Isatuximab in Combination With Novel Agents in RRMM - Master Protocol

Phase 2RecruitingNCT04643002

Sanofi258 enrolled

Overview

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. Substudy 01 is the control Substudy. Substudies 02, 03, and 06 are controlled experimental substudies. Substudies 04 and 05 are independent experimental substudies.

Participants will continue study treatment until disease progression, death, unacceptable toxicity, participant request to stop treatment, Investigator decision, or study termination by the Sponsor i.e., up to Aapproximately 28 months.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

258

Conditions

Plasma Cell Myeloma Refractory

Interventions

IsatuximabDRUG

Pharmaceutical form: Concentrated solution for intravenous infusion; Route of administration: Intravenous infusion

DexamethasoneDRUG

Pharmaceutical form: Tablet; Route of administration: Oral

PomalidomideDRUG

Pharmaceutical form: Capsule; Route of administration: Oral

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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 2 prior lines of therapy for MM, including PIs and IMiDs (eg, Induction regimen with autologous stem cell transplant followed by maintenance is considered one line). * 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. * Substudy 01, 06: Anti-CD38 therapy naïve or prior exposure to such drugs with a wash out of at least 12 months after the last dose. "Exposure" is defined as at least 2 cycles of therapy. * Substudies 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: Anti-CD38 and anti-B cell maturation antigen (BCMA) therapy (if available) prior exposed participants with RRMM. For anti-CD38, "Exposure" is defined as at least 2 cycles of therapy. For anti-BCMA therapy if available, exposure is defined by at least 2 cycles of therapy. * Substudy 05: Participants with RRMM with at least 2 cycles of prior exposure to anti-CD38 therapy. For participants to whom BCMA targeted therapy is available (ie, approved in their region and can be reimbursed), at least 2 cycles of prior exposure to a BCMA targeted agent is mandatory. 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. * Seasonal flu and COVID-19 vaccines that do not contain live virus are permitted. * Hemoglobin \<8 g/dL. * Platelets \<50 × 10\^9/L. * Absolute neutrophil count \<1.0 × 10\^9/L. * Creatinine clearance \<30 mL/min/1.73m2. * Total bilirubin \>1.5 × ULN, except for known Gilbert syndrome in which direct bilirubin should be ≤2.5 × ULN. * Aspartate aminotransferase and/or alanine aminotransferase \>3 × 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. * Active, known, or suspected autoimmune disease that has required systemic treatment in the past 2 years (ie, with use of disease modifying agents, corticosteroids or immunosuppressive drugs), except controlled by replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc). The following are not exclusionary: vitiligo, childhood asthma that has resolved, psoriasis that does not require systemic treatment. * Prior allogeneic hematopoietic stem cell transplant (allo-HSCT). Substudy 05: \- Participant unable to swallow tablets. Substudy 06: * History of active autoimmune disorders. * History of autoimmune hemolytic anemia or autoimmune. thrombocytopenia. * Active graft versus host disease (GVHD) or ongoing immunosuppression for GVHD. * Prior allogenic hematopoietic stem cell transplant (allo-HSCT). * Patient with chronic active EBV infection. * Patients with known history of HLH. * Hemoglobin \< 9 g/dL. * Prior therapy with any anti-CD47 or anti signal regulatory protein alpha agent. The above information is not intended to contain all considerations relevant to a patient's potential participation in a clinical trial.

Locations (26)

Outcomes

Primary Outcomes

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.

Time frame: Through the end of cycle 1 (approximately 6 weeks)

Part 2 (expansion, controlled experimental substudies): VGPR Rate (Rate of Very Good Partial Response Rate or Better)

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.

Time frame: Up to approximately 28 months after the First patient in or scheduled assessment

Part 2 (expansion, independent experimental substudies): Overall Response Rate (ORR) in independent experimental substudies

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.

Time frame: Up to approximately 28 months after the First patient in or scheduled assessment

Secondary Outcomes

Part 1 (dose finding, experimental substudies): ORR

Time frame: Up to approximately 28 months after the First patient in or scheduled assessment

Part 2 (expansion, controlled experimental substudies): ORR

Central Contacts

Trial Transparency email recommended (Toll free number for US & Canada)

CONTACT

800-633-1610 contact-us@sanofi.com

Data from ClinicalTrials.gov

This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.

Pharmaceutical form: Solution for infusion; Route of administration: Intravenous

PegenzileukinDRUG

Pharmaceutical form: Solution for infusion; Route of administration: Intravenous

SAR439459DRUG

Pharmaceutical form: Solution for injection; Route of administration: Intravenous

BelumosudilDRUG

Pharmaceutical form: tablet; route of administration: oral

EvorpaceptDRUG

Pharmaceutical form: Solution for infusion; Route of administration: Intravenous

Winship Cancer Institute of Emory University- Site Number : 8400010

Atlanta, Georgia, United States

RECRUITING

University of Illinois-Chicago - College of Medicine- Site Number : 8400007

Chicago, Illinois, United States

COMPLETED

University of Michigan Health System - Ann Arbor- Site Number : 8400004

Ann Arbor, Michigan, United States

RECRUITING

Roswell Park Cancer Institute- Site Number : 8400008

Buffalo, New York, United States

RECRUITING

The Ohio State University- Site Number : 8400012

Columbus, Ohio, United States

RECRUITING

Investigational Site Number : 0360006

Wollongong, New South Wales, Australia

RECRUITING

Investigational Site Number : 0360002

Melbourne, Victoria, Australia

RECRUITING

Investigational Site Number : 0360001

Richmond, Victoria, Australia

RECRUITING

Investigational Site Number : 2500003

Paris, Washington, France

RECRUITING

Investigational Site Number : 2500002

Lille, France

RECRUITING

...and 16 more locations

Time frame: Up to approximately 28 months after the First patient in or scheduled assessment

Part 1 (dose finding, experimental substudies): VGPR or better

Time frame: Up to approximately 28 months after the First patient in or scheduled assessment

Part 2 (expansion, independent experimental substudies): VGPR or better

Time frame: Up to approximately 28 months after the First patient in or scheduled assessment

Clinical benefit rate (CBR) in each treatment arm

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.

Time frame: Up to approximately 28 months after the First patient in or scheduled assessment

Duration of Response (DOR) in each treatment arm

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.

Time frame: Up to approximately 28 months after the First patient in or scheduled assessment

Time to First Response (TT1R) in each treatment arm

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

Time frame: Up to approximately 28 months after the First patient in or scheduled assessment

Time to Best Response (TTBR) in each treatment arm

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.

Time frame: Up to approximately 28 months after the First patient in or scheduled assessment

Number of participants with treatment emergent adverse events and serious adverse events in each treatment arm

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

Time frame: Up to approximately 28 months after the First patient in or scheduled assessment

Progression-free survival (PFS) in each treatment arm

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.

Time frame: Up to approximately 28 months after the First patient in or scheduled assessment

Overall Survival (OS) in each treatment arm

OS is defined as the time from the date of first treatment to death from any cause.

Time frame: Up to approximately 28 months after the First patient in or scheduled assessment

Immunogenicity of isatuximab and novel agents

Incidence of anti-drug antibodies (ADAs) for novel agents (experimental arms) and isatuximab.

Time frame: Multiple timepoints up to approximately 28 months after the First patient in or scheduled assessment

Concentration of novel agents (experimental arms) and isatuximab (Ctrough)

Time frame: Multiple timepoints during Cycle 1. The cycle is 28 days.

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. This endpoint will be assessed for Part 1 (dose optimization, independent and controlled experimental substudies) and Part 2 (expansion, independent and controlled experimental substudies).

Time frame: 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. This endpoint will be assessed for Part 1 (dose optimization, independent and controlled experimental substudies) and Part 2 (expansion, independent and controlled experimental substudies).

Time frame: 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)

A single item from the FACT-G GP5 will be used to assess the global impact of side effects. This endpoint will be assessed for Part 1 (dose optimization, independent and controlled experimental substudies) and Part 2 (expansion, independent and controlled experimental substudies).

Time frame: 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. This endpoint will be assessed for Part 1 (dose optimization, independent and controlled experimental substudies) and Part 2 (expansion, independent and controlled experimental substudies).

Time frame: 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

Time frame: 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 for control and experimental arms- Substudy 02

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 frame: Continuous throughout study assessment (up to approximately 28 months)

Time to First Occurrence of SRE Assessment for control and experimental arms (Substudy 02)

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

Time frame: Continuous throughout study assessment (up to approximately 28 months)

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.

Time frame: 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.

To assess patient-reported visual functioning for experimental arm only -Substudy 03

An NEI VFQ-25 will be used to assess patient-reported visual functioning.

Time frame: On Day1 Cycle 1, End of treatment and at first follow-up visit. The cycle is 28 days.

Maximum concentration observed after the first infusion (Cmax) for Belumosudil - Substudy 05

Time frame: Multiple timepoints during Cycle 1. The cycle is 28 days.

Time to reach Cmax (tmax) for Belumosudil - Substudy 05

Time frame: Multiple timepoints during Cycle 1. The cycle is 28 days.

Area under the concentration versus time curve calculated using the trapezoidal method from 0 to 8h (AUC0-8h) for Belumosudil - Substudy 05

Time frame: Multiple timepoints during Cycle 1. The cycle is 28 days.

Maximum concentration observed after the first infusion (Cmax) for Evorpacept - Substudy 06

Time frame: Multiple timepoints during Cycle 1. The cycle is 28 days.

Time to reach Cmax (tmax) for Evorpacept - Substudy 06

Time frame: Multiple timepoints during Cycle 1. The cycle is 28 days.

Area under the concentration versus time curve calculated using the trapezoidal method over the dosing interval for evorpacept (AUC0-t)- Substudy 06

Time frame: Multiple timepoints during Cycle 1. The cycle is 28 days.