Clinical trial NCT06393751: Testing the Addition of ASTX660 (Tolinapant) to the Usual Chemotherapy Treatment (Paclitaxel With or Without Bevacizumab) in Patients With Recurrent Ovarian Cancer
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
Study type: INTERVENTIONAL
Overall status: WITHDRAWN
Phase: PHASE1
PHASE2
Conditions: Platinum-Refractory Fallopian Tube Carcinoma
Platinum-Refractory Ovarian Carcinoma
Platinum-Refractory Primary Peritoneal Carcinoma
Recurrent Fallopian Tube Adenocarcinoma
Recurrent Fallopian Tube Carcinosarcoma
Recurrent Fallopian Tube Clear Cell Adenocarcinoma
Recurrent Fallopian Tube High Grade Serous Adenocarcinoma
Recurrent Fallopian Tube Undifferentiated Carcinoma
Recurrent High Grade Endometrioid Adenocarcinoma
Recurrent Ovarian Adenocarcinoma
Recurrent Ovarian Carcinosarcoma
Recurrent Ovarian Clear Cell Adenocarcinoma
Recurrent Ovarian High Grade Serous 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 Adenocarcinoma
Recurrent Primary Peritoneal Carcinosarcoma
Recurrent Primary Peritoneal Clear Cell Adenocarcinoma
Recurrent Primary Peritoneal High Grade Serous Adenocarcinoma
Recurrent Primary Peritoneal Undifferentiated Carcinoma
Lead sponsor: National Cancer Institute (NCI)
Sponsor class: NIH
First posted: 2024-05-01
Enrollment: 0
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

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.

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.

Eligibility criteria: 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)

Primary outcomes:
measure: Incidence of dose-limiting toxicity (Phase I)
timeFrame: At 28 days
measure: Progression free survival (PFS) (Phase II)
timeFrame: At randomization to progressive disease or death, assessed up to 5 years after completion of study treatment
Secondary outcomes:
measure: Incidence of adverse events (AEs)
timeFrame: Up to 30 days after last dose of study treatment
measure: Overall survival (OS)
timeFrame: At randomization to death, assessed up to 5 years after completion of study treatment
measure: Objective response rate (ORR)
timeFrame: At start of treatment to disease progression/recurrence, assessed up to 5 years after completion of treatment
measure: Duration of response (DOR)
timeFrame: At first response to progression or death, assessed up to 5 years after completion of study treatment
Other outcomes:
measure: Lack of cIAP1 expression
timeFrame: Up to 5 years after completion of study treatment
measure: ORR (Phase I/Ib)
timeFrame: Up to 5 years after completion of study treatment
measure: PFS (Phase I/Ib)
timeFrame: Up to 6 months after starting treatment
measure: OS (Phase I/Ib)
timeFrame: Up to 6 months after starting treatment
Locations:
Study officials:
affiliation: NRG Oncology
name: Kristen P Zeligs
role: PRINCIPAL_INVESTIGATOR
References: