Marizomib Central Nervous System (CNS)

NCT05050305 | Withdrawn Phase 2 DMC FDA Drug

• 1 other identifier: 20-551
• Study Type: interventional
• Target: N/A
• Locations: 1 country
• Sites: 2

Brief Summary

This research is being done to test whether the investigational drug marizomib is safe and effective when used in combination with standard of care drugs for the treatment of multiple myeloma.

Conditions

Multiple Myeloma; Multiple Myeloma in Relapse; Multiple Myeloma, Refractory

Keywords

Multiple Myeloma; Multiple Myeloma in Relapse; Multiple Myeloma, Refractory; CNS Myeloma

Outcome Measures

Primary Outcomes (4)

• Maximum Tolerated Dose (MTD) Safety Run-In

  MTD is defined as the highest dose level where no patients (of the 6 treated) develop a dose limiting toxicity (DLT)

  From date of enrollment until the date of first documented progression or date of death from any cause, whichever came first, up to 5 years

• Dose Limiting Toxicity (DLT)

  Toxicity summaries will be stratified by dose level, grade, and treatment attribution

  From date of enrollment until the date of first documented progression or date of death from any cause, whichever came first, up to 5 years

• The number and proportion of adverse events, graded as defined by CTCAE version 5.0.

  CTCAE version 5.0.

  From date of enrollment until the date of first documented progression or date of death from any cause, whichever came first, up to 5 years

• Overall response rate (ORR)

  Assessed using the updated International Myeloma Working Group Response Criteria (IMWG) (Rajkumar 2011).

  From date of enrollment until the date of first documented progression or date of death from any cause, whichever came first, up to 5 years

Secondary Outcomes (4)

• Time to response (TTR)

  From date of enrollment until the date of first documented progression or date of death from any cause, whichever came first, up to 5 years

• Progression free survival (PFS)

  From date of enrollment until the date of first documented progression or date of death from any cause, whichever came first. up to 5 years

• Duration of response (DOR)

  From date of enrollment until the date of first documented progression or date of death from any cause, whichever came first, up to 5 years

• Overall survival (OS)

  From date of enrollment until date of death from any cause, up to 5 years

Study Arms (1)

Marizomib plus pomalidomide and dexamethasone

EXPERIMENTAL

A safety run-in using a modified 3+3 dose de-escalation design with relapsed/refractory multiple myeloma (RRMM) cohort, expanded to a total of 16 participants once recommended phase 2 does (RP2D) has been identified. * Marizomib (MRZ) at a pre-determined dose on Days 1, 8, 15, 22 of a 28 day study cycle * Pomalidomide (POM) at a daily predetermined dose on Days 1-21 of a 28 day study cycle * Dexamethasone (DEX) at a daily predetermined dose on Days 1, 2, 8, 9, 15, 16, 22, 23 of a 28 day study cycle Simultaneously, relapsed/refractory multiple myeloma (RRMM) with central nervous system (CNS) involvement cohort will receive an identical modified 3+3 dose de-escalation design and expanded to an efficacy-evaluable total of 30 patients once recommended phase 2 does (RP2D has been identified

Drug: Marizomib; Drug: Pomalidomide; Drug: Dexamethasone

Interventions

Marizomib DRUG

Intravenous Infusion

Also known as: Salinosporamide A

Marizomib plus pomalidomide and dexamethasone

Pomalidomide DRUG

Taken orally

Also known as: Pomalyst

Marizomib plus pomalidomide and dexamethasone

Dexamethasone DRUG

Taken orally

Also known as: Decadron, Dexasone, Hexadrol, Maxidex

Marizomib plus pomalidomide and dexamethasone

Eligibility Criteria

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

You may qualify if:

• Previously diagnosed with MM based on standard IMWG criteria and currently requires treatment.
• Patients in the CNS-involved cohort must have CNS involvement of MM as defined by meningeal myelomatosis and/or radiological evidence of leptomeningeal disease and/or intracranial plasmacytoma involving brain parenchyma.
• Patients in the CNS-involved cohort must have received at least one or more previous lines of therapy including an IMiD and a proteasome inhibitor and have demonstrated disease progression on or within 60 days of completion of the last therapy.
• Patients in the RRMM cohort must have received at least two or more previous therapies including lenalidomide and a proteasome inhibitor and have demonstrated disease progression on or within 60 days of completion of the last therapy.
• Patients in the RRMM cohort must have measurable disease defined as at least one of the following:
• Serum M protein ≥ 0.5 g/dL (≥5 g/L)
• Urine M protein ≥200 mg/24 hours
• Serum free light chain (FLC) assay: Involved FLC assay ≥10 mg/dL (≥100 mg/L) and an abnormal serum FLC ratio (\<0.26 or \>1.65)
• Screening Laboratory evaluations within the following parameters
• Absolute neutrophil count (ANC) ≥ 1,000 cells/dL (1.0 x 109/L) (Growth factors cannot be used within 14 days before first drug administration)
• Platelet count ≥ 75,000 cells/dL (75 x 109/L) (without transfusions required during the 14 days prior to initiation of therapy)
• Hemoglobin ≥ 8.0 g/dl (RBC transfusions are permitted)
• Total Bilirubin ≤ 1.5 X upper limit of normal (ULN) (except subjects with Gilbert Syndrome, who can have total bilirubin \< 3.0 mg/dL)
• AST (SGOT) and ALT (SGPT) ≤ 3.0 x ULN
• Calculated creatinine clearance ≥ 45 mL/min

You may not qualify if:

• Prior exposure to marizomib. and primary refractoriness to pomalidomide or a pomalidomide combination. Prior pomalidomide exposure is permitted but patients must have shown tolerance (defined as no grade 3 or greater non-hematologic toxicity), as well as responsiveness to pomalidomide-based therapy (defined as MR or better).
• Diagnosed or treated for another malignancy within 3 years prior to enrollment, with the exception of complete resection of basal cell carcinoma or squamous cell carcinoma of the skin, an in situ malignancy, or low risk prostate cancer after curative therapy/watchful waiting.
• Known GI disease or GI procedure that could interfere with the oral absorption of pomalidomide including difficulty swallowing.
• Systemic treatment, within 14 days before the first dose of pomalidomide, with strong CYP3A inducers (rifampin, rifapentine, rifabutin, carbamazepine, phenytoin, phenobarbital), or use of St. John's wort.
• Peripheral neuropathy ≥ Grade 3, or Grade 2 with pain on clinical examination during the screening period.
• Any medical or psychiatric illness that in the investigator's opinion, would impose excessive risk to the patient or would adversely affect his/her participating in this study.
• Current uncontrolled cardiovascular conditions, including uncontrolled hypertension, uncontrolled cardiac arrhythmias, symptomatic congestive heart failure, unstable angina, Grade 3 thromboembolic event or myocardial infarction within the past 6 months.
• The following therapies within the stated time frames prior to initiation of therapy: previous cytotoxic therapies, including cytotoxic investigational agents, for MM within 3 weeks; IMiDs, PIs, corticosteroids, other approved therapeutics and monoclonal antibodies (Mabs) within 2 weeks; and investigational therapies within 4 weeks. Please note consideration of the interval for investigational agents from already approved classes of drug in MM (e.g. Cell-Mods, Mabs) can be considered on a case by case basis with the PI. Prior peripheral stem cell transplant within 12 weeks and the use of live vaccines within 30 days.
• Prior allogeneic stem cell transplantation with active graft-versus-host-disease (grade 2 or greater).
• Prior major surgical procedure or radiation therapy within 4 weeks of initiation of therapy (this does not include limited course of radiation used for management of bone pain within 7 days of initiation of therapy).
• Daily requirement for corticosteroids equivalent to \> 10 mg/day prednisone, except for inhalation corticosteroids, for the RRMM cohort. For patients with CNS involvement who require a higher dose of corticosteroids for control of vasogenic edema (e.g. 16 mg/day dexamethasone), eligibility will be determined on a case-by-case basis after discussion with the PI.
• Any \> Grade 1 adverse reaction unresolved from previous treatments according to the National Cancer Institute - Common Terminology Criteria for Adverse Events Version 5.0 (NCI CTC AE v.5.0). The presence of alopecia any grade or peripheral neuropathy ≤ Grade 2 without pain is allowed.
• Concurrent symptomatic amyloidosis or plasma cell leukemia.
• POEMS syndrome (plasma cell dyscrasia with polyneuropathy, organomegaly, endocrinopathy, monoclonal protein and skin changes).
• Known active infection requiring parenteral or oral anti-infective treatment within 7 days of start of therapy.

Sponsors & Collaborators

• Dana-Farber Cancer Institute: lead
• Bristol-Myers Squibb: collaborator

Study Sites (2)

Massachusetts General Hospital Cancer Center

Boston, Massachusetts, 02114, United States

Location

Dana-Farber Cancer Institute

Boston, Massachusetts, 02115, United States

Location

MeSH Terms

Conditions

Multiple Myeloma

Interventions

marizomib; pomalidomide; Dexamethasone; Calcium Dobesilate

Condition Hierarchy (Ancestors)

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; Benzenesulfonates; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Arylsulfonates; Arylsulfonic Acids; Sulfonic Acids; Sulfur Acids; Sulfur Compounds

Study Officials

• Clifton Mo, MD

  Dana-Farber Cancer Institute

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: April 14, 2021
• First Posted: September 20, 2021
• Study Start: March 1, 2024
• Primary Completion: December 1, 2025
• Study Completion (Estimated): December 1, 2027
• Last Updated: July 16, 2024

Record last verified: 2024-07

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF
• Time Frame: Data can be shared no earlier than 1 year following the date of publication
• Access Criteria: Contact the Belfer Office for Dana-Farber Innovations (BODFI) at innovation@dfci.harvard.edu

Locations

US (2)