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Albumin-Bound Paclitaxel

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Patients receive paclitaxel IV on days 1, 8 and 15, bevacizumab IV on days 1 and 15, and ASTX660 PO on days 1-7 and 15-21 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Additionally, patients undergo blood sample collection, CT and MRI throughout the study.

Patients receive paclitaxel IV on days 1, 8, and 15 of each cycle. Patients may also receive bevacizumab IV on days 1 and 15 of each cycle per provider. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Additionally, patients undergo blood sample collection, CT and MRI throughout the study.

Patients receive paclitaxel IV on days 1, 8, and 15 and ASTX660 PO on days 1-7 and 15-21 of each cycle. Patients may also receive bevacizumab IV on days 1 and 15 of each cycle per provider. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Additionally, patients undergo blood sample collection, CT and MRI throughout the study.

Biospecimen Collection

Computed Tomography

Magnetic Resonance Imaging

Tolinapant

Kristen P Zeligs

This phase I/II trial tests the safety, best dose and effectiveness of adding tolinapant (ASTX660) to paclitaxel with or without bevacizumab in treating patients with ovarian cancer that has come back after a period of improvement (recurrent). Tolinapant may stop the growth of tumor cells by blocking proteins, such as XIAP and cIAP1, that promote the growth of tumor cells and increase resistance to chemotherapy. Paclitaxel is in a class of medications called antimicrotubule agents. It stops tumor cells from growing and dividing and may kill them. Bevacizumab is in a class of medications called antiangiogenic agents. It works by stopping the formation of blood vessels that bring oxygen and nutrients to the tumor. This may slow the growth and spread of tumor cells. Adding ASTX660 to paclitaxel with or without bevacizumab may be safe, tolerable and/or effective in treating patients with recurrent ovarian cancer.

PRIMARY OBJECTIVES:

I. To assess the safety and tolerability of adding ASTX660 (tolinapant) to a regimen of weekly paclitaxel with bevacizumab. (Phase I) II. To determine the recommended phase 2 dose (RP2D) for the combination of ASTX660 (tolinapant) and weekly paclitaxel with bevacizumab. (Phase I) III. To assess the efficacy of adding ASTX660 (tolinapant) to weekly paclitaxel, with or without bevacizumab (investigator choice), as measured by progression free survival (PFS). (Phase II)

SECONDARY OBJECTIVES:

I. To assess the objective response rate (ORR) of the addition of ASTX660 (tolinapant) to weekly paclitaxel with or without bevacizumab as compared to weekly paclitaxel with or without bevacizumab.

II. To assess overall survival.

EXPLORATORY OBJECTIVE:

I. To explore whether lack of cIAP1 expression results in no benefit for the addition of ASTX660 (tolinapant) to weekly paclitaxel +/- bevacizumab.

OUTLINE: This is a phase I, dose escalation study of ASTX660 and paclitaxel with or without bevacizumab followed by a dose expansion study. The phase II study will follow completion of the phase I study.

PHASE I:

Patients receive paclitaxel intravenously (IV) on days 1, 8 and 15, bevacizumab IV on days 1 and 15, and ASTX660 orally (PO) on days 1-7 and 15-21 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Additionally, patients undergo blood sample collection, computed tomography (CT) and magnetic resonance imaging (MRI) throughout the study.

PHASE II: Patients are randomized to 1 of 2 arms.

ARM I (CONTROL): Patients receive paclitaxel IV on days 1, 8, and 15 of each cycle. Patients may also receive bevacizumab IV on days 1 and 15 of each cycle per provider. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Additionally, patients undergo blood sample collection, CT and MRI throughout the study.

ARM II (EXPERIMENTAL): Patients receive paclitaxel IV on days 1, 8, and 15 and ASTX660 PO on days 1-7 and 15-21 of each cycle. Patients may also receive bevacizumab IV on days 1 and 15 of each cycle per provider. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Additionally, patients undergo blood sample collection, CT and MRI throughout the study.

After completion of study treatment, patients are followed up every 3 months for 2 years then every 6 months for 3 years.

Testing the Addition of ASTX660 (Tolinapant) to the Usual Chemotherapy Treatment (Paclitaxel With or Without Bevacizumab) in Patients With Recurrent Ovarian Cancer

A Randomized Phase 1/2 Trial Evaluating the Addition of Tolinapant to Weekly Paclitaxel With or Without Bevacizumab in Patients With Recurrent Epithelial Ovarian Cancer

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.

