Multi-center, Open-label, Phase 1b Study in Patients With Relapsed/Refractory Multiple Myeloma (RRMM)

• ClinicalTrials.gov Identifier: NCT04045795
• Recruitment Status: Active, not recruiting
• First Posted: August 6, 2019
• Last Update Posted: May 9, 2022
• Sponsor: Sanofi
• Information provided by (Responsible Party): Sanofi

Tracking Information

• First Submitted Date: August 2, 2019
• First Posted Date: August 6, 2019
• Last Update Posted Date: May 9, 2022
• Actual Study Start Date: August 6, 2019
• Estimated Primary Completion Date: February 15, 2024 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: August 5, 2019)

• Assessment of adverse events (AEs) [ Time Frame: Baseline to 30 days after last study treatment administration (up to approximately 14 months after first study treatment administration) ]
  Number of participants with adverse events
• Pharmacokinetic (PK) assessment: Ceoi [ Time Frame: Baseline to end of treatment (EOT) after isatuximab SC and to Cycle 10 after IV (28 days per Cycle) ]
  Concentration observed at the end of infusion (Ceoi)
• PK assessment: Cmax [ Time Frame: Baseline to EOT after isatuximab SC and to Cycle 10 after IV (28 days per Cycle) ]
  Maximum concentration observed after the first infusion (Cmax)
• PK assessment: tmax [ Time Frame: Baseline to EOT after isatuximab SC and to Cycle 10 after IV (28 days per Cycle) ]
  Time to reach Cmax (tmax)
• PK assessment: Clast [ Time Frame: Baseline to EOT after isatuximab SC and to Cycle 10 after IV (28 days per Cycle) ]
  Last concentration observed above the lower limit of quantification after the first infusion (Clast)
• PK assessment: tlast [ Time Frame: Baseline to EOT after isatuximab SC and to Cycle 10 after IV (28 days per Cycle) ]
  Time of Clast (tlast)
• PK assessment: Ctrough [ Time Frame: Baseline to EOT after isatuximab SC and to Cycle 10 after IV (28 days per Cycle) ]
  Concentration observed just before treatment administration during repeated dosing (Ctrough)
• PK assessment: AUClast [ Time Frame: Baseline to EOT after isatuximab SC and to Cycle 10 after IV (28 days per Cycle) ]
  Area under the plasma concentration versus time curve calculated using the trapezoidal method from time zero to time of the last concentration observed above the lower limit of quantification (ie, Clast) (AUClast)
• PK assessment: AUC0 T [ Time Frame: Baseline to EOT after isatuximab SC and to Cycle 10 after IV (28 days per Cycle) ]
  Area under the plasma concentration versus time curve calculated over the dosing interval T (168h or 336h) (AUC0 T)

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: August 5, 2019)

• Estimation of absolute bioavailability of isatuximab [ Time Frame: Day 8 ]
  Absolute bioavailability of isatuximab SC, expressed as a percentage, estimated from AUC0-168h obtained after intravenous (IV) and extravascular (EV) administration
• Overall response rate (ORR) [ Time Frame: From day -21 to day 60 after last study treatment (up to approximately 14 months after first study treatment administration) ]
  ORR is the proportion of patients with stringent complete response (sCR), complete response (CR), very good partial response (VGPR), and partial response (PR) using the IMWG response criteria
• Duration of response (DOR) [ Time Frame: From day -21 to day 60 after last study treatment (up to approximately 14 months after first study treatment administration) ]
  Time from the date of the first response to the date of first progressive disease (PD) or death, whichever happens first
• Time to response (TTR) [ Time Frame: From day -21 to day 60 after last study treatment (up to approximately 14 months after first study treatment administration) ]
  Time from the date of first study treatment to the first response
• Time to progression (TTP) [ Time Frame: From day -21 to day 60 after last study treatment (up to approximately 14 months after first study treatment administration) ]
  Time from date of first study treatment to date of first documentation of progressive disease
• Overall survival (OS) [ Time Frame: From day -21 to day 60 after last study treatment (up to approximately 14 months after first study treatment administration) ]
  Time from the date of first study treatment to date of death from any cause
• Clinical benefit rate (CBR) [ Time Frame: From day -21 to day 60 after last study treatment (up to approximately 14 months after first study treatment administration) ]
  Proportion of patients with sCR, CR, VGPR, PR or minimal response (MR) according to IMWG criteria
• Progression free survival (PFS) [ Time Frame: From day -21 to day 60 after last study treatment (up to approximately 14 months after first study treatment administration) ]
  Time from date of first study treatment to date of first documentation of progressive disease or death
• Comparison of patient expectations and satisfaction: Patient Expectations and Satisfaction Questionnaires [ Time Frame: Cycles 1 and 2 (28 days per Cycle), and 30 days after last isatuximab administration (up to approximately 14 months after first study treatment administration) ]
  Comparison of patient expectations and satisfaction will be assessed using Patient Expectations and Satisfaction Questionnaires before and after subcutaneous (SC) administration, where a score of 1 = not satisfied and a score of 5 = extremely satisfied
• Immunogenicity: Anti drug antibody levels [ Time Frame: Baseline to EOT after isatuximab SC and to Cycle 10 after IV (28 days per Cycle) ]
  Incidence of patients with anti drug antibodies against isatuximab
• Biomarker: Change in CD38 receptor occupancy [ Time Frame: At screening and at Day 1 of Cycle 2 (28 days per Cycle) (predose); to be stopped once the isatuximab SC dose has been selected. ]
  Change in CD38 receptor occupancy from baseline

