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Antineoplastic Agents

All Drugs and Chemicals

Anti-Infective Agents

Doxorubicin

Liposomal doxorubicin

Peposertib

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Antibiotics, Antitubercular

Enzyme Inhibitors

Protein Kinase Inhibitors

Patients receive peposertib PO BID on days 1-21, days 1-28, or days 1-7 (depending on dose level) and pegylated liposomal doxorubicin hydrochloride 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 CT scan or MRI during screening and every 8 weeks and after 6 months of study treatment, every 12 weeks. Patients undergo ECHO during screening and every 6 months. Starting in cycle 13, patients undergo ECHO or MUGA scan every 2 cycles.

Biospecimen Collection

Computed Tomography

Echocardiography

Magnetic Resonance Imaging

Multigated Acquisition Scan

Pegylated Liposomal Doxorubicin Hydrochloride

Site Public Contact

Bradley R. Corr

Kristen Starbuck

Panagiotis A. Konstantinopoulos

Rachel N. Grisham

Kristin L. Bixel

Kathleen N. Moore

Sarah E. Taylor

Linda R. Duska

Lisa M. Barroilhet

Rachel N Grisham

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.

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.

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

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)

NCI is committed to sharing data in accordance with NIH policy. For more details on how clinical trial data is shared, access the link to the NIH data sharing policy page.

Tumor response will be defined according to Response Evaluation Criteria in Solid Tumors 1.1 and refers to the best overall response occurring.

Will be estimated using Kaplan-Meier method.

The descriptions and grading scales found in the revised National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0 will be utilized for adverse event reporting.

Individual PK parameters will be estimated for maximum of concentration, area under the curve, T1/2, apparent clearance/oral bioavailability, and apparent volume using non-compartmental methods. The PK variables will be tabulated and descriptive statistics (e.g., geometric means and coefficients of variation) calculated for each dose level. Pharmacokinetic parameters will be reported descriptively for exploratory comparison with historical data. Samples from the expansion phase may also be analyzed for M3814 for the purpose of population-PK analyses.

National Cancer Institute (NCI)

Fallopian Tube Neoplasms

Fallopian Tube Diseases

Paclitaxel

Albumin-Bound Paclitaxel

Bevacizumab

Antibodies

Topotecan

Immunomodulating Agents

Durvalumab

Olaparib

Immunoglobulins

Immunoglobulin G

Immunoglobulins, Intravenous

Poly(ADP-ribose) Polymerase Inhibitors

Maleic acid

Cediranib

Antibodies, Monoclonal

Tubulin Modulators

Antimitotic Agents

Antineoplastic Agents, Immunological

Immunologic Factors

Topoisomerase I Inhibitors

Patients receive paclitaxel IV over 60 minutes on days 1, 8, and 15, or pegylated liposomal doxorubicin hydrochloride IV over 60 minutes on day 1, or topotecan hydrochloride IV over 30 minutes on days 1, 8 and 15 or days 1-5 per the discretion of the treating physician. Cycles repeat every 21 or 28 days in the absence of disease progression or unacceptable toxicity. Patients may undergo ECHO or MUGA during screening and as clinically indicated on study. Patients also undergo collection of blood and CT with contrast during screening, and CT or MRI scans throughout the trial.

Patients receive durvalumab IV over 60 minutes on day 1, cediranib maleate PO QD Monday through Friday, and olaparib PO BID on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients may undergo ECHO or MUGA during screening and as clinically indicated on study. Patients also undergo collection of blood and CT with contrast during screening, and CT or MRI scans throughout the trial.

Patients receive durvalumab IV over 60 minutes on day 1 and cediranib maleate PO QD Monday through Friday. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients may undergo ECHO or MUGA during screening and as clinically indicated on study. Patients also undergo collection of blood and CT with contrast during screening, and CT or MRI scans throughout the trial.

