A Clinical Trial of Four Medicines (Elranatamab Plus Carfilzomib and Dexamethasone or Maplirpacept) in People With Relapsed Refractory Multiple Myeloma

Study Overview
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Brief Summary
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The main purpose of the study is to evaluate the safety and tolerability of the combination of elranatamab and carfilzomib and dexamethasone or elranatamab and maplirpacept. There are 2 parts to this study. Part 1 will evaluate the safety and tolerability of elranatamab when given in combination with carfilzomib plus dexamethasone. Part 2 has 2 arms. The first will evaluate the safety and tolerability of elranatamab when given in combination with maplirpacept. The second will identify the optimal dose(s) of elranatamab plus maplirpacept. All study medicines are given over 4-week cycles. Everyone taking part in this study will receive elranatamab as a shot under the skin. Participants in Part 1 will also receive weekly carfilzomib as an IV infusion (given directly into a vein) and dexamethasone either by mouth (as a pill) or by IV infusion. Participants in Part 2 will receive elranatamab in combination with maplirpacept as an IV infusion (given directly into a vein) The investigators will examine the experiences of people receiving the study medicines. This will help determine if the study medicines are safe and can be used for multiple myeloma treatment. Participants will take part in this study for about 2 years after the first dose.

Official Title
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A PHASE 1B, OPEN-LABEL STUDY OF ELRANATAMAB IN COMBINATION WITH CARFILZOMIB PLUS DEXAMETHASONE AND ELRANATAMAB IN COMBINATION WITH PF-07901801 IN PARTICIPANTS WITH RELAPSED REFRACTORY MULTIPLE MYELOMA

Conditions
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Multiple Myeloma

Intervention / Treatment
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* Drug: Elranatamab
* Drug: Carfilzomib
* Drug: Maplirpacept


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Prior diagnosis of multiple myeloma as defined by IMWG criteria. Measurable disease based on IMWG criteria as defined by at least 1 of the following: Serum M-protein ≥0.5 g/dL. Urinary M-protein excretion ≥200 mg/24 hours. Serum immunoglobulin FLC ≥10 mg/dL (≥100 mg/L) AND abnormal serum immunoglobulin kappa to lambda FLC ratio (<0.26 or >1.65). Part 1: Received at least 1 but not more than 3 prior lines of therapy for multiple myeloma (induction therapy followed by stem cell transplant and consolidation/maintenance therapy will be considered as 1 line of therapy). Part 2: Received at least 3 prior lines of therapy for multiple myeloma who are refractory to at least one IMiD, one PI and one anti-CD38 antibody. ECOG performance status 0-1. Resolved acute effects of any prior therapy to baseline severity or CTCAE Grade ≤1. Not pregnant or breastfeeding and willing to use contraception. Prior therapy with carfilzomib is allowed as long as the participant had (all apply): responded to most recent therapy with carfilzomib; Carfilzomib was not discontinued due to toxicity; Did not relapse within 60 days from discontinuation of carfilzomib; Will have at least a 6-month carfilzomib treatment-free interval from last dose received until first study treatment. Exclusion Criteria: Plasma cell leukemia, Smouldering MM, Waldenströms macroglobulinemia, Amyloidosis, POEMS Syndrome, Primary refractory MM Impaired cardiovascular function or clinically significant cardiovascular diseases. Participants with any active, uncontrolled bacterial, fungal, or viral infection. Stem cell transplant within 12 weeks prior to enrollment, or active graft versus host disease. Any other active malignancy within 3 years prior to enrollment, except for adequately treated basal cell or squamous cell skin cancer, or carcinoma in situ. Part 1: Previous treatment with a BCMA-directed therapy. Part 2: Previous treatment with any anti-BCMA directed therapy, with the exception of CAR-T. Previous treatment with a CD47-SIRP alpha-directed therapy. Live attenuated vaccine within 4 weeks of the first dose of study intervention. Administration with an investigational product (e.g. drug or vaccine) concurrent with study intervention or within 30 days preceding the first dose of study intervention used in this study. Any of the following within 3 months of enrollment: erosive esophagitis, treatment resistant peptic ulcer, infectious or inflammatory bowel disease, pulmonary embolism or uncontrolled thromboembolic event. Participants who are unable to tolerate carfilzomib due to suspected carfilzomib-related congestive heart failure or thrombotic microangiopathy.

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: Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part 1 Dose Escalation<br>Non randomized Elranatamab plus Carfilzomib and Dexamethasone | Drug: Elranatamab<br>* BCMA-CD3 bispecific antibody<br>* Other names: PF-06863135;Drug: Carfilzomib<br>* proteasome inhibitor<br>* Other names: Kyprolis;|
| Experimental: Part 2A Dose Escalation<br>Non randomized Elranatamab plus Maplirpacept | Drug: Elranatamab<br>* BCMA-CD3 bispecific antibody<br>* Other names: PF-06863135;Drug: Maplirpacept<br>* CD47-SIRP alpha-directed<br>* Other names: PF-07901801, TTI-622;|
| Experimental: Part 2B Dose Randomization<br>Randomized dose level Elranatamab plus Maplirpacept | Drug: Elranatamab<br>* BCMA-CD3 bispecific antibody<br>* Other names: PF-06863135;Drug: Maplirpacept<br>* CD47-SIRP alpha-directed<br>* Other names: PF-07901801, TTI-622;|

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) | Dose limiting toxicity rate based on dose limiting toxicity evaluable participants. | From first dose of elranatamab through the end of the first cycle of combination treatment, about 42 days. | 
| Part 2A Number of participants with dose limiting toxicity | Dose limiting toxicity based on dose limiting toxicity evaluable participants. | From the first dose of maplirpacept through the first cycle of combination treatment, about 64 days. | 
| Part 2B Number of participants with dose limiting Toxicity | Dose limiting toxicity rate based on dose limiting toxicity evaluable participants. | From first dose of elranatamab through the first cycle of combination treatment, about 42 days. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1: Number of Participants with Treatment Emergent Adverse Events (TEAE) by Seriousness and Relationship to Treatment | Counts of participants who had TEAEs, defined as newly occurring or worsening after first dose. Relatedness to study drug was assessed by the investigator. Participants with multiple occurrences of an AE within a category were counted once within the category. | Assessed from baseline up to 90 days after last dose of study treatment. | 
| Part 1: Number of Participants with Adverse Events (AE) characterized by type, frequency, severity. | An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. | Assessed from baseline up to 90 days after last dose of study treatment. | 
| Part 1: Number of Participants with Clinically Significant Change From Baseline in Laboratory Abnormalities | Laboratory abnormalities as characterized by type, frequency, severity. | Accessed from baseline up to 90 days after the last dose of study treatment. | 
| Part 1: Percent of participants with Best Overall Response (BOR) | BOR is defined as the best response recorded from treatment start until disease progression/recurrence based on International Myeloma Working Group (IMWG) response criteria. | Assessed for approximately 2 years | 
| Part 1: Percentage of Participants with an Objective Response Rate (ORR) | ORR rate is defined as the percent of participants having a Best Overall Response (BOR) of confirmed Stringent Complete Response (sCR), Complete Response (CR), Very Good Partial Response (VGPR), or Partial Response (PR) according to IMWG. | Assessed from enrollment for approximately 2 years. | 
| Part 1: Percentage of participants with a complete response rate (CRR) | Complete Response/ stringent Complete Response (CR+sCR) rate per IMWG response criteria as determined by investigator. | Assessed for approximately 2 years | 
| Part 1: Time to Response (TTR) | TTR is defined, for participants with an objective response per IMWG criteria, as the time from the date of first dose to the first documentation of objective response that is subsequently confirmed. | Assessed for approximately 2 years. | 
| Part 1: Duration of Response (DOR) | DOR is defined, for participants with an objective response per IMWG criteria, as the time from the first documentation of objective response that is subsequently confirmed, until the first documentation of confirmed progressive disease (PD) per IMWG criteria. | Assessed for approximately 2 years. | 
| Part 1: Duration of Complete Response (DOCR) | DOCR is defined, for participants with a Complete Response/stringent Complete Response (CR+sCR) per IMWG criteria, as the time from the first documentation of CR/sCR that is subsequently confirmed, until the first documentation of confirmed progressive disease (PD) per IMWG criteria. | Assessed for approximately 2 years. | 
| Part 1: Time of Progression Free Survival (PFS) | Progression free survival (IMWG response criteria) | Assessed from enrollment until Progressive Disease or death for approximately 2 years. | 
| Part 1: Time of Overall Survival (OS) | OS is the duration of time from first dose of study treatment to death. | Assessed for approximately 2 years | 