Will evaluate whether lack of cIAP1 expression results in no benefit for the addition of ASTX660 to weekly paclitaxel. The null hypothesis of no predictive effect of cIAP1 on clinical outcomes will be assessed using the type 3 score test for the interaction of the randomized treatment assignment and the patient-level cIAP1 histopathological-score classification (positive, reference negative). The type 3 test result will be obtained from a multivariable Cox regression model model specified with main effects for the randomized treatment assignment and the cIAP1 classification (negative/positive), and the interaction term. The model may be stratified by bevacizumab use. Treatment hazard ratios and 95% confidence intervals will be estimated within the cIAP1 subgroups, and graphed in a forest plot to assess qualitative interactions.

ORR will be compared among patients enrolled in the phase I/Ib parts of the trial. Treatment effect estimates of clinical benefit will be descriptive.

PFS will be compared among patients enrolled in the phase I/Ib parts of the trial. Treatment effect estimates of clinical benefit will be descriptive. Dose level effects on PFS will be described using Kaplan Meier methods. Treatment effectiveness will be quantified using estimates for the proportion of patients who are alive without documented progression 6 months after starting treatment.

OS will be compared among patients enrolled in the phase I/Ib parts of the trial. Treatment effect estimates of clinical benefit will be descriptive. Dose level effects on oS will be described using Kaplan Meier methods. Treatment effectiveness will be quantified using estimates for the proportion of patients who are alive 6 months after starting treatment.

Assessed using the Bayesian Optimal Interval design. Toxicity will be graded using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version (v)5.0.

The primary hypothesis test will be based on a logrank test, stratified on factors declared at randomization. The PFS hazard ratio will be estimated by Cox regression, stratified by factors declared at randomization. The treatment hazard ratio estimates and their 95% confidence intervals will be estimated using proportional hazards models specified to be consistent with the logrank tests.

AEs will be defined as any untoward medical occurrence associated wtih the use of a drug in humans, whether or not considered drug related. AEs will be graded using NCI CTCAE v5.0. All AEs will be summarized.

OS will be defined as the time from randomization to death from any cause. The OS treatment hypothesis will be based on a logrank test, stratified by the factors specified at randomization. Comparisons of the OS distributions by treatment arm will be described using Kaplan-Meier methods. Treatment hazard ratio estimates and their 95% confidence intervals will be estimated using a multivariable proportional hazards model specified with main effects for the randomization treatment assignment and stratified by the factors declared at randomization.

ORR will be defined as the binomial proportion of evaluable patients with a best overall response of complete response (CR) or partial response (PR) by Response Evaluation Criteria in Solid Tumors. The ORR estimates by treatment arm will be supported by their 2-sided, 95% Wilson-Score confidence intervals. The relative odds of response in the experimental arm will be estimated using a multivariable logistic regression model specified with main effects for the treatment groups and stratified by the stratification factors reported at baseline.

DOR will be defined as the time from first documentation of either PR or CR until disease progression or death, whichever is observed first. Treatment group differences in response duration will be graphed using Kaplan-Meier methods and compared using logrank tests, stratified by the factors declared at randomization. The relative hazards of progression or death in each group will be estimated using similarly stratified proportional hazards regression model specified with main effects for the treatment indicator.

National Cancer Institute (NCI)

Carcinoma, Transitional Cell

Adenocarcinoma, Mucinous

Transitional Cell Carcinoma

Anti-Infective Agents

Doxorubicin

Liposomal doxorubicin

Topotecan

Immunomodulating Agents

Durvalumab

Olaparib

Poly(ADP-ribose) Polymerase Inhibitors

Maleic acid

Cediranib

Anti-Bacterial Agents

Antibiotics, Antitubercular

Enzyme Inhibitors

Topoisomerase I Inhibitors

Protein Kinase 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

Echocardiography

Multigated Acquisition Scan

Pegylated Liposomal Doxorubicin Hydrochloride

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
Testing the Addition of ASTX660 (Tolinapant) to the Usual Chemotherapy Treatment (Paclitaxel With or Without Bevacizumab) in Patients With Recurrent Ovarian Cancer	NCT06393751	Platinum-Refrac... Platinum-Refrac... Platinum-Refrac... Recurrent Fallo... Recurrent Fallo... Recurrent Fallo... Recurrent Fallo... Recurrent Fallo... Recurrent High ... 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...	Bevacizumab Biospecimen Col... Computed Tomogr... Magnetic Resona... Paclitaxel Tolinapant	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 ovarian seromucinous carcinoma