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

• Status: Not yet recruiting
• Trial end date: 2025-01-31
• Target enrollment: 0
• Participant gender: All

Summary

This phase I/II trial studies the side effects and best dose of temozolomide and M1774 and how well they works in treating patients with cancer that has spread from where it first started (primary site) to other places in the body (metastatic) and may have spread to nearby tissue, lymph nodes, or distant parts of the body (advanced). Temozolomide is in a class of medications called alkylating agents. It works by damaging the cell's deoxyribonucleic acid (DNA) and may kill tumor cells and slow down or stop tumor growth. M1774 may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Adding M1774 to temozolomide may shrink or stabilize cancer for longer than temozolomide alone.

• Phase: Phase 1/Phase 2
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: National Cancer Institute (NCI)
• Treatments: Temozolomide

Criteria

Inclusion Criteria:

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

• In dose escalation, any solid tumor patients with either O6-Methylguanine DNA Methyltransferase (MGMT) promoter hypermethylation positivity on testing / pre-screening of archival tissue OR an extracranial solid tumor where TMZ is considered a standard of care (Neuroendocrine tumor, small cell lung cancer, melanoma or soft tissue sarcoma).

• In dose expansion, patients with colorectal cancer must have MGMT promoter hypermethylation positivity on pre-screening of archival tissue.

• In dose escalation, patients must have progressed after treatment with all available therapies for metastatic disease that are known to confer clinical benefit, or are intolerant to treatment, or refuse standard treatment. Patients may not have previously received temozolomide or an ataxia telangiectasia and rad3-related (ATR) inhibitor.

• For patients in the colorectal cancer safety cohort, patients must have received prior therapy with 1 or more systemic therapies in the metastatic setting that includes 5-fluorouracil, irinotecan, and oxaliplatin.

The use of 5-fluoruracil 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.

• Measurable disease on computerized tomography (CT) and/or magnetic resonance imaging (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 (packed red blood cells and platelet transfusions) in the past 28 days. Blood transfusions are allowed to reach desired hemoglobin level if they occur at least 14 days prior to enrollment.

• 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 case they must be =<5 x institutional ULN

• Glomerular filtration rate (GFR) >=60 mL/min/1.73 m^2 unless data exists supporting safe use at lower kidney function values, no lower than 30 mL/min/1.73 m^2

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

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

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

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

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

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

• The effects of M1774 on the developing human fetus are unknown. For this reason and because ATR inhibitors agents as well as other therapeutic agents used in this trial are known to be teratogenic, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 4 months after completion of M1774 administration.

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

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 and neuropathy, which may be =< grade 2.

• History of allergic reactions or hypersensitivity attributed to compounds of similar chemical 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 agent with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with M1774 breastfeeding should be discontinued if the mother is treated with M1774. These potential risks may also apply to other agents used in this study.

• Patients with a prior history of ataxia telangiectasia

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

• Patients who cannot discontinue proton-pump inhibitors (PPIs). H-2-receptor antagonist and antacids should be held during the 7 days of concurrent dosing with M1774. There is no H-2-receptor antagonist or antacid restriction during the time without M1774 dosing.