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Sacituzumab Govitecan with Bevacizumab Compared to Usual Chemotherapy (Carboplatin, Pegylated Liposomal Doxorubicin and Bevacizumab) for Treating Recurrent Platinum-Sensitive Ovarian Cancer after PARP Inhibitor Maintenance Therapy
Trial Status: active
This phase II trial compares the effect of sacituzumab govitecan and bevacizumab to standard care (carboplatin, pegylated liposomal doxorubicin, and bevacizumab) in patients with ovarian cancer that has come back after an initial response to platinum therapy (platinum-sensitive), that has progressed after poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitor maintenance therapy (recurrent), and that has a mutation in the BRCA1 or BRCA2 genes or is homologous recombination deficient. Sacituzumab govitecan is a monoclonal antibody, called sacituzumab, linked to a drug called govitecan. Sacituzumab is a form of targeted therapy because it attaches to specific molecules (receptors) on the surface of cancer cells, known as TROP2 receptors, and delivers govitecan to 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 tumor. This may slow the growth and spread of tumor cells. Carboplatin is in a class of medications known as platinum-containing compounds. Carboplatin works by killing, stopping or slowing the growth of cancer cells. Doxorubicin is in a class of medications called anthracyclines. Doxorubicin damages the cell’s deoxyribonucleic acid (DNA) and may kill cancer cells. It also blocks a certain enzyme needed for cell division and DNA repair. Liposomal doxorubicin is a form of the anticancer drug doxorubicin that is contained inside very tiny, fat-like particles. Liposomal doxorubicin may have fewer side effects and work better than other forms of the drug. Giving sacituzumab govitecan and bevacizumab may kill more tumor cells than standard care (carboplatin, pegylated liposomal doxorubicin, and bevacizumab) in patients with recurrent platinum-sensitive ovarian cancers that have BRCA1/2 mutations or homologous recombination deficiency.
Inclusion Criteria
Patients must have histologic diagnosis of high grade serous or endometrioid epithelial ovarian cancer
* Ovarian cancer = fallopian tube, ovarian, and primary peritoneal cancer
Disease must be platinum sensitive, as defined by progression documented ≥ 6 months (182 days) from the last receipt of platinum
Disease must have progressed during first line maintenance PARP inhibitor (PARPi) for advanced ovarian cancer. NO intervening therapies between progression on PARPi and study registration are permitted
Disease must be germline or somatic BRCA1 or BRCA2 mutated or homologous recombination deficiency test positive
Disease must be measurable or non-measurable as defined by Response Evaluation Criteria in Solid Tumors (RECIST) version (v.) 1.1
Secondary or cytoreductive surgery, after start of treatment on this trial, and prior to documentation of disease progression, is NOT permitted
No previous receipt of any topoisomerase-I inhibiting agents
No investigational agents within 4 weeks of study registration
No current treatment with any other (non-study) cytotoxic chemotherapy, targeted therapy, biologic therapy, immunotherapy or endocrine therapy for the treatment of the disease under the current study
Last dose of PARP inhibitor treatment must be ≥ 3 weeks before study registration
Patients with treated brain metastases are eligible if follow-up brain imaging 4 weeks after CNS-directed therapy shows no evidence of disease progression. Patients with brain metastases must have follow up imaging demonstrating no evidence of disease progression and that the disease is stable off of steroids
Age ≥ 18
Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2
Hemoglobin ≥ 9 g/dl (Note: The use of transfusion or other intervention to achieve hemoglobin [Hgb] ≥ 9 g/dl is acceptable)
Creatinine clearance (CrCL) of ≥ 30 mL/min by the Cockcroft-Gault formula
Urinalysis with ≤ 1+ protein and/or urine protein < 1.0 g/24 hours (hrs)
Total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN) (patients with known Gilbert’s disease who have bilirubin level ≤ 3 x institutional ULN may be enrolled)
Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3 x institutional ULN
Patients with 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
No active infection requiring parenteral antibiotics
No non-healing wound, ulcer, or bone fracture
No current evidence of intra-abdominal abscess, abdominal/pelvic fistula (not diverted), gastrointestinal perforation, gastrointestinal (GI) obstruction, and/or need for drainage nasogastric or gastrostomy tube
No clinically significant bleeding within 28 days prior to registration
No uncontrolled hypertension, defined as systolic ≥ 160 mm Hg or diastolic ≥ 100 mm Hg
Patients who have not recovered from adverse events due to prior anti-cancer therapy (i.e., have residual toxicities > grade 1) with the following exceptions:
* Patients with grade 2 or lower neuropathy, any grade alopecia, well controlled hypertension, thyroid disease controlled with therapy, and history of thromboembolic disease on anticoagulation are eligible
* Patients with laboratory-based grade 2 or higher adverse events (AEs) that meet the criteria outlined above are eligible
No major surgery within 3 weeks prior to study registration
Patients who underwent major surgery must have recovered adequately from any toxicity and/or complications from surgery prior to study registration
No strong inhibitors or inducers of UGT1A1
No history of allergic reaction to the study agent(s), compounds of similar chemical or biologic composition to the study agent(s) (or any of its excipients)
Study sponsor and potential other locations can be found on ClinicalTrials.gov for NCT07504588.
I. To assess the clinical activity of sacituzumab govitecan (sacituzumab govitecan-hziy [SG]) and bevacizumab (or an anti-VEGF antibody biosimilar) compared to standard of care carboplatin, pegylated liposomal doxorubicin hydrochloride (pegylated liposomal doxorubicin [PLD]) and bevacizumab (or an anti-VEGF antibody biosimilar), as measured by progression-free survival, in patients with platinum-sensitive ovarian cancer that has progressed while receiving first-line PARP inhibitor maintenance therapy.
SECONDARY OBJECTIVES:
I. To assess additional measures of clinical activity of SG and bevacizumab compared to standard of care carboplatin, PLD and bevacizumab in patients with recurrent platinum-sensitive ovarian cancer, as measured by the overall response rate, duration of response, and overall survival.
II. To assess the safety of SG and bevacizumab in patients with recurrent platinum-sensitive ovarian cancer.
III. To assess the effect of SG and bevacizumab on overall survival in recurrent platinum-sensitive ovarian cancer.
EXPLORATORY OBJECTIVES:
I. To correlate clinical activity of SG and bevacizumab with TROP2 expression and tumor-specific cell-free deoxyribonucleic acid (cfDNA).
II. To assess time to first subsequent therapy or death (TFST).
III. To assess time to second subsequent therapy or death (TSST).
OUTLINE: Patients are randomized to 1 of 2 arms.
ARM I: Patients receive carboplatin intravenously (IV) on day 1, PLD IV on day 1 (or gemcitabine IV on days 1 and 8), and bevacizumab (or anti-VEGF antibody biosimilar) IV on days 1 and 15 of each cycle. Cycles repeat every 21 days for 6-10 cycles in the absence of disease progression or unacceptable toxicity. After 6-10 cycles, patients proceed to maintenance therapy.
ARM II: Patients receive SG IV over 1-3 hours on days 1 and 8 and bevacizumab (or anti-VEGF antibody biosimilar) IV on day 1 of each cycle. Cycles repeat every 21 days for 6-10 cycles in the absence of disease progression or unacceptable toxicity. After 6-10 cycles, patients proceed to maintenance therapy.
MAINTENANCE: Patients receive bevacizumab (or anti-VEGF antibody biosimilar) IV on day 1 of each cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.
Patients in Arm I also undergo echocardiography (ECHO) or multigated acquisition scan (MUGA) at screening and all patients undergo computed tomography (CT) and/or magnetic resonance imaging (MRI) and collection of blood samples throughout the trial.
After completion of study treatment, patients are followed up every 3 months for 2 years and then every 6 months for 3 years.
