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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)

Spots Global Cancer Trial Database for recurrent primary peritoneal adenocarcinoma