A Phase I/Ib Dose Escalation Study of Pegylated Liposomal Doxorubicin (PLD) With Peposertib (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)

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.

Inclusion Criteria:

- 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

- 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

- Patients must have measurable disease by defined Response Evaluation Criteria in Solid
Tumors (RECIST) 1.1 criteria

- 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

- 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

- 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

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

- Patients must have a cardiac ejection fraction >= the institutional lower limit of
normal (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-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. The
patient must be off steroids and clinically stable

- 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)

- 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

- 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

- 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

Exclusion Criteria:

- Patients are 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)

- Patients may not have received prior anthracyclines (doxorubicin or pegylated
liposomal 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, thyroid
dysfunction, or neuropathy

- Patients who are receiving any other investigational agents within 28 days prior to
start of treatment

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

- Patients who cannot discontinue concomitant medications or herbal supplements that
potentially interact with peposertib (M3814)

- The following categories of medications and herbal supplements must be
discontinued prior to starting study treatment:

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

- Substrates of CYP3A4/5, CYP1A2, and CYP2B6 with a narrow therapeutic index

- Use caution with other substrates of CYP3A4/5, CYP1A2, CYP2B6 and substrates of
P-gp, BCRP, OCT1, OATP1B1, and OATP1B3 with a narrow therapeutic index. Close
monitoring is advised

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

- Patients who cannot discontinue concomitant proton-pump inhibitors (PPIs). Patients
may confer with the study doctor to determine if such medications can be discontinued.
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 as brivudine)
are excluded

- Patients who have received a live attenuated vaccine within 30 days of dosing with
peposertib (M3814)

- Patients with uncontrolled intercurrent illness, including but not limited to ongoing
or active infection

- Patients with psychiatric illness/social situations that would limit compliance with
study requirements

- Pregnant women are excluded from this study because peposertib (M3814) is DNA-PK
inhibitor 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 peposertib (M3814), breastfeeding should be
discontinued if the mother is treated with peposertib (M3814). These potential risks
may also apply to other agents used in this study

- Patients with significant (uncontrolled) cardiac conduction abnormalities are excluded