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Isatuximab in Combination With Novel Agents in RRMM - Master Protocol

PHASE1PHASE2RECRUITING

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.

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Study details:

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.

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Eligibility criteria

Researchers look for people who fit a certain description, called eligibility criteria. See if you qualify.

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.

Malabsorption syndrome or any condition that can significantly impact the absorption of pomalidomide.

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).

Current corneal epithelial disease except mild punctate keratopathy.

Patients who have received prior therapy with belantamab mafodotin.

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).

Participant unable to swallow tablets.

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.

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Eligibility

Age eligible for study : 18 and older

Healthy volunteers accepted : No

Gender eligible for study: All

Things to know

Study dates

Study start: 2021-01-25

Primary completion: 2027-07-28

Study completion finish: 2028-03-31

Study type

TREATMENT

Phase

PHASE1

PHASE2

Trial ID

NCT04643002

Intervention or treatment

DRUG: Isatuximab

DRUG: Dexamethasone

DRUG: Pomalidomide

DRUG: Belantamab mafodotin

DRUG: Pegenzileukin

DRUG: SAR439459

DRUG: Belumosudil

DRUG: Evorpacept

Conditions

• Plasma Cell Myeloma Refractory

$Image related to Plasma Cell Myeloma Refractory$

Condition: Plasma Cell Myeloma Refractory
DRUG: Isatuximab and other drugs
Wollongong, New South Wales, Australia and more
Sponsor: Sanofi

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Find a site

Closest Location:

Investigational Site Number : 0360006

Research sites nearby

Select from list below to view details:

Investigational Site Number : 0360006
Wollongong, New South Wales, Australia
Investigational Site Number : 0360002
Fitzroy, Victoria, Australia
Investigational Site Number : 0360001
Richmond, Victoria, Australia

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Participant Group/Arm	Intervention/Treatment
ACTIVE_COMPARATOR: Control Arm: isatuximab + pomalidomide + dexamethasone (Substudy 01) * Isatuximab, intravenous (IV) doseweekly (QW) × 4 weeks (Cycle 1), followed by every two weeks (Q2W) (subsequent cycles). * Pomalidomide dose by mouth daily Day 1 to Day 21. * Dexamethasone dose by mouth QW.	DRUG: Isatuximab Pharmaceutical form: Solution for infusion; Route of administration: Intravenous
EXPERIMENTAL: isatuximab + SAR439459 + dexamethasone (Substudy 02) SAR439459 in combination with isatuximab and dexamethasone Part 1: 2 dose levels (DLs) of IV SAR439459: * DL1 SAR439459 dose Q2W. * DL2 SAR439459 dose Q2W. * Isatuximab dose IV QW × 5 weeks (Cycle 1), followed by Q2W administrations (subsequent cycles). * Dexamethasone fixed dose and schedule: QW by mouth 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 IV dose Q2W. * Isatuximab IV dose QW × 5 weeks (Cycle 1), followed by Q2W administrations (subsequent cycles). * Dexamethasone fixed dose and schedule: QW by mouth. 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).	DRUG: Isatuximab Pharmaceutical form: Solution for infusion; Route of administration: Intravenous
EXPERIMENTAL: isatuximab + dexamethasone + belantamab mafodotin (Substudy 03) Belantamab mafodotin in combination with isatuximab and dexamethasone Part 1: 1 DL of IV belantamab mafodotin in Part 1 and de-escalation dose DL-1: * DL1 belantamab mafodotin IV dose QW4 or de-escalation dose DL-1 QW8 * Isatuximab dose, IV QW × 4 weeks (Cycle 1), followed by Q2W (subsequent cycles). * Dexamethasone fixed dose and schedule: QW by mouth. Part 2: * Isatuximab IV dose QW × 4 weeks (Cycle 1), followed by Q2W (subsequent cycles). * Belantamab mafodotin IV dose Q4W or Q8W * Dexamethasone fixed dose and schedule: QW by mouth.	DRUG: Isatuximab Pharmaceutical form: Solution for infusion; Route of administration: Intravenous
EXPERIMENTAL: Isatuximab + pegenzileukin (Substudy 04) 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 IV dose QW × 4 weeks, followed by Q2W (subsequent cycles). Part 1 - dose optimization: * Isatuximab IV dose QW × 4 weeks, followed by Q2W (subsequent cycles). * Pegenzileukin at potential doses (DL A and DL B) Q2W. Part 2 (dose expansion): * Isatuximab IV dose QW × 4 weeks, followed by Q2W (subsequent cycles). * Pegenzileukin IV dose Q2W.	DRUG: Isatuximab Pharmaceutical form: Solution for infusion; Route of administration: Intravenous
EXPERIMENTAL: Experimental: Isatuximab + Dexamethasone + Belumosudil (Substudy 05) Isatuximab in combination with belumosudil and dexamethasone Part 1- dose escalation: During the first cycle, belumosudil will be evaluated in monotherapy during 2 to 4 weeks, then isatuximab and dexamethasone will be added, and continued for the subsequent cycles. * Belumosudil by mouth at Dose Level (DL) 1, DL2, DL3, and DL4 * Isatuximab IV dose QW × 4 weeks, followed by Q2W (subsequent cycles) * Dexamethasone fixed dose and schedule: QW by mouth Part 1- dose optimization: * Belumosudil at potential doses (DL A and DL B), daily by mouth * Isatuximab IV dose QW × 4 weeks, followed by Q2W (subsequent cycles) * Dexamethasone fixed dose and schedule: QW by mouth Part 2- dose expansion: * Belumosudil dose daily, by mouth * Isatuximab IV dose QW × 4 weeks, followed by Q2W (subsequent cycles) * Dexamethasone fixed dose and schedule: QW by mouth	DRUG: Isatuximab Pharmaceutical form: Solution for infusion; Route of administration: Intravenous
EXPERIMENTAL: Isatuximab + evorpacept + dexamethasone (Substudy 06) Isatuximab in combination with evorpacept and dexamethasone Part 1- dose escalation: * Evorpacept IV dose Q2W * Isatuximab IV dose QW × 4 weeks, followed by Q2W (subsequent cycles) * Dexamethasone fixed dose and schedule: QW by mouth Part 1- dose optimization * Evorpacept IV at potential doses (DL A and DL B), Q2W * Isatuximab IV dose QW × 4 weeks, followed by Q2W (subsequent cycles) * Dexamethasone fixed dose and schedule: QW by mouth Part 2- dose expansion: * Evorpacept IV dose Q2W * Isatuximab IV dose QW × 4 weeks, followed by Q2W (subsequent cycles) * Dexamethasone fixed dose and schedule: QW by mouth	DRUG: Isatuximab Pharmaceutical form: Solution for infusion; Route of administration: Intravenous

What is the study measuring?

Primary outcome

Primary Outcome Measure	Primary Outcome Description	Primary Outcome Time Frame
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.	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.	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.	Up to approximately 28 months after the First patient in or scheduled assessment

Secondary outcome

Secondary Outcome Measure	Secondary Outcome Description	Secondary Outcome Time Frame
Part 1 (dose finding, experimental substudies): ORR	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.	Up to approximately 28 months after the First patient in or scheduled assessment
Part 2 (expansion, controlled experimental substudies): ORR	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.	Up to approximately 28 months after the First patient in or scheduled assessment
Part 1 (dose finding, experimental substudies): VGPR 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.	Up to approximately 28 months after the First patient in or scheduled assessment
Part 2 (expansion, independent experimental substudies): VGPR 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.	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.	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.	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.	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.	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.	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.	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.	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.	Multiple timepoints up to approximately 28 months after the First patient in or scheduled assessment
Pharmacokinetics (PK) Parameters for Novel agents and isatuximab	Concentration of novel agents (experimental arms) and isatuximab	Multiple timepoints up to approximately 28 months after the First patient in or scheduled assessment
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).	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).	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).	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).	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 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.	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.	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.	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.	On Day1 Cycle 1, End of treatment and at first follow-up visit. The cycle is 28 days.

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References

Clinical Trials Gov: Isatuximab in Combination With Novel Agents in RRMM - Master Protocol