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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/study/NCT04643002




Registration number
NCT04643002
Ethics application status
Date submitted
20/10/2020
Date registered
24/11/2020

Titles & IDs
Public title
Isatuximab in Combination With Novel Agents in RRMM - Master Protocol
Scientific 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
Secondary ID [1] 0 0
U1111-1244-2598
Secondary ID [2] 0 0
ACT16482
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Plasma Cell Myeloma Refractory 0 0
Condition category
Condition code
Cancer 0 0 0 0
Other cancer types

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - Isatuximab
Treatment: Drugs - Dexamethasone
Treatment: Drugs - Pomalidomide
Treatment: Drugs - Belantamab mafodotin
Treatment: Drugs - Pegenzileukin
Treatment: Drugs - SAR439459
Treatment: Drugs - Belumosudil
Treatment: Drugs - Evorpacept

Active comparator: Control Arm: isatuximab + pomalidomide + dexamethasone (Substudy 01) - * Isatuximab, intravenous (IV) doseweekly (QW) × 4 weeks (Cycle 1), followed by every two weeks (Q2W) (subsequent cycles).
* Pomalidomide dose by mouth daily Day 1 to Day 21.
* Dexamethasone dose by mouth QW.

Experimental: isatuximab + SAR439459 + dexamethasone (Substudy 02) - SAR439459 in combination with isatuximab and dexamethasone

Part 1:

2 dose levels (DLs) of IV SAR439459:

* DL1 SAR439459 dose Q2W.
* DL2 SAR439459 dose Q2W.
* Isatuximab dose IV QW × 5 weeks (Cycle 1), followed by Q2W administrations (subsequent cycles).
* Dexamethasone fixed dose and schedule: QW by mouth In Cycle 1, the first administration of SAR439459 (Day 1) will precede isatuximab by 1 week (first dose of isatuximab will be at Cycle 1 Day 8).

Part 2:

* SAR439459 IV dose Q2W.
* Isatuximab IV dose QW × 5 weeks (Cycle 1), followed by Q2W administrations (subsequent cycles).
* Dexamethasone fixed dose and schedule: QW by mouth. In Cycle 1, the first administration of SAR439459 (Day 1) will precede isatuximab by 1 week (first dose of isatuximab will be at Cycle 1 Day 8).

Experimental: isatuximab + dexamethasone + belantamab mafodotin (Substudy 03) - Belantamab mafodotin in combination with isatuximab and dexamethasone

Part 1:

1 DL of IV belantamab mafodotin in Part 1 and de-escalation dose DL-1:

* DL1 belantamab mafodotin IV dose QW4 or de-escalation dose DL-1 QW8
* Isatuximab dose, IV QW × 4 weeks (Cycle 1), followed by Q2W (subsequent cycles).
* Dexamethasone fixed dose and schedule: QW by mouth.

Part 2:

* Isatuximab IV dose QW × 4 weeks (Cycle 1), followed by Q2W (subsequent cycles).
* Belantamab mafodotin IV dose Q4W or Q8W
* Dexamethasone fixed dose and schedule: QW by mouth.

Experimental: Isatuximab + pegenzileukin (Substudy 04) - Pegenzileukin in combination with isatuximab

Part 1- dose escalation:

* Up to 3 DLs of IV pegenzileukin are planned to be evaluated:

* DL1 will explore pegenzileukin at Q2W.
* DL2 will explore pegenzileukin at Q2W.
* DL3 will explore pegenzileukin at Q2W.
* Isatuximab IV dose QW × 4 weeks, followed by Q2W (subsequent cycles).

Part 1 - dose optimization:

* Isatuximab IV doseQW × 4 weeks, followed by Q2W (subsequent cycles).
* Pegenzileukin at potential doses (DL A and DL B) Q2W.

Part 2 (dose expansion):

* Isatuximab IV dose QW × 4 weeks, followed by Q2W (subsequent cycles).
* Pegenzileukin IV dose Q2W.

Experimental: Experimental: Isatuximab + Dexamethasone + Belumosudil (Substudy 05) - Isatuximab in combination with belumosudil and dexamethasone Part 1- dose escalation: During the first cycle, belumosudil will be evaluated in monotherapy during 2 to 4 weeks, then isatuximab and dexamethasone will be added, and continued for the subsequent cycles.

