Pembrolizumab, Bevacizumab, and Cyclophosphamide in Treating Patients With Recurrent Ovarian, Fallopian Tube, or Primary Peritoneal Cancer
Condition: Fallopian Tube Clear Cell Adenocarcinoma; Fallopian Tube Endometrioid Adenocarcinoma; Fallopian Tube Mucinous Adenocarcinoma; Fallopian Tube Serous Adenocarcinoma; Ovarian Clear Cell Adenocarcinoma; Ovarian Endometrioid Adenocarcinoma; Ovarian Mucinous Adenocarcinoma; Ovarian Serous Adenocarcinoma; Primary Peritoneal Serous Adenocarcinoma; Recurrent Fallopian Tube Carcinoma; Recurrent Ovarian Carcinoma; Recurrent Primary Peritoneal Carcinoma; Undifferentiated Fallopian Tube Carcinoma; Undifferentiated Ovarian Carcinoma
MeSH terms: Carcinoma; Adenocarcinoma; Ovarian Neoplasms; Carcinoma, Ovarian Epithelial; Cystadenocarcinoma, Serous; Fallopian Tube Neoplasms; Carcinoma, Endometrioid; Adenocarcinoma, Clear Cell; Adenocarcinoma, Mucinous; Cystadenocarcinoma; Recurrence
Intervention: Bevacizumab; Cyclophosphamide; Laboratory Biomarker Analysis; Pembrolizumab
Intervention description: Given IV; Given PO; Correlative studies; Given IV
Intervention MeSH terms: Cyclophosphamide; Bevacizumab; Pembrolizumab; Antineoplastic Agents, Immunological; Antibodies; Immunoglobulins; Antibodies, Monoclonal; Immunoglobulin G; Endothelial Growth Factors
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 40.0
Sex: Female
Minimum age: 18 Years
Healthy volunteers: No

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.
    

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)

          -  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