CC-92480 + Other Drugs for Multiple Myeloma
Recruiting in Palo Alto (17 mi)
+26 other locations
Age: 18+
Sex: Any
Travel: May be covered
Time Reimbursement: Varies
Trial Phase: Phase 1 & 2
Recruiting
Sponsor: Bristol-Myers Squibb
No Placebo Group
Breakthrough Therapy
Trial Summary
What is the purpose of this trial?The purpose of this study is to assess the safety, tolerability and preliminary effectiveness of CC-92480 (BMS-986348) in novel therapeutic combinations for the treatment of Relapsed or Refractory Multiple Myeloma (RRMM).
Will I have to stop taking my current medications?
The trial information does not specify if you need to stop taking your current medications. However, you cannot have used any systemic anti-myeloma drug therapy within 14 days before starting the study treatment.
What data supports the effectiveness of the drug CC-92480 in treating multiple myeloma?
Research shows that CC-92480, a cereblon E3 ubiquitin ligase modulating drug, has potent antimyeloma activity. Mezigdomide, a similar drug, has shown strong tumor-killing effects in multiple myeloma models, even in cases resistant to other treatments.
12345Is CC-92480 safe for humans?
The safety of CC-92480 in humans is not directly addressed in the provided research articles. However, it is a cereblon E3 ubiquitin ligase modulator with potent antimyeloma activity, and similar drugs in this class have been used in multiple myeloma treatment. Further clinical trials would be needed to determine its safety in humans.
23456What makes the drug CC-92480 unique for treating multiple myeloma?
CC-92480, also known as Mezigdomide, is unique because it is a cereblon E3 ubiquitin ligase modulator that shows strong activity against multiple myeloma, even in cases resistant to other similar drugs like lenalidomide and pomalidomide. This drug works by targeting specific proteins essential for the growth of myeloma cells, making it a promising option for patients with relapsed or refractory multiple myeloma.
12346Eligibility Criteria
This trial is for adults with Multiple Myeloma that has come back or didn't respond to treatment. They must have measurable disease, be in good physical condition (ECOG PS of 0 or 1), and not suitable for other effective treatments. Participants can't join if they've had certain prior therapies, recent stem-cell transplants, CNS involvement by MM, recent SARS-CoV-2 infection, major surgery, radiation therapy, anti-myeloma drugs or investigational agents within specific time frames.Inclusion Criteria
My multiple myeloma has worsened despite treatment.
My multiple myeloma hasn't responded to, or I can't tolerate, standard treatments.
I am fully active or can carry out light work.
Exclusion Criteria
I have previously been treated with CC-92480, tazemetostat, BMS-986158, or trametinib.
I have had a stem-cell transplant from a donor or my own within the last 12 weeks.
My multiple myeloma has affected or previously affected my brain or spinal cord.
I have a specific blood disorder such as plasma cell leukemia, Waldenstrom's macroglobulinemia, POEMS syndrome, or significant light-chain amyloidosis.
I have heart problems that affect my daily activities.
Participant Groups
The study tests the safety and effectiveness of CC-92480 (BMS-986348) combined with other drugs like BMS-986158, Trametinib, Dexamethasone and Tazemetostat in treating Relapsed/Refractory Multiple Myeloma. It aims to find out how well these combinations work together.
7Treatment groups
Experimental Treatment
Active Control
Group I: Part 2 Arm G: Dose ExpansionExperimental Treatment3 Interventions
Group II: Part 2 Arm F: Dose ExpansionExperimental Treatment3 Interventions
Group III: Part 2 Arm E: Dose ExpansionExperimental Treatment3 Interventions
Group IV: Part 1 Arm C: Dose FindingExperimental Treatment3 Interventions
Group V: Part 1 Arm B: Dose FindingExperimental Treatment3 Interventions
Group VI: Part 1 Arm A: Dose FindingExperimental Treatment3 Interventions
Group VII: Part 2 Arm D: Dose ExpansionActive Control2 Interventions
Find A Clinic Near You
Research locations nearbySelect from list below to view details:
Dana-Farber Cancer InstituteBoston, MA
Local Institution - 0004Toronto, Canada
Uab Comprehensive Cancer CenterBirmingham, AL
Local Institution - 0009Calgary, Canada
More Trial Locations
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Who is running the clinical trial?
Bristol-Myers SquibbLead Sponsor
References
Expression of the cereblon binding protein argonaute 2 plays an important role for multiple myeloma cell growth and survival. [2020]Immunomodulatory drugs (IMiDs), such as lenalidomide, are therapeutically active compounds that bind and modulate the E3 ubiquitin ligase substrate recruiter cereblon, thereby affect steady-state levels of cereblon and cereblon binding partners, such as ikaros and aiolos, and induce many cellular responses, including cytotoxicity to multiple myeloma (MM) cells. Nevertheless, it takes many days for MM cells to die after IMiD induced depletion of ikaros and aiolos and thus we searched for other cereblon binding partners that participate in IMiD cytotoxicity.
Mezigdomide plus Dexamethasone in Relapsed and Refractory Multiple Myeloma. [2023]Despite recent progress, multiple myeloma remains incurable. Mezigdomide is a novel cereblon E3 ubiquitin ligase modulator with potent antiproliferative and tumoricidal activity in preclinical models of multiple myeloma, including those resistant to lenalidomide and pomalidomide.
Pharmacokinetics, bioavailability and metabolism of CC-92480 in rat by liquid chromatography combined with electrospray ionization tandem mass spectrometry. [2021]CC-92480 is a cereblon E3 ubiquitin ligase modulating drug with potent antimyeloma activity. In this study, we developed a sensitive UHPLC-MS/MS method for the determination of CC-92480 in rat plasma. The plasma samples were prepared with acetonitrile and the samples were then separated on an Acquity BEH C18 column (2.1 × 50 mm, 1.7 μm) with water containing 0.1% formic acid (A) and acetonitrile (B) as mobile phase. The MS detection was performed using multiple reaction monitoring mode with precursor-to-product ion transitions at m/z 568.3 > 363.1 for CC-92480 and m/z 441.2 > 138.1 for ibrutinib (internal standard). The assay showed excellent linearity over the concentration range of 1-1,000 ng/ml, with correlation coefficient >0.995. The method was further validated for selectivity, precision, accuracy, recovery and stability according to the US Food and Drug Administration's guideline. The validated method was successfully applied to the pharmacokinetic and bioavailability studies of CC-92480 in rat plasma. Based on the pharmacokinetic results, the oral bioavailability of CC-92480 was >63%. In addition, the circulating metabolites of CC-92480 were detected by UHPLC-HRMS and the structures were proposed according to their accurate masses and fragment ions. The proposed metabolic pathways of CC-92480 were oxidative dealkylation and amide hydrolysis.
From anecdote to targeted therapy: the curious case of thalidomide in multiple myeloma. [2021]Thalidomide and related drugs are key drugs for the treatment of multiple myeloma (MM). These agents bind to cereblon, a component of a ubiquitin ligase complex, altering the specificity of the complex to induce the ubiquitylation and degradation of Ikaros (IKZF1) and Aiolos (IKZF3), transcription factors essential for MM growth.
Iberdomide plus dexamethasone in heavily pretreated late-line relapsed or refractory multiple myeloma (CC-220-MM-001): a multicentre, multicohort, open-label, phase 1/2 trial. [2022]Iberdomide is a novel cereblon E3 ligase modulator with enhanced tumouricidal and immune-stimulatory effects compared with immunomodulatory drugs. In preclinical myeloma models, iberdomide has shown synergy with dexamethasone, proteasome inhibitors, and CD38 monoclonal antibodies. We aimed to evaluate the safety and clinical activity of iberdomide plus dexamethasone in patients with heavily pretreated relapsed or refractory multiple myeloma.
[Thalidomide, cereblon and multiple myeloma]. [2020]Cereblon was identified as a direct target of thalidomide by Prof. H. Handa, and this pioneering work triggered active research on IMiDs (immunomodulatory drugs), which include thalidomide-derivatives, such as lenalidomide and pomalidomide. These small molecules have been shown to bind to cereblon (CRBN) to modulate its activity as a substrate receptor. In addition, structural analyses on CRBN have revealed unique actions of these small agents, by which degradation of transcription factors is controlled in a specific and unique way. I summarize recent progress on CRBN-CRLA ubiquitin ligase and IMiDs, focusing on the therapeutic application of these drugs for treatment of multiple myeloma.