 fluid ounces) of water at least 1 hour before a meal. For once-daily dosing, Compound A will be taken daily in the morning (± 1 hour from dose time on Day 1). For BID dosing, Compound A will be taken in the morning (± 1 hour from dose time on Day 1) and in the evening, with approximately 12 (± 1) hours between doses. After the DLT evaluation period, dose interruptions and decreases are allowed.

[0184] After the last patient in each dose level reaches Cycle 1 Day 28, cumulative safety data including DLTs, or serious adverse events (SAEs), and safety data for routine safety events will be reviewed to confirm adequate safety to proceed with dose escalation. 3 to 6 patients then will be enrolled at the 50 mg, 100 mg, 200 mg, 350 mg, 550 mg, and 800 mg total daily dose levels in the once-daily arm. The BID arm will begin with Dose level 3 (100 mg BID) after the corresponding once-daily arm (200 mg) based on total daily dose has been cleared. For Dose level 4, Compound A 350 mg once-daily must be cleared before starting Compound A 150 mg BID. For Dose level 5, Compound A 550 mg once-daily must be cleared before starting Compound A 250 mg BID. For Dose level 6, Compound A 800 mg once-daily must be cleared before starting Compound A 400 mg BID. See, Table 1.

[0185] If a DLT is experienced in any dose level, an additional 3 patients will be enrolled. If 2 patients in a dose level experience a DLT, then that group will be discontinued and the prior dose will be determined as the MTD.

[0186] The dose of Compound A may be increased (Table 1) to a dose level that is already declared to be safe in the dose escalation period of Part 1. Additional patients may be enrolled at previously cleared dose levels in order to obtain further data for PK and / or pharmacodynamic (PD) analysis. Intermediate dose levels may be explored based on emerging safety, tolerability, and PK / PD data. Additional doses and schedules may be explored based on emerging safety and PK / PD data.

[0187] (b) Part 2 (dose expansion)106265.000233

[0188] Patients with known loss of CCNC or CDK8 are not eligible for enrolment into the dose expansion

[0189] After the MTD for once-daily Compound A and MTD for BID Compound A are each determined from Part 1, up to 30 additional patients may be enrolled in each arm (total 60 patients) at the recommended phase 2 dose (R2PD). Patients will continue on 28-day cycles with safety and efficacy evaluations performed. There are no PK evaluations in dose expansion. For Cycle 1, patients will have in-clinic visits on Days 1, 7, 14, and 28 with a safety evaluation by phone on Day 21. For Cycle 2 and onward, patients will have a safety evaluation by phone on Day 14 and return to clinic on Day 28 for study assessments. Efficacy assessments, including SOC tumor biomarkers and Response Evaluation Criteria in Solid Tumors (RECIST) imaging or Prostate Cancer Working Group 3 (PCWG3) criteria for metastatic castration-resistant prostate cancer (mCRPC), will be obtained on Day 28 of every even-numbered cycle.

[0190] Patients will self-administer Compound A (once-daily or BID) on an outpatient basis. As with Part 1, each dose of Compound A should be taken with 240 mL (8 fluid ounces) of water one hour before a meal. Patients in the once-daily arm will take Compound A in the morning at approximately the same time each day. Patients in the BID arm will take Compound A once in the morning and once in the evening, approximately 12 (± 1) hours apart.

[0191] Patients can continue to receive Compound A until disease progression, unacceptable toxicity, lost to follow-up or withdrawal of consent (whichever occurs first). If a patient develops progressive disease and the Investigator determines that the patient is receiving benefit from Compound A through less rapid progression, then the patient is permitted to continue on study treatment after discussion with the Sponsor or Medical Monitor.

[0192] (c) Dose Limiting Toxicity

[0193] Part 1 Cycle 1 (Day 1-28) of both the once-daily arm and the BID arm includes a DLT evaluation period to determine the respective Compound A MTD / R2PD to be used in Part 2. A DLT is defined for any of the following events, if assessed as possibly related to study medication that occur during the defined DLT assessment period (Day 1 to 28) in the Part 1 following first dose of Compound A:• Grade 4 neutropenia lasting >7 days106265.000233• Grade 4 febrile neutropenia (ANC <l,000 / mm3with a single temperature episode of 38.3°C or a sustained temperature of 38°C for >1 hour) or Grade 3 febrile neutropenia that does not respond to optimal therapy lasting more than 3 days.• Grade 3 thrombocytopenia with clinically significant bleeding or Grade 4 thrombocytopenia on 2 separate days, or requiring a platelet transfusion on 2 separate days, within a 7-day.• Grade 4 anemia.• Grade 3 or higher non-hematologic toxicity including Grade 3 or higher nausea, vomiting, and diarrhea that continues for more than 3 days despite optimal medical management• Any death not clearly due to underlying disease or extraneous cause

[0194] Any patient who does not take at least 75% of the doses or does not complete the DLT assessment 28-day DLT assessment period for any reason other than a DLT will be considered non-evaluable for dose-escalation decisions and MTD assessment and will be replaced by an additional patient at that same dose level.

[0195] The once-daily arm and BID arm include 6 and 4 dose levels, respectively. For the once-daily arm, after 3 patients have completed the first dose level of 50 mg once- daily without a DLT, patients will be enrolled sequentially at the 100 mg, 200 mg, 350 mg, 550 mg, and 800 mg dose levels (total daily doses). For the BID arm, after 3 patients have completed the 100 mg BID dose level without a DLT, patients will be enrolled sequentially at 300 mg (150 mg BID), 500 mg (250 mg BID) and 800 mg (400 mg BID) total daily dose levels only after the corresponding once-daily dose level based on total daily dose of Compound A has been cleared.

[0196] After the last patient in each dose level of Part 1 reaches Day 28, any DLT or SAE will be reviewed to confirm adequate safety to proceed with dose escalations patients then will be sequentially enrolled in the subsequent once-daily dose levels at 50 mg, 100 mg, 200 mg, 350 mg, 550 mg, and 800 mg doses and in the BID arm at the 200 mg (100 mg BID), 300 mg (150 mg BID), 500 mg (250 mg BID), and 800 mg (400 mg BID) total daily doses.106265.000233

[0197] If a DLT is experienced in any cohort, the cohort will be expanded to six (6) subjects. If two (2) DLTs are experienced in any cohort, the study will be paused until the safety events are evaluated. The MTD will be defined as the dose level below that at which two (2) DLTs are experienced. The MTD for once-daily Compound A and the MTD for Compound A will be determined, e.g., 2 separate MTDs.

[0198] If the patient is tolerating Compound A with an acceptable level of toxicity, defined as one grade above the grade at which the patient entered the study (CTCAE v5.0) or per investigator assessment, they may continue on it after discussion with the Sponsor or Medical Monitor and according to the Schedule of Study Procedures until disease progression, unacceptable toxicity, lost to follow-up or withdrawal of consent. If a patient develops progressive disease and it is determined that the patient is benefitting from Compound A, the patient may continue on it.

[0199] (d) Dose Modifications

[0200] Patients who are enrolled in lower dose levels and tolerating Compound A with acceptable toxicity (defined as one grade above the grade at which the patient entered the study per CTCAE v5.0 may have their dose of Compound A increased, if safety is demonstrated in the dose escalation period of Part 1 of the study, and this decision is approved.

[0201] For adverse events (AEs), it should, whenever possible, be determined which medication is causing the toxicity. When the AE is considered at least possibly related to Compound A, it should be considered if a dose modification or interruption in dose (i.e., drug holiday) is appropriate. Any dose reduction / modification or interruption of study medication should be balanced by consideration of potential benefits observed in the patient. The following rules apply when modifying the dose of Compound A:• Assessment of causality must be determined.• Dose interruptions or reductions should be considered if the AE is considered as at least possibly related to Compound A.• Following implementation of a dose reduction of Compound A, the dose should not be re-escalated.• If the same AE reoccurs despite dose reduction, a second dose reduction can be implemented.

[0202] Dose Reduction Guidelines106265.000233

[0203] The guidelines below apply when assessing a dose reduction of Compound A• For any Grade 3 or higher hematologic AE, including laboratory abnormalities, discontinue Compound A until the event resolves to Grade < 2 or baseline grade for creatinine increase. If the event reoccurs after resuming therapy, discontinue Compound A until the event resolves to Grade < 2 or baseline grade for creatinine increase and reintroduce therapy with a reduction in dose by one dose level in the dose escalation scheme. If the event reoccurs, a second dose reduction is permitted.• For any Grade 3 drug-related neutropenia or Grade 3 thrombocytopenia lasting for 7 or more days, discontinue Compound A until the event resolves to Grade < 1 and reintroduce therapy with a reduction in dose by one dose level in the dose escalation scheme. If the event reoccurs, a second dose reduction is permitted.• For any Grade 3 or higher non -hematologic AE, discontinue Compound A until the event resolves to Grade < 1 and reintroduce therapy with a reduction in dose by one dose level in the dose escalation scheme. If the event reoccurs, a second dose reduction is permitted.• For any other Grade 2 intolerable drug-related AE that persists for 7 or more days, discontinue Compound A until the event resolves to Grade < 1 or baseline. If the event reoccurs after resuming therapy, reduce dose by one dose level in the dose escalation scheme. If the event reoccurs, a second dose reduction is permitted.

[0204] (e) Assessment Windows

[0205] Assessment windows are as follows: Day 7 visit ±1 day window, Days 14 to 28 visits ±2 days window, Day 28 visit ±3 days window, end of treatment visit ±7 days window, and follow-up visit ±14 days window, and follow-up phone calls approximately every 3 months up to 1 year.

[0206] (ii) Study Endpoints

[0207] (a) Primary Endpoints106265.000233

[0208] Primary endpoints include AEs, DLTs, changes in physical examinations, vital signs, Eastern Cooperative Oncology Group Performance Scale (ECOG PS), electrocardiograms (ECGs), and clinical laboratory values to evaluate the safety profile of escalating doses of daily oral Compound A as well as determine the MTD and RP2D. In addition, PK parameters will be assessed to characterize the PK profile of oral Compound A and Compound B.

[0209] (b) Secondary and Exploratory Endpoints

[0210] Secondary and exploratory endpoints include serum biomarkers, RECIST (version 1.1) response and, for subjects with metastatic Castration-Resistant Prostate Cancer (mCRPC), radiographic disease progression per PCWG3 criteria to evaluate antitumor activity of oral Compound A in various solid tumors and explore the association between mutations identified in tumor tissue and clinical outcomes. Serum biomarkers include SOC tumor markers routinely used for a patient’s tumor type (e.g., PSA for prostate cancer, CA- 125 for ovarian cancer, CEA for colorectal cancer), if the specific tumor marker is medically relevant for the patient’s care and assessment of tumor status.

[0211] C. Concomitant Medications

[0212] (i) Prior and Concomitant Medications

[0213] Prior medications are defined as medications that were taken within 30 days prior to initial dosing with study drug.

[0214] Concomitant medications are defined as medications taken any time after the start of dosing (Day 1) until the final study visit.

[0215] During the clinical trial, standard supportive care for the underlying malignancy including antihypertensive, antibiotic, antifungal, and antiemetic medications may be administered according to standard medical practice. All concomitant medications including prophylactic antibiotic therapy, anti emetics, and stimulating factors of blood components (erythropoietin, granulocyte-colony stimulating factors, platelet stimulators), or transfusions will be recorded.

[0216] (ii) Prohibited Concomitant Medications

[0217] Strong inhibitors / inducers of CYP3A4 / 5 are prohibited during treatment with Compound A and must be discontinued > 5 half-lives prior to Cycle 1 Day 1. The patient should advise if taking any agent that is known or has the potential to strongly affect106265.000233CYP3A4 / 5 isoenzymes. The following medications are prohibited, and the lists below are not comprehensive and only meant to be used as a guide.• Strong inhibitors of CYP3A4 / 5, e.g., ceritinib, clarithromycin, cobicistat, elvitegravir and ritonavir, idelalisib, indinavir and ritonavir, itraconazole, ketoconazole, lopinavir and ritonavir, nefazodone, nelfinavir, paritaprevir and ritonavir and (ombitasvir and / or dasabuvir), posacon zole, ritonavir, saquinavir and ritonavir, telithromycin, tipranavir and ritonavir, voriconazole• Strong inducers of CYP3A4 / 5, e.g., apalutamide, arbamazepine, enzalutamide, ivosidenib, lumacaftor and ivacaftor, mitotane, phenytoin, rifampin, St. John’s Wort• For strong inhibitors or strong inducers of other CYP isozymes, e.g., CYP2D6, CYP2C9, CYP2C19, CYP1 A2, their use should be discussed• Use of any other investigational medical product or systemic antineoplastic therapies is prohibited, with the exception of ongoing adjuvant treatment for prior malignancy

[0218] (iii) Concomitant Medications Requiring Caution

[0219] Concomitant use of Compound A and moderate inhibitors / inducers of CYP3A4 / 5 warrants caution as total exposure to Compound A and Compound B may be altered. In vitro, Compound A is a moderate inhibitor of the CYP3A4 / 5 isoenzyme. Therefore, caution is advised with concomitant administration of Compound A and CYP3A4 / 5 sensitive substrates with a narrow therapeutic index. Treatment should only be initiated with a plan to monitor for adverse reactions. CYP3 A-substrates with narrow therapeutic index, include, for example, warfarin, digoxin, phenytoin, theophylline, tacrolimus, atorvastatin, sildenafil, and fentanyl. This list is not comprehensive and only meant to be used as a guide. Please refer to Flockhart (https: / / www.aafp.org / pubs / afp / issues / 2007 / 0801 / p391.html).

