Plasma Cell Myeloma Refractory
Conditions
Keywords
anti-CD38 monoclonal antibody, master protocol, combination therapy, CD38 resistance, interleukin 2, ROCK2 inhibitor, anti-CD47 agent
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. Substudy 01 is the control Substudy. Substudies 02, 03, and 06 are controlled experimental substudies. Substudies 04 and 05 are independent experimental substudies.
Detailed description
Participants will continue study treatment until disease progression, death, unacceptable toxicity, participant request to stop treatment, Investigator decision, or study termination by the Sponsor i.e., up to Aapproximately 28 months.
Interventions
DRUGIsatuximab
Pharmaceutical form: Concentrated solution for intravenous infusion; Route of administration: Intravenous infusion
DRUGDexamethasone
Pharmaceutical form: Tablet; Route of administration: Oral
DRUGPomalidomide
Pharmaceutical form: Capsule; Route of administration: Oral
DRUGBelantamab mafodotin
Pharmaceutical form: Solution for infusion; Route of administration: Intravenous
DRUGPegenzileukin
Pharmaceutical form: Solution for infusion; Route of administration: Intravenous
DRUGSAR439459
Pharmaceutical form: Solution for injection; Route of administration: Intravenous
DRUGBelumosudil
Pharmaceutical form: tablet; route of administration: oral
DRUGEvorpacept
Pharmaceutical form: Solution for infusion; Route of administration: Intravenous
Sponsors
Sanofi
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
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 2 prior lines of therapy for MM, including PIs and IMiDs (eg, Induction regimen with autologous stem cell transplant followed by maintenance is considered one line). * 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, 06: Anti-CD38 therapy naïve or prior exposure to such drugs with a wash out of at least 12 months after the last dose. "Exposure" is defined as at least 2 cycles of therapy. * Substudies 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. * Substudy 04: Anti-CD38 and anti-B cell maturation antigen (BCMA) therapy (if available) prior exposed participants with RRMM. For anti-CD38, "Exposure" is defined as at least 2 cycles of therapy. For anti-BCMA therapy if available, exposure is defined by at least 2 cycles of therapy. * Substudy 05: Participants with RRMM with at least 2 cycles of prior exposure to anti-CD38 therapy. For participants to whom BCMA targeted therapy is available (ie, approved in their region and can be reimbursed), at least 2 cycles of prior exposure to a BCMA targeted agent is mandatory.
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. * Seasonal flu and COVID-19 vaccines that do not contain live virus are permitted. * Hemoglobin \<8 g/dL. * Platelets \<50 × 10\^9/L. * Absolute neutrophil count \<1.0 × 10\^9/L. * Creatinine clearance \<30 mL/min/1.73m2. * 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. 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. 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. * Active, known, or suspected autoimmune disease that has required systemic treatment in the past 2 years (ie, with use of disease modifying agents, corticosteroids or immunosuppressive drugs), except controlled by replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc). The following are not exclusionary: vitiligo, childhood asthma that has resolved, psoriasis that does not require systemic treatment. * Prior allogeneic hematopoietic stem cell transplant (allo-HSCT). Substudy 05: \- Participant unable to swallow tablets. Substudy 06: * History of active autoimmune disorders. * History of autoimmune hemolytic anemia or autoimmune. thrombocytopenia. * Active graft versus host disease (GVHD) or ongoing immunosuppression for GVHD. * Prior allogenic hematopoietic stem cell transplant (allo-HSCT). * Patient with chronic active EBV infection. * Patients with known history of HLH. * Hemoglobin \< 9 g/dL. * Prior therapy with any anti-CD47 or anti signal regulatory protein alpha agent. The above information is not intended to contain all considerations relevant to a patient's potential participation in a clinical trial.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| Part 2 (expansion, controlled experimental substudies): VGPR Rate (Rate of Very Good Partial Response Rate or Better) | 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. |
| Part 2 (expansion, independent experimental substudies): Overall Response Rate (ORR) in independent experimental substudies | 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, or partial response (PR), according to the 2016 IMWG criteria assessed by Investigator based on central laboratory values and local imaging. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Part 1 (dose finding, experimental substudies): ORR | 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, or partial response (PR), according to the 2016 IMWG criteria assessed by Investigator based on central laboratory values and local imaging. |
