Clinical trial NCT05839626: A Study to Investigate Safety and Efficacy With SAR445514 in Participants With Relapsed/Refractory Multiple Myeloma (RRMM) and Relapsed/Refractory Light-chain Amyloidosis (RRLCA)
Official title: First-in-human, Open-label Phase 1/2 Study to Investigate Safety and Efficacy of SAR445514, an NKcell Engager (NKCE) Targeting B-cell Maturation Antigen (BCMA) in Monotherapy in Participants With Relapsed/Refractory Multiple Myeloma (RRMM) and in Relapsed/Refractory Light-chain Amyloidosis (RRLCA)
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
PHASE2
Conditions: Relapsed/Refractory Multiple Myeloma
Amyloid Light-chain Amyloidosis
Lead sponsor: Sanofi
Sponsor class: INDUSTRY
First posted: 2023-05-03
Enrollment: 32
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

Brief summary: 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

Detailed description: 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.

Eligibility criteria: Inclusion Criteria:

Participants must have a documented diagnosis of multiple myeloma (Part 1a, 2, and 3a) or light chain amyloidosis (Part 1b and 3b).

Participants with RRMM (Part 1, 2, and 3a)

* Participants with measurable disease for RRMM
* Participants with MM must have received at least 2 prior lines of therapy which must include at least 2 consecutive cycles of a second or third generation immunomodulator, steroid, proteasome inhibitor and anti-CD38 monoclonal antibody (MoAb).
* Participants must have documented evidence of progressive disease (PD), as per IMWG 2016 criteria.

Participants with RR LCA (Part 1b and 3b) must have received at least 1 prior line of treatment comprising at least 1 proteasome inhibitor.

* Participants with measurable disease according to ISA 2012.
* Participants must have documented evidence of progressive disease (PD), as per ISA 2012 criteria.
* One or more organ impacted by amyloidosis as per National comprehensive cancer network (NCCN) guidelines.

For dose escalation, body weight within 40 to 120 kg

Capable of giving signed informed consent

Exclusion Criteria:

Participants are excluded from the study if any of the following criteria apply:

Medical conditions

* Primary refractory MM defined as participants who never achieved at least a minimal response with any treatment during the disease course
* Second primary malignancy

Participants with RRMM (Part 1a, 2, and 3a)

* For MM participants, primary systemic LCA and plasma cell leukemia
* For MM participants, congestive heart failure (New York Heart Association \[NYHA\]) Grade ≥II; cardiomyopathy, active ischemia, or any other uncontrolled cardiac condition

Participants with RR LCA (Part 1b and 3b)

* For LCA participants, evidence of clinically significant cardiovascular condition, defined as one or more of the following:

  1. N-terminal prohormone of brain natriuretic peptide (NT-proBNP) \>8500 ng/mL
  2. New York Heart Association (NYHA) classification III or IV heart failure
  3. Heart failure that, in the opinion of the Investigator, is not primarily related to LCA cardiomyopathy (including, but not limited to, ischemic heart disease, uncorrected valvular disease, infections)
  4. Prior event (history) in the last 6 months of acute coronary syndrome, myocardial infarction or unstable angina as well as participants who during the last 6 months experienced a percutaneous cardiac intervention with stent and/or a coronary artery bypass
  5. Hospitalization in the last 4 weeks prior to treatment related to a cardiovascular event
  6. Participants with prior history of arrhythmia and/or cardiac conduction disorders for which a pacemaker or an implantable cardioverter defibrillator (ICD) is required but has not been placed. This includes, but may not be limited to, sustained ventricular tachycardia, association of an atrioventricular, or sinoatrial nodal dysfunction
* For LCA participants, a systolic blood pressure \<100 mmHg or a diastolic blood pressure \<55 mmHg.
* For LCA participants: previous or current diagnosis of symptomatic MM, including the presence of lytic bone disease, plasmacytomas, ≥60% plasma cells in the BM, or hypercalcemia.

All participants

* Uncontrolled infection within 14 days prior to study treatment.
* Known acquired immunodeficiency syndrome-related illness or known human immunodeficiency virus (HIV) disease requiring antiviral treatment or active hepatitis A (defined as positive hepatitis A antigen or positive IgM); HIV serology at screening will be tested for participants in countries where it is required by local regulations.
* Uncontrolled or active hepatitis B virus (HBV) infection: participants with positive B surface antigen (HBsAg) and/or HBV deoxyribonucleic acid (DNA)
* Active hepatitis C virus (HCV) infection: positive HCV ribonucleic acid (RNA) and negative anti-HCV.

Prior/concomitant therapy

* Any anti-MM drug treatment within 14 days before study treatment
* Prior allogenic hematopoietic stem cell (HSC) transplant with active graft-versus-host disease (GvHD) (GvHD any grade and/or being under immunosuppressive treatment within the last 2 months prior to first IMP).
* Any major procedure within 14 days before the initiation of the study treatment
* Administration of an anti-CD38 monoclonal antibody (isatuximab or daratumumab) less than 90 days prior to the first administration of study treatment.
* Administration of an anti-BCMA agent (including, but not limited to, CAR T-cells, TCEs, antibody drug conjugate) less than 21 days prior to the administration of study treatment.
* Unresolved toxicities from prior anticancer therapy, defined as not having resolved to CTCAE Version 5.0 Grade 1, at the exception of residual Grade 2 peripheral neurotoxicity related to bortezomib and/or thalidomide and considered as stable.
* Participants with a contraindication to dexamethasone.

Prior/concurrent clinical study experience

* Received any other investigational drugs or prohibited therapy for this study within 28 days or 5 half-lives from study treatment, whichever is shorter

Diagnostic assessments

* Hemoglobin \<8 g/dL (5.0 mmol/L)
* Platelets \<50 × 10\^9/L (not permissible to transfuse a participant within 1 week prior to the screening platelet count to reach this level).
* Absolute neutrophil count (ANC) \<1000 μL (1 × 10\^9/L).
* Creatinine clearance \<30 mL/min (Modification of Diet in Renal Disease Formula).
* Total bilirubin \>1.5 × upper limit of normal (ULN) (unless the subject has documented Gilbert syndrome in which case direct bilirubin should not be \>2.5 × ULN).
* Aspartate aminotransferase (AST/SGOT) or Alanine aminotransferase (ALT/SGPT) \>2.5 × ULN.
* Participants with Grade 3 or 4 hypercalcemia (corrected serum calcium of \>12.5 mg/dL; \>3.1 mmol/L; ionized calcium \>1.6 mmol/L; or requiring hospitalization) will not be eligible unless participants recover to Grade 2 or less under anti-hypercalcemia treatment.

Other exclusions

* Individuals accommodated in an institution because of regulatory or legal order; prisoners or participants who are legally institutionalized
* Participant not suitable for participation, whatever the reason, as judged by the Investigator
* Sensitivity to any of the study interventions, or components thereof, or drug or other allergy that, in the opinion of the Investigator, contraindicates participation in the study.

Primary outcomes:
measure: Dose escalation (part 1a - RRMM) Presence of dose limiting toxicities (DLT)
timeFrame: Cycle 1 - 4 weeks per cycle
measure: Dose escalation (part 1a - RRMM) Percentage of participants experiencing treatment-emergent adverse events (TEAEs)
timeFrame: From Baseline to end of follow-up (approx. 15 months)
measure: Dose optimization (part 2 - RRMM) Overall response rate (ORR)
timeFrame: Cycles 1 to 4 - 4 weeks per cycle
measure: Dose escalation (part 1b - RRLCA) Presence of dose limiting toxicities (DLT) at cycle 1
timeFrame: Cycle 1 - 4 weeks per cycle
measure: Dose escalation (part 1b - RRLCA) Percentage of participants experiencing treatment-emergent adverse events (TEAEs)
timeFrame: From baseline to end of follow-up (approx. 15 months)
measure: Dose expansion (part 3 - RRMM) Overall response rate (ORR)
timeFrame: Cycles 1 to 4 - 4 weeks per cycle
measure: Dose expansion (part 3-RRLCA) Hematological response (HR)
timeFrame: Cycles 1 to 4 - 4 weeks per cycle
Secondary outcomes:
measure: Dose escalation (part 1 - RRMM) Overall response rate (ORR)
timeFrame: Cycle 1 to first progressive disease or end of follow-up whichever comes first (approx. 15 months with cycle of 28 days)
measure: Dose optimization (part 2 - RRMM) Presence of dose limiting toxicities (DLT)
timeFrame: Cycles 1 to 4 - 4 weeks per cycle
measure: Dose optimization (part 2 - RRMM) Percentage of participants experiencing treatment-emergent adverse events (TEAEs)
timeFrame: From first dose of study treatment up to 30 days after last dose of study treatment (approx. 1 year with cycle of 28 days)
measure: Dose optimization & expansion (Part 2 & Part 3a - RRMM) Very Good Partial Response (VGPR) or Better Rate
timeFrame: Cycle 1 to first progressive disease or end of follow-up whichever comes first (approx. 15 months with cycle of 28 days)
measure: Dose optimization & expansion (Part 2 & Part 3a - RRMM) Duration of response (DOR)
timeFrame: Cycle 1 to first progressive disease or end of follow-up whichever comes first (approx. 15 months with cycle of 28 days)
measure: Dose optimization & expansion (Part 2 & Part 3a - RRMM) Time to first response (TT1R)
timeFrame: Cycle 1 to first progressive disease or end of treatment whichever comes first (approx. 1 year with cycle of 28 days)
measure: Dose optimization & expansion (Part 2 & Part 3a -RRMM) Time to best response (TTBR)
timeFrame: Cycle 1 to first progressive disease or end of treatment whichever comes first (approx. 1 year with cycle of 28 days)
measure: Dose optimization & expansion (Part 2 & Part 3a - RRMM) Progression free survival (PFS)
timeFrame: Cycle 1 to first progressive disease or end of follow-up whichever comes first (approx. 15 months with cycle of 28 days)
measure: Dose optimization & expansion (Part 2 & Part 3a - RRMM) Overall survival (OS)
timeFrame: Cycle 1 to end of follow-up or death (approx. 15 months with cycle of 28 days)
measure: Dose optimization & expansion (Part 2 & Part 3a - RRMM) Clinical benefit rate (CBR)
timeFrame: Cycle 1 to first progressive disease or end of follow-up whichever comes first (approx. 15 months with cycle of 28 days)
measure: Dose escalation (part 1b - RRLCA) Overall Hematological Response (OHR)
timeFrame: Cycle 1 to first progressive disease or end of follow-up whichever comes first (approx. 15 months with cycle of 28 days)
measure: Dose extension (part 3b - RRLCA) Hematological complete response rate (HCR).
timeFrame: Cycle 1 to first progressive disease or end of follow-up whichever comes first (approx. 15 months with cycle of 28 days)
measure: Dose extension (part 3b - RRLCA) Hematological very good partial response rate or better (HVGPR)
timeFrame: Cycle 1 to first progressive disease or end of follow-up whichever comes first (approx. 15 months with cycle of 28 days)
measure: Dose expansion (part 3b - RRLCA) Overall survival (OS)
timeFrame: Cycle 1 to death or end of follow-up whichever comes first (approx. 15 months with cycle of 28 days)
measure: Dose expansion (part 3b - RRLCA) Progression-Free Survival (PFS)
timeFrame: 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)
measure: Dose expansion (part 3b - RRLCA) Time to first hematological response (TT1HR)
timeFrame: Cycle 1 to first progressive disease or end of follow-up whichever comes first (approx. 15 months with cycle of 28 days)
measure: Dose expansion (part 3b - RRLCA) Duration of hematological response (DOHR)
timeFrame: Cycle 1 to first progressive disease or end of follow-up whichever comes first (approx. 15 months with cycle of 28 days)
measure: Dose expansion (Part 3 - RRMM & RRLCA) Percentage of participants experiencing treatment-emergent adverse events (TEAEs)
timeFrame: From first dose of study treatment up to 30 days after last dose of study treatment (approx. 15 months with cycle of 28 days)
measure: Incidence rate of infusion associated reactions (IARs)
timeFrame: From cycle 1 to end of treatment (approx. 1 year with cycle of 28 days)
measure: Incidence rate of injection site reactions (ISR)
timeFrame: From cycle 1 to end of treatment (approx. 1 year with cycle of 28 days)
measure: Incidence of laboratory abnormalities
timeFrame: From cycle 1 to end of follow-up (approx. 15 months with cycle of 28 days)
measure: Assessment of pharmacokinetics (PK) parameter of SAR445514: Ctrough
timeFrame: From cycle 1 to end of treatment (approx. 1 year with cycle of 28 days)
measure: Assessment of pharmacokinetics (PK) parameter of SAR445514: AUClast
timeFrame: From cycle 1 to end of treatment (approx. 1 year with cycle of 28 days)
measure: Assessment of pharmacokinetics (PK) parameter of SAR445514: Cmax
timeFrame: From cycle 1 to end of treatment (approx. 1 year with cycle of 28 days)
measure: Assessment of pharmacokinetics (PK) parameter of SAR445514: Tmax
timeFrame: From cycle 1 to end of treatment (approx. 1 year with cycle of 28 days)
measure: Incidence of anti-drug antibody (ADA) against SAR445514
timeFrame: From cycle 1 to end of treatment (approx. 1 year with cycle of 28 days)
measure: Dose extension (Part 3 - RRMM & RRLCA) Minimum Residual Disease (MRD) negativity rate
timeFrame: Cycle 1 to first progressive disease or end of follow-up whichever comes first (approx. 15 months with cycle of 28 days)
Other outcomes:
Locations:
city: Wollongong
country: Australia
facility: Investigational Site Number : 0360001
state: New South Wales
city: Richmond
country: Australia
facility: Investigational Site Number : 0360002
state: Victoria
city: Anderlecht
country: Belgium
facility: Institut Jules Bordet_Site Number : 0560002
city: Antwerpen
country: Belgium
facility: Het Ziekenhuisnetwerk Antwerpen vzw - ZNA Middelheim_Site Number : 0560001-2
city: Antwerpen
country: Belgium
facility: Het Ziekenhuisnetwerk Antwerpen vzw - ZNA Cadix_Site Number : 0560001-1
city: Antwerp
country: Belgium
facility: Investigational Site Number : 0560001
city: Brno
country: Czechia
facility: Investigational Site Number : 2030002
city: Ostrava
country: Czechia
facility: Investigational Site Number : 2030001
city: Budapest
country: Hungary
facility: Investigational Site Number : 3480001
city: Rozzano
country: Italy
facility: Investigational Site Number : 3800001
state: Lombardia
city: Santander
country: Spain
facility: Hospital Universitario Marqués de Valdecilla_Site Number : 7240001
state: Cantabria
city: Badalona
country: Spain
facility: Institut Catala d´oncologia - Badalona_Site Number : 7240002
state: Cataluña
city: Barcelona
country: Spain
facility: HOSPITAL CLINIC i PROVINCIAL BARCELONA_Site Number : 7240003
city: Birmingham
country: United Kingdom
facility: Investigational Site Number : 8260003
city: London
country: United Kingdom
facility: Investigational Site Number : 8260002
city: Manchester
country: United Kingdom
facility: Investigational Site Number : 8260001
Study officials:
affiliation: Sanofi
name: Clinical Sciences & Operations
role: STUDY_DIRECTOR
References: