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Pembrolizumab and Ipilimumab in Treating Patients with Previously Treated Advanced Melanoma

Trial Status: Closed to Accrual

This phase II trial studies how well pembrolizumab and ipilimumab work in treating patients with previously treated melanoma that has spread to other parts of the body. Immunotherapy with monoclonal antibodies, such as pembrolizumab and ipilimumab, may help the body’s immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread.

Inclusion Criteria

  • Unresectable or metastatic melanoma with known BRAF mutation status
  • Be willing and able to provide written informed consent for the trial
  • Have experienced disease progression during treatment with an anti-PD1/L1 antibody as the treatment regimen immediately prior to accrual to this study or disease progression within 6 months of adjuvant anti-PD1 antibody
  • Have measurable disease based on irRECIST 1.1
  • Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) performance scale
  • Absolute neutrophil count (ANC) >= 1,500 /mcL
  • Platelets >= 100,000/mcL
  • Hemoglobin >= 8 g/dL or >= 4.96 mmol/L
  • Serum creatinine =< 1.5 X upper limit of normal (ULN) OR measured or calculated creatinine clearance (glomerular filtration rate [GFR] can also be used in place of creatinine or creatinine clearance [CrCl]) >= 60 mL/min for subject with creatinine levels > 1.5 X institutional ULN
  • Serum total bilirubin =< 1.5 X ULN OR direct bilirubin =< ULN for subjects with total bilirubin levels > 1.5 ULN
  • Aspartate aminotransaminase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 X ULN OR =< 5 X ULN for subjects with liver metastases
  • Albumin >= 2.5 mg/dL
  • Female subject of childbearing potential should 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
  • 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
  • Male subjects should agree to use an adequate method of contraception starting with the first dose of study therapy through 120 days after the last dose of study therapy

Exclusion Criteria

  • Has received study therapy (including investigational device) as part of a clinical trial within 4 weeks of the first dose of treatment, with the exclusion of an anti-PD1/L1 antibody given as either a single agent or non-CTLA-4 antibody containing combination
  • 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
  • Has a known history of active tuberculosis (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 (excluding commercial or investigational anti-PD1 or anti-PD-L1 antibodies as single agents) or who has not recovered (i.e., =< grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier; patients who have autoimmune adverse events controlled by replacement therapy (i.e. hypothyroidism) due to previous treatment are eligible provided replacement therapy has been initiated and toxicity has returned to grade 1
  • 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, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy
  • 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 (eg., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment; patients with previous grade III/IV toxicity from immunotherapy that led to treatment discontinuation are excluded
  • Patients with uveal/ocular melanoma are excluded
  • 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 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 or father children 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-CTLA4 agent in the unresectable or metastatic disease setting; prior treatment with ipilimumab in the adjuvant setting is allowed
  • 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 allowed; however intranasal influenza vaccines (e.g., Flu-Mist) are not allowed


University of South Alabama Mitchell Cancer Institute
Contact: Arthur Edward Frankel
Phone: 251-665-8000


Miami Beach
Mount Sinai Medical Center
Contact: Yvonne E. Nunez
Phone: 305-674-2625
Moffitt Cancer Center
Contact: Nikhil I. Khushalani
Phone: 813-745-3437


University of Chicago Comprehensive Cancer Center
Contact: Thomas Frank Gajewski
Phone: 773-702-4601
Decatur Memorial Hospital
Contact: Heather Noel Burks
NorthShore University HealthSystem-Evanston Hospital
Contact: Bruce E. Brockstein
Phone: 847-570-2515
Park Ridge
Oncology Specialists SC
Contact: Sigrun Hallmeyer
Phone: 847-268-8200
Illinois CancerCare-Peoria
Contact: Paul A. S. Fishkin
Phone: 309-243-3000


Fort Wayne
Fort Wayne Medical Oncology and Hematology Inc - Jefferson Boulevard
Contact: Sunil Babu
Phone: 260-484-8830


Virginia Commonwealth University / Massey Cancer Center
Contact: Faith McFadden
Phone: 804-628-0616


I. To determine the immune-related Response Evaluation Criteria in Solid Tumors (irRECIST) response rate of pembrolizumab with ipilimumab following initial progression to anti-PD1/L1 antibody (or combination not containing anti-CTLA4) in subjects with advanced melanoma.


I. To summarize the progression-free survival (Response Evaluation Criteria in Solid Tumors [RECIST] version [v]1.1 and immune-related Response Criteria [irRC]) of the combination following prior treatment with anti-PD1/L1 antibody.

II. To assess the safety of the combination following prior treatment with anti-PD1/L1 antibody.


I. To evaluate changes in the tumor microenvironment and other biospecimens before and after adding ipilimumab to pembrolizumab.


Patients receive pembrolizumab intravenously (IV) over 30 minutes on day 1. Patients also receive ipilimumab IV over 30-90 minutes on day 1 for up to 4 doses. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients who stop pembrolizumab with stable disease or better may receive pembrolizumab IV over 30 minutes for up to 1 additional year.

After completion of study treatment, patients are followed up every 12 weeks for 2 years.

Trial Phase Phase II

Trial Type Treatment

Lead Organization
University of Chicago Comprehensive Cancer Center

Principal Investigator
Thomas Frank Gajewski

  • Primary ID IRB17-0686
  • Secondary IDs NCI-2016-00731, IRB15-1788
  • ID NCT02743819