[0220] D. Study Population

[0221] (i) Inclusion Criteria

[0222] For a patient to be eligible for this study, s / he must meet ALL of the following criteria:1. Male or female subjects 12 years of age or older106265.0002332. Patients may be enrolled with advanced solid tumor that has at least one of the following DDR mutations documented in the past medical record or confirmed during the screening period. Gene mutations in tumor tissue must be determined by a CLIA-certified NGS method (such as, e.g., FoundationOne CDx NGS assay). Liquid biopsy in lieu of tumor tissue may be used to confirm DDR mutations during screening. DDR genomic variants will be reviewed during eligibility.- ARID1A, ATM, ATR, BRCA1, BRCA2, CCNE1, CCNK, CDK12, CDKN2A, CHEK1, DNAJC9, FANCA, FANCM, HP1BP3, HUS1, KRAS, MLH1, MRE11 A, MSH2, MSH6, MTAP, MYC, NBN, NEDD4, PALB2, PARP1, PMS2, POLDI, POLE, PPP2R2A, RAD51, RBI, RNASEH2B, RPA1, SETD2, SIAH1, SMARCA4, TOPBP1, TP53, TPT1, UBR5, USP9X, WRN, XRCC1, XRCC2, XRCC5Or advanced MCC regardless of known mutation status.3. Measurable disease defined by RECIST 1.1 or, for mCRPC subjects, by PCWG3 criteria.4. Patient must have failed (demonstrated progression or intolerable safety events) at least one prior approved standard of care (SOC) therapy prior to entry into the study.5. Life expectancy > 3 months.6. Patient must be capable of oral administration of study medication and not have any clinically significant gastrointestinal abnormalities that may alter absorption.7. Signed written informed consent. Patient or legally authorized representative (LAR) has signed and dated the written informed consent, according to local guidelines, prior to the performance of any study-specific procedures, sampling, or analyses. Patient is able to comply with protocol requirements. Participants with impaired decision-making capacity must have a close caregiver or LAR present.8. If receiving corticosteroids, patient must be on a stable or decreasing dose for at least 7 days prior to Day 1.106265.0002339. Adequate bone marrow, renal, and liver function as manifested by any of the following: a. Complete blood cell count (CBC): ANC > 1,500 / mm3, platelets > 100,000 / mm3, hemoglobin > 9.0 g / dL, b. Coagulation profile with prothrombin time (PT) and international normalized ratio (INR), each < 1.5 x upper limit of normal (ULN), c. Creatinine clearance > 60 mL / min calculated by Cockcroft-Gault formula, d. Proteinuria < 200 mg by 24- hour urine collection (only required if dipstick indicates proteinuria >1+) without evidence of active sediment or clinically significant hematuria. e. Serum bilirubin < 1.5 x ULN (< 3 x ULN for liver metastases) or if Gilbert syndrome then > 1.5 x ULN with normal direct bilirubin, AST, and ALT <3 x ULN (< 5 x ULN for liver metastases).10. Corrected serum total calcium <11.5 mg / dL11. Eastern Cooperative Oncology Group (ECOG) performance status < 1 or Karnofsky Performance Status (KPS) > 70% for > 16 years old and Lansky Play- Performance Scale > 70% for < 16 years old.12. If female, is not pregnant or breastfeeding based on the following: a. a negative serum pregnancy test (B-hCG) at Screening and negative urine pregnancy test at Baseline; or b. is of nonchildbearing potential defined as clinically infertile as the result of surgical sterilization (hysterectomy, bilateral tubal ligation, and / or bilateral oophorectomy); or c. is confirmed postmenopausal status (defined as either having amenorrhea for > 12 consecutive months without another cause and documented serum follicle- stimulating hormone [FSH] level > 40 mIU / mL or another documented medical condition (e.g., was born without a uterus)), or agree to the use of highly effective contraceptive methods at screening until 45 days or 5 halflives (whichever is longer) after the last day of study drug. The following are considered highly effective contraceptive methods: hormonal oral106265.000233 contraceptives, injectables, and patches; intrauterine devices; double-barrier methods (synthetic condom, diaphragm, or cervical cap used with spermicidal foam, cream, or gel); and male partner sterilization.13. If male (with or without vasectomy), agree to the use of highly effective contraceptive methods (as listed in Criterion #10 above) at screening until 45 days or 5 half-lives (whichever is longer) after the last day of study drug.

[0223] (ii) Exclusion Criteria

[0224] Patients must NOT meet any of the following exclusion criteria to be eligible for enrollment:1. Patient has had a cytotoxic chemotherapy, immunotherapy, radiotherapy, or other targeted therapies within 4 weeks (6 weeks in cases of mitomycin C, nitrosourea, lomustine) or at least 5 half-lives (whichever is shorter, but no less than 2 weeks) before the study drug administration, and all investigated medicinal product (IMP) related AEs (excluding alopecia) have not either returned to baseline or stabilized.2. Surgical procedure performed within 7 days prior to first scheduled dose of Compound A.3. Concomitant treatment with strong inhibitors or inducers of liver metabolism.4. Known human immunodeficiency virus infection (HIV).5. Known loss of CCNC or CDK8 (dose expansion only).6. Patients with active viral or bacterial infections and / or receiving systemic antibiotics or anti-viral medications.7. Current or past diagnosis of leukemia within the past 5 years.8. Prior radiotherapy at the target lesion unless there is evidence of disease progression.9. Known CNS metastases or clinical evidence of CNS involvement that is not stable for previous 1 month by radiology documentation (magnetic resonance imaging [MRI] brain).106265.00023310. History of non-malignant gastrointestinal (GI) bleeding, gastric stress ulcerations, or peptic ulcer disease within the past 3 -months that may place the patient at risk of side effects on an anti-angiogenesis product.11. Patient has uncontrolled hypertension at time of enrollment.12. Complete left bundle branch block (LBBB), bifascicular block (right bundle branch block [RBBB] with either left anterior hemiblock or left posterior hemiblock).13. Any clinically significant ST segment and / or T-wave abnormalities.14. Presence of unstable atrial fibrillation (ventricular response rate > 100 bpm). Patients with stable atrial fibrillation are allowed in the study provided they do not meet another exclusion criteria.15. Myocardial infarction or unstable angina pectoris within 6 months prior to starting study medication.16. Congestive heart failure (New York Heart Association class III-IV).17. History of other significant cardiovascular disease or vascular disease within the last 6 months (e.g., such as hypertensive crisis, hypertensive encephalopathy, stroke, or transient ischemic attack [TIA], or significant peripheral vascular disease).18. QTcF >470 msec for male and female subjects, based on the average of three ECG measurements at the screening visit.19. Echocardiogram or multiple gated acquisition scanning (MUGA) (within 2 months) with left ventricular ejection fraction (LVEF) <50%.20. History of clinically significant glomerulonephritis, biopsy proven tubulointerstitial nephritis, crystal nephropathy, or other renal insufficiencies.21. Treatment with an investigational agent within the longest time frame of either 5 half-lives or 30 days of initiating study drug.106265.00023322. Medical illness that may impact the safety of the patient or objectives of the study. Known recreational substance use or psychiatric illness that may affect compliance with scheduled visits.23. Known hypersensitivity to Compound A or components of the formulation.24. History of clinically significant renal impairment.25. History of clinically significant liver disease, liver impairment or any other liver anomality which may affect drug metabolism.

[0225] E. Safety Assessments

[0226] Data regarding treatment-emergent AEs (TEAEs) will be collected in this study. TEAEs are events that are not present at baseline, or if present at baseline, have worsened in severity. AEs will be assessed after the first dose in Part 1 and Part 2 and continued for at least 30 days following the last dose of Compound A. In addition, all serious adverse events (SAEs), regardless of suspected causality, must be reported up until at least 30 days after the patient has stopped Compound A. Any SAEs experienced after this 30-day period should only be reported if a causal relationship to Compound A is suspected.

[0227] The following information will be recorded for each AE: description of the event, date and time of onset, date and time of resolution, severity, causal relationship to study drug, outcome, action taken with the study drug and any treatment given.

[0228] All clinically significant abnormal changes from baseline in physical examination findings, vital signs, ECGs, and laboratory evaluations will be collected, graded with regards to severity or clinical significance, assessed for causal relationship and recorded.

[0229] F. Pharmacokinetics

[0230] PK analysis will be performed for both once-daily and BID dosing. For Part 1 Cycle 1, blood samples for PK analysis will be collected (fasted condition) just prior to dosing (predose) on Cycle 1 Days 1, 2, 7, 14, and 28 (up to 60 minutes prior to dosing). PK analysis will be performed after dosing (postdose) on Cycle 1 Days 1 and 7 at 15 (± 5) min, 30 (± 5) min and 60 (± 5) min, and 2 hours (± 15 min), 4 hours (± 15 min), 6 hours (± 15 min), and 8 hours (± 15 min). During Cycle 2, PK analysis will be on Day 28 (predose, up to 60 minutes prior to dosing).106265.000233

[0231] Plasma samples will be evaluated by a validated liquid chromatography tandem mass spectrometry (LC / MS / MS) method capable of detecting Compound A and Compound B.

[0232] G. Pharmacodynamics

[0233] Standard clinical serum tumor markers routinely used for the patient’s tumor type will be measured via serum samples collected.

[0234] H. Efficacy

[0235] Tumor evaluations will include imaging scans by an appropriate technique for determination of response assessed by RECIST 1.1. For subjects with mCRPC, radiographic disease progression per PCWG3 criteria.

[0236] I. Study Visits

[0237] (i) Part 1 and Part 2 Screening Evaluations (Days -28 to -1)

[0238] Screening evaluations may be performed up to 28 days in advance of dosing but must be completed at least one (1) day prior to dosing.

[0239] Screening evaluation will include:• Medical history including solid tumor history• Confirmation of DDR mutation or MCC regardless of known mutation status• Complete physical examination• Vital signs• Height and weight• Serum B-hCG pregnancy test• Echocardiogram• Concomitant medication• 12-lead ECG (in triplicate)• Hematology, chemistry, urinalysis• aPTT, INR (incl. haptoglobin and FDPs)• HIV antibody, HbSAg, and hepatitis C antibody• ECOG PS• RECIST or PCWG3

[0240] (ii) Part 1 Evaluations (Dose Escalation Including DLT Assessment)

[0241] (a) Baseline Evaluations (Day -3 to 1)106265.000233

[0242] Baseline assessments will not be repeated if completed during the Screening period within the 72 hour window. Baseline assessments include the followings:• Targeted physical examination• Vital signs• Weight• Urine B-hCG pregnancy test (result must be available prior to dosing)• Concomitant medication• 12-lead ECG (in triplicate)• Hematology, chemistry, urinalysis (result must be available prior to dosing)• Serum biomarkers (within 7 days of first dose Day 1)• aPTT, INR (incl. haptoglobin and FDPs)• ECOG PS

[0243] In the event that a baseline assessment needs to be repeated, the entire baseline visit does not necessarily need to be repeated.

[0244] (b) DLT Assessment Period (Cycle 1 Day 1)

[0245] Predose assessments include the following:• Targeted physical examination (repeat only if clinically indicated)• 12-lead ECG (in triplicate)• Vital signs• Urine B-hCG pregnancy test (result must be available prior to dosing)• Hematology, chemistry, urinalysis (repeat only if clinically indicated)• aPTT, INR (incl. haptoglobin and FDPs)• Concomitant medications• Blood sample for PK• Medication instructions• Dispense medication diary

[0246] Compound A will be given once daily in the morning at least 1 hour prior to a meal. For patients in the once-daily arm, this is the only dose of the day. For patients in106265.000233 the BID arm, patients will self-administer the evening dose at home 12 (± 1) hours after the morning dose.

[0247] Postdose assessments include the following:• Targeted physical examination (only if clinically indicated)• Vital signs• 12-lead ECG (in triplicate)• AE and DLT assessment• Blood samples for PK

[0248] (c) DLT Assessment Period (Cycle 1 Day 2)

[0249] Patients will return to the site on Day 2 for a predose blood sample for PK (fasted condition). Assessments include the following:• Targeted physical examination• Vital signs• 12-lead ECG (in triplicate)• Blood sample for PK (predose only)• Concomitant medications• AE and DLT assessment

[0250] Compound A will be given in the morning at least 1 hour prior to a meal. For patients in the once-daily arm, this is the only dose of the day. For patients in the BID arm, patients will self-administer the evening dose at home 12 (± 1) hours after the morning dose.

[0251] (d) DLT Assessment Period (Cycle 1 Days 3 through 6)

[0252] On Days 3 through 6, patients will self-administer study drug at home (once-daily or BID). A safety evaluation phone contact will be conducted on Day 5 for:• Concomitant medications• AE and DLT assessment

[0253] (e) DLT Assessment Period (Cycle 1 Day 7)106265.000233

[0254] Patients will return to the site on Day 7 for predose (fasted condition) and postdose blood sample for PK.

[0255] Predose assessments include the following:• Targeted physical examination• Vital signs• Weight• 12-lead ECG (in triplicate)• Blood sample for PK• Concomitant medications• AE and DLT assessments• Hematology, chemistry, urinalysis• aPTT, INR (incl. haptoglobin and FDPs)

[0256] Compound A will be given once daily in the morning at least at least 1 hour prior to a meal. For patients in the once-daily arm, this is the only dose of the day. For patients in the BID arm, patients will self-administer the evening dose at home 12 (± 1) hours after the morning dose.

[0257] Postdose assessments include the following:• Targeted physical examination (only if clinically indicated)• Vital signs• 12-lead ECG (in triplicate)• AE and DLT assessments• Blood sample for PK

[0258] If Compound A is tolerated with acceptable toxicity, patients will receive a supply of Compound A to allow for dosing on an outpatient basis until the next clinic visit. Patients will self-administer Compound A at home (once-daily, BID).

[0259] (f) DLT Assessment Period (Cycle 1 Day 14)106265.000233

[0260] Patients will return to the site on Day 14 for a predose (fasted condition) blood sample for PK.

[0261] Predose assessments include the following:• Targeted physical examination• Vital signs• Weight• 12-lead ECG (in triplicate)• Blood sample for PK• Concomitant medications• AE and DLT assessments• Hematology, chemistry, urinalysis• aPTT, INR (incl. haptoglobin and FDPs)

[0262] Compound A will be given once daily in the morning at least 1 hour prior to a meal. For patients in the once-daily arm, this is the only dose for the day. For patients in the BID arm, patients will self-administer the evening dose at home 12 (± 1) hours after the morning dose.

[0263] If Compound A is tolerated with acceptable toxicity, patients will receive a supply of Compound A to allow for dosing on an outpatient basis until the next clinic visit. Patients will self-administer Compound A at home (once-daily, BID).

[0264] (g) DLT Assessment Period (Cycle 1 Day 21)

[0265] On Day 21, patients will self-administer study drug at home (once-daily or BID). A safety evaluation phone contact will be conducted on for:• Concomitant medications• AE and DLT assessment

[0266] (h) DLT Assessment Period (Cycle 1 Day 28)

[0267] Patients will return to the site on Day 28 for a predose blood sample for PK.

[0268] Predose assessments include the following:• Targeted physical examination106265.000233• Vital signs• Urine B-hCG pregnancy test (result must be available prior to dosing for next cycle)• Weight• 12-lead ECG (in triplicate)• Blood sample for PK• Concomitant medications• Medication diary (dispense for next cycle)• AE and DLT assessments• Hematology, chemistry, urinalysis• aPTT, INR (incl. haptoglobin and FDPs)• ECOG

[0269] Compound A will be given once daily in the morning at least 1 hour prior to a meal. For patients in the once-daily arm, this is the only dose for the day. For patients in the BID arm, patients will self-administer the evening dose at home 12 (± 1) hours after the morning dose.

[0270] If Compound A is tolerated with acceptable toxicity, patients will receive a supply of Compound A to allow for dosing on an outpatient basis until the next clinic visit. Patients will self-administer Compound A at home (once-daily, BID).

[0271] (i) Dose Escalation (Cycle 2 Days 7 and 14)

[0272] For subjects in the dose escalation period of this study, if the initial dose is tolerated with acceptable toxicity the subjects will receive a supply of Compound A to allow for dosing (once-daily, BID) on an outpatient until basis until the next clinic visit. 28.

