A Randomized Phase 2 Study of Cabozantinib in Combination With Nivolumab in Advanced, Recurrent Metastatic Endometrial Cancer
Overview
- Phase
- Phase 2
- Intervention
- Biopsy Procedure
- Conditions
- Not specified
- Sponsor
- National Cancer Institute (NCI)
- Enrollment
- 82
- Locations
- 34
- Primary Endpoint
- Progression free survival (PFS)
- Status
- Active, not recruiting
- Last Updated
- 9 months ago
Overview
Brief Summary
This randomized phase II trial studies how well cabozantinib s-malate and nivolumab work in treating patients with endometrial cancer that has come back (recurrent) or spread to other places in the body (advanced or metastatic). Cabozantinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Immunotherapy with monoclonal antibodies, such as nivolumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving cabozantinib and nivolumab may work better in treating endometrial cancer.
Detailed Description
PRIMARY OBJECTIVE: I. To evaluate the clinical anti-tumor activity of cabozantinib s-malate (XL184 (\[cabozantinib\]) and nivolumab based on progression free survival (PFS) in patients with advanced, recurrent or metastatic endometrial cancer previously treated with at least one line of platinum-based chemotherapy compared to patients receiving nivolumab alone. SECONDARY OBJECTIVES: I. To evaluate the efficacy of XL184 and nivolumab in terms of overall response rate (ORR) compared to nivolumab alone. II. To evaluate overall survival (OS) of patients receiving XL184 and nivolumab compared to patients receiving nivolumab alone. III. To evaluate the safety of combination treatment using XL184 and nivolumab in patients with advanced, recurrent metastatic endometrial cancer. IV. To evaluate correlation between PD-L1 expression, CD3, CD4 and CD8 infiltrates and outcome (PFS, ORR, OS). V. To compare PD-L1 expression, CD3, CD4 and CD8 infiltrates in the primary tumor (archival tissue) and in the tissue from baseline biopsy. VI. To assess activity (PFS, ORR and OS) of nivolumab alone or in combination with XL184 according to microsatellite instability (MSI)/mismatched repair (MMR) status. EXPLORATORY OBJECTIVES: I. To assess activity (PFS, ORR and OS) of XL184 and nivolumab in patients progressed after previous exposure to anti PD-1, PD-L1 or PD-L2 agents or crossed-over from single agent nivolumab, and in patients with diagnosis of carcinosarcoma. II. To compare microsatellite (MS) and MMR status, in the primary tumor (archival tissue) and in the tissue from baseline biopsy. III. To assess the genomic and immune-markers landscape at baseline on tumor tissue and changes in immune landscape in peripheral blood during treatment and correlate with outcome. OUTLINE: Patients are randomized to 1 of 2 arms. ARM A: Patients receive cabozantinib s-malate orally (PO) once daily (QD) on days 1-28 and nivolumab intravenously (IV) over 30 minutes on days 1 and 15, then on day 1 beginning cycle 5. Patients undergo computed tomography (CT) scan, magnetic resonance imaging (MRI), and blood sample collection throughout the study and undergo biopsy at screening and optionally at follow up. ARM B: Patients receive nivolumab as in Arm A. Patients may cross-over to Arm A at the time of disease progression. Patients undergo CT scan, MRI, and blood sample collection throughout the study and undergo biopsy at screening and optionally at follow up. In both arms, cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up at 30-37 days, then every 8-12 weeks.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Patients must have histologically or cytologically confirmed epithelial endometrial carcinoma; all histologies are accepted; patients with diagnosis of endometrial carcinosarcoma will be enrolled in the exploratory cohort (arm C) and will receive combination of cabozantinib and nivolumab
- •Patients must have advance, recurrent or metastatic endometrial cancer
- •Patients must have radiological evidence of disease progression following the most recent treatment
- •Patients must have measurable disease according Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1 criteria
- •Must have MS/MMR result available at time of registration; MS/MMR status is to be determined per local practice (i.e. immunohistochemistry \[IHC\], polymerase chain reaction \[PCR\], or other methods)
- •Prior therapy: eligible subjects must have had at least one line of platinum-based chemotherapy; this may be adjuvant therapy or first line of cytotoxic therapy for metastatic disease; prior hormonal therapy for metastatic/recurrent disease, prior targeted therapy, and prior radiotherapy are allowed; no maximum number of previous lines of chemotherapies; concomitant chemo-radiation is not considered as previous line of systemic chemotherapy
- •Availability of archival tissue for correlative analysis
- •Age \>=18 years. Because no dosing or adverse event data are currently available on the use of cabozantinib and nivolumab in patients \< 18 years of age, children are excluded from this study, but will be eligible for future pediatric trials
- •Eastern Cooperative Oncology Group (ECOG) performance status 0-2
- •Absolute neutrophil count \>= 1,500/mcL
Exclusion Criteria
- •Patients who have had chemotherapy (including investigational cytotoxic chemotherapy), biologic agents (e.g. targeted therapy or antibodies) or radiotherapy within 4 weeks prior to the first dose of study treatment
- •Patients who have not recovered from adverse events attributed to prior anti-cancer therapy (i.e. have residual toxicities \> grade 1, except for alopecia, neuropathy, lymphocytopenia and other non-clinically significant adverse events)
- •Patients who are receiving any other investigational agents
- •Patients should be excluded if they have had prior treatment with anti-CTLA-4 antibody or any other antibody or drug specifically targeting T-cell co-stimulation; previous treatment with anti-PD-1, anti-PD-L1 or anti-PD-L2 is allowed and patients will be enrolled in the exploratory cohort (arm C) at the time of progression from last line of treatment (treatment with immune check point inhibitor does not have to necessary be the last line of treatment)
- •Patients should be excluded if they have had prior treatment with cabozantinib; previous use of other antiangiogenic agents other than cabozantinib is allowed
- •Any other active malignancy other than the endometrial cancer, that is progressing or requiring active treatment with the exception of basal or squamous cell skin cancer, superficial bladder cancer, carcinoma in situ of any site
- •Patients with known brain metastases should be excluded from this clinical trial because of their poor prognosis and because of the possible increased risk of bleeding if treatment with antiangiogenic agents is provided; patients with history of brain metastases can enroll provided the brain metastases were removed and controlled with no radiological evidence within the past 6 months
- •Patients requiring concomitant treatment, in therapeutic doses, with anticoagulants such as warfarin or warfarin-related agents, heparin, thrombin or factor Xa inhibitors, antiplatelet agents (e.g. clopidogrel) or new oral anticoagulants; low-dose aspirin (=\< 81 mg/day), and prophylactic low molecular weight heparin (LMWH) are permitted
- •History of allergic reactions attributed to compounds of similar chemical or biologic composition to cabozantinib or nivolumab
- •Patients require chronic concomitant treatment of strong CYP450 3A4 inducers (e.g. dexamethasone, phenytoin, carbamazepine, rifampicin, rifabutin, rifapentine, phenobarbital, St. John's wort) or inhibitors (e.g. ketoconazole, miconazole, itraconazole, voriconazole, posaconazole, clarithromycin, telithromycin, indinavir, saquinavir, ritonavir, nelfinavir, amprenavir, fosamprenavir nefazodone, lopinavir, troleandomycin, mibefradil and conivaptan); because the lists of these agents are constantly changing, it is important to regularly consult a frequently-updated list, medical reference texts such as the Physicians' Desk Reference may also provide this information; as part of the enrollment/informed consent procedures, the patient will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the patient is considering a new over-the-counter medicine or herbal product
Arms & Interventions
Arm A (cabozantinib s-malate, nivolumab)
Patients receive cabozantinib s-malate PO QD on days 1-28 and nivolumab IV over 30 minutes on days 1 and 15, then on day 1 beginning cycle 5. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo CT scan, MRI, and blood sample collection throughout the study and undergo biopsy at screening and optionally at follow up.
Intervention: Biopsy Procedure
Arm A (cabozantinib s-malate, nivolumab)
Patients receive cabozantinib s-malate PO QD on days 1-28 and nivolumab IV over 30 minutes on days 1 and 15, then on day 1 beginning cycle 5. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo CT scan, MRI, and blood sample collection throughout the study and undergo biopsy at screening and optionally at follow up.
Intervention: Biospecimen Collection
Arm A (cabozantinib s-malate, nivolumab)
Patients receive cabozantinib s-malate PO QD on days 1-28 and nivolumab IV over 30 minutes on days 1 and 15, then on day 1 beginning cycle 5. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo CT scan, MRI, and blood sample collection throughout the study and undergo biopsy at screening and optionally at follow up.
Intervention: Cabozantinib S-malate
Arm A (cabozantinib s-malate, nivolumab)
Patients receive cabozantinib s-malate PO QD on days 1-28 and nivolumab IV over 30 minutes on days 1 and 15, then on day 1 beginning cycle 5. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo CT scan, MRI, and blood sample collection throughout the study and undergo biopsy at screening and optionally at follow up.
Intervention: Computed Tomography
Arm A (cabozantinib s-malate, nivolumab)
Patients receive cabozantinib s-malate PO QD on days 1-28 and nivolumab IV over 30 minutes on days 1 and 15, then on day 1 beginning cycle 5. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo CT scan, MRI, and blood sample collection throughout the study and undergo biopsy at screening and optionally at follow up.
Intervention: Magnetic Resonance Imaging
Arm A (cabozantinib s-malate, nivolumab)
Patients receive cabozantinib s-malate PO QD on days 1-28 and nivolumab IV over 30 minutes on days 1 and 15, then on day 1 beginning cycle 5. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo CT scan, MRI, and blood sample collection throughout the study and undergo biopsy at screening and optionally at follow up.
Intervention: Nivolumab
Arm B (nivolumab)
Patients receive nivolumab as in Arm A. Patients may cross-over to Arm A at the time of disease progression. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo CT scan, MRI, and blood sample collection throughout the study and undergo biopsy at screening and optionally at follow up.
Intervention: Biopsy Procedure
Arm B (nivolumab)
Patients receive nivolumab as in Arm A. Patients may cross-over to Arm A at the time of disease progression. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo CT scan, MRI, and blood sample collection throughout the study and undergo biopsy at screening and optionally at follow up.
Intervention: Biospecimen Collection
Arm B (nivolumab)
Patients receive nivolumab as in Arm A. Patients may cross-over to Arm A at the time of disease progression. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo CT scan, MRI, and blood sample collection throughout the study and undergo biopsy at screening and optionally at follow up.
Intervention: Computed Tomography
Arm B (nivolumab)
Patients receive nivolumab as in Arm A. Patients may cross-over to Arm A at the time of disease progression. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo CT scan, MRI, and blood sample collection throughout the study and undergo biopsy at screening and optionally at follow up.
Intervention: Magnetic Resonance Imaging
Arm B (nivolumab)
Patients receive nivolumab as in Arm A. Patients may cross-over to Arm A at the time of disease progression. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo CT scan, MRI, and blood sample collection throughout the study and undergo biopsy at screening and optionally at follow up.
Intervention: Nivolumab
Outcomes
Primary Outcomes
Progression free survival (PFS)
Time Frame: Up to 1 year
Secondary Outcomes
- Overall response rate (ORR)(Up to 1 year)
- Overall survival (OS)(Up to 1 year)
- Incidence of adverse events(Up to 1 year)
- PD-L1 expression, CD3, CD4 and CD8 analysis(Up to 1 year)