Clinical trial NCT04643002: Isatuximab in Combination With Novel Agents in RRMM - Master Protocol
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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
PHASE2
Conditions: Plasma Cell Myeloma Refractory
Keywords: anti-CD38 monoclonal antibody
master protocol
combination therapy
CD38 resistance
interleukin 2
ROCK2 inhibitor
anti-CD47 agent
Lead sponsor: Sanofi
Sponsor class: INDUSTRY
First posted: 2020-11-24
Enrollment: 258
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility 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 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.

Primary outcomes:
measure: Part 1 (dose finding, experimental substudies): Determination of recommended dose of novel agents in combination with isatuximab
timeFrame: Through the end of cycle 1 (approximately 6 weeks)
measure: Part 2 (expansion, controlled experimental substudies): VGPR Rate (Rate of Very Good Partial Response Rate or Better)
timeFrame: Up to approximately 28 months after the First patient in or scheduled assessment
measure: Part 2 (expansion, independent experimental substudies): Overall Response Rate (ORR) in independent experimental substudies
timeFrame: Up to approximately 28 months after the First patient in or scheduled assessment
Secondary outcomes:
measure: Part 1 (dose finding, experimental substudies): ORR
timeFrame: Up to approximately 28 months after the First patient in or scheduled assessment
measure: Part 2 (expansion, controlled experimental substudies): ORR
timeFrame: Up to approximately 28 months after the First patient in or scheduled assessment
measure: Part 1 (dose finding, experimental substudies): VGPR or better
timeFrame: Up to approximately 28 months after the First patient in or scheduled assessment
measure: Part 2 (expansion, independent experimental substudies): VGPR or better
timeFrame: Up to approximately 28 months after the First patient in or scheduled assessment
measure: Clinical benefit rate (CBR) in each treatment arm
timeFrame: Up to approximately 28 months after the First patient in or scheduled assessment
measure: Duration of Response (DOR) in each treatment arm
timeFrame: Up to approximately 28 months after the First patient in or scheduled assessment
measure: Time to First Response (TT1R) in each treatment arm
timeFrame: Up to approximately 28 months after the First patient in or scheduled assessment
measure: Time to Best Response (TTBR) in each treatment arm
timeFrame: Up to approximately 28 months after the First patient in or scheduled assessment
measure: Number of participants with treatment emergent adverse events and serious adverse events in each treatment arm
timeFrame: Up to approximately 28 months after the First patient in or scheduled assessment
measure: Progression-free survival (PFS) in each treatment arm
timeFrame: Up to approximately 28 months after the First patient in or scheduled assessment
measure: Overall Survival (OS) in each treatment arm
timeFrame: Up to approximately 28 months after the First patient in or scheduled assessment
measure: Immunogenicity of isatuximab and novel agents
timeFrame: Multiple timepoints up to approximately 28 months after the First patient in or scheduled assessment
measure: Concentration of novel agents (experimental arms) and isatuximab (Ctrough)
timeFrame: Multiple timepoints during Cycle 1. The cycle is 28 days.
measure: Disease-specific HRQL will be assessed using the European Organization for Research and Treatment of Cancer (EORTC) core quality of life questionnaire (QLQ-C30)
timeFrame: 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.
measure: Disease- and treatment-related quality of life will be assessed using the EORTC multiple myeloma module (QLQ-MY20) questionnaire
timeFrame: 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.
measure: Global impact of side effects will be assessed using the Functional Assessment of Cancer Therapy (FACT-G) (GP5)
timeFrame: 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.
measure: 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
timeFrame: 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.
measure: 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
timeFrame: 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.
measure: SRE Incidence for control and experimental arms- Substudy 02
timeFrame: Continuous throughout study assessment (up to approximately 28 months)
measure: Time to First Occurrence of SRE Assessment for control and experimental arms (Substudy 02)
timeFrame: Continuous throughout study assessment (up to approximately 28 months)
measure: Assessment of Health care resource utilization related with SREs for control and experimental arms -Substudy 02
timeFrame: 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.
measure: To assess patient-reported visual functioning for experimental arm only -Substudy 03
timeFrame: On Day1 Cycle 1, End of treatment and at first follow-up visit. The cycle is 28 days.
measure: Maximum concentration observed after the first infusion (Cmax) for Belumosudil - Substudy 05
timeFrame: Multiple timepoints during Cycle 1. The cycle is 28 days.
measure: Time to reach Cmax (tmax) for Belumosudil - Substudy 05
timeFrame: Multiple timepoints during Cycle 1. The cycle is 28 days.
measure: Area under the concentration versus time curve calculated using the trapezoidal method from 0 to 8h (AUC0-8h) for Belumosudil - Substudy 05
timeFrame: Multiple timepoints during Cycle 1. The cycle is 28 days.
measure: Maximum concentration observed after the first infusion (Cmax) for Evorpacept - Substudy 06
timeFrame: Multiple timepoints during Cycle 1. The cycle is 28 days.
measure: Time to reach Cmax (tmax) for Evorpacept - Substudy 06
timeFrame: Multiple timepoints during Cycle 1. The cycle is 28 days.
measure: Area under the concentration versus time curve calculated using the trapezoidal method over the dosing interval for evorpacept (AUC0-t)- Substudy 06
timeFrame: Multiple timepoints during Cycle 1. The cycle is 28 days.
Other outcomes:
Locations:
city: Ann Arbor
country: United States
facility: University of Michigan Health System - Ann Arbor- Site Number : 8400004
state: Michigan
city: Buffalo
country: United States
facility: Roswell Park Cancer Institute- Site Number : 8400008
state: New York
city: Wollongong
country: Australia
facility: Investigational Site Number : 0360006
state: New South Wales
city: Melbourne
country: Australia
facility: Investigational Site Number : 0360002
state: Victoria
city: Richmond
country: Australia
facility: Investigational Site Number : 0360001
state: Victoria
city: Lille
country: France
facility: Investigational Site Number : 2500002
city: Nantes
country: France
facility: Investigational Site Number : 2500001
city: Paris
country: France
facility: Investigational Site Number : 2500004
city: Paris
country: France
facility: Investigational Site Number : 2500003
city: Frankfurt
country: Germany
facility: Investigational Site Number : 2760006
city: Lübeck
country: Germany
facility: Investigational Site Number : 2760008
city: Athens
country: Greece
facility: Investigational Site Number : 3000002
city: Athens
country: Greece
facility: Investigational Site Number : 3000001
city: Jerusalem
country: Israel
facility: Investigational Site Number : 3760002
city: Ramat Gan
country: Israel
facility: Investigational Site Number : 3760003
city: Tel Aviv
country: Israel
facility: Investigational Site Number : 3760001
city: Meldola
country: Italy
facility: Investigational Site Number : 3800001
state: Reggio Emilia
city: Seoul
country: Korea, Republic of
facility: Investigational Site Number : 4100004
state: Seoul-teukbyeolsi
city: Seoul
country: Korea, Republic of
facility: Investigational Site Number : 4100002
state: Seoul-teukbyeolsi
city: Seoul
country: Korea, Republic of
facility: Investigational Site Number : 4100003
state: Seoul-teukbyeolsi
city: Seoul
country: Korea, Republic of
facility: Investigational Site Number : 4100001
state: Seoul-teukbyeolsi
city: Oslo
country: Norway
facility: Investigational Site Number : 5780001
city: Coimbra
country: Portugal
facility: Investigational Site Number : 6200001
city: Porto
country: Portugal
facility: Investigational Site Number : 6200002
city: Hato Rey
country: Puerto Rico
facility: Puerto Rico Medical Research Center- Site Number : 8400005
Study officials:
affiliation: Sanofi
name: Clinical Sciences & Operations
role: STUDY_DIRECTOR
References: