rrCLL, rrDLBCL, rrMM
Conditions
Brief summary
The purpose of this study is to evaluate the safety and efficacy of pembrolizumab (MK-3475) used in combination with dinaciclib (MK-7965) in the treatment of relapsed or refractory chronic lymphocytic leukemia (rrCLL), multiple myeloma (rrMM), or diffuse large B-cell lymphoma (rrDLBCL).
Interventions
BIOLOGICALpembrolizumab
200 mg administered as an intravenous (IV) infusion on Day 1 of infusion Cycles 1-35. Each cycle is 21 days.
DRUGdinaciclib
dinaciclib 7 mg/m\^2 administered as an IV infusion on Day 1 of infusion Cycle 1, dinaciclib 10 mg/m\^2 administered as an IV infusion on Day 8 of infusion Cycle 1, dinaciclib 14 mg/m\^2 administered as an IV infusion on Days 1 and 8 of infusion Cycles 2-35. Each cycle is 21 days.
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Females must not be pregnant (negative urine or serum human chorionic gonadotropin test within 72 hours of study start) * Female and male participants of reproductive potential must agree to use adequate contraception starting from the first dose of study medication, throughout the study period, and for up to 120 days after the last dose of study medication * Eastern Cooperative Oncology Group (ECOG) performance status 0-1 * Cardiac function suitable for protocol-required hydration as determined by the investigator and/or cardiologist * Must be able to provide biopsy specimens obtained ≤3 months for biomarker analysis. If bone marrow biopsy was performed 3 months before screening but subject had anti-cancer treatment after biopsy, the bone marrow biopsy and aspiration should be repeated Relapsed or refractory chronic lymphocytic leukemia (rrCLL) participants: * Must have a confirmed diagnosis of CLL defined by 2008 International Workshop on Chronic Lymphocytic Leukemia (iwCLL) criteria * Must have received one prior therapy for CLL * Must meet one or more of the consensus criteria for initiating treatment Relapsed or refractory multiple myelolma (rrMM) participants: * Must have a confirmed diagnosis of active MM * Must have undergone prior treatment with ≥2 treatment lines of anti-myeloma therapy and failed last line of treatment (disease progression ≤60 days of completion of last therapy) * Must have failed prior anti-myeloma treatments that have included an immunomodulatory drug (IMiD) (pomalidomide, lenalidomide, or thalidomide) AND proteasome inhibitor (bortezomib, carfilzomib, or ixazomib) alone or in combination Diffuse large B-cell lymphoma (rrDLBCL) participants: * Must have a confirmed diagnosis of DLBCL and have progressed following ≥2 lines of previous therapy, after autologous stem cell transplant, or not a candidate for autologous stem cell transplant * Must have measurable disease (≥1 lesion that is \>15 mm in the longest diameter or by \>10 mm in the short axis)
Exclusion criteria
* Has been treated with a cytochrome P450 3A4 (CYP3A4) strong inhibitor or inducer within 7 days of enrollment * Has been treated with anti-cancer therapy or thoracic radiation therapy within 14 days * Has known clinically active central nervous system (CNS) involvement * Has a known history of immunosuppression or is receiving systemic steroid therapy or any other form of systemic immunosuppressive therapy within 7 days * Has had prior anti-cancer monoclonal antibody within 4 weeks of Study Day 1 or who has not recovered from adverse events due to agents administered \>4 weeks earlier * Has undergone prior allogeneic hematopoetic stem cell transplantation within the last 5 years * Has a known additional malignancy that is progressing or requires active treatment * Has active autoimmune disease that has required systemic treatment in past 2 years * Has an active infection requiring intravenous systemic therapy * Has received prior therapy with an anti-programmed cell death-1 (PD-1), anti-programmed cell death ligand (PD-L) 1, 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) or chimeric antigen receptor (CAR)-T cell therapy or with an