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Study of Pembrolizumab (MK-3475) Versus Chemotherapy in Participants With Advanced Melanoma (P08719/KEYNOTE-002)

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
Merck Sharp & Dohme Corp.
ClinicalTrials.gov Identifier:
NCT01704287
First received: October 8, 2012
Last updated: March 28, 2017
Last verified: March 2017
  Purpose

This study is being done to compare survival using pembrolizumab (SCH 900475, MK-3475) or standard chemotherapy for participants with advanced melanoma (MEL) who have progressed after prior therapy. Participants were initially randomized to receive either low dose pembrolizumab, higher dose pembrolizumab or Investigator-choice chemotherapy (ICC). The randomization to either pembrolizumab or Investigator choice chemotherapy was conducted in an open-label fashion.

The pembrolizumab dose was initially blinded to Investigators and participants until Amendment 03. With Amendment 03, all ongoing pembrolizumab participants will be treated with open-label, fixed dose pembrolizumab 200 mg every 3 weeks (Q3W), instead of weight-based dosing of pembrolizumab.

The four standard chemotherapy choices were carboplatin + paclitaxel, paclitaxel alone, dacarbazine, or temozolomide. Participants on standard chemotherapy who experienced disease progression may have been eligible to crossover to treatment with pembrolizumab provided they met protocol-specified requirements for crossover. With Amendment 03, all crossover participants will be treated with open-label, fixed dose pembrolizumab 200 mg Q3W instead of weight-based dosing of pembrolizumab.


Condition Intervention Phase
Malignant Melanoma
Biological: Pembrolizumab
Drug: Carboplatin
Drug: Paclitaxel
Drug: Dacarbazine
Drug: Temozolomide
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Participant, Investigator
Primary Purpose: Treatment
Official Title: Randomized, Phase II Study of Pembrolizumab (MK-3475) Versus Chemotherapy in Patients With Advanced Melanoma (KEYNOTE 002)

Resource links provided by NLM:


Further study details as provided by Merck Sharp & Dohme Corp.:

Primary Outcome Measures:
  • Progression-free Survival (PFS) [ Time Frame: Up to approximately 33 months ]
    PFS was defined as the time from randomization to the first documented disease progression, or death due to any cause, whichever occurred first. Per Response Criteria in Solid Tumors version 1.1 (RECIST 1.1), progressive disease was defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference 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 was also considered progression. PFS analysis was based on an integrated radiology and oncology (IRO) assessment. PFS was not analyzed for the crossover populations.

  • Overall Survival (OS) [ Time Frame: Up to approximately 33 months ]
    OS was defined as the time from randomization to death due to any cause. OS was not analyzed for the crossover populations.


Secondary Outcome Measures:
  • Best Overall Response - Initial Treatment Period [ Time Frame: Up to approximately 33 months ]
    The best overall response was assessed by independent radiology review using RECIST 1.1 and was recorded from the start of the study treatment until the end of treatment. Response categories included: Complete Response (CR): disappearance of all target lesions; Partial Response (PR): at least a 30% decrease in the sum of diameters of target lesions; Progressive Disease (PD): at least a 20% increase in the sum of diameters of target lesions; and Stable Disease (SD): neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. Best overall response for the Initial Treatment Period was based on IRO.

  • Best Overall Response Among Participants Receiving ICC Who Switched to Receiving Pembrolizumab [ Time Frame: Up to approximately 29 months ]
    The best overall response was assessed by independent radiology review using RECIST 1.1 and was recorded from the start of the second line of study treatment until the end of treatment. Response categories included: Complete Response (CR): disappearance of all target lesions; Partial Response (PR): at least a 30% decrease in the sum of diameters of target lesions; Progressive Disease (PD): at least a 20% increase in the sum of diameters of target lesions; and Stable Disease (SD): neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. Best overall response was based based on independent review committee (IRC) for the crossover populations.