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Multi-center, Open-label, Phase 1b Study in Patients With Relapsed/Refractory Multiple Myeloma (RRMM)
• Official Title: A Multi-center, Open-label, Phase 1b Study to Assess the Pharmacokinetics, Safety, and Efficacy of Subcutaneous and Intravenous Isatuximab (SAR650984) in Combination With Pomalidomide and Dexamethasone, in Patients With Relapsed/Refractory Multiple Myeloma (RRMM)

Brief Summary

Primary Objectives:

• To evaluate the safety and tolerability of isatuximab administered subcutaneously (SC) versus intravenously (IV)
• To assess the safety and tolerability (including local injection site tolerability) of isatuximab using the (investigational) isatuximab injector device
• To evaluate the pharmacokinetics (PK) of SC and IV isatuximab

Secondary Objectives:

• To estimate absolute bioavailability of SC and IV isatuximab
• To measure receptor occupancy (RO) after isatuximab SC versus IV administration
• To assess efficacy of isatuximab after SC and IV administration
• To assess patient expectations prior to and patient experience and satisfaction after SC administration
• To evaluate potential immunogenicity of SC or IV isatuximab

• Detailed Description: Total study duration is variable depending on treatment and follow-up periods, including 21 days of screening, and treatment period until disease progression, unacceptable adverse reaction or other reason for discontinuation. End of treatment will be 30 days after last administration of investigational medicinal product, or before further anti-myeloma therapy, whichever comes first; approximately 14 months after first study treatment administration.
• Study Type: Interventional
• Study Phase: Phase 1
• Study Design: Allocation: Randomized; Intervention Model: Sequential Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Multiple Myeloma

Intervention

• Drug: isatuximab SAR650984 IV

  Pharmaceutical form: solution

  Route of administration: intravenous

  Other Name: Sarclisa
• Drug: pomalidomide

  Pharmaceutical form: tablet

  Route of administration: oral

  Other Name: Pomalyst®
• Drug: dexamethasone

  Pharmaceutical form: tablet

  Route of administration: oral

  Other Name: Decadron®
• Drug: isatuximab SAR650984 SC

  Pharmaceutical form: solution

  Route of administration: subcutaneous

• Device: Investigational injector device
  Subcutaneous administration

Study Arms

• Experimental: Dose regimen 1
  Isatuximab SC administration dose level 1 once weekly for 4 weeks (Cycle 1) and on Day 1 and Day 15 of each subsequent cycle
  Interventions:

  • Drug: pomalidomide
  • Drug: dexamethasone
  • Drug: isatuximab SAR650984 SC
• Experimental: Dose regimen 2
  Isatuximab SC administration dose level 2 once weekly for 4 weeks (Cycle 1) and on Day 1 and Day 15 of each subsequent cycle
  Interventions:

  • Drug: pomalidomide
  • Drug: dexamethasone
  • Drug: isatuximab SAR650984 SC
• Experimental: Dose regimen 3
  Isatuximab SC administration dose level 3 using the investigational injector device once weekly for 4 weeks (Cycle 1) and on Day 1 and Day 15 of each subsequent cycle
  Interventions:

  • Drug: pomalidomide
  • Drug: dexamethasone
  • Drug: isatuximab SAR650984 SC
  • Device: Investigational injector device
• Experimental: Dose regimen 4
  Isatuximab IV administration once weekly for 4 weeks (Cycle 1) and on Day 1 and Day 15 of each subsequent cycle
  Interventions:

  • Drug: isatuximab SAR650984 IV
  • Drug: pomalidomide
  • Drug: dexamethasone
• Experimental: Dose regimen 5
  Isatuximab IV administration once weekly for 4 weeks (Cycle 1) and on Day 1 and Day 15 of each subsequent cycle
  Interventions:

  • Drug: isatuximab SAR650984 IV
  • Drug: pomalidomide
  • Drug: dexamethasone

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: February 10, 2022): 56
• Original Estimated Enrollment (submitted: August 5, 2019): 46
• Estimated Study Completion Date: February 15, 2024
• Estimated Primary Completion Date: February 15, 2024 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion criteria:

• Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in the protocol.
• Participant must be above 18 years of age or country's legal age of majority if the legal age is >18 years old, at the time of signing the informed consent.
• Participant has been previously diagnosed with multiple myeloma (MM) based on standard criteria and currently requires treatment because MM has relapsed following a response, according to International Myeloma Working Group (IMWG) criteria.
• Participant has received at least two previous therapies including lenalidomide and a proteasome inhibitor and has demonstrated disease progression on last therapy or after completion of the last therapy.
• Participants with measurable disease defined as at least one of the following:
• Serum M protein ≥ 0.5 g/dL (≥5 g/L).
• Urine M protein ≥ 200 mg/24 hours.
• Serum free light chain (FLC) assay: Involved FLC assay ≥ 10 mg/dL (≥ 100 mg/L) and an abnormal serum FLC ratio (<0.26 or >1.65).
• Male or female: Contraceptive use by men or women

Exclusion criteria:

• Malignancy within 3 years prior to enrollment.
• Eastern Cooperative Oncology Group (ECOG) performance status score >2.
• Inadequate hematological, liver or renal function.
• Serum calcium (corrected for albumin) level above the upper limit of normal (ULN) range.

• Patients with prior anti-CD38 treatment are excluded if:

  • Refractory to anti-CD38 treatment defined as progression on or within 60 days of the last dose of the anti-CD38 or,
  • Intolerant to the anti-CD38 previously received or,
  • Progression after initial response on anti-CD38 therapy with a washout period inferior to 9 months before the first dose of isatuximab SC or IV.
• Participant did not achieve a minimal response or better to at least one of the previous lines of treatment (ie, primary refractory disease is not eligible).
• Received any investigational drug within 14 days or 5 half-lives of the investigational drug, whichever is longer.
• Prior anti-cancer therapy within 14 days.
• Any >Grade 1 adverse reaction unresolved from previous treatments according to the NCI-CTCAE v5.0. The presence of alopecia or peripheral neuropathy ≤ Grade 2 without pain is allowed.
• Previous allogeneic stem cell transplantation with active Graft Versus Host Disease or being under immunosuppressive therapy in the last 2 months previously to the inclusion in the trial.
• Daily requirement for corticosteroids.
• Known to be HIV+ or to have hepatitis A or uncontrolled or active hepatitis B virus (HBV) infection (patients with positive HBsAg [HBsAg] and/or HBV DNA) or active HCV (HCV) infection (positive HCV RNA and negative anti-HCV).
• Active tuberculosis and severe infections requiring treatment with antibiotic parenteral administration.
• Any clinically significant, uncontrolled medical conditions that, in the Investigator's opinion, would expose excessive risk to the patient or may interfere with compliance or interpretation of the study results.
• History of erythema multiforme or severe hypersensitivity to prior immunomodulatory drugs (IMiDs).
• Hypersensitivity or history of intolerance to immunomodulatory drugs (IMiDs), dexamethasone, mannitol, pregelatinized starch, sodium stearyl fumarate, histidine (as base and hydrochloride salt), arginine hydrochloride, poloxamer 188, sucrose or any of the other components of study therapy that are not amenable to premedication with steroids and histamine H2 blockers or would prohibit further treatment with these agents.
• Inability to tolerate thromboprophylaxis.

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Australia, Belgium, France, Japan, Spain, United States

Administrative Information

• NCT Number: NCT04045795
• Other Study ID Numbers: TCD15484; 2018-001996-19 ( EudraCT Number ); U1111-1211-9525 ( Registry Identifier: ICTRP )
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: Yes
• Product Manufactured in and Exported from the U.S.: Yes

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

• Current Responsible Party: Sanofi
• Original Responsible Party: Same as current
• Current Study Sponsor: Sanofi
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Clinical Sciences & Operations; Sanofi

• PRS Account: Sanofi
• Verification Date: May 2022