A Study of Pembrolizumab (MK-3475) in Combination With Standard of Care Treatments in Participants With Multiple Myeloma (MK-3475-023/KEYNOTE-023)
Condition: Multiple Myeloma
MeSH terms: Multiple Myeloma; Neoplasms, Plasma Cell
Intervention: Pembrolizumab; Lenalidomide; Dexamethasone; Carfilzomib
Intervention description: Intravenous (IV) infusion; Oral capsule; Oral tablet IV infusion; IV infusion
Intervention MeSH terms: Dexamethasone; Pembrolizumab; Lenalidomide
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 77.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: PD1; PD-1; PDL1; PD-L1

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.
    

Eligibility criteria:

        Inclusion Criteria:

        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

          -  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

          -  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

          -  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:

          -  Clinically active central nervous system (CNS) involvement

          -  Known gastrointestinal disease that may significantly alter the absorption of
             lenalidomide

          -  Unable or unwilling to undergo antithrombotic prophylactic treatment

          -  Known symptomatic congestive heart failure, unstable angina pectoris, or cardiac
             arrhythmia

        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