IRB Study Number 21-658
Status Recruiting
Institute Taussig Cancer Institute
Description
Primary objective:
• To compare the efficacy of iberdomide, daratumumab and dexamethasone (IberDd) to that of daratumumab, bortezomib and dexamethasone (DVd) in terms of progression-free survival (PFS) in subjects with RRMM
Secondary objectives:
• In Stage 1, to determine the dose of iberdomide in combination with dexamethasone and daratumumab to continue in Stage 2 of the study
• In Stage 1, to assess the pharmacokinetics (PK) of iberdomide in combination with daratumumab and dexamethasone
• To evaluate overall survival (OS) 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
Inclusion Criteria
Subject is ≥ 18 years of age at the time of signing the informed consent form (ICF).
Subject must understand and voluntarily sign an ICF prior to any study-related assessments/procedures being conducted.
Subject is willing and able to adhere to the study visit schedule and other protocol requirements.
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.
Subject has received one to 2 prior lines of anti-myeloma therapy. Note: One line can contain several phases [eg, induction, (with or without) hematopoietic stem cell transplant, (with or without) consolidation, and/or (with or without) maintenance therapy]. Refer to APPENDIX I.
Subject achieved a response (partial response [PR] or better) to at least 1 prior antimyeloma regimen.
Subject must have documented disease progression during or after their last anti-myeloma regimen.
Prior treatment with CD38-directed therapy:
In Stage 1, subjects with prior CD38-directed 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-containing 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.
- 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.
- Subject has an Eastern Cooperative Oncology Group (ECOG) performance status score of
0, 1 or 2.
- Individuals of childbearing potential (IOCBP) must:
a. Have two negative pregnancy tests as verified by the Investigator prior to starting study
treatment. They 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. 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). Note: An IOCBP is a subject who: 1) has achieved menarche at some point and, 2) has not undergone a hysterectomy or bilateral oophorectomy or bilateral salpingectomy, or 3) has not been naturally postmenopausal (amenorrhea following cancer therapy or amenorrhea due to other medical reasons does not rule out childbearing potential) for at least 12 consecutive months (ie, has had menses at any time in the preceding 12 consecutive months).
- Individuals assigned male at birth 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 partner or an individual of childbearing potential while participating in the study, during dose interruptions and for at least 28 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).
* True abstinence is acceptable when this is in line with the preferred and usual lifestyle of the subject. [Periodic abstinence (eg, calendar, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception.]
Male (as assigned at birth) subjects must agree to refrain from donating sperm while receiving iberdomide, during dose interruptions and for at least 28 days following last dose of iberdomide, 3 months after the last dose of daratumumab or 4 months after the last dose of bortezomib whichever is later.
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.
All subjects must follow all requirements defined in the Pregnancy Prevention Program (v8.0). See APPENDIX E and local PI of bortezomib and daratumumab (see current version of PI, SmPC, or equivalent document for the specific country/region).
Exclusion Criteria
Subject has any significant medical condition, including active or uncontrolled infection, presence of laboratory abnormality, or psychiatric illness that places the subject at an unacceptable risk for treatment-related complications, if he/she were to participate in the study.
Coronavirus Disease 2019 (COVID-19) within 7 days for mild or asymptomatic infections or 14 days for moderate/severe infections prior to initiating study treatment. A longer duration may be needed based on the investigator’s clinical judgment.
a. Acute symptoms must have resolved and there must be no sequelae that would place the subject at a higher risk of clinically significant complications from receiving study treatment, based on the Investigator’s assessment in consultation with the Sponsor Medical Monitor. No repeat/follow-up COVID-19 testing is required.
Subject has any condition that confounds the ability to interpret data from the study.
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: < 50,000 cells/μL. 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 adjusted for actual BSA (refer to APPENDIX G).
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.
Subject has plasma cell leukemia, Waldenstrom’s macroglobulinemia or POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes), or clinically significant amyloidosis.
Subject has peripheral neuropathy Grade 3, Grade 4 or Grade 2 with pain.
Subject has gastrointestinal disease that may significantly alter the absorption of iberdomide and/or other oral study treatment.
Subject has prior history of malignancies, other than MM, unless the subject has been free of the disease for ≥ 3 years with the exception of the following noninvasive malignancies:
a. Squamous or basal cell skin cancer treated with curative intent, with no evidence of disease.
b. Carcinoma in situ of breast and cervix treated with curative intent.
c. Prostate cancer: low risk prostate cancer in active surveillance; low risk is defined as T1-T2a, Gleason ≤ 6 and PSA ≤ 10 ng/mL (per National Comprehensive Cancer Network [NCCN] and European Society for Medical Oncology [ESMO] risk groups).
Subject with known central nervous system involvement with MM.
Subject has received immunosuppressive medication within the last 14 days of initiating study treatment. The following are exceptions to this criterion:
a. Intranasal, inhaled, topical or local corticosteroid injections (eg, intra-articular injection).
b. Systemic corticosteroids at doses that do not exceed 10 mg/day of prednisone (or an equivalent dose of an alternative glucocorticoid, see Table 8).
c. Steroids as premedication for hypersensitivity reactions (eg, computed tomography [CT] scan premedication).
- Subject has impaired cardiac function or clinically significant cardiac disease, including:
a. Myocardial infarction within 6 months before randomization, or an unstable or uncontrolled disease/condition related to or affecting cardiac function (eg, unstable angina, congestive heart failure New York Heart Association Class III-IV).
b. Uncontrolled cardiac arrhythmia (National Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE] version 5.0 Grade 2 or higher) or clinically significant electrocardiogram (ECG) abnormalities.
Subject received prior therapy with iberdomide.
Subject received any of the following:
a. Plasmapheresis within the last 28 days of initiating study treatment.
b. Major surgery (as defined by the Investigator) 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.
- Subject received any investigational agent within 28 days.
a. Subjects who are participating in other interventional trials may not participate in BMS clinical trials, except for those who have completed treatment with the prior investigational agent(s) and are currently in Long-term Follow up.
b. Trial participation for subjects who have received an investigational vaccine (such as an investigational SARS-CoV-2 vaccine) will be determined by discussion between the Investigator and Sponsor Medical Monitor.
Subject has previously received a live vaccine within 3 months of initiating study treatment.
Concurrent administration of a strong inhibitor or inducer of cytochrome P450 (CYP3A4/5) (including within 14 days of initiating study treatment).
Subject is unable or unwilling to undergo protocol required thromboembolism or herpes zoster prophylaxis.
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.
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.
Subject has known moderate or severe persistent asthma within the last 2 years, or currently has uncontrolled asthma of any classification.
Subject is an individual of childbearing potential who is pregnant, nursing or breastfeeding, or who intends to become pregnant during participation in the study.
Subject is positive for human immunodeficiency virus (HIV), chronic or active hepatitis B, active hepatitis A, or active hepatitis C:
a. Known to be seropositive for HIV.
b. Seropositive for hepatitis B (defined by a positive test for hepatitis B surface antigen [HBsAg]). Subjects with resolved infection (ie, subjects who are HBsAg negative but positive for antibodies to hepatitis B core antigen [anti-HBc] and/or antibodies to hepatitis B surface antigen [anti-HBs]) must be screened using real-time polymerase chain reaction (PCR) measurement of hepatitis B virus (HBV) deoxyribonucleic acid (DNA) levels. Those who are PCR positive will be excluded. EXCEPTION: Subjects with serologic findings suggestive of HBV vaccination (anti-HBs 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. Known to be seropositive for hepatitis C virus (HCV); anti-HCV antibody positive or HCV- ribonucleic acid (RNA) quantitation positive.
Subject has prior history of systemic or clinically significant 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 mammalianderived products.
Subject has any contraindications to daratumumab, bortezomib or dexamethasone, per local PI.
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 (Refer to Appendix L for country-specific requirements).