* Belumosudil by mouth at Dose Level (DL) 1, DL2, DL3, and DL4
* Isatuximab IV dose QW × 4 weeks, followed by Q2W (subsequent cycles)
* Dexamethasone fixed dose and schedule: QW by mouth

Part 1- dose optimization:

* Belumosudil at potential doses (DL A and DL B), daily by mouth
* Isatuximab IV dose QW × 4 weeks, followed by Q2W (subsequent cycles)
* Dexamethasone fixed dose and schedule: QW by mouth

Part 2- dose expansion:

* Belumosudil dose daily, by mouth
* Isatuximab IV dose QW × 4 weeks, followed by Q2W (subsequent cycles)
* Dexamethasone fixed dose and schedule: QW by mouth

Experimental: Isatuximab + evorpacept + dexamethasone (Substudy 06) - Isatuximab in combination with evorpacept and dexamethasone

Part 1- dose escalation:

* Evorpacept IV dose Q2W
* Isatuximab IV dose QW × 4 weeks, followed by Q2W (subsequent cycles)
* Dexamethasone fixed dose and schedule: QW by mouth Part 1- dose optimization
* Evorpacept IV at potential doses (DL A and DL B), Q2W
* Isatuximab IV dose QW × 4 weeks, followed by Q2W (subsequent cycles)
* Dexamethasone fixed dose and schedule: QW by mouth

Part 2- dose expansion:

* Evorpacept IV dose Q2W
* Isatuximab IV dose QW × 4 weeks, followed by Q2W (subsequent cycles)
* Dexamethasone fixed dose and schedule: QW by mouth


Treatment: Drugs: Isatuximab
Pharmaceutical form: Solution for infusion; Route of administration: Intravenous

Treatment: Drugs: Dexamethasone
Pharmaceutical form: Tablet; Route of administration: Oral

Treatment: Drugs: Pomalidomide
Pharmaceutical form: Capsule; Route of administration: Oral

Treatment: Drugs: Belantamab mafodotin
Pharmaceutical form: Solution for infusion; Route of administration: Intravenous

Treatment: Drugs: Pegenzileukin
Pharmaceutical form: Solution for infusion; Route of administration: Intravenous

Treatment: Drugs: SAR439459
Pharmaceutical form: Solution for injection; Route of administration: Intravenous

Treatment: Drugs: Belumosudil
Pharmaceutical form: tablet; route of administration: oral

Treatment: Drugs: Evorpacept
Pharmaceutical form: Solution for infusion; Route of administration: Intravenous
Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Part 1 (dose finding, experimental substudies): Determination of recommended dose of novel agents in combination with isatuximab
Timepoint [1] 0 0
Through the end of cycle 1 (approximately 6 weeks)
Primary outcome [2] 0 0
Part 2 (expansion, controlled experimental substudies): VGPR Rate (Rate of Very Good Partial Response Rate or Better)
Timepoint [2] 0 0
Up to approximately 28 months after the First patient in or scheduled assessment
Primary outcome [3] 0 0
Part 2 (expansion, independent experimental substudies): Overall Response Rate (ORR) in independent experimental substudies
Timepoint [3] 0 0
Up to approximately 28 months after the First patient in or scheduled assessment
Secondary outcome [1] 0 0
Part 1 (dose finding, experimental substudies): ORR
Timepoint [1] 0 0
Up to approximately 28 months after the First patient in or scheduled assessment
Secondary outcome [2] 0 0
Part 2 (expansion, controlled experimental substudies): ORR
Timepoint [2] 0 0
Up to approximately 28 months after the First patient in or scheduled assessment
Secondary outcome [3] 0 0
Part 1 (dose finding, experimental substudies): VGPR or better
Timepoint [3] 0 0
Up to approximately 28 months after the First patient in or scheduled assessment
Secondary outcome [4] 0 0
Part 2 (expansion, independent experimental substudies): VGPR or better
Timepoint [4] 0 0
Up to approximately 28 months after the First patient in or scheduled assessment
Secondary outcome [5] 0 0
Clinical benefit rate (CBR) in each treatment arm
Timepoint [5] 0 0
Up to approximately 28 months after the First patient in or scheduled assessment
Secondary outcome [6] 0 0
Duration of Response (DOR) in each treatment arm
Timepoint [6] 0 0
Up to approximately 28 months after the First patient in or scheduled assessment
Secondary outcome [7] 0 0
Time to First Response (TT1R) in each treatment arm
Timepoint [7] 0 0
Up to approximately 28 months after the First patient in or scheduled assessment
Secondary outcome [8] 0 0
Time to Best Response (TTBR) in each treatment arm
Timepoint [8] 0 0
Up to approximately 28 months after the First patient in or scheduled assessment
Secondary outcome [9] 0 0
Number of participants with treatment emergent adverse events and serious adverse events in each treatment arm
Timepoint [9] 0 0
Up to approximately 28 months after the First patient in or scheduled assessment
Secondary outcome [10] 0 0
Progression-free survival (PFS) in each treatment arm
Timepoint [10] 0 0
Up to approximately 28 months after the First patient in or scheduled assessment
Secondary outcome [11] 0 0
Overall Survival (OS) in each treatment arm
Timepoint [11] 0 0
Up to approximately 28 months after the First patient in or scheduled assessment
Secondary outcome [12] 0 0
Immunogenicity of isatuximab and novel agents
Timepoint [12] 0 0
Multiple timepoints up to approximately 28 months after the First patient in or scheduled assessment
Secondary outcome [13] 0 0
Pharmacokinetics (PK) Parameters for Novel agents and isatuximab
Timepoint [13] 0 0
Multiple timepoints up to approximately 28 months after the First patient in or scheduled assessment
Secondary outcome [14] 0 0
Disease-specific HRQL will be assessed using the European Organization for Research and Treatment of Cancer (EORTC) core quality of life questionnaire (QLQ-C30)
Timepoint [14] 0 0
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.
Secondary outcome [15] 0 0
Disease- and treatment-related quality of life will be assessed using the EORTC multiple myeloma module (QLQ-MY20) questionnaire
Timepoint [15] 0 0
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.
Secondary outcome [16] 0 0
Global impact of side effects will be assessed using the Functional Assessment of Cancer Therapy (FACT-G) (GP5)
Timepoint [16] 0 0
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.
Secondary outcome [17] 0 0
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
Timepoint [17] 0 0
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.
Secondary outcome [18] 0 0
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)
Timepoint [18] 0 0
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.
Secondary outcome [19] 0 0
SRE Incidence for control and experimental arms (Substudy 02)
Timepoint [19] 0 0
Continuous throughout study assessment (up to approximately 28 months)
Secondary outcome [20] 0 0
Time to First Occurrence of SRE Assessment for control and experimental arms (Substudy 02)
Timepoint [20] 0 0
Continuous throughout study assessment (up to approximately 28 months)
Secondary outcome [21] 0 0
Assessment of Health care resource utilization related with SREs for control and experimental arms (Substudy 02)
Timepoint [21] 0 0
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.
Secondary outcome [22] 0 0
To assess patient-reported visual functioning for experimental arm only (Substudy 03)
Timepoint [22] 0 0
On Day1 Cycle 1, End of treatment and at first follow-up visit. The cycle is 28 days.

Eligibility
Key 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.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key 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.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 1
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Recruiting
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
25/01/2021
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
31/03/2028
Actual
Sample size
Target
258
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW,VIC
Recruitment hospital [1] 0 0
Investigational Site Number : 0360006 - Wollongong
Recruitment hospital [2] 0 0
Investigational Site Number : 0360002 - Fitzroy
Recruitment hospital [3] 0 0
Investigational Site Number : 0360001 - Richmond
Recruitment postcode(s) [1] 0 0
2500 - Wollongong
Recruitment postcode(s) [2] 0 0
3065 - Fitzroy
Recruitment postcode(s) [3] 0 0
3121 - Richmond
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
Illinois
Country [2] 0 0
United States of America
State/province [2] 0 0
Michigan
Country [3] 0 0
United States of America
State/province [3] 0 0
New York
Country [4] 0 0
France
State/province [4] 0 0
Lille
Country [5] 0 0
France
State/province [5] 0 0
Nantes
Country [6] 0 0
France
State/province [6] 0 0
Paris
Country [7] 0 0
Germany
State/province [7] 0 0
Frankfurt am Main
Country [8] 0 0
Greece
State/province [8] 0 0
Athens
Country [9] 0 0
Israel
State/province [9] 0 0
Jerusalem
Country [10] 0 0
Israel
State/province [10] 0 0
Tel HaShomer
Country [11] 0 0
Italy
State/province [11] 0 0
Forlì-Cesena
Country [12] 0 0
Italy
State/province [12] 0 0
Bologna
Country [13] 0 0
Norway
State/province [13] 0 0
Oslo
Country [14] 0 0
Portugal
State/province [14] 0 0
Coimbra
Country [15] 0 0
Portugal
State/province [15] 0 0
Vila Nova Gaia
Country [16] 0 0
Puerto Rico
State/province [16] 0 0
Hato Rey

Funding & Sponsors
Primary sponsor type
Commercial sector/industry
Name
Sanofi
Address
Country

Ethics approval
Ethics application status

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Clinical Sciences & Operations
Address 0 0
Sanofi
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Trial Transparency email recommended (Toll free number for US & Canada)
Address 0 0
Country 0 0
Phone 0 0
800-633-1610
Fax 0 0
Email 0 0
Contact-US@sanofi.com
Contact person for scientific queries

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
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
When will data be available (start and end dates)?
Available to whom?
Available for what types of analyses?
How or where can data be obtained?


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

No documents have been uploaded by study researchers.


Results not provided in https://clinicaltrials.gov/study/NCT04643002