Isatuximab in Combination With Novel Agents in RRMM - Master Protocol

Phase 1-2 UMBRELLA Trial Evaluating Isatuximab With or Without Dexamethasone in Combination With Novel Agents in Relapsed or Refractory Multiple Myeloma (RRMM) - Master Protocol

The purpose of this umbrella study is to evaluate isatuximab when combined with novel agents with or without dexamethasone in participants with relapsed or refractory myeloma.

Isatuximab dose, intravenous (IV) weekly (QW) x 4 weeks (Cycle 1), followed by Q2W (subsequent cycles). Pomalidomide dose os (PO) daily Day 1 to Day 21. Dexamethasone dose PO QW.

Part 1: SAR439459 in combination with isatuximab and dexamethasone 2 dose levels (DLs) of intravenous (IV) SAR439459: DL1 SAR439459 dose Q2W. DL2 SAR439459 dose Q2W. Isatuximab dose IV every week (QW) × 5 weeks (Cycle 1), followed by Q2W administrations (subsequent cycles). Dexamethasone fixed dose and schedule: QW per os (PO) In Cycle 1, the first administration of SAR439459 (Day 1) will precede isatuximab by 1 week (first dose of isatuximab will be at Cycle 1 Day 8). Part 2: SAR439459 dose, IV Q2W. Isatuximab dose, IV QW × 5 weeks (Cycle 1), followed by Q2W administrations (subsequent cycles). Dexamethasone fixed dose and schedule: QW PO. In Cycle 1, the first administration of SAR439459 (Day 1) will precede isatuximab by 1 week (first dose of isatuximab will be at Cycle 1 Day 8).

Part 1: belantamab mafodotin in combination with isatuximab and dexamethasone 1 dose level (DL) of intravenous (IV) belantamab mafodotin in Part 1 and de-escalation dose DL-1: DL1 belantamab mafodotin dose QW4 or de-escalation dose DL-1 QW8 Isatuximab dose, intravenous (IV) weekly (QW) x 4 weeks (Cycle 1), followed by Q2W (subsequent cycles). Dexamethasone fixed dose and schedule: QW PO. Part 2: Isatuximab dose, intravenous (IV) weekly (QW) x 4 weeks (Cycle 1), followed by Q2W (subsequent cycles). belantamab mafodotin dose IV Q4W or Q8W Dexamethasone fixed dose and schedule: QW PO.

Pegenzileukin in combination with isatuximab Part 1- dose escalation: Up to 3 DLs of IV pegenzileukin are planned to be evaluated: DL1 will explore pegenzileukin at Q2W. DL2 will explore pegenzileukin at Q2W. DL3 will explore pegenzileukin at Q2W. Isatuximab dose, IV, QW × 4 weeks, followed by Q2W (subsequent cycles). Part 1 - dose optimization: Isatuximab dose, IV, QW × 4 weeks, followed by Q2W (subsequent cycles). Pegenzileukin at potential doses (DL A and DL B) Q2W. Part 2 (dose expansion): Isatuximab dose, IV, QW × 4 weeks, followed by Q2W (subsequent cycles). Pegenzileukin dose, IV, Q2W.

Part 1 (dose finding, experimental substudies): Determination of recommended dose of novel agents in combination with isatuximab

Determination or confirmation of the dose will be based on: safety and tolerability in terms of TEAEs/SAEs, dose-limiting toxicity occurrence, and laboratory parameters available information on PK (if appropriate) and biomarkers.

VGPR or better rate is defined as the percentage of participants with a VGPR or better as defined by the 2016 IMWG response criteria, assessed by Investigator based on central laboratory values and local imaging.

ORR, defined as the proportion of participants with stringent complete response (sCR), complete response (CR), VGPR, or partial response (PR), according to the 2016 IMWG criteria assessed by Investigator based on central laboratory values and local imaging.

ORR, defined as the proportion of participants with stringent complete response (sCR), complete response (CR), VGPR, or partial response (PR), according to the 2016 IMWG criteria assessed by Investigator based on central laboratory values and local imaging.

VGPR or better rate is defined as the percentage of participants with a VGPR or better as defined by the 2016 IMWG response criteria, assessed by Investigator based on central laboratory values and local imaging.

CBR, defined as the proportion of participants with sCR, CR, VGPR, PR, or minimal response, according to the 2016 IMWG criteria assessed by Investigator based on central laboratory values and local imaging.

DOR, defined as the time from the date of the first response that is subsequently confirmed for patients achieving PR or better to the date of first documented PD or death, whichever happens first.

TT1R, defined as the time from the date of first treatment to the date of first response (PR or better) that is subsequently confirmed.

TTBR, defined as the time from the date of first treatment to the date of first occurrence of best overall response (PR or better) that is subsequently confirmed.

Safety and tolerability assessed in terms of adverse events/SAEs, including second primary malignancies, laboratory parameters, vital signs, and findings from physical examination.

PFS is defined as the time from the date of first treatment to disease progression based on the Investigator assessment according to 2016 IMWG criteria or death from any cause, whichever happens first.

Disease-specific HRQL will be assessed using the European Organization for Research and Treatment of Cancer (EORTC) core quality of life questionnaire (QLQ-C30)

The EORTC QLQ-C30 will be used to assess cancer-specific HRQL, disease and treatment-related symptoms and impact of symptoms.

On Day1 Cycle 1, then every 2 cycles for the first year; then every 3 cycles thereafter, at end of treatment and at first follow-up visit. The cycle is 28 days.

Disease- and treatment-related quality of life will be assessed using the EORTC multiple myeloma module (QLQ-MY20) questionnaire

The EORTC QLQ-MY20 will be used to measure myeloma-specific HRQL, disease and treatment-related symptoms and impact of symptoms.

On Day1 Cycle 1, then every 2 cycles for the first year; then every 3 cycles thereafter, at end of treatment and at first follow-up visit. The cycle is 28 days.

Global impact of side effects will be assessed using the Functional Assessment of Cancer Therapy (FACT-G) (GP5)

On Day1 Cycle 1, then every 2 cycles for the first year; then every 3 cycles thereafter, at end of treatment and at first follow-up visit. The cycle is 28 days.

Estimate/Confirm established clinically meaningful change scores for clinical outcome assessments (COAs)/domain scores using the Patient Global Impression of Severity (PGIS) and Patient Global Impression of Change (PGIC) scales

Patient Global Impression of Severity (PGIS) and Patient Global Impression of Change (PGIC) scales will be utilized as anchors to estimate/confirm established clinically meaningful change scores for clinical outcome assessments (COAs)/domain scores.

On Day1 Cycle 1, then every 2 cycles for the first year; then every 3 cycles thereafter, at end of treatment and at first follow-up visit. The cycle is 28 days.

The intensity of skeletal-related events (SRE)- related bone pain will be assessed using the skeletal-related bone pain numeric rating scale (SRE-BP-NRS) for control and experimental arms (Substudy 02)

The SRE-BP-NRS) will be used to assess the intensity of SRE-related bone pain (on average and at its worst) for control arm only

On Day1 Cycle 1, then every 2 cycles for the first year; then every 3 cycles thereafter, at end of treatment and at first follow-up visit. The cycle is 28 days.

SRE incidence, defined as the proportion of participants who experienced pathological fracture, radiation to bone, spinal cord compression, or surgery to bone as a first bone event.

Time to first occurrence of SRE is defined as time from the date of randomization to the occurrence of first SRE.

Assessment of Health care resource utilization related with SREs for control and experimental arms (Substudy 02)

The Health Care Resource Use-SREs questionnaire (HCRU-SREs) will be used to assess the use of health care resources associated with these events.

On Day1 Cycle 1, then every 2 cycles for the first year; then every 3 cycles thereafter, at End of treatment and at first follow-up visit. The cycle is 28 days.

Inclusion Criteria: Participant must be 18 years of age inclusive or older Eastern Cooperative Oncology Group (ECOG) performance status 0-1. Participants with relapsed or refractory MM who have received at least 3 prior lines of therapy for MM, including PIs and IMiDs or at least 2 prior lines if at least one of these lines consisted of 2 or more multiagent regimens (eg, Induction regimen with autologous stem cell transplant followed by maintenance). RRMM with measurable disease: Serum M protein ≥0.5 g/dL measured using serum protein immunoelectrophoresis and/or Urine M protein ≥200 mg/24 hours measured using urine protein immunoelectrophoresis and/or Serum free light chain (sFLC) MM without measurable M protein in serum or urine per previous criteria (serum Ig free light chain ≥10 mg/dL and abnormal serum Ig kappa lambda free light chain ratio <0.26 or >1.65). Men or woman or childbearing potential should agree to use contraception. Substudies 01, 02, 03: Anti-CD38 therapy naïve or prior exposure to such drugs without being refractory but with a wash out of at least 6 months after the last dose. "Refractory" is defined as progressing within 60 days of last dose of anti-CD38 targeting therapy. Substudy 04: Participants must be exposed to anti-CD38 and anti-BCMA therapy Exclusion Criteria: Primary systemic amyloid light chain amyloidosis, plasma cell leukemia, monoclonal gammopathy of undetermined significance, or smoldering myeloma. Uncontrolled infection within 14 days prior to first study intervention administration. Clinically significant cardiac (including valvular) or vascular disease within 3 months prior to first study intervention administration, eg, myocardial infarction, unstable angina, coronary (eg, coronary artery bypass graft, percutaneous coronary intervention) or peripheral artery revascularization, left ventricular ejection fraction <40%, heart failure New York Heart Association Classes III and IV, stroke, transient ischemic attack, pulmonary embolism, other thromboembolic event, or cardiac arrhythmia (Grade 3 or higher by NCI CTCAE Version 5.0). Known acquired immunodeficiency syndrome-related illness or known human immunodeficiency virus (HIV) disease requiring antiviral treatment or active hepatitis A. Uncontrolled or active hepatitis B virus (HBV) infection. Active hepatitis C virus (HCV) infection. Any of the following within 3 months prior to first study intervention administration: treatment resistant peptic ulcer disease, erosive esophagitis or gastritis, infectious or inflammatory bowel disease. Second malignancy other than basal cell or squamous cell carcinoma of the skin or in situ carcinoma, unless they are successfully treated with curative intent for more than 3 years before first study intervention administration. Any anti-MM drug treatment within 14 days before first study intervention administration, including dexamethasone. Participants with a contraindication to treatment. Vaccination with a live vaccine 4 weeks before the start of the study. Hemoglobin <8 g/dL. Platelets <50 x 10^9/L. Absolute neutrophil count <1.5 x 10^9/L. Creatinine clearance <30 mL/min. Total bilirubin >1.5 x ULN, except for known Gilbert syndrome in which direct bilirubin should be ≤2.5 x ULN. Aspartate aminotransferase and/or alanine aminotransferase >3 x ULN. Patients with grade 3 or 4 hypercalcemia. Substudy 01: --Malabsorption syndrome or any condition that can significantly impact the absorption of pomalidomide. Substudy 02: History of resected/ablated basal or squamous cell carcinoma (SCC) of the skin or carcinoma in situ of the cervix, or other local tumors, even if considered cured by local treatment. Therapeutic doses of anticoagulants or antiplatelet agents within 7 days prior to the first dose of SAR439459. Prothrombin time or INR >1.5 × upper limit of normal (ULN). Substudy 03: Current corneal epithelial disease except mild punctate keratopathy Patients who have received prior therapy with belantamab mafodotin Substudy 04: Central nervous system or leptomeningeal disease. Medical history of seizure. Participants currently receiving hepatically metabolized narrow therapeutic index drugs (eg, digoxin, warfarin) if cannot be closely monitored. The above information is not intended to contain all considerations relevant to a patient's potential participation in a clinical trial.

Qualified researchers may request access to patient level data and related study documents including the clinical study report, study protocol with any amendments, blank case report form, statistical analysis plan, and dataset specifications. Patient level data will be anonymized and study documents will be redacted to protect the privacy of trial participants. Further details on Sanofi's data sharing criteria, eligible studies, and process for requesting access can be found at: https://vivli.org