Phase 1b Study to Assess Safety and Efficacy of Elotuzumab, CC-92480, and Dexamethasone in Relapsed/Refractory Myeloma After CD38- and BCMA-Targeted Therapies
Overview
- Phase
- Phase 1
- Status
- Recruiting
- Sponsor
- Abdullah Khan
- Enrollment
- 27
- Locations
- 2
- Primary Endpoint
- The recommended phase 2 dose of mezigdomide (CC-92480) in combination with elotuzumab and dexamethasone
Overview
Brief Summary
This phase Ib trial tests the safety, side effects, and best dose of CC-92480 in combination with elotuzumab and dexamethasone in treating patients with multiple myeloma that has come back after a period of improvement (relapsed) or that does not respond to treatment or has not responded to previous treatment (refractory). Multiple myeloma (MM) remains the second most common hematologic malignancy in the United States. A number of therapies have been approved for patients with MM, including CD38- and B-cell maturating antigen (BCMA)-targeted therapies (antibody and plasma cell treatments that help the body's immune system to kill cancer cells); however, patients will often relapse and become refractory to these therapies. Because of this, it is important to identify effective treatment options for patients progressing on anti-CD38 therapy and BCMA-directed therapies. Elotuzumab is a humanized IgG1 monoclonal antibody, which is a type of protein that can bind to other target cells to prevent them from working the way they should or cause them to act differently. Elotuzumab works by targeting a protein called SLAMF7, which is present on myeloma cells, and makes it easier for the immune system to target the cancer. CC-92480 works by binding to a protein called CRBN that triggers the breakdown of proteins: Ikaros and Aiolos, leading to cell death in multiple myeloma cells. Dexamethasone is a synthetic adrenocortical steroid, or steroid normally naturally made by the adrenal gland in the brain which has been produced in a laboratory, that helps to regulate the amount of different chemicals and water that are being processed by the kidneys. It is also used in patients with myeloma to help treat their disease. The combination of CC-92480 with elotuzumab and dexamethasone may be a safe and effective treatment when given to patients with relapsed or recurrent MM.
Detailed Description
PRIMARY OBJECTIVE:
I. To evaluate the safety and tolerability of elotuzumab, mezigdomide (CC-92480), and dexamethasone (E480d) in patients with relapsed/refractory multiple myeloma (RRMM) who have received >= 2 prior regimens including CD38- and BCMA-targeted therapies.
SECONDARY OBJECTIVES:
I. Determine the time to response (TTR), the duration of response (DOR), very good partial response [VGPR] or better and complete response [CR] rates, progression free survival (PFS) at 1 year, and overall survival (OS) at 1 year.
II. Check minimal residual disease (MRD) negativity rates by next generation sequencing in patients who are suspected of attaining a complete response (CR).
III. Correlative studies will include changes in lymphocyte subsets with therapy, immunophenotype of MM cells, and expression of CRBN, Ikaros, and Aiolos.
IV. Quality of life (QOL) will be assessed.
OUTLINE: This is a dose-escalation study of CC-92480, followed by a dose-expansion study.
Patients receive elotuzumab intravenously (IV) on days 1, 8, 15, and 22 of cycles 1 and 2 and then on day 1 of each subsequent cycle. Patients also receive CC-92480 orally (PO) on days 1-21 of each cycle and dexamethasone IV or PO on days 1, 8, 15, and 22 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients may undergo an echocardiography (ECHO) during screening and undergo magnetic resonance imaging (MRI), computed tomography (CT), or x-ray imaging during screening and on study as clinically indicated. Patients also undergo blood sample collection as well as bone marrow biopsy and aspiration during screening and on study.
After completion of study treatment, patients are followed up at 30 and 60 days and then every 12 weeks for up to 2 years.
Study Design
- Study Type
- Interventional
- Allocation
- Na
- Intervention Model
- Single Group
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- 18 Years to — (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •Patients 18 years of age or older with evidence of relapsed or refractory disease as defined by International Myeloma Working Group (IMWG) criteria and measurable disease as defined by any of the following:
- •Serum M-protein \>= 1.0 g/dl
- •Urine monoclonal protein \>= 200 mg/24h
- •Involved free light chain (FLC) level \>= 10mg/dl (\>= 100mg/l) and an abnormal serum free light chain ratio (\< 0.26, or \> 1.65)
- •Patients must have had at least 2 prior lines of therapy including lenalidomide, proteasome inhibitor (PI), anti-CD38 directed antibody, and BCMA-targeted therapy
- •Prior elotuzumab is permitted but patients with progressive disease (PD) as best reponse on elotuzumab are excluded; at least 6 months must have lapsed from prior elotuzumab exposure
- •Patients must have hemoglobin \>= 7g/dL
- •Absolute neutrophil count (ANC) \>= 1000/uL
- •Platelets \>= 70,000/uL
- •If plasma cell percentage on bone marrow biopsy aspirate or core is \> 30%, platelet requirement will be adjusted to 50,000/ul
Exclusion Criteria
- •Patients with Waldenstrom macroglobulinemia, primary amyloid light chain (AL) amyloidosis, primary plasma cell leukemia, or polyneuropathy, organomegaly, endocrinopathy, monoclonal plasma cell disorder, skin changes (POEMS) syndrome
- •Patients with secondary plasma cell leukemia are permitted
- •Patients with peripheral neuropathy \> National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) grade 2, or grade 2 peripheral neuropathy with pain
- •Patients receiving concurrent corticosteroids at the time protocol therapy is initiated other than for physiologic maintenance treatment
- •Concurrent use of complementary or alternative medicines that would confound the interpretation of toxicities and antitumor activity of the study drugs
- •Patients with history of anaphylaxis or hypersensitivity to elotuzumab, lenalidomide, or pomalidomide
- •Concurrent use of strong CYP3A modulators ≤ 2weeks; concurrent use of proton-pump inhibitors =\< 1 weeks prior to started CC-92480; potassium competitive acid blockers ≤ 2days prior to starting CC-92480
- •Unacceptable respiratory risk factors defined by any one of the following criteria:
- •Chronic obstructive pulmonary disease (COPD) with a forced expiratory volume in 1 second (FEV1) less than 50% of predicted normal
- •Moderate or severe persistent asthma within the past 2 years, or currently has uncontrolled asthma of any classification
Arms & Interventions
Treatment (elotuzumab, CC-92480, dexamethasone)
Patients receive elotuzumab IV on days 1, 8, 15, and 22 of cycles 1 and 2 and then on day 1 of each subsequent cycle. Patients also receive CC-92480 PO on days 1-21 of each cycle and dexamethasone IV or PO on days 1, 8, 15, and 22 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients may undergo an ECHO during screening and undergo MRI, CT, or x-ray imaging during screening and on study as clinically indicated. Patients also undergo blood sample collection as well as bone marrow biopsy and aspiration during screening and on study.
Intervention: Biospecimen Collection (Procedure)
Treatment (elotuzumab, CC-92480, dexamethasone)
Patients receive elotuzumab IV on days 1, 8, 15, and 22 of cycles 1 and 2 and then on day 1 of each subsequent cycle. Patients also receive CC-92480 PO on days 1-21 of each cycle and dexamethasone IV or PO on days 1, 8, 15, and 22 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients may undergo an ECHO during screening and undergo MRI, CT, or x-ray imaging during screening and on study as clinically indicated. Patients also undergo blood sample collection as well as bone marrow biopsy and aspiration during screening and on study.
Intervention: Bone Marrow Aspiration (Procedure)
Treatment (elotuzumab, CC-92480, dexamethasone)
Patients receive elotuzumab IV on days 1, 8, 15, and 22 of cycles 1 and 2 and then on day 1 of each subsequent cycle. Patients also receive CC-92480 PO on days 1-21 of each cycle and dexamethasone IV or PO on days 1, 8, 15, and 22 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients may undergo an ECHO during screening and undergo MRI, CT, or x-ray imaging during screening and on study as clinically indicated. Patients also undergo blood sample collection as well as bone marrow biopsy and aspiration during screening and on study.
Intervention: Bone Marrow Biopsy (Procedure)
Treatment (elotuzumab, CC-92480, dexamethasone)
Patients receive elotuzumab IV on days 1, 8, 15, and 22 of cycles 1 and 2 and then on day 1 of each subsequent cycle. Patients also receive CC-92480 PO on days 1-21 of each cycle and dexamethasone IV or PO on days 1, 8, 15, and 22 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients may undergo an ECHO during screening and undergo MRI, CT, or x-ray imaging during screening and on study as clinically indicated. Patients also undergo blood sample collection as well as bone marrow biopsy and aspiration during screening and on study.
Intervention: Computed Tomography (Procedure)
Treatment (elotuzumab, CC-92480, dexamethasone)
Patients receive elotuzumab IV on days 1, 8, 15, and 22 of cycles 1 and 2 and then on day 1 of each subsequent cycle. Patients also receive CC-92480 PO on days 1-21 of each cycle and dexamethasone IV or PO on days 1, 8, 15, and 22 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients may undergo an ECHO during screening and undergo MRI, CT, or x-ray imaging during screening and on study as clinically indicated. Patients also undergo blood sample collection as well as bone marrow biopsy and aspiration during screening and on study.
Intervention: Dexamethasone (Drug)
Treatment (elotuzumab, CC-92480, dexamethasone)
Patients receive elotuzumab IV on days 1, 8, 15, and 22 of cycles 1 and 2 and then on day 1 of each subsequent cycle. Patients also receive CC-92480 PO on days 1-21 of each cycle and dexamethasone IV or PO on days 1, 8, 15, and 22 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients may undergo an ECHO during screening and undergo MRI, CT, or x-ray imaging during screening and on study as clinically indicated. Patients also undergo blood sample collection as well as bone marrow biopsy and aspiration during screening and on study.
Intervention: Echocardiography (Procedure)
Treatment (elotuzumab, CC-92480, dexamethasone)
Patients receive elotuzumab IV on days 1, 8, 15, and 22 of cycles 1 and 2 and then on day 1 of each subsequent cycle. Patients also receive CC-92480 PO on days 1-21 of each cycle and dexamethasone IV or PO on days 1, 8, 15, and 22 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients may undergo an ECHO during screening and undergo MRI, CT, or x-ray imaging during screening and on study as clinically indicated. Patients also undergo blood sample collection as well as bone marrow biopsy and aspiration during screening and on study.
Intervention: Elotuzumab (Biological)
Treatment (elotuzumab, CC-92480, dexamethasone)
Patients receive elotuzumab IV on days 1, 8, 15, and 22 of cycles 1 and 2 and then on day 1 of each subsequent cycle. Patients also receive CC-92480 PO on days 1-21 of each cycle and dexamethasone IV or PO on days 1, 8, 15, and 22 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients may undergo an ECHO during screening and undergo MRI, CT, or x-ray imaging during screening and on study as clinically indicated. Patients also undergo blood sample collection as well as bone marrow biopsy and aspiration during screening and on study.
Intervention: Magnetic Resonance Imaging (Procedure)
Treatment (elotuzumab, CC-92480, dexamethasone)
Patients receive elotuzumab IV on days 1, 8, 15, and 22 of cycles 1 and 2 and then on day 1 of each subsequent cycle. Patients also receive CC-92480 PO on days 1-21 of each cycle and dexamethasone IV or PO on days 1, 8, 15, and 22 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients may undergo an ECHO during screening and undergo MRI, CT, or x-ray imaging during screening and on study as clinically indicated. Patients also undergo blood sample collection as well as bone marrow biopsy and aspiration during screening and on study.
Intervention: Mezigdomide (Biological)
Treatment (elotuzumab, CC-92480, dexamethasone)
Patients receive elotuzumab IV on days 1, 8, 15, and 22 of cycles 1 and 2 and then on day 1 of each subsequent cycle. Patients also receive CC-92480 PO on days 1-21 of each cycle and dexamethasone IV or PO on days 1, 8, 15, and 22 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients may undergo an ECHO during screening and undergo MRI, CT, or x-ray imaging during screening and on study as clinically indicated. Patients also undergo blood sample collection as well as bone marrow biopsy and aspiration during screening and on study.
Intervention: X-Ray Imaging (Procedure)
Outcomes
Primary Outcomes
The recommended phase 2 dose of mezigdomide (CC-92480) in combination with elotuzumab and dexamethasone
Time Frame: Up to 28 days (Cycle 1)
The dose limiting toxicity (DLT) will be defined as one or more of the following toxicities considered to be at least possibly related to the study drug, occurring during cycle 1 of therapy. Furthermore, inability to take \>= 75% of the planned CC-92480 doses, or receive cycle 2 day 1 doses due to a drug-related adverse event occurring in cycle 1 will be considered a DLT.
Incidence of adverse events
Time Frame: Up to 2 years
Adverse events and toxicities of the combination regimen will be summarized using the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0. Toxicities will be assessed overall, as well as by dose level. The maximum grade for each type of toxicity will be recorded for each patient, and frequency tables will be reviewed to determine toxicity patterns. The incidence of severe (grade 3+) adverse events or toxicities will be described. Will also assess tolerability of the regimen through assessing the number of patients who required dose modifications and/or dose delays. In addition, will capture the proportion of patients who go off treatment due to adverse reactions. All patients who have received at least one dose of any of the study regimen will be evaluable for toxicity.
Secondary Outcomes
- Duration of response (DOR)(From the time measurement criteria are first met for partial response or better (whichever status is recorded first) until the first date of progressive disease or death, assessed at 1 year)
- Overall survival (OS)(From start of treatment to the date of his or her death, assessed at 1 year)
- Minimal residual disease (MRD)(At final study visit, up to 2 years)
- Time to progression (TTP)(From start of treatment until objective tumor progression; with death as a competing risk, assessed at 1 year)
- Time to response (TTR)(From start of treatment until measurement criteria are first met for PR, very good partial response (VGPR), or complete response (CR) (whichever status is recorded first), assessed at 1 year)
- Very good partial response (VGPR) or better rates(From start of treatment until disease progression or death, assessed at 1 year)
- Progression free survival (PFS)(From start of treatment until disease progression or death, assessed at 1 year)
- Changes in immunophenotype of multiple myeloma cells(Up to 2 years)
- Changes in expression of CRBN, Ikaros, and Aiolos with therapy(Up to 2 years)
- Complete Response (CR)(From start of treatment until disease progression or death, assessed at 1 year)
- Changes in lymphocyte subsets with therapy(Up to 2 years)
- Quality of life (QOL)(At baseline and monthly until study completion, up to 2 years)
Investigators
Abdullah Khan
Principal Investigator
Ohio State University Comprehensive Cancer Center