A Study of Pembrolizumab With Standard Treatment in Patients With Recurrent Platinum-resistant Ovarian Cancer

This is a single-arm, open-label, phase II trial to evaluate the efficacy and safety of anti-PD-1 antibody MK-3475 (pembrolizumab) in combination with standard of care gemcitabine and cisplatin chemotherapy in women with recurrent platinum-resistant ovarian cancer (encompasses ovarian, peritoneal and fallopian tube cancer). Subjects will receive 2 cycles of gemcitabine and cisplatin chemotherapy followed by 4 cycles of gemcitabine and cisplatin combined with pembrolizumab in 21-day treatment cycles. Subjects will continue to receive single-agent pembrolizumab every 21 days as maintenance therapy for up to 2 year until progression or the subject meets withdrawal criteria. Tumor imaging with CT scan will occur at baseline and every 6 weeks (after each second cycle) during chemotherapy treatment and every 9 weeks thereafter. The primary endpoint is efficacy as defined overall response rate by Response Evaluation Criteria in Solid Tumors (RECIST v.1.1). Secondary endpoints for efficacy include progression free survival at 6 and 12 months, time to progression, duration of response and overall survival. Safety and tolerability of the regimen will be determined by assessing the frequency and intensity of adverse events as defined by the Common Terminology Criteria for Adverse Events (CTCAE v.4). Quality of life will be measured using the European Organization for Research and Treatment of Cancer quality of life questionnaire (QLQ-C30).

Inclusion criteria

• Be willing and able to provide written informed consent/ for the trial.
• Be at least 18 years of age on day of signing informed consent.
• Have histologically confirmed diagnosis of recurrent epithelial ovarian, peritoneal or fallopian tube carcinoma that has progressed within 6 months of prior cytotoxic chemotherapy. Histologic confirmation of the primary tumor by review of the pathology report is required. Patients must have had at least one prior platinum-based chemotherapeutic regimen. Initial treatment may have been administered as an intraperitoneal, intravenous or dose-dense regimen. Progression within 6 months of a non-platinum containing regimen is eligible if the patient is considered platinum-resistant to the last platinum-containing regimen. Patients who have received prior cisplatin and gemcitabine treatment are eligible to participate.
• Have measurable disease based on RECIST 1.1
• Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) Performance Scale.
• Demonstrate adequate organ function, all screening labs should be performed within 28 days of treatment initiation.
• Female subject of childbearing potential should have a negative urine or serum pregnancy test 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. Patients who have had prior hysterectomy and/or bilateral oophorectomy are not required to have a pregnancy test.
• Female subjects of childbearing potential should 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. Subjects of childbearing potential are those who have not been surgically sterilized or have not been free from menses for > 1 year.

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 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.
• Has a known history of active TB (Bacillus Tuberculosis)
• Hypersensitivity to 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: Subjects with ≤ Grade 2 neuropathy are an exception to this criterion and may qualify for the study.

Note: If subject received major surgery including (curative or palliative surgery), they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy.

Note: Patients who have hypertension as an adverse event related to prior angiogenesis targeted therapy may be allowed if ≤ Grade 2 and considered by investigator to be well-controlled on anti-hypertensive agents.

• 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 in situ cervical cancer.
• Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Subjects 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 2 years (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, etc.) is not considered a form of systemic treatment.
• Has a history of (non-infectious) pneumonitis that required steroids or current 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 subject's participation for the full duration of the trial, or is not in the best interest of the subject 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 children within the projected duration of the trial, starting with screening visit through 120 days after the last dose of trial treatment.
• Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent.
• Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies) or positive serum test for HIV as per testing at screening
• Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA [qualitative] is detected) as per test at screening
• 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., Flu-Mist®) are live attenuated vaccines, and are not allowed.