[0273] The following assessments will be conducted in the clinic:• Targeted physical examination• Vital signs• Weight106265.000233• Concomitant medications• AEs• 12-lead ECG (in triplicate)• Hematology, chemistry, urinalysis• aPTT, INR (incl. haptoglobin and FDPs)

[0274] (j) Dose Escalation (Cycle 2 Day 21)

[0275] On Day 21, subjects will self-administer study drug at home (once-daily or BID). A safety evaluation phone contact will be conducted on for:• Concomitant medications• AE

[0276] (k) Dose Escalation (Cycle 2 Day 28)

[0277] Patients will return to the clinic site on Day 28 for study assessments, including a predose blood sample for PK (fasted condition). Assessments include the following:• Targeted physical examination• Vital signs• Urine B-hCG pregnancy test (result must be available prior to dosing for next cycle)• Weight• Concomitant medications• Medication diary (dispense for next cycle)• AEs• 12-lead ECG (in triplicate)• Hematology, chemistry, urinalysis• aPTT, INR (incl. haptoglobin and FDPs)• Blood sample for PK (predose only)• ECOG106265.000233• Serum biomarkers• RECIST or PCWG3

[0278] Compound A will be given in the morning at least 1 hour prior to a meal. For patients in the once-daily arm, this is the only dose of the day. For patients in the BID arm, patients will self-administer the evening dose at home 12 (± 1) hours after the morning dose.

[0279] If Compound A is tolerated with acceptable toxicity, patients will receive a supply of Compound A to allow for dosing on an outpatient basis until the next clinic visit. Patients will self-administer Compound A at home (once-daily, BID).

[0280] (1) Dose Escalation (Cycles 3 and 4, Days 14 and 28)

[0281] For subjects in the dose escalation period of this study, if the initial dose is tolerated with acceptable toxicity the subjects will receive a supply of Compound A to allow for dosing (once-daily, BID) on an outpatient until basis until the next clinic visit. The following assessments will be conducted in the clinic:• Targeted physical examination• Vital signs• Urine B-hCG pregnancy test (Day 28; result must be available prior to dosing for next cycle)• Weight• Concomitant medications• Medication diary (dispense for next cycle on Day 28)• AEs• 12-lead ECG (in triplicate)• Hematology, chemistry, urinalysis• aPTT, INR (incl. haptoglobin and FDPs)• ECOG PS (Day 28)• Serum biomarkers (Day 28 of even-numbered cycles only)106265.000233• RECIST or PCWG3 (Day 28 of even-numbered cycles only)

[0282] (m) Dose Escalation (Cycle 5 and subsequent cycles, Days 14 and 28)

[0283] On Day 14, subjects will self-administer study drug at home (once-daily or BID). A safety evaluation phone contact will be conducted on for:• Concomitant medications• AE

[0284] Patients will return to the clinic site on Day 28 for study assessments. Assessments include the following:• Targeted physical examination• Vital signs• Urine B-hCG pregnancy test (result must be available prior to dosing for next cycle)• Weight• Concomitant medications• Medication diary (dispense for next cycle)• AEs• 12-lead ECG (in triplicate)• Hematology, chemistry, urinalysis• aPTT, INR (incl. haptoglobin and FDPs)• ECOG• Serum biomarkers (even-numbered cycles only)• RECIST or PCWG3 (even-numbered cycles only)

[0285] Compound A will be given in the morning at least 1 hour prior to a meal. For patients in the once-daily arm, this is the only dose of the day. For patients in the BID arm, patients will self-administer the evening dose at home 12 (± 1) hours after the morning dose.106265.000233

[0286] If Compound A is tolerated with acceptable toxicity, patients will receive a supply of Compound A to allow for dosing on an outpatient basis until the next clinic visit. Patients will self-administer Compound A at home (once-daily, BID).

[0287] (iii) Part 2 (Dose Expansion at R2PD)

[0288] (a) Baseline Evaluations (Days -3 to 1)

[0289] Baseline assessments will not be repeated if completed during the Screening period within the 72 hour window. Baseline assessments include the followings:• Targeted physical examination• Vital signs• Weight• Urine B-hCG pregnancy test (results must be available prior to dosing)• 12-lead ECG (in triplicate)• Concomitant medication• Hematology, chemistry, urinalysis (results must be available prior to dosing)• aPTT, INR (incl. haptoglobin and FDPs)• ECOG PS• Serum biomarkers (within 7 days of first dose Day 1)

[0290] (b) Dose Expansion (Cycle 1 Days 1, 7 and 14)• Targeted physical examination• Vital signs• Weight• Concomitant medications• 12-lead ECG (in triplicate)• AEs• Hematology, chemistry, urinalysis (repeat only if clinically indicated for Day 1)• aPTT, INR (incl. haptoglobin and FDPs)• Medication instructions (Day 1)• Dispense medication diary (Day 1)

[0291] (c) Dose Expansion (Cycle 1 Day 21)106265.000233

[0292] On Day 21, subjects will self-administer study drug at home (once-daily or BID). A safety evaluation phone contact will be conducted on for:• Concomitant medications• AE

[0293] (d) Dose Expansion (Cycle 1 Day 28)

[0294] For subjects in the dose expansion period of this study, if the initial dose is tolerated with acceptable toxicity the subjects will receive a supply of Compound A to allow for dosing (once-daily, BID) on an outpatient until basis until the next clinic visit. The following assessments will be conducted in the clinic:• Targeted physical examination• Vital signs• Urine B-hCG pregnancy test (results must be available prior to dosing)• Weight• Concomitant medications• Medication diary (dispense for next cycle)• 12-lead ECG (in triplicate)• AEs• Hematology, chemistry, urinalysis• aPTT, INR (incl. haptoglobin and FDPs)• ECOG PS

[0295] (e) Dose Expansion (Cycle 2 and subsequent cycles, Days 14 and 28)

[0296] On Day 14, subjects will self-administer study drug at home (once-daily or BID). A safety evaluation phone contact will be conducted on for:• Concomitant medications• AE

[0297] Patients will return to the clinic site on Day 28 for study assessments, including the following:106265.000233• Targeted physical examination• Vital signs• Urine B-hCG pregnancy test (result must be available prior to dosing for next cycle)• Weight• Concomitant medications• Medication diary (dispense for next cycle)• AEs• 12-lead ECG (in triplicate)• Hematology, chemistry, urinalysis• aPTT, INR (incl. haptoglobin and FDPs)• Blood sample for PK (predose only)• ECOG PS• Serum biomarkers (even-numbered cycles only)• RECIST or PCWG3 (even-numbered cycles only)

[0298] (iv) Parts 1 and 2 End of Treatment Visit, Follow-up Visit and Phone Follow-up

[0299] Assessments include the followings:• Targeted physical examination• Vital signs• Weight• Concomitant medication• AEs• 12-lead ECG (in triplicate)• Hematology, chemistry, urinalysis• aPTT, INR (incl. haptoglobin and FDPs)• Serum biomarkers (end-of-treatment visit and follow-up)• ECOG PS (end-of-treatment visit and follow-up)106265.000233• RECIST or PCWG3 (end-of-treatment visit and follow-up)

[0300] A phone call to check on patient’s overall status will be performed every 3 months after the last dose of Compound A up to 1 year.

[0301] J. Product Specifications

[0302] (i) Description

[0303] Compound A is a capsule formulation that will be supplied as 50 mg and / or 100 mg hydroxypropyl methylcellulose (HPMC) capsules packed in sealed plastic bottles (n=30) and dispensed by the site pharmacist in combinations to provide the appropriate dose. Additional strengths may be available.

[0304] (ii) Administration of Study Drug

[0305] Compound A may be initially supplied as 50 mg and / or 100 mg HPMC capsules in plastic bottles (30 units each). In Part 1 (dose escalation), there will be 6 dose levels of the once-daily arm and 4 dose levels of the BID arm. In the once-daily arm, patients will be enrolled at the 50 mg, 100 mg, 200 mg, 350 mg, 550 mg, and 800 mg total daily dose levels. In the BID arm, patients will be enrolled at the 200 mg (100 mg BID), 300 mg (150 mg BID), 500 mg (250 mg to BID), and 800 mg (400 mg BID) total daily dose levels. In Part 2, up to an additional 60 patients (30 patients for each dosing arm) will be enrolled and receive Compound A at the respective R2PD.

[0306] Except for PK assessments in clinic that require fasted condition, Compound A will be taken at least 1 hour prior to a meal and with 240 mL (8 fluid ounces) of water. For once-daily dosing, Compound A will be taken daily in the morning (± 1 hour from dose time on Day 1). For BID dosing, Compound A will be taken BID, in the morning (± 1 hour from dose time on Day 1) and in the evening, with approximately 12 (± 1) hours between doses.

[0307] Regardless of dosing schedule (once-daily, BID), if a patient vomits a dose, the patient should not take a second dose that calendar day. The patient should resume daily dosing the following day. If a patient misses a dose, he / she should take the dose as soon as possible, but not more than 6 hours after the missed scheduled dose. If the dose is missed by more than 6 hours, the missed dose should be skipped, and the patient should resume daily dosing the following day.

[0308] If a patient is on once-daily dosing and misses a dose, he / she should take the dose as soon as possible, but not more than 6 hours after the missed scheduled dose. If the106265.000233 dose is missed by more than 6 hours, the missed dose should be skipped, and the patient should resume daily dosing the following day. If a patient is on BID dosing and misses a dose, he / she should take the dose as soon as possible, but not more than 4 hours after the missed scheduled dose. If the dose is missed by more than 4 hours, the missed dose should be skipped, and the patient should resume dosing at the next scheduled administration.

[0309] K. Safety Monitoring and Adverse Events

[0310] (i) Adverse Events

[0311] Data regarding TEAEs will be collected in this study. TEAEs are events that are not present at baseline, or if present at baseline, have worsened in severity. In addition to safety monitoring during active treatment, patients will be followed for 30 days after their last dose of study drug. In addition, all serious adverse events (SAEs), regardless of suspected causality, must be reported up until at least 30 days after the patient has stopped Compound A. Any SAEs experienced after this 30-day period should only be reported if a causal relationship to Compound A is suspected.

[0312] (ii) Definition of Adverse Events

[0313] AEs will be classified according to the most recent Food and Drug Administration (FDA) definitions and in a manner consistent with International Conference on Harmonization (ICH) guidelines. As such, the following definitions will be used:

[0314] AEs will be assessed for severity, relationship to study drug, and as to whether the event meets one or more of the definitions of an SAE, using the categories defined in Table 2.106265.000233

[0315] For those AEs that are not described on the CTCAE v5.0, such AEs will be graded on a 5-point scale (mild, moderate, severe) and reported. Intensity of such an AE is defined in Table 3.106265.000233

[0316] Example 2

[0317] A. Purpose and Study Objectives

[0318] (i) Purpose

[0319] The purpose of this study is to assess the safety and efficacy of Compound A through the performance of a Phase l / 2a, open-label, safety, PK, and preliminary efficacy study of oral Compound A in patients with advanced solid tumors.

[0320] (ii) Study Objectives

[0321] Primary Objectives

[0322] The primary objectives of this study are to evaluate the safety profile of escalating doses of daily oral Compound A and to determine the maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D) as well as to characterize the PK profile of oral Compound A and Compound B.

[0323] Secondary Objective

[0324] The secondary objective is to evaluate antitumor activity of oral Compound A in various solid tumors.

[0325] Exploratory Objective

[0326] The exploratory objective is to explore the association between mutations identified in tumor tissue and clinical outcome.

[0327] B. Investigational Plan

[0328] (i) Study Design

[0329] This Phase l / 2a study will include two Parts. Part 1 will be a dose escalation to evaluate the safety, dose limiting toxicity (DLT), MTD, and PK of Compound A administered once-daily (QDay) and BID. It will include a sequential evaluation of 3-6 patients per dose level in a standard 3+3 design in the once daily and BID schedules (Table106265.0002334). One treatment cycle is 28 days. The BID schedule will be initiated in Amendment 6 of this protocol at the once daily dose level being assess for safety (Table 4); other doses may be determined by the DSMC but will not exceed the total dose of the once daily dosing schedule being evaluated. Part 2 will include two independent dose expansion cohorts that will begin once the respective RP2D for the QDay and BID schedule is determined from dose escalation. Each expansion cohort (QDay and BID schedules will enroll up to an additional 30 patients at the R2PD.

[0330] The dose escalation for once daily and the BID administration will be studied independently and concurrently. Once Amendment 6 is activated, enrollment of 3 patients in the Compound A BID dosing schedule will begin at the once daily dose level being assess for safety (Table 4); other doses may be determined by the DSMC but will not exceed the total dose of the once daily dosing schedule being evaluated. For example, if the 800 mg PO QDay dose level is cleared for safety and dose level 7 (1100 mg PO QDay) is currently open for enrollment, then the BID dosing schedule will begin at 550 mg PO BID (dose level 7). If the MTD of once daily administration is determined before initiating BID dosing then the BID dosing will begin at 50% of Compound A MTD once daily dose (e.g., if the once daily MTD is 800 mg PO QDay, then BID dosing would start at 400 mg PO BID) and rounded to the nearest feasible dose based on available dosage form strengths. Enrollment of a study patient into either the once daily schedule or the BID schedule will be assigned by the Sponsor or designee.106265.000233

[0331] Adverse event monitoring should be continued for at least 30 days following the last dose of Compound A. In addition, all serious adverse events (SAEs), regardless of suspected causality, must be reported up until at least 30 days after the patient has stopped Compound A. Any SAEs experienced after this 30-day period should only be reported if a causal relationship to Compound A is suspected.

[0332] If a patient discontinues Compound A at any time, an end-of-treatment visit at 7 (± 7) days after the last dose of Compound A and a follow-up visit at 30 (± 14) days after the last dose of Compound A are required. For the follow-up visit, not all laboratory and AE assessments may be needed, e.g., affected by concomitant therapies. Follow-up phone calls will be performed approximately every 3 months after the last dose of Compound A up to 1 year.

[0333] Patients receiving clinical benefit from Compound A may continue on treatment while the study remains opens. The duration of study will depend on recruitment rates, the number of dose levels required, and the timing of patients’ participation in the study (withdrawal rates due to toxicity or progression). The end of the study will be when each patient has been followed for up to one year from his / her start of treatment, or all patients have died, been lost to follow-up or withdrawn consent; whichever occurs first.

[0334] Up to 132 patients may be enrolled in the study, including up to 72 patients (54 patients in the once daily schedule and 18 patients in the BID schedule) in dose escalation (Part 1). Dose expansion will enroll up to a total of 60 patients with up to 30 additional patients enrolled at the RP2D of each dosing schedule (QDay and BID).

[0335] Overall duration of the study will take at least 18 months depending on the rate of enrollment and number of subjects enrolled.

[0336] (a) Part 1 (dose escalation)

[0337] The once-daily arm will begin with Dose level 1 and the BID arm will begin with Dose level 7 or upon determination of the once daily MTD. Each dose level will start with 3 patients. A food effect PK study will be initiated for all patients enrolling in dose escalation starting under Version 6 of this protocol.

