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Isatuximab in Combination With Novel Agents in RRMM

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ClinicalTrials.gov Identifier: NCT04643002
Recruitment Status : Recruiting
First Posted : November 24, 2020
Last Update Posted : February 25, 2022
Sponsor:
Information provided by (Responsible Party):
Sanofi

Study Description
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Brief Summary:

Primary Objectives:

  • Part 1 (dose finding, experimental substudies):

    -To determine or confirm the recommended dose of novel agents when combined with isatuximab with or without dexamethasone in participants with RRMM.

  • Part 2 (expansion, experimental substudies):

    • To demonstrate the clinical benefit of novel agents combined with isatuximab with or without dexamethasone in terms of rate of very good partial response (VGPR) or better.

Secondary Objectives:

  • Master Protocol:

    • To assess the overall response rate (ORR) in each treatment arm.
    • To assess the clinical benefit rate (CBR) in each treatment arm.
    • To assess the duration of response (DOR) in each treatment arm.
    • To assess the time to first response (TT1R) in each treatment arm.
    • To assess the time to best response (TTBR) in each treatment arm.
    • To assess safety and tolerability in each treatment arm
    • To assess progression free survival (PFS) in each treatment arm.
    • To assess overall survival (OS) in each treatment arm.
    • To evaluate the potential immunogenicity of isatuximab and novel agents when applicable.
    • To characterize the PK of isatuximab and novel agents.
    • To assess disease and treatment related symptoms, cancer and disease specific health-related quality of life, global impact of side effects and confirm/establish clinically meaningful change scores for clinical outcome assessments (COAs)/domain scores.

  • Substudy 1-ACT16482-01 (Control Arm):

    • To assess clinical outcomes assessments (COAs).
    • To assess the incidence of skeletal related events (SREs).
    • To assess the time to first occurrence of SRE.
    • To assess health care resource utilization related with SREs.

  • Substudy 2-ACT16482-02:

    • To assess pain intensity related to skeletal related events (SREs).
    • To assess the incidence of SREs.
    • To assess the time to first occurrence of SRE.
    • To assess health care resource utilization related with SREs.

  • Substudy 3-ACT16482-03:

    • To assess patient-reported visual functioning.

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

Detailed Description:
Approximately 28 months
Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 66 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 Compared to Isatuximab With Pomalidomide and Dexamethasone in Relapsed or Refractory Multiple Myeloma (RRMM) - Master Protocol
Actual Study Start Date : January 25, 2021
Estimated Primary Completion Date : February 11, 2026
Estimated Study Completion Date : February 11, 2026

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Multiple Myeloma

Arms and Interventions
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Arm Intervention/treatment
Active Comparator: Control Arm: isatuximab + pomalidomide + dexamethasone (Substudy 1)

Isatuximab dose, intravenous (IV) weekly (QW) × 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: Experimental: isatuximab + SAR439459 + dexamethasone) (Substudy 2

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

Route of administration: Intravenous
Experimental: experimental: isatuximab + dexamethasone + belantamab mafodotin (Substudy 3)

Part 1: belantamab mafodotin in combination with isatuximab and dexamethasone. 2 dose levels (DLs) of intravenous (IV) belantamab mafodotin: DL1 belantamab mafodotin dose Q4W.

  • DL2 belantamab mafodotin dose Q4W.
  • Isatuximab dose, intravenous (IV) weekly (QW) × 4 weeks (Cycle 1), followed by Q2W (subsequent cycles).
  • Dexamethasone fixed dose and schedule: QW PO.

Part 2:

  • Isatuximab dose, intravenous (IV) weekly (QW) × 4 weeks (Cycle 1), followed by Q2W (subsequent cycles).
  • belantamab mafodotin dose IV Q4W.
  • 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


Outcome Measures
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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.


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.

  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

  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 theFirst patient in or scheduled assessment ]
    TT1R, defined as the time from the date of randomization 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 randomization to the date of first occurrence of best overall response (PR or better) that is subsequently confirmed.

  6. Time to Best Response (TTBR) 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 randomization 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 randomization to death from any cause.

  9. Immunogenicity of isatuximab and novel agents [ Time Frame: Cycle 1 day 1, Day 2 (only substudy 03), Day8, Day15, day 22/29; from Cycle2 to Cycle4 day 1 and day 15 and from Cycle5 and after day 1 only. The cycle is 28 days. ]
    Incidence of anti-drug antibodies (ADAs) for novel agents (experimental arms) and isatuximab.

  10. Pharmacokinetics (PK) Parameters for Novel agents and isatuximab [ Time Frame: Cycle 1 day 1, Day 2 (only substudy 03), Day8, Day15, day 22/29; from Cycle2 to Cycle4 day 1 and day 15 and from Cycle5 and after day 1 only. The cycle is 28 days. ]
    Concentration of novel agents (experimental arms) and isatuximab.

  11. 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.

  12. 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.

  13. 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.

  14. 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.

  15. 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 [ 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.

  16. SRE Incidence for control and experimental arms [ 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.

  17. Time to First Occurrence of SRE Assessment for control and experimental arms [ Time Frame: Continuous throughout study assessment (up to approximately 28 months) ]
    Time to First Occurrence of SRE Assessment for control and experimental arms.

  18. Assessment of Health care resource utilization related with SREs for control and experimental arms [ 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.

  19. To assess patient-reported visual functioning for experimental arm only [ 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
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Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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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, 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

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 randomization.
  • Clinically significant cardiac (including valvular) or vascular disease within 3 months prior to randomization, 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 randomization: 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 randomization.
  • Any anti-MM drug treatment within 14 days before randomization, 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 × 109/L.
  • Absolute neutrophil count <1.5 × 109/L.
  • Creatinine clearance <30 mL/min.
  • 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.
  • For the first 10 participants: Body weight ≤70 kg

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

The above information is not intended to contain all considerations relevant to a patient's potential participation in a clinical trial.

Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04643002


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

Locations
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Sponsors and Collaborators
Sanofi
Investigators
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Study Director: Clinical Sciences & Operations Sanofi
More Information
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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    Key Record Dates
Last Update Posted: February 25, 2022
Last Verified: February 9, 2022
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

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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:
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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