agent directed to another stimulatory or co-inhibitory T-cell receptor * Has been previously treated with a cyclin-dependent kinase (CDK) inhibitor * Has a known history of Human Immunodeficiency Virus (HIV) infection * Has a known history of or is positive for hepatitis B (hepatitis B surface antigen reactive) or hepatitis C (hepatitis C virus RNA \[qualitative\] is detected) * Has received a live vaccine within 30 days prior to the first dose of trial treatment * Has a history of (non-infectious) pneumonitis that required steroids or current pneumonitis * Has known current symptomatic congestive heart failure, unstable angina pectoris, or cardiac arrhythmia Relapsed or refractory chronic lymphocytic leukemia (rrCLL) participants: * Has Richter's Transformation Relapsed or refractory multiple myelolma (rrMM) participants: * Participants with non-secretory or oligo-secretory myeloma, plasma cell leukemia or Waldenström's macroglobulinemia * History of primary amyloidosis, hyperviscosity or POEMS syndrome (plasma cell dyscrasia with polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes) Diffuse large B-cell lymphoma (rrDLBCL) participants: * Participants with primary mediastinal B-cell lymphoma (PMBCL) * Has Richter's Transformation
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Dose Limiting Toxicity (DLT) | Up to 42 days | DLTs consisted of the following if observed during treatment Cycles 1 or 2 and assessed by investigator to be possibly, probably, or definitely related to pembrolizumab or dinaciclib: grade 4 non-laboratory nonhematologic toxicity; grade 4 hematologic toxicity lasting \>7 days (except thrombocytopenia); grade 4 thrombocytopenia of any duration; grade 3 thrombocytopenia if associated with bleeding; any grade 3 non-laboratory nonhematologic toxicity, except grade 3 nausea, vomiting, or diarrhea, which was not considered a DLT unless lasting more than 3 days despite optimal supportive care; Grade 3 or Grade 4 nonhematologic laboratory abnormality that required medical intervention, led to hospitalization, or persisted for \>1 week; grade 3 or 4 febrile neutropenia; any drug-related AE that caused participant to discontinue treatment during Cycles 1 or 2; grade 5 toxicity; treatment-related toxicity that caused a \>2-week delay in initiation of treatment Cycle 2 or 3. Each cycle was 21 days. |
| Number of Participants Who Experienced an Adverse Event | Up to approximately 582 days | An adverse event (AE) was defined as any untoward medical occurrence in a participant administered study treatment and which did not necessarily have to have a causal relationship with this treatment. The number of participants who experienced an AE was presented. |
| Number of Participants Who Discontinued Treatment Due to an Adverse Event | Up to 492 days | An AE was defined as any untoward medical occurrence in a participant administered study treatment and which did not necessarily have to have a causal relationship with this treatment. The number of participants who discontinued study drug due to an adverse event is presented. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate (ORR) | Up to approximately 26 months | ORR is defined in participants with CLL as the percentage of participants who have a confirmed Complete Response (CR) or Partial Response (PR) per the International Workshop on Chronic Lymphocytic Leukemia (iwCLL) guidelines (2008) as assessed by the investigator; in participants with DLBCL as the above definition but per the Revised Response Criteria for Malignant Lymphoma (2007) as assessed by the investigator; and in participants with MM as the percentage of participants who have a confirmed Stringent Complete Response (sCR), CR, PR, or Very Good Partial Remission (VGPR) per the International Uniform Response Criteria for Multiple Myeloma (2006) as assessed by the investigator. |
| Overall Survival (OS) | Up to approximately 44 months | OS was defined as the time from first dose of study treatment to death due to any cause. Data were censored at the date of a participant's last follow-up. OS was analyzed using the product-limit (Kaplan-Meier) method for censored data. |
| Duration of Response (DOR) | Up to approximately 26 months | DOR is the time from initial response to Progressive Disease (PD) or death, whichever occurred first. A response was: in participants with CLL, a confirmed Complete Response (CR) or Partial Response (PR) per the International Workshop on Chronic Lymphocytic Leukemia (iwCLL) guidelines (2008); in participants with DLBCL, as above but per the Revised Response Criteria for Malignant Lymphoma (2007); and in participants with MM, a confirmed Stringent Complete Response (sCR), CR, PR, or Very Good Partial Remission (VGPR) per the International Uniform Response Criteria for Multiple Myeloma (2006). The above guidelines also define PD by disease. Assessments were by investigator. Data were censored at last disease assessment documenting absence of PD for participants who: had no PD and were still on the trial; received antitumor treatment other than that of the trial; or were removed from trial prior to PD. DOR was analyzed using the product-limit (Kaplan-Meier) method for censored data. |
| Progression-Free Survival (PFS) | Up to approximately 26 months | PFS was defined as the time from first dose of study treatment to the first documented progressive disease (PD) or death due to any cause, whichever occurred first. PD evaluations were done based on the cancer-specific criteria of: the International Workshop on Chronic Lymphocytic Leukemia (iwCLL) guidelines (2008) in participants with CLL; the Revised Response Criteria for Malignant Lymphoma (2007) in participants with DLBCL; and the International Uniform Response Criteria for Multiple Myeloma (2006) in participants with MM. Assessments were by investigator. PFS data were censored for participants with no PD or death at their last disease assessment, or at their last disease assessment prior to starting new anticancer treatment for those who did so. PFS was analyzed using the product-limit (Kaplan-Meier) method for censored data. |
Participant flow
Recruitment details
The rrMM Cohort was closed to enrollment on 07-AUG-2017 due to lack of efficacy. The rrCLL Cohort was closed to enrollment on 30-APR-2019 due to lack of efficacy.
Participants by arm
| Arm | Count |
|---|---|
| rrCLL Cohort Participants with refractory chronic lymphocytic leukemia (rrCLL) received an infusion of pembrolizumab 200 mg followed by infusion of dinaciclib 7 mg/m\^2 on Cycle 1 Day 1, and infusion of dinaciclib 10 mg/m\^2 alone on Cycle 1 Day 8. Participants then received an infusion of pembrolizumab 200 mg followed by infusion of dinaciclib 14 mg/m\^2 on Cycles 2-35 Day 1 and infusion of dinaciclib 14 mg/m\^2 alone on Cycles 2-35 Day 8. Each cycle is 21 days. | 17 |
| rrMM Cohort Participants with relapsed or refractory multiple myeloma (rrMM) received an infusion of pembrolizumab 200 mg followed by infusion of dinaciclib 7 mg/m\^2 on Cycle 1 Day 1, and infusion of dinaciclib 10 mg/m\^2 alone on Cycle 1 Day 8. Participants then received an infusion of pembrolizumab 200 mg followed by infusion of dinaciclib 14 mg/m\^2 on Cycles 2-35 Day 1 and infusion of dinaciclib 14 mg/m\^2 alone on Cycles 2-35 Day 8. Each cycle is 21 days. | 17 |
| rrDLBCL Cohort Participants with relapsed or refractory diffuse large B-cell lymphoma (rrDLBCL) received an infusion of pembrolizumab 200 mg followed by infusion of dinaciclib 7 mg/m\^2 on Cycle 1 Day 1, and infusion of dinaciclib 10 mg/m\^2 alone on Cycle 1 Day 8. Participants then received an infusion of pembrolizumab 200 mg followed by infusion of dinaciclib 14 mg/m\^2 on Cycles 2-35 Day 1 and infusion of dinaciclib 14 mg/m\^2 alone on Cycles 2-35 Day 8. Each cycle is 21 days. | 38 |
| Total | 72 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 | 1 |
| Overall Study | Death | 8 | 16 | 28 |
| Overall Study | Screen Failure | 1 | 0 | 2 |
| Overall Study | Study Terminated by Sponsor | 6 | 1 | 5 |
| Overall Study | Withdrawal by Subject | 2 | 0 | 4 |
Baseline characteristics
| Characteristic | rrCLL Cohort | rrMM Cohort | rrDLBCL Cohort | Total |
|---|---|---|---|---|
| Age, Continuous | 68.1 Years STANDARD_DEVIATION 10.9 | 60.8 Years STANDARD_DEVIATION 9.5 | 64.1 Years STANDARD_DEVIATION 11.1 | 64.3 Years STANDARD_DEVIATION 10.9 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 1 Participants | 4 Participants | 5 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 17 Participants | 16 Participants | 34 Participants | 67 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 4 Participants | 4 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 3 Participants | 2 Participants | 6 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 16 Participants | 14 Participants | 32 Participants | 62 Participants |
| Sex: Female, Male Female | 3 Participants | 11 Participants | 15 Participants | 29 Participants |
| Sex: Female, Male Male | 14 Participants | 6 Participants | 23 Participants | 43 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 9 / 17 | 16 / 17 | 32 / 38 |
| other Total, other adverse events | 17 / 17 | 16 / 17 | 37 / 38 |
| serious Total, serious adverse events | 13 / 17 | 6 / 17 | 17 / 38 |
Outcome results
Primary
Number of Participants Who Discontinued Treatment Due to an Adverse Event
An AE was defined as any untoward medical occurrence in a participant administered study treatment and which did not necessarily have to have a causal relationship with this treatment. The number of participants who discontinued study drug due to an adverse event is presented.
Time frame: Up to 492 days
Population: The analysis population included all participants who received ≥1 dose of study treatment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| rrCLL Cohort | Number of Participants Who Discontinued Treatment Due to an Adverse Event | 4 Participants |
| rrMM Cohort | Number of Participants Who Discontinued Treatment Due to an Adverse Event | 2 Participants |
| rrDLBCL Cohort | Number of Participants Who Discontinued Treatment Due to an Adverse Event | 0 Participants |
Primary
Number of Participants Who Experienced an Adverse Event
An adverse event (AE) was defined as any untoward medical occurrence in a participant administered study treatment and which did not necessarily have to have a causal relationship with this treatment. The number of participants who experienced an AE was presented.
Time frame: Up to approximately 582 days
Population: The analysis population included all participants who received ≥1 dose of study treatment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| rrCLL Cohort | Number of Participants Who Experienced an Adverse Event | 17 Participants |
| rrMM Cohort | Number of Participants Who Experienced an Adverse Event | 16 Participants |
| rrDLBCL Cohort | Number of Participants Who Experienced an Adverse Event | 37 Participants |
Primary
Number of Participants With Dose Limiting Toxicity (DLT)
DLTs consisted of the following if observed during treatment Cycles 1 or 2 and assessed by investigator to be possibly, probably, or definitely related to pembrolizumab or dinaciclib: grade 4 non-laboratory nonhematologic toxicity; grade 4 hematologic toxicity lasting \>7 days (except thrombocytopenia); grade 4 thrombocytopenia of any duration; grade 3 thrombocytopenia if associated with bleeding; any grade 3 non-laboratory nonhematologic toxicity, except grade 3 nausea, vomiting, or diarrhea, which was not considered a DLT unless lasting more than 3 days despite optimal supportive care; Grade 3 or Grade 4 nonhematologic laboratory abnormality that required medical intervention, led to hospitalization, or persisted for \>1 week; grade 3 or 4 febrile neutropenia; any drug-related AE that caused participant to discontinue treatment during Cycles 1 or 2; grade 5 toxicity; treatment-related toxicity that caused a \>2-week delay in initiation of treatment Cycle 2 or 3. Each cycle was 21 days.
Time frame: Up to 42 days
Population: The analysis population included all participants who received ≥1 dose of study medication, and who did not discontinue within the first two 21-day cycles of treatment or who experienced a DLT prior to completing the first two cycles of treatment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| rrCLL Cohort | Number of Participants With Dose Limiting Toxicity (DLT) | 1 Participants |
| rrMM Cohort | Number of Participants With Dose Limiting Toxicity (DLT) | 1 Participants |
| rrDLBCL Cohort | Number of Participants With Dose Limiting Toxicity (DLT) | 1 Participants |
Secondary
Duration of Response (DOR)
DOR is the time from initial response to Progressive Disease (PD) or death, whichever occurred first. A response was: in participants with CLL, a confirmed Complete Response (CR) or Partial Response (PR) per the International Workshop on Chronic Lymphocytic Leukemia (iwCLL) guidelines (2008); in participants with DLBCL, as above but per the Revised Response Criteria for Malignant Lymphoma (2007); and in participants with MM, a confirmed Stringent Complete Response (sCR), CR, PR, or Very Good Partial Remission (VGPR) per the International Uniform Response Criteria for Multiple Myeloma (2006). The above guidelines also define PD by disease. Assessments were by investigator. Data were censored at last disease assessment documenting absence of PD for participants who: had no PD and were still on the trial; received antitumor treatment other than that of the trial; or were removed from trial prior to PD. DOR was analyzed using the product-limit (Kaplan-Meier) method for censored data.
Time frame: Up to approximately 26 months
Population: The analysis population included all participants who received ≥1 dose of study treatment and experienced a response to study treatment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| rrCLL Cohort | Duration of Response (DOR) | NA Months |
| rrDLBCL Cohort | Duration of Response (DOR) | 4.9 Months |
Secondary
Objective Response Rate (ORR)
ORR is defined in participants with CLL as the percentage of participants who have a confirmed Complete Response (CR) or Partial Response (PR) per the International Workshop on Chronic Lymphocytic Leukemia (iwCLL) guidelines (2008) as assessed by the investigator; in participants with DLBCL as the above definition but per the Revised Response Criteria for Malignant Lymphoma (2007) as assessed by the investigator; and in participants with MM as the percentage of participants who have a confirmed Stringent Complete Response (sCR), CR, PR, or Very Good Partial Remission (VGPR) per the International Uniform Response Criteria for Multiple Myeloma (2006) as assessed by the investigator.
Time frame: Up to approximately 26 months
Population: The analysis population included all participants who received ≥1 dose of study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| rrCLL Cohort | Objective Response Rate (ORR) | 29.4 Percentage of Participants |
| rrMM Cohort | Objective Response Rate (ORR) | 0.0 Percentage of Participants |
| rrDLBCL Cohort | Objective Response Rate (ORR) | 21.1 Percentage of Participants |
Secondary
Overall Survival (OS)
OS was defined as the time from first dose of study treatment to death due to any cause. Data were censored at the date of a participant's last follow-up. OS was analyzed using the product-limit (Kaplan-Meier) method for censored data.
Time frame: Up to approximately 44 months
Population: The analysis population included all participants who received ≥1 dose of study treatment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| rrCLL Cohort | Overall Survival (OS) | 21.7 Months |
| rrMM Cohort | Overall Survival (OS) | 10.5 Months |
| rrDLBCL Cohort | Overall Survival (OS) | 7.9 Months |
Secondary
Progression-Free Survival (PFS)
PFS was defined as the time from first dose of study treatment to the first documented progressive disease (PD) or death due to any cause, whichever occurred first. PD evaluations were done based on the cancer-specific criteria of: the International Workshop on Chronic Lymphocytic Leukemia (iwCLL) guidelines (2008) in participants with CLL; the Revised Response Criteria for Malignant Lymphoma (2007) in participants with DLBCL; and the International Uniform Response Criteria for Multiple Myeloma (2006) in participants with MM. Assessments were by investigator. PFS data were censored for participants with no PD or death at their last disease assessment, or at their last disease assessment prior to starting new anticancer treatment for those who did so. PFS was analyzed using the product-limit (Kaplan-Meier) method for censored data.
Time frame: Up to approximately 26 months
Population: The analysis population included all participants who received ≥1 dose of study treatment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| rrCLL Cohort | Progression-Free Survival (PFS) | 5.2 Months |
| rrMM Cohort | Progression-Free Survival (PFS) | 1.6 Months |
| rrDLBCL Cohort | Progression-Free Survival (PFS) | 2.1 Months |