A Phase II Evaluation of Pembrolizumab in Combination With IV Bevacizumab and Oral Metronomic Cyclophosphamide in the Treatment of Recurrent Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer
Overview
- Phase
- Phase 2
- Intervention
- Bevacizumab
- Conditions
- Fallopian Tube Clear Cell Adenocarcinoma
- Sponsor
- Roswell Park Cancer Institute
- Enrollment
- 40
- Locations
- 1
- Primary Endpoint
- Incidence of Adverse Events Assessed by Common Terminology Criteria for Adverse Events
- Status
- Completed
- Last Updated
- 4 years ago
Overview
Brief Summary
This phase II trial studies the combination of pembrolizumab, bevacizumab, and low dose oral cyclophosphamide in treating patients with recurrent ovarian, fallopian tube, or primary peritoneal cancer. Monoclonal antibodies, such as pembrolizumab and bevacizumab, may block tumor growth in different ways such as boosting your own immune system to find, recognize and kill tumor cells as well as by blocking the growth of new blood vessels necessary for tumor growth and nutrition. Drugs used in chemotherapy, such as low dose oral cyclophosphamide, work in different ways to stop the growth of tumor cells, either by killing the cells, as well as by further enhancing your own body's immune response against cancer cells. As these three drugs have all been shown to improve the immune response against cancer cells giving pembrolizumab, bevacizumab, and cyclophosphamide together may work better in treating patients with recurrent ovarian, fallopian tube, or primary peritoneal cancer.
Detailed Description
PRIMARY OBJECTIVES: I. To evaluate improvement in progression-free survival for patients treated with anti-programmed cell death 1 (anti-PD1) pembrolizumab in combination with intravenous (IV) bevacizumab and oral metronomic cyclophosphamide as compared to patients treated with other second line chemotherapeutic agents. SECONDARY OBJECTIVES: I. To obtain pilot data on clinical response rates using both Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria and immune related response criteria (irRECIST). II. To obtain data on changes in tumor microenvironment prior to and subsequent to therapy and, to screen for potential biomarkers to predict clinical benefit. III. To determine the safety and tolerability of the treatment combination in the study population. IV. To evaluate overall survival in patients treated with anti-PD1 pembrolizumab in combination with IV bevacizumab and oral metronomic cyclophosphamide. V. To assess the impact of the combination of anti-PD1 pembrolizumab, IV bevacizumab and oral metronomic cyclophosphamide on anti-tumor immune responses in ovarian cancer. OUTLINE: Patients receive pembrolizumab IV over 30 minutes and bevacizumab IV over 30-90 minutes on day 1 and cyclophosphamide orally (PO) once daily (QD) on days 1-21. Treatment repeats every 3 weeks for up to 12 months (or 17 courses) in the absence of disease progression or unacceptable toxicity. Patients without evidence of disease progression may continue treatment in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up at 30 days, then every 3 months for 1 year, and every 12 weeks and 6 months thereafter.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
- •Have measurable disease per RECIST 1.1 criteria present
- •Participant may have serous, endometrioid, clear cell, mucinous or undifferentiated type of recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer
- •Histologic confirmation of the original primary tumor is required via the pathology report
- •Participant can be either platinum-sensitive (platinum free interval \[PFI\] \>= 6 months prior to recent recurrence) or platinum-resistant (PFI \< 6 months prior to recent recurrence). If the participant has a platinum sensitive disease, she may only enroll in this clinical trial if there is a contraindication for her to receive further treatment with platinum-based chemotherapy (such as serious, persistent toxicity or sever hypersensitivity to platinum agents or she declines standard of care).
- •Participant must be willing to undergo core or excisional biopsy of a tumor lesion within 4 weeks (28 days) prior to initiation of treatment on day 1 and after 3 cyles of study treatment; participants for whom newly obtained samples cannot be provided (e.g. inaccessible or subject safety concern) may submit an archived specimen only upon agreement from the principal investigator
- •Absolute neutrophil count (ANC): \>= 1,500 /mcL
- •Platelets: \>= 100,000 / mcL
- •Hemoglobin: \>= 9 g/dL or 5.6 mmol/L without transfusion or erythropoietin (EPO) dependency (within 7 days of assessment)
- •Serum creatinine: =\< 1.5 X upper limit of normal (ULN) OR measured or calculated creatinine clearance \>= 60 mL/min for participant with creatinine levels \> 1.5 X institutional ULN; glomerular filtration rate (GFR) can also be used in place of creatinine or creatinine clearance (CrCl)
Exclusion Criteria
- •Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks of the first dose of treatment
- •Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment or, is taking any other medication that might affect immune function
- •Has a known history of active bacillus tuberculosis (TB)
- •Hypersensitivity to bevacizumab, cyclophosphamide, pembrolizumab or any of its excipients
- •Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study day 1 or who has not recovered (i.e., =\< grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier
- •Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to study day 1 or who has not recovered (i.e., =\< grade 1 or at baseline) from adverse events due to a previously administered agent
- •Note: participants with =\< grade 2 neuropathy are an exception to this criterion and may qualify for the study
- •Note: if participant received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy and, has to be at least 28 days after the surgery
- •Has a known additional malignancy that is progressing or requires active treatment: exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or cervical cancer in situ that has undergone potentially curative therapy
- •Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis; participants with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment; this exception does not include carcinomatous meningitis which is excluded regardless of clinical stability
Arms & Interventions
Treatment (pembrolizumab, bevacizumab, cyclophosphamide)
Patients receive pembrolizumab IV over 30 minutes and bevacizumab IV over 30-90 minutes on day 1 and cyclophosphamide PO QD on days 1-21. Treatment repeats every 3 weeks for up to 17 courses in the absence of disease progression or unacceptable toxicity. Patients without evidence of disease progression may continue treatment in the absence of disease progression or unacceptable toxicity.
Intervention: Bevacizumab
Treatment (pembrolizumab, bevacizumab, cyclophosphamide)
Patients receive pembrolizumab IV over 30 minutes and bevacizumab IV over 30-90 minutes on day 1 and cyclophosphamide PO QD on days 1-21. Treatment repeats every 3 weeks for up to 17 courses in the absence of disease progression or unacceptable toxicity. Patients without evidence of disease progression may continue treatment in the absence of disease progression or unacceptable toxicity.
Intervention: Cyclophosphamide
Treatment (pembrolizumab, bevacizumab, cyclophosphamide)
Patients receive pembrolizumab IV over 30 minutes and bevacizumab IV over 30-90 minutes on day 1 and cyclophosphamide PO QD on days 1-21. Treatment repeats every 3 weeks for up to 17 courses in the absence of disease progression or unacceptable toxicity. Patients without evidence of disease progression may continue treatment in the absence of disease progression or unacceptable toxicity.
Intervention: Laboratory Biomarker Analysis
Treatment (pembrolizumab, bevacizumab, cyclophosphamide)
Patients receive pembrolizumab IV over 30 minutes and bevacizumab IV over 30-90 minutes on day 1 and cyclophosphamide PO QD on days 1-21. Treatment repeats every 3 weeks for up to 17 courses in the absence of disease progression or unacceptable toxicity. Patients without evidence of disease progression may continue treatment in the absence of disease progression or unacceptable toxicity.
Intervention: Pembrolizumab
Outcomes
Primary Outcomes
Incidence of Adverse Events Assessed by Common Terminology Criteria for Adverse Events
Time Frame: Up to 1 year
The highest observed adverse event will be tabulated by grade across all dose levels and cycles.
Progression-free Survival (PFS)
Time Frame: Time from the start of the study treatment until PFS event, assessed up to 1 year after the last subject enrolls
Will be summarized using standard Kaplan-Meier methods, with estimates of median survival and given survival rates will be obtained with 90% confidence intervals.
Secondary Outcomes
- Duration of Overall Survival(Up to 1 year after enrollment of the last subject)
- An Anti-tumor Immune Response in Circulation and Tumor Tissue(Up to 1 year)
- Objective Tumor Response Assessed by Modified RECIST Version 1.1 Criteria(Up to 6 months after enrollment start of treatment)