A Study of the Combination of Talquetamab and Teclistamab in Participants With Relapsed or Refractory Multiple Myeloma

Study Overview
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Brief Summary
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The purpose of this study is to identify the recommended Phase 2 regimen(s) (RP2R[s]) and schedule for the study treatment (Part 1), to characterize the safety of the RP2R(s) for the study treatment (Part 2) and to evaluate the anticancer activity of talquetamab + teclistamab in participants with relapsed or refractory multiple myeloma and extramedullary disease (EMD) (Part 3).

Detailed Description
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Multiple myeloma is a malignant plasma cell disorder characterized by production of monoclonal proteins (M proteins), which are comprised of pathologic immunoglobulins (Ig) or fragments of such, which have subsequently lost their normal function. Rationale for combining talquetamab and teclistamab is the targeting of multiple proteins on the surface of multiple myeloma cells resulting in cell lysis. This study consists of 3 periods: screening phase (up to 28 days), treatment phase (start of study drug administration and continues until the completion of the end of treatment [EOT] visit); and a post-treatment follow-up phase (after end of treatment and up to 16 weeks after last dose of study drug(s) for each participant). End of study is defined as 2 years after the last participant has received his or her initial dose of the treatment combination. Total duration of study is Approximately 5 years. Efficacy, safety, pharmacokinetics (PK), immunogenicity, and biomarkers will be assessed at specified time points during this study. Participants safety and study conduct will be monitored throughout the study.

Official Title
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A Phase 1b/2 Dose Escalation and Expansion Study of the Combination of the Bispecific T Cell Redirection Antibodies Talquetamab and Teclistamab in Participants With Relapsed or Refractory Multiple Myeloma

Conditions
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Multiple Myeloma

Intervention / Treatment
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* Drug: Talquetamab
* Drug: Teclistamab
* Drug: Daratumumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Documented initial diagnosis of multiple myeloma according to International Myeloma Working Group (IMWG) diagnostic criteria Part 1 and 2: Participant could not tolerate or has disease that is relapsed or refractory to established therapies, including the last line of therapy. Part 3: (a) Relapsed or refractory disease, and exposed to a PI, IMiD, and an anti-CD38 mAb; (b) Documented evidence of progressive disease based on investigator's determination of response by IMWG criteria on or after their last regimen Part 1 and Part 2: Eastern Cooperative Oncology Group (ECOG) performance status grade of 0 or 1 at screening and immediately before the start of study drug administration. Part 3: ECOG performance status grade of 0, 1, or 2 at screening and immediately before the start of study drug administration Exclusion Criteria: All Parts: Targeted therapy, epigenetic therapy, or treatment with an investigational treatment or an invasive investigational medical device within 21 days or at least 5 half-lives, whichever is less. Part 3: prior BCMA targeted bispecific antibody therapy; prior GPRC5D targeted therapy All Parts: Allogeneic stem cell transplant within 6 months before the first dose of study treatment. All Parts: Central nervous system involvement or clinical signs of meningeal involvement of multiple myeloma. All Parts: Active plasma cell leukemia (greater than [>]2.0*10^9/L plasma cells by standard differential), Waldenström's macroglobulinemia, POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, M- protein, and skin changes), or primary amyloid light chain amyloidosis

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part 1: Dose Escalation<br>Participants will receive tec+tal with or without daratumumab in 28-day cycles following initial step-up doses. | Drug: Talquetamab<br>* Talquetamab will be administered by subcutaneous (SC) injection.<br>* Other names: JNJ-64407564;Drug: Teclistamab<br>* Teclistamab will be administered by SC injection.<br>* Other names: JNJ-64007957;Drug: Daratumumab<br>* Daratumumab will be administered by SC injection.<br>|
| Experimental: Part 2: Dose Expansion<br>Participants will receive treatment doses (combination of tal+tec and dara+tal+tec regimens) which will be determined by the recommended Phase 2 regimen (s) (RP2R[s]) of the study treatment identified in Part 1. | Drug: Talquetamab<br>* Talquetamab will be administered by subcutaneous (SC) injection.<br>* Other names: JNJ-64407564;Drug: Teclistamab<br>* Teclistamab will be administered by SC injection.<br>* Other names: JNJ-64007957;Drug: Daratumumab<br>* Daratumumab will be administered by SC injection.<br>|
| Experimental: Part 3: Phase 2<br>Participants will receive teclistamab + talquetamab combination therapy, at the RP2R selected from Part 1 and Part 2. | Drug: Talquetamab<br>* Talquetamab will be administered by subcutaneous (SC) injection.<br>* Other names: JNJ-64407564;Drug: Teclistamab<br>* Teclistamab will be administered by SC injection.<br>* Other names: JNJ-64007957;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Approximately 5 years | 
| Part 1: Severity of DLT as Assessed by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) | Severity will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0. Severity scale ranges from Grade 1 (Mild) to Grade 5 (Death). Grade 1= Mild, Grade 2= Moderate, Grade 3= Severe, Grade 4= Life-threatening, and Grade 5= Death related to adverse event. | Approximately 5 years | 
| Part 2: Number of Participants with Adverse Events (AEs) and Serious Adverse Events (SAEs) as a Measure of Safety and Tolerability | 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, is medically important. | Approximately 5 years | 
| Part 2: Number of Participants with Adverse Events and SAEs by Severity | Severity will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0. Severity scale ranges from Grade 1 (Mild) to Grade 5 (Death). Grade 1= Mild, Grade 2= Moderate, Grade 3= Severe, Grade 4= Life-threatening, and Grade 5= Death related to adverse event. | Approximately 5 years | 
| Part 3: Overall Response Rate (ORR) | ORR is defined as the percentage of participants who have a partial response (PR) or better according Independent Review Committees (IRC). | Approximately 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Parts 1, 2 and 3: Serum Concentration of Talquetamab | Serum samples will be analyzed to determine concentrations of talquetamab using a validated, specific, and sensitive immunoassay method. | Approximately 5 years | 
| Parts 1, 2 and 3: Serum Concentration of Teclistamab | Serum samples will be analyzed to determine concentrations of teclistamab using a validated, specific, and sensitive immunoassay method. | Approximately 5 years | 
| Part 1 and Part 2: Serum Concentration of Daratumumab | Serum samples will be analyzed to determine concentrations of daratumumab using a validated, specific, and sensitive immunoassay method. | Approximately 5 years | 
| Parts 1, 2 and 3: Number of Participants with Anti-Drug Antibodies to Talquetamab | Number of participants with anti-drug antibodies to talquetamab will be assessed. | Approximately 5 years | 
| Parts 1, 2 and 3: Number of Participants with Anti-Drug Antibodies to Teclistamab | Number of participants with anti-drug antibodies to teclistamab will be assessed. | Approximately 5 years | 
| Part 1 and Part 2: Number of Participants with Anti-Drug Antibodies to Daratumumab | Number of participants with anti-drug antibodies to daratumumab will be assessed. | Approximately 5 years | 
| Part 1 and Part 2: 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. | Approximately 5 years | 
| Parts 1, 2 and 3: Very Good Partial Response (VGPR) or Better Response Rate | VGPR or better response rate (sCR+CR+VGPR) is defined as the percentage of participants who achieve a VGPR or better response according to the IMWG criteria. | Approximately 5 years | 
| Parts 1, 2 and 3: Complete Response (CR) or Better Response Rate | CR or better response rate (sCR+CR) is defined as the percentage of participants who achieve a CR or better response according to the IMWG criteria. | Approximately 5 years | 
| Part 1 and Part 2: Stringent Complete Response (sCR) Rate | sCR rate is defined as the percentage of participants who achieve a sCR according to the IMWG criteria. | Approximately 5 years | 
| Parts 1, 2 and 3: Duration of Response (DOR) | DOR will be calculated among responders (with PR or better) 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. | Approximately 5 years | 
| Parts 1, 2 and 3: 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. | Approximately 5 years | 
| Part 3: Progression free Survival (PFS) | PFS is defined as the time from the date of first dose to the date of first documented disease progression, as defined in the IMWG criteria, or death due to any cause, whichever occurs first. | Approximately 5 years | 
| Part 3: Overall Survival (OS) | OS is measured from the date of first dose to the date of the participant's death. | Approximately 5 years | 
| Part 3: Number of Participants with Adverse Events | 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. | Approximately 5 years | 
| Part 3: Number of Participants with Adverse Events by Severity | Severity will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0. Severity scale ranges from Grade 1 (Mild) to Grade 5 (Death). Grade 1= Mild, Grade 2= Moderate, Grade 3= Severe, Grade 4= Life-threatening, and Grade 5= Death related to adverse event. | Approximately 5 years |