| Part 1: Minimal Residual Disease (MRD) Negativity Rate | MRD negativity rate is the proportion of participants acheiving CR+sCR with negative MRD, per IMWG sequencing criteria, from the date of first dose until the first documentation of confirmed progressive disease (PD), death or start of new anticancer therapy. | Assessed for approximately 2 years | 
| Part 1: Concentrations of carfilzomib | Pre-dose and post-dose concentrations of cafilzomib | Once approximately 7 weeks from enrollment. | 
| Part 1: Concentrations of elranatamab | Pre-dose and post-dose concentrations of elranatamab | Assessed for approximately 2 years. | 
| Part 1: Percentage of participants with positive anti-drug antibodies (ADA) against elranatamab | Percent of participants with positive ADA to elranatamab when given in combination with carfilzomib and dexamethasone | Assessed for approximately 2 years. | 
| Part 2A: Number of Participants with Treatment Emergent Adverse Events (TEAE) by Seriousness and Relationship to Treatment | Counts of participants who had TEAEs, defined as newly occurring or worsening after first dose. Relatedness to study drug was assessed by the investigator. Participants with multiple occurrences of an AE within a category were counted once within the category. | Assessed from baseline up to 90 days after last dose of study treatment. | 
| Part 2A: Number of Participants with Adverse Events (AE) characterized by type, frequency, severity. | An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. | Assessed from baseline up to 90 days after last dose of study treatment. | 
| Part 2A: Number of Participants with Clinically Significant Change From Baseline in Laboratory Abnormalities | Laboratory abnormalities as characterized by type, frequency, severity. | Accessed from baseline up to 90 days after the last dose of study treatment. | 
| Part 2A: Percent of participants with Best Overall Response (BOR) | BOR is defined as the best response recorded from treatment start until disease progression/recurrence based on International Myeloma Working Group (IMWG) response criteria. | Assessed for approximately 2 years | 
| Part 2A: Percentage of Participants with an Objective Response Rate (ORR) | ORR rate is defined as the percent of participants having a Best Overall Response (BOR) of confirmed Stringent Complete Response (sCR), Complete Response (CR), Very Good Partial Response (VGPR), or Partial Response (PR) according to IMWG. | Assessed from enrollment for approximately 2 years. | 
| Part 2A: Percentage of participants with a complete response rate (CRR) | Complete Response/ stringent Complete Response (CR+sCR) rate per IMWG response criteria as determined by investigator. | Assessed for approximately 2 years | 
| Part 2A: Time to Response (TTR) | TTR is defined, for participants with an objective response per IMWG criteria, as the time from the date of first dose to the first documentation of objective response that is subsequently confirmed. | Assessed for approximately 2 years. | 
| Part 2A: Duration of Response (DOR) | DOR is defined, for participants with an objective response per IMWG criteria, as the time from the first documentation of objective response that is subsequently confirmed, until the first documentation of confirmed progressive disease (PD) per IMWG criteria. | Assessed for approximately 2 years. | 
| Part 2A: Duration of Complete Response (DOCR) | DOCR is defined, for participants with a Complete Response/stringent Complete Response (CR+sCR) per IMWG criteria, as the time from the first documentation of CR/sCR that is subsequently confirmed, until the first documentation of confirmed progressive disease (PD) per IMWG criteria. | Assessed for approximately 2 years. | 
| Part 2A: Time of Progression Free Survival (PFS) | Progression free survival (IMWG response criteria) | Assessed from enrollment until Progressive Disease or death for approximately 2 years. | 
| Part 2A: Time of Overall Survival (OS) | OS is the duration of time from first dose of study treatment to death. | Assessed for approximately 2 years | 
| Part 2A: Minimal Residual Disease (MRD) Negativity Rate | MRD negativity rate is the proportion of participants achieving CR+sCR with negative MRD, per IMWG sequencing criteria, from the date of first dose until the first documentation of confirmed progressive disease (PD), death or start of new anticancer therapy. | Assessed for approximately 2 years | 
| Part 2A: Concentrations of maplirpacept | Pre-dose and post-dose concentrations of maplirpacept | Assessed for approximately 2 years. | 
| Part 2A: Concentrations of elranatamab | Pre-dose and post-dose concentrations of elranatamab | Assessed for approximately 2 years. | 
| Part 2A: Percentage of participants with positive anti-drug antibodies (ADA) against elranatamab | Percent of participants with positive ADA to elranatamab when given in combination with maplirpacept | Assessed for approximately 2 years. | 
| Part 2A: Percentage of participants with positive anti-drug antibodies (ADA) against maplirpacept | Percent of participants with positive ADA to elranatamab when given in combination with elranatamab | Assessed for approximately 2 years. | 
| Part 2B: Number of Participants with Treatment Emergent Adverse Events (TEAE) by Seriousness and Relationship to Treatment | Counts of participants who had TEAEs, defined as newly occurring or worsening after first dose. Relatedness to study drug was assessed by the investigator. Participants with multiple occurrences of an AE within a category were counted once within the category. | Assessed from baseline up to 90 days after last dose of study treatment. | 
| Part 2B: Number of Participants with Adverse Events (AE) characterized by type, frequency, severity. | An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. | Assessed from baseline up to 90 days after last dose of study treatment. | 
| Part 2B: Number of Participants with Clinically Significant Change From Baseline in Laboratory Abnormalities | Laboratory abnormalities as characterized by type, frequency, severity. | Accessed from baseline up to 90 days after the last dose of study treatment. | 
| Part 2B: Percent of participants with Best Overall Response (BOR) | BOR is defined as the best response recorded from treatment start until disease progression/recurrence based on International Myeloma Working Group (IMWG) response criteria. | Assessed for approximately 2 years | 
| Part 2B: Percentage of Participants with an Objective Response Rate (ORR) | ORR rate is defined as the percent of participants having a Best Overall Response (BOR) of confirmed Stringent Complete Response (sCR), Complete Response (CR), Very Good Partial Response (VGPR), or Partial Response (PR) according to IMWG. | Assessed from enrollment for approximately 2 years. | 
| Part 2B: Percentage of participants with a complete response rate (CRR) | Complete Response/ stringent Complete Response (CR+sCR) rate per IMWG response criteria as determined by investigator. | Assessed for approximately 2 years | 
| Part 2B: Time to Response (TTR) | TTR is defined, for participants with an objective response per IMWG criteria, as the time from the date of first dose to the first documentation of objective response that is subsequently confirmed. | Assessed for approximately 2 years. | 
| Part 2B: Duration of Response (DOR) | DOR is defined, for participants with an objective response per IMWG criteria, as the time from the first documentation of objective response that is subsequently confirmed, until the first documentation of confirmed progressive disease (PD) per IMWG criteria. | Assessed for approximately 2 years. | 
| Part 2B: Duration of Complete Response (DOCR) | DOCR is defined, for participants with a Complete Response/stringent Complete Response (CR+sCR) per IMWG criteria, as the time from the first documentation of CR/sCR that is subsequently confirmed, until the first documentation of confirmed progressive disease (PD) per IMWG criteria. | Assessed for approximately 2 years. | 
| Part 2B: Time of Progression Free Survival (PFS) | Progression free survival (IMWG response criteria) | Assessed from enrollment until Progressive Disease or death for approximately 2 years. | 
| Part 2B: Time of Overall Survival (OS) | OS is the duration of time from first dose of study treatment to death. | Assessed for approximately 2 years | 
| Part 2B: Minimal Residual Disease (MRD) Negativity Rate | MRD negativity rate is the proportion of participants achieving CR+sCR with negative MRD, per IMWG sequencing criteria, from the date of first dose until the first documentation of confirmed progressive disease (PD), death or start of new anticancer therapy. | Assessed for approximately 2 years | 
| Part 2B: Concentrations of maplirpacept | Pre-dose and post-dose concentrations of maplirpacept | Assessed for approximately 2 years. | 
| Part 2B: Concentrations of elranatamab | Pre-dose and post-dose concentrations of elranatamab | Assessed for approximately 2 years. | 
| Part 2B: Percentage of participants with positive anti-drug antibodies (ADA) against elranatamab | Percent of participants with positive ADA to elranatamab when given in combination with maplirpacept | Assessed for approximately 2 years. | 
| Part 2B: Percentage of participants with positive anti-drug antibodies (ADA) against maplirpacept | Percent of participants with positive ADA to elranatamab when given in combination with elranatamab | Assessed for approximately 2 years. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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elranatamab, relapsed, RRMM, BCMA, C1071020, MagnetisMM, maplipacelt, PF-06863135, carfilzomib, Bispecific antibody, PF-07901801, TTI-622, SIRPα, CD47