| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Multiple myeloma patients who received one prior line of therapy containing Lenalidomide and a Proteasome Inhibitor. |
|
| E.1.1.1 | Medical condition in easily understood language |
| Patients with multiple myeloma how have already received one line of therapy. |
|
| 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 | 21.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10028228 |
| E.1.2 | Term | Multiple myeloma |
| 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 |
| To evaluate the effect of isatuximab plus pomalidomide and low-dose dexamethasone on the 6-month overall response rate (ORR) in patients with multiple myeloma (MM) who are relapsing for the first time, having previously received one line of treatment that contained lenalidomide and a proteasome inhibitor. |
|
| E.2.2 | Secondary objectives of the trial |
To evaluate the effect of isatuximab in combination with pomalidomide and low-dose dexamethasone on:
1. Progression-Free Survival (PFS)
2. Overall Survival (OS)
3. Minimal Residual Disease (MRD) negativity rate
4. Time to Response (TTR)
5. Duration of Response (DoR)
6. Safety
Exploratory
To explore the effect of once-monthly isatuximab plus pomalidomide/low-dose dexamethasone on the PFS of patients who attained ≥ very good partial response (VGPR) after six cycles of treatment with isatuximab Q2W plus pomalidomide/low-dose dexamethasone. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Patient has signed an informed consent form (ICF) indicating that he or she understands the purpose of the procedures required for the study and is willing to participate in the study. Patients must be willing and able to adhere to the prohibitions and restrictions specified in this protocol, as referenced in the ICF.
2. Male or female patients aged 18 years or older at the time of the ICF signature.
3. Patients who have received ONLY one prior line of anti-myeloma therapy, which included lenalidomide (at least 2 cycles, either alone or in combination) and a proteasome inhibitor (e.g. bortezomib, carfilzomib, ixazomib). Patients must have achieved at least a response of MR or better based on the investigator’s determination of response as defined by the IMWG criteria.
Note 1:
An induction treatment followed by ASCT and consolidation/maintenance will be considered as one line of treatment.
Note 2: The number of prior lines will be defined according to the guidelines for
determination of the number of prior lines of therapy in multiple myeloma (Appendix
F).
4. Patients with a documented diagnosis of MM and with current evidence of measurable disease defined as:
-Serum monoclonal protein (M-protein) level ≥0.5 g/dL, measured using serum protein electrophoresis (SPEP) and/or
-Urine M-protein level ≥200 mg/24 hours, measured using urine protein electrophoresis (UPEP), or
-Serum immunoglobulin free light chain ≥10 mg/dL and abnormal serum immunoglobulin kappa lambda free light chain ratio.
5. Patients must have documented evidence of PD, based on the investigator’s determination of response as defined by the IMWG criteria, on or after the last line of treatment.
6. Adequate bone marrow and hepatic function as defined by ALL the laboratory criteria :
-Absolute Neutrophil Count (ANC) ≥1.0 x 109/L; GCSF administration is not allowed to reach this level
-Hemoglobin level ≥7.5 g/dL (≥4.65 mmol/L);
-Platelet count ≥75 x 109/L in patients in whom <50% of bone marrow nucleated cells are plasma cells OR Platelet count ≥50 x 109/L in patients in whom ≥50% of bone marrow nucleated cells are plasma cells; [transfusions are not permitted to reach this level]
-Alanine aminotransferase (ALT) level ≤2.5 x ULN
-Aspartate aminotransferase (AST) level ≤2.5 x ULN
-Total bilirubin level ≤1.5 x ULN (except for Gilbert Syndrome: direct bilirubin ≤1.5 x ULN)
-Creatinine clearance ≥30 mL/min; calculated using Cockcroft Gault
-Serum calcium corrected for albumin ≤14.0 mg/dL (≤3.5 mmol/L), or free ionized calcium ≤ 6.5 mg/dL (≤1.6 mmol/L)
7. Eastern Cooperative Oncology Group Performance Status (ECOG PS) ≤2 (see Appendix B).
8. For patients experiencing toxicities resulting from previous therapy, the toxicities must be resolved or stabilized to ≤ Grade 1. |
|
| E.4 | Principal exclusion criteria |
1. Previous therapy with any anti-CD38 monoclonal antibody within 12 months before C1D1.
2. Previous exposure to pomalidomide.
3. Patient has received anti-myeloma treatment within two weeks or five pharmacokinetic half-lives of the treatment, whichever is longer, before Cycle 1, Day 1. The only exception is emergency use of a short course of corticosteroids (the equivalent of dexamethasone 40 mg/day for a maximum of 4 days) for palliative treatment before C1D1.
4. Previous allogeneic stem cell transplant or autologous stem cell transplantation (ASCT) within 12 weeks before C1D1.
5. History of malignancy (other than MM) within three years before C1D1.
6. Clinical signs of meningeal involvement of MM.
7. Clinically significant cardiac disease, including:
a) Myocardial infarction within six months before C1D1, or unstable or uncontrolled condition (e.g., unstable angina, congestive heart failure, New York Heart Association Class III-IV).
b) Cardiac arrhythmia (Common Terminology Criteria for Adverse Events [CTCAE] Grade 3 or higher) or clinically significant electrocardiogram (ECG) abnormalities.
c) Electrocardiogram showing a baseline QT interval as corrected QTc >470 msec.
8. Known:
a) Active hepatitis A
b) To be seropositive for hepatitis B (defined by a positive test for hepatitis B surface antigen [HBsAg]). Patients with resolved infection must be screened using real-time polymerase chain reaction (PCR) measurement of hepatitis B virus (HBV) DNA levels. Those who are PCR positive will be excluded. EXCEPTION: Patients with serologic findings suggestive of HBV vaccination (antiHBs positivity as the only serologic marker) AND a known history of prior HBV vaccination, do not need to be tested for HBV DNA by PCR.
c) To be seropositive for hepatitis C.
9. Known to be seropositive for human immunodeficiency virus (defined by positive testing for human immunodeficiency virus (HIV) antibodies).
10. Gastrointestinal disease that may significantly alter the absorption of pomalidomide.
11. Patient has plasma cell leukemia (>2.0 × 109/L circulating plasma cells by standard differential) or Waldenström’s macroglobulinemia or POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes) or amyloidosis.
12. Any concurrent medical or psychiatric condition or disease that is likely to interfere with the study procedures or results or that, in the opinion of the investigator, would constitute a hazard for participating in this study.
13. Ongoing ≥Grade 2 peripheral neuropathy.
14. Patient had ≥Grade 3 rash during prior therapy.
15. Patient has had major surgery within two weeks before C1D1, or has not fully recovered from an earlier surgery, or has a surgery planned during the time the patient is expected to participate in the study or within two weeks after the last dose of study drug administration. Note: patients with planned surgical procedures to be conducted under local anesthesia may participate. Kyphoplasty or vertebroplasty are not considered major surgery.
16. Patient has known allergies, hypersensitivity, or intolerance to any of the study drugs, monoclonal antibodies, human proteins, or their excipients (refer to isatuximab IB) or known sensitivity to mammalian-derived products.
17. Patient was vaccinated with live vaccines within four weeks prior to C1D1.
18. Pregnant or nursing women.
19. a. Females of childbearing potential (FCBP) unwilling to prevent pregnancy with the use of two reliable methods of contraception for ≥4 weeks before the start of study treatment, during treatment (including dose interruptions), and up to five months following the last dose of isatuximab or three months following the last dose of the rest of the study treatment, whichever is longer. This includes one highly effective form of contraception (tubal ligation, intrauterine device, hormonal [birth control pills, injections, hormonal patches, vaginal rings or implants] or partner’s vasectomy) and one additional effective contraceptive method (male latex or synthetic condom, diaphragm, or cervical cap).
b. FCBP who are unwilling or unable to be tested for pregnancy: a) before study treatment initiation, b) weekly during 1st month of treatment and then prior to each treatment cycle administration or c) every two weeks in case of irregular menstrual cycles, and d) up to five months following the last dose of isatuximab or three months following the last dose of the rest of the study treatment, whichever is longer.
20. Male participants who refuse to practice true abstinence or use a condom during sexual contact with a pregnant female or an FCBP while participating in the study, during dose interruptions and at least five months following the last dose of isatuximab or three months following the last dose of the rest of the study treatment, whichever is longer, even if he has undergone a successful vasectomy. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary endpoint is the ORR at six months of treatment with isatuximab in combination with pomalidomide, and low-dose dexamethasone.
ORR is defined as the proportion of patients with stringent complete response (sCR), CR, VGPR, and PR, as assessed by the Investigator using the IMWG response criteria (see Appendix A). |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| At six months of treatment with isatuximab in combination with pomalidomide, and low-dose dexamethasone. |
|
| E.5.2 | Secondary end point(s) |
Progression-free survival (PFS) is defined as the time from study treatment initiation (Cycle 1, Day 1) to the day of first documentation of PD, as assessed by the Investigator using the IMWG response criteria (see Appendix A), or the date of death from any cause, or initiation of further anti-myeloma treatment, or data cut-off, whichever occurs first.
Overall Survival (OS) is defined as the time from study treatment initiation (Cycle 1, Day 1) to the day of death from any cause. OS will be assessed throughout the treatment period and post EOT during long term follow-up visits until the end of the study.
Minimal Residual Disease (MRD) negativity is defined as the proportion of patients achieving MRD-negative status, assessed at suspected CR.
Time to Response (TTR) is defined as the time from study treatment initiation (Cycle 1, Day 1) to the day of first objective response of PR or better.
Duration of Response (DoR) is defined as the time from the day of the first response, as determined by the Investigator, to the day of first PD (based on the IMWG response criteria, see Appendix A) or death, whichever occurs first. DoR will be determined only for patients who have achieved ≥PR.
Safety: The incidence of AEs, TEAEs and serious adverse events (SAEs) recorded continuously from ICF until 30 days after last study treatment. AEs and laboratory parameters will be graded using the NCI-CTCAE version 5.0 (see Appendix C) and will be reported in the eCRF. Specific safety laboratory tests are planned in case of infusion reaction (see Study Flow Chart in Section 1.2 and Section 10.9.1). Full details of safety reporting and AE monitoring procedures are provided in Section 10.7.2 and Section 10.10. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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 | No |
| 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 | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| 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 | No |
| 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 | No |
| 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 | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| 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 | 9 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 9 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| 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 | 4 |
| E.8.9.1 | In the Member State concerned months | 5 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 5 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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