Testing the Combination of Two Anti-cancer Drugs, Peposertib (M3814) and Tuvusertib (M1774) for Advanced Solid Tumors

Inclusion Criteria:

• Patients must have histologically confirmed solid malignancy that is metastatic orunresectable and for which standard curative or palliative measures do not exist orare no longer effective.

• For the dose escalation and dose expansion phases, patients must have genomic (tumornext-generation sequencing [NGS], circulating tumor deoxyribonucleic acid [ctDNA],fluorescence in situ hybridization [FISH], etc.) or immunohistochemical evidence ofinactivating ATM mutations, MYC amplification, mutation of FBXW7, CCNE1amplification, SWI/SNF member mutation (ARID1A, PBRM1, SMARCA4, ARID2, ARID1b,SMARCB1, SMARCA2, SS18), and ATRX/DAXX. Mutations may be germline or somatic. Allmutations/alterations must be approved by the overall principal investigator (PI).Other SWI/SNF mutations may be considered after discussion with the overall PI.

• Progression on at least one prior standard therapy.

• Age >= 18 years. Because no dosing or adverse event data are currently available onthe use of peposertib (M3814) in combination with tuvusertib (M1774) in patients < 18 years of age, children are excluded from this study.

• Life expectancy > 3 months.

• Eastern cooperative oncology group (ECOG) performance status =< 2 (Karnofsky >= 60%).

• Measurable disease by response evaluation criteria in solid tumors (RECIST) 1.1 (RECIST) 1.1 non-measurable disease permitted for the dose escalation portion).

• Hemoglobin >= 9 g/dL.

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

• Platelets >= 1000,000/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 × institutional ULN or =< 5.0X the ULN if liver metastases are present.

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

• Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviraltherapy with undetectable viral load within 6 months are eligible for this trial.Anti-retroviral therapy agents must be considered for potential drug-druginteractions per exclusion.

• 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 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.

• Able to swallow whole capsules or tablets.

• Willing to undergo paired biopsies (expansion arm).

• Female patients of childbearing potential must have a negative urine or serumpregnancy test within 72 hours prior to receiving the first dose of studymedication. If the urine test is positive or cannot be confirmed as negative, aserum pregnancy test will be required.

• Female patients of childbearing potential must be willing to use an adequatemethod of contraception for the course of the study through 6 months after thelast dose of study medication.

• Male patients of reproductive potential must agree to avoid impregnating apartner while receiving study drug and for 3 months after the last dose ofstudy drug by complying with adequate methods of contraception.

• Note: Abstinence is acceptable if this is the usual lifestyle and preferredcontraception for the patient.

• Ability to understand and the willingness to sign a written informed consentdocument. Participants with impaired decision-making capacity who have alegally-authorized representative (LAR) and/or family member available will also beeligible.

Exclusion Criteria:

• Patients who have received immunotherapy within 21 days of Cycle 1 Day 1.

• Patients who have received therapeutic radiation therapy within 21 days, orpalliative radiation therapy within 7 days, of Cycle 1 Day 1.

• Patients who have undergone major surgery within 21 days of Cycle 1 Day 1.

• 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,controlled endocrine toxicity (e.g., hypothyroidism), and cutaneous toxicity whichwill be permitted at Grade 2.

• Patients who are receiving any other investigational agents.

• Patients with new or progressive brain metastases (active brain metastases) orleptomeningeal disease are eligible if the treating physician determines thatimmediate central nervous system (CNS) specific treatment is not required and isunlikely to be required during the first cycle of therapy.

• History of allergic reactions attributed to compounds of similar chemical orbiologic composition to peposertib (M3814) and tuvusertib (M1774).

• Patients who cannot discontinue concomitant medications or herbal supplements thatare strong inhibitors or strong inducers of cytochrome P450 (CYP) isoenzymes,CYP1A2, CYP3A4/5, CYP2C19, and CYP2C9. Concomitant use of substrates hMATE1, hMATE2,and CYP3A4/5 substrates with a narrow therapeutic index are also excluded. Opioidsmay interact with these enzymes; use of opioids while on study is allowed but shouldbe closely monitored. Concomitant administration of sensitive substrates of P-gp,BCRP, OCT1, OATP1B1, and OATP1B3 should be avoided (if the use is unavoidable,carefully monitor patients for signs of increased toxicity). Patients may conferwith the study doctor to determine if alternative medications can be used. Thefollowing categories of medications and herbal supplements must be discontinued forat least the specified period of time before the patient can be treated:

• Strong inducers of CYP1A2, CYP3A4/5, CYP2C19, and CYP2C9: >= 3 weeks prior tostudy treatment.

• Strong inhibitors of CYP1A2, CYP3A4/5, CYP2C19, and CYP2C9: >= 1 week prior tostudy treatment.

• Substrates of hMATE1, hMATE2, CYP3A4/5, P-gp, BCRP, OCT1, OATP1B1, and OATP1B3with a narrow therapeutic index: >= 1 day prior to study treatment.

• Patients who cannot discontinue proton-pump inhibitors (PPIs). H-2-receptorantagonist should be held during the 2 weeks of concurrent dosing with peposertib (M3814). There is no H-2-receptor antagonist restriction during the off weekswithout peposertib (M3814) dosing. H-2-receptor antagonists should not be takenwithin 12 hours before or 2 hours after tuvusertib (M1774). Antacids should not betaken within 2 hours before or 2 hours after tuvusertib (M1774).

• Patients who received hematopoietic growth factor (e.g., granulocytecolony-stimulating factor, erythropoietin) within 14 days prior to the first dose ofstudy intervention.

• Patients with uncontrolled intercurrent illness including, but not limited to:ongoing or active infection, symptomatic congestive heart failure, unstable anginapectoris, or cardiac arrhythmia.

• QTcF (using the Fridericia correction calculation) of >= 470 msec

• Pregnant women and women who are breastfeeding are excluded from this study becausethe effects of the study drugs on the developing fetus are unknown.

• 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 as assessed by the treating investigator may be includedwith the approval of the sponsor-investigator.