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About
This phase I/II trial tests the safety, side effects, best dose, and effectiveness of iberdomide in combination with belantamab mafodotin and dexamethasone in treating patients with multiple myeloma (MM) that has come back after a period of improvement (relapsed) or that does not respond to treatment (refractory). Multiple myeloma is a cancer that affects white blood cells called plasma cells, which are made in the bone marrow and are part of the immune system. Multiple myeloma cells have a protein on their surface called B-cell maturation antigen (BCMA) that allows the cancer cells to survive and grow. Immunotherapy with iberdomide, may induce changes in body's immune system and may interfere with the ability of cancer cells to grow and spread. Belantamab mafodotin has been designed to attach to the BCMA protein, which may cause the myeloma cell to become damaged and die. Dexamethasone is in a class of medications called corticosteroids. It is used to reduce inflammation and lower the body's immune response to help lessen the side effects of chemotherapy drugs. Iberdomide plus belantamab mafodotin may help slow or stop the growth of cancer in patients with multiple myeloma.
Full description
PRIMARY OBJECTIVES:
I. To determine maximum tolerated dose (MTD) of iberdomide (CC-220) in combination with belantamab mafodotin and dexamethasone in patients with relapsed or refractory multiple myeloma (RRMM). (PHASE I) II. To determine whether the combination of belantamab mafodotin/ iberdomide/dexamethasone improves progression-free survival (PFS) relative to belantamab mafodotin/dexamethasone in patients with RRMM. (PHASE II)
SECONDARY OBJECTIVES:
I. To summarize the incidence and cause for treatment delays, modifications and omissions. (PHASE I) II. To assess treatment response. (PHASE I) III. To obtain an estimate of the progression-free survival (PFS) and overall survival (OS) distribution. (PHASE I) IV. To determine minimal residual disease (MRD) negativity. (PHASE I) V. To observe and record anti-tumor activity. (PHASE I) VI. To determine whether the combination of belantamab mafodotin/ iberdomide/dexamethasone improves overall survival (OS) compared to belantamab mafadotin/dexamethasone in patients with RRMM. (PHASE II) VII. To evaluate the safety profile. (PHASE II) VIII. To estimate the ORR (per International Myeloma Working Group [IMWG] criteria), duration of response (DoR), and time to relapse (TTR). (PHASE II) XI. To determine MRD status. (PHASE II)
EXPLORATORY OBJECTIVES:
I. To examine changes in T, NK, and B-cell subsets and quantitative immunoglobulin levels after 1, 3, 6 and 12 cycles of treatment.
II. To investigate whether BCMA protein expression on MM cells at diagnosis as well as at relapse or end of study (including loss of expression) is associated with outcome (OS and PFS).
OUTLINE: This is a phase I, dose-escalation study of iberdomide followed by a phase II study.
PHASE I: Patients receive iberdomide orally on days 1-21 and 29-49, belantamab mafodotin intravenously (IV) on day 1, and dexamethasone orally (PO) on days 1, 8, 15, 22, 29, 36, 43, and 50 of each cycle. Cycles repeat every 56 days in the absence of disease progression or unacceptable toxicity. Patients undergo echocardiography (ECHO) during screening as clinically indicated and computed tomography (CT), magnetic resonance imaging (MRI) and/or positron emission tomography (PET) scans during screening and as clinically indicated on study. Patients also undergo a bone marrow biopsy and aspiration and blood sample collection throughout trial.
PHASE II: Patients are randomized to 1 of 2 arms.
ARM I: Patients receive belantamab mafodotin IV on day 1 and dexamethasone PO on days 1, 8, 15, 22, 29, 36, 43, and 50 of each cycle. Cycles repeat every 56 days in the absence of disease progression or unacceptable toxicity. Patients who progress may cross over to Arm II. Patients undergo ECHO during screening as clinically indicated and CT, MRI and/or PET scans during screening and as clinically indicated on study. Patients also undergo a bone marrow biopsy and aspiration and blood sample collection throughout trial.
ARM II: Patients receive iberdomide orally on days 1-21 and 29-49, belantamab mafodotin IV on day 1, and dexamethasone PO on days 1, 8, 15, 22, 29, 36, 43, and 50 of each cycle. Cycles repeat every 56 days in the absence of disease progression or unacceptable toxicity. Patients undergo ECHO during screening as clinically indicated and CT, MRI and/or PET scans during screening and as clinically indicated on study. Patients also undergo bone marrow biopsy and aspiration and blood sample collection throughout trial.
After completion of study treatment, patients are followed up every 6 months for 3 years from study entry.
Enrollment
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Inclusion and exclusion criteria
Documentation of disease: Diagnosis of multiple myeloma and have relapsed or refractory disease according to the IMWG criteria where:
Progression of myeloma is defined by IMWG criteria as recurrence of disease after prior response, indicated as any of the following:
Refractory myeloma as defined by IMWG criteria as disease which become non-responsive or progresses on therapy or within 60 days of last treatment in patients who had achieved a minimal response or better on prior therapy.
Measurable disease defined by IMWG criteria as:
Two or more prior lines of therapies, triple-class exposed (exposed /refractory to an immunodulatory derivative (IMiD) and/or proteasome inhibitors (PI) and/or to daratumumab or other anti-CD38 monoclonal antibody).
No prior exposure to iberdomide or belamaf.
No prior BCMA-directed therapy.
No prior treatment with a monoclonal antibody within 2 weeks of registration.
No history of severe allergic reaction (including erythema nodosum) to lenalidomide, pomalidoimide or other prior IMiD therapy.
No prior allogeneic stem cell transplant. NOTE: Participants who have undergone syngeneic transplant will be allowed only if no history of or no currently active GvHD.
Participant must not have received a live or live-attenuated vaccine within 30 days prior to registration.
No plasmapheresis within 7 days prior to registration.
Age ≥ 18 years.
Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2.
Absolute neutrophil count (ANC) ≥ 1,000/mm^3.
Platelet count ≥ 75,000/mm^3 (or ≥ 50,000/mm^3 in Phase II if bone marrow (BM) plasma cells > 50%).
Calculated (Calc.) creatinine clearance ≥ 30 mL/min using Cockcroft-Gault equation.
Spot urine (albumin/creatinine ratios) < 500 mg/g (56 mg/mmol) OR urine dipstick ≥ 1+ if confirmed.
Total bilirubin ≤ 2 mg/dL.
Aspartate aminotransferase (AST)/alanine transaminase (ALT) ≤ 2.5 x upper limit of normal (ULN).
Not pregnant and not nursing, because this study involves an investigational agent whose genotoxic, mutagenic and teratogenic effect on the developing fetus and newborn are unknown. FCBP (female of childbearing potential) is a female who: 1) has achieved menarche (first menstrual cycle) at some point, 2) has not undergone a hysterectomy (the surgical removal of the uterus) or bilateral oophorectomy (the surgical removal of both ovaries) or 3) has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months (ie, has had menses at any time during the preceding 24 consecutive months). Women of childbearing potential (WOCBP):
Archival tissue must be available for submission for the mandatory correlative studies.
Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial.
* Patients with treated brain metastases are eligible if follow up brain imaging after central nervous system (CNS) directed therapy shows no evidence of progression.
No patients with uncontrolled human immunodeficiency virus (HIV), hepatitis C and B. Testing for HIV and hepatitis C and B are not required prior to registration.
* HIV-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial.
No positive hepatitis C antibody test result or positive hepatitis C ribonucleic acid (RNA) test result at screening or within 3 months prior to registration unless the participant can meet the following criteria:
Patients with hepatitis B will be excluded unless the following criteria can be met.
No patients with unacceptable cardiac risk factors defined by any of the following criteria:
No patients who have received targeted (non-monoclonal antibodies [mAb]) or investigational agents within 2 weeks prior to rgistration and who have not recovered from side effects of those therapies.
No patients who have undergone major surgery ≤ 2 weeks prior to registration or who have not recovered from the side-effects of surgery.
No known medical condition causing an inability to swallow oral formulations of agents.
No active bacterial, viral or fungal infection (s) present.
Patients cannot have a Child-Pugh score greater than 1 (absent ascites, total bilirubin < 2, international normalized ratio (INR) <1.7 (unless on anticoagulation), and no encephalopathy; esophageal or gastric varices, and cirrhosis. Note: Stable non-cirrhotic chronic liver disease (including Gilbert's syndrome or asymptomatic gallstones) or hepatobiliary involvement of malignancy is acceptable if otherwise meets entry criteria.
No presence of active renal condition (infection, requirement for dialysis or any other condition that could affect participant's safety). Participants with isolated proteinuria resulting from MM are eligible, provided they fulfill inclusion criteria.
No evidence of active mucosal or internal bleeding.
No known immediate or delayed hypersensitivity reaction or idiosyncratic reactions to belamaf or drugs chemically related to belamaf, or any of the components of the study treatment.
Symptomatic amyloidosis, active POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal plasma proliferative disorder, skin changes) or active plasma cell leukemia at the time of screening.
Chronic concomitant treatment with strong inhibitors of CYP3A4 is not allowed on this study. Patients on strong CYP3A4 inhibitors must discontinue the drug for 14 days prior to registration on the study. Chronic concomitant treatment with strong CYP3A4 inducers is not allowed. Patients must discontinue the drug 14 days prior to the start of study treatment. Participant must not have current corneal epithelial disease except mild changes in corneal epithelium. For belantamab mafodotin, concomitant administration with strong inhibitors of OATP should be avoided.
RE-REGISTRATION ELIGIBILITY CRITERIA: Patients must meet criteria for progression of myeloma as defined by IMWG criteria indicated as any of the following:
RE-REGISTRATION ELIGIBILITY CRITERIA: Measurable disease defined by IMWG criteria as:
RE-REGISTRATION ELIGIBILITY CRITERIA: Absolute neutrophil count (ANC) ≥ 1,000/mm^3.
RE-REGISTRATION ELIGIBILITY CRITERIA: Platelet Count ≥ 75,000/mm^3 (or ≥ 50,000/mm^3 if BM plasma cells > 50%).
RE-REGISTRATION ELIGIBILITY CRITERIA: Calc. creatinine clearance ≥ 30 mL/min using Cockcroft-Gault equation.
RE-REGISTRATION ELIGIBILITY CRITERIA: Total bilirubin ≤ 2 mg/dL.
RE-REGISTRATION ELIGIBILITY CRITERIA: AST/ALT ≤ 2.5 x upper limit of normal (ULN).
RE-REGISTRATION ELIGIBILITY CRITERIA: Alkaline phosphatase ≤ 3 x ULN.
Primary purpose
Allocation
Interventional model
Masking
88 participants in 3 patient groups
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Central trial contact
Destin Carlisle; Monique Hartley-Brown, MD
Data sourced from clinicaltrials.gov
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