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

NCT02036502 | Terminated Phase 1 Results FDA Drug

• 4 other identifiers: 3475-0232013-003512-44MK-3475-023KEYNOTE-023
• Study Type: interventional
• Target: 77
• Locations: 0 countries
• Sites: N/A

Brief Summary

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 was 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. There was no primary hypothesis associated with this study. On 03-Jul-2017, the United States Food and Drug Administration (US FDA) placed the rrMM cohort of this protocol on clinical hold based on safety data from two other pembrolizumab protocols: MK-3475-183 (NCT02576977) and MK-3475-185 (NCT02579863) presented to the Data Monitoring Committee. On 15-Sep-2017, the US FDA placed the rMM cohort of this study on partial clinical hold. Enrollment was stopped and will not be reopened. Participants who are deriving clinical benefit were 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.

Conditions

Multiple Myeloma

Keywords

PD1; PD-1; PDL1; PD-L1

Outcome Measures

Primary Outcomes (3)

• Number of Participants Experiencing Dose-Limiting Toxicities (DLTs) According to National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 (NCI-CTCAE v.4.0)

  DLTs were assessed during Cycle 1 (28 days) and were defined as the occurrence of any of the following judged by the investigator to be possibly, probably or definitely related to study drug: Grade (Gr) 4 non-hematologic toxicity; Gr 4 hematologic toxicity lasting ≥7 days; Gr 3 non-hematologic toxicity lasting \>3 days; Gr 3 non-hematologic laboratory value if: medical intervention was required, abnormality led to hospitalization, was renal or liver function related, or persisted for \>1 week; Gr 3/4 febrile neutropenia; thrombocytopenia \<25,000 cells/mm\^3 (associated with bleeding requiring platelet transfusion or life-threatening bleeding); Gr 5 toxicity; or delay of \>1 week in initiating Cycle 2 or unable to complete 80% of treatment during the first course of therapy due to drug-related toxicity. DLTs for the rMM cohort were any drug-related adverse events that cannot be managed by dose modification. DLTs are reported for the maximum tolerated dose.

  Up to 28 days in Cycle 1

• Number of Participants Who Experienced One or More Adverse Events (AEs)

  An adverse event was defined as any untoward medical occurrence in a participant administered study treatment and did not necessarily have a causal relationship with this treatment. An adverse event could be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol-specified procedure. Any worsening of a preexisting condition that was temporally associated with the use of the study treatment was also an adverse event.

  Up to approximately 72.7 months

• Number of Participants Who Discontinued Study Treatment Due to an Adverse Event (AE)

  An adverse event was defined as any untoward medical occurrence in a participant administered study treatment and did not necessarily have a causal relationship with this treatment. An adverse event could be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol-specified procedure. Any worsening of a preexisting condition that was temporally associated with the use of the study treatment was also an adverse event.

  Up to approximately 72.7 months

Secondary Outcomes (2)

• Objective Response Rate (ORR) Evaluated According to the International Myeloma Working Group (IMWG) 2006 Response Criteria by Confirmed Investigator Assessment

  Up to approximately 72.7 months

• Disease Control Rate (DCR) Evaluated According to the International Myeloma Working Group (IMWG) 2006 Response Criteria by Confirmed Investigator Assessment

  Up to approximately 72.7 months

Other Outcomes (4)

• Duration of Response (DOR) Evaluated According to the International Myeloma Working Group (IMWG) 2006 Response Criteria by Confirmed Investigator Assessment

  Up to approximately 72.7 months

• Overall Survival (OS)

  Up to approximately 72.7 months

• Progression Free Survival (PFS) Evaluated According to the International Myeloma Working Group (IMWG) 2006 Response Criteria by Confirmed Investigator Assessment

  Up to approximately 72.7 months

Study Arms (8)

Part 1:pembro 2mg/kg+len 25mg+dex 40 mg

EXPERIMENTAL

Participants in Part 1 with refractory or relapsed and refractory multiple myeloma (rrMM) received pembrolizumab 2 mg/kg 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 Cycle 1 (28-day cycle).

Biological: Pembrolizumab; Drug: Lenalidomide; Drug: Dexamethasone

Part 1:pembro 2mg/kg+len 10 mg+dex 40 mg

EXPERIMENTAL

Participants in Part 1 with refractory or relapsed and refractory multiple myeloma (rrMM) received pembrolizumab 2 mg/kg Q2W (Days 1 and 15) in combination with lenalidomide 10 mg (Days 1-21) and dexamethasone 40 mg Q1W during Cycle 1 (28-day cycle).