Patients receive cediranib maleate PO QD on days 1-28 and olaparib PO BID on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients may undergo ECHO or MUGA during screening and as clinically indicated on study. Patients also undergo collection of blood and CT with contrast during screening, and CT or MRI scans throughout the trial.

Cediranib Maleate

Computed Tomography with Contrast

Topotecan Hydrochloride

Jung-min Lee

This phase II trial studies the possible benefits of treatment with different combinations of the drugs durvalumab, olaparib and cediranib vs. the usual treatment in patients with ovarian, primary peritoneal, or fallopian tube cancer that has come back after a period of improvement with platinum therapy (recurrent platinum resistant). Usual treatment is the type of treatment most patients with this condition receive if they are not part of a clinical study. Combination therapies studied in this trial include MEDI4736 (durvalumab) plus olaparib and cediranib, durvalumab and cediranib, or olaparib and cediranib. Monoclonal antibodies, such as durvalumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumors cells to grow and spread. Olaparib is an inhibitor of PARP, an enzyme that helps repair deoxyribonucleic acid (DNA) when it becomes damaged. Blocking PARP may help keep cancer cells from repairing their damaged DNA, causing them to die. PARP inhibitors are a type of targeted therapy. Cediranib may stop the growth of tumor cells by blocking VEGF (an enzyme). needed for cell growth. Giving different combinations of durvalumab, olaparib and cediranib may work better in increasing the duration of time that the cancer does not progress compared to the usual treatment.

PRIMARY OBJECTIVE:

I. To assess the efficacy of the combinations durvalumab (MEDI4736) plus olaparib and cediranib, durvalumab (MEDI4736) plus cediranib, or olaparib and cediranib, as measured by progression-free survival (PFS), as compared to physician's choice standard of care chemotherapy, in patients with recurrent platinum-resistant ovarian, primary peritoneal or fallopian tube cancer who had prior bevacizumab.

SECONDARY OBJECTIVES:

I. To assess the efficacy of the combinations durvalumab (MEDI4736) plus olaparib and cediranib, durvalumab (MEDI4736) plus cediranib, or olaparib and cediranib, as measured by overall response rate (ORR) by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, as compared to physician's choice standard of care chemotherapy, in patients with recurrent platinum-resistant ovarian, primary peritoneal or fallopian tube cancer who had prior bevacizumab.

II. To assess the efficacy of the combinations durvalumab (MEDI4736) plus olaparib and cediranib, durvalumab (MEDI4736) plus cediranib, or olaparib and cediranib, as measured by overall survival (OS), as compared to physician's choice standard of care chemotherapy, in patients with recurrent platinum-resistant ovarian, primary peritoneal or fallopian tube cancer who had prior bevacizumab.

OUTLINE: Patients are randomized to 1 of 4 arms.

ARM I: Patients receive paclitaxel intravenously (IV) over 60 minutes on days 1, 8, and 15, or pegylated liposomal doxorubicin hydrochloride IV over 60 minutes on day 1, or topotecan hydrochloride IV over 30 minutes on days 1, 8 and 15 or days 1-5 per the discretion of the treating physician. Cycles repeat every 21 or 28 days in the absence of disease progression or unacceptable toxicity. Patients may undergo echocardiography (ECHO) or multigated acquisition scan (MUGA) during screening and as clinically indicated on study. Patients also undergo collection of blood and computed tomography (CT) with contrast during screening, and CT or magnetic resonance imaging (MRI) scans throughout the trial.

ARM II: Patients receive durvalumab IV over 60 minutes on day 1, cediranib maleate orally (PO) once daily (QD) Monday through Friday, and olaparib PO twice daily (BID) on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients may undergo ECHO or MUGA during screening and as clinically indicated on study. Patients also undergo collection of blood and CT with contrast during screening, and CT or MRI scans throughout the trial.

ARM III: Patients receive durvalumab IV over 60 minutes on day 1 and cediranib maleate PO QD Monday through Friday. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients may undergo ECHO or MUGA during screening and as clinically indicated on study. Patients also undergo collection of blood and CT with contrast during screening, and CT or MRI scans throughout the trial.

