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

Study Overview
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Brief Summary
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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
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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.

Official Title
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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)

Conditions
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Multiple Myeloma

Intervention / Treatment
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* Drug: isatuximab SAR650984 IV
* Drug: pomalidomide
* Drug: dexamethasone
* Drug: isatuximab SAR650984 SC
* Device: Investigational injector device


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dose regimen 1<br>Isatuximab SC administration dose level 1 once weekly for 4 weeks (Cycle 1) and on Day 1 and Day 15 of each subsequent cycle | Drug: pomalidomide<br>* Pharmaceutical form: tablet Route of administration: oral<br>* Other names: Pomalyst®;Drug: dexamethasone<br>* Pharmaceutical form: tablet Route of administration: oral<br>* Other names: Decadron®;Drug: isatuximab SAR650984 SC<br>* Pharmaceutical form: solution Route of administration: subcutaneous<br>|
| Experimental: Dose regimen 2<br>Isatuximab SC administration dose level 2 once weekly for 4 weeks (Cycle 1) and on Day 1 and Day 15 of each subsequent cycle | Drug: pomalidomide<br>* Pharmaceutical form: tablet Route of administration: oral<br>* Other names: Pomalyst®;Drug: dexamethasone<br>* Pharmaceutical form: tablet Route of administration: oral<br>* Other names: Decadron®;Drug: isatuximab SAR650984 SC<br>* Pharmaceutical form: solution Route of administration: subcutaneous<br>|
| Experimental: Dose regimen 3<br>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 | Drug: pomalidomide<br>* Pharmaceutical form: tablet Route of administration: oral<br>* Other names: Pomalyst®;Drug: dexamethasone<br>* Pharmaceutical form: tablet Route of administration: oral<br>* Other names: Decadron®;Drug: isatuximab SAR650984 SC<br>* Pharmaceutical form: solution Route of administration: subcutaneous<br>Device: Investigational injector device<br>* Subcutaneous administration<br>|
| Experimental: Dose regimen 4<br>Isatuximab IV administration once weekly for 4 weeks (Cycle 1) and on Day 1 and Day 15 of each subsequent cycle | Drug: isatuximab SAR650984 IV<br>* Pharmaceutical form: solution Route of administration: intravenous<br>* Other names: Sarclisa;Drug: pomalidomide<br>* Pharmaceutical form: tablet Route of administration: oral<br>* Other names: Pomalyst®;Drug: dexamethasone<br>* Pharmaceutical form: tablet Route of administration: oral<br>* Other names: Decadron®;|
| Experimental: Dose regimen 5<br>Isatuximab IV administration once weekly for 4 weeks (Cycle 1) and on Day 1 and Day 15 of each subsequent cycle | Drug: isatuximab SAR650984 IV<br>* Pharmaceutical form: solution Route of administration: intravenous<br>* Other names: Sarclisa;Drug: pomalidomide<br>* Pharmaceutical form: tablet Route of administration: oral<br>* Other names: Pomalyst®;Drug: dexamethasone<br>* Pharmaceutical form: tablet Route of administration: oral<br>* Other names: Decadron®;|

What is the study measuring?
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Primary Outcome Measures

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

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Estimation of absolute bioavailability of isatuximab | Absolute bioavailability of isatuximab SC, expressed as a percentage, estimated from AUC0-168h obtained after intravenous (IV) and extravascular (EV) administration | Day 8 | 
| Overall response rate (ORR) | 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 | From day -21 to day 60 after last study treatment (up to approximately 14 months after first study treatment administration) | 
| Duration of response (DOR) | Time from the date of the first response to the date of first progressive disease (PD) or death, whichever happens first | From day -21 to day 60 after last study treatment (up to approximately 14 months after first study treatment administration) | 
| Time to response (TTR) | Time from the date of first study treatment to the first response | From day -21 to day 60 after last study treatment (up to approximately 14 months after first study treatment administration) | 
| Time to progression (TTP) | Time from date of first study treatment to date of first documentation of progressive disease | From day -21 to day 60 after last study treatment (up to approximately 14 months after first study treatment administration) | 
| Overall survival (OS) | Time from the date of first study treatment to date of death from any cause | From day -21 to day 60 after last study treatment (up to approximately 14 months after first study treatment administration) | 
| Clinical benefit rate (CBR) | Proportion of patients with sCR, CR, VGPR, PR or minimal response (MR) according to IMWG criteria | From day -21 to day 60 after last study treatment (up to approximately 14 months after first study treatment administration) | 
| Progression free survival (PFS) | Time from date of first study treatment to date of first documentation of progressive disease or death | From day -21 to day 60 after last study treatment (up to approximately 14 months after first study treatment administration) | 
| Comparison of patient expectations and satisfaction: Patient Expectations and Satisfaction Questionnaires | 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 | 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) | 
| Immunogenicity: Anti drug antibody levels | Incidence of patients with anti drug antibodies against isatuximab | Baseline to EOT after isatuximab SC and to Cycle 10 after IV (28 days per Cycle) | 
| Biomarker: Change in CD38 receptor occupancy | Change in CD38 receptor occupancy from baseline | 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. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Anti-CD38 monoclonal antibody