Biological: Pembrolizumab; Drug: Lenalidomide; Drug: Dexamethasone

Part 2:pembro 200 mg+len 25 mg+dex 40 mg

EXPERIMENTAL

Participants in Part 2 with refractory or relapsed and refractory multiple myeloma (rrMM) received pembrolizumab 200 mg Q2W (Days 1 and 15) in combination with lenalidomide 25 mg (Days 1-21) and dexamethasone 40 mg Q1W during Cycle 1 (28-day cycle).

Biological: Pembrolizumab; Drug: Lenalidomide; Drug: Dexamethasone

Part 2:pembro 200 mg+len 25 mg+dex 20 mg

EXPERIMENTAL

Participants in Part 2 with refractory or relapsed and refractory multiple myeloma (rrMM) received pembrolizumab 200 mg Q2W (Days 1 and 15) in combination with lenalidomide 25 mg (Days 1-21) and dexamethasone 20 mg Q1W during Cycle 1 (28- day cycle).

Biological: Pembrolizumab; Drug: Lenalidomide; Drug: Dexamethasone

Part 2:pembro 200 mg+len 10 mg+dex 40 mg

EXPERIMENTAL

Participants in Part 2 with refractory or relapsed and refractory multiple myeloma (rrMM) received pembrolizumab 200 mg Q2W (Days 1 and 15) in combination with lenalidomide 10 mg (Days 1-21) and dexamethasone 40 mg Q1W during Cycle 1 (28-day cycle).

Biological: Pembrolizumab; Drug: Lenalidomide; Drug: Dexamethasone

Part 3:pembro 200 mg+len 25 mg+dex 40 mg

EXPERIMENTAL

Participants in Part 3 with refractory or relapsed and refractory multiple myeloma (rrMM) received pembrolizumab 200 mg Q2W (Days 1 and 15) in combination with lenalidomide 25 mg (Days 1-21) and dexamethasone 40 mg Q1W weekly during each 28-day cycle.

Biological: Pembrolizumab; Drug: Lenalidomide; Drug: Dexamethasone

Part 3:pembro 200 mg+len 25 mg+dex 20 mg

EXPERIMENTAL

Participants in Part 3 with refractory or relapsed and refractory multiple myeloma (rrMM) received pembrolizumab 200 mg Q2W (Days 1 and 15) in combination with lenalidomide 25 mg (Days 1-21) and dexamethasone 20 mg Q1W weekly during each 28-day cycle.

Biological: Pembrolizumab; Drug: Lenalidomide; Drug: Dexamethasone

Part 3:pembro 200 mg+carf 56 mg/m^2+dex 20 mg

EXPERIMENTAL

Participants in Part 3 with relapsed or refractory multiple myeloma (rMM) received pembrolizumab 200 mg Q3W in combination with carfilzomib 56 mg/m\^2 (Days 1, 2, 8, 9, 15, 16) and dexamethasone 20 mg once or twice weekly (Days 1, 2, 8, 9, 15, 16, 22, 23) during each 28-day cycle.

Biological: Pembrolizumab; Drug: Dexamethasone; Drug: Carfilzomib

Interventions

Pembrolizumab BIOLOGICAL

Intravenous (IV) infusion

Also known as: MK-3475, KEYTRUDA®

Part 1:pembro 2mg/kg+len 10 mg+dex 40 mg; Part 1:pembro 2mg/kg+len 25mg+dex 40 mg; Part 2:pembro 200 mg+len 10 mg+dex 40 mg; Part 2:pembro 200 mg+len 25 mg+dex 20 mg; Part 2:pembro 200 mg+len 25 mg+dex 40 mg; Part 3:pembro 200 mg+carf 56 mg/m^2+dex 20 mg; Part 3:pembro 200 mg+len 25 mg+dex 20 mg; Part 3:pembro 200 mg+len 25 mg+dex 40 mg

