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A Study of Pembrolizumab (MK-3475) in Combination With Standard of Care Treatments in Participants With Multiple Myeloma (MK-3475-023/KEYNOTE-023)

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ClinicalTrials.gov Identifier: NCT02036502
Recruitment Status : Active, not recruiting
First Posted : January 15, 2014
Last Update Posted : April 25, 2018
Sponsor:
Information provided by (Responsible Party):
Merck Sharp & Dohme Corp.

January 13, 2014
January 15, 2014
April 25, 2018
February 14, 2014
October 23, 2019   (Final data collection date for primary outcome measure)
  • Number of Participants With Dose-Limiting Toxicities (DLTs) [ Time Frame: Cycle 1 (up to 28 days) ]
  • Number of Participants Experiencing AEs [ Time Frame: Up to 4 years ]
  • Number of Participants Discontinuing Study Drug Due to an AE [ Time Frame: Up to 4 years ]
  • Number of Participants With Dose-Limiting Toxicities (DLTs) [ Time Frame: Cycle 1 (up to 28 days) ]
  • Number of participants experiencing adverse events [ Time Frame: Up to 2 years ]
  • Number of participants discontinuing study drug because of adverse events [ Time Frame: Up to 2 years ]
Complete list of historical versions of study NCT02036502 on ClinicalTrials.gov Archive Site
  • Objective Response Rate (ORR) [ Time Frame: Baseline and Day 1 of each 28-day cycle (up to 4 years) ]
  • Number of Participants with Complete Response (CR) [ Time Frame: Baseline and Day 1 of each 28-day cycle (up to 4 years) ]
  • Number of Participants with Stringent CR (sCR) [ Time Frame: Baseline and Day 1 of each 28-day cycle (up to 4 years) ]
  • Time to Progression (TTP) [ Time Frame: Up to 4 years ]
  • Duration of Response (DOR) [ Time Frame: Up to 4 years ]
  • Progression-Free Survival (PFS) [ Time Frame: Up to 4 years ]
  • Overall Survival (OS) [ Time Frame: Up to 4 years ]
  • Change from Baseline in Programmed Cell Death Ligand 1 (PD-L1) Expression in Responders Versus Non-Responders [ Time Frame: Baseline and Day 1 of each 28-day cycle (up to 4 years) ]
  • Disease Control Rate (DCR) [ Time Frame: Up to 4 years ]
  • Objective Response Rate (ORR) [ Time Frame: Baseline and Day 1 of each 28-day cycle (up to 2 years) ]
  • Number of Participants with Complete Response (CR) [ Time Frame: Baseline and Day 1 of each 28-day cycle (up to 2 years) ]
  • Number of Participants with Stringent CR (sCR) [ Time Frame: Baseline and Day 1 of each 28-day cycle (up to 2 years) ]
  • Time to Progression (TTP) [ Time Frame: Up to 2 years ]
  • Duration of Response (DOR) [ Time Frame: Up to 2 years ]
  • Progression-Free Survival (PFS) [ Time Frame: Up to 2 years ]
  • Overall Survival (OS) [ Time Frame: Up to 2 years ]
  • Change from Baseline in Programmed Cell Death Ligand 1 (PD-L1) Expression in Responders Versus Non-Responders [ Time Frame: Baseline and Day 1 of each 28-day cycle (up to 2 years) ]
Not Provided
Not Provided
 
A Study of Pembrolizumab (MK-3475) in Combination With Standard of Care Treatments in Participants With Multiple Myeloma (MK-3475-023/KEYNOTE-023)
A Phase I Multi-Cohort Trial of Pembrolizumab (MK-3475) in Combination With Backbone Treatments for Subjects With Multiple Myeloma.

This is a study of pembrolizumab (MK-3475) in combination with lenalidomide and low-dose dexamethasone in participants with refractory or relapsed and refractory Multiple Myeloma (rrMM), and in combination with carfilzomib and low-dose dexamethasone in participants with relapsed or refractory Multiple Myeloma (rMM).

This study is being done to find the maximum tolerated dose (MTD)/maximum administered dose (MAD) and recommended Phase 2 dose (RP2D), and to evaluate the safety and tolerability of pembrolizumab when given in combination with standard of care (SOC) treatments in participants with rrMM or rMM. Preliminary efficacy data will also be assessed. The primary study hypothesis is that these combinations are sufficiently well tolerated to permit further clinical investigation.

On 03-Jul-2017, the United States Food and Drug Administration (US FDA) placed Cohort 1 of this protocol on clinical hold based on safety data from two other pembrolizumab protocols: MK-2375-183 (NCT02576977) and MK-3475-185 (NCT02579863) presented to the Data Monitoring Committee.

