ATRA + Carfilzomib for Multiple Myeloma

(ATRA Trial)

Overseen By Sai Ravi Pingali, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: The Methodist Hospital Research Institute

Must not be taking: Investigational therapies

Disqualifiers: Plasma cell leukemia, Amyloidosis, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: 24 weeks

42 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new combination treatment for multiple myeloma, a type of blood cancer affecting plasma cells. Researchers aim to determine if adding All-Trans Retinoic Acid (ATRA), a form of vitamin A, can enhance the effectiveness of carfilzomib for patients whose cancer no longer responds to certain treatments. The trial seeks participants who have tried at least three other treatments without success and have previously used carfilzomib. For those with multiple myeloma experiencing treatment resistance, this trial might be suitable. 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.

Will I have to stop taking my current medications?

The trial information does not specify if you need to stop taking your current medications. It's best to discuss your specific medications with the trial team to get a clear answer.

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

Research has shown that All-Trans Retinoic Acid (ATRA) is usually well-tolerated. In early studies with multiple myeloma patients, the number of side effects did not change significantly, suggesting ATRA might not cause many side effects.

Carfilzomib has already been approved for use in certain combinations for multiple myeloma, indicating it has passed safety checks for those uses. While side effects can occur, carfilzomib is considered safe enough for patients who have tried other treatments.

A recent study suggests that when ATRA and carfilzomib are used together, they may work well without adding significant risks. Specifically, the study found that ATRA could enhance carfilzomib's effectiveness against cancer cells.

Overall, current evidence suggests this combination is likely safe, but like any treatment, side effects could occur. Always discuss any concerns with a doctor or healthcare provider. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Unlike the standard treatments for multiple myeloma, which often include drugs like lenalidomide, bortezomib, and dexamethasone, the combination of All-Trans Retinoic Acid (ATRA) and Carfilzomib offers a unique approach. ATRA, a derivative of Vitamin A, may help in differentiating cancer cells, potentially making them more vulnerable to treatment. Carfilzomib, on the other hand, is a proteasome inhibitor that disrupts protein breakdown in cancer cells, leading to their death. Researchers are excited because this combination might enhance the effectiveness of treatment, offering a novel mechanism that could improve outcomes for patients who don't respond well to current therapies.

What evidence suggests that this treatment might be an effective treatment for multiple myeloma?

Research shows that combining All-Trans Retinoic Acid (ATRA) with Carfilzomib might effectively treat multiple myeloma, especially in patients unresponsive to certain treatments. This trial will administer a combination of ATRA, Carfilzomib, and Dexamethasone to participants. Lab studies found that ATRA enhances Carfilzomib's ability to kill cancer cells by triggering a specific response in the body. Carfilzomib attacks and breaks down certain proteins in cancer cells, slowing their growth. ATRA, a type of vitamin A, helps control cell growth and development. Early results suggest that this combination could make multiple myeloma cells more responsive to treatment, potentially improving outcomes for patients with limited options. ^{1 2 4 6 7}

Who Is on the Research Team?

Sai Ravi Pingali, MD

Principal Investigator

Houston Methodist Neal Cancer Center

Are You a Good Fit for This Trial?

This trial is for patients with Multiple Myeloma, specifically those who have not responded to proteasome inhibitors. Participants should be adults likely over 55 years old, given the disease's prevalence in this age group.

Inclusion Criteria

I am over 18 and my multiple myeloma has returned or is not responding to treatment.

Patient or legal guardian voluntarily can sign informed consent

Life Expectancy ≥ 6 months

Exclusion Criteria

On investigational therapies within 12 weeks of enrollment

Or deemed unfit for the study on evaluation by Investigator

I do not have severe heart issues that limit my daily activities.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive combination therapy with ATRA, Carfilzomib, and Dexamethasone. Carfilzomib is administered in cycles, with ATRA given for 3 weeks out of every 4 weeks, up to a maximum of 24 weeks.

24 weeks

Weekly visits for drug administration

Follow-up

Participants are monitored for safety and effectiveness after treatment, with assessments for disease progression and adverse events.

7 months

What Are the Treatments Tested in This Trial?

Interventions

• All-Trans Retinoic Acid (ATRA)
• Carfilzomib

Trial Overview

The study tests different doses of All-Trans Retinoic Acid (ATRA) combined with Carfilzomib on patients resistant to standard treatments. It aims to see if ATRA can make myeloma cells more sensitive to Carfilzomib.

How Is the Trial Designed?

Group I: All-Trans Retinoic Acid (ATRA), Carfilzomib, and Dexamethasone Experimental Treatment 3 Interventions

Carfilzomib will be given at Cycle 1 (20 mg/m2 on Days 1, 70 mg/m2 on Days 8 and 15) and Cycles 2 - onward (70 mg/m2 on Days 1, 8, and 15) as a 30-minute intravenous (IV) infusion to evaluate tolerability to treatment. Dexamethasone will be given \[20 mg, PO/IV\] on the days of carfilzomib treatment. ATRA will be given for 3 weeks (21 days) out of every 4 weeks (28 days) up to a maximum of 24 weeks (6 cycles). Only for Cycle 1, patients will start oral ATRA 25 mg/m2 7 days prior to Cycle 1 Day 1 through Cycle 1 Day 21 for a total of 28 days of dosing. To assign a dose to the next cohort of patients, dose escalation/de-escalation according to the trials Bayesian Optimal Interval (BOIN) Design is conducted. In patients who respond and do not have any dose limiting toxicity (DLT), treatment will continue for a total of 6 cycles in the phase II expansion cohort and subsequently transitioned to standard -of-care options.

All-Trans Retinoic Acid (ATRA) is already approved in United States, European Union for the following indications:

Approved in United States as Vesanoid for:

• Acute promyelocytic leukemia

Approved in European Union as Tretinoin for:

• Acute promyelocytic leukemia

Who Is Running the Clinical Trial?

The Methodist Hospital Research Institute

Lead Sponsor

Trials

299

Recruited

82,500+

Cancer Prevention Research Institute of Texas

Collaborator

Trials

55

Recruited

98,900+

Published Research Related to This Trial

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]

A combination treatment of all-trans retinoic acid (ATRA), dexamethasone (DEX), and alpha-interferon (IFN) was tested in 10 patients with advanced, refractory multiple myeloma, showing promising results with two patients achieving a partial response lasting 15 to 17 months.

Three additional patients experienced a stable plateau phase lasting between 4 to 11 months, indicating improved performance status and reduced bone pain, suggesting that this combination therapy may be beneficial for some myeloma patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

All-trans retinoic acid in combination with alpha-interferon and dexamethasone for advanced multiple myeloma. Musto, P., Sajeva, MR., Sanpaolo, G., et al.[2013]

All-trans retinoic acid (ATRA) was effective in inhibiting the growth of human myeloma cells in vitro, showing promise as a potential treatment for multiple myeloma.

However, ATRA did not affect the growth of myeloma cells in vivo in immunodeficient mice, indicating that its efficacy in treating multiple myeloma in a living organism is still uncertain.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Differential in vitro and in vivo effects of all-trans retinoic acid on the growth of human myeloma cells. Labaume, S., Chopin, M., Pla, M., et al.[2019]

All-trans retinoic acid (ATRA) was found to enhance the sensitivity of multiple myeloma (MM) cells to the proteasome inhibitor carfilzomib (Cfz), even resensitizing Cfz-resistant cells in laboratory tests.

The mechanism involves ATRA activating the retinoic acid receptor (RAR)γ, which leads to increased expression of IRF1 and subsequent cellular processes that promote cell death, suggesting that RARγ agonists could be a promising strategy to combat resistance to Cfz in MM patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

RARγ activation sensitizes human myeloma cells to carfilzomib treatment through the OAS-RNase L innate immune pathway. Wang, Q., Lin, Z., Wang, Z., et al.[2023]

All-trans retinoic acid (ATRA) significantly inhibits the growth of RARα2-positive myeloma cells (OPM2), especially when combined with granulocyte colony-stimulating factor (G-CSF), indicating a potential therapeutic strategy for treating certain types of myeloma.

The study found that ATRA promotes differentiation in RARα2-positive myeloma cells, as evidenced by changes in cell morphology and increased expression of RARα2, while having minimal effects on RARα2-negative cells (U266).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Effect of all-trans retinoid acid and G-CSF on growth, differentiation and RARα2 expression of myeloma cells]. Jiang, DF., He, YJ., Li, L., et al.[2022]

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 is an effective second-generation proteasome inhibitor approved for treating relapsed/refractory multiple myeloma, showing efficacy both as a standalone treatment and in combination with dexamethasone or lenalidomide.

Current research is exploring various dosing regimens of carfilzomib, indicating its potential for use not only in relapsed cases but also in newly diagnosed multiple myeloma, while maintaining a favorable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An overview of the role of carfilzomib in the treatment of multiple myeloma. Ziogas, DC., Terpos, E., Kastritis, E., et al.[2018]

Carfilzomib has shown a 23.7% overall response rate and a median overall survival of 15.6 months in heavily pretreated patients with relapsed and refractory multiple myeloma, leading to its FDA approval for this condition.

The ongoing phase 3 FOCUS trial aims to compare the overall survival of patients receiving carfilzomib to those receiving best supportive care, providing more rigorous data on its efficacy and safety as the primary endpoint.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Design and rationale of FOCUS (PX-171-011): a randomized, open-label, phase 3 study of carfilzomib versus best supportive care regimen in patients with relapsed and refractory multiple myeloma (R/R MM). Hájek, R., Bryce, R., Ro, S., et al.[2021]

Carfilzomib-containing combinations as frontline therapy for multiple myeloma showed a high overall response rate of 94% and a complete response rate of 21% across 13 trials involving 704 subjects.

The combination of carfilzomib with lenalidomide and dexamethasone (CFZ-LEN-DEX) resulted in a significantly higher complete response rate of 49% compared to other combinations, indicating it may be the most effective regimen for newly diagnosed patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Carfilzomib-containing combinations as frontline therapy for multiple myeloma: A meta-analysis of 13 trials. Sheng, Z., Li, G., Li, B., et al.[2018]

All-trans retinoic acid (ATRA) effectively inhibits the growth of myeloma cells from patients in a dose-dependent manner, showing potential as a new therapeutic agent for myeloma.

ATRA works by downregulating the interleukin-6 receptor (IL-6R) and glycoprotein 130 (gp130) on myeloma cells, as well as inhibiting IL-6 production, which is crucial for myeloma cell proliferation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Inhibitory effect of all-trans retinoic acid on the growth of freshly isolated myeloma cells via interference with interleukin-6 signal transduction. Ogata, A., Nishimoto, N., Shima, Y., et al.[2022]

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