Lenalidomide DRUG

Oral capsule

Also known as: REVLIMID®

Part 1:pembro 2mg/kg+len 10 mg+dex 40 mg; Part 1:pembro 2mg/kg+len 25mg+dex 40 mg; Part 2:pembro 200 mg+len 10 mg+dex 40 mg; Part 2:pembro 200 mg+len 25 mg+dex 20 mg; Part 2:pembro 200 mg+len 25 mg+dex 40 mg; Part 3:pembro 200 mg+len 25 mg+dex 20 mg; Part 3:pembro 200 mg+len 25 mg+dex 40 mg

Dexamethasone DRUG

Oral tablet IV infusion

Also known as: DECADRON®

Part 1:pembro 2mg/kg+len 10 mg+dex 40 mg; Part 1:pembro 2mg/kg+len 25mg+dex 40 mg; Part 2:pembro 200 mg+len 10 mg+dex 40 mg; Part 2:pembro 200 mg+len 25 mg+dex 20 mg; Part 2:pembro 200 mg+len 25 mg+dex 40 mg; Part 3:pembro 200 mg+carf 56 mg/m^2+dex 20 mg; Part 3:pembro 200 mg+len 25 mg+dex 20 mg; Part 3:pembro 200 mg+len 25 mg+dex 40 mg

Carfilzomib DRUG

IV infusion

Also known as: KYPROLIS®

Part 3:pembro 200 mg+carf 56 mg/m^2+dex 20 mg

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• All Participants:
• Confirmed diagnosis of multiple myeloma (MM)
• MM with 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:
• Must have undergone prior treatment with ≥ 2 treatment lines of anti-myeloma therapy and must have failed their last line of treatment
• Prior anti-myeloma 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

You may not qualify if:

• 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
• 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) antibody
• Known Human Immunodeficiency Virus (HIV), Hepatitis B Virus (HBV), or Hepatitis C Virus (HCV) infection
• Clinically significant coagulopathy

Sponsors & Collaborators

• Merck Sharp & Dohme LLC: lead

Related Publications (1)

• Mateos MV, Orlowski RZ, Ocio EM, Rodriguez-Otero P, Reece D, Moreau P, Munshi N, Avigan DE, Siegel DS, Ghori R, Farooqui MZH, Marinello P, San-Miguel J. Pembrolizumab combined with lenalidomide and low-dose dexamethasone for relapsed or refractory multiple myeloma: phase I KEYNOTE-023 study. Br J Haematol. 2019 Sep;186(5):e117-e121. doi: 10.1111/bjh.15946. Epub 2019 May 15. No abstract available.

  PMID: 31090915 RESULT

Related Links

• Merck Oncology Clinical Trials Information

MeSH Terms

Conditions

Multiple Myeloma

Interventions

pembrolizumab; Lenalidomide; Dexamethasone; Calcium Dobesilate; carfilzomib

Condition Hierarchy (Ancestors)

Neoplasms, Plasma Cell; Neoplasms by Histologic Type; Neoplasms; Hemostatic Disorders; Vascular Diseases; Cardiovascular Diseases; Paraproteinemias; Blood Protein Disorders; Hematologic Diseases; Hemic and Lymphatic Diseases; Hemorrhagic Disorders; Lymphoproliferative Disorders; Immunoproliferative Disorders; Immune System Diseases

Intervention Hierarchy (Ancestors)

Phthalimides; Phthalic Acids; Acids, Carbocyclic; Carboxylic Acids; Organic Chemicals; Piperidones; Piperidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Isoindoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Pregnadienetriols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Steroids, Fluorinated; Benzenesulfonates; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Arylsulfonates; Arylsulfonic Acids; Sulfonic Acids; Sulfur Acids; Sulfur Compounds

Limitations and Caveats

Enrollment of participants into this study was stopped after the FDA implemented a clinical hold after determining the risks of pembrolizumab + pomalidomide or lenalidomide outweighed any potential benefit for participants with multiple myeloma.

Results Point of Contact

• Title: Senior Vice President, Global Clinical Development
• Organization: Merck Sharp & Dohme Corp.

ClinicalTrialsDisclosure@merck.com

1-800-672-6372

Study Officials

• Medical Director

  Merck Sharp & Dohme LLC

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 13, 2014
• First Posted: January 15, 2014
• Study Start: February 14, 2014
• Primary Completion: March 19, 2020
• Study Completion: March 19, 2020
• Last Updated: April 8, 2021
• Results First Posted: April 8, 2021

Record last verified: 2021-03

Data Sharing

• IPD Sharing: Will share