Testing the Combination of the Anti-Cancer Drugs Temozolomide and M1774 to Evaluate Their Safety and Effectiveness

Inclusion Criteria:

• Patients must have histologically or cytologically confirmed diagnosis of metastaticadvanced cancer.

• In dose escalation, any solid tumor patients with either O6-methylguanine DNAmethyltransferase (MGMT) promoter hypermethylation positivity on testing /pre-screening of archival tissue OR an extracranial solid tumor where TMZ isconsidered a standard of care per National Comprehensive Cancer Network (NCCN)guidelines (neuroendocrine tumor, small cell lung cancer, melanoma or soft tissuesarcoma). The tumor lesion must be safely accessible to a mandatory biopsy. Patientswith MGMT promoter hypermethylated colorectal cancer must be mismatch repairproficient / microsatellite stable.

• In phase 2, only patients with mismatch repair proficient / microsatellite stablecolorectal cancer that have MGMT promoter hypermethylation positivity onpre-screening of archival tissue will be eligible.

• In dose escalation, patients must have progressed after treatment with all availabletherapies including immunotherapies for metastatic disease that are known to conferclinical benefit, or are intolerant to treatment, or refuse standard treatment.Patients may not have previously received temozolomide or an ataxia telangiectasiaand rad3-related (ATR) inhibitor.

• For patients with mismatch repair proficient / microsatellite stable colorectalcancer in the phase 2 portion, patients must have received prior therapy with 1 ormore systemic therapies in the metastatic setting that includes 5-fluorouracil,irinotecan, and oxaliplatin. Patients with microsatellite stable colorectal cancer (mCRC) need to have had exposure, unless contraindicated, to all 3 of oxaliplatin,irinotecan, and fluoropyrimidine (FP).

The use of 5-fluorouracil and oxaliplatin in the adjuvant setting is acceptable, provided the development of metastatic disease was less than 6 months after the completion of adjuvant therapy.

Patients with a prior hypersensitivity reaction to oxaliplatin in the adjuvant setting do not require retreatment in the metastatic setting.

• Age >=18 years. Because no dosing or adverse event data are currently available onthe use of M1774 in combination with temozolomide in patients < 18 years of age,children are excluded from this study.

• Measurable disease on CT and/or MRI per Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1 criteria.

• Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (or Karnofsky >= 60%).

• Hemoglobin >=10 g/dL (No blood transfusions are allowed within 14 days of cycle 1day 1 [C1D1]).

• White blood cells (WBC) > 3 x 10^9/L.

• Absolute neutrophil count >= 1,500/mcL.

• Platelets >= 100,000/mcL.

• Total bilirubin =< 1.5 x institutional upper limit of normal (ULN).

• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine-aminotransferase (ALT) (serum glutamic-pyruvic transaminase [SGPT]) =< 3 x institutional ULN except for when liver metastases are present, in which casethey must be =< 5 x institutional ULN.

• Glomerular filtration rate (GFR) >= 60 mL/min/1.73 m^2.

• Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviraltherapy with undetectable viral load within 6 months are eligible for this trial.

• For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBVviral load must be undetectable on suppressive therapy, if indicated.

• Patients with a history of hepatitis C virus (HCV) infection must have been treatedand cured. For patients with HCV infection who are currently on treatment, they areeligible if they have an undetectable HCV viral load.

• Patients with treated brain metastases are eligible if follow-up brain imaging aftercentral nervous system (CNS)-directed therapy shows no evidence of progression for 4weeks.

• Patients with a prior or concurrent malignancy whose natural history or treatmentdoes not have the potential to interfere with the safety or efficacy assessment ofthe investigational regimen are eligible for this trial.

• Patients with known history or current symptoms of cardiac disease, or history oftreatment with cardiotoxic agents, should have a clinical risk assessment of cardiacfunction using the New York Heart Association Functional Classification. To beeligible for this trial, patients should be class 2B or better.

• The effects of M1774 on the developing human fetus are unknown. For this reason andbecause ATR inhibitors agents as well as other therapeutic agents used in this trialare known to be teratogenic, women of child-bearing potential must agree to useadequate contraception (hormonal or barrier method of birth control; abstinence)prior to study entry, for the duration of study participation, and 6 months aftercompletion of M1774 administration. Should a woman become pregnant or suspect she ispregnant while she or her partner is participating in this study, she should informher treating physician immediately. Men treated or enrolled on this protocol mustalso agree to use adequate contraception prior to the study, for the duration ofstudy participation, and 3 months after completion of M1774 administration.

• Ability to understand and the willingness to sign a written informed consentdocument.

Exclusion Criteria:

• Patients who have not recovered from adverse events due to prior anti-cancer therapy (i.e., have residual toxicities > grade 1) with the exception of alopecia andneuropathy, which may be =< grade 2.

• History of allergic reactions or hypersensitivity attributed to compounds of similarchemical or biologic composition to M1774 or temozolomide, including dacarbazine.

• Patients with uncontrolled intercurrent illness.

• Pregnant women are excluded from this study because M1774 is an ATR inhibiting agentwith the potential for teratogenic or abortifacient effects. Because there is anunknown but potential risk for adverse events in nursing infants secondary totreatment of the mother with M1774 breastfeeding should be discontinued if themother is treated with M1774. These potential risks also apply to temozolomide.

• Patients with a prior history of ataxia telangiectasia.

• Patients who are not able to swallow orally administered medication or havegastrointestinal disorders likely to interfere with absorption of the studymedication.

• Patients who cannot discontinue proton-pump inhibitors (PPIs) while taking M1774.H-2 receptor antagonists are allowed but should not be taken within 12 hours beforeor 2 hours after M1774. Antacids are also allowed, but should not be taken 2 hoursbefore 2 hours after M1774.

• Extensive RT involving greater than 30% of the bone marrow is not permitted duringthe study.

• A Fridericia's correction formula (QTcF) > 480 ms is exclusionary given thepotential for QT.