Narazaciclib + Dexamethasone for Multiple Myeloma

Overseen By Adriana Rossi, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Adriana Rossi

Must be taking: Dexamethasone

Must not be taking: CYP2C8, CYP3A4

Disqualifiers: Active infections, Cardiac conditions, others

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

Compensation: Varies

Number of Visits: 28

Duration: Up to 2 years

36 Participants Needed

Trial Summary

What is the purpose of this trial?

Multiple myeloma (MM) is a malignancy characterized by uncontrolled proliferation of plasma cells for which there is an urgent and unmet need to develop new, effective therapeutics. Onconova Therapeutics has developed a first-in-class oral inhibitor of CDK4 and ARK5 ON 123300 (NARAZACICLIB) which shows potent anti-myeloma activity in vitro and in vivo in preclinical models, and is undergoing evaluation in Phase 1-2 trials worldwide. In this study, the researchers will test the safety and preliminary efficacy of inhibition of CDK4 and ARK5 by ON 123300 (NARAZACICLIB) in combination with dexamethasone in myeloma patients in a Phase I/II clinical trial.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, it mentions that you should not be taking strong inducers or inhibitors of certain liver enzymes (CYP2C8 and CYP3A4) and that all previous cancer therapies should be stopped at least 14 days before starting the trial.

What data supports the effectiveness of the drug Narazaciclib + Dexamethasone for Multiple Myeloma?

Dexamethasone, a part of the treatment, has been used effectively in multiple myeloma for many years, often combined with other drugs to improve patient outcomes. It is known to enhance the effectiveness of other treatments in multiple myeloma, suggesting potential benefits when combined with new drugs like Narazaciclib. ^{1 2 3 4 5}

What safety data exists for dexamethasone in combination treatments for multiple myeloma?

Dexamethasone has been studied in combination with other drugs for multiple myeloma, and these studies generally assess both the effectiveness and safety of the treatment. While specific safety data for narazaciclib is not provided, dexamethasone is commonly used and its safety profile is well-documented in these contexts. ^{1 2 4 6 7}

What makes the drug Narazaciclib + Dexamethasone unique for treating multiple myeloma?

Narazaciclib combined with dexamethasone is unique because it involves a novel compound, Narazaciclib, which is not commonly used in standard multiple myeloma treatments. This combination may offer a new mechanism of action or improved outcomes compared to existing therapies that typically include dexamethasone with other agents like bortezomib or ixazomib. ^{1 2 3 5 8}

Research Team

Adriana Rossi, MD

Principal Investigator

Icahn School of Medicine at Mount Sinai

Samir Parekh, MBBS

Principal Investigator

Icahn School of Medicine at Mount Sinai

Eligibility Criteria

This trial is for people with multiple myeloma, a type of blood cancer, who have tried other treatments that didn't work or stopped working. Participants should be able to take oral medication and handle steroid treatment.

Inclusion Criteria

Able to provide a signed Written Informed Consent before any study-related procedure

I am able to care for myself but may not be able to do heavy physical work.

I am 18 years old or older.

Exclusion Criteria

I agree to use two effective birth control methods if I can have children.

I have had a stem cell transplant or other cell therapy within the last 2 months.

I do not have specific blood disorders or brain involvement.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive ON 123300 (NARAZACICLIB) and dexamethasone in 28-day cycles, continuing as long as the drug shows anti-myeloma activity and the patient does not exhibit any dose-limiting toxicities.

Up to 2 years

Per Cycle/Every 28 Days

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Dexamethasone
• Narazaciclib

Trial Overview Researchers are testing ON 123300 (Narazaciclib), a new pill that targets specific proteins in cancer cells, combined with dexamethasone, a steroid. They want to see if this combo is safe and helps control the disease better than current options.

Participant Groups

Group I: ON 123300 (NARAZACICLIB) + dexamethasone Experimental Treatment 2 Interventions

Participants will continue 28-day cycles of ON 123300 (NARAZACICLIB) + dexamethasone as long as the drug shows anti-myeloma activity with a disease response ≥PR (PR, VGPR, CR) and the patient does not exhibit any DLTs and the study is open. Patients will continue the regimen until disease progression/intolerable toxicity/death, withdrawal OR for a maximum up to 2 years after enrollment.

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

Approved in European Union as Dexamethasone for:

• Inflammation
• Allergic reactions
• Respiratory diseases
• Skin conditions
• Eye diseases
• Immune system disorders

Approved in United States as Dexamethasone for:

• Inflammatory conditions
• Allergic states
• Respiratory diseases
• Blood disorders
• Neoplastic diseases
• Nervous system disorders

Approved in Canada as Dexamethasone for:

• Inflammation
• Allergic reactions
• Respiratory diseases
• Skin conditions
• Eye diseases

Approved in Japan as Dexamethasone for:

• Inflammatory conditions
• Allergic states
• Respiratory diseases
• Blood disorders

Who Is Running the Clinical Trial?

Adriana Rossi

Lead Sponsor

Trials

1

Recruited

40+

Findings from Research

In a phase II study involving 65 intermediate-fit patients with newly diagnosed multiple myeloma, the combination of Ixazomib, Daratumumab, and low-dose dexamethasone resulted in a 71% overall response rate during induction therapy, indicating its efficacy as a first-line treatment.

While the treatment improved global quality of life significantly, it also led to frequent dose modifications due to low-grade polyneuropathy, suggesting that the regimen's long-term tolerability may be a concern for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ixazomib, daratumumab and low-dose dexamethasone in intermediate-fit patients with newly diagnosed multiple myeloma: an open-label phase 2 trial. Groen, K., Stege, CAM., Nasserinejad, K., et al.[2023]

In two phase 2 studies involving 256 patients with relapsed or refractory multiple myeloma, adding dexamethasone to bortezomib improved treatment responses, with 18% of patients in the SUMMIT study and 33% in the CREST study showing better outcomes.

The combination therapy did not significantly increase the type or number of adverse events, indicating that dexamethasone can enhance efficacy without adding prohibitive toxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bortezomib in combination with dexamethasone for the treatment of patients with relapsed and/or refractory multiple myeloma with less than optimal response to bortezomib alone. Jagannath, S., Richardson, PG., Barlogie, B., et al.[2022]

Dexamethasone remains a crucial part of multiple myeloma treatment, enhancing the effectiveness of novel therapies and improving response rates across all treatment phases.

New formulations of dexamethasone aim to reduce the number of pills patients need to take, which could help improve adherence to treatment and minimize medication errors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

From mechanism to resistance - changes in the use of dexamethasone in the treatment of multiple myeloma. Rosenberg, AS.[2023]

In a study of 80 newly diagnosed multiple myeloma patients, ixazomib combined with dexamethasone showed a higher complete remission rate compared to lenalidomide with dexamethasone, indicating it may be a more effective treatment option.

Both treatment combinations resulted in similar progression-free survival and overall survival rates, but ixazomib was associated with a higher incidence of mild peripheral neuropathy, suggesting it is generally safe but may have some side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A comparison of the efficacy and safety of ixazomib and lenalidomide combined with dexamethasone in the treatment of multiple myeloma. Zheng, Z., Lin, K.[2021]

In a study of 90 patients with relapsed/refractory multiple myeloma, the combination of ixazomib, thalidomide, and dexamethasone showed a 51.1% overall response rate, indicating significant efficacy in treating this condition.

The treatment was well tolerated, with rare occurrences of severe toxicities, and ixazomib maintenance therapy improved response depth in 12.4% of patients, suggesting a beneficial long-term effect.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ixazomib-Thalidomide-Dexamethasone for induction therapy followed by Ixazomib maintenance treatment in patients with relapsed/refractory multiple myeloma. Ludwig, H., Poenisch, W., Knop, S., et al.[2021]

The combination of ixazomib, cyclophosphamide, and dexamethasone (ICd) followed by ixazomib maintenance showed a 33% complete response (CR) and very good partial response (VGPR) rate in elderly patients with newly diagnosed multiple myeloma, indicating its efficacy as a treatment option.

The treatment was generally well-tolerated, with 73% of patients experiencing grade ≥3 adverse events, but only 3% discontinued maintenance due to adverse effects, suggesting a manageable safety profile for this regimen.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

All-oral ixazomib, cyclophosphamide, and dexamethasone for transplant-ineligible patients with newly diagnosed multiple myeloma. Dimopoulos, MA., Grosicki, S., Jędrzejczak, WW., et al.[2020]

In a study of 16 patients with relapsed or refractory multiple myeloma, the combination of bortezomib and dexamethasone resulted in a high clinical response rate of 87.5%, with 6 patients achieving near complete response.

The treatment was associated with manageable side effects, primarily gastrointestinal issues and thrombocytopenia, which were alleviated with supportive care, indicating a favorable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Bortezomib in combination with dexamethasone for the treatment of relapsed or refractory multiple myeloma]. Yuan, ZG., Hou, J., Zhou, F., et al.[2015]

In a phase 3 trial involving 402 patients with previously treated multiple myeloma, the combination of selinexor, bortezomib, and dexamethasone resulted in a median progression-free survival of 13.93 months, significantly longer than the 9.46 months observed with standard bortezomib and dexamethasone (p=0.0075).

The selinexor combination therapy was associated with lower rates of peripheral neuropathy (21%) compared to the standard treatment (34%), suggesting a safer profile regarding this common side effect.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Once-per-week selinexor, bortezomib, and dexamethasone versus twice-per-week bortezomib and dexamethasone in patients with multiple myeloma (BOSTON): a randomised, open-label, phase 3 trial. Grosicki, S., Simonova, M., Spicka, I., et al.[2022]

References

1. England pubmed.ncbi.nlm.nih.gov

Ixazomib, daratumumab and low-dose dexamethasone in intermediate-fit patients with newly diagnosed multiple myeloma: an open-label phase 2 trial. [2023]

2. Italy pubmed.ncbi.nlm.nih.gov

Bortezomib in combination with dexamethasone for the treatment of patients with relapsed and/or refractory multiple myeloma with less than optimal response to bortezomib alone. [2022]

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

From mechanism to resistance - changes in the use of dexamethasone in the treatment of multiple myeloma. [2023]

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

A comparison of the efficacy and safety of ixazomib and lenalidomide combined with dexamethasone in the treatment of multiple myeloma. [2021]

5. England pubmed.ncbi.nlm.nih.gov

Ixazomib-Thalidomide-Dexamethasone for induction therapy followed by Ixazomib maintenance treatment in patients with relapsed/refractory multiple myeloma. [2021]

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

All-oral ixazomib, cyclophosphamide, and dexamethasone for transplant-ineligible patients with newly diagnosed multiple myeloma. [2020]

7. China pubmed.ncbi.nlm.nih.gov

[Bortezomib in combination with dexamethasone for the treatment of relapsed or refractory multiple myeloma]. [2015]

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

Once-per-week selinexor, bortezomib, and dexamethasone versus twice-per-week bortezomib and dexamethasone in patients with multiple myeloma (BOSTON): a randomised, open-label, phase 3 trial. [2022]