| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Relapsed or Refractory Multiple Myeloma (RRMM) |
|
| E.1.1.1 | Medical condition in easily understood language |
| Multiple Myeloma which becomes non-responsive or progressive on therapy |
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| 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 compare the efficacy of iberdomide (also known as BMS-986382), daratumumab, and dexamethasone (IberDd) to that of daratumumab, bortezomib and dexamethasone (DVd) in terms of progression-free survival (PFS) in subjects with RRMM |
|
| E.2.2 | Secondary objectives of the trial |
In Stage 1, to determine the dose of IberDd in combination with dexamethasone and daratumumab to continue in Stage 2 of the study
In Stage 1, to assess the PK of IberDd in combination with daratumumab and dexamethasone
To evaluate overall survival in subjects with RRMM treated with IberDd compared to DVd
To evaluate achievement of minimal residual disease (MRD) negative status in subjects with RRMM (who achieve complete response [CR] or better) when treated with IberDd compared to DVd
To evaluate additional efficacy parameters in subjects with RRMM treated with IberDd compared to DVd
To evaluate safety of IberDd compared to DVd in subjects with RRMM
•To evaluate cancer-related symptoms and health-related quality of life (HRQoL) using the European Organization for Research and Treatment of Cancer – Quality of Life C30 questionnaire (EORTC QLQ-C30) and the European Quality of Life Multiple Myeloma Module (EORTC QLQ-MY20) in subjects with RRMM treated with IberDd compared to DVd
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1.Subject is ≥ 18 years of age at the time of signing the ICF.
2.Subject must understand and voluntarily sign an ICF prior to any study-related assessments/procedures being conducted.
3.Subject is willing and able to adhere to the study visit schedule and other protocol requirements.
4.Subject has documented diagnosis of MM and measurable disease, defined as any of the following:
a.M-protein quantities ≥ 1 g/dL by serum protein electrophoresis (sPEP) or ≥ 200 mg/24-hour urine collection by urine protein electrophoresis (uPEP); or
b.Light chain MM without measurable disease in serum or urine: serum free light chain (FLC) levels > 100 mg/L (10 mg/dL) involved light chain and an abnormal kappa/lambda FLC ratio
5.Subject has received one to 2 prior lines of anti-myeloma therapy.
6.Subject achieved a response (partial response [PR] or better) to at least 1 prior anti-myeloma regimen.
7.Subject must have documented disease progression during or after their last anti-myeloma regimen.
8.Prior treatment with CD38-directed therapy:
In Stage 1, subjects with prior CD38-directed- containing therapy are not eligible.
In Stage 2, prior treatment with CD38-directed therapy is permitted only if all the following are fulfilled:
a.Best response achieved during CD38-directed therapy was > PR.
b.Subject did not progress while receiving CD38-directed therapy or within 60 days of last dose of therapy.
c.Subject did not discontinue CD38-directed therapy due to a related AE.
d.Last dose of daratumumab was ≥ 3 months prior to randomization.
9.Prior treatment with bortezomib therapy is permitted, if all the following are fulfilled:
a.Best response achieved during bortezomib- containing therapy was at least a minimal response (MR).
b.Subject did not progress while receiving bortezomib therapy or within 60 days of last dose of therapy.
10.Subject has an Eastern Cooperative Oncology Group (ECOG) performance status score of 0, 1 or 2.
11.Females of childbearing potential (FCBP) must:
a.Have two negative pregnancy tests as verified by the Investigator prior to starting study treatment. She must agree to ongoing pregnancy testing during the course of the study, and after end of study treatment. This applies even if the subject practices true abstinence from heterosexual contact.
b.Either commit to true abstinence from heterosexual contact (which must be reviewed on a monthly basis and source documented) or agree to use, and be able to comply with, 2 forms of contraception: one highly effective, and one additional effective (barrier) measure of contraception without interruption 28 days prior to starting study treatment, during the study treatment (including dose interruptions), and for at least 28 days after the last dose of iberdomide, 3 months after the last dose of daratumumab or 7 months after the last dose of bortezomib, whichever is longest.
12.Male subjects must:
a.Practice true abstinence (which must be reviewed on a monthly basis and source documented) or agree to use a condom (Appendix E) during sexual contact with a pregnant female or a female of childbearing potential while participating in the study, during dose interruptions and for at least 90 days after the last dose of iberdomide, 3 months after the last dose of daratumumab, or 4 months after the last dose of bortezomib, whichever is longer even if he has undergone a successful vasectomy. Contraception requirements are detailed in APPENDIX E and local PI of bortezomib
and daratumumab (see current version of PI, SmPC, or equivalent document for the specific country/region).
13.Male subjects must agree to refrain from donating sperm while on study treatment, during dose interruptions and for at least 90 days following last dose of study treatment.
14.Subjects must agree to refrain from donating blood while on study treatment, during dose interruptions and for at least 28 days following the last dose of study treatment.
15.All male and female subjects must follow all requirements defined in the Pregnancy Prevention Program. See APPENDIX E and local PI of bortezomib and daratumumab (see current version of PI, SmPC, or equivalent document for the specific country/region).
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|
| E.4 | Principal exclusion criteria |
1.Subject has any significant medical condition
2.Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection within 14 days for mild or asymptomatic infections or within 28 days for severe/critical illness prior to randomization
3.Subject has any condition that confounds the ability to interpret data from the study.
4.Subject has any of the following laboratory abnormalities:
a.Absolute neutrophil count (ANC) < 1,000 cells/µL. It is not permissible to administer granulocyte colony-stimulating factor (GCSF) to achieve minimum ANC levels.
b.Platelet count: < 75,000 cells/µL for subjects in whom < 50% of bone marrow nucleated cells are plasma cells; or a platelet count < 50,000 cells/µL for subjects in whom ≥ 50% of bone marrow nucleated cells are plasma cells. It is not permissible to transfuse subjects to achieve minimum platelet counts
c.Hemoglobin < 8 g/dL (< 4.9 mmol/L)
d.Estimated glomerular filtration rate (eGFR) < 30 mL/min or requiring dialysis. The eGFR should be calculated using the modification of diet in renal disease (MDRD) formula adjust for actual BSA
e.Corrected serum calcium > 13.5 mg/dL (> 3.4 mmol/L).
f.Serum aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 2.5 × upper limit of normal (ULN)
g.Serum total bilirubin > 1.5 × ULN or > 3.0 mg/dL for subjects with documented Gilbert’s syndrome.
5.Subject has plasma cell leukemia, Waldenstrom’s macroglobulinemia or POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes), or clinically significant amyloidosis
6.Subject has peripheral neuropathy Grade 3, Grade 4 or Grade 2 with pain.
7.Subject has gastrointestinal disease that may significantly alter the absorption of iberdomide and/or other oral study treatment.
8.Subject has prior history of malignancies, other than MM, unless the subject has been free of the disease for ≥ 5 years with the exception of the following noninvasive malignancies:
•Basal cell carcinoma of the skin
•Squamous cell carcinoma of the skin in situ (stage 0)
•Carcinoma in situ of the cervix
•Carcinoma in situ of the breast
•Incidental histologic finding of prostate cancer or prostate cancer that is curative
9.Subject with known central nervous system involvement with MM.
10.Subject has received immunosuppressive medication within the last 14 days of initiating study treatment.
11.Subject has impaired cardiac function or clinically significant cardiac disease.
12.Subject received prior therapy with iberdomide.
13.Subject received any of the following:
a.Plasmapheresis within the last 28 days of initiating study treatment
b.Major surgery within 28 days of initiating study treatment
c.Radiation therapy, other than local palliative therapy, for myeloma associated bone lesions within 14 days of initiating study treatment
d.Use of any systemic anti-myeloma drug therapy within 14 days of initiating study treatment
14.Subject received any investigational agent within 28 days.
15.Subject has previously received a live vaccine within 3 months of initiating study treatment.
16.Concurrent administration of a strong inhibitor or inducer of cytochrome P450 (including within 14 days of initiating study treatment).
17.Subject is unable or unwilling to undergo protocol required thromboembolism or herpes zoster prophylaxis.
18.Subject has previously received allogeneic stem cell transplantation at any time during prior therapy or received autologous stem cell transplantation within 12 weeks of initiating study treatment.
19.Subject has known chronic obstructive pulmonary disease (COPD) with a forced expiratory volume in 1 second (FEV1) < 50% of predicted normal. Note that forced expiratory testing (FEV1) is required for subjects suspected of having COPD.
20.Subject has known moderate or severe persistent asthma within the last 2 years, or currently has uncontrolled asthma of any classification.
21.Subject is a female who is pregnant, nursing or breastfeeding, or who intends to become pregnant during participation in the study.
22.Subject is positive for human immunodeficiency virus, chronic or active hepatitis B, active hepatitis A, or active hepatitis C.
23.Subject has known allergies, hypersensitivity, or intolerance to boron or mannitol, hyaluronidase, sorbitol, corticosteroids, monoclonal antibodies or human proteins, cereblon modulating agents or their excipients (refer to respective package inserts or Investigator's Brochure) or known sensitivity to mammalian-derived products.
24.Subject has any contraindications to daratumumab, bortezomib or dexamethasone, per local PI.
25. Vulnerable, under judicial protection, people without freedom by administrative or judicial decision, people with psychiatric conditions without their consent, people accepted in a health or social institution for other purposes than the research, adults under legal guardianship, curatorship, and people incapable of giving consent personally.
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|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Progression-free survival (PFS): Time from randomization to the first documentation of progressive disease according to the IMWG Uniform Response Criteria for Multiple Myeloma or death due to any cause, whichever occurs first |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Time from randomization to the first documentation of progressive disease (IMWG) or death |
|
| E.5.2 | Secondary end point(s) |
Recommended iberdomide dose: Recommended iberdomide dose for Stage 2, based on the totality of safety, efficacy, PK and PD data
Pharmacokinetics: In Stage 1, PK of iberdomide, eg, area under the plasma concentration-time curve from time zero to tau, where tau is the dosing interval, AUC(TAU), Cmax, time to Cmax (Tmax), as appropriate
Overall survival (OS): Time from randomization to time of death due to any cause
Minimal Residual Disease (MRD) negativity rate: Proportion of subjects who achieve complete response (CR) or better and are MRD negative (defined at a sensitivity of a minimum of 1 in 105 nucleated cells by next generation flow cytometry)
Overall response rate (ORR): Percentage of subjects who achieve best response of partial response (PR) or better according to the IMWG Uniform Response Criteria for Multiple Myeloma
Time to response (TTR): Time from randomization to the first documentation of response (PR or better)
Duration of response (DoR): Time from the first documentation of response (PR or better) to the first documentation of progressive disease (PD) or death due to any cause, whichever occurs first
Time to progression (TTP): Time from randomization to the first documentation of PD
Time to next treatment (TTNT): Time from randomization to the start of the next anti-myeloma treatment
Progression-free survival 2 (PFS2):Time from randomization to progression on the next anti-myeloma treatment or death due to any cause, whichever occurs first
Safety: Type, frequency, seriousness and severity of adverse events (AEs), and relationship of AEs to study treatment
European Organization for Research and Treatment of Cancer – Quality of Life C30 questionnaire (EORTC QLQ-C30) and European Quality of Life Multiple Myeloma Module (EORTC QLQ-MY20): Mean changes from baseline in subscale scores in subject-reported health related quality of life outcomes and multiple myeloma-related symptoms as measured by the EORTC QLQ-C30 and the EORTC QLQ-MY20 |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
OS:Time from randomization to time of death due to any cause
ORR:Percentage of subjects who achieve best response of PR or better according to the IMWG Uniform Response Criteria for Multiple Myeloma
TTR:Time from randomization to the first documentation of response.
DoR: Time from the first documentation of response to the first documentation of PD or death due to any cause, whichever occurs first
TTP:Time from randomization to the first documentation of PD
TTNT:Time from randomization to the start of the next anti-myeloma treatment
PFS2: Time from randomization to progression on the next anti-myeloma treatment or death due to any cause, whichever occurs first.
Safety:Type, frequency, seriousness and severity of AE, and relationship of AEs to study treatment |
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| 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 | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | Yes |
| 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) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| 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 | 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) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 4 |
| 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 | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 117 |
| 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 |
| Argentina |
| Switzerland |
| Taiwan |
| Australia |
| Brazil |
| Canada |
| China |
| India |
| Israel |
| Japan |
| Korea, Republic of |
| Mexico |
| Russian Federation |
| United Kingdom |
| United States |
| Austria |
| Belgium |
| Czechia |
| Denmark |
| Finland |
| France |
| Germany |
| Greece |
| Ireland |
| Italy |
| Netherlands |
| Norway |
| Poland |
| Portugal |
| Spain |
| Sweden |
| Türkiye |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| 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
|
| The End of Trial is defined as either the date when 507 subjects have died or 5 years after the last subject is randomized, whichever is the later date. |
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 6 |
| E.8.9.1 | In the Member State concerned months | 8 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 7 |
| E.8.9.2 | In all countries concerned by the trial months | 3 |
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