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

A Phase II Study of Pembrolizumab With Cisplatin and Gemcitabine Treatment in Patients With Recurrent Platinum-resistant Ovarian Cancer

To evaluate the efficacy and safety of anti-PD-1 antibody MK-3475 (pembrolizumab) in combination with gemcitabine and cisplatin chemotherapy in women with recurrent platinum-resistant ovarian cancer.

Study Overview

• Status: Completed
• Conditions: Ovarian Cancer
• Intervention / Treatment: Drug: Pembrolizumab; Drug: Gemcitabine; Drug: Cisplatin

Detailed Description

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).

• Study Type: Interventional
• Enrollment (Actual): 21
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • California
    • Los Angeles, California, United States, 90048
      • Cedars-Sinai Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

EXPERIMENTAL: Cisplatin+Gemcitabine+Pembrolizumab; 2 cycles of 750mg gemcitabine and 30mg cisplatin chemotherapy (standard of care) followed by 4 cycles of gemcitabine and cisplatin combined with pembrolizumab in 21-day treatment cycles followed by single-agent pembrolizumab maintenance therapy for up to 2 years of treatment (6 cycles combination treatment + 28 cycles maintenance). Gemcitabine 750 mg/m2 every 3 weeks (Q3W) x 6 cycles IV infusion -Day 1 and Day 8 of each 3 week cycle Standard of care Cisplatin 30 mg/m2 Q3W x 6 cycles IV infusion -Day 1 and Day 8 of each 3 week cycle after gemcitabine Standard of care Pembrolizumab 200 mg Q3W starting with cycle 3 IV infusion -Day 1 of each 3 week cycle after gemcitabine and cisplatin Experimental

Drug: Pembrolizumab; Pembrolizumab IV solution; Other Names: Keytruda; MK-3475; Drug: Gemcitabine; Gemcitabine IV solution; Other Names: Gemzar; Drug: Cisplatin; Cisplatin IV solution; Other Names: Platinol

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Response Rate (ORR)	Defined as complete or partial response per RECIST 1.1 criteria with assessment every 6 weeks during first 6 cycles of therapy and every 9 weeks thereafter. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by CT or MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.	Up to 2 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Response Rate by iRECIST	Per Immune Response Evaluation Criteria In Solid Tumors Criteria (iRECIST) for target lesions and assessed by CT or MRI, where the threshold is reset if RECIST 1.1 progression is followed at the next assessment by tumor shrinkage: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.	Up to 2 years
Progression-free Survival (PFS) at 6 Months and at 12 Months	Percentage of patients who have not progressed at 6 and 12 months with progression-free survival calculated from the start of treatment to the date of progression or death from any cause. Progression is measured by Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by CT or MRI: Progressive Disease (PD), At least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest sum on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. Note: the appearance of one or more new lesions is also considered progression.	6 months and 12 months
Time to Progression	Calculated in months from the start of treatment to disease progression as defined by Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by CT or MRI: Progressive Disease (PD), At least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest sum on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. Note: the appearance of one or more new lesions is also considered progression.	Up to 2 years
Duration of Response	Calculated in months as time from documentation of tumor response to disease progression	Up to 2 years
Overall Survival (OS)	Calculated in months from the start of treatment to the date of death from any cause	Up to 2 years
Frequency and Intensity of Adverse Events (CTCAE v.4), Deemed at Least Possibly Related to Study Participation	As measured at each visit, during safety follow up (30 days after discontinuation of treatment) and during follow up (every nine weeks after discontinuation). Adverse events graded using Common Terminology Criteria for Adverse Events (CTCAE) version 4, with events graded from 1 to 5, where a higher grade reflects greater symptom severity.	Up to 2 years

Collaborators and Investigators

• Sponsor: Cedars-Sinai Medical Center
• Collaborators: Merck Sharp & Dohme LLC
• Investigators: Principal Investigator: Bobbie J Rimel, MD, Cedars-Sinal Medical Center

Study record dates

Study Major Dates

• Study Start (ACTUAL): February 8, 2016
• Primary Completion (ACTUAL): May 17, 2019
• Study Completion (ACTUAL): March 7, 2022

Study Registration Dates

• First Submitted: November 12, 2015
• First Submitted That Met QC Criteria: November 17, 2015
• First Posted (ESTIMATE): November 20, 2015

Study Record Updates

• Last Update Posted (ACTUAL): March 23, 2022
• Last Update Submitted That Met QC Criteria: March 14, 2022
• Last Verified: March 1, 2022

More Information

Terms related to this study

• Keywords: immunotherapy; immune checkpoint inhibitors; platinum-resistant ovarian cancer
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Carcinoma; Neoplasms, Glandular and Epithelial; Genital Neoplasms, Female; Endocrine System Diseases; Ovarian Diseases; Adnexal Diseases; Gonadal Disorders; Endocrine Gland Neoplasms; Ovarian Neoplasms; Carcinoma, Ovarian Epithelial; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Immunological; Gemcitabine; Cisplatin; Pembrolizumab
• Other Study ID Numbers: IIT2015-13-Walsh-PemCiGem

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO