| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Plasma cell myeloma refractory |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 22.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10081847 |
| E.1.2 | Term | Plasma cell myeloma refractory |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
- Part 1 (dose finding, experimental substudies):
• To determine or confirm the recommended dose of novel agents when combined with isatuximab with or without dexamethasone in participants with RRMM.
- Part 2 (expansion, controlled experimental substudies):
• To demonstrate the clinical benefit of novel agents combined with isatuximab with or without dexamethasone in terms of rate of very good partial response (VGPR) or better SS02 and SS03, and in terms of overall response rate (ORR) for SS04.
• Part 2 (expansion, independent experimental substudies):
-To demonstrate the clinical benefit of novel agents combined with
isatuximab with or without dexamethasone in terms of overall response
rate (ORR). |
|
| E.2.2 | Secondary objectives of the trial |
-Master Protocol and Substudy 1-ACT16482-01 (Control Arm):
Assess the overall response rate (ORR) in each treatment arm
-ORR in Part 1 and Part 2
- VGPR in Part 1 and Part 2
Assess the clinical benefit rate (CBR) in each treatment arm
Assess the duration of response (DOR) in each treatment arm
Assess the time to first response (TT1R) in each treatment arm
Assess the time to best response (TTBR) in each treatment arm
Assess safety and tolerability in each treatment arm
Assess progression free survival (PFS) in each treatment arm
Assess overall survival (OS) in each treatment arm
Evaluate the potential immunogenicity of isatuximab and novel agents
when applicable
Characterize the PK of isatuximab and novel agents
Assess disease and treatment related symptoms, cancer and disease
specific health-related quality of life, global impact of side effects and
confirm/establish clinically meaningful change scores for clinical
outcome assessments (COAs)/domain scores |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Sub-study 01 (SAR650984-ACT16482-01 protocol, version 1 dated 02-April-2021) :
- Full 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) - control arm
- Objectives:
The purpose of this substudy is to collect additional information on the efficacy and safety on the combination of isatuximab + dexamethasone + pomalidomide, which is the approved standard of care, in patients who have not been previously exposed to antibodies such as isatuximab or daratumumab.
Sub-study 03 (Terminated) (SAR650984-ACT16482-03 protocol, version 1 dated 02-April-2021) :
- Full Title: Phase 1-2 trial evaluating belantamab-mafodotin in combination with isatuximab and dexamethasone in relapsed or refractory multiple myeloma (RRMM)
- Objectives:
Part 1: Dose finding
The purpose of this part is to determine the dose and feasibility of belantamab-mafodotin when combined with isatuximab and dexamethasone in participants with relapsed or refractory multiple myeloma (RRMM).
Part 2: Dose expansion
The purpose of this part is to find out if belantamab-mafodotin combined with isatuximab and dexamethasone will have a significant activity in your disease. This will also allow to identify side effects associated with the use of the drugs taken in combination
Sub-study 04 (SAR650984-ACT16482-04 protocol, version 1 dated 14-Dec-2022) :
- Full title: Phase 1/2 trial evaluating isatuximab in combination with SAR444245 (THOR-707) in relapsed or refractory multiple myeloma (RRMM) previously exposed to anti-CD38 and anti-BCMA
- Objectives:
To explore modulation of immune cells and impact on
tumor response. To explore cytokines expression as safety biomarker. To assess plasma daratumumab concentration before the first isatuximab treatment in participants previously treated with daratumumab (≤6 months). |
|
| E.3 | Principal 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 6 months after the last dose.
"Exposure" is defined as at least 2 cycles of therapy.
- Substudy 02 (Terminated), 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. |
|
| E.4 | Principal exclusion criteria |
Medical conditions:
- 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.
Prior concomitant therapy:
- Any anti-MM drug treatment within 14 days before randomization, 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.
Criteria diagnostic assessment:
- Hemoglobin <8 g/dL
- Platelets <50 × 109/L
- Absolute neutrophil count <1.5 × 109/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
-> For the first 10 participants: Body weight ≤70 kg
- Substudy 03 (Terminated):
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 < 9g/dL
- Prior therapy with any anti-CD47 or anti signal regulatory protein alpha agent |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
1. Part 1 (dose finding, experimental substudies): Determination of recommended dose of novel agents in combination with isatiximab
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
2. Part 2 (expansion, controlled experimental substudies): VGPR Rate (Rate of Very Good Partial Response Rate or Better) in experimental substudies
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
3. Part 2 (expansion, independent experimental substudies): Overall Response Rate (ORR) in experimental substudies: 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. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
1. Through the end of cycle 1 (approximately 6 weeks)
2. Up to approximately 28 months after the First patient in or scheduled assessment
3. Up to approximately 28 months after the First patient in or scheduled
assessment
|
|
| E.5.2 | Secondary end point(s) |
1. Part 1: ORR and VGPR or better according to the 2016 IMWG criteria assessed by Investigator based on central laboratory values and local imaging.
2. Part 2:ORR defined as the proportion of participants with stringent complete response, complete response, VGPR, or partial response,
according to the 2016 IMWG criteria assessed by Investigator based on central laboratory values and local imaging.
3. Part 1: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.
5. CBR: CBR, defined as the proportion of participants with sCR, CR, VGPR, PR, or MR, according to the 2016 IMWG criteria assessed by Investigator based on central laboratory values and local imaging.
6. DOR in each treatment arm: 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.
7. Time to First Response in each treatment arm: TT1R, defined as the time from the date of first treatment to the date of first response (PR or better) that is subsequently confirmed.
8. Time to Best Response in each treatment arm: 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
9. Number of participants with treatment emergent AEs and SAEs in each treatment arm: Safety and tolerability assessed in terms of AEs/SAEs, including second primary malignancies, laboratory parameters, vital signs, and findings from physical examination
10. Progression-free survivalin each treatment arm: 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
11. OS: OS is defined as the time from the date of first treatment to death from any cause
12. Immunogenicity of isatuximab and novel agents: Incidence of antidrug antibodies (ADAs) for novel agents (experimental arms) and isatuximab
13. PK Parameters for Novel agents and isatuximab: Concentration of novel agents (experimental arms) and isatuximab
14. Disease-specific HRQL will be assessed using the European Organization for Research and Treatment of Cancer (EORTC) core quality of life questionnaire (QLQ-C30): The EORTC QLQ-C30 will be used to assess cancer specific HRQL, disease and treatment related symptoms and impact of symptoms
15. Disease- and treatment-related quality of life will be assessed using the EORTC multiple myeloma module (QLQ-MY20) questionnaire: The EORTC QLQ MY20 will be used to measure myeloma-specific HRQL, disease and treatment related symptoms and impact of symptoms
16. Global impact of side effects will be assessed using the Functional
Assessment of Cancer Therapy (FACT-G) (GP5): A single item from the FACT-G GP5 will be used to assess the global impact of side effects
17. 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: 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
18. 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 (Substudy02): 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
19. SRE Incidence for control and experimental arms (Substudy02): 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.
20. Time to First Occurrence of SRE Assessment for control and experimental arms (Substudy02): TTFO of SRE is defined as time from the date of randomization to the occurrence of first SRE.
21. Assessment of Health care resource utilization related with SREs for control and experimental arms (Substudy02): The Health Care Resource
Use-SREs questionnaire (HCRU-SREs) will be used to assess the use of health care resources associated with these events.
22. To assess patient-reported visual functioning for experimental arm only (Substudy03): An NEI VFQ-25 will be used to assess patient reported visual functioning |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1.,2., 3., 4., 5., 6., 7., 8, 9., 10., 11.: Up to approximately 28 months after
the First patient in or scheduled assessment
12., 13.: Multiple timepoints up to approximately 28 months after the
First patient in or scheduled assessment
14., 15., 16., 17., 18., 21: 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.
19., 20.: Continuous throughout study assessment (up to approximately
28 months)
22:. On Day1 Cycle 1, End of treatment and at first follow-up visit. The
cycle is 28 days. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | Yes |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
|
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
|
| E.8.2.4 | Number of treatment arms in the trial | 6 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 30 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Australia |
| United Kingdom |
| United States |
| France |
| Germany |
| Greece |
| Italy |
| Norway |
| Portugal |
|
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 7 |
| E.8.9.1 | In the Member State concerned days | 12 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 4 |
Print