  • Duration of Response (DOR) [ Time Frame: Up to approximately 33 months ]
    For participants who demonstrated a confirmed response (CR or PR) per RECIST 1.1, response duration was defined as the time from first documented evidence of CR or PR until disease progression or death. Response duration for participants who had not progressed or died at the time of analysis was to be censored at the date of their last tumor assessment. DOR analysis was based on IRO assessment. DOR was not analyzed for the crossover populations.

  • Number of Participants Who Experienced an Adverse Event (AE) [ Time Frame: Up to approximately 36 months ]
    An AE is defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the study drug, whether or not considered related to the use of the product. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a pre-existing condition which is temporally associated with the use of study drug, is also an AE.

  • Number of Participants Who Discontinued Study Drug Due to an AE [ Time Frame: Up to approximately 33 months ]
    An AE is defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the study drug, whether or not considered related to the use of the product. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a pre-existing condition which is temporally associated with the use of study drug, is also an AE.


Enrollment: 540
Actual Study Start Date: November 20, 2012
Estimated Study Completion Date: July 2, 2018
Primary Completion Date: November 16, 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Pembrolizumab 2 mg/kg
Participants initially received pembrolizumab 2 mg/kg intravenously (IV) Q3W. This dosing was discontinued with Amendment 03. With Amendment 03, all study participants will be treated with fixed-dose pembrolizumab 200 mg IV Q3W.
Biological: Pembrolizumab
IV infusion
Other Names:
  • SCH 900475
  • MK-3475
  • KEYTRUDA®
Experimental: Pembrolizumab 10 mg/kg
Participants initially received pembrolizumab 10 mg/kg IV Q3W. This dosing was discontinued with Amendment 03. With Amendment 03, all study participants will be treated with fixed-dose pembrolizumab 200 mg IV Q3W.
Biological: Pembrolizumab
IV infusion
Other Names:
  • SCH 900475
  • MK-3475
  • KEYTRUDA®
Active Comparator: Investigator-Choice Chemotherapy (ICC)
Participants received one of four possible chemotherapy regimens decided at the treating institution (carboplatin + paclitaxel, paclitaxel alone, dacarbazine, or temozolomide).
Drug: Carboplatin
Carboplatin per institutional standard.
Other Name: PARAPLATIN®
Drug: Paclitaxel
Paclitaxel per institutional standard.
Other Name: TAXOL®
Drug: Dacarbazine
Dacarbazine per institutional standard.
Other Name: DTIC
Drug: Temozolomide
Temozolomide per institutional standard.
Other Name: TEMODAR®
Experimental: ICC→Pembrolizumab 2 mg/kg
Participants who were assigned to ICC, experienced confirmed progressive disease (PD) and met all crossover criteria at study treatment Week 12, had the opportunity to switch to receive pembrolizumab 2 mg/kg or 10 mg/kg in a double-blind fashion. Participants who qualified to switch to pembrolizumab, must have completed a washout period of ≥28 days from last dose of chemotherapy before receiving pembrolizumab. Participants received pembrolizumab 2 mg/kg IV Q3W. This dosing was discontinued with Amendment 03. With Amendment 03, all study participants will be treated with fixed-dose pembrolizumab 200 mg IV Q3W.
Biological: Pembrolizumab
IV infusion
Other Names:
  • SCH 900475
  • MK-3475
  • KEYTRUDA®
Drug: Carboplatin
Carboplatin per institutional standard.
Other Name: PARAPLATIN®
Drug: Paclitaxel
Paclitaxel per institutional standard.
Other Name: TAXOL®
Drug: Dacarbazine
Dacarbazine per institutional standard.
Other Name: DTIC
Drug: Temozolomide
Temozolomide per institutional standard.
Other Name: TEMODAR®
Experimental: ICC→Pembrolizumab 10 mg/kg
Participants who were assigned to ICC, experienced confirmed PD and met all crossover criteria at study treatment Week 12, had the opportunity to switch to receive pembrolizumab 2 mg/kg or 10 mg/kg in a double-blind fashion. Participants who qualified to switch to pembrolizumab, must have completed a washout period of ≥28 days from last dose of chemotherapy before receiving pembrolizumab. Participants received pembrolizumab 10 mg/kg IV Q3W. This dosing was discontinued with Amendment 03. With Amendment 03, all study participants will be treated with fixed-dose pembrolizumab 200 mg IV Q3W.
Biological: Pembrolizumab
IV infusion
Other Names:
  • SCH 900475
  • MK-3475
  • KEYTRUDA®
Drug: Carboplatin
Carboplatin per institutional standard.
Other Name: PARAPLATIN®
Drug: Paclitaxel
Paclitaxel per institutional standard.
Other Name: TAXOL®
Drug: Dacarbazine
Dacarbazine per institutional standard.
Other Name: DTIC
Drug: Temozolomide
Temozolomide per institutional standard.
Other Name: TEMODAR®

  Eligibility

Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Histologically or cytologically confirmed diagnosis of unresectable Stage III or metastatic MEL not amenable to local therapy
  • Participants must be refractory to ipilimumab
  • Participants with BRAF gene mutant melanoma must have had a prior treatment regimen that included vemurafenib, dabrafenib, or an approved BRAF gene and/or mitogen-activated protein kinase (MEK) protein inhibitor
  • Must consent to allow correlative studies; must provide a newly obtained tissue/biopsy specimen (or specimen obtained within 60 days of consenting)
  • Radiographically measurable disease
  • Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1

Exclusion criteria:

  • Chemotherapy, radiation therapy, or biological cancer therapy within 4 weeks prior to the first dose of study drug, or not recovered from the adverse events due to cancer therapies administered more than 4 weeks earlier
  • Disease progression within 24 weeks of last dose of ipilimumab
  • Participating or has participated in a study of an investigational agent or using an investigational device within 30 days of the first dose of study drug
  • Expected to require any other form of systemic or localized antineoplastic therapy while on study
  • Chronic systemic steroid therapy within 2 weeks before the planned date for first dose randomized treatment or on any other form of immunosuppressive medication
  • Known history of any other than the current malignancy excepting adequately treated basal or squamous cell carcinoma of the skin, superficial bladder cancer, in situ cervical cancer, breast cancer, or other in situ cancers
  • Known active central nervous system (CNS) metastases and/or carcinomatous meningitis
  • Active autoimmune disease or a history of autoimmune disease or syndrome that requires systemic steroids or immunosuppressive agents
  • Prior treatment with any other anti-programmed cell death (PD) agent
  • Active infection requiring systemic therapy
  • Known history of Human Immunodeficiency Virus (HIV)
  • Active Hepatitis B or Hepatitis C
  • Regular user (including recreational use of) illicit drugs or had a recent history (within the last year) of substance abuse (including alcohol)
  • Pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the study through 120 days after last dose of study drug
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01704287

Sponsors and Collaborators
Merck Sharp & Dohme Corp.
Investigators
Study Director: Medical Director Merck Sharp & Dohme Corp.
  More Information

Publications:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Merck Sharp & Dohme Corp.
ClinicalTrials.gov Identifier: NCT01704287     History of Changes
Other Study ID Numbers: P08719
MK-3475-002 ( Other Identifier: Merck Protocol Number )
2012-003030-17 ( EudraCT Number )
Study First Received: October 8, 2012
Results First Received: October 17, 2016
Last Updated: March 28, 2017

Keywords provided by Merck Sharp & Dohme Corp.:
PD-1
PD1
PD-L1
PDL1

Additional relevant MeSH terms:
Pembrolizumab
Melanoma
Neuroendocrine Tumors
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Nerve Tissue
Nevi and Melanomas
Paclitaxel
Temozolomide
Albumin-Bound Paclitaxel
Carboplatin
Antineoplastic Agents, Phytogenic
Antineoplastic Agents
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents, Alkylating
Alkylating Agents

ClinicalTrials.gov processed this record on May 23, 2017