The purpose of this study is to identify recommended Phase 2 doses (RP2Ds) for each treatment combination (between daratumumab plus talquetamab and teclistamab plus daratumumab with or without pomalidomide) and to characterize the safety of each RP2D for selected treatment combinations.
Multiple myeloma is a malignant plasma cell disorder characterized by osteolytic lesions, increased susceptibility to infections, hypercalcemia, and renal failure. Overall rationale of study is that daratumumab in combination with talquetamab or teclistamab with or without pomalidomide may lead to enhanced clinical responses in treatment of relapsed or refractory multiple myeloma through multiple mechanisms of action. Daratumumab is human immunoglobulin G1 kappa monoclonal antibody (IgG1k) that binds with high affinity to a unique epitope on cluster of differentiation 38 (CD38) in a variety of hematological malignancies including multiple myeloma. Talquetamab and teclistamab are bispecific T cell redirection antibodies. Talquetamab binds to cluster of differentiation 3 (CD3) receptor complex on T cells and to G protein-coupled receptor family C group 5-member D (GPRC5D), a 7-transmembrane receptor protein on plasma cells and teclistamab binds to human and cynomolgus-CD3 and B cell maturation antigen (BCMA). Purpose of study is to evaluate safety of daratumumab in combination with talquetamab and teclistamab with or without pomalidomide, and to evaluate preliminary antitumor activity of each combination. Study consists of a screening period, treatment period (Part 1: dose escalation and Part 2: dose expansion), a Post-treatment Follow-up Period (after the last dose of study drug and will continue for up to 16 weeks for each subject), and a Long-term Extension Period. The study will end when one of the following occurs: 1) the study drug has received marketing authorization and, if regionally applicable, government reimbursement is available; 2) a long-term extension rollover study has commenced for participants who are still benefiting from study treatment as determined by their investigator; or 3) all participants have discontinued study treatment. Total duration of study is approximately 5 years and 6 months. Efficacy, safety, pharmacokinetics (PK), immunogenicity, and biomarkers will be assessed at specified time points. Participants safety will be monitored throughout study by Study Evaluation Team (SET). SET consists of members of sponsor's study team and participating investigators.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
290
Participants will receive daratumumab.
Participants will receive talquetamab.
Participants will receive teclistamab.
City of Hope National Medical Center
Duarte, California, United States
Part 1: Number of Participants With Dose Limiting Toxicity (DLT)
The dose limiting toxicities are based on drug related adverse events and defined as any of the following events: hematological or non-hematological toxicity of grade 3 or higher.
Time frame: Up to 52 Weeks
Part 1: Number of Participants With Dose Limiting Toxicity by Severity
The dose limiting toxicities are based on drug related adverse events and defined as any of the following events: hematological or non-hematological toxicity of grade 3 or higher.
Time frame: Up to 52 Weeks
Part 2: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
An AE is any untoward medical occurrence in a clinical study participant administered a medicinal (investigational or non-investigational) product. An AE does not necessarily have a causal relationship with the intervention. SAE is any AE that results in: death, persistent or significant disability/incapacity, requires inpatient hospitalization or prolongation of existing hospitalization, is life-threatening experience, is a congenital anomaly/birth defect, and suspects transmission of any infectious agent via a medicinal product.
Time frame: Up to 48 Weeks
Part 2: Number of Participants With Adverse Events and SAEs by Severity
An AE is any untoward medical occurrence in a clinical study participant administered a medicinal (investigational or non-investigational) product. An AE does not necessarily have a causal relationship with the intervention. SAE is any AE that results in: death, persistent or significant disability/incapacity, requires inpatient hospitalization or prolongation of existing hospitalization, is life-threatening experience, is a congenital anomaly/birth defect, and suspects transmission of any infectious agent via a medicinal product.
Time frame: Up to 48 Weeks
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Participants will receive pomalidomide.
City of Hope Orange County Lennar Foundation Cancer Center
Irvine, California, United States
University of California San Francisco
San Francisco, California, United States
The Blavatnik Family Chelsea Medical Center at Mount Sinai
New York, New York, United States
Mount Sinai Medical Center
New York, New York, United States
Levine Cancer Institute
Charlotte, North Carolina, United States
Wake Forest Baptist Medical Center
Winston-Salem, North Carolina, United States
University of Pennsylvania
Philadelphia, Pennsylvania, United States
Vanderbilt Ingram Cancer Center
Nashville, Tennessee, United States
Medical College Of Wisconsin
Milwaukee, Wisconsin, United States
...and 14 more locations
Serum Concentration of Daratumumab
Serum concentration of daratumumab will be assessed.
Time frame: Up to 52 Weeks
Serum Concentration of Talquetamab
Serum concentration of talquetamab will be assessed.
Time frame: Up to 52 Weeks
Serum Concentration of Teclistamab
Serum concentration of teclistamab will be assessed.
Time frame: Up to 52 Weeks
Biomarker Assessment of Daratumumab
Serum cytokine concentrations will be measured at the time of drug infusion of daratumumab for biomarker assessment.
Time frame: Up to Cycle 7 Day 1 (each cycle of 28-days)
Biomarker Assessment of Talquetamab
Serum cytokine concentrations will be measured at the time of drug infusion of talquetamab for biomarker assessment.
Time frame: Up to Cycle 7 Day 1 (each cycle of 28-days)
Biomarker Assessment of Teclistamab
Serum cytokine concentrations will be measured at the time of drug infusion of teclistamab for biomarker assessment.
Time frame: Up to Cycle 7 Day 1 (each cycle of 28-days)
Number of Participants With Anti-Drug Antibodies to Daratumumab
Number of participants with anti-drug antibodies to daratumumab will be assessed.
Time frame: Up to 52 Weeks
Number of Participants With Anti-Drug Antibodies to Talquetamab
Number of participants with anti-drug antibodies to talquetamab will be assessed.
Time frame: Up to 52 Weeks
Number of Participants With Anti-Drug Antibodies to Teclistamab
Number of Participants with anti-drug antibodies to teclistamab will be assessed.
Time frame: Up to 52 Weeks
Overall Response Rate (ORR)
ORR is defined as the percentage of participants who have a partial response (PR) or better according to the International Myeloma Working Group (IMWG) criteria.
Time frame: Up to 48 Weeks
Clinical Benefit Rate
Clinical benefit rate (ORR + minimal response \[MR\]) is defined as the of participants who have a MR or better according to the IMWG criteria.
Time frame: Up to 48 Weeks
Duration of Response (DOR)
DOR is defined as the time from the date of initial documentation of a response (PR or better) to the date of first documented evidence of progressive disease, as defined in the IMWG criteria.
Time frame: Up to 48 Weeks
Time to Response
Time to response is defined as the time between date of first dose of study drug and the first efficacy evaluation that the participant has met all criteria for PR or better.
Time frame: Up to 48 Weeks