On 15-Sep-2017, the US FDA placed Cohort 2 of this study on partial clinical hold. Enrollment has been stopped and will not be reopened. Participants who are deriving clinical benefit will be allowed to continue receiving study treatment until protocol-specific end of treatment, and then progress into long term safety and survival follow up. Participants who are not deriving clinical benefit, must stop study treatment and move into the long term safety and survival follow up.

Not Provided
Interventional
Phase 1
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Multiple Myeloma
  • Biological: Pembrolizumab
    Intravenous (IV) infusion
    Other Names:
    • MK-3475
    • KEYTRUDA®
  • Drug: Lenalidomide
    Oral capsule
    Other Name: REVLIMID®
  • Drug: Dexamethasone
    Oral tablet
    Other Name: DECADRON®
  • Drug: Carfilzomib
    IV infusion
    Other Name: KYPROLIS®
  • Experimental: Dose Determination Arm
    Participants receive pembrolizumab 2 mg/kg every 2 weeks (Q2W, Days 1 and 15) in combination with lenalidomide 10 mg or 25 mg (Days 1-21) and dexamethasone 40 mg weekly during each 28-day cycle.
    Interventions:
    • Biological: Pembrolizumab
    • Drug: Lenalidomide
    • Drug: Dexamethasone
  • Experimental: Dose Confirmation Arm
    Participants receive pembrolizumab 200 mg Q2W (Days 1 and 15) in combination with lenalidomide 10 mg or 25 mg (Days 1-21) and dexamethasone 40 mg weekly during each 28-day cycle.
    Interventions:
    • Biological: Pembrolizumab
    • Drug: Lenalidomide
    • Drug: Dexamethasone
  • Experimental: Cohort 1: rrMM
    Cohort 1 is closed. All participants must stop study treatment and move into long term safety and survival follow up. Participants previously received pembrolizumab 200 mg once every 2 weeks (Q2W; Days 1 and 15) in combination with lenalidomide 25 mg (Days 1-21) and dexamethasone 40 mg once weekly (Q1W) during each 28-day cycle.
    Interventions:
    • Biological: Pembrolizumab
    • Drug: Lenalidomide
    • Drug: Dexamethasone
  • Experimental: Cohort 2: rMM
    Cohort 2 is closed to enrollment. Participants who are enrolled and not deriving clinical benefit must stop study treatment and move into the long term safety and survival follow up. Participants who are already enrolled and deriving clinical benefit from study treatment may continue in the study until protocol-specific end of treatment, and then progress into long term safety and survival follow up. Participants receive pembrolizumab 200 mg once every 3 weeks (Q3W) in combination with carfilzomib 56 mg/m^2 (Days 1, 2, 8, 9, 15, 16) and dexamethasone 20 mg (Days 1, 2, 8, 9, 15, 16, 22, 23) during each 28-day cycle.
    Interventions:
    • Biological: Pembrolizumab
    • Drug: Dexamethasone
    • Drug: Carfilzomib
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Active, not recruiting
84
44
October 23, 2019
October 23, 2019   (Final data collection date for primary outcome measure)

Inclusion Criteria:

All Participants:

  • Confirmed diagnosis of multiple myeloma (MM)
  • Measurable disease
  • Archival or newly obtained bone marrow material available. In addition, for participants in the United States (US) and Canada, able to provide newly obtained bone marrow aspirate for biomarker analysis.
  • Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
  • Adequate organ function
  • Female 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 treatment
  • Male participants must agree to use a latex condom during sexual contact with females of childbearing potential even if they have had a successful vasectomy starting with the first dose of study treatment through 120 days after the last dose of study treatment
  • Able to swallow capsules and able to take or tolerate oral medications on a continuous basis

Dose Determination Arm, Dose Confirmation Arm and Cohort 1 Participants:

  • Failed at least 2 lines of prior therapy (e.g. bortezomib or carfilzomib and either thalidomide, pomalidomide, or lenalidomide)
  • Prior anti-MM treatments must have included an immunomodulatory (IMiD) treatment (lenalidomide, pomalidomide or thalidomide) AND proteasome inhibitor (bortezomib or carfilzomib) alone or in combination and participant must have failed therapy with an IMiD OR proteasome inhibitor
  • Must agree to follow the regional requirements for lenalidomide counseling, pregnancy testing, and birth control; willing and able to comply with the regional requirements (for example, periodic pregnancy tests and safety labs)

Cohort 2 Participants:

  • MM with relapsing or refractory disease at study entry
  • Received prior treatment with 1 to 3 lines for MM
  • Achieved a partial response to at least one prior regimen (defined as ≥50% decrease in tumor burden)
  • Left ventricular ejection fraction of at least 40%

Exclusion Criteria:

All Participants:

  • Currently participating in and receiving study therapy or has participated in a study of an investigational agent or using an investigational device within 4 weeks of the first dose of study treatment
  • History of repeated infections; primary amyloidosis; hyperviscosity; plasma cell leukemia; polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes (POEMS) syndrome or Waldenström's macroglobulinemia
  • Diagnosis of immunosuppressive disorder or on any other immunosuppressive therapy within 7 days prior to the first dose of study treatment
  • Received a prior monoclonal antibody (mAb) within 4 weeks prior to study Day 1 or who has not recovered (i.e. ≤ Grade 1 or at baseline) from a baseline AE or a Grade 1 AE associated with agents administered more than 4 weeks earlier
  • Prior anti-MM therapy (including dexamethasone), targeted small molecule therapy, or radiation therapy within 2 weeks prior to study Day 1 or not recovered from AEs due to a previously administered agent
  • An additional malignancy that is progressing or requires active treatment within the last 5 years
  • Clinically active central nervous system (CNS) involvement
  • Active autoimmune disease or a documented history of autoimmune disease, or a syndrome that requires systemic steroids or immunosuppressive agents
  • Has a history of (non-infectious) pneumonitis that required steroids or current pneumonitis
  • Active infection requiring intravenous systemic therapy
  • Known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the study
  • Pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the study, starting with the pre-screening or screening visit through 120 days after the last dose of study treatment
  • Prior therapy with an anti-programmed cell death (PD)-1, anti-PD ligand 1 (anti-PD-L1), anti-PD-L2, anti-CD137 antibody, or anti-Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) agent
  • Known Human Immunodeficiency Virus (HIV), Hepatitis B Virus (HBV), or Hepatitis C Virus (HCV) infection
  • Clinically significant coagulopathy
  • Known symptomatic congestive heart failure, unstable angina pectoris, or cardiac arrhythmia
  • Has had or is planning for allogeneic stem cell transplant
  • Autologous stem cell transplant within 12 weeks before the first infusion
  • History of Grade 4 rash associated with thalidomide treatment
  • Known hypersensitivity to thalidomide, lenalidomide or pomalidomide
  • Received a live vaccine within 30 days of planned start of study treatment

Dose Determination Arm, Dose Confirmation Arm and Cohort 1 Participants:

  • Known gastrointestinal disease that may significantly alter the absorption of lenalidomide
  • Unable or unwilling to undergo antithrombotic prophylactic treatment

Cohort 2 Participants:

  • Smoldering MM (SMM), monoclonal gammopathy of undetermined significance (MGUS), plasma cell leukemia or Waldenström's macroglobulinemia
  • Significant neuropathy (Grades 3-4, or Grade 2 with pain) within 14 days prior to the first dose of study treatment
  • Myocardial infarction within 4 months prior to randomization, New York Heart Association (NYHA) Class III or IV heart failure, uncontrolled angina, history of severe coronary artery disease, severe uncontrolled ventricular arrhythmias, sick sinus syndrome, or electrocardiographic evidence of acute ischemia or Grade 3 conduction system abnormalities unless participant has a pacemaker.
  • Known history of allergy to CAPTISOL® (a cyclodextrin derivative used to solubilize carfilzomib)
  • Hypersensitivity to carfilzomib, bortezomib, boron, or mannitol
  • Contraindication to any of the required concomitant drugs or supportive treatments, including hypersensitivity to all anticoagulation and antiplatelet options, antiviral drugs, or intolerance to hydration due to pre-existing pulmonary or cardiac impairment
  • Uncontrolled hypertension or uncontrolled diabetes within 14 days prior to the first dose of study treatment
  • Pleural effusions requiring thoracentesis or ascites requiring paracentesis within 14 days prior to the first dose of study treatment
Sexes Eligible for Study: All
18 Years and older   (Adult, Older Adult)
No
Contact information is only displayed when the study is recruiting subjects
Not Provided
Canada,   France,   Spain,   United States
 
NCT02036502
3475-023
2013-003512-44 ( EudraCT Number )
MK-3475-023 ( Other Identifier: Merck Protocol Number )
No
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Not Provided
Merck Sharp & Dohme Corp.
Merck Sharp & Dohme Corp.
Not Provided
Study Director: Medical Director Merck Sharp & Dohme Corp.
Merck Sharp & Dohme Corp.
April 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP