Mezigdomide Plus Ixazomib and Dexamethasone for Relapsed and Refractory Multiple Myeloma

NCT ID: NCT06050512

Last Updated: 2024-11-19

Basic Information

• Recruitment Status: WITHDRAWN
• Clinical Phase: PHASE1/PHASE2
• Study Classification: INTERVENTIONAL
• Study Start Date: 2023-10-02
• Study Completion Date: 2026-10-31

Brief Summary

Multiple myeloma (MM) is the second most common hematologic malignancy with an estimated annual incidence of nearly 35,000 cases. While still considered an incurable disease, new treatments have improved outcomes dramatically over the last two decades. Around the turn of the millennium, classical cytotoxic chemotherapy and radiation were the only available treatment modalities and median OS was estimated at 2-3 years. Currently, there are now 17 FDA-approved anti-myeloma agents and median OS is approaching 10 years. More recently, next generation cellular and immune therapies are demonstrating unprecedented efficacy in highly refractory patients with otherwise a very short life expectancy. In this study, the starting dose of ixazomib will be reduced to 3mg, as this is the first FDA-recommended dose recommendation (from 4mg). The starting dose of mezigdomide will be 0.6mg. Frequent toxicity and AE monitoring as outlined in this trial (weekly in C1, every 2 weeks in C2-C4) asserts maximization of patient safety. Dexamethasone (DEX) will be dosed at 40mg weekly in patients < 75 years old and 20mg for patients > 76 years old. Additionally, the staring dose of DEX may be reduced to 20mg in any patient, per study provider discretion, based on several factors such frailty, prior adverse side effects or existing comorbidities.

Detailed Description

Mezigdomide is a novel cereblon E3 ligase modulator (CELMoD). It is an oral small-molecule compound that potentiates the cereblon-mediated ubiquitination of key cellular transcription factors (Ikaros and Aiolos), which ultimately results in multiple myeloma cell death and other immunomodulatory activity. Mezigdomide has demonstrated acceptable safety in two phase I clinical trials in combination with DEX as a "doublet," and as a "triplet" in combination with bortezomib and DEX. Early estimates of efficacy are high compared to historical date: 55% ORR in combination with DEX in a highly pre-treated and refractory patient population, and 75% in combination with bortezomib. By comparison, the most recent oral therapy approved by the FDA for RRMM was Selinexor, which demonstrated a 25% ORR in patients who received a median of 7 prior lines of therapy and 100% of whom were refractory to a PI, IMID and DARA. This comparison serves as very exploratory estimate as no conclusions can be drawn from cross-trial comparisons, especially with very small patient populations. While important efficacy measures such overall survival, progression-free survival and duration of response are maturing, these estimates suggest mezigdomide could be an efficacious, oral treatment option for patients with RRMM.

Conditions

Relapsed and Refractory Multiple Myeloma

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: SEQUENTIAL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Phase l: Mezigdomide + Ixazomib + Dexamethasone

Dose level -2: Mezigdomide: 0.3 mg daily on days 1-21 of a 28-day schedule; Ixazomib: 2.3 mg PO weekly on days 1, 8 and 15 of a 28-day schedule; Dexamethasone: 40 or 20 mg on days 1, 8, 15 and 22 Dose level -1: Mezigdomide: 0.6 mg daily on days 1-21 of a 28-day schedule; Ixazomib: 2.3 mg PO weekly on days 1, 8 and 15 of a 28-day schedule; Dexamethasone: 40 or 20 mg on days 1, 8, 15 and 22 Dose level 0 (Starting dose): Mezigdomide: 0.6 mg daily on days 1-21 of a 28-day schedule; Ixazomib: 3.0 mg PO weekly on days 1, 8 and 15 of a 28-day schedule; Dexamethasone: 40 or 20 mg on days 1, 8, 15 and 22 Dose level +1: Mezigdomide: 1.0 mg daily on days 1-21 of a 28-day schedule; Ixazomib: 3.0 mg PO weekly on days 1, 8 and 15 of a 28-day schedule; Dexamethasone: 40 or 20 mg on days 1, 8, 15 and 22 Dose level +2: Mezigdomide: 1.0 mg daily on days 1-21 of a 28-day schedule; Ixazomib: 4.0 mg PO weekly on days 1, 8 and 15 of a 28-day schedule; Dexamethasone: 40 or 20 mg on days 1, 8, 15 and 22

Group Type: EXPERIMENTAL

Mezigdomide

Intervention Type: DRUG

Mezigdomide (MEZI), a novel oral CELMoD® agent with enhanced tumoricidal and immune-stimulatory effects compared to immunomodulatory drugs (IMiDs®), induces maximal degradation of Ikaros and Aiolos, leading to increased apoptosis in myeloma cells.

Ixazomib

Intervention Type: DRUG

Ixazomib, a second-generation proteasome inhibitor, is used primarily in the treatment of multiple myeloma. This activity outlines the mechanism of action, indications, and contraindications for ixazomib as a valuable agent for treating multiple myeloma.

Dexamethasone

Intervention Type: DRUG

Corticosteroids, such as dexamethasone and prednisone, are an important part of the treatment of multiple myeloma. They can be used alone or combined with other drugs as a part of treatment. Corticosteroids are also used to help decrease the nausea and vomiting that chemo might cause.

Phase ll (RP2D): Mezigdomide + Ixazomib + Dexamethasone

Mezigdomide: RP2D daily on days 1-21 of a 28-day schedule Ixazomib: RP2D PO weekly on days 1, 8 and 15 of a 28-day schedule Dexamethasone: RP2D on days 1, 8, 15 and 22

Group Type: EXPERIMENTAL

Mezigdomide

Intervention Type: DRUG

Mezigdomide (MEZI), a novel oral CELMoD® agent with enhanced tumoricidal and immune-stimulatory effects compared to immunomodulatory drugs (IMiDs®), induces maximal degradation of Ikaros and Aiolos, leading to increased apoptosis in myeloma cells.

Ixazomib

Intervention Type: DRUG

Ixazomib, a second-generation proteasome inhibitor, is used primarily in the treatment of multiple myeloma. This activity outlines the mechanism of action, indications, and contraindications for ixazomib as a valuable agent for treating multiple myeloma.

Dexamethasone

Intervention Type: DRUG

Corticosteroids, such as dexamethasone and prednisone, are an important part of the treatment of multiple myeloma. They can be used alone or combined with other drugs as a part of treatment. Corticosteroids are also used to help decrease the nausea and vomiting that chemo might cause.

Interventions

Mezigdomide

Mezigdomide (MEZI), a novel oral CELMoD® agent with enhanced tumoricidal and immune-stimulatory effects compared to immunomodulatory drugs (IMiDs®), induces maximal degradation of Ikaros and Aiolos, leading to increased apoptosis in myeloma cells.

Intervention Type: DRUG

Ixazomib

Ixazomib, a second-generation proteasome inhibitor, is used primarily in the treatment of multiple myeloma. This activity outlines the mechanism of action, indications, and contraindications for ixazomib as a valuable agent for treating multiple myeloma.

Intervention Type: DRUG

Dexamethasone

Corticosteroids, such as dexamethasone and prednisone, are an important part of the treatment of multiple myeloma. They can be used alone or combined with other drugs as a part of treatment. Corticosteroids are also used to help decrease the nausea and vomiting that chemo might cause.

Intervention Type: DRUG

Other Intervention Names

CC-92480; MEZI; NINLARO®; Dex

Eligibility Criteria

Inclusion Criteria

• ECOG performance status < 2
• Patients must have a confirmed diagnosis of multiple myeloma and have received 1-3 prior lines of therapy and must be:
• Exposed to a proteasome inhibitor, IMiD, and anti-CD38 antibody prior to enrollment. Patients must have measurable evidence of multiple myeloma defined as one of the following:

• Serum M protein ≥ 0.5 g/dL
• Abnormal free light chain ratio, provided involved light chain is >10mg/dL
• Urine M protein ≥ 200 mg/24 hours
• Hematologic laboratory parameters of:

• Absolute neutrophil count (ANC) > 1,000/mm3
• Hemoglobin > 8g/dL
• Platelet count > 75,000/μL if plasma cells account for < 50% bone marrow
• Nucleated cells and > 50,000/μL if plasma cells account for > 50% of bone marrow nucleated cells
• Non-hematologic laboratory parameters of:

• Total Bilirubin of < 2 times the upper limit of normal
• ALT and AST < 3 times the upper limit of normal
• Corrected serum calcium >13 mg/dL
• Estimated creatinine clearance (CrCl) of ≥ 45 mL/min, calculated using the formula of Cockroft and Gault (may need adjusted per mezigdomide pharmacokinetic report)
• Access to ixazomib
• Females of childbearing potential (FCBP) must:

o Have two negative pregnancy tests prior to starting study treatment and agree to ongoing pregnancy testing during the course of the study, and after end of study treatment.

• All male and female participants must follow all requirements defined in the pregnancy prevention plan

Exclusion Criteria

• Central Nervous system involvement of multiple myeloma
• Plasma cell leukemia defined as clonal plasma cells constituting > 20% of peripheral leukocyte differential
• Waldenstrom's Macroglobulinemia, POEMS syndrome or Light Chain (AL) AmyloidosisF
• Prior refractoriness to a proteasome inhibitor (bortezomib, carfilzomib, ixazomib), defined as documented progression within 60 days of a PI-containing regimen
• Prior intolerance of ixazomib
• Prior exposure to mezigdomide
• Females with positive pregnancy test during screening or females who wish to become pregnant
• Unwillingness to strictly adhere to the Pregnancy Prevention Plan
• Concomitant or recent (within 2 weeks of starting study therapy) use of strong CYP3A modulators and proton pump inhibitors (PPIs)
• Active cardiopulmonary conditions including documented myocardial ischemia within 6 months, unstable angina, congestive heart failure (New York Heart Association class III or IV), uncontrolled arrythmias, Grade 3 conduction block without a pacemaker, uncontrolled hypertension, baseline QTc >470ms or chronic obstructive pulmonary disease with FEV1 <50%
• Any other malignancy diagnosed within 2 years of enrollment with documented or presumed residual disease, excluding non-melanomatous skin cancer if completely resected
• Active bacterial or fungal infection requiring antimicrobial therapy (not standard prophylactic prophylaxis)
• HIV, chronic or active hepatitis B, or active hepatitis A or C
• Unwillingness to adhere to antithrombotic and antiviral prophylaxis
• Major surgery within 30 days of enrollment
• Radiotherapy within 14 days of initiating study treatment
• Known allergy to any study compounds (mezigdomide, ixazomib)
• Intolerance of dexamethasone
• Documented gastrointestinal disease resulting reduced absorption of oral medications
• Grade > 3 neuropathy
• Active participation in another clinical trial or recent participation within 1 month of enrollment
• Any medical or psychiatric condition interfere with the patient's ability to tolerate or complete this treatment protocol, as determined by principal investigator

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Bristol-Myers Squibb

INDUSTRY

Sponsor Role: collaborator

Kathleen Dorritie

OTHER

Sponsor Role: lead

Responsible Party

Kathleen Dorritie

Assistant Professor Hematology/Oncology

Responsibility Role: SPONSOR_INVESTIGATOR

Principal Investigators

Kathleen A Dorritie, MD

Role: PRINCIPAL_INVESTIGATOR

UPMC Hillman Cancer Center

Other Identifiers

HCC 21-200

Identifier Type: -

Identifier Source: org_study_id