| Part 2 (expansion, controlled experimental substudies): ORR | 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, or partial response (PR), according to the 2016 IMWG criteria assessed by Investigator based on central laboratory values and local imaging. |
| Part 1 (dose finding, experimental substudies): VGPR or better | 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. |
| Part 2 (expansion, independent experimental substudies): VGPR or better | 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. |
| 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 and local imaging. |
| 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. |
| 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 first treatment to the date of first response (PR or better) that is subsequently confirmed. |
| 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 first treatment to the date of first occurrence of best overall response (PR or better) that is subsequently confirmed. |
| Number of participants with treatment emergent adverse events and serious adverse events 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. |
| 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 first treatment to disease progression based on the Investigator assessment according to 2016 IMWG criteria or death from any cause, whichever happens first. |
| 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 first treatment to death from any cause. |
| Immunogenicity of isatuximab and novel agents | Multiple timepoints up to approximately 28 months after the First patient in or scheduled assessment | Incidence of anti-drug antibodies (ADAs) for novel agents (experimental arms) and isatuximab. |
| Concentration of novel agents (experimental arms) and isatuximab (Ctrough) | Multiple timepoints during Cycle 1. The cycle is 28 days. | — |
| 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. This endpoint will be assessed for Part 1 (dose optimization, independent and controlled experimental substudies) and Part 2 (expansion, independent and controlled experimental substudies). |
| 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. This endpoint will be assessed for Part 1 (dose optimization, independent and controlled experimental substudies) and Part 2 (expansion, independent and controlled experimental substudies). |
| 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. This endpoint will be assessed for Part 1 (dose optimization, independent and controlled experimental substudies) and Part 2 (expansion, independent and controlled experimental substudies). |
| 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. This endpoint will be assessed for Part 1 (dose optimization, independent and controlled experimental substudies) and Part 2 (expansion, independent and controlled experimental substudies). |
| 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 -Substudy 02 | 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 |
| SRE Incidence for control and experimental arms- Substudy 02 | 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. |
| Time to First Occurrence of SRE Assessment for control and experimental arms (Substudy 02) | 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. |
| Assessment of Health care resource utilization related with SREs for control and experimental arms -Substudy 02 | 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. |
| To assess patient-reported visual functioning for experimental arm only -Substudy 03 | 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. |
| Maximum concentration observed after the first infusion (Cmax) for Belumosudil - Substudy 05 | Multiple timepoints during Cycle 1. The cycle is 28 days. | — |
| Time to reach Cmax (tmax) for Belumosudil - Substudy 05 | Multiple timepoints during Cycle 1. The cycle is 28 days. | — |
| Area under the concentration versus time curve calculated using the trapezoidal method from 0 to 8h (AUC0-8h) for Belumosudil - Substudy 05 | Multiple timepoints during Cycle 1. The cycle is 28 days. | — |
| Maximum concentration observed after the first infusion (Cmax) for Evorpacept - Substudy 06 | Multiple timepoints during Cycle 1. The cycle is 28 days. | — |
| Time to reach Cmax (tmax) for Evorpacept - Substudy 06 | Multiple timepoints during Cycle 1. The cycle is 28 days. | — |
| Area under the concentration versus time curve calculated using the trapezoidal method over the dosing interval for evorpacept (AUC0-t)- Substudy 06 | Multiple timepoints during Cycle 1. The cycle is 28 days. | — |
Countries
Australia, France, Germany, Greece, Israel, Italy, Norway, Portugal, Puerto Rico, South Korea, United States
Contacts
CONTACTTrial Transparency email recommended (Toll free number for US & Canada)
STUDY_DIRECTORClinical Sciences & Operations
Sanofi
Outcome results
None listed