[0338] On Day 1, there will be PK evaluation in the fasted state; patients will be instructed to fast overnight for last least 10 hours before coming to clinic. A predose blood sample will be obtained and then Compound A will be administered. Water can be allowed as desired except for 1 hour before taking Compound A on Cycle 1 Day 1. After receiving106265.000233Compound A, patients will be monitored in the clinic to obtain blood samples for further PK evaluation (over 8 hours) and for safety monitoring. At the Investigator’s discretion, patients are allowed to return home if they tolerate Compound A with no concerns for toxicity.

[0339] Patients assigned to BID administration will be administered Compound A only once a day at their assigned dose on Cycle 1 Day 1 and 2; BID administration will begin on Cycle 1 Day 3 (e.g. a patient is assigned to 550 mg PO BID, they will receive 550 mg once on Day 1 and 2 and will begin 550 mg PO BID on C1D3 onward).

[0340] Patients will return to the clinic site on Day 2 in the morning for PK evaluation in the fed state after an overnight fast of at least 10 hours. Prior to eating a high- fat, high-calorie meal in clinic, a predose blood sample will be obtained. Thereafter, patients will eat a high-fat, high-calorie breakfast defined as having a total caloric value of 800 to 1000 calories, with approximately 50% of the caloric content from fat. An example meal would be two eggs fried in butter, two strips of bacon, two slices of toast with butter, four ounces of hash brown potatoes, and eight ounces of whole milk. Substitutions in this meal can be made as long as the meal provides a similar number of calories from protein, carbohydrate, and fat and has comparable meal volume and viscosity. Patients should start the meal 30 minutes prior to administration of Compound A. Patients should eat the meal in 25 minutes or less; Compound A should be administered 30 minutes after the start of the meal and after at least 5 minutes of rest. No additional food is allowed for at least 4 hours following Compound A dosing. After receiving Compound A, patients will be monitored in the clinic to obtain blood samples for further PK evaluation (over 8 hours) and for safety monitoring. At the Investigator’s discretion, patients are allowed to return home if they tolerate Compound A with no concerns for toxicity. Patients will return to clinic on Day 3 for PK evaluation 24-hour post-dosing on Cycle 1 Day 2. Patients assigned to BID administration will start receiving Compound A BID on Cycle 1 Day 3.

[0341] Patients will return to the clinic site on Day 8 and Day 15, and a safety evaluation will be conducted by phone on Day 22. Patients will return to clinic on Cycle 2 Day 1 for safety assessments to complete the DLT evaluation period. Extensive PK evaluation (at steady state) will also occur on Cycle 2, Day 1 in fasted state after an overnight fast of at least 10 hours, per instruction for Cycle 1 Day 1.

[0342] After the DLT evaluation period (Cycle 1), patients will continue to take Compound A on an outpatient basis. For Cycle 2, patients will have in-clinic visits on Days106265.0002331, 8, and 15. For Cycles 3 and 4, patients will return to clinic on Days 1 and 28 for study assessments. Cycle 5 and onward, patients will return to the clinic on DI for study assessments. Efficacy assessments, including SOC tumor biomarkers will be obtained on DI of every odd cycle and Response Evaluation Criteria in Solid Tumors (RECIST] imaging or Prostate Cancer Working Group 3 (PCWG3] criteria for metastatic castration-resistant prostate cancer (mCRPC), will be obtained between Day 22-28 of every even-numbered cycle.

[0343] Each dose of Compound A should be taken with 240 mL (8 fluid ounces) of water at least 1 hour before a meal, or at least 1 hour after a meal, and waiting at least 1 hour before eating again after administration. For once-daily dosing, Compound A will be taken daily in the morning. For BID dosing, Compound A will be taken in the morning and in the evening, with approximately 12 hours between doses. After the DLT evaluation period, dose interruptions and decreases are allowed.

[0344] After the last patient in each dose level reaches Cycle 21 Day 1, cumulative safety data including DLTs, or serious adverse events (SAEs), and safety data for routine safety events will be reviewed to confirm adequate safety to proceed with dose escalation. See, Table 4.

[0345] If a DLT is experienced in any dose level, an additional 3 patients will be enrolled. If 2 patients in a dose level experience a DLT, then that group will be discontinued and the prior dose will be determined as the MTD.

[0346] For patients enrolled in dose escalation, the dose of Compound A may be increased (Table 4) to a dose level that is already declared to be safe. Patients will stay in their assigned dosing schedule (QDay or BID). Additional patients may be enrolled at previously cleared dose levels in order to obtain further data for PK and / or pharmacodynamic (PD) analysis. Intermediate dose levels may be explored based on emerging safety, tolerability, and PK / PD data.

[0347] Food-effect assessment

[0348] During the dose escalation study, if a positive food-effect is observed, the DSMC may recommend transitioning to fed-state administration of Compound A. A positive food-effect is defined as follows:106265.0002331. The 90% confidence interval for the ratio of population geometric means between fed and fasted treatments, based on log-transformed data, exceeds the equivalence limits of 80 - 125% for AUCO-INF and Cmax.2. The DSMC, considering the totality of available evidence (including safety, preliminary efficacy, and pharmacodynamics), deems the transition appropriate.

[0349] If approved, the transition would proceed as follows:1. Patients would receive an estimated equivalent fed dose, calculated based on the AUCo -INF and Cmax ratios between fed and fasted states at the current cleared dose and schedule.2. Example: Example: If a 2-fold increase in exposure is observed in the fed vs. fasted state, and the 1100 mg PO QDay fasting dose is declared safe while the 1300 mg PO QDay dose level is opening for recruitment, new patients enrolled would be dosed at 650 mg PO QDay (50% of planned fasted dose) in the fed state.3. Newly enrolled patients would begin fed-state dosing on Cycle 1 Day 3, with the food-effect study continuing on Cycle 1 Days 1 and 2. This would apply to both daily and BID administrations schedules and all language for fasting administration would change to administering Compound A with a meal or up to 30 minutes after a meal starting at Cycle 1 Day 3.4. Patients on study at the time of transition to fed dosing could also be administered Compound A in the fed state at their estimated equivalent fasting to fed dose. To be eligible for the transition patients must have completed at least two cycles of treatment, have absence of clinically relevant toxicity, and after a documented discussion with the Medical Monitor.This transition would be implemented via a note to file, with a formal amendment to follow.

[0350] (b) Part 2 (dose expansion)

[0351] After completion of dose escalation (Part 1) and the MTD or maximum feasible dose for once-daily Compound A and / or the MTD or maximum feasible dose for BID Compound A are determined in dose escalation, up to 30 additional patients may be enrolled at the Compound A recommended phase 2 dose (R2PD) for each schedule (QDay or BID) in dose expansion (total of up to 60 patients). All available safety, tolerability, PK106265.000233(including food effect data), PD and preliminary efficacy data generated and available from dose escalation for each schedule will be reviewed. The Compound A RP2D and administration instructions with respect to food for each schedule (QDay or BID) to be utilized in the respective dose expansion cohorts will be conveyed to the patient.

[0352] Patients will continue on 28-day cycles with safety and efficacy evaluations performed. Extensive PK evaluation in the fasted state after an overnight fast of at least 10 hours will occur on Cycle 1 Day 1. A predose blood sample will be obtained and then Compound A will be administered. Water can be allowed as desired except for 1 hour before taking Compound A on Cycle 1 Day 1. After receiving Compound A, patients will be monitored in the clinic to obtain blood samples for further PK evaluation (over 8 hours) and for safety monitoring. At the Investigator’s discretion, patients are allowed to return home if they tolerate Compound A with no concerns for toxicity. Patients assigned to BID administration will be administered Compound A only once a day at their assigned dose on Cycle 1 Day 1; BID administration will begin on Cycle 1 Day 2 (e.g. a patient is assigned to 550 mg PO BID, they will receive 550 mg once on Day 1 and will begin 550 mg PO BID on C1D2 onward). Additional PK assessment will occur on Cycle 1, Day 2, Day 8, Day 15, and Cycle 2 Day 1.

[0353] For Cycle 1, patients will have in-clinic visits on Days 1, 8, 15, and safety evaluation by phone on Day 22. For Cycle 2, patients will have a safety evaluation and assessments in clinic on Days 1 and 15. Efficacy assessments, including SOC will be obtained on Day 1 of every odd cycle and Response Evaluation Criteria in Solid Tumors (RECIST) imaging or Prostate Cancer Working Group 3 (PCWG3) criteria for metastatic castration-resistant prostate cancer (mCRPC), will be obtained between Day 2228 of every even-numbered cycle.

[0354] Patients will self-administer Compound A (once-daily or BID) on an outpatient basis. As with Part 1, each dose of Compound A should be taken with 240 mL (8 fluid ounces) of water at least one hour before a meal, or at least one hour after a meal. Patients will be instructed to wait at least 1 hour after taking Compound A before eating again. Patients will either take Compound A once daily in the morning at approximately the same time each day or BID once in the morning and once in the evening, approximately 12 hours apart, depending on the recommended phase 2 dosing schedule.106265.000233

[0355] Patients can continue to receive Compound A until disease progression, unacceptable toxicity, lost to follow-up or withdrawal of consent (whichever occurs first). If a patient develops progressive disease and the Investigator determines that the patient is receiving benefit from Compound A through less rapid progression, then the patient is permitted to continue on study treatment after discussion with the Sponsor or Medical Monitor.

[0356] (c) Dose Limiting Toxicity

[0357] In dose escalation (Part 1) the first Cycle 1 (Day 1-28) of both the once- daily and BID schedules includes a DLT evaluation period to determine the respective Compound A MTD / R2PD to be used in Part 2 (dose expansion). A DLT is defined for any of the following events, if assessed as possibly related to study medication that occur during the defined DLT assessment period (Day 1 to 28) in dose escalation following first dose of Compound A:• Grade 4 neutropenia lasting >7 days• Grade 4 febrile neutropenia (ANC <l,000 / mm3with a single temperature episode of 38.3°C or a sustained temperature of 38°C for >1 hour) or Grade 3 febrile neutropenia that does not respond to optimal therapy lasting more than 3 days.• Grade 3 thrombocytopenia with clinically significant bleeding or Grade 4 thrombocytopenia on 2 separate days, or requiring a platelet transfusion on 2 separate days, within a 7-day.• Grade 4 anemia.• Grade 3 or 4 non-hematologic toxicity, excluding the following: Grade 3 or 4 nausea, vomiting, and / or diarrhea for less than 72 hours with adequate antiemetic and other supportive care Grade 3 or 4 increase in amylase or lipase that is not associated with symptoms or clinical manifestations of pancreatitis Grade 3 fatigue for less than 1 week106265.000233 Grade 3 or 4 electrolyte abnormality that lasts up to 72 hours, is not clinically complicated, and resolves spontaneously or responds to conventional medical interventions• Any death not clearly due to underlying disease or extraneous cause

[0358] Any patient who does not take at least 75% of the doses or does not complete 28-day DLT assessment period for any reason other than a DLT will be considered non-evaluable for dose-escalation decisions and MTD assessment and will be replaced by an additional patient at that same dose level.

[0359] After the last patient in each dose level of Part 1 (dose escalation) reaches Day 28, any DLT or SAE will be reviewed to confirm adequate safety to proceed with the next dose level escalation If a DLT is experienced in any cohort, the cohort will be expanded to six (6) subjects. If two (2) DLTs are experienced in any cohort, the study will be paused until the safety events are evaluated. The MTD will be defined as the dose level below that at which two (2) DLTs are experienced.

[0360] (d) Dose Modifications

[0361] Patients who are enrolled in lower dose levels and tolerating Compound A with acceptable toxicity (defined as one grade above the grade at which the patient entered the study per CTCAE v5.0) may have their dose of Compound A increased to the next higher dose level approved by the DSMC (i.e. no DLT in three patients).

[0362] For adverse events (AEs), it should, whenever possible, be determined which medication is causing the toxicity. When the AE is considered at least possibly related to Compound A, it should be considered if a dose modification or interruption in dose (i.e., drug holiday) is appropriate. Any dose reduction / modification or interruption of study medication should be balanced by consideration of potential benefits observed in the patient. The following rules apply when modifying the dose of Compound A:• Assessment of causality must be determined.• Dose interruptions or reductions should be considered if the AE is deemed as at least possibly related to Compound A.• Following implementation of a dose reduction of Compound A, the dose should not be increased.• If the same AE reoccurs despite dose reduction, a second dose reduction can be implemented.106265.000233• For dosing interruptions < 28 consecutive days from the last dose and there is clear benefit (e.g. stable disease, response), patient may resume Compound A.

[0363] Dose Reduction Guidelines

[0364] The guidelines below apply when assessing a dose reduction of Compound A.• For any Grade 3 or higher hematologic AE, including laboratory abnormalities, discontinue Compound A until the event resolves to Grade < 2 or baseline grade for creatinine increase. If the event reoccurs after resuming therapy, discontinue Compound A until the event resolves to Grade < 2 or baseline grade for creatinine increase and reintroduce therapy with a reduction in dose by one dose level in the dose escalation scheme. If the event reoccurs, a second dose reduction is permitted.• For any Grade 3 drug-related neutropenia or Grade 3 thrombocytopenia lasting for 7 or more days, discontinue Compound A until the event resolves to Grade < 1 and reintroduce therapy with a reduction in dose by one dose level in the dose escalation scheme. If the event reoccurs, a second dose reduction is permitted.• For any Grade 3 or higher non -hematologic AE, discontinue Compound A until the event resolves to Grade < 1 and reintroduce therapy with a reduction in dose by one dose level in the dose escalation scheme. If the event reoccurs, a second dose reduction is permitted.• For any other Grade 2 intolerable drug-related AE that persists for 7 or more days, discontinue Compound A until the event resolves to Grade < 1 or baseline. If the event reoccurs after resuming therapy, reduce dose by one dose level in the dose escalation scheme. If the event reoccurs, a second dose reduction is permitted.

[0365] (e) Assessment Windows

[0366] Assessment windows are as follows:

[0367] Day 8 visit ±1 day window,

[0368] Day 15 ±2 days window,

[0369] Day 1 visit on all cycles after Cycle 1 ±±3 days window, except for Cycle 2 Day 1, which should occur without interruption of treatment, except for safety considerations106265.000233

[0370] End of treatment visit up to 7 days after last dose of Compound A, and

[0371] Safety follow-up visit 30 days after the last dose (±14 days), and

[0372] follow-up phone calls approximately every 3 months up to 1 year.

[0373] (ii) Study Endpoints

[0374] (a) Primary Endpoints

[0375] The primary objectives of this study are to evaluate the safety profile of escalating doses of oral Compound A and to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D), and to characterize the PK profile of oral Compound A and its active metabolite Compound B.

[0376] Primary endpoints include AEs, DLTs, changes in physical examinations, vital signs, Eastern Cooperative Oncology Group Performance Scale (ECOG PS), electrocardiograms (ECGs), and clinical laboratory values to evaluate the safety profile of escalating doses of daily oral Compound A as well as determine the MTD and RP2D, and comparison of Compound A PK characteristics in the fasted and fed state.

[0377] (b) Secondary and Exploratory Endpoints

[0378] The secondary endpoint is to evaluate antitumor activity of oral Compound A in various solid tumors. Endpoints include serum biomarkers and RECIST (version 1.1) response and, for subjects with metastatic Castration-Resistant Prostate Cancer (mCRPC), radiographic disease progression per PCWG3 criteria to evaluate antitumor activity of oral Compound A in various solid tumors. Serum biomarkers include SOC tumor markers routinely used for a patient’s tumor type (e.g., PSA for prostate cancer, CA-125 for ovarian cancer, CEA for colorectal cancer), if the specific tumor marker is medically relevant for the patient’s care and assessment of tumor status.

[1000] Exploratory Objective and EndpointsThe exploratory objective is the association between mutations identified in tumor tissue and clinical outcome.

[0379] C. Concomitant Medications

[0380] (i) Prior and Concomitant Medications

[0381] Prior medications are defined as medications that were taken within 30 days prior to initial dosing with study drug.

[0382] Concomitant medications are defined as medications taken any time after the start of dosing (Day 1) until the follow-up visit.106265.000233

[0383] During the clinical trial, standard supportive care for the underlying malignancy including antihypertensive, antibiotic, antifungal, and antiemetic medications may be administered according to standard medical practice. All concomitant medications including prophylactic antibiotic therapy, anti emetics, and stimulating factors of blood components (erythropoietin, granulocyte-colony stimulating factors, platelet stimulators), or transfusions will be recorded.

[0384] Patients with prostate cancer may remain on luteinizing hormone releasing hormone (LHRH) agonists or antagonists. Patients with prior history of hormone positive breast cancer may remain on endocrine therapy, as long as it is not the disease under study.

[0385] (ii) Prohibited Concomitant Medications

[0386] Strong inhibitors / inducers of CYP3A4 / 5 are prohibited during treatment with Compound A and must be discontinued > 5 half-lives prior to Cycle 1 Day 1. The patient should advise if taking any agent that is known or has the potential to strongly affect CYP isoenzymes. The following medications are prohibited, and the lists below are not comprehensive and only meant to be used as a guide.• Strong inhibitors of CYP3A4 / 5, e.g., ceritinib, clarithromycin, cobicistat, elvitegravir and ritonavir, idelalisib, indinavir and ritonavir, itraconazole, ketoconazole, lopinavir and ritonavir, nefazodone, nelfinavir, paritaprevir and ritonavir and (ombitasvir and / or dasabuvir), posaconazole, ritonavir, saquinavir and ritonavir, telithromycin, tipranavir and ritonavir, voriconazole• Strong inducers of CYP3A4 / 5, e.g., apalutamide, carbamazepine, enzalutamide, ivosidenib, lumacaftor and ivacaftor, mitotane, phenytoin, rifampin, St. John’s Wort• For strong inhibitors or strong inducers of other CYP isozymes, e.g., CYP2D6, CYP2C9, CYP2C19, CYP1 A2, their use should be discussed• Use of any other investigational medical product or systemic antineoplastic therapies is prohibited, with the exception of ongoing adjuvant treatment for prior malignancy

[0387] (iii) Concomitant Medications Requiring Caution

[0388] Concomitant use of Compound A and moderate inhibitors / inducers of CYP3A4 / 5 warrants caution as total exposure to Compound A and Compound B may be altered. In vitro, Compound A is a moderate inhibitor of the CYP3A4 / 5 isoenzyme.106265.000233Therefore, caution is advised with concomitant administration of Compound A and CYP3A4 / 5 sensitive substrates with a narrow therapeutic index. Treatment should only be initiated with a plan to monitor for adverse reactions. CYP3 A-substrates with narrow therapeutic index, include, for example, warfarin, digoxin, phenytoin, theophylline, tacrolimus, atorvastatin, sildenafil, and fentanyl. This list is not comprehensive and only meant to be used as a guide. Please refer to Flockhart (https: / / www.aafp.org / pubs / afp / issues / 2007 / 0801 / p391.html) and FDA table of example substrates, inhibitors, and inducers (https: / / www.fda.gov / drugs / drug-interactions- labeling / drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers).

[0389] D. Study Population

[0390] (i) Inclusion Criteria

[0391] For a patient to be eligible for this study, s / he must meet ALL of the following criteria:14. 12 years of age or older15. Patients may be enrolled with advanced solid tumor that has at least one of the following DDR mutations documented in the past medical record or confirmed during the screening period. Gene mutations in tumor tissue must be determined by a CLIA-certified NGS method (such as, e.g., FoundationOne CDx NGS assay). Liquid biopsy in lieu of tumor tissue may be used to confirm DDR mutations during screening. Eligible patients must have documented presence of at least one of the following:Any mutation in ARID1 A, including but not limited to missense mutations, nonsense mutations, truncating mutations, frameshift mutations, splicing mutations, and deep deletions.Any missense mutation in KRAS at Glyl2 and / or Gly 13.- Probable loss of function mutations (including nonsense mutations, truncating mutations, frameshift mutations, splicing mutations, and deep deletions) in ATM, ATR, ATRX, BRCA1, BRCA2, BRIP1, CCNK, CDK12, CDKN2A, CHEK1, EZH2, FANCA, FANCC, FANCM, HP1BP3, HUS1, MDC1, MLH1, MRE11 A, MSH2, MSH6, MTAP, NBN, NEDD4, PALB2, PARP1, PMS2, POLDI, POLE, PPP2R2A, RAD50, RAD51, RAD51B, RBI,106265.000233RNASEH2B, RPA1, SETD2, SIAH1, SMARCA2, SMARCA4, TOPBP 1, TPT1, UBR5, USP9X, WRN, XRCC1, XRCC2, or XRCC5Amplification (>4 genomic copies in total) of MYC, CCNE1 or CCNE2. Patients with advanced Merkel cell carcinoma (MCC) are eligible for both dose escalation and dose expansion regardless of known mutation status.16. Measurable disease defined by RECIST 1.1 or, for mCRPC subjects, by PCWG3 criteria.17. Patient must have failed (demonstrated progression or intolerable safety events) at least one prior approved standard of care (SOC) therapy prior to entry into the study.18. Life expectancy > 3 months.19. Patient must be capable of oral administration of study medication and not have any clinically significant gastrointestinal abnormalities that may alter absorption.20. Signed written informed consent. Patient or legally authorized representative (LAR) has signed and dated the written informed consent, according to local guidelines, prior to the performance of any study-specific procedures, sampling, or analyses. Patient is able to comply with protocol requirements. Participants with impaired decision-making capacity must have a close caregiver or LAR present.21. If receiving corticosteroids, patient must be on a stable or decreasing dose for at least 7 days prior to Day 1.22. Adequate bone marrow, renal, and liver function as manifested by any of the following: f. Complete blood cell count (CBC): ANC > 1,500 / mm3, platelets > 100,000 / mm3, and hemoglobin > 9.0 g / dL, g. Coagulation profile with prothrombin time (PT) and international normalized ratio (INR), each < 1.5 x upper limit of normal (ULN). Patients with stable prophylactic anticoagulant therapy and PT and / or INR > 1.5 x ULN, but within the intended therapeutic range, may be approved,106265.000233 h. Creatinine clearance > 50 mL / min calculated by Cockcroft-Gault formula, i. Serum bilirubin < 1.5 x ULN (< 3 x ULN for liver metastases) or if Gilbert syndrome then > 1.5 x ULN with normal direct bilirubin, AST and ALT <3 x ULN (< 5 x ULN for liver metastases).23. Corrected serum total calcium <11.5 mg / dL24. Eastern Cooperative Oncology Group (ECOG) performance status < 1 or Karnofsky Performance Status (KPS) > 70% for > 16 years old and Lansky Play- Performance Scale > 70% for < 16 years old.25. If female, is not pregnant or breastfeeding based on the following: d. a negative serum pregnancy test (B-hCG) at Screening and negative urine or serum pregnancy test at Baseline; or e. is of nonchildbearing potential defined as clinically infertile as the result of surgical sterilization (hysterectomy, bilateral tubal ligation, and / or bilateral oophorectomy); or f. is confirmed postmenopausal status (defined as either having amenorrhea for > 12 consecutive months without another cause and documented serum follicle- stimulating hormone [FSH] level > 40 mIU / mL or another documented medical condition (e.g., was born without a uterus)), or agree to the use of highly effective contraceptive methods at screening until 45 days or 5 halflives (whichever is longer) after the last day of study drug. The following are considered highly effective contraceptive methods: hormonal oral contraceptives, injectables, and patches; intrauterine devices; double-barrier methods (synthetic condom, diaphragm, or cervical cap used with spermicidal foam, cream, or gel); and male partner sterilization.26. If male (with or without vasectomy), agree to the use of highly effective contraceptive methods (as listed in Criterion #10 above) at screening until 45 days or 5 half-lives (whichever is longer) after the last day of study drug.

[0392] (ii) Exclusion Criteria106265.000233

[0393] Patients must NOT meet any of the following exclusion criteria to be eligible for enrollment:26. Known loss of function mutation in CCNC or CDK8.27. Cytotoxic chemotherapy, immunotherapy, radiotherapy, or other targeted therapies within 4 weeks (6 weeks in cases of mitomycin C, nitrosourea, lomustine) or at least 5 half-lives (whichever is shorter, but no less than 2 weeks) before the study drug administration, and all treatment-related AEs (excluding alopecia) have not either returned to baseline or stabilized. Patients with prostate cancer may remain on luteinizing hormone releasing hormone (LHRH) agonists or antagonists. Patients with prior history of hormone positive breast cancer or prostate cancer may remain on adjuvant endocrine therapy, as long as it is not the disease under study.28. Have a known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma or squamous cell carcinoma of the skin that has undergone potentially curative therapy, in situ cervical cancer, ductal carcinoma in situ, incidentally discovered asymptomatic thyroid cancer, and a previous diagnosis of malignancy that has shown no evidence of disease progression for 5 years or longer.29. Surgical procedure performed within 7 days prior to first scheduled dose of Compound A.30. Concomitant treatment with strong inhibitors or inducers of liver metabolism.31. Known human immunodeficiency virus infection (HIV).32. Patients with active viral or bacterial infections and / or receiving systemic antibiotics or anti-viral medications.33. Current or past diagnosis of leukemia within the past 5 years.34. Prior radiotherapy at the target lesion unless there is evidence of disease progression.106265.00023335. Known CNS metastases or clinical evidence of CNS involvement that is not stable for previous 1 month by radiology documentation (magnetic resonance imaging [MRI] brain).36. History of non-malignant gastrointestinal (GI) bleeding, gastric stress ulcerations, or peptic ulcer disease within the past 3 -months that may place the patient at risk of side effects on an anti-angiogenesis product.37. Patient has uncontrolled hypertension at time of enrollment.38. Complete left bundle branch block (LBBB), bifascicular block (right bundle branch block [RBBB] with either left anterior hemiblock or left posterior hemiblock).39. Any clinically significant ST segment and / or T-wave abnormalities.40. Presence of unstable atrial fibrillation (ventricular response rate > 100 bpm). Patients with stable atrial fibrillation are allowed in the study provided they do not meet another exclusion criteria.41. Myocardial infarction or unstable angina pectoris within 6 months prior to starting study medication.42. Congestive heart failure (New York Heart Association class III-IV).43. History of other significant cardiovascular disease or vascular disease within the last 6 months (e.g., such as hypertensive crisis, hypertensive encephalopathy, stroke, or transient ischemic attack [TIA], or significant peripheral vascular disease).44. QTcF >470 msec for male and female patients, based on the average of three ECG measurements at the screening visit.45. Echocardiogram or multiple gated acquisition scanning (MUGA) (within 2 months) with left ventricular ejection fraction (LVEF) <50%.46. Recent history of clinically significant glomerulonephritis, biopsy proven tubulointerstitial nephritis, crystal nephropathy, or other renal insufficiencies.106265.00023347. Treatment with an investigational agent within the longest time frame of either 5 half-lives or 30 days of initiating study drug.48. Medical illness that may impact the safety of the patient or objectives of the patient or study. Known recreational substance use or psychiatric illness that may affect compliance with scheduled visits.49. Known hypersensitivity to Compound A or components of the formulation.50. History of clinically significant renal impairment.51. History of clinically significant liver disease, liver impairment or any other liver anomality which may affect drug metabolism.

[0394] E. Safety Assessments

[0395] Data regarding treatment-emergent AEs (TEAEs) will be collected in this study. TEAEs are events that are not present at baseline, or if present at baseline, have worsened in severity. AEs will be assessed after the first dose in Part 1 and Part 2 and continued for at least 30 days following the last dose of Compound A. In addition, all serious adverse events (SAEs), regardless of suspected causality, must be reported up until at least 30 days after the patient has stopped Compound A. Any SAEs experienced after this 30-day period should only be reported if a causal relationship to Compound A is suspected.

[0396] The following information will be recorded for each AE: description of the event, date and time of onset, date and time of resolution, severity, causal relationship to study drug, outcome, action taken with the study drug and any treatment given.

[0397] All clinically significant abnormal changes from baseline in physical examination findings, vital signs, ECGs, and laboratory evaluations will be collected, graded with regards to severity or clinical significance, assessed for causal relationship and recorded.

[0398] F. Pharmacokinetics

[0399] PK analysis will be performed in dose escalation (for both once-daily and BID dosing) and dose expansion. See, Table 5 for PK collections times and windows during dose escalation. See, Table 6 for PK collection times and window in dose expansion. Samples collected for PK analysis may also be used to assess factors influencing adsorption, distribution, metabolism, and excretion.106265.000233

[0400] A food effect PK study will be initiated for all patients enrolling in dose escalation under Version 6 of this protocol. On Cycle 1 Day 1, Compound A will be taken after an overnight fast of at least 10 hours. On Cycle 1 Day 2, Compound A will be taken after an overnight fast of at least 10 hours with a high -fat, high-calorie meal. On Cycle 2 Day 1 PK evaluation will be repeated after an overnight fast of at least 10 hours. All other time points are trough collections, with a sample collected prior to dosing on the indicated day.

[0401] During dose expansion, all patients will undergo extensive PK evaluation on Cycle 1 Day 1 under fasting conditions after an overnight fast of at least 10 hours. All other times points are trough collections, with a sample collected prior to dosing on the indicated day.106265.000233106265.000233

[0402] G. Screening Evaluations

[0403] (i) Part 1 and Part 2 Screening Evaluations (Days -28 to -1)106265.000233

[0404] After subjects have signed an Institutional Review Board / Ethics Committee (IRBZEC) approved ICF for the purpose of this study, they will begin the screening process. Screening evaluations may be performed up to 28 days in advance of dosing but must be completed at least one (1) day prior to dosing.

[0405] Screening evaluation will include:• Medical history including solid tumor history• Confirmation of DDR mutation or MCC regardless of known mutation status• Complete physical examination• Vital signs• Height and weight• Serum B-hCG pregnancy test• Echocardiogram or MUGA• Concomitant medication• 12-lead ECG (in triplicate)• Hematology, chemistry, urinalysis• Coagulation labs (aPTT, INR, haptoglobin, and D-dimer)• HIV antibody, HbSAg, and hepatitis C antibody• ECOG PS• Liquid biopsy in lieu of tumor tissue may be used to confirm DDR mutation• Imaging per RECIST or PCWG3

[0406] (ii) Part 1 Evaluations (Dose Escalation Including DLT Assessment)

[0407] (a) Baseline Evaluations (Day -3 to 1)

[0408] Baseline assessments will not be repeated if completed during the Screening period within the 72-hour window prior to dosing on Cycle 1 Day 1. Baseline assessments include the followings:• Targeted physical examination• Vital signs• Weight• Urine B-hCG pregnancy test (result must be available prior to dosing). If a serum pregnancy test was completed within 3 days of Cycle 1 Day 1, a urine106265.000233 hCG pregnancy test is not required to be repeated. Serum pregnancy testing can be conducted if urine testing is not available or feasible.• Concomitant medication• 12-lead ECG (in triplicate)• Hematology, chemistry, urinalysis (result must be available prior to dosing)• CTC and / or PBMC evaluation• Serum biomarkers, if relevant (within 7 days of first dose Day 1)• Coagulation labs (aPTT, INR, haptoglobin, and D-dimer)• ECOG PSC

[0409] In the event that a baseline assessment needs to be repeated, the entire baseline visit does not necessarily need to be repeated. Please discuss with the Medical Monitor, particularly if treatment is scheduled to start within 1 week.

[0410] (b) DLT Assessment Period (Cycle 1, dose escalation)

[0411] Cycle 1 Day 1 (dose escalation)

[0412] Patients will return to the site on Day 1 for predose and postdose blood samples for PK. Assessments include the following:

[0413] Predose assessments include the following:• Targeted physical examination (repeat only if clinically indicated)• 12-lead ECG (in triplicate), see Table 5• Vital signs, see Table 5• Urine B-hCG pregnancy test (result must be available prior to dosing). Serum pregnancy testing can be conducted if urine testing is not available or feasible• Hematology, chemistry, urinalysis (repeat from baseline only if clinically indicated)• Coagulation labs (aPTT, INR, haptoglobin, and D-dimer)• Concomitant medications• Blood sample for PK, see Table 5• Medication instructions• Dispense medication diary106265.000233

[0414] Patients will fast overnight for at least 10 hours before coming to clinic on Cycle 1 Day 1. After dosing, no food is allowed for 4 hours (water is permitted). All patients regardless of dosing schedule (QDay or BID) will receive a single dose of Compound A on Cycle 1 Day 1. Patients assigned to BID administration will start receiving Compound A BID on Cycle 1 Day 3.

[0415] Postdose assessments include the following:• Targeted physical examination (only if clinically indicated)• Vital signs, see Table 5• 12-lead ECG (in triplicate), see Table 5• AE and DLT assessment• Blood samples for PK, see Table 5

[0416] Cycle 1 Day 2 (dose escalation)

[0417] Patients will fast overnight before coming to clinic on Cycle 1 Day 2. Patients will return to the site on Day 2 for a predose blood sample for PK.

[0418] Predose assessments include the following:• Targeted physical examination• Vital signs, see Table 5• 12-lead ECG (in triplicate), see Table 5• Blood sample for PK, see Table 5• Concomitant medications• AE and DLT assessment

[0419] Patients will remain in clinic after receiving their dose of Compound A for postdose PK evaluation under fed conditions. Patients will eat a high-fat, high-calorie meal (fed state). Patients should start the meal 30 minutes prior to administration of Compound A. Patients should eat the meal in 25 minutes or less; Compound A should be administered 30 minutes after the start of the meal and after at least 5 minutes of rest. No additional food is allowed for at least 4 hours following Compound A dosing. All patients regardless of dosing schedule (QDay or BID) will receive a single dose of Compound A on Cycle 1 Day 2.106265.000233Patients assigned to BID administration will start receiving Compound A BID on Cycle 1 Day 3.

[0420] Postdose assessments include the following:• Targeted physical examination (only if clinically indicated)• Vital signs, see Table 5• 12-lead ECG (in triplicate), see Table 5• AE and DLT assessment• Blood samples for PK, see Table 5

[0421] Cycle 1 Day 3 (dose escalation)

[0422] Patients will return to clinic on Day 3.

[0423] Predose assessments include the following:• Targeted physical examination• Vital signs, see Table 5 Concomitant medications• AE and DLT assessment

[0424] Before receiving Compound A, a blood sample will be drawn for PK assessment. Compound A will be given once daily in the morning at least 1 hour before a meal, or at least 1 hour after a meal. Patients will be instructed to wait at least 1 hour before eating again after administration. For patients assigned to the once daily schedule, this is the only dose of the day. For patients assigned to the BID schedule, patients will self-administer the evening dose at home approximately 12 hours after the morning dose.

[0425] Patients will self-administer Compound A at home (once daily or BID) under fasting conditions: at least 1 hour before a meal, or at least 1 hour after a meal, and waiting at least 1 hour before eating again after administration.

[0426] Cycle 1 Days 8 and 15 (dose escalation)

[0427] Patients will return to the site on Days 8 and 15 for predose blood samples for PK.

[0428] Predose assessments include the following:• Targeted physical examination• Vital signs, see Table 5106265.000233• Weight• 12-lead ECG (in triplicate), see Table 5• Blood sample for PK, see Table 5• Concomitant medications• AE and DLT assessments• Hematology, chemistry, urinalysis• Coagulation labs (aPTT, INR, haptoglobin, and D-dimer)• CTC and / or PBMC evaluation (Day 15 only)

[0429] Before dosing Compound A, a blood sample will be drawn for PK assessment. Compound A will be given once daily in the morning at least 1 hour before a meal, or at least 1 hour after a meal, and waiting at least 1 hour before eating again after administration. For patients assigned to the once daily schedule, this is the only dose of the day. For patients assigned to the BID schedule, patients will self-administer the evening dose at home approximately 12 hours after the morning dose.

[0430] Patients will self-administer Compound A at home (once daily or BID) under fasting conditions: at least 1 hour before a meal, or at least 1 hour after a meal, and waiting at least 1 hour before eating again after administration.

[0431] Cycle 1 Day 22 (dose escalation)

[0432] On Day 22, patients will self-administer study drug at home (once daily or BID) under fasting conditions: at least 1 hour before a meal, or at least 1 hour after a meal, and waiting at least 1 hour before eating again after administration. A safety evaluation phone contact will be conducted for:• Concomitant medications• AE and DLT assessment

[0433] Cycle 2 Day 1 (dose escalation)

[0434] Patients will return to the site on Day 1 for a predose and postdose blood sample for PK.

[0435] Predose assessments include the following:• Targeted physical examination106265.000233• Vital signs, see Table 5• Urine B-hCG pregnancy test (result must be available prior to dosing). Serum pregnancy testing can be conducted if urine testing is not available or feasible• Weight• 12-lead ECG (in triplicate), see Table 5• Blood sample for PK, see Table 5• Concomitant medications• Medication instructions• Dispense medication diary• AE and DLT assessments• Hematology, chemistry, urinalysis• Coagulation labs (aPTT, INR, haptoglobin, and D-dimer)• ECOG

[0436] Patients will fast overnight for at least 10 hours before coming to clinic on Cycle 2 Day 1. For these patients, after the predose PK is collected, no food is allowed for 4 hours (water is permitted). Compound A will be given once daily in the morning. For patients assigned to the once daily schedule, this is the only dose of the day. For patients assigned to the BID schedule, patients will self-administer the evening dose at home approximately 12 hours after the morning dose.

[0437] Postdose assessments include the following:• Targeted physical examination (only if clinically indicated)• Vital signs, see Table 5• 12-lead ECG (in triplicate), see Table 5• AE and DLT assessment• Blood samples for PK, see Table 5106265.000233

[0438] Patients will self-administer Compound A at home (once daily or BID) under fasting conditions: at least 1 hour before a meal, or at least 1 hour after a meal, and waiting at least 1 hour before eating again after administration.

[0439] Cycle 2 Days 8 and 15 (dose escalation)

[0440] Patients will return to clinic on Cycle 2 Days 8 and 15. Predose assessments include the following:• Targeted physical examination• Vital signs, see Table 5• Weight• 12-lead ECG (in triplicate), see Table 5• Concomitant medications• AEs• Hematology, chemistry, urinalysis• Coagulation labs (aPTT, INR, haptoglobin, and D-dimer)

[0441] Compound A will be given once daily in the morning at least 1 hour before a meal, or at least 1 hour after a meal, and waiting at least 1 hour before eating again after administration. For patients assigned to the once daily schedule, this is the only dose of the day. For patients assigned to the BID schedule, patients will self-administer the evening dose at home approximately 12 hours after the morning dose.

[0442] Patients will self-administer Compound A at home (once daily or BID) under fasting conditions: at least 1 hour before a meal, or at least 1 hour after a meal, and waiting at least 1 hour before eating again after administration.

[0443] Cycle 2 Day 22 - 28 (dose escalation)

[0444] Patients will have imaging performed (RECIST or PCWG3) but do not need to be seen by study clinic staff. Imaging can be performed between Day 22 and Day 28.

[0445] Cycles 3 and 4 Day 1 (dose escalation)

[0446] Patients will return to the clinic site on Cycle 3 and Cycle 4 Day 1. Predose assessments include the following:• Targeted physical examination106265.000233• Vital signs, see Table 5• Urine B-hCG pregnancy test (result must be available prior to dosing for next cycle). Serum pregnancy testing can be conducted if urine testing is not available or feasible• Weight• Concomitant medications• Medication diary (dispense for next cycle)• AEs• 12-lead ECG (in triplicate), see Table 5• Hematology, chemistry, urinalysis• Coagulation labs (aPTT, INR, haptoglobin, and D-dimer)• ECOG• Serum biomarkers (Cycle 3 only if relevant)

[0447] Compound A will be given once daily in the morning at least 1 hour before a meal, or at least 1 hour after a meal, and waiting at least 1 hour before eating again after administration. For patients assigned to the once daily schedule, this is the only dose of the day. For patients assigned to the BID schedule, patients will self-administer the evening dose at home approximately 12 hours after the morning dose.

[0448] Patients will self-administer Compound A at home (once daily or BID) under fasting conditions: at least 1 hour before a meal, or at least 1 hour after a meal, and waiting at least 1 hour before eating again after administration.

[0449] Cycles 3 and 4 Day 15 (dose escalation)

[0450] Patients will return to clinic on Cycle 3 and Cycle 4 Day 15. Compound A will be given once daily in the morning at least 1 hour before a meal, or at least 1 hour after a meal, and waiting at least 1 hour before eating again after administration. For patients assigned to the once daily schedule, this is the only dose of the day. For patients assigned to the BID schedule, patients will self-administer the evening dose at home approximately 12 hours after the morning dose.

[0451] The following predose assessments will be conducted in the clinic:106265.000233• Targeted physical examination• Vital signs, see Table 5• Weight• Concomitant medications• AEs• 12-lead ECG (in triplicate), see Table 5• Blood sample for PK, see Table 5• Hematology, chemistry, urinalysis• Coagulation labs (aPTT, INR, haptoglobin, and D-dimer)

[0452] Patients will self-administer Compound A at home (once daily or BID) under fasting conditions: at least 1 hour before a meal, or at least 1 hour after a meal, and waiting at least 1 hour before eating again after administration.

[0453] Cycle 4 Day 22 - 28 (dose escalation)

[0454] Patients will have imaging performed (RECIST or PCWG3) but do not need to be seen by study clinic staff. Imaging can be performed between Day 22 and Day 28.

[0455] Cycle 5 and subsequent cycles Day 1 (dose escalation)

[0456] Patients will return to the site on Day 1. Predose assessments include the following:• Targeted physical examination• Vital signs, see Table 5• Urine B-hCG pregnancy test (result must be available prior to dosing for next cycle). Serum pregnancy testing can be conducted if urine testing is not available or feasible• Weight• Concomitant medications• Medication diary (dispense for next cycle)• AEs106265.000233• 12-lead ECG (in triplicate), see Table 5• Blood sample for PK, see Table 5• Hematology, chemistry, urinalysis• Coagulation labs (aPTT, INR, haptoglobin, and D-dimer)• ECOG• Serum biomarkers, odd cycles only if relevant

[0457] Compound A will be given once daily in the morning at least 1 hour before a meal, or at least 1 hour after a meal, and waiting at least 1 hour before eating again after administration. For patients assigned to the once daily schedule, this is the only dose of the day. For patients assigned to the BID schedule, patients will self-administer the evening dose at home approximately 12 hours after the morning dose.

[0458] Patients will self-administer Compound A at home (once daily or BID) under fasting conditions: at least 1 hour before a meal, or at least 1 hour after a meal, and waiting at least 1 hour before eating again after administration.

[0459] Cycle 6 and subsequent cycles, Day 22 - 28 (dose escalation)

[0460] Patients will have imaging performed (RECIST or PCWG3) on even- numbered cycles only but do not need to be seen by study clinic staff. Imaging can be performed between Day 22 and Day 28.

[0461] (iii) Part 2 (Dose Expansion at R2PD and schedule)

[0462] (a) Baseline Evaluations (Days -3 to 1)

[0463] Baseline assessments will not be repeated if completed during the Screening period within the 72-hour window. Baseline assessments include the followings:• Targeted physical examination• Vital signs• Weight• Urine B-hCG pregnancy test (results must be available prior to dosing). If a serum pregnancy test was completed within 3 days of Cycle 1 Day 1, a urine B-hCG pregnancy test is not required to be repeated. Serum pregnancy testing can be conducted if urine testing is not available or feasible• 12-lead ECG (in triplicate)106265.000233• Concomitant medication• Hematology, chemistry, urinalysis (results must be available prior to dosing)• Coagulation labs (aPTT, INR, haptoglobin, and D-dimer)• CTC and / or PBMC evaluation• ECOG PS• Serum biomarkers, if relevant (within 7 days of first dose Day 1)

[0464] (b) Dose Expansion (Cycle 1 Day 1)

[0465] Patients will return to the site on Day 1 for a predose and postdose blood samples for PK. Predose assessments include the following:• Targeted physical examination (repeat only if clinically indicated)• 12-lead ECG (in triplicate), see Table 6• Vital signs, see Table 6• Urine B-hCG pregnancy test (result must be available prior to dosing). Serum pregnancy testing can be conducted if urine testing is not available or feasible• Hematology, chemistry, urinalysis (repeat only if clinically indicated)• Coagulation labs (aPTT, INR, haptoglobin, and D-dimer)• Concomitant medications• Blood sample for PK, see Table 6• Medication instructions• Dispense medication diary

[0466] On Cycle 1 Day 1 before coming to clinic, patients will have fasted overnight for at least 10 hours before coming to clinic on Cycle 1 Day 1. After dosing, no food is allowed for 4 hours (water is permitted). All patients regardless of dosing schedule (QDay or BID) will receive a single dose of Compound A on Cycle 1 Day 1. Patients assigned to BID administration will start receiving Compound A BID on Cycle 1 Day 2.

