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

Recurrent Platinum-Resistant Ovarian Carcinoma Clinical Trial

Official title:

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

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT06393751
• Other study ID #: NCI-2024-03344
• Secondary ID: NCI-2024-03344NR
• Status: Not yet recruiting
• Phase: Phase 1/Phase 2
• Start date: June 21, 2024
• Est. completion date: February 9, 2028

Study information

• Verified date: May 2024
• Source: National Cancer Institute (NCI)
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Description:

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.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 127
• Est. completion date: February 9, 2028
• Est. primary completion date: February 9, 2028
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Pathologically (histologically or cytologically) proven diagnosis of high grade epithelial ovarian, fallopian tube, or primary peritoneal cancer. Required: submission of pathology report

• Patients with the following histologic cell types are eligible:

• High grade serous

• Endometrioid, grade 3

• Clear cell

• Undifferentiated

• Mixed epithelial

• Carcinosarcoma

• Adenocarcinoma, not otherwise specified (NOS)

• Patients must be considered to have platinum-resistant or platinum-refractory recurrent ovarian cancer to be enrolled in this trial

• Platinum-resistant disease is defined as progression within < 6 months from completion of platinum-based therapy. The date should be calculated from the last administered dose of platinum therapy

• Platinum-refractory disease is defined as progression within 30 days of completing the last dose of platinum during initial therapy. The date should be calculated from the last administered dose of platinum therapy

• Patients must have evaluable disease or measurable disease defined by Response Evaluation Criteria in Solid Tumors (RECIST) version (v) 1.1. Measurable disease is defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded). Each lesion must be = 10 mm when measured by CT or MRI. Lymph nodes must be = 15 mm in short axis when measured by CT or MRI. Previously irradiated lesions can be considered as measurable disease only if progressive disease has been unequivocally documented at that site since radiation

• Patients with treated brain metastases are eligible if follow up brain imaging after central nervous system (CNS) directed therapy shows no evidence of progression

• Patients must have received = 1 platinum-based therapy and not more than 5 prior lines of therapies. Notes:

• Adjuvant/neoadjuvant therapy is counted as only 1 regimen in the absence of intervening progression.

• Maintenance therapy (e.g., bevacizumab, poly adenosine diphosphate-ribose polymerase [PARP] inhibitor will be considered part of the preceding line of therapy [i.e., not counted independently])

• Therapy changed due to toxicity in the absence of progression will be considered part of the same line (i.e., not counted independently)

• Hormonal therapy will not be counted as a separate line of therapy

• Age = 18

• Eastern Cooperative Oncology Group (ECOG) performance status = 2

• Absolute neutrophil count (ANC) = 1,500 cells/mm^3

• Platelets = 100,000 cells/mm^3

• Hemoglobin = 8 g/dl

• Creatinine = institutional upper limit of normal (ULN), OR calculated creatinine clearance (CrCL) of = 50 mL/min by the Cockcroft-Gault formula

• Total bilirubin = 1.5 x institutional upper limit of normal (ULN) (patients with known Gilbert's disease who have bilirubin level = 3 x ULN may be enrolled)

• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) = 3 x institutional ULN

• Patients with a 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

• 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

• The patient or a legally authorized representative must provide study-specific informed consent prior to study entry and, for patients treated in the United States (U.S.), authorization permitting release of personal health information

• No active infection requiring parental antibiotics

• No evidence of intra-abdominal abscess, abdominal/pelvic fistula, gastrointestinal perforation, gastrointestinal (GI) obstruction, and/or with drainage gastrostomy tube required. NOTE: required interval since last bowel obstruction: 30 day minimum for incomplete obstruction, resolved with conservative means; 6 months for fistula

Exclusion Criteria:

• Patients who have received prior weekly paclitaxel in a platinum-resistant setting

• Major surgical procedure within 28 days prior to registration, or anticipation of need for major surgical procedure during the study. Note: Placement of a vascular access device, thoracentesis, and/or paracentesis will not be considered major surgery

• Women who are pregnant or are unwilling to discontinue nursing

• Evidence of bleeding diathesis or clinically significant coagulopathy within the past 3 months. Patients are not excluded for past or current use of anticoagulation

• Uncontrolled hypertension (systolic blood pressure [SBP] > 150 and/or diastolic blood pressure [DBP] > 90)

• Patients currently taking and unwilling/unable to discontinue the use of drugs that are known to inhibit or induce P-glycoprotein (gp)

Related Conditions & MeSH terms

• Adenocarcinoma
• Carcinoma
• Carcinoma, Endometrioid
• Carcinoma, Ovarian Epithelial
• Carcinosarcoma
• Fallopian Tube Neoplasms
• Mixed Tumor, Mullerian
• Ovarian Neoplasms
• Platinum-Refractory Fallopian Tube Carcinoma
• Platinum-Refractory Ovarian Carcinoma
• Platinum-Refractory Primary Peritoneal Carcinoma
• Recurrence
• Recurrent Fallopian Tube Clear Cell Adenocarcinoma
• Recurrent Fallopian Tube Undifferentiated Carcinoma
• Recurrent Ovarian Carcinosarcoma
• Recurrent Ovarian Clear Cell Adenocarcinoma
• Recurrent Ovarian Seromucinous Carcinoma
• Recurrent Ovarian Undifferentiated Carcinoma
• Recurrent Platinum-Resistant Fallopian Tube Carcinoma
• Recurrent Platinum-Resistant Ovarian Carcinoma
• Recurrent Platinum-Resistant Primary Peritoneal Carcinoma
• Recurrent Primary Peritoneal Clear Cell Adenocarcinoma
• Recurrent Primary Peritoneal High Grade Serous Adenocarcinoma
• Recurrent Primary Peritoneal Undifferentiated Carcinoma

Intervention

Biological:
• Bevacizumab
Given IV

Procedure:
• Biospecimen Collection
Undergo blood sample collection
• Computed Tomography
Undergo CT
• Magnetic Resonance Imaging
Undergo MRI

Drug:
• Paclitaxel
Given IV
• Tolinapant
Given PO

Locations

Country	Name	City	State
n/a

Sponsors (1)

Lead Sponsor	Collaborator
National Cancer Institute (NCI)

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Lack of cIAP1 expression	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.	Up to 5 years after completion of study treatment
Other	ORR (Phase I/Ib)	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.	Up to 5 years after completion of study treatment
Other	PFS (Phase I/Ib)	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.	Up to 6 months after starting treatment
Other	OS (Phase I/Ib)	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.	Up to 6 months after starting treatment
Primary	Incidence of dose-limiting toxicity (Phase I)	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.	At 28 days
Primary	Progression free survival (PFS) (Phase II)	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.	At randomization to progressive disease or death, assessed up to 5 years after completion of study treatment
Secondary	Incidence of adverse events (AEs)	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.	Up to 30 days after last dose of study treatment
Secondary	Overall survival (OS)	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.	At randomization to death, assessed up to 5 years after completion of study treatment
Secondary	Objective response rate (ORR)	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.	At start of treatment to disease progression/recurrence, assessed up to 5 years after completion of treatment
Secondary	Duration of response (DOR)	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.	At first response to progression or death, assessed up to 5 years after completion of study treatment