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Study of Lenalidomide and Dexamethasone With or Without Pembrolizumab (MK-3475) in Participants With Newly Diagnosed Treatment Naive Multiple Myeloma (MK-3475-185/KEYNOTE-185)

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ClinicalTrials.gov Identifier: NCT02579863
Recruitment Status : Active, not recruiting
First Posted : October 20, 2015
Results First Posted : September 17, 2019
Last Update Posted : September 17, 2019
Sponsor:
Information provided by (Responsible Party):
Merck Sharp & Dohme Corp.

Tracking Information
First Submitted Date  ICMJE October 16, 2015
First Posted Date  ICMJE October 20, 2015
Results First Submitted Date  ICMJE June 7, 2019
Results First Posted Date  ICMJE September 17, 2019
Last Update Posted Date September 17, 2019
Actual Study Start Date  ICMJE October 19, 2015
Actual Primary Completion Date July 9, 2018   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: August 29, 2019)
Progression Free Survival (PFS) Assessed by Clinical Adjudication Committee (CAC) Blinded Central Review According to the International Myeloma Working Group (IMWG) Response Criteria [ Time Frame: Up to approximately 30 months ]
PFS was defined as the time from randomization to the first documented disease progression (events of new bone lesions, soft tissue plasmacytomas or an increase in existing lesions, or death due to any cause). The median PFS was calculated from the product-limit (Kaplan-Meier) method for censored data. The data cutoff date was July 9, 2018. Due to the smaller number of events, the tail of the estimated survival distribution was close to the median for both arms. The higher variability of the tail estimates resulted in observing the median estimate in the experimental arm but not in the standard of care arm even when number of events in 2 arms were similar. Additionally, since median of the experimental arm was in the tail of the estimated survival distribution, standard error of the survival estimates was missing before upper limit of the 95% confidence interval was reached, resulting in a missing upper limit of 95% confidence interval for the experimental arm.
Original Primary Outcome Measures  ICMJE
 (submitted: October 16, 2015)
Progression Free Survival (PFS) [ Time Frame: Up to 41 months ]
Change History Complete list of historical versions of study NCT02579863 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: August 29, 2019)
  • Overall Survival (OS) [ Time Frame: Up to approximately 30 months ]
    OS was defined as the time from randomization to death due to any cause. Participants without documented death at the time of the final analysis were censored at the date of the last follow-up. The data cutoff date was July 9, 2018. This is an event-driven (events of death) outcome measure. At the time of data cut-off, there were an insufficient number of events from the censored data to be able to estimate certain parameters (e.g. medians).
  • Overall Response Rate (ORR) Evaluated According to the IMWG Response Criteria by CAC Blinded Central Review [ Time Frame: Up to approximately 30 months ]
    ORR was defined as the percentage of the participants in the analysis population who achieved at least a partial response (stringent complete response [sCR]+complete response [CR]+very good partial response [VGPR]+partial response [PR]) according to the IMWG. CR = negative immunofixation of serum and urine AND disappearance of any soft tissue plasmacytomas AND <5% plasmacytomas in the bone marrow; sCR=stringent complete response, CR as above PLUS normal serum free light-chain (FLC) assay ratio and absence of clonal cells in bone marrow by immunohistochemistry or immunofluorescence; VGPR = serum and urine M-component detectable by immunofixation but not on electrophoresis OR ≥ 90% reduction in serum M-component plus urine M-component <100 mg/24 hr; PR = ≥50% reduction of serum M-protein and reduction in 24-hour urinary M-protein by ≥90% or to <200 mg/24 hours. The data cutoff date was July 9, 2018.
  • Duration of Response (DOR) Evaluated According to IMWG Response Criteria by CAC Blinded Central Review [ Time Frame: Up to approximately 30 months ]
    Response duration was defined as the time from first documented evidence of at least a partial response (sCR+CR+VGPR+PR]), until confirmed disease progression or death. DOR was calculated from product-limit (Kaplan-Meier) method for censored data. The data cutoff date was July 9, 2018. This is an event-driven (events of disease progression and death) outcome measure. At the time of data cut-off, there were an insufficient number of events from the censored data to be able to estimate certain parameters (e.g. medians). Full Range is the minimum and maximum of the observed duration of response.
  • Disease Control Rate (DCR) Evaluated According to the IMWG Response Criteria by CAC Blinded Central Review [ Time Frame: Up to approximately 30 months ]
    Disease control rate was defined as the percentage of participants who achieved confirmed sCR, CR, VGPR, PR, or have demonstrated SD for at least 12 weeks prior to any evidence of progression. CR = negative immunofixation of serum and urine AND disappearance of any soft tissue plasmacytomas AND <5% plasmacytomas in the bone marrow; VGPR = serum and urine M-component detectable by immunofixation but not on electrophoresis OR ≥ 90% reduction in serum M-component plus urine M-component <100 mg/24 hr; PR = ≥50% reduction of serum M-protein and reduction in 24-hour urinary M-protein by ≥90% or to <200 mg/24 hours; SD = not meeting the criteria for CR, VGPR, PR, or PD; PD = development of new bone lesions or soft tissue plasmacytomas or on a definite increase in the size of existing bone lesions or soft tissue plasmacytomas. Data cutoff date was July 9, 2018.
  • Second Progression Free Survival (PFS2) [ Time Frame: Up to approximately 30 months ]
    PFS2 was defined as the time from randomization to subsequent disease progression after initiation of new anti-cancer therapy, or death from any cause, whichever occurred first, by investigator assessment. PFS was assessed by Clinical Adjudication Committee (CAC) blinded central review according to the IMWG response criteria based on the development of new bone lesions or soft tissue plasmacytomas or on a definite increase in the size of existing bone lesions or soft tissue plasmacytomas. PFS2 was not completed due to incomplete enrollment for a clinical hold.
  • Number of Participants Who Experienced One or More Adverse Events (AEs) [ Time Frame: Up to approximately 30 months ]
    An AE was defined as any unfavorable and unintended sign including an abnormal laboratory finding, symptom or disease associated with the use of a medical treatment or procedure, regardless of whether it was considered related to the medical treatment or procedure, that occurred during the course of the study.
  • Number of Participants Discontinuing Study Treatment Due to an AE [ Time Frame: Up to approximately 30 months ]
    An AE was defined as any unfavorable and unintended sign including an abnormal laboratory finding, symptom or disease associated with the use of a medical treatment or procedure, regardless of whether it was considered related to the medical treatment or procedure, that occurred during the course of the study.
Original Secondary Outcome Measures  ICMJE
 (submitted: October 16, 2015)
Overall Survival (OS) [ Time Frame: Up to 41 months ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Study of Lenalidomide and Dexamethasone With or Without Pembrolizumab (MK-3475) in Participants With Newly Diagnosed Treatment Naive Multiple Myeloma (MK-3475-185/KEYNOTE-185)
Official Title  ICMJE A Phase III Study of Lenalidomide and Low-Dose Dexamethasone With or Without Pembrolizumab (MK3475) in Newly Diagnosed and Treatment Naïve Multiple Myeloma (KEYNOTE 185).
Brief Summary The purpose of this study is to compare the efficacy of lenalidomide and low dose dexamethasone with pembrolizumab (MK-3475) to that of lenalidomide and low dose dexamethasone without pembrolizumab in terms of progression-free survival (PFS) in participants with newly diagnosed and treatment-naïve multiple myeloma who are ineligible for autologous stem cell transplant (Auto-SCT). The study's primary hypothesis is that pembrolizumab in dexamethasone prolongs progression free survival (PFS) as assessed by Clinical Adjudication Committee (CAC) blinded central review using International Myeloma Working Group (IMWG) response criteria compared to treatment combination with lenalidomide and low-dose with lenalidomide and low-dose dexamethasone (standard of care, SOC) alone.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Multiple Myeloma
Intervention  ICMJE
  • Biological: Pembrolizumab
    IV infusion
    Other Name: MK-3475
  • Drug: Lenalidomide
    oral capsules
  • Drug: Dexamethasone
    oral tablets
Study Arms  ICMJE
  • Experimental: Pembrolizumab + Lenalidomide + Dexamethasone
    Participants received pembrolizumab 200 mg intravenously (IV) on Day 1 of each 21-day cycle PLUS lenalidomide 25 mg orally (PO) on Days 1 to 21 of each 21-day treatment cycle, and dexamethasone 40 mg PO on Days 1, 8, 15 and 22 of each 28-day cycle for up to 18 cycles.
    Interventions:
    • Biological: Pembrolizumab
    • Drug: Lenalidomide
    • Drug: Dexamethasone
  • Active Comparator: Lenalidomide + Dexamethasone
    Participants received lenalidomide 25 mg PO on Days 1 to 21 of each 21-day treatment cycle, and dexamethasone 40 mg PO on Days 1, 8, 15 and 22 of each 28-day cycle for up to 18 cycles.
    Interventions:
    • Drug: Lenalidomide
    • Drug: Dexamethasone
Publications * Usmani SZ, Schjesvold F, Oriol A, Karlin L, Cavo M, Rifkin RM, Yimer HA, LeBlanc R, Takezako N, McCroskey RD, Lim ABM, Suzuki K, Kosugi H, Grigoriadis G, Avivi I, Facon T, Jagannath S, Lonial S, Ghori RU, Farooqui MZH, Marinello P, San-Miguel J; KEYNOTE-185 Investigators. Pembrolizumab plus lenalidomide and dexamethasone for patients with treatment-naive multiple myeloma (KEYNOTE-185): a randomised, open-label, phase 3 trial. Lancet Haematol. 2019 Sep;6(9):e448-e458. doi: 10.1016/S2352-3026(19)30109-7. Epub 2019 Jul 18.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Actual Enrollment  ICMJE
 (submitted: February 26, 2019)
310
Original Estimated Enrollment  ICMJE
 (submitted: October 16, 2015)
640
Estimated Study Completion Date  ICMJE September 30, 2020
Actual Primary Completion Date July 9, 2018   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Confirmed diagnosis of active multiple myeloma and measurable disease.
  • Ineligible to receive treatment with auto-SCT due to age (≥65 years old) or any significant coexisting medical condition (cardiac, renal, pulmonary or hepatic dysfunction), likely to have a negative impact on tolerability of auto-SCT. Participants <65 years of age who refuse auto-SCT are not eligible for this study.
  • Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1.
  • Female participants of childbearing potential must have 2 negative urine pregnancy tests (with a sensitivity of at least 25 Milli-international units/milliliter) within 10 to 14 days and within 24 hours prior to receiving study medication.
  • Female participants of childbearing potential must agree to use adequate contraception 28 days prior to study start, continuing throughout the study, and for up to 28 days after the last dose of lenalidomide (or 120 days after the last dose of pembrolizumab).
  • Male participants of childbearing potential must agree to use adequate contraception from the first dose of study medication, continuing throughout the study, and for up to 28 days after the last dose of lenalidomide (or 120 days after the last dose of pembrolizumab).

Exclusion Criteria:

  • Has undergone prior allogeneic hematopoietic stem cell transplantation within the last 5 years.
  • Has peripheral neuropathy ≥ Grade 2.
  • Has a known additional malignancy that is progressing or requires active treatment within the last 5 years (except for basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or in situ cervical cancer that has undergone potentially curative therapy).
  • Has history of non-infectious pneumonitis that required steroids or current pneumonitis
  • Has received prior therapy with an anti-programmed cell death 1 receptor (anti-PD-1), anti-programmed death-ligand 1 (anti-PD-L1), anti-PD-L2, anti-CD137, or anti-cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody (including ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways).
  • Has a known Human Immunodeficiency Virus (HIV), or a known, active Hepatitis B (HBV), or a known, active Hepatitis C (HCV) infection.
  • Is unable or unwilling to undergo thromboembolic prophylaxis including, as clinically indicated, aspirin, Coumadin (warfarin) or low-molecular weight heparin.
  • Has lactose intolerance.
  • Has an invasive fungal infection.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Not Provided
Removed Location Countries Australia,   Canada,   France,   Germany,   Ireland,   Israel,   Italy,   Japan,   New Zealand,   Norway,   Russian Federation,   South Africa,   Spain,   United Kingdom,   United States
 
Administrative Information
NCT Number  ICMJE NCT02579863
Other Study ID Numbers  ICMJE 3475-185
2015-002901-12 ( EudraCT Number )
163239 ( Registry Identifier: JAPIC-CTI )
MK-3475-185 ( Other Identifier: Merck )
KEYNOTE-185 ( Other Identifier: Merck )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Merck Sharp & Dohme Corp.
Study Sponsor  ICMJE Merck Sharp & Dohme Corp.
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Medical Director Merck Sharp & Dohme Corp.
PRS Account Merck Sharp & Dohme Corp.
Verification Date August 2019

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