CC-92480 + Dexamethasone for Multiple Myeloma

Not currently recruiting at 117 trial locations

Overseen By First line of the email MUST contain the NCT# and Site #.

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Celgene

Must be taking: Lenalidomide, Pomalidomide, Proteasome inhibitors, CD38 antibody

Must not be taking: Strong CYP3A modulators, Proton-pump inhibitors

Disqualifiers: Dialysis, Cardiac disease, HIV, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: Unknown

Duration: Up to approximately 28 days

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new treatment, CC-92480 (a Cereblon E3 Ligase Modulation Drug), both alone and with dexamethasone, to determine its effectiveness for people with relapsed and refractory multiple myeloma (RRMM) who have not responded well to other treatments. The research aims to assess the safety and effectiveness of these treatments. Individuals treated with at least three different myeloma regimens, including drugs like lenalidomide and a CD38 antibody, and whose disease worsened after their last therapy, might be suitable for this trial. As a Phase 1 trial, this research focuses on understanding how the treatment works in people, offering participants the chance to be among the first to receive this new treatment.

Do I need to stop my current medications for the trial?

The trial protocol does not specify if you need to stop your current medications. However, you cannot take strong CYP3A modulators or proton-pump inhibitors within 2 weeks before starting the trial medication.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that CC-92480, both alone and with dexamethasone, is generally safe for patients, meaning most tolerated the treatment well. Some side effects occurred, but they were not severe for most participants.

When combined with dexamethasone, studies found CC-92480 to be effective and safe, indicating patients could handle the treatment without major issues. These studies included patients who had tried other medications, suggesting the treatment is safe even for those with complex medical histories.

Although specific side effects were not listed, the use of CC-92480 in these trials indicates confidence in its safety for further research. Prospective trial participants should discuss these findings with their doctor to understand what they might mean personally. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about CC-92480 for multiple myeloma because it introduces a novel mechanism of action by specifically targeting proteins essential for cancer cell survival, potentially offering a more precise attack on cancer cells. Unlike traditional treatments such as proteasome inhibitors or immunomodulatory drugs, CC-92480 is designed to degrade specific disease-causing proteins rather than just inhibiting them, which might lead to more effective cancer cell eradication. Additionally, when used in combination with dexamethasone, CC-92480 may enhance the effectiveness of treatment by working synergistically to combat the disease. This innovative approach could mean improved outcomes for patients who have become resistant to existing therapies.

What evidence suggests that CC-92480 and dexamethasone could be effective for multiple myeloma?

Research has shown that combining CC-92480 with dexamethasone, one of the treatment arms in this trial, holds promise for patients with multiple myeloma who have tried many treatments. This combination targets a protein that helps break down certain cells, leading to cancer cell death. Early results suggest it is effective and safe, even at different doses. Patients previously treated with other drugs responded positively to this treatment. Another arm of this trial involves CC-92480 monotherapy, which also appears effective by disrupting specific proteins in cancer cells. Overall, evidence supports that CC-92480, especially with dexamethasone, could be an effective treatment for multiple myeloma. ^{1 3 5 6 7}

Who Is on the Research Team?

Bristol-Myers Squibb

Principal Investigator

Bristol-Myers Squibb

Are You a Good Fit for This Trial?

This trial is for adults over 18 with relapsed and refractory multiple myeloma who've had at least 3 prior treatments, including specific medications, and are not responding to their last therapy. They must have measurable disease, meet certain lab value criteria, be able to follow the study plan, and use contraception if of childbearing potential.

Inclusion Criteria

My myeloma worsened within 2 months after my last treatment.

Subject is willing and able to adhere to the study visit schedule and other protocol requirements.

I can take care of myself and am up and about more than half of my waking hours.

Exclusion Criteria

Subject has a significant medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from participating in the study.

Subject has any condition including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study.

I had major surgery recently.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive escalating doses of CC-92480 monotherapy or in combination with dexamethasone

Up to approximately 28 days

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to approximately 3 years

What Are the Treatments Tested in This Trial?

Interventions

• CC-92480
• Dexamethasone

Trial Overview The trial is testing CC-92480 alone and combined with Dexamethasone in patients whose multiple myeloma has returned or resisted treatment. It's an open-label Phase 1/2 study assessing safety, how the body processes the drug (PK), and its effectiveness against this cancer.

How Is the Trial Designed?

Group I: Administration of CC-92480 monotherapy Experimental Treatment 1 Intervention

Escalating doses of CC-92480 Monotherapy administered according to different dosing schedules

Group II: Administration of CC-92480 in combination with dexamethasone Experimental Treatment 2 Interventions

Part 1: Escalating doses of CC-92480 plus a fixed dose of dexamethasone Part 2: RP2D of CC-92480 in combination with dexamethasone

Who Is Running the Clinical Trial?

Celgene

Lead Sponsor

Trials

649

Recruited

130,000+

Top Products

>- **Revlimid (lenalidomide)**: Multiple myeloma, myelodysplastic syndromes, and mantle cell lymphoma treatment. - **Pomalyst (pomalidomide)**: Relapsed/refractory multiple myeloma treatment. - **Otezla (apremilast)**: Psoriatic arthritis treatment. - **Thalomid (thalidomide)**: Erythema nodosum leprosum and multiple myeloma treatment.

Jay Backstrom

Celgene

Chief Medical Officer since 2016

MD

Mark Alles

Celgene

Chief Executive Officer since 2016

Bachelor's degree from Lock Haven University of Pennsylvania

Published Research Related to This Trial

In a phase 1-2 study involving 178 patients with relapsed and refractory multiple myeloma, the combination of mezigdomide and dexamethasone demonstrated an overall response rate of 41%, indicating promising efficacy for this treatment in heavily pretreated patients.

The most common side effects were neutropenia and infections, which were mostly reversible, suggesting that while the treatment has myelotoxic effects, it does not present unexpected toxicities.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Mezigdomide plus Dexamethasone in Relapsed and Refractory Multiple Myeloma. Richardson, PG., Trudel, S., Popat, R., et al.[2023]

A sensitive method was developed to measure CC-92480 levels in rat plasma, showing excellent accuracy and reliability, which is crucial for understanding its pharmacokinetics.

CC-92480 demonstrated a high oral bioavailability of over 63%, and its metabolic pathways were identified, indicating potential routes for drug metabolism that could inform future studies on its efficacy in treating myeloma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetics, bioavailability and metabolism of CC-92480 in rat by liquid chromatography combined with electrospray ionization tandem mass spectrometry. You, W., Pang, J.[2021]

Thalidomide and similar drugs are important treatments for multiple myeloma, as they target cereblon, a protein that plays a crucial role in protein degradation.

By binding to cereblon, these drugs change how the ubiquitin ligase complex works, leading to the destruction of Ikaros and Aiolos, which are key transcription factors needed for the growth of multiple myeloma cells.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

From anecdote to targeted therapy: the curious case of thalidomide in multiple myeloma. Licht, JD., Shortt, J., Johnstone, R.[2021]

Iberdomide combined with dexamethasone demonstrated meaningful clinical activity in heavily pretreated patients with relapsed or refractory multiple myeloma, achieving an overall response rate of 32% in the dose-escalation cohort and 26% in the dose-expansion cohort, indicating its potential effectiveness even in difficult-to-treat cases.

The treatment was generally safe, with a recommended phase 2 dose established at 1.6 mg, although some patients experienced serious adverse events, including neutropenia and infections, highlighting the need for careful monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

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. Lonial, S., Popat, R., Hulin, C., et al.[2022]

Cereblon (CRBN) is a key target for thalidomide and its derivatives, which are known as immunomodulatory drugs (IMiDs), including lenalidomide and pomalidomide, highlighting their role in modulating CRBN activity.

Recent structural analyses have shown that IMiDs uniquely control the degradation of specific transcription factors through the CRBN-CRLA ubiquitin ligase pathway, suggesting a targeted mechanism of action that is particularly relevant for treating multiple myeloma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Thalidomide, cereblon and multiple myeloma]. Ogura, T.[2020]

The study identified argonaute 2 (AGO2) as a key cereblon binding partner that is regulated by the immunomodulatory drug lenalidomide, which affects multiple myeloma (MM) cell survival.

Silencing AGO2 in MM cells led to significant cell death, suggesting that targeting AGO2 could be a promising strategy to overcome resistance to IMiDs like lenalidomide in treating multiple myeloma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Expression of the cereblon binding protein argonaute 2 plays an important role for multiple myeloma cell growth and survival. Xu, Q., Hou, YX., Langlais, P., et al.[2020]

Citations

1. nejm.org nejm.org/doi/full/10.1056/NEJMoa2303194

Mezigdomide plus Dexamethasone in Relapsed and ... The all-oral combination of mezigdomide plus dexamethasone showed promising efficacy in patients with heavily pretreated multiple myeloma.

2. clinicaltrials.gov clinicaltrials.gov/study/NCT06048250

Study Details | NCT06048250 | Mezigdomide (CC-92480) ... 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.

3. multiplemyelomahub.com multiplemyelomahub.com/medical-information/celmods-for-the-treatment-of-mm-latest-clinical-trial-data

CELMoDs for the treatment of MM: Latest clinical trial data Here, we summarize the latest clinical trial data from studies evaluating the novel CELMoDs, iberdomide and mezigdomide, for the treatment ...

4. onclive.com onclive.com/view/preliminary-efficacy-safety-data-drive-further-exploration-of-mezigdomide-based-combinations-in-r-r-myeloma

Preliminary Efficacy, Safety Data Drive Further Exploration ... Siegel, MD, PhD, discusses early safety and efficacy data that support further development of mezigdomide-based combinations in multiple myeloma

5. sparkcures.com sparkcures.com/treatment/307/mezigdomide

Mezigdomide Myeloma Trials Results: As of May 9, 2024, 104 pts were enrolled in Cohorts A, C, and D; 28 pts received MeziVd (Cohort A) and 27 pts received MeziKd (Cohort C) in the ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT05372354

NCT05372354 | A Study to Evaluate Safety, Drug Levels ... 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 ...

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10969776/

Mezigdomide—A Novel Cereblon E3 Ligase Modulator ... Patients diagnosed with multiple myeloma today can expect to live for substantially longer than in the past thanks to the range of highly active treatment ...