Isatuximab in Combination With Novel Agents in RRMM - Master Protocol

• ClinicalTrials.gov Identifier: NCT04643002
• Recruitment Status: Recruiting
• First Posted: November 24, 2020
• Last Update Posted: May 3, 2023
• Sponsor: Sanofi
• Information provided by (Responsible Party): Sanofi

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Plasma Cell Myeloma Refractory	Drug: Isatuximab SAR650984; Drug: Dexamethasone; Drug: Pomalidomide; Drug: belantamab mafodotin; Drug: SAR444245; Drug: SAR439459	Phase 1; Phase 2

Detailed Description:

Approximately 28 months

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 123 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: 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
• Actual Study Start Date: January 25, 2021
• Estimated Primary Completion Date: February 26, 2026
• Estimated Study Completion Date: February 26, 2026

Arms and Interventions

Arm	Intervention/treatment
Active Comparator: for controlled substudies: Control Arm: isatuximab + pomalidomide + dexamethasone (Substudy 1); 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.	Drug: Isatuximab SAR650984; Pharmaceutical form: Solution for infusion Route of administration: Intravenous; Other Name: Sarclisa®; Drug: Dexamethasone; Pharmaceutical form: Tablet Route of administration: Oral; Drug: Pomalidomide; Pharmaceutical form: Capsule Route of administration: Oral; Other Name: Pomalyst®
Experimental: isatuximab + SAR439459 + dexamethasone) (Substudy 2 terminated); 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).	Drug: Isatuximab SAR650984; Pharmaceutical form: Solution for infusion Route of administration: Intravenous; Other Name: Sarclisa®; Drug: Dexamethasone; Pharmaceutical form: Tablet Route of administration: Oral; Drug: SAR439459; Pharmaceutical form: Solution for injection.
Experimental: isatuximab + dexamethasone + belantamab mafodotin (Substudy 3 terminated); 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.	Drug: Isatuximab SAR650984; Pharmaceutical form: Solution for infusion Route of administration: Intravenous; Other Name: Sarclisa®; Drug: Dexamethasone; Pharmaceutical form: Tablet Route of administration: Oral; Drug: belantamab mafodotin; Pharmaceutical form: Solution for infusion Route of administration: Intravenous; Other Name: BLENREP®
Experimental: Isatuximab + SAR444245 (Substudy 4); Part 1- dose escalation SAR444245 in combination with isatuximab: Up to 2 DLs of IV SAR444245 are planned to be evaluated: DL1 will explore SAR444245 at Q2W. DL2 will explore SAR444245 at Q2W. In case of excessive toxicity at DL1, a de-escalation dose DL-1 will be explored 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).; SAR444245 at potential doses (DL A and DL B) Q2W. Part 2 (dose expansion): Isatuximab dose, IV, QW × 4 weeks, followed by Q2W (subsequent cycles).; SAR444245 dose, IV, Q2W.	Drug: SAR444245; Pharmaceutical form: Solution for infusion. Route of administration: Intravenous

Outcome Measures

Primary Outcome Measures :

1. Part 1 (dose finding, experimental substudies): Determination of recommended dose of novel agents in combination with isatuximab [ Time Frame: Through the end of cycle 1 (approximately 6 weeks) ]
   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.
2. VGPR Rate (Rate of Very Good Partial Response Rate or Better) in experimental substudies [ Time Frame: Up to approximately 28 months after the First patient in or scheduled assessment ]
   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. (Note: for some sub-studies, primary outcome will be Overall Response Rate (ORR) rather than VGPR Rate)

Secondary Outcome Measures :

1. Overall Response Rate (ORR) in each treatment arm [ Time Frame: Up to approximately 28 months after the First patient in or scheduled assessment ]
   ORR, defined as the proportion of participants with stringent complete response (sCR), complete response (CR), VGPR, and partial response (PR), according to the 2016 IMWG criteria assessed by Investigator based on central laboratory values and local imaging. (Note: for sub-studies where ORR is primary outcome, secondary outcome will be VGPR Rate)
2. To assess the clinical benefit rate (CBR) in each treatment arm. [ Time Frame: Up to approximately 28 months after the First patient in or scheduled assessment ]
   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.
3. Duration of Response (DOR) in each treatment arm [ Time Frame: Up to approximately 28 months after the First patient in or scheduled assessment ]
   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.
4. Time to First Response (TT1R) in each treatment arm [ Time Frame: Up to approximately 28 months after the First patient in or scheduled assessment ]
   TT1R, defined as the time from the date of first treatment to the date of first response (PR or better) that is subsequently confirmed.
5. Time to Best Response (TTBR) in each treatment arm [ Time Frame: Up to approximately 28 months after the First patient in or scheduled assessment ]
   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.
6. Safety and Tolerability in each treatment arm [ Time Frame: Up to approximately 28 months after the First patient in or scheduled assessment ]
   Safety and tolerability assessed in terms of adverse events/SAEs, including second primary malignancies, laboratory parameters, vital signs, and findings from physical examination.
7. Progression-free survival (PFS) in each treatment arm [ Time Frame: Up to approximately 28 months after the First patient in or scheduled assessment ]
   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.
8. Overall Survival (OS) in each treatment arm [ Time Frame: Up to approximately 28 months after the First patient in or scheduled assessment ]
   OS is defined as the time from the date of first treatment to death from any cause.
9. Immunogenicity of isatuximab and novel agents [ Time Frame: Day 1 at pre-specified cycles up to primary cutoff date (i.e., 24 weeks after Last Patient In at the latest) ]
   Incidence of anti-drug antibodies (ADAs) for novel agents (experimental arms) and isatuximab.
10. Disease-specific HRQL will be assessed using the European Organization for Research and Treatment of Cancer (EORTC) core quality of life questionnaire (QLQ-C30) [ 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 EORTC QLQ-C30 will be used to assess cancer-specific HRQL, disease and treatment-related symptoms and impact of symptoms.)
11. Disease- and treatment-related quality of life will be assessed using the EORTC multiple myeloma module (QLQ-MY20) questionnaire [ 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 EORTC QLQ-MY20 will be used to measure myeloma-specific HRQL, disease and treatment-related symptoms and impact of symptoms.
12. Global impact of side effects will be assessed using the Functional Assessment of Cancer Therapy (FACT-G) (GP5) [ 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. ]
    A single item from the FACT-G GP5 will be used to assess the global impact of side effects.
13. 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 [ 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. ]
    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.
14. 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 (Substudy02) [ 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 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
15. SRE Incidence for control and experimental arms (Substudy02) [ Time Frame: Continuous throughout study assessment (up to approximately 28 months) ]
    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.
16. Time to First Occurrence of SRE Assessment for control and experimental arms (Substudy02) [ Time Frame: Continuous throughout study assessment (up to approximately 28 months) ]
    Time to first occurrence of SRE is defined as time from the date of randomization to the occurrence of first SRE.
17. Assessment of Health care resource utilization related with SREs for control and experimental arms (Substudy02) [ 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 Health Care Resource Use-SREs questionnaire (HCRU-SREs) will be used to assess the use of health care resources associated with these events.
18. To assess patient-reported visual functioning for experimental arm only (Substudy03) [ Time Frame: On Day1 Cycle 1, End of treatment and at first follow-up visit. The cycle is 28 days. ]
    An NEI VFQ-25 will be used to assess patient-reported visual functioning.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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.
• Substudy 01, 02 (Terminated), 03 (Terminated): 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.
  • For the first 10 participants: Body weight ≤70 kg

• Substudy 02 (terminated):

  • 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 (terminated):

  • 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.

Contacts and Locations

Contacts

Contact: Trial Transparency email recommended (Toll free number for US & Canada); 800-633-1610 ext option 6; Contact-US@sanofi.com

Locations

United States, Illinois

University of Illinois-Site Number:8400007; Recruiting

Chicago, Illinois, United States, 60612

United States, Michigan

University of Michigan-Site Number:8400004; Recruiting

Ann Arbor, Michigan, United States, 48109

United States, New York

Roswell Park Cancer Institute-Site Number:8400008; Recruiting

Buffalo, New York, United States, 14263

Australia, New South Wales

Investigational Site Number :0360006; Recruiting

Wollongong, New South Wales, Australia, 2500

Australia, Victoria

Investigational Site Number :0360002; Recruiting

Fitzroy, Victoria, Australia, 3065

Investigational Site Number :0360001; Recruiting

Richmond, Victoria, Australia, 3121

France

Investigational Site Number :2500002; Recruiting

Lille, France, 59037

Investigational Site Number :2500001; Recruiting

Nantes, France, 44093

Investigational Site Number :2500003; Recruiting

Paris, France, 75013

Investigational Site Number :2500004; Recruiting

Paris, France, 75015

Greece

Investigational Site Number :3000002; Recruiting

Athens, Greece, 10676

Investigational Site Number :3000001; Recruiting

Athens, Greece, 11528

Italy

Investigational Site Number :3800001; Recruiting

Meldola, Forlì-Cesena, Italy, 47014

Investigational Site Number :3800002; Recruiting

Bologna, Italy, 40138

Norway

Investigational Site Number :5780001; Recruiting

Oslo, Norway, 0450

Portugal

Investigational Site Number :6200001; Recruiting

Coimbra, Portugal, 3000-075

Investigational Site Number :6200002; Recruiting

Vila Nova Gaia, Portugal, 4434-502

Puerto Rico

Puerto Rico Medical Research Center, LLC-Site Number:8400005; Recruiting

Hato Rey, Puerto Rico, 00917

Sponsors and Collaborators

Sanofi

Investigators

• Study Director: Clinical Sciences & Operations; Sanofi

More Information

• Responsible Party: Sanofi
• ClinicalTrials.gov Identifier: NCT04643002
• Other Study ID Numbers: ACT16482; 2020-003024-16 ( EudraCT Number ); U1111-1244-2598 ( Registry Identifier: ICTRP )
• First Posted: November 24, 2020
• Last Update Posted: May 3, 2023
• Last Verified: May 2, 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: 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

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No

Additional relevant MeSH terms:

Multiple Myeloma; Neoplasms, Plasma Cell; Neoplasms by Histologic Type; Neoplasms; Hemostatic Disorders; Vascular Diseases; Cardiovascular Diseases; Paraproteinemias; Blood Protein Disorders; Hematologic Diseases; Hemorrhagic Disorders; Lymphoproliferative Disorders; Immunoproliferative Disorders; Immune System Diseases; Dexamethasone; Pomalidomide; Anti-Inflammatory Agents; Antiemetics; Autonomic Agents; Peripheral Nervous System Agents; Physiological Effects of Drugs; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Antineoplastic Agents; Immunologic Factors; Angiogenesis Inhibitors; Angiogenesis Modulating Agents