A Study Combining the Peposertib (M3814) Pill With Standard Chemotherapy in Patients With Ovarian Cancer With an Expansion in High Grade Serous Ovarian Cancer and Low Grade Serous Ovarian Cancer

Inclusion Criteria:

• DOSE ESCALATION PHASE: Women with recurrent or persistent epithelial ovarian,fallopian tube or primary peritoneal cancer are eligible. This includes, but is notlimited to, the following histologic types: serous adenocarcinoma (grade 1,2, or 3/high grade or low grade), endometrioid adenocarcinoma, carcinosarcoma, mucinousadenocarcinoma, undifferentiated carcinoma, clear cell adenocarcinoma, mixedepithelial adenocarcinoma, transitional cell carcinoma, or adenocarcinoma nototherwise specified

• NOTE: Patients who have evidence of DDR deficiency /HRD are eligible if theyare at the point in their disease course where they are appropriate candidatesfor single agent Doxil

• EXPANSION PHASE: The expansion phase will simultaneously accrue to 2 cohorts, lowgrade serous ovarian cancer (LGSOC) and high grade serous ovarian cancer (HGSOC)

• Patients accrued to the LGSOC cohort will have recurrent or persistent lowgrade serous ovarian cancer or grade 1 serous ovarian cancer

• Patients accrued to the HGSOC cohort will have recurrent or persistent highgrade serous ovarian cancer

• Patients must have measurable disease by defined Response Evaluation Criteria inSolid Tumors (RECIST) 1.1 criteria

• Prior therapy:

• Patients must have received at least one prior line of platinum-basedchemotherapy

• Patients can have received an unlimited number of additional lines ofchemotherapy, targeted therapy, biologic therapy, or hormonal therapy

• Any prior therapy directed at the malignant tumor, including chemotherapy,biologic/targeted therapy, immunotherapy, or hormonal therapy must bediscontinued at least 4 weeks, one cycle, or 5 half-lives (whichever isshortest) prior to study treatment initiation

• Age >= 18 years. Because no dosing or adverse event data are currently available onthe use of peposertib (M3814) in combination with pegylated liposomal doxorubicin inpatients < 18 years of age, children are excluded from this study, but will beeligible for future pediatric trials

• Patients with platinum-sensitive ovarian cancer are eligible for only the doseexpansion phase if their provider feels that PLD would be an appropriate treatmentoption for them. Patients with platinum-sensitive ovarian cancer should also beoffered any higher priority studies for which they are potentially eligible and/orplatinum based chemotherapy or a PARP inhibitor if they are eligible for suchtherapy

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

• Patients must have a cardiac ejection fraction >= the institutional lower limit ofnormal (LLN)

• Hemoglobin >= 9 g/dL

• 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 glutamate pyruvate transaminase [SGPT]) =< 3 x institutional ULN

• Alkaline phosphatase =< 2.5 x institutional ULN

• Creatinine clearance > 30 ml/min

• 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. Thepatient must be off steroids and clinically stable

• 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

• The effects of peposertib (M3814) and liposomal doxorubicin on the developinghuman fetus are unknown and there is the potential for teratogenic orabortifacient effects. For this reason, women and men of child-bearingpotential must agree to use adequate contraception (hormonal or barrier methodof birth control; abstinence) prior to study entry, for the duration of studytreatment, and for 6 months after completion of peposertib (M3814)administration. Should a woman become pregnant or suspect she is pregnant whileshe or her partner is participating in this study, she should inform hertreating physician immediately. Because there is an unknown but potential riskfor adverse events in nursing infants secondary to treatment of the mother withpeposertib (M3814), breastfeeding should be discontinued if the mother istreated with peposertib (M3814)

• 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

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

• Archival formalin-fixed paraffin-embedded (FFPE) tissue collected within the past 36months prior to registration must be available for submission for deoxyribonucleicacid (DNA)/ribonucleic acid (RNA) analysis

Exclusion Criteria:

• Patients are excluded from the dose-escalation phase of the study if they areeligible for any available therapies known to confer clinical benefit

• Inability to swallow and/or absorb oral medication (patients with a drainage peg areineligible)

• Patients may not have received prior anthracyclines (doxorubicin or pegylatedliposomal doxorubicin) for treatment of their ovarian cancer

• 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, thyroiddysfunction, or neuropathy

• Patients who are receiving any other investigational agents within 28 days prior tostart of treatment

• History of allergic reactions attributed to compounds of similar chemical orbiologic composition to peposertib (M3814) or pegylated liposomal doxorubicin

• Patients who cannot discontinue concomitant medications or herbal supplements thatpotentially interact with peposertib (M3814)

• The following categories of medications and herbal supplements must bediscontinued prior to starting study treatment:

• Strong inducers/inhibitors of CYP3A4/5, CYP2C9, and CYP2C19

• Substrates with a narrow therapeutic index that are metabolized by CYP1A2, 2B6, 2C8, and 3A4/5

• Use caution with other substrates of CYP3A4/5, CYP1A2, CYP2B6, CYP2C8 andsubstrates of P-gp, BCRP, OCT1, OAT3, OATP1B1, OATP1B3, MATE1, and MATE-2K witha narrow therapeutic index. Close monitoring is advised

• Because the lists of these agents are constantly changing, it is important toregularly consult a frequently-updated medical reference. As part of theenrollment/informed consent procedures, the patient will be counseled on therisk of interactions with other agents, and what to do if new medications needto be prescribed or if the patient is considering a new over-the-countermedicine or herbal product. Patient Drug Interactions Handout and Wallet Card)should be provided to patients

• Patients who cannot discontinue concomitant proton-pump inhibitors (PPIs). Patientsmay confer with the study doctor to determine if such medications can bediscontinued. These must be discontinued >= 5 days prior to study treatment.Patients do not need to discontinue calcium carbonate

• Patients receiving sorivudine or any chemically related analogues (such asbrivudine) are excluded

• Patients who have received a live attenuated vaccine within 30 days of dosing withpeposertib (M3814)

• Patients with uncontrolled intercurrent illness, including but not limited toongoing or active infection

• Patients with psychiatric illness/social situations that would limit compliance withstudy requirements

• Pregnant women are excluded from this study because peposertib (M3814) is DNA-PKinhibitor agent with the potential for teratogenic or abortifacient effects. Becausethere is an unknown but potential risk for adverse events in nursing infantssecondary to treatment of the mother with peposertib (M3814), breastfeeding shouldbe discontinued if the mother is treated with peposertib (M3814). These potentialrisks may also apply to other agents used in this study

• Patients with significant (uncontrolled) cardiac conduction abnormalities areexcluded