[0467] Postdose assessments include the following:• Targeted physical examination (only if clinically indicated)106265.000233• Vital signs, see Table 6• 12-lead ECG (in triplicate), see Table 6• AE and DLT assessment• Blood samples for PK, see Table 6

[0468] (c) Cycle 1 Day 2 (dose expansion)

[0469] Patients will return to clinic on Cycle 1 Day 2.

[0470] Predose assessments include the following:• Targeted physical examination• Vital signs, see Table 6• 12-lead ECG (in triplicate), see Table 6• Blood sample for PK, see Table 6• Concomitant medications• AE assessment

[0471] Before dosing Compound A, a blood sample will be drawn for PK assessment. Compound A will be given once daily in the morning at least 1 hour before a meal, or at least 1 hour after a meal. Patients will be instructed to wait at least 1 hour before eating again after administration. For patients assigned to the once daily schedule, this is the only dose of the day. For patients assigned to the BID schedule, patients will self-administer the evening dose at home approximately 12 hours after the morning dose.

[0472] Patients will self-administer Compound A at home (once daily or BID) under fasting conditions: at least 1 hour before a meal, or at least 1 hour after a meal, and waiting at least 1 hour before eating again after administration.

[0473] (d) Cycle 1 Days 8 and 15 (dose expansion)

[0474] Patients will return to the site on Days 8 and 15 for predose blood samples for PK.

[0475] Predose assessments include the following:• Targeted physical examination• Vital signs, see Table 6• Weight106265.000233• 12-lead ECG (in triplicate), see Table 6• Blood sample for PK, see Table 6• Concomitant medications• AE assessment• Hematology, chemistry, urinalysis• Coagulation labs (aPTT, INR, haptoglobin, and D-dimer)• CTC and / or PBMC evaluation (Day 15 only)

[0476] Before dosing Compound A, a blood sample will be drawn for PK assessment. Compound A will be given once daily in the morning at least 1 hour before a meal, or at least 1 hour after a meal, and waiting at least 1 hour before eating again after administration. For patients assigned to the once daily schedule, this is the only dose of the day. For patients assigned to the BID schedule, patients will self-administer the evening dose at home approximately 12 hours after the morning dose.

[0477] Patients will self-administer Compound A at home (once daily or BID) under fasting conditions: at least 1 hour before a meal, or at least 1 hour after a meal, and waiting at least 1 hour before eating again after administration.

[0478] (e) Cycle 1 Day 22 (dose expansion)

[0479] On Day 22, patients will self-administer study drug at home (once daily or BID based on recommended phase 2 schedule) under fasting conditions: at least 1 hour before a meal, or at least 1 hour after a meal, and waiting at least 1 hour before eating again after administration. A safety evaluation phone contact will be conducted for:• Concomitant medications• AE assessment

[0480] (f) Cycle 2 Day 1 (dose expansion)

[0481] Patients will return to the site on Day 1 for a predose blood sample for PK.

[0482] Predose assessments include the following:• Targeted physical examination• Vital signs, see Table 6106265.000233• Urine B-hCG pregnancy test (result must be available prior to dosing for next cycle). Serum pregnancy testing can be conducted if urine testing is not available or feasible• Weight• 12-lead ECG (in triplicate), see Table 6• Blood sample for PK, see Table 6• Concomitant medications• Medication diary (dispense for next cycle)• AE assessment• Hematology, chemistry, urinalysis• Coagulation labs (aPTT, INR, haptoglobin, and D-dimer)• ECOG

[0483] Before dosing Compound A, a blood sample will be drawn for PK assessment. Compound A will be given once daily in the morning at least 1 hour before a meal, or at least 1 hour after a meal. Patients will be instructed to wait at least 1 hour before eating again after administration. For patients assigned to the once daily schedule, this is the only dose of the day. For patients assigned to the BID schedule, patients will self-administer the evening dose at home approximately 12 hours after the morning dose.

[0484] Patients will self-administer Compound A at home (once daily or BID) under fasting conditions: at least 1 hour before a meal, or at least 1 hour after a meal, and waiting at least 1 hour before eating again after administration.

[0485] (g) Cycle 2 Day 15 (dose expansion)

[0486] Patients will return to the clinic site on Day 15.

[0487] Predose assessments include the following:• Targeted physical examination• Vital signs, see Table 6• Weight• 12-lead ECG (in triplicate), see Table 6• Concomitant medications106265.000233• AE assessment• Hematology, chemistry, urinalysis• Coagulation labs (aPTT, INR, haptoglobin, and D-dimer)

[0488] Compound A will be given once daily in the morning at least 1 hour before a meal, or at least 1 hour after a meal. Patients will be instructed to wait at least 1 hour before eating again after administration. For patients assigned to the once daily schedule, this is the only dose of the day. For patients assigned to the BID schedule, patients will selfadminister the evening dose at home approximately 12 hours after the morning dose.

[0489] If Compound A is tolerated with acceptable toxicity, patients will receive a supply of Compound A to allow for dosing on an outpatient basis until the next clinic visit. Patients will self-administer Compound A at home (once daily or BID) under fasting conditions: at least 1 hour before a meal, or at least 1 hour after a meal, and waiting at least 1 hour before eating again after administration.

[0490] (h) Cycle 2 Day 22 - 28 (dose expansion)

[0491] Patients will have imaging performed (RECIST or PCWG3) but do not need to be seen by study clinic staff. Imaging can be performed between Day 22 and Day 28.

[0492] (i) Cycle 3 and subsequent cycles, Day 1 (dose expansion)

[0493] Patients will return to the site on Day 1.

[0494] Predose assessments include the following:• Targeted physical examination• Vital signs, see Table 6• Urine B-hCG pregnancy test (result must be available prior to dosing for next cycle). Serum pregnancy testing can be conducted if urine testing is not available or feasible• Weight• 12-lead ECG (in triplicate), see Table 6• Concomitant medications• Medication diary (dispense for next cycle)• AE assessments106265.000233• Hematology, chemistry, urinalysis• Coagulation labs (aPTT, INR, haptoglobin, and D-dimer)• Serum biomarkers, if relevant on odd cycles only• ECOG

[0495] Before dosing Compound A, a blood sample will be drawn for PK assessment. Compound A will be given once daily in the morning at least 1 hour before a meal, or at least 1 hour after a meal. Patients will be instructed to wait least 1 hour before eating again after administration. For patients assigned to the once daily schedule, this is the only dose of the day. For patients assigned to the BID schedule, patients will self-administer the evening dose at home approximately 12 hours after the morning dose.

[0496] Patients will self-administer Compound A at home (once daily or BID) under fasting conditions: at least 1 hour before a meal, or at least 1 hour after a meal, and waiting at least 1 hour before eating again after administration.

[0497] (j) Cycle 4 and subsequent even cycles, Day 22 - 28 (dose expansion)

[0498] Patients will have imaging performed (RECIST or PCWG3) on even- numbered cycles only but do not need to be seen by study clinic staff. Imaging can be performed between Day 22 and Day 28 on all even cycles.

[0499] (iv) Parts 1 and 2 End of Treatment (EOT) Visit, Follow-up Visit and Phone Follow-up

[0500] If a decision is made that the patient will permanently discontinue study drug, then the EOT visit should be conducted. If the EOT visit coincides with a regular study visit, then the EOT evaluations will supersede those of that scheduled visit, and the data should be entered in the EOT visit in the CRF. The primary reason for discontinuation of study drug should be documented.

[0501] Assessments include the following:• Targeted physical examination• Vital signs• Urine B-hCG pregnancy test. Serum pregnancy testing can be conducted if urine testing is not available or feasible• Weight106265.000233• Concomitant medication• AEs• 12-lead ECG (in triplicate)• Hematology, chemistry, urinalysis• Coagulation labs (aPTT, INR, haptoglobin, and D-dimer)• Serum biomarkers, if relevant• ECOG PS• RECIST or PCWG3 (not required if performed within 6 weeks of end-of- treatment visit.)

[0502] Patients will return to clinic for the safety follow-up visit 30 days (+ 14 days) after the EOT visit. Assessments include the following:• Concomitant medication• AEs• ECOG PS

[0503] A phone call to check on patient’s overall status (vital status) will be performed every 3 months after the last dose of Compound A up to 1 year from the EOT visit.

[0504] J. Product Specifications

[0505] (i) Administration of Study Drug

[0506] Compound A may be initially supplied as 50 mg, 100 mg and / or 200 mg HPMC capsules in plastic bottles (30 units each). In Part 1 (dose escalation), patients will be assigned to a dose level and schedule per Table 4. In Part 2, up to an additional 30 patients will be enrolled and receive Compound A at the R2PD and schedule.

[0507] Unless instructed otherwise, e.g., PK assessments for the food effect study (Cycle 1 Day 1 and 2 in dose escalation) and on extensive PK days (Cycle 2 Day 2) will include overnight fasting for at least 10 hours. On all other days, Compound A will be administered under fasting conditions defined as: at least 1 hour before a meal, or at least 1 hour after a meal, and waiting at least 1 hour before eating again after administration.

[0508] Compound A should be taken with 240 mL (8 fluid ounces) of water or clear liquids. For the once daily schedule, Compound A will be taken daily in the morning. For the BID schedule, Compound A will be taken twice, once in the morning and again approximately 12 hours later in the evening.106265.000233

[0509] Regardless of dosing schedule (once-daily or BIC, BID), if a patient vomits a dose, the patient should not immediately take a another dose. The patient should resume dosing at their next scheduled administration.

[0510] If a patient misses a dose on the once daily schedule, he / she should take the dose as soon as possible, but not more than 6 hours after the missed scheduled dose. If the dose is missed by more than 6 hours, the missed dose should be skipped, and the patient should resume daily dosing the following day.

[0511] If a patient misses a dose on the BID schedule, he / she should take the dose as soon as possible, but not more than 4 hours after the missed scheduled dose. If the dose is missed by more than 4 hours, the missed dose should be skipped, and the patient should resume dosing at the next scheduled administration.

[0512] K. Safety Monitoring and Adverse Events

[0513] (i) Adverse Events

[0514] Data regarding TEAEs will be collected in this study. TEAEs are events that are not present at baseline, or if present at baseline, have worsened in severity. In addition to safety monitoring during active treatment, patients will be followed for 30 days after their last dose of study drug. In addition, all serious adverse events (SAEs), regardless of suspected causality, must be reported up until at least 30 days after the patient has stopped Compound A. Any SAEs experienced after this 30-day period should only be reported if a causal relationship to Compound A is suspected.

[0515] (ii) Definition of Adverse Events

[0516] An AE is any unfavorable and unintended sign, symptom, or disease temporally associated with the use of an investigational (medicinal) product or other protocol-imposed intervention, regardless of attribution. An AE may include intercurrent illnesses or injuries that represent an exacerbation (increase in frequency, severity, or specificity) of pre-existing conditions (e.g., worsening of asthma). A laboratory abnormality will be reported on the “Adverse Event” case report form only if it is associated with clinical sequelae or requires therapeutic intervention. Whenever possible, it is preferable to record a diagnosis as the AE term rather than a series of symptoms relating to a diagnosis. AEs will be coded according to Medical Dictionary for Regulatory Activities (MedDRA) and graded according to the Common Terminology Criteria for Adverse Events (CTCAE) v5.0.106265.000233

[0517] The reporting period for non-serious AEs starts after the first administration of study drug on Day 1 and ends at 30 days after last dose or until new anticancer therapy is started.

[0518] If an AE remains unresolved at the final study visit, the patient will be followed, at the Investigator’s discretion, until resolution of the event. Any study drug related AEs and SAEs must be followed until resolution by the Investigator, even if this extends beyond the study-reporting period. Resolution is defined as the return to baseline status or stabilization of the condition with the expectation that it will remain chronic.

[0519] AEs will be assessed for severity, relationship to study drug, and as to whether the event meets one or more of the definitions of an SAE, using the categories defined in Table 7.106265.000233

[0520] For those AEs that are not described on the CTCAE v5.0, such AEs will be graded on a 5-point scale (mild, moderate, severe) and reported. Intensity of such an AE is defined in Table 8.

[0521] Example 3

[0522] An oral formulation was prepared using the components of Tables 9 and10.106265.000233

[0523] The intragranular components are blended, passed through a roller- compacter, and then milled to provide granules. The subsequent granules are blended with the extragranular components and put through the tablet press.106265.000233

[0524] It is to be understood that while the invention has been described in conjunction with the preferred specific embodiments thereof, that the foregoing description and the examples are intended to illustrate and not limit the scope of the invention. It will be understood by those skilled in the art that various changes may be made and equivalents may be substituted without departing from the scope of the invention, and further that other aspects, advantages and modifications will be apparent to those skilled in the art to which the invention pertains. In addition to the embodiments described herein, the present disclosure contemplates and claims those inventions resulting from the combination of features of the invention cited herein and those of the cited prior art references which complement the features of the present invention. Similarly, it will be appreciated that any described material, feature, or article may be used in combination with any other material, feature, or article, and such combinations are considered within the scope of this invention.

[0525] The disclosures of each patent, patent application, and publication cited or described in this document are hereby incorporated herein by reference, each in its entirety, for all purposes.

Claims

1. 106265.000233What is claimed is:

1. A compound that is Compound A, Compound B, or a salt thereof:for use in treating an advanced solid cancer tumor, comprising a treatment regimen comprising orally administering 50-1500 mg / day of the compound to a human in need thereof.

2. The compound of claim 1, wherein the compound is compound A.

3. The compound of claim 1 or 2, wherein the compound is a salt of compound A.

4. The compound of any one of claims 1-3, wherein the compound is5. The compound of claim 1, wherein the compound is compound B.

6. The compound of any one of the preceding claims, wherein the treatment regimen comprises administering 50 mg / day of the compound.106265.0002337. The compound of any one of claims 1-5, wherein the treatment regimen comprises administering 100 mg / day of the compound.

8. The compound of any one of claims 1-5, wherein the treatment regimen comprises administering 200 mg / day of the compound.

9. The compound of any one of claims 1-5, wherein the treatment regimen comprises administering 300 mg / day of the compound.

10. The compound of any one of claims 1-5, wherein the treatment regimen comprises administering 350 mg / day of the compound.

11. The compound of any one of claims 1-5, wherein the treatment regimen comprises administering 500 mg / day of the compound.

