NCT02036502 · REGISTRY CONDITION SEARCH
A Study of Pembrolizumab (MK-3475) in Combination With Standard of Care Treatments in Participants With Multiple Myeloma (MK-3475-023/KEYNOTE-023)
Found through the registry condition index, not selected as a treatment recommendation. This discovery collection was restricted to studies with posted results.
- Phase
- PHASE1
- Status at capture
- TERMINATED
- Registry last update
- 2021-04-08
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.
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What did the study report?
Outcomes, safety and baseline populations are separate source sections. Quality-of-life measures appear under their original outcome titles.
Participant flow
Baseline characteristics
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)
Number of Participants Who Experienced One or More Adverse Events (AEs)
Number of Participants Who Discontinued Study Treatment Due to an Adverse Event (AE)
Objective Response Rate (ORR) Evaluated According to the International Myeloma Working Group (IMWG) 2006 Response Criteria by Confirmed Investigator Assessment
Disease Control Rate (DCR) Evaluated According to the International Myeloma Working Group (IMWG) 2006 Response Criteria by Confirmed Investigator Assessment
Duration of Response (DOR) Evaluated According to the International Myeloma Working Group (IMWG) 2006 Response Criteria by Confirmed Investigator Assessment
Overall Survival (OS)
Progression Free Survival (PFS) Evaluated According to the International Myeloma Working Group (IMWG) 2006 Response Criteria by Confirmed Investigator Assessment
Time to Progression (TTP) Evaluated According to the International Myeloma Working Group (IMWG) 2006 Response Criteria by Confirmed Investigator Assessment
Adverse events
Limitations, agreements, and source contact
Who could take part
- 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
- healthy Volunteers
- false
- minimum Age
- 18 Years
- sex
- ALL
- std Ages
- ADULT
- OLDER_ADULT
Treatment arms and interventions
- arm Groups
- description
- 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).
- intervention Names
- Biological: Pembrolizumab
- Drug: Lenalidomide
- Drug: Dexamethasone
- label
- Part 1:pembro 2mg/kg+len 25mg+dex 40 mg
- type
- EXPERIMENTAL
- description
- 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).
- intervention Names
- Biological: Pembrolizumab
- Drug: Lenalidomide
- Drug: Dexamethasone
- label
- Part 1:pembro 2mg/kg+len 10 mg+dex 40 mg
- type
- EXPERIMENTAL
- description
- 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).
- intervention Names
- Biological: Pembrolizumab
- Drug: Lenalidomide
- Drug: Dexamethasone
- label
- Part 2:pembro 200 mg+len 25 mg+dex 40 mg
- type
- EXPERIMENTAL
- description
- 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).
- intervention Names
- Biological: Pembrolizumab
- Drug: Lenalidomide
- Drug: Dexamethasone
- label
- Part 2:pembro 200 mg+len 25 mg+dex 20 mg
- type
- EXPERIMENTAL
- description
- 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).
- intervention Names
- Biological: Pembrolizumab
- Drug: Lenalidomide
- Drug: Dexamethasone
- label
- Part 2:pembro 200 mg+len 10 mg+dex 40 mg
- type
- EXPERIMENTAL
- description
- 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.
- intervention Names
- Biological: Pembrolizumab
- Drug: Lenalidomide
- Drug: Dexamethasone
- label
- Part 3:pembro 200 mg+len 25 mg+dex 40 mg
- type
- EXPERIMENTAL
- description
- 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.
- intervention Names
- Biological: Pembrolizumab
- Drug: Lenalidomide
- Drug: Dexamethasone
- label
- Part 3:pembro 200 mg+len 25 mg+dex 20 mg
- type
- EXPERIMENTAL
- description
- 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.
- intervention Names
- Biological: Pembrolizumab
- Drug: Dexamethasone
- Drug: Carfilzomib
- label
- Part 3:pembro 200 mg+carf 56 mg/m^2+dex 20 mg
- type
- EXPERIMENTAL
- interventions
- arm Group Labels
- 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
- description
- Intravenous (IV) infusion
- name
- Pembrolizumab
- other Names
- MK-3475
- KEYTRUDA®
- type
- BIOLOGICAL
- arm Group Labels
- 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
- description
- Oral capsule
- name
- Lenalidomide
- other Names
- REVLIMID®
- type
- DRUG
- arm Group Labels
- 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
- description
- Oral tablet IV infusion
- name
- Dexamethasone
- other Names
- DECADRON®
- type
- DRUG
- arm Group Labels
- Part 3:pembro 200 mg+carf 56 mg/m^2+dex 20 mg
- description
- IV infusion
- name
- Carfilzomib
- other Names
- KYPROLIS®
- type
- DRUG
Study design
- allocation
- NON_RANDOMIZED
- intervention Model
- PARALLEL
- masking Info
- masking
- NONE
- primary Purpose
- TREATMENT
Enrollment
- count
- 77
- type
- ACTUAL
Registered outcome plans (not posted results)
- other Outcomes
- description
- DOR was the time from first evidence of response (stringent complete response \[sCR\]+complete response \[CR\], very good partial response \[VGPR\], partial response \[PR\]) until disease progression (PD) or death. CR=negative immunofixation of serum and urine+no tissue plasmacytomas+≤5% plasmacytomas in bone marrow; sCR=stringent complete response, CR+normal free light chain (FLC) ratio+no clonal cells in bone marrow; VGPR=serum+urine M-protein detectable by immunofixation but not electrophoresis OR ≥90% reduction in serum M-protein+urine M-protein \<100 mg/24 hour(hr); PR = ≥50% reduction of serum M-protein+reduction in 24hr urinary M-protein by ≥90% or to \<200 mg/24 hrs. PD=≥1 of the following: ≥25% increase from baseline serum/urine M-protein; hypercalcemia; increase between involved/uninvolved FLC levels; ≥10% bone marrow plasma cells; new or increase in the size of existing bone lesions or tissue plasmacytomas. DOR was calculated using the Kaplan-Meier method for censored data.
- measure
- Duration of Response (DOR) Evaluated According to the International Myeloma Working Group (IMWG) 2006 Response Criteria by Confirmed Investigator Assessment
- time Frame
- Up to approximately 72.7 months
- description
- OS was defined as the time from randomization to death due to any cause. OS was calculated from product-limit (Kaplan-Meier) method for censored data. Participants without documented death at the time of the final analysis were censored at the date of the last follow-up.
- measure
- Overall Survival (OS)
- time Frame
- Up to approximately 72.7 months
- description
- PFS was defined as the time from randomization to the first documented disease progression (PD) or death due to any cause. PD= ≥1 of the following: ≥25% increase from baseline in serum/urine M-protein; hypercalcemia; increase in FLC ratio; ≥10% bone marrow plasma cells; new or increase in the size of existing bone lesions or tissue plasmacytomas. The median PFS was calculated from the Kaplan-Meier method for censored data.
- measure
- Progression Free Survival (PFS) Evaluated According to the International Myeloma Working Group (IMWG) 2006 Response Criteria by Confirmed Investigator Assessment
- time Frame
- Up to approximately 72.7 months
- description
- TTP was defined as the time from the first dose to first documented disease progression (PD) or death due to any cause. PD= ≥1 of the following: ≥25% increase from baseline in serum/urine M-protein; hypercalcemia; increase in FLC ratio; ≥10% bone marrow plasma cells; new or increase in the size of existing bone lesions or tissue plasmacytomas.
- measure
- Time to Progression (TTP) Evaluated According to the International Myeloma Working Group (IMWG) 2006 Response Criteria by Confirmed Investigator Assessment
- time Frame
- Up to approximately 72.7 months
- primary Outcomes
- description
- 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.
- measure
- 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)
- time Frame
- Up to 28 days in Cycle 1
- description
- 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.
- measure
- Number of Participants Who Experienced One or More Adverse Events (AEs)
- time Frame
- Up to approximately 72.7 months
- description
- 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.
- measure
- Number of Participants Who Discontinued Study Treatment Due to an Adverse Event (AE)
- time Frame
- Up to approximately 72.7 months
- secondary Outcomes
- description
- ORR was the percentage of the participants who achieved at least a partial response (stringent complete response \[sCR\]+complete response \[CR\]+very good partial response \[VGPR\]+partial response \[PR\]). CR=negative immunofixation of serum and urine+no tissue plasmacytomas+≤5% plasmacytomas in bone marrow; sCR=stringent complete response, CR+normal free light chain (FLC) ratio+no clonal cells in bone marrow; VGPR=serum+urine M-protein detectable by immunofixation but not electrophoresis OR ≥90% reduction in serum M-protein+urine M-protein \<100 mg/24 hour(hr); PR = ≥50% reduction of serum M-protein+reduction in 24hr urinary M-protein by ≥90% or to \<200 mg/24 hrs.
- measure
- Objective Response Rate (ORR) Evaluated According to the International Myeloma Working Group (IMWG) 2006 Response Criteria by Confirmed Investigator Assessment
- time Frame
- Up to approximately 72.7 months
- description
- DCR was the percentage of participants who achieved stringent complete response (sCR), complete response (CR), very good partial response (VGPR), partial response (PR), or stable disease (SD) ≥12 weeks prior to evidence of disease progression (PD). CR=negative immunofixation of serum and urine+no tissue plasmacytomas+ ≤5% plasmacytomas in bone marrow; sCR=stringent complete response, CR+normal free light chain (FLC) ratio+no clonal cells in bone marrow; VGPR=serum+urine M-protein detectable by immunofixation but not on electrophoresis OR ≥90% reduction in serum M-protein+urine M-protein \<100 mg/24 hour(hr); PR=≥50% reduction of serum M-protein+reduction in 24 hr urinary M-protein by ≥90% or to \<200 mg/24 hrs; SD=not meeting the criteria for CR, VGPR, PR, or PD. PD=≥1 of the following: ≥25% increase from baseline in serum/urine M-protein; hypercalcemia; increase in FLC ratio; ≥10% bone marrow plasma cells; new or increase in the size of existing bone lesions or tissue plasmacytomas.
- measure
- Disease Control Rate (DCR) Evaluated According to the International Myeloma Working Group (IMWG) 2006 Response Criteria by Confirmed Investigator Assessment
- time Frame
- Up to approximately 72.7 months
Full study description
- 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.
Source references
- references
- citation
- 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
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- see Also Links
- label
- Merck Oncology Clinical Trials Information
Source notices and limitations
Discovery and provenance
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Preserved source evidence · Not medical advice
Triangle