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

Trial Summary

What is the purpose of this trial?

This is a Phase IB/II trial that will investigate the safety, tolerability and efficacy of combination therapy using All-Trans Retinoic Acid (ATRA) with Carfilzomib based therapies in plasma cell myeloma also commonly referred as Multiple Myeloma (MM), in patients considered refractory to proteasome inhibitors (PIs). Multiple myeloma is an incurable clonal plasma cell disorder that comprises 10% of all hematologic malignancies. Over the past 30 years the global prevalence of multiple myeloma has risen to 126%, with 85% of diagnoses occurring in patients \>55 years of age. In the past 15 years, survival has improved considerably, which is attributed to the development of multiple different classes of medications, including proteasome inhibitors. Proteasome inhibitors are the foundation of many multiple myeloma treatments in both transplant eligible and ineligible patients for the past 2 decades. While proteasome inhibitors have improved both progression free survival (PFS) and overall survival (OS), many patients eventually develop disease progression arising from resistance to therapies. As a result, there is an unmet need to overcome resistance and find ways to enhance multiple myeloma sensitivity to proteasome inhibitor toxicity. Carfilzomib, a modified peptide epoxyketone that selectively targets intracellular proteasome enzymes, is approved in combination with dexamethasone in patients that have received ≥1 line of therapy or in combination. There are few studies assessing ways to enhance carfilzomib-mediated multiple myeloma toxicity. All-Trans Retinoic Acid (ATRA) is an oxidative metabolite of retinol (vitamin A) and plays an important role in the regulation of cellular proliferation and differentiation. In a recent pre-clinical study, ATRA was found to enhance sensitivity of carfilzomib-mediated apoptosis in vitro via an interferon beta (IFN-β) response pathway. In the clinical setting, ATRA is a well-tolerated drug that has shown little change in the rate of adverse events in early clinical trials with multiple myeloma. The investigators hypothesize that ATRA enhances sensitivity of multiple myeloma to carfilzomib 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.

What data supports the effectiveness of the drug combination ATRA and Carfilzomib for treating multiple myeloma?

Research shows that all-trans retinoic acid (ATRA) can enhance the effectiveness of carfilzomib in treating multiple myeloma by making cancer cells more sensitive to the drug, even in cases where resistance to carfilzomib has developed. Additionally, ATRA has been shown to inhibit the growth of myeloma cells by interfering with signals that promote their growth. ^{1 2 3 4 5}

Is the combination of ATRA and Carfilzomib safe for treating multiple myeloma?

ATRA and Carfilzomib have been studied separately and in combination for multiple myeloma, showing potential benefits in making cancer cells more sensitive to treatment. However, specific safety data for this combination is not detailed in the available studies, so discussing potential risks with a healthcare provider is important. ^{1 3 4 5 6}

What makes the drug combination of ATRA and Carfilzomib unique for treating multiple myeloma?

The combination of ATRA (All-Trans Retinoic Acid) and Carfilzomib is unique because it pairs a retinoic acid, which is often used in cancer treatments to promote cell differentiation, with Carfilzomib, a proteasome inhibitor that blocks protein breakdown in cancer cells, potentially offering a novel approach to treating multiple myeloma by targeting the cancer cells in two different ways. ^{3 7 8 9 10}

Research Team

Sai Ravi Pingali, MD

Principal Investigator

Houston Methodist Neal Cancer Center

Eligibility Criteria

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

Patient or legal guardian voluntarily can sign informed consent

Life Expectancy ≥ 6 months

I am willing to have a bone marrow biopsy if needed.

Exclusion Criteria

On investigational therapies within 12 weeks of enrollment

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

Or deemed unfit for the study on evaluation by Investigator

Timeline

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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) 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]

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]

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]

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]

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]

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, 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]

References

1. Italy pubmed.ncbi.nlm.nih.gov

All-trans retinoic acid in combination with alpha-interferon and dexamethasone for advanced multiple myeloma. [2013]

2. United States 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. [2022]

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

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

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

RARγ activation sensitizes human myeloma cells to carfilzomib treatment through the OAS-RNase L innate immune pathway. [2023]

5. China pubmed.ncbi.nlm.nih.gov

[Effect of all-trans retinoid acid and G-CSF on growth, differentiation and RARα2 expression of myeloma cells]. [2022]

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

Differential in vitro and in vivo effects of all-trans retinoic acid on the growth of human myeloma cells. [2019]

7. England 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). [2021]

8. England pubmed.ncbi.nlm.nih.gov

Carfilzomib-containing combinations as frontline therapy for multiple myeloma: A meta-analysis of 13 trials. [2018]

9. England pubmed.ncbi.nlm.nih.gov

An overview of the role of carfilzomib in the treatment of multiple myeloma. [2018]

10. France pubmed.ncbi.nlm.nih.gov

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