This is a first-in-human (FIH) Phase 1/Phase 2 study for evaluating SAR445514 in monotherapy in participants with relapsed/refractory multiple myeloma (RRMM) and relapsed/refractory light chain amyloidosis (RRLCA). The study will comprise 3 parts: A dose escalation phase (Part 1) in RRMM participants (Part 1a) that will evaluate several doses administered to determine 2 doses that will be tested in the dose optimization part. A dose escalation will also be done in RRLCA participants (Part 1b) but started sequentially after the end of the dose escalation in RRMM participants. This dose escalation will evaluate the 2 doses planned to be used in dose optimization in RRMM, to ensure those doses are safe also for RRLCA participants. A dose optimization phase (Part 2) that will be evaluating 2 doses determined from Part 1 to determine the preliminary recommended Phase 2 dose (pRP2D) and schedule for SAR445514 in RRMM. A dose expansion phase (Part 3) that will evaluate the preliminary efficacy of pRP2D and schedule for SAR445514 in RRMM (Part 3a) and RRLCA (Part 3b). Approximately 111 participants will be enrolled and treated by study intervention and separated as such: Part 1a: Approximately 30 to 40 participants Part 1b: Approximately 6 to 12 participants Part 2: Approximately 30 participants Part 3a: Approximately 15 participants Part 3b: Approximately 14 participants
The duration of the study for a participant will include A screening period: up to 28 days prior day 1 of cycle 1 (C1D1) A treatment period: enrolled participants will receive administration of 4 weeks cycles of SAR445514 subcutaneously. The End of treatment visit will occur 30 days (+/- 7 days) from last investigational medicinal product (IMP) administration or prior initiation of further therapy, whichever comes first. The follow-up period will continue until death, participant's request to discontinue study, final Overall Survival analysis or upon cancellation of survival follow-up at the discretion of the Sponsor at any timepoint.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
32
Powder for solution for injection. Sub Cutaneous administration.
Investigational Site Number : 0360001
Wollongong, New South Wales, Australia
Investigational Site Number : 0360002
Richmond, Victoria, Australia
Institut Jules Bordet_Site Number : 0560002
Anderlecht, Belgium
Het Ziekenhuisnetwerk Antwerpen vzw - ZNA Middelheim_Site Number : 0560001-2
Antwerp, Belgium
Het Ziekenhuisnetwerk Antwerpen vzw - ZNA Cadix_Site Number : 0560001-1
Antwerp, Belgium
Investigational Site Number : 0560001
Antwerp, Belgium
Investigational Site Number : 2030002
Brno, Czechia
Investigational Site Number : 2030001
Ostrava, Czechia
Investigational Site Number : 3480001
Budapest, Hungary
Investigational Site Number : 3800001
Rozzano, Lombardy, Italy
...and 6 more locations
Dose escalation (part 1a - RRMM) Presence of dose limiting toxicities (DLT)
DLTs will be defined using NCI CTCAE version 5.0 or ASTCT criteria for CRS or ICANS.
Time frame: Cycle 1 - 4 weeks per cycle
Dose escalation (part 1a - RRMM) Percentage of participants experiencing treatment-emergent adverse events (TEAEs)
Presence of TEAEs, SAEs, and lab abnormalities, according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0 and American Society for Transplantation and Cellular Therapy (ASTCT) consensus grading
Time frame: From Baseline to end of follow-up (approx. 15 months)
Dose optimization (part 2 - RRMM) Overall response rate (ORR)
ORR is defined as the proportion of participants with stringent complete response (sCR), complete response (CR), very good partial response (VGPR), and partial response (PR) according to the 2016 International Myeloma Working Group (IMWG) criteria, after the last participant is treated for at least 4 cycles or prematurely discontinued.
Time frame: Cycles 1 to 4 - 4 weeks per cycle
Dose escalation (part 1b - RRLCA) Presence of dose limiting toxicities (DLT) at cycle 1
Time frame: Cycle 1 - 4 weeks per cycle
Dose escalation (part 1b - RRLCA) Percentage of participants experiencing treatment-emergent adverse events (TEAEs)
Time frame: From baseline to end of follow-up (approx. 15 months)
Dose expansion (part 3 - RRMM) Overall response rate (ORR)
ORR is defined as the proportion of participants with stringent complete response (sCR), complete response (CR), very good partial response (VGPR), and partial response (PR) according to the 2016 International Myeloma Working Group (IMWG) criteria.
Time frame: Cycles 1 to 4 - 4 weeks per cycle
Dose expansion (part 3-RRLCA) Hematological response (HR)
HR is defined as the proportion of participants with sCR, CR, VGPR, and PR according to the European society of hematology/International society of hematology working group guidelines.
Time frame: Cycles 1 to 4 - 4 weeks per cycle
Dose escalation (part 1 - RRMM) Overall response rate (ORR)
ORR defined as the proportion of participants with sCR, CR, VGPR, and PR according to the 2016 IMWG criteria.
Time frame: Cycle 1 to first progressive disease or end of follow-up whichever comes first (approx. 15 months with cycle of 28 days)
Dose optimization (part 2 - RRMM) Presence of dose limiting toxicities (DLT)
Time frame: Cycles 1 to 4 - 4 weeks per cycle
Dose optimization (part 2 - RRMM) Percentage of participants experiencing treatment-emergent adverse events (TEAEs)
Treatment-emergent adverse events (AEs) are defined as AEs that develop, worsen, or become serious during the treatment period. The treatment period is defined as the time from first dose of study treatment up to 30 days after last dose of study treatment.
Time frame: From first dose of study treatment up to 30 days after last dose of study treatment (approx. 1 year with cycle of 28 days)
Dose optimization & expansion (Part 2 & Part 3a - RRMM) Very Good Partial Response (VGPR) or Better Rate
VGPR is defined as the proportion of participants with sCR, CR, and VGPR according to the 2016 IMWG criteria.
Time frame: Cycle 1 to first progressive disease or end of follow-up whichever comes first (approx. 15 months with cycle of 28 days)
Dose optimization & expansion (Part 2 & Part 3a - RRMM) Duration of response (DOR)
DOR is defined as the time from the date of the first response to the date of the first occurrence of progressive disease (PD as determined by the investigator or death from any cause, whichever happens first. DOR is determined only for participants who have achieved a response (PR or better).
Time frame: Cycle 1 to first progressive disease or end of follow-up whichever comes first (approx. 15 months with cycle of 28 days)
Dose optimization & expansion (Part 2 & Part 3a - RRMM) Time to first response (TT1R)
TT1R is defined as the time from the date of the first response to the date of the first occurrence of progressive disease (PD as determined by the investigator or death from any cause, whichever happens first. DOR is determined only for participants who have achieved a response (PR or better).
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Time frame: Cycle 1 to first progressive disease or end of treatment whichever comes first (approx. 1 year with cycle of 28 days)
Dose optimization & expansion (Part 2 & Part 3a -RRMM) Time to best response (TTBR)
TTBR is defined as the time from the first administration of the IMP to the date of first occurrence of best overall response (PR or better that is subsequently confirmed.
Time frame: Cycle 1 to first progressive disease or end of treatment whichever comes first (approx. 1 year with cycle of 28 days)
Dose optimization & expansion (Part 2 & Part 3a - RRMM) Progression free survival (PFS)
PFS is defined as the time from the date of the first administration of the IMP to the date of first documentation of progressive disease or the date of death from any cause, whichever comes first. Responses will be determined according to IMWG criteria. Progression based on paraprotein will be confirmed based on two consecutive assessments.
Time frame: Cycle 1 to first progressive disease or end of follow-up whichever comes first (approx. 15 months with cycle of 28 days)
Dose optimization & expansion (Part 2 & Part 3a - RRMM) Overall survival (OS)
OS is defined as the time from the date of the first administration of the IMP to death from any cause
Time frame: Cycle 1 to end of follow-up or death (approx. 15 months with cycle of 28 days)
Dose optimization & expansion (Part 2 & Part 3a - RRMM) Clinical benefit rate (CBR)
CBR is the rate of participants with confirmed CR or PR at any time or stable disease (SD) of at least 6 months from the first IMP administration determined by the Investigator per IMWG 2016 criteria.
Time frame: Cycle 1 to first progressive disease or end of follow-up whichever comes first (approx. 15 months with cycle of 28 days)
Dose escalation (part 1b - RRLCA) Overall Hematological Response (OHR)
OHR is defined as the proportion of participants with CR, VGPR, and PR according to the International Society of Amyloidosis guidelines (ISA 2012).
Time frame: Cycle 1 to first progressive disease or end of follow-up whichever comes first (approx. 15 months with cycle of 28 days)
Dose extension (part 3b - RRLCA) Hematological complete response rate (HCR).
HCR is defined as the proportion of participants with complete response according to the ISA 2012.
Time frame: Cycle 1 to first progressive disease or end of follow-up whichever comes first (approx. 15 months with cycle of 28 days)
Dose extension (part 3b - RRLCA) Hematological very good partial response rate or better (HVGPR)
HVGPR defined as proportion of participants with very good partial response and CR as per ISA 2012 criteria
Time frame: Cycle 1 to first progressive disease or end of follow-up whichever comes first (approx. 15 months with cycle of 28 days)
Dose expansion (part 3b - RRLCA) Overall survival (OS)
OS is defined as the time from the date of study entry to death from any cause.
Time frame: Cycle 1 to death or end of follow-up whichever comes first (approx. 15 months with cycle of 28 days)
Dose expansion (part 3b - RRLCA) Progression-Free Survival (PFS)
PFS is defined as time from the time from the first administration of the IMP to any of the following: hematological progression, major organ progression (cardiac, kidney or liver) according to ISA 2012 criteria or death by any cause.
Time frame: Cycle 1 to first progressive disease (organ or hematological) or end of follow-up whichever comes first (approx. 15 months with cycle of 28 days)
Dose expansion (part 3b - RRLCA) Time to first hematological response (TT1HR)
TT1HR is defined as the time from the first administration of the IMP to the date of first hematological response (PR or better) that is subsequently confirmed.
Time frame: Cycle 1 to first progressive disease or end of follow-up whichever comes first (approx. 15 months with cycle of 28 days)
Dose expansion (part 3b - RRLCA) Duration of hematological response (DOHR)
DOHR is defined as time from the time from the first administration of the IMP to any of the following: hematological progression, major organ progression (cardiac, kidney or liver) according to ISA 2012 criteria or death by any cause.
Time frame: Cycle 1 to first progressive disease or end of follow-up whichever comes first (approx. 15 months with cycle of 28 days)
Dose expansion (Part 3 - RRMM & RRLCA) Percentage of participants experiencing treatment-emergent adverse events (TEAEs)
Treatment-emergent adverse events (AEs) are defined as AEs that develop, worsen, or become serious during the treatment-emergent period.
Time frame: From first dose of study treatment up to 30 days after last dose of study treatment (approx. 15 months with cycle of 28 days)
Incidence rate of infusion associated reactions (IARs)
Time frame: From cycle 1 to end of treatment (approx. 1 year with cycle of 28 days)
Incidence rate of injection site reactions (ISR)
Time frame: From cycle 1 to end of treatment (approx. 1 year with cycle of 28 days)
Incidence of laboratory abnormalities
Time frame: From cycle 1 to end of follow-up (approx. 15 months with cycle of 28 days)
Assessment of pharmacokinetics (PK) parameter of SAR445514: Ctrough
Time frame: From cycle 1 to end of treatment (approx. 1 year with cycle of 28 days)
Assessment of pharmacokinetics (PK) parameter of SAR445514: AUClast
Area under the plasma concentration versus time curve calculated using the trapezoidal method from time zero to time of the last concentration observed above the lower limit of quantification (ie, Clast)
Time frame: From cycle 1 to end of treatment (approx. 1 year with cycle of 28 days)
Assessment of pharmacokinetics (PK) parameter of SAR445514: Cmax
Maximum observed concentration
Time frame: From cycle 1 to end of treatment (approx. 1 year with cycle of 28 days)
Assessment of pharmacokinetics (PK) parameter of SAR445514: Tmax
First time to reach Cmax
Time frame: From cycle 1 to end of treatment (approx. 1 year with cycle of 28 days)
Incidence of anti-drug antibody (ADA) against SAR445514
Time frame: From cycle 1 to end of treatment (approx. 1 year with cycle of 28 days)
Dose extension (Part 3 - RRMM & RRLCA) Minimum Residual Disease (MRD) negativity rate
MRD status in participants with response of VGPR or better
Time frame: Cycle 1 to first progressive disease or end of follow-up whichever comes first (approx. 15 months with cycle of 28 days)