Summary

This phase I trial studies the side effects and best dose of peposertib when given together with pegylated liposomal doxorubicin hydrochloride in treating patients with high or low grade ovarian cancer that has come back after a period of improvement (recurrent). Peposertib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as pegylated liposomal doxorubicin hydrochloride, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving peposertib and pegylated liposomal doxorubicin hydrochloride may work better in treating patients with ovarian cancer compared to pegylated liposomal doxorubicin hydrochloride alone.

Objectives

PRIMARY OBJECTIVE:
I. To determine the safety and tolerability of peposertib (M3814) in combination with pegylated liposomal doxorubicin hydrochloride (PLD) and determine the recommended phase 2 dose (RP2D) of the combination in women with recurrent ovarian cancer.

SECONDARY OBJECTIVES:
I. To observe and record anti-tumor activity.
II. To evaluate the pharmacokinetics of peposertib (M3814) when given in combination with PLD.

EXPLORATORY OBJECTIVE:
I. To correlate response to treatment (as defined by response rate and progression free survival) with PLD exposure (in area under the curve [AUC]) and PLD associated toxicities in women with recurrent high grade serous and low grade serous ovarian cancer treated in the expansion cohorts.

OUTLINE: This is a dose-escalation study of peposertib followed by a dose-expansion study.

Patients receive peposertib orally (PO) twice daily (BID) on days 1-21, days 1-28, or days 1-7 (depending on dose level) and pegylated liposomal doxorubicin hydrochloride intravenously (IV) on day 1. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Patients undergo blood sample collection cycle 1 weeks 1 and 3. Patients also undergo computed tomography (CT) scan or magnetic resonance imaging (MRI) during screening and every 8 weeks throughout the study and after 6 months of study treatment, every 12 weeks. Patients undergo echocardiography (ECHO) during screening and every 6 months. Starting in cycle 13, patients undergo ECHO or multigated acquisition (MUGA) scan every 2 cycles.

After completion of study treatment, patients are followed up for 30 days.

Eligibility

1. DOSE ESCALATION PHASE: Women with recurrent or persistent epithelial ovarian, fallopian tube or primary peritoneal cancer are eligible. This includes, but is not limited to, the following histologic types: serous adenocarcinoma (grade 1,2, or 3/ high grade or low grade), endometrioid adenocarcinoma, carcinosarcoma, mucinous adenocarcinoma, undifferentiated carcinoma, clear cell adenocarcinoma, mixed epithelial adenocarcinoma, transitional cell carcinoma, or adenocarcinoma not otherwise specified * NOTE: Patients who have evidence of DDR deficiency /HRD are eligible if they are at the point in their disease course where they are appropriate candidates for single agent Doxil
2. EXPANSION PHASE: The expansion phase will simultaneously accrue to 2 cohorts, low grade serous ovarian cancer (LGSOC) and high grade serous ovarian cancer (HGSOC) * Patients accrued to the LGSOC cohort will have recurrent or persistent low grade serous ovarian cancer or grade 1 serous ovarian cancer * Patients accrued to the HGSOC cohort will have recurrent or persistent high grade serous ovarian cancer
3. Patients must have measurable disease by defined Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria
4. Prior therapy: * Patients must have received at least one prior line of platinum-based chemotherapy * Patients can have received an unlimited number of additional lines of chemotherapy, 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 be discontinued at least 4 weeks, one cycle, or 5 half-lives (whichever is shortest) prior to study treatment initiation
5. Age >= 18 years. Because no dosing or adverse event data are currently available on the use of peposertib (M3814) in combination with pegylated liposomal doxorubicin in patients < 18 years of age, children are excluded from this study, but will be eligible for future pediatric trials
6. Patients with platinum-sensitive ovarian cancer are eligible for only the dose expansion phase if their provider feels that PLD would be an appropriate treatment option for them. Patients with platinum-sensitive ovarian cancer should also be offered any higher priority studies for which they are potentially eligible and/or platinum based chemotherapy or a PARP inhibitor if they are eligible for such therapy
7. Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)
8. Patients must have a cardiac ejection fraction >= the institutional lower limit of normal (LLN)
9. Hemoglobin >= 9 g/dL
10. Absolute neutrophil count >= 1,500/mcL
11. Platelets >= 100,000/mcL
12. Total bilirubin =< 1.5 x institutional upper limit of normal (ULN)
13. Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3 x institutional ULN
14. Alkaline phosphatase =< 2.5 x institutional ULN
15. Creatinine clearance > 30 ml/min
16. Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial
17. For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated
18. 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
19. Patients with treated brain metastases are eligible if follow-up brain imaging after central nervous system (CNS)-directed therapy shows no evidence of progression. The patient must be off steroids and clinically stable
20. Female patients of childbearing potential must have a negative urine or serum pregnancy test within 72 hours prior to receiving the first dose of study medication. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required * The effects of peposertib (M3814) and liposomal doxorubicin on the developing human fetus are unknown and there is the potential for teratogenic or abortifacient effects. For this reason, women and men of child-bearing potential must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study treatment, and for 6 months after completion of peposertib (M3814) administration. 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. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with peposertib (M3814), breastfeeding should be discontinued if the mother is treated with peposertib (M3814)
21. 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
22. 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
23. Ability to understand and the willingness to sign a written informed consent document. Participants with impaired decision-making capacity (IDMC) who have a legally-authorized representative (LAR) and/or family member available will also be eligible
24. Archival formalin-fixed paraffin-embedded (FFPE) tissue collected within the past 36 months prior to registration must be available for submission for deoxyribonucleic acid (DNA)/ribonucleic acid (RNA) analysis

Treatment Sites in Georgia