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
Trial Snapshot
- Phase
- Phase 1
- Status
- Withdrawn
- Enrollment
- 127
- Primary Endpoint
- Incidence of dose-limiting toxicity (Phase I)
Study Overview
Brief 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.
Detailed 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.
Study Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Sequential
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- 18 Years to — (Adult, Older Adult)
- Sex
- Female
- Accepts Healthy Volunteers
- No
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.
- •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
- •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)
Arms & Interventions
Phase II, Arm I (paclitaxel, bevacizumab)
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.
Intervention: Paclitaxel (Drug)
Phase I (paclitaxel, tolinapant, bevacizumab)
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.
Intervention: Bevacizumab (Biological)
Phase I (paclitaxel, tolinapant, bevacizumab)
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.
Intervention: Biospecimen Collection (Procedure)
Phase I (paclitaxel, tolinapant, bevacizumab)
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.
Intervention: Computed Tomography (Procedure)
Phase I (paclitaxel, tolinapant, bevacizumab)
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.
Intervention: Magnetic Resonance Imaging (Procedure)
Phase I (paclitaxel, tolinapant, bevacizumab)
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.
Intervention: Paclitaxel (Drug)
Phase I (paclitaxel, tolinapant, bevacizumab)
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.
Intervention: Tolinapant (Drug)
Phase II, Arm I (paclitaxel, bevacizumab)
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.
Intervention: Bevacizumab (Biological)
Phase II, Arm I (paclitaxel, bevacizumab)
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.
Intervention: Biospecimen Collection (Procedure)
Phase II, Arm I (paclitaxel, bevacizumab)
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.
Intervention: Computed Tomography (Procedure)
Phase II, Arm I (paclitaxel, bevacizumab)
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.
Intervention: Magnetic Resonance Imaging (Procedure)
Phase II, Arm II (paclitaxel, tolinapant, bevacizumab)
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.
Intervention: Bevacizumab (Biological)
Phase II, Arm II (paclitaxel, tolinapant, bevacizumab)
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.
Intervention: Biospecimen Collection (Procedure)
Phase II, Arm II (paclitaxel, tolinapant, bevacizumab)
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.
Intervention: Computed Tomography (Procedure)
Phase II, Arm II (paclitaxel, tolinapant, bevacizumab)
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.
Intervention: Magnetic Resonance Imaging (Procedure)
Phase II, Arm II (paclitaxel, tolinapant, bevacizumab)
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.
Intervention: Paclitaxel (Drug)
Phase II, Arm II (paclitaxel, tolinapant, bevacizumab)
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.
Intervention: Tolinapant (Drug)
Outcomes
Primary Outcomes
Incidence of dose-limiting toxicity (Phase I)
Time Frame: At 28 days
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.
Progression free survival (PFS) (Phase II)
Time Frame: At randomization to progressive disease or death, assessed up to 5 years after completion of study treatment
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.
Secondary Outcomes
- Incidence of adverse events (AEs)(Up to 30 days after last dose of study treatment)
- Duration of response (DOR)(At first response to progression or death, assessed up to 5 years after completion of study treatment)
- Overall survival (OS)(At randomization to death, assessed up to 5 years after completion of study treatment)
- Objective response rate (ORR)(At start of treatment to disease progression/recurrence, assessed up to 5 years after completion of treatment)