Telaglenastat + Carfilzomib + Dexamethasone for Multiple Myeloma

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

36 Participants Needed

Trial Summary

What is the purpose of this trial?

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 that has come back or does not respond to previous treatment. CB-839 HCl and carfilzomib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as dexamethasone work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving CB-839 HCl, carfilzomib, and dexamethasone may work better in treating patients with multiple myeloma.

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.

What data supports the effectiveness of the drug combination Telaglenastat, Carfilzomib, and Dexamethasone for treating multiple myeloma?

Research shows that Carfilzomib combined with Dexamethasone has significant activity in treating relapsed and refractory multiple myeloma, with a high overall response rate and manageable side effects. In a study, this combination achieved a 90% overall response rate in newly diagnosed patients, indicating strong effectiveness. ^{1 2 3 4 5}

Is the combination of Telaglenastat, Carfilzomib, and Dexamethasone safe for humans?

Carfilzomib and dexamethasone have been studied together in multiple myeloma patients, showing a generally manageable safety profile, though some serious side effects like cardiovascular issues and rare fatal pulmonary toxicity have been reported. The combination of Carfilzomib with other drugs has shown tolerable safety in relapsed multiple myeloma, but specific safety data for Telaglenastat in this combination is not provided. ^{1 2 4 6 7}

What makes the drug combination of Telaglenastat, Carfilzomib, and Dexamethasone unique for treating multiple myeloma?

This drug combination is unique because it includes Telaglenastat, which targets cancer cell metabolism, alongside Carfilzomib, a proteasome inhibitor that disrupts protein breakdown in cancer cells, and Dexamethasone, a steroid that reduces inflammation and suppresses the immune response. This combination aims to enhance the effectiveness of treatment by attacking multiple pathways that cancer cells use to survive. ^{1 2 3 4 6}

Research Team

Wilson Gonsalves, MD

Principal Investigator

Mayo Clinic Cancer Center LAO

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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 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]

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]

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]

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]

References

1. United States pubmed.ncbi.nlm.nih.gov

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

2. France pubmed.ncbi.nlm.nih.gov

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

3. England 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. [2022]

4. United States pubmed.ncbi.nlm.nih.gov

Phase II study of carfilzomib and dexamethasone therapy for newly diagnosed multiple myeloma. [2020]

5. Germany 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). [2023]

6. England pubmed.ncbi.nlm.nih.gov

Fatal pulmonary toxicity due to carfilzomib (Kyprolis™). [2020]

7. England 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. [2020]