Isatuximab in Combination With Novel Agents in RRMM - Master Protocol

Sponsor
Sanofi (Industry)
Overall Status
Recruiting
CT.gov ID
NCT04643002
Collaborator
(none)
66
19
2
80.5
3.5
0

Study Details

Study Description

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

  • 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 3-ACT16482-03:

  • To assess patient-reported visual functioning.

Condition or Disease Intervention/Treatment Phase
Phase 1/Phase 2

Detailed Description

Approximately 28 months

Study Design

Study Type:
Interventional
Anticipated 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 :
Jan 25, 2021
Anticipated Primary Completion Date :
Oct 10, 2027
Anticipated Study Completion Date :
Oct 10, 2027

Arms and Interventions

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 Names:
  • Sarclisa®
  • Drug: Dexamethasone
    Pharmaceutical form: Tablet Route of administration: Oral

    Drug: Pomalidomide
    Pharmaceutical form: Capsule Route of administration: Oral
    Other Names:
  • Pomalyst®
  • Experimental: experimental: isatuximab + dexamethasone + belantamab mafodotin (Substudy 3)

    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) × 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 or Q8W Dexamethasone fixed dose and schedule: QW PO.

    Drug: Isatuximab SAR650984
    Pharmaceutical form: Solution for infusion Route of administration: Intravenous
    Other Names:
  • Sarclisa®
  • Drug: Dexamethasone
    Pharmaceutical form: Tablet Route of administration: Oral

    Drug: SAR439459
    Pharmaceutical form: Solution for injection Route of administration: Intravenous
    Other Names:
  • BLENREP®
  • Drug: belantamab mafodotin
    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 [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 [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 [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. [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 [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 [Up to approximately 28 months after the First 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 [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. Safety and Tolerability in each treatment arm [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 [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 [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 [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. Disease-specific HRQL will be assessed using the European Organization for Research and Treatment of Cancer (EORTC) core quality of life questionnaire (QLQ-C30) [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 [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) [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 [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. To assess patient-reported visual functioning for experimental arm only [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

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    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 01-03:

    • 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

    • 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 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

    Locations

    Site City State Country Postal Code
    1 University of Illinois-Site Number:8400007 Chicago Illinois United States 60612
    2 University of Michigan-Site Number:8400004 Ann Arbor Michigan United States 48109
    3 Roswell Park Cancer Institute-Site Number:8400008 Buffalo New York United States 14263
    4 Investigational Site Number :0360006 Wollongong New South Wales Australia 2500
    5 Investigational Site Number :0360002 Fitzroy Victoria Australia 3065
    6 Investigational Site Number :0360003 Heidelberg West Victoria Australia 3081
    7 Investigational Site Number :0360005 Melbourne Victoria Australia 3004
    8 Investigational Site Number :0360001 Richmond Victoria Australia 3121
    9 Investigational Site Number :2500002 Lille France 59037
    10 Investigational Site Number :2500001 Nantes France 44093
    11 Investigational Site Number :2500004 Paris France 75015
    12 Investigational Site Number :3000002 Athens Greece 10676
    13 Investigational Site Number :3000001 Athens Greece 11528
    14 Investigational Site Number :3800002 Bologna Italy 40138
    15 Investigational Site Number :3800001 Meldola Italy 47014
    16 Investigational Site Number :5780001 Oslo Norway 0450
    17 Investigational Site Number :6200001 Coimbra Portugal 3000-075
    18 Investigational Site Number :6200002 Vila Nova Gaia Portugal 4434-502
    19 Puerto Rico Medical Research Center, LLC-Site Number:8400005 Hato Rey Puerto Rico 00917

    Sponsors and Collaborators

    • Sanofi

    Investigators

    • Study Director: Clinical Sciences & Operations, Sanofi

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    None provided.
    Responsible Party:
    Sanofi
    ClinicalTrials.gov Identifier:
    NCT04643002
    Other Study ID Numbers:
    • ACT16482
    • 2020-003024-16
    • U1111-1244-2598
    First Posted:
    Nov 24, 2020
    Last Update Posted:
    Aug 3, 2022
    Last Verified:
    Aug 2, 2022
    Individual Participant Data (IPD) Sharing Statement:
    Yes
    Plan to Share IPD:
    Yes
    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:

    Study Results

    No Results Posted as of Aug 3, 2022