Carfilzomib + Lenalidomide + Vorinostat + Dexamethasone for Multiple Myeloma

(QUAD Trial)

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Hackensack Meridian Health

Must be taking: Aspirin, Warfarin, Heparin

Must not be taking: Corticosteroids, HDAC inhibitors

Disqualifiers: Pregnancy, Heart failure, HIV, others

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

Compensation: Varies

Number of Visits: 42

Duration: 48 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a combination of four medications to evaluate their effectiveness against multiple myeloma, a type of blood cancer. The medications include Carfilzomib (Kyprolis), Lenalidomide (Revlimid), Vorinostat (Zolinza), and Dexamethasone. Researchers aim to determine if this drug combination can effectively treat patients whose cancer has returned or resisted other treatments. Individuals with symptomatic multiple myeloma who have tried at least one previous treatment might be suitable for this study. As a Phase 1, Phase 2 trial, the study focuses on understanding how the treatment works in people and measuring its effectiveness in an initial, smaller group.

Will I have to stop taking my current medications?

The trial requires a washout period (time without taking certain medications) for patients who have used HDAC inhibitors, including valproic acid, before starting vorinostat. Other specific medication requirements are not detailed, so it's best to discuss your current medications with the trial team.

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

Research has shown that the combination of carfilzomib, lenalidomide, vorinostat, and dexamethasone has been studied for safety in treating multiple myeloma. In earlier studies, this treatment was generally safe. Some patients experienced serious side effects, such as anemia (a low red blood cell count) and thrombocytopenia (a low platelet count), occurring in 24% and 29% of cases, respectively. These side effects are important but manageable with medical care. Overall, the treatment is promising due to its effectiveness and manageable risks. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about this combination treatment for multiple myeloma because it brings together four powerful drugs: Carfilzomib, Lenalidomide, Vorinostat, and Dexamethasone, each with unique mechanisms that enhance their effectiveness. Unlike standard treatments that often focus on one pathway, this regimen targets multiple pathways involved in cancer cell survival and proliferation. Carfilzomib is a proteasome inhibitor, which disrupts protein breakdown in cancer cells, while Vorinostat inhibits histone deacetylases, affecting gene expression. This multi-faceted approach aims to tackle the cancer more comprehensively, potentially offering hope for patients with relapsed or refractory multiple myeloma.

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

Research shows that a combination of four drugs—carfilzomib, lenalidomide, vorinostat, and dexamethasone—may effectively treat multiple myeloma, especially in patients whose cancer has returned or didn't respond to previous treatments. This trial will administer this combination to participants to evaluate its effectiveness. Carfilzomib, which prevents certain proteins in cancer cells from breaking down, has proven effective in advanced cases. Adding vorinostat to lenalidomide and dexamethasone appears to enhance the treatment's effectiveness. Studies suggest that using these drugs together can help more patients experience a reduction in cancer symptoms. This trial carefully examines whether this combination can provide better results for those with relapsed or treatment-resistant multiple myeloma. ^{2 3 6 7 8}

Who Is on the Research Team?

David S Siegel

Principal Investigator

Hackensack Meridian Health

Are You a Good Fit for This Trial?

Adults with symptomatic multiple myeloma who have relapsed or are refractory after at least one treatment can join. They must have measurable disease, adequate organ function, and a life expectancy over three months. Women of childbearing age must test negative for pregnancy and use two forms of birth control; men must use condoms.

Inclusion Criteria

I can follow the study's schedule and visit the institute for treatment and tests.

My liver is functioning well, with normal bilirubin levels.

Alanine aminotransferase (ALT) < 3 times ULN

Exclusion Criteria

I am currently taking a medication like Valproic acid.

I haven't used any experimental drugs or therapies in the last 28 days.

I do not have any mental health or medical conditions that could affect my treatment.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive carfilzomib, lenalidomide, vorinostat, and dexamethasone in 28-day cycles for up to 12 cycles or until disease progression or unacceptable toxicity develops

48 weeks

12 cycles with 3 weeks of treatment and 1 week of rest per cycle

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Within 30 days of the last administration of study treatment

What Are the Treatments Tested in This Trial?

Interventions

• Carfilzomib
• Dexamethasone
• Lenalidomide
• Vorinostat

Trial Overview The trial is testing the combination of Carfilzomib, Lenalidomide, Vorinostat, and Dexamethasone in patients with multiple myeloma that has come back or hasn't responded to treatment. It aims to see if these four drugs work better together.

How Is the Trial Designed?

Group I: carfilzomib for MML Experimental Treatment 1 Intervention

Vorinostat, Lenalidomide, Carfilzomib, Dexamethasone - This study will be conducted as an open-label Phase I/II, single-center study in which subjects will receive carfilzomib, lenalidomide, vorinostat and dexamethasone, for relapsed and/or refractory multiple myeloma. Study treatment will be administered in sequential cohorts, with 3-6 subjects in each cohort. Treatment will be administered in 28-day cycles, with the fourth week as a rest week, for 12 cycles or until disease progression or unacceptable toxicity develops.

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?

Hackensack Meridian Health

Lead Sponsor

Trials

141

Recruited

42,900+

Published Research Related to This Trial

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 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 792 patients with relapsed multiple myeloma, the combination of carfilzomib with lenalidomide and dexamethasone significantly improved progression-free survival, with a median of 26.3 months compared to 17.6 months for the control group.

The carfilzomib group also showed a higher overall response rate (87.1% vs. 66.7%) and better health-related quality of life, indicating a favorable risk-benefit profile despite similar rates of serious adverse events between the two groups.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Carfilzomib, lenalidomide, and dexamethasone for relapsed multiple myeloma. Stewart, AK., Rajkumar, SV., Dimopoulos, MA., 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]

FK-037, a new cephalosporin antibiotic, demonstrated superior in vitro activity compared to ceftazidime, aztreonam, and piperacillin against various bacterial isolates from cancer patients, being 2 to 16 times more effective against Enterobacteriaceae.

FK-037 showed significant effectiveness against many gram-positive bacteria, including some methicillin-resistant staphylococci, indicating its potential as a broad-spectrum antimicrobial agent, although some organisms like Enterococcus spp. were resistant.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

In vitro activity of FK-037, a novel parenteral cephalosporin, against bacterial isolates from neutropenic cancer patients. Dholakia, N., Rolston, KV., Ho, DH., et al.[2019]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT01297764

A Study of Carfilzomib, Lenalidomide, Vorinostat, and ... Phase I/II studies of the novel proteasome inhibitor, carfilzomib, have shown it to have significant activity in patients with advanced multiple myeloma, ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC4325627/

Targeted treatments for multiple myeloma: specific role of ... Results from pivotal Phase III studies are in the early stages of reporting data evaluating carfilzomib's efficacy. In the FOCUS trial, a ...

3. nature.com nature.com/articles/bcj20141

Vorinostat in combination with lenalidomide and ... The addition of vorinostat to lenalidomide/dexamethasone represents a novel combination therapy in multiple myeloma (MM), ...

4. sciencedirect.com sciencedirect.com/science/article/pii/S0006497120316852

Treatment options for relapsed and refractory multiple ... With the addition of dexamethasone (DEX) (TD) the overall responses rates (ORRs) were augmented to 55% compared with the ORR of 24% with THAL ...

5. kyprolis-hcp.com kyprolis-hcp.com/combinations/kd-efficacy

Kd Efficacy | KYPROLIS® (carfilzomib) Analyze clinical results from the ENDEAVOR study comparing outcomes of KYPROLIS® + dexamethasone (Kd) against Bortezomib + Dexamethasone (Vd) in RRMM.

6. clinicaltrials.gov clinicaltrials.gov/study/NCT01297764

A Study of Carfilzomib, Lenalidomide, Vorinostat, and ... Phase I/II studies of the novel proteasome inhibitor, carfilzomib, have shown it to have significant activity in patients with advanced multiple myeloma, ...

7. ashpublications.org ashpublications.org/blood/article-abstract/125/20/3085/33956

Treatment options for relapsed and refractory multiple myeloma A phase I study of carfilzomib, lenalidomide, vorinostat, and dexamethasone (QUAD) in relapsed and/or refractory multiple myeloma (MM). ASCO ...

8. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0037196309000316

Emerging Treatments for Multiple Myeloma This review focuses on a series of new therapeutics that have shown promising preclinical results, as well as encouraging safety profiles and early evidence of ...