Pembrolizumab, Bevacizumab, and Cyclophosphamide in Treating Patients With Recurrent Ovarian, Fallopian Tube, or Primary Peritoneal Cancer

NCT02853318CompletedPHASE2INTERVENTIONAL

Summary

Key Facts

Lead Sponsor

Roswell Park Cancer Institute

Enrollment

40

Start Date

2016-09-01

Completion Date

2019-06-27

Study Type

INTERVENTIONAL

Official Title

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

Interventions

BevacizumabCyclophosphamideLaboratory Biomarker AnalysisPembrolizumab

Conditions

Fallopian Tube Clear Cell AdenocarcinomaFallopian Tube Endometrioid AdenocarcinomaFallopian Tube Mucinous AdenocarcinomaFallopian Tube Serous AdenocarcinomaOvarian Clear Cell AdenocarcinomaOvarian Endometrioid AdenocarcinomaOvarian Mucinous AdenocarcinomaOvarian Serous AdenocarcinomaPrimary Peritoneal Serous AdenocarcinomaRecurrent Fallopian Tube CarcinomaRecurrent Ovarian CarcinomaRecurrent Primary Peritoneal CarcinomaUndifferentiated Fallopian Tube CarcinomaUndifferentiated Ovarian Carcinoma

Eligibility

Age Range

18 Years+

Sex

FEMALE

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)
* Urine protein creatine ratio (UPCR) \< 1 prior to enrollment
* Serum total bilirubin: =\< 1.5 X ULN OR direct bilirubin =\< ULN for participants with total bilirubin levels \> 1.5 ULN
* Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase\[SGOT\]) and alanine transaminase (ALT) (serum glutamic pyruvic transaminase \[SGPT\]): =\< 2.5 X ULN OR =\< 5 X ULN for participants with liver metastases
* Albumin: \> 2.5 mg/dL
* International normalized ratio (INR) or prothrombin time (PT): =\< 1.5 unless participant is receiving anticoagulant therapy as long as PT or partial thromboplastin time (PTT) is within therapeutic range of intended use of anticoagulants
* Activated partial thromboplastin time (aPTT): =\< 1.5 X ULN unless participant is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants
* Participants of childbearing potential must have a negative urine or serum pregnancy within 72 hours prior to receiving the first dose of study medication; if the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required
* Participants of childbearing potential must be willing to use 2 methods of birth control or be surgically sterile, or abstain from heterosexual activity for the course of the study through 120 days after the last dose of study medication (participants of childbearing potential are those who have not been surgically sterilized or have not been free from menses for \> 1 year); should a woman become pregnant or suspect she is pregnant while she is participating in this study, she should inform her treating physician immediately
* Participant has recovered from toxicities of prior chemotherapy or other therapy (to grade 2 or less)
* Participant may have received prior investigational therapy (including immune therapy)
* Participant may have received prior hormonal therapy
* Participant may have received bevacizumab (or other antiangiogenic agent) and/or cyclophosphamide in the past
* Participant has had at least 4 weeks of postoperative recovery from surgery prior to enrollment to ensure complete wound healing; participants with bowel resections at surgery should begin protocol at least 42 days after surgery
* Ability to swallow and retain oral medication
* Participant or legal representative must understand the investigational nature of this study and sign an Independent Ethics Committee/Institutional Review Board approved written informed consent form prior to receiving any study related procedure

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
* Has active autoimmune disease that has required systemic treatment in the past 6 months (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs); replacement therapy (e.g. thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment
* Has known history of, or any evidence of active, non-infectious pneumonitis
* Has an active infection requiring systemic therapy
* Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the participant's participation for the full duration of the trial, or is not in the best interest of the patient to participate, in the opinion of the treating investigator
* Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial
* Is pregnant or breastfeeding, or expecting to conceive within the projected duration of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of trial treatment
* Has received prior therapy with an anti-PD-1, anti-programmed cell death 1 ligand 1 (PD-L1), or anti-programmed cell death 1 ligand 2 (PD-L2) agent
* Has a known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies)
* Has known active hepatitis B (e.g., hepatitis B surface antigen \[HBsAg\] reactive) or hepatitis C (e.g., hepatitis C virus \[HCV\] ribonucleic acid \[RNA\] \[qualitative\] is detected)
* Has received a live vaccine within 30 days of planned start of study therapy

  * Note: seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however intranasal influenza vaccines (e.g., FluMist) are live attenuated vaccines, and are not allowed
* Active or history of inflammatory bowel disease (colitis, Crohn's), diverticulitis, irritable bowel disease, celiac disease, or other serious, chronic, gastrointestinal conditions associated with diarrhea; active or history of systemic lupus erythematosus or Wegener's granulomatosis
* Participant has clinical symptoms or signs of partial or complete gastrointestinal obstruction or, requires parenteral hydration and/or nutrition
* Participant requires, or is likely to require, more than a two-week course of corticosteroids for intercurrent illness; participant must complete the course of corticosteroids 2 weeks before screening to meet eligibility
* Participant has a serious, non-healing wound, ulcer, or bone fracture
* Participant has a clinically significant cardiovascular disease including:

  * Uncontrolled hypertension, defined as systolic \> 150 mmHg or diastolic \> 90 mmHg
  * Myocardial infarction or unstable angina within 6 months prior to enrollment
  * New York Heart Association (NYHA) grade II or greater congestive heart failure
  * Participant has a grade II or greater peripheral vascular disease
  * Participant has a clinically significant peripheral artery disease (e.g. those with claudication, within 6 months)
* Participant has organ allografts
* Participant is receiving medication(s) that might affect immune function
* Unwilling or unable to follow protocol requirements

Outcome Measures

Primary Outcomes

Incidence of Adverse Events Assessed by Common Terminology Criteria for Adverse Events

The highest observed adverse event will be tabulated by grade across all dose levels and cycles.

Time frame: Up to 1 year

Progression-free Survival (PFS)

Will be summarized using standard Kaplan-Meier methods, with estimates of median survival and given survival rates will be obtained with 90% confidence intervals.

Time frame: Time from the start of the study treatment until PFS event, assessed up to 1 year after the last subject enrolls

Secondary Outcomes

Duration of Overall Survival

Will be summarized using standard Kaplan-Meier methods, with estimates of median survival and given survival rates will be obtained with 90% confidence intervals.

Time frame: Up to 1 year after enrollment of the last subject

An Anti-tumor Immune Response in Circulation and Tumor Tissue

Assessed with immunohistochemistry (IHC), Nannostring, Flow Cytometry and Luminex assay.

Time frame: Up to 1 year

Objective Tumor Response Assessed by Modified RECIST Version 1.1 Criteria

Frequency of response will be summarized with a 90% confidence interval. An objective response is defined as a CR or PR, while a non-responder is defined as a SD or PD.

Time frame: Up to 6 months after enrollment start of treatment

Locations

Roswell Park Cancer Institute, Buffalo, United States

Linked Papers

Efficacy and Safety of Pembrolizumab in Combination With Bevacizumab and Oral Metronomic Cyclophosphamide in the Treatment of Recurrent Ovarian Cancer

Treatment options for recurrent ovarian cancer are of limited clinical benefit and adversely affect patient quality of life, representing an unmet need for tolerable effective therapies. To assess the efficacy and safety of a combination of pembrolizumab with bevacizumab and oral metronomic cyclophosphamide in patients with recurrent platinum-sensitive, platinum-resistant, or refractory epithelial ovarian, fallopian tube, or primary peritoneal cancer. This open-label, single-arm phase 2 cohort study enrolled patients from September 6, 2016, to June 27, 2018, at a single institution in the United States. Eligible patients had recurrent ovarian cancer, measurable disease per immune-related Response Evaluation Criteria In Solid Tumors (irRECIST), and Eastern Cooperative Oncology Group performance status of 0 to 1. Data were analyzed from September 6, 2016, to February 20, 2020. Patients received intravenous pembrolizumab, 200 mg, and bevacizumab, 15 mg/kg, every 3 weeks and oral cyclophosphamide, 50 mg, once daily during the treatment cycle until disease progression, unacceptable toxic effects, or withdrawal of consent. Primary outcomes were objective response rate (ORR) and progression-free survival (PFS). Of the 40 women enrolled, 30 (75.0%) had platinum-resistant and 10 (25.0%) had platinum-sensitive ovarian cancer with a mean (SD) age of 62.2 (9.4) years. Three women (7.5%) had complete responses, 16 (40.0%) had partial responses, and 19 (47.5%) had stable disease in response to treatment based on irRECIST criteria, with an ORR of 47.5%, clinical benefit in 38 (95.0%), and durable response in 10 (25.0%). Median PFS was 10.0 (90% CI, 6.5-17.4) months. The most common grade 3 to 4 treatment-related adverse events were hypertension (6 [15.0%]) and lymphopenia (3 [7.5%]). The most frequently reported adverse events included fatigue (18 [45.0%]), diarrhea (13 [32.5%]), and hypertension (11 [27.5%]). In this phase 2 nonrandomized clinical trial, the combination of pembrolizumab with bevacizumab and oral cyclophosphamide was well tolerated and demonstrated clinical benefit in 95.0% and durable treatment responses (>12 months) in 25.0% of patients with recurrent ovarian cancer. This combination may represent a future treatment strategy for recurrent ovarian cancer. ClinicalTrials.gov Identifier: NCT02853318.

Pembrolizumab, Bevacizumab, and Cyclophosphamide in Treating Patients With Recurrent Ovarian, Fallopian Tube, or Primary Peritoneal Cancer