Multiple Myeloma
Conditions
Keywords
Relapsed/Refractory, MK-3475 & Pomalidomide, Immunotherapy
Brief summary
This is an open label trial of Anti PD1/MD-3475, Pomalidomide and dexamethasone. The study will use standard (FDA approved) doses for both pomalidomide and dexamethasone. The experimental drug Anti PD-1 (MK 3475) given on days 1 and 14.
Detailed description
This phase I/II study is focused on patients with relapsed or refractory multiple myeloma. MK-3475 will be given as an intravenous infusion at every 2 weeks. Treatment will be administered on an outpatient basis.
Interventions
DRUGMK-3475
Anti PD-1 (MD 3475) will be given as an intravenous infusion at 200 mg every 2 weeks.
DRUGPomalidomide
Pomalidomide is given at standard dose of 4 mg daily orally for 21 days
DRUGDexamethasone
Dexamethasone is given at 40 mg orally weekly
Sponsors
Merck Sharp & Dohme LLC
Ashraf Badros
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Confirmed diagnosis of relapsed and/or refractory MM according to International Myeloma Working Group guidelines (2003) 2. Received two lines of prior therapy that includes an IMiD (lenalidomide or thalidomide) and a proteasome inhibitor (bortezomib and/or carfilzomib) (used either separately or in combination). (a). Prior pomalidomide therapy is permitted, provided the patient achieved at least a partial remission and had not progressed for 3 months after stopping therapy. 3. Measureable disease as defined by the protocol (assessed within 28 days prior to registration). 4. Be willing and able to provide written informed consent/assent for the trial. 5. Be over 18 years of age on day of signing informed consent. 6. Have a performance status of 2 on the ECOG Performance Scale. 7. Demonstrate adequate organ function as defined by the protocol. 8. Female subject of childbearing potential should have a negative serum pregnancy within 72 hours prior to receiving the first dose of study drug. 9. Male subjects should agree to use an adequate method of contraception.
Exclusion criteria
1. Is currently participating in or has participated in a study of an investigational agent or using an investigational device within 4 weeks of the first dose of treatment. 2. Has a diagnosis of immunodeficiency (HIV) or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment. 3. Has had a prior monoclonal antibody within 4 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier. 4. Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to a previously administered agent. (Subjects with ≤ Grade 2 neuropathy are an exception to this criterion and may qualify for the study.) 5. Has a known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or situ cervical cancer that has undergone potentially curative therapy. 6. Has known active central nervous system disease and/or carcinomatous meningitis. 7. Has an active autoimmune disease requiring systemic treatment within the past 3 months or a documented history of clinically severe autoimmune disease, or a syndrome that requires systemic steroids or immunosuppressive agents. 8. Has evidence of interstitial lung disease or active, non-infectious pneumonitis. 9. Has an active infection requiring systemic therapy. 10. Has a history or current evidence of any condition, therapy, or lab abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator. 11. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial. 12. Pregnant or breastfeeding, or expecting to conceive or father children during study participation. 13. Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody as per the protocol. 14. has known active Hepatitis B or Hepatitis C. 15. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies) 16. Has received a live vaccine within 30 days prior to the first dose of trial treatment.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The Number of Participants With Adverse Events | 24 month | Establish the safety and tolerability of Pomalidomide and Dexamethasone in combination with MK-3475 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| PD-LI Expression On Myeloma Cells | Tissue sample collection will take place before starting study therapy with MK-3475 at baseline and again at time of relapse as defined by the International Myeloma Working Group Response Criteria (Average of up to 24months) | The identification of a biomarker for response by evaluating PD-1/PDL-1 expression in patients' bone marrow aspirate samples will be analyzed in order to help select patients for future anti-PD-1 therapy. The main exploratory biomarker analysis was to examine potential correlation between expression of PD-1 on T cells and PD-L1 on myeloma cells with clinical outcome using the following parameters: response rate focusing on responses ≥ very good partial response (VGPR) and PFS. SAS software (v.9.4; SAS Institute, Inc, Cary, NC) was used for statistical analyses. |
| Time to Progression Free Survival (PFS) | PFS assessments will take place after starting study therapy with MD-3475 and will continue until the start of a new anti-neoplastic therapy, disease progression, death, or the end of study up to an average of 24 months. | PFS will be measured in all participants. Survival and PFS functions were estimated using the Kaplan-Meier method. The Cox regression model was used to assess the following plausible risk factors for OS and PFS: age, isotype, number of cycles of therapy, and cytogenetic profile. |
Countries
United States
Participant flow
Recruitment details
Participants were recruited from the University of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer Center between December 2014 and May 2016.