12. The compound of any one of claims 1-5, wherein the treatment regimen comprises administering 550 mg / day of the compound.

13. The compound of any one of claims 1-5, wherein the treatment regimen comprises administering 800 mg / day of the compound.

14. The compound of any one of claims 1-5, wherein the treatment regimen comprises administering 1100 mg / day of the compound.

15. The compound of any one of claims 1-5, wherein the treatment regimen comprises administering 1300 mg / day of the compound.

16. The compound of any one of claims 1-5, wherein the treatment regimen comprises administering 1500 mg / day of the compound.

17. The compound of any one of the preceding claims, wherein the total daily amount of the compound is administered once a day.

18. The compound of any one of claims 1-17, wherein the total daily amount of the compound is administered in divided doses.106265.00023319. The compound of claim 18, wherein the total daily amount of the compound is administered in two doses.

20. The compound of claim 19, wherein each of the two doses comprises about half of the total daily amount of the compound.

21. The compound of claim 19 or 20, wherein the doses of the compound are administered about twelve hours apart.

22. The compound of any one of the preceding claims, wherein the advanced solid cancer tumor has a mutation.

23. The compound of claim 22, wherein the mutation is an AT -rich interactive domaincontaining protein 1A (ARID 1 A), such as a ARID 1 A missense mutation, ARID 1 A nonsense mutation, ARID 1 A truncating mutation, ARID 1 A frameshift mutation, ARID 1 A splicing mutation, or ARID 1 A deep deletion.

24. The compound of claim 22, wherein the mutation is a missense mutation in KRAS at Glyl2, missense mutation in KRAS at Gly 13, or missense mutation in KRAS at Glu 12 and Gly 13.

25. The compound of claim 22, wherein the mutation is a loss of function mutation (e.g., nonsense mutation, truncating mutation frameshift mutation, splicing mutation, or deep deletion), such as ataxia telangiectasia mutated (ATM), ataxia telangiectasia and Rad3 -related kinase (ATR), alpha thalassemia / mental retardation syndrome X-linked (ATRX), breast cancer 1 gene (BRCA1), breast cancer 2 gene (BRCA2), BRCA1 interacting protein C-terminal helicase 1 (BRIP1), cyclin K (CCNK), cyclin dependent kinase 12 (CDK12), cyclin dependent kinase inhibitor 2 A (CDKN2A), checkpoint kinase 2 (CHEK1), FA complementation group A (FANCA), FA complementation group C (FANCC), FA complementation group M (FANCM), heterochromatin protein 1 binding protein 3 (HP1BP3), HUS1 checkpoint clamp component (HUS1), microdystrophin construct 2 (MDC2), MutL homolog 1 (MLH1), MRE1 1 homolog, double strand break repair nuclease (MRE11 A), MutS homolog 2 (MSH2), MutS homolog 6 (MSH6), methylthioadenosine phosphorylase (MTAP), nibrin (NBN), neuronal precursor cell -expressed developmentally downregulated 4106265.000233(NEDD4), partner and localizer of BRCA2 (PALB2), poly-ADP ribose polymerase 1 (PARP1), PMS1 homolog 2, mismatch repair system component (PMS2), polymerase delta 1 (POLDI), DNA polymerase epsilon, catalytic subunit (POLE), protein phosphatase 2 regulatory subunit Balpha (PPP2R2A), RAD50, RAD51 recombinase (RAD51), RB transcriptional corepressor 1 (RBI), ribonuclease H2 subunit B (RNASEH2B), replication protein Al (RPA1), SET domain containing 2, histone lysine methyltransferase (SETD2), Siah E3 ubiquitin protein ligase 1 (SIAH1), SWI / SNF related, matrix associated, actin dependent regulator of chromatin, subfamily A, member 4 (SMARCA4), DNA topoisomerase II binding protein 1 (TOPBP1), tumor protein, translationally-controlled 1 (TPT1), ubiquitin protein ligase E3 component N-recognin 5 (UBR5), ubiquitin specific peptidase 9 X-linked (USP9X), WRN RecQ like helicase (WRN), x-ray repair cross complementing 1 (XRCC1), x-ray repair cross complementing 2 (XRCC2), or x-ray repair cross complementing 5 (XRCC5) mutation.

26. The compound of any one of claims 1-21, wherein the advanced solid cancer tumor has an amplification of myelocytomatosis oncogene (MYC), cyclin El (CCNE1), or cyclin E2 (CCNE2), or such as more than four genomic copies in total.

27. The compound of any one of the preceding claims, wherein the advanced solid cancer tumor is merkel cell carcinoma (MCC), such as advanced MCC, or such as MCC regardless of mutation status.

28. The compound of any one of claims 1-25, wherein the advanced solid cancer tumor is metastatic castration-resistant prostate cancer (mCRPC).

29. The compound of any one of the preceding claims, wherein prior to the treatment regimen, the advanced solid cancer tumor was treated with another cancer therapy.

30. The compound of claim 29, wherein the another cancer therapy failed.

31. The compound of any one of the preceding claims, wherein the human has at least one solid tumor.106265.00023332. The compound of any one of the preceding claims, wherein, prior to the treatment regimen, the tumor is: at least 20 mm in at least one dimension as measured by chest x-ray, at least 10 mm in at least one dimension as measured by CT scan, at least 10 mm in at least one dimension as measured by MRI, and / or at least 10 mm in at least one dimension as measured by calipers by clinical exam.

33. The compound of any one of the preceding claims, wherein, prior to the treatment regimen, the human has mCRPC and radiographic disease progression, as measured by prostate cancer working group 3 (PCWG3) criteria.

34. The compound of claim 33, wherein:(g) the cancer progressed to the pelvic and / or extrapelvic region;(h) the cancer progressed to the bone;(i) the cancer progressed to one or more lymph nodes;(j) the cancer progressed to the one or more soft tissues;(k) the cancer progress to one or more visceral sites; or(l) any combination of (a)-(e).

35. The compound of claim 34, wherein:(a) the human has up to five tumors in the pelvic and / or extrapelvic region;(b) the human has new lesions and the new lesions are in the bone;(c) the lymph node grew by 5 mm or more in the short axis, when compared to the size of the lymph node when measured at an earlier timepoint, and the lymph node is 1 cm or more in the short axis;(d) the visceral site is one or both lungs, the adrenal system, or the central nervous system; or(e) any combination of (a)-(c).

36. The compound of any one of the preceding claims, wherein the human is an adult of 18 years of age or older.

37. The compound of any one of claims 1-35, wherein the human is a child of 12 to 17 years of age.106265.00023338. The compound of any one of claims 1-35, wherein the human is 16 years of age or older and has an Eastern Cooperative Oncology Group (ECOG) performance status of 1 or less before the treatment regimen.

39. The compound of claim 38, wherein the EGOG performance status improves after the treatment regimen.

40. The compound of any one of claims 1-35, wherein the human is 16 years of age or older and has a Karnofsky Performance Status (KPS) of 70% or greater before the treatment regimen.

41. The compound of claim 40, wherein the KPS improves after the treatment regimen.

42. The compound of any one of claims 1-35, wherein the human is less than 16 years of age and has a Lansky Play-Performance Scale (LPPS) of 70% or greater before the treatment regimen.

43. The compound of claim 42, wherein the LPPS improves after the treatment regimen.

44. The compound of any one of the preceding claims, further comprising measuring one or more serum biomarker for the cancer.

45. The compound of claim 44, wherein the cancer is prostate cancer and the serum biomarker is prostate specific antigen (PSA).

46. The compound of claim 44, wherein the cancer is ovarian cancer and the serum biomarker is cancer antigen 125 (CA-125).

47. The compound of claim 44, wherein the cancer is colorectal cancer and the serum biomarker is carcinoembryonic antigen (CEA).

48. The compound of any one of the preceding claims, wherein the treatment regimen is correlated with a decrease in the tumor size.

49. The compound of claim 48, wherein the treatment regimen is correlated with the tumor size being less than 20 mm in at least one dimension as measured by chest x-ray,106265.000233 less than 10 mm in at least one dimension as measured by CT scan, less than 10 mm in at least one dimension as measured by MRI, or less than 10 mm in at least one dimension as measured by calipers by clinical exam.

50. The compound of any one of claims 1-12, 17-34, 39, or 40, wherein the human has mCRPC and the treatment regimen is correlated with a reduction in radiographic disease progression, as measured by PCWG3 criteria.

51. The compound of claim 50, wherein, after the treatment regimen, there is no evidence of the cancer in the humans’ pelvic region, extrapelvic region, bone, one or more lymph node, or one or more soft tissue, or any combination thereof.

52. The compound of claim 50 or 51, wherein:(a) the human has less than five tumors in the pelvic and / or extrapelvic region;(b) the human less than two tumors in the bone;(c) the lymph nodes are normal in size; or(e) any combination of (a)-(c).

47. A compound that isalt thereof.

48. An oral formulation, comprising:(iv) about 45 to about 65 wt%, based on the weight of the oral formulation, of CompoundA, or a salt thereof:106265.000233(v) one or more intragranular excipients; and(vi) one or more extragranular excipients.

49. The oral formulation of claim 48, wherein the intragranular excipient comprises one or more of an intragranular diluent.

50. The oral formulation of claim 48 or 49, comprising about 40 to about 45 wt%, or about 41 to about 44 wt%, or about 42 to about 43 wt%, based on the weight of the oral formulation, of the intragranular diluent.

51. The oral formulation of claim 49 or 50, wherein at least one intragranular diluent is microcrystalline cellulose.

52. The oral formulation of claim 51, comprising about 10 to about 25 wt%, or about 10 to about 20 wt%, or about 20 to about 25 wt%, or about 21 to about 24 wt%, or about 22 to about 23 wt%, or about 22.5 wt%, based on the weight of the oral formulation, of the microcrystalline cellulose.

53. The oral formulation of any one of claims 49-52, wherein at least one intragranular diluent is lactose.

54. The oral formulation of claim 53, comprising about 10 to about 20 wt%, or about 12.5 to about 17.5 wt%, or about 14 to about 16 wt%, or about 15 wt%, based on the weight of the oral formulation, of the lactose.

55. The oral formulation of claims 53 or 54, wherein the lactose is spray dried.

56. The oral formulation of any one of claims 49-55, further comprising at least one intragranular binder.106265.00023357. The oral formulation of claim 56, wherein the intragranular binder is starch.

58. The oral formulation of claim 56 or 57, comprising about 2.5 to about 7.5 wt%, or about 4 to about 6 wt%, or about 5 wt%, based on the weight of the oral formulation, of the binder.

59. The oral formulation of claim 57 or 58, wherein the starch is pregelatinized starch.

60. The oral formulation of any one of claims 49-59, further comprising at least one intragranular disintegrant.

61. The oral formulation of claim 60, wherein the intragranular disintegrant is croscarmellose sodium.

62. The oral formulation of claim 60 or 61, comprising about 1.5 to about 3.5 wt%, or about 2 to about 3 wt%, or about 2.5 wt%, based on the weight of the oral formulation, of the intragranular disintegrant.

63. The oral formulation of any one of claims 49-62, further comprising at least one intragranular glidant.

64. The oral formulation of claim 63, wherein the intragranular glidant is silicon dioxide.

65. The oral formulation of claim 63 or 64, comprising about 0.25 to about 1.5 wt%, or about 0.4 to about 0.6 wt%, or about 0.5%, based on the weight of the oral formulation, of the intragranular glidant.

66. The oral formulation of claim 64 or 65, wherein the silicon dioxide is colloidal silicon dioxide.

67. The oral formulation of any one of claims 49-66, further comprising at least one intragranular lubricant.

68. The oral formulation of claim 67, wherein the intragranular lubricant is sodium stearyl fumarate.106265.00023369. The oral formulation of claim 67 or 68, comprising about 0.5 to about 3 wt%, or about 1 to about 2 wt%, or about 1.25 wt%, based on the weight of the oral formulation, of the intragranular lubricant.

70. The oral formulation of any one of claims 48-69, wherein the extragranular excipient comprises at least one extragranular disintegrant.

71. The oral formulation of claim 70, wherein the extragranular disintegrant is croscarmellose sodium.

72. The oral formulation of claim 70 or 71, comprising about 1.5 to about 3.5 wt%, or about 2 to about 3 wt%, or about 2.5 wt%, based on the weight of the oral formulation, of the extragranular disintegrant.

73. The oral formulation of any one of claims 48-72, wherein the extragranular excipient further comprises at least one extragranular glidant.

74. The oral formulation of claim 73, wherein the extragranular glidant is silicon dioxide.

75. The oral formulation of claim 73 or 74, comprising about 0.05 to about 1 wt%, about 0.1 to about 0.5 wt%, or about 0.25%, based on the weight of the oral formulation, of the extragranular glidant.

76. The oral formulation of claim 74 or 75, wherein the silicon dioxide is colloidal silicon dioxide.

77. The oral formulation of any one of claims 48-76, wherein the extragranular excipient further comprises at least one extragranular lubricant.

78. The oral formulation of claim 77, wherein the extragranular lubricant sodium stearyl fumarate.

79. The oral formulation of claim 77 or 78, comprising about 0.1 to about 1 wt%, about 0.25 to about 0.75 wt%, or about 0.5 wt%, based on the weight of the oral formulation, of the extragranular lubricant.106265.00023380. The oral formulation of any one of claims 48-79, comprising about 95 to about 98 wt%, or about 96 to about 97 wt%, or about 96.75 wt%, based on the weight of the oral formulation, of the Compound A and intragranular excipients.

81. The oral formulation of any one of claims 48-80, comprising about 2 to about 5 wt%, about 2.5 to about 4 wt%, or about 3.25 wt%, based on the weight of the oral formulation, of the extragranular excipients.

82. The oral formulation of any one of claims 48-81, comprising about 45 to about 55 mg of Compound A.

83. A tablet comprising the oral formulation of any one of claims 48-82.

84. The tablet of claim 83, further comprising one or more coating layers.

85. The tablet of claim 84, wherein the one or more coating layers is an immediate release layer, such as an immediate release layer comprising the Opadry® II product.

86. The tablet of claim 84 or 85, comprising about 1 to about 5 wt% of the one or more coating layers, such as about 2 to about 4 wt%, or about 3 wt%.

87. The tablet of any one of claims 83-86, comprising one coating layer.

88. An oral formulation of any one of claims 48-82 or tablet of any one of claims 83-87 for treating an advanced solid cancer tumor.

89. A process for preparing the oral formulation of any one of claims 48-82, comprising:(i) blending the Compound A and intragranular excipients;(ii) roller compacting the product of step (i);(iii) milling the product of step (ii) to provide granules; and(iv) blending the granules of step (iii) with the extragranular excipients.

90. The process of claim 89, further comprising compacting the product of step (iv) to provide a tablet.

91. The process of claim 90, further comprising coating the tablet.106265.00023392. The process of claim 91, wherein the coating is performed by spraying a suspension comprising a polymer onto the tablet and drying the coating.

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