ARM IV: Patients receive cediranib maleate PO QD on days 1-28 and olaparib PO BID on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients may undergo ECHO or MUGA during screening and as clinically indicated on study. Patients also undergo collection of blood and CT with contrast during screening, and CT or MRI scans throughout the trial.

After completion of study treatment, patients are followed up periodically for up to 5 years.

Comparison of Standard of Care Treatment With a Triplet Combination of Targeted Immunotherapeutic Agents

A Randomized Phase II Trial of Triplet Therapy (A PD-L1 Inhibitor Durvalumab (MEDI4736) in Combination With Olaparib and Cediranib) Compared to Olaparib and Cediranib or Durvalumab (MEDI4736) and Cediranib or Standard of Care Chemotherapy in Women With Platinum-Resistant Recurrent Epithelial Ovarian Cancer, Primary Peritoneal or Fallopian Cancer Who Have Received Prior Bevacizumab

Will be presented by Kaplan Meier methods.

Quantified as the binomial proportion of patients with measurable disease at enrollment who have a best overall response of complete response (CR) or partial response (PR).

All adverse events, including severe adverse events and treatment-related adverse events, will be categorized and graded for severity according to National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0.

NRG Oncology

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
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	NCT04092270	Endometrial Hig... Fallopian Tube ... Fallopian Tube ... Fallopian Tube ... Fallopian Tube ... Fallopian Tube ... Fallopian Tube ... Fallopian Tube ... FIGO Grade 1 En... FIGO Grade 2 En... Ovarian High Gr... Ovarian Seromuc... Ovarian Undiffe... Platinum-Sensit... Primary Periton... Primary Periton... Primary Periton... Primary Periton... Recurrent Fallo... Recurrent Low G... Recurrent Ovari... Recurrent Ovari... Recurrent Ovari... Recurrent Ovari... Recurrent Ovari... Recurrent Ovari... Recurrent Ovari... Recurrent Prima... Recurrent Prima...	Biospecimen Col... Computed Tomogr... Echocardiograph... Magnetic Resona... Multigated Acqu... Pegylated Lipos... Peposertib	18 Years -	National Cancer Institute (NCI)
Comparison of Standard of Care Treatment With a Triplet Combination of Targeted Immunotherapeutic Agents	NCT04739800	Fallopian Tube ... Ovarian Seromuc... Platinum-Refrac... Platinum-Refrac... Platinum-Refrac... Recurrent Fallo... Recurrent Fallo... Recurrent Fallo... Recurrent Fallo... Recurrent Fallo... Recurrent Fallo... Recurrent Low G... Recurrent Ovari... Recurrent Ovari... Recurrent Ovari... Recurrent Ovari... Recurrent Ovari... Recurrent Ovari... Recurrent Ovari... Recurrent Ovari... Recurrent Plati... Recurrent Plati... Recurrent Plati... Recurrent Prima... Recurrent Prima... Recurrent Prima... Recurrent Prima... Recurrent Prima... Recurrent Prima... Refractory Fall... Refractory Fall... Refractory Fall... Refractory Fall... Refractory Fall... Refractory Fall... Refractory Low ... Refractory Ovar... Refractory Ovar... Refractory Ovar... Refractory Ovar... Refractory Ovar... Refractory Ovar... Refractory Ovar... Refractory Ovar... Refractory Prim... Refractory Prim... Refractory Prim... Refractory Prim... Refractory Prim... Refractory Prim...	Biospecimen Col... Cediranib Malea... Computed Tomogr... Computed Tomogr... Durvalumab Echocardiograph... Magnetic Resona... Multigated Acqu... Olaparib Paclitaxel Pegylated Lipos... Topotecan Hydro...	18 Years -	National Cancer Institute (NCI)

Spots Global Cancer Trial Database for recurrent primary peritoneal low grade serous adenocarcinoma