Telaglenastat + Carfilzomib + Dexamethasone for Multiple Myeloma

Not currently recruiting at 4 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: National Cancer Institute (NCI)

Must not be taking: Alkylators, Anthracyclines, Monoclonal antibodies, others

Disqualifiers: Cardiac history, CNS involvement, Amyloidosis, others

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

Compensation: Varies

Number of Visits: 30

Duration: 28 days per cycle

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new drug combination to determine the best dose for treating multiple myeloma that has returned or is unresponsive to previous treatments. The combination includes CB-839 HCl (telaglenastat), carfilzomib, and dexamethasone, which work together to inhibit cancer cell growth. Ideal participants have already tried at least two other treatments for multiple myeloma and are currently experiencing a recurrence. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new combination therapy.

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

The trial does not specify if you need to stop taking your current medications, but you cannot be on high-dose corticosteroids or certain recent chemotherapy treatments. It's best to discuss your specific medications with the trial team.

Is there any evidence suggesting that this treatment is likely to be safe for humans?

Research shows that the combination of CB-839 HCl, carfilzomib, and dexamethasone is undergoing safety testing in people with multiple myeloma. Earlier studies have found that CB-839 HCl, when combined with carfilzomib, is usually well-tolerated by patients with blood cancers. Common side effects include tiredness, nausea, and diarrhea, but these were not severe for most individuals.

Carfilzomib and dexamethasone have already received approval for treating multiple myeloma. These drugs can cause side effects such as low blood cell counts, fatigue, and elevated blood sugar levels. However, they are generally safe under healthcare professional supervision.

In summary, while CB-839 HCl remains under study, early results suggest it is generally well-tolerated when combined with carfilzomib and dexamethasone. Always discuss potential risks with a doctor before joining a trial. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination treatment of Telaglenastat, Carfilzomib, and Dexamethasone for multiple myeloma because it introduces a new mechanism of action to the treatment landscape. Unlike most treatments that focus primarily on targeting the cancer cells themselves, Telaglenastat inhibits glutaminase, an enzyme crucial for cancer cell metabolism, essentially starving the cancer cells by cutting off their nutrient supply. This metabolic approach, combined with the proven efficacy of Carfilzomib and Dexamethasone, offers a unique multi-faceted attack on multiple myeloma, which could potentially enhance treatment effectiveness and provide new hope for patients with this challenging condition.

What evidence suggests that this trial's treatments could be effective for multiple myeloma?

Research has shown that combining CB-839 HCl, carfilzomib, and dexamethasone might help treat multiple myeloma. In this trial, participants will receive this combination treatment. CB-839 HCl blocks the enzymes that cancer cells need to grow. Carfilzomib has already been shown to help patients live longer without their cancer worsening. Dexamethasone helps kill cancer cells or stop them from multiplying. Early studies suggest that using these drugs together could enhance their effectiveness against multiple myeloma compared to using each one alone. ^{3 6 7 8 9}

Who Is on the Research Team?

Wilson Gonsalves, MD

Principal Investigator

Mayo Clinic Cancer Center LAO

Are You a Good Fit for This Trial?

This trial is for adults with multiple myeloma that has returned or isn't responding to treatment. They must have had at least two prior treatments, including a proteasome inhibitor and an immunomodulatory drug. Participants need adequate blood counts, organ function, and agree to use effective contraception. Those who can't join include those intolerant to carfilzomib, on other trials, with uncontrolled illnesses, pregnant or nursing women, and those with certain medical conditions.

Inclusion Criteria

I am willing to have a bone marrow test during the study.

Ability to understand and the willingness to sign a written informed consent document

Your hemoglobin level is at least 8 grams per deciliter within 14 days before joining the study.

Exclusion Criteria

I have a stomach or intestine condition that affects how I absorb pills.

I cannot tolerate or did not respond to carfilzomib treatment.

My cancer has spread to my brain or spinal cord.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive CB-839 HCl orally every 12 hours, dexamethasone orally on specified days, and carfilzomib intravenously on specified days. Cycles repeat every 28 days.

28 days per cycle

Multiple visits per cycle for drug administration

Follow-up

Participants are monitored for safety and effectiveness after treatment completion

Up to 1 year

Follow-up at 30 days and periodically up to 1 year

What Are the Treatments Tested in This Trial?

Interventions

• Carfilzomib
• CB-839 HCl
• Dexamethasone

Trial Overview The trial tests the best dose of CB-839 HCl combined with carfilzomib and dexamethasone in patients whose multiple myeloma has relapsed or is refractory. The goal is to find out if this combination can better halt cancer growth by blocking enzymes needed for cell growth compared to current treatments.

How Is the Trial Designed?

Group I: Treatment (CB-839 HCI, dexamethasone, carfilzomib) Experimental Treatment 3 Interventions

Patients receive glutaminase inhibitor CB-839 Patients receive glutaminase inhibitor CB-839 hydrochloride PO every 12 hours on days 1-28, dexamethasone PO on days 1, 2, 8, 9, 15, 16, and 23, and carfilzomib IV over 10 minutes on days 1, 2, 8, 9, 15, and 16. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity

Carfilzomib is already approved in United States, European Union, Canada, Japan for the following indications:

Approved in United States as Kyprolis for:

• Multiple myeloma

Approved in European Union as Kyprolis for:

• Multiple myeloma

Approved in Canada as Kyprolis for:

• Multiple myeloma

Approved in Japan as Kyprolis for:

• Multiple myeloma

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

In the ENDURANCE trial involving patients with newly diagnosed multiple myeloma, the combination of carfilzomib, lenalidomide, and dexamethasone (KRd) did not improve progression-free survival compared to the standard treatment of bortezomib, lenalidomide, and dexamethasone (VRd).

These findings suggest that KRd may not be a more effective treatment option than the current standard of care for patients with NDMM.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Carfilzomib Triplet Fails to Induce Superior PFS in Newly Diagnosed Multiple Myeloma. Skarzynski, J.[2021]

In a study involving 929 patients with relapsed or refractory multiple myeloma, carfilzomib combined with dexamethasone significantly improved median progression-free survival (18.7 months) compared to bortezomib with dexamethasone (9.4 months), indicating greater efficacy of carfilzomib.

While both treatments had serious adverse events, carfilzomib was associated with a higher rate of serious adverse events (48%) compared to bortezomib (36%), suggesting that while carfilzomib may be more effective, it also carries a higher risk of serious side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Carfilzomib and dexamethasone versus bortezomib and dexamethasone for patients with relapsed or refractory multiple myeloma (ENDEAVOR): a randomised, phase 3, open-label, multicentre study. Dimopoulos, MA., Moreau, P., Palumbo, A., et al.[2022]

In a real-world study of 152 patients with relapsed and/or refractory multiple myeloma treated with carfilzomib plus dexamethasone, the overall response rate was 71.1%, indicating that this treatment is effective in a clinical setting.

Patients classified as trial-unfit had significantly shorter progression-free survival (3.6 months) and overall survival (15.0 months) compared to trial-fit patients (7.3 months and 36.8 months, respectively), highlighting the importance of patient fitness in treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Real-world treatment outcomes of carfilzomib plus dexamethasone in patients with relapsed and/or refractory multiple myeloma, focusing on the impact of trial-fitness: CAtholic REsearch network for Multiple Myeloma study (CAREMM-2203). Park, SS., Goo, SY., Jeon, YW., et al.[2023]

In a phase 3 study involving 466 patients with relapsed or refractory multiple myeloma, the combination of carfilzomib, dexamethasone, and daratumumab (KdD) significantly improved progression-free survival compared to carfilzomib and dexamethasone alone (Kd), with a hazard ratio of 0.63, indicating a 37% reduction in the risk of disease progression.

Despite a higher incidence of grade 3 or higher adverse events in the KdD group (82%) compared to the Kd group (74%), the overall safety profile was considered favorable, with similar rates of treatment discontinuation due to adverse events in both groups.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Carfilzomib, dexamethasone, and daratumumab versus carfilzomib and dexamethasone for patients with relapsed or refractory multiple myeloma (CANDOR): results from a randomised, multicentre, open-label, phase 3 study. Dimopoulos, M., Quach, H., Mateos, MV., et al.[2020]

In a phase 2 study involving 72 patients with newly diagnosed multiple myeloma, the combination of carfilzomib and dexamethasone (Kd) achieved a remarkable overall response rate of 90%, with 7% of patients reaching a complete response and 58% achieving a very good partial response.

The treatment was generally well-tolerated, with most adverse events being low grade; however, there was an 11.1% incidence of grade 3 or higher cardiovascular events, indicating a need for monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II study of carfilzomib and dexamethasone therapy for newly diagnosed multiple myeloma. Forsberg, PA., Rossi, AC., Boyer, A., et al.[2020]

Carfilzomib, when used in combination with lenalidomide and dexamethasone, significantly prolongs progression-free survival (PFS) by 8.7 months in patients with relapsed multiple myeloma, based on results from the phase III ASPIRE study involving a multinational patient population.

The combination therapy has a manageable safety profile, with low incidences of severe adverse events, suggesting it is a viable treatment option for patients who have received prior therapies, although overall survival data is still pending.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Carfilzomib Triple Combination Therapy: A Review in Relapsed Multiple Myeloma. Hoy, SM.[2018]

Carfilzomib, a proteasome inhibitor approved for relapsing multiple myeloma, was associated with a case of fatal pulmonary toxicity in a 61-year-old male patient, highlighting a potential serious side effect of the drug.

The patient developed acute respiratory distress syndrome and diffuse alveolar hemorrhage shortly after starting carfilzomib, suggesting a direct link between the medication and the severe lung complications, which had not been previously reported.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fatal pulmonary toxicity due to carfilzomib (Kyprolis™). Lataifeh, AR., Nusair, A.[2020]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT03798678?term=AREA%5BBasicSearch%5D(AREA%5BBasicSearch%5D(CB-839))&rank=7

CB-839 HCl in Combination With Carfilzomib and ... This phase I trial studies the best dose of CB-839 HCl when given together with carfilzomib and dexamethasone in treating patients with multiple myeloma ...

2. ashpublications.org ashpublications.org/blood/article/140/Supplement%201/7315/490111/A-Multicenter-Phase-I-Dose-Escalation-Trial-of-a

A Multicenter Phase I Dose-Escalation Trial of a Novel ... Methods: This study was a phase 1, multicenter clinical trial of telaglenastat in combination with carfilzomib and dexamethasone for patients ...

3. mayo.edu mayo.edu/research/clinical-trials/cls-20457165

A Study to Evaluate CB-839 HCl in Combination With ... Giving CB-839 HCl, carfilzomib, and dexamethasone may work better in treating patients with multiple myeloma. Participation eligibility. Participant ...

4. ashpublications.org ashpublications.org/blood/article/134/Supplement_1/3160/423962/Trial-in-Progress-Phase-I-Dose-Escalation-and-Dose

Phase I Dose-Escalation and Dose-Expansion Trial of a Novel ... Methods: This study is a phase 1, multicenter clinical trial of CB-839 HCl in combination with carfilzomib and dexamethasone for patients with ...

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10368773/

Final analysis of carfilzomib, dexamethasone, and ... The final analysis of CANDOR confirmed a PFS benefit and showed a trend in OS favoring KdD vs Kd. Results reinforce KdD as a standard of care for RRMM, ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT03798678

Study Details | NCT03798678 | CB-839 HCl in ... This phase I trial studies the best dose of CB-839 HCl when given together with carfilzomib and dexamethasone in treating patients with multiple myeloma ...

7. sciencedirect.com sciencedirect.com/science/article/pii/S0006497118610894

Phase I Dose-Escalation and Dose-Expansion Trial of a ... In the phase 1 study, CX-839-002, the safety and tolerability of CB-839 HCl was evaluated in patients with hematological tumors (multiple myeloma (MM) and non- ...

8. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC5482623/

Glutaminase inhibitor CB-839 synergizes with carfilzomib ... We found that CB-839 synergistically enhanced the activity of multiple PIs with the most dramatic synergy being observed with carfilzomib (Crflz).

9. go.drugbank.com go.drugbank.com/conditions/DBCOND0028542

Refractory Multiple Myeloma (DBCOND0028542) Study of Carfilzomib, Daratumumab and Dexamethasone for Patients With Relapsed and/or Refractory Multiple Myeloma. Carfilzomib · Daratumumab · Dexamethasone.