Title
A Phase I/Ib Dose Escalation Study of Pegylated Liposomal Doxorubicin (PLD) With M3814 in Platinum-Resistant or Ineligible Ovarian and Related Cancers with Planned Expansions in High Grade Serous (HGSOC) and Low Grade Serous Ovarian Cancer (LGSOC)

Description
Phase I/Ib Study of Pegylated Liposomal Doxorubicin with M3814 in Ovarian and Related Cancers

Objective
The purpose of this study is to test the safety and tolerability (side effects) of a drug called peposertib (M3814) in combination with pegylated liposomal doxorubicin. Pegylated liposomal doxorubicin has already been approved by the FDA for treatment of patients with recurrent ovarian cancer. peposertib (M3814) has been tested in animals and patients with other types of cancer, but has not been tested in people with ovarian cancer before. This study tests different doses of peposertib (M3814) in combination with pegylated liposomal doxorubicin to see which dose is safest and most tolerable for people. There will be about 49 people taking part in the first part of this study (the dose escalation part), and up to 28 will be taking part in the second part or the expansion part, which will further assess the safety of the recommended dose determined in the dose finding part

Another purpose of the study is to determine if your cancer is shrinking or getting worse. This will be done using the usual standard of care procedures (radiographic imaging)

Another purpose is to check the level of the study drugs in your blood (Pharmacokinetics). In addition, another objective of the study is for genetic research to see if the study drug combination may work best in certain people and to measure for tumor cells in the blood

Treatment Peposertib (M3814) by mouth, in combination with IV pegylated liposomal doxorubicin

Key Eligibility
Dose escalation phase: Women with recurrent or persistent epithelial ovarian, fallopian tube or primary peritoneal cancer are eligible. This includes the following histologic types: serous adenocarcinoma (Grade 1,2, or 3/ high grade or low grade), endometrioid adenocarcinoma, mucinous adenocarcinoma, undifferentiated carcinoma, clear cell adenocarcinoma, mixed epithelial adenocarcinoma, transitional cell carcinoma, or adenocarcinoma not otherwise specified

Expansion phase: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

Must have measurable disease by defined RECIST 1.1

Must have received at least one prior line of platinum-based chemotherapy

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 be discontinued at least 4 weeks or one cycle (whichever is shorter) prior to study treatment initiation

18 years of age or olfer

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

ECOG PS 0-2

Must have a cardiac ejection fraction greater than or equal to the institutional lower limit of normal

Adequate organ and marrow function as defined by the protocol

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

Evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated

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

Treated brain metastases are eligible as long as no evidence of progression

Can not be pregnant or breastfeeding and must agree to adequate birth control as defined by the protocol

Known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents as defined by the protocol

Archival FFPE tissue collected within the past 36 months prior to registration must be available for submission for DNA/RNA analysis

EXCLUSION

Excluded from the dose-escalation phase of the study if they are eligible for any available therapies known to confer clinical benefit

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

No prior anthracyclines (doxorubicin or pegylated liposomal doxorubicin) for treatment of their ovarian cancer

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

No concomitant medications or herbal supplements that are strong inhibitors or strong inducers of cytochrome P450 (CYP) isoenzymes CYP3A4/5 and CYP2C19

No concomitant proton-pump inhibitors (PPIs)

Receiving sorivudine or any chemically related analogues (such as brivudine) are excluded

Oral or parenteral anticoagulants or thrombolytic agents for therapeutic or prophylactic purposes (including coumadin) are not permitted within 10 days of the first dose of peposertib (M3814) or throughout the trial. High-molecular weight heparins are permitted as long as INR are within normal

Applicable Disease Sites
Ovary

Participating Institutions
UW Health University Hospital