Participants by arm
| Arm | Count |
|---|---|
| Pomalidomide, Dexamethasone & MK-3475 Pomalidomide is given at standard dose of 4 mg daily orally for 21 days and dexamethasone is given at 40 mg orally weekly. MK3475 will be given as an intravenous infusion at 200 mg every 2 weeks (days 1 and 14).
MK-3475: Anti PD-1 (MD 3475) will be given as an intravenous infusion at 200 mg every 2 weeks.
Pomalidomide: Pomalidomide is given at standard dose of 4 mg daily orally for 21 days
Dexamethasone: Dexamethasone is given at 40 mg orally weekly | 48 |
| Total | 48 |
Baseline characteristics
| Characteristic | Pomalidomide, Dexamethasone & MK-3475 |
|---|---|
| Age, Continuous | 64 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 46 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 2 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants |
| Race (NIH/OMB) Black or African American | 18 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants |
| Race (NIH/OMB) White | 26 Participants |
| Sex: Female, Male Female | 16 Participants |
| Sex: Female, Male Male | 32 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 2 / 48 |
| other Total, other adverse events | 48 / 48 |
| serious Total, serious adverse events | 27 / 48 |
Outcome results
Primary
The Number of Participants With Adverse Events
Establish the safety and tolerability of Pomalidomide and Dexamethasone in combination with MK-3475
Time frame: 24 month
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Pomalidomide, Dexamethasone & MK-3475 | The Number of Participants With Adverse Events | 48 Participants |
Secondary
PD-LI Expression On Myeloma Cells
The identification of a biomarker for response by evaluating PD-1/PDL-1 expression in patients' bone marrow aspirate samples will be analyzed in order to help select patients for future anti-PD-1 therapy. The main exploratory biomarker analysis was to examine potential correlation between expression of PD-1 on T cells and PD-L1 on myeloma cells with clinical outcome using the following parameters: response rate focusing on responses ≥ very good partial response (VGPR) and PFS. SAS software (v.9.4; SAS Institute, Inc, Cary, NC) was used for statistical analyses.
Time frame: Tissue sample collection will take place before starting study therapy with MK-3475 at baseline and again at time of relapse as defined by the International Myeloma Working Group Response Criteria (Average of up to 24months)
Population: Data were analyzed for 29 samples.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Pomalidomide, Dexamethasone & MK-3475 | PD-LI Expression On Myeloma Cells | Negative | 10 Participants |
| Pomalidomide, Dexamethasone & MK-3475 | PD-LI Expression On Myeloma Cells | Weak Positive | 6 Participants |
| Pomalidomide, Dexamethasone & MK-3475 | PD-LI Expression On Myeloma Cells | Positive | 13 Participants |
Secondary
Time to Progression Free Survival (PFS)
PFS will be measured in all participants. Survival and PFS functions were estimated using the Kaplan-Meier method. The Cox regression model was used to assess the following plausible risk factors for OS and PFS: age, isotype, number of cycles of therapy, and cytogenetic profile.
Time frame: PFS assessments will take place after starting study therapy with MD-3475 and will continue until the start of a new anti-neoplastic therapy, disease progression, death, or the end of study up to an average of 24 months.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pomalidomide, Dexamethasone & MK-3475 | Time to Progression Free Survival (PFS) | 17.4 Months |