Mezigdomide Plus Ixazomib and Dexamethasone for Relapsed and Refractory Multiple Myeloma

NCT06050512 | Withdrawn Phase 1 DMC FDA Drug

• 1 other identifier: HCC 21-200
• Study Type: interventional
• Target: N/A
• Locations: 0 countries
• Sites: N/A

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.

Conditions

Relapsed and Refractory Multiple Myeloma

Keywords

Bi-specific T-cell engaging antibodies (BITE); cereblon E3 ligase modulator (CELMoD); cereblon-mediated ubiquitination; cellular transcription factors (Ikaros and Aiolos)

Outcome Measures

Primary Outcomes (2)

• Phase l: Recommended Phase II Dose (RP2D)

  Dose-limiting toxicity (DLT) per adverse events as defined using National Cancer Institute (NCI) CTCAE v5.0. Hematologic DLTs: Grade 4 neutropenia \< 500/μL for more than 5 days, Grade 3 neutropenia with fever \> 38.3°C (one time) or fever \> 38.0°C sustained for one hour, Grade 4 thrombocytopenia, Grade 3 thrombocytopenia with bleeding; Non-Hematologic DLTs: Grade 3 diarrhea lasting \>3 days (not recovering to \< grade 2) despite supportive care, Grade 3 nausea or vomiting \>3 days (not recovering to \< grade 2) days despite supportive care, Grade 3 fatigue lasting \>7 days (not recovering to \< grade 2) days despite supportive care, Grade 4 diarrhea, Grade 4 nausea or vomiting, Allergic reaction or hypersensitivity if unable to be corrected to \<grade 1 within 48 hours, Any other non-hematologic grade \>3 toxicity for which there is not a clear alternative explanation; General: dose modification or delay of mezigdomide or ixazomib during cycle 1 due to treatment related toxicity.

  Up to 17 months

• Phase ll: Overall Response Rate (ORR)

  Preliminary efficacy of mezigdomide when given in combination with ixazomib and dexamethasone as estimated by ORR, as defined by the International Myeloma Working Group (IMWG) response criteria. This will be expressed as the proportion of patients who achieve complete response (CR) or partial response (PR). CR is defined as negative serum and urine M-protein immunofixation (IF), along with the presence of \< 5% plasma cells (PCs) in bone marrow (BM) biopsy. PR is defined as ≥ 50% reduction of serum M-Protein and reduction in 24-hour urinary M-protein by ≥ 90% or to \< 200 mg per 24 hours.

  Up to 36 months

Secondary Outcomes (4)

• Incidence and severity of Adverse Events

  Up to 36 months

• Depth of Response

  Up to 36 months

• Duration of Response (DOR)

  Up to 36 months

• Progression-free Survival (PFS)

  Up to 36 months

Study Arms (2)

Phase l: Mezigdomide + Ixazomib + Dexamethasone

EXPERIMENTAL

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

Drug: Mezigdomide; Drug: Ixazomib; Drug: Dexamethasone

Phase ll (RP2D): Mezigdomide + Ixazomib + Dexamethasone

EXPERIMENTAL

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

Drug: Mezigdomide; Drug: Ixazomib; Drug: Dexamethasone

Interventions

Mezigdomide 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.

Also known as: CC-92480, MEZI

Phase l: Mezigdomide + Ixazomib + Dexamethasone; Phase ll (RP2D): Mezigdomide + Ixazomib + Dexamethasone

Ixazomib 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.

Also known as: NINLARO®

Phase l: Mezigdomide + Ixazomib + Dexamethasone; Phase ll (RP2D): Mezigdomide + Ixazomib + Dexamethasone

Dexamethasone 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.

Also known as: Dex

Phase l: Mezigdomide + Ixazomib + Dexamethasone; Phase ll (RP2D): Mezigdomide + Ixazomib + Dexamethasone

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Kathleen Dorritie: lead
• Bristol-Myers Squibb: collaborator

MeSH Terms

Conditions

Recurrence; Multiple Myeloma

Interventions

ixazomib; Dexamethasone

Condition Hierarchy (Ancestors)

Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Neoplasms, Plasma Cell; Neoplasms by Histologic Type; Neoplasms; Hemostatic Disorders; Vascular Diseases; Cardiovascular Diseases; Paraproteinemias; Blood Protein Disorders; Hematologic Diseases; Hemic and Lymphatic Diseases; Hemorrhagic Disorders; Lymphoproliferative Disorders; Immunoproliferative Disorders; Immune System Diseases

Intervention Hierarchy (Ancestors)

Pregnadienetriols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Steroids, Fluorinated

Study Officials

• Kathleen A Dorritie, MD

  UPMC Hillman Cancer Center

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Assistant Professor Hematology/Oncology

Study Record Dates

• First Submitted: September 15, 2023
• First Posted: September 22, 2023
• Study Start: October 2, 2023
• Primary Completion (Estimated): October 1, 2026
• Study Completion (Estimated): October 1, 2026
• Last Updated: November 19, 2024

Record last verified: 2024-11

Data Sharing

• IPD Sharing: Will not share