CFI-400945 + Azacitidine for Leukemia

(TWT-202 Trial)

Recruiting at 8 trial locations

Overseen By Treadwell Therapeutics Clinical Trials

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Treadwell Therapeutics, Inc

Must not be taking: Immunosuppressants, Chemotherapy

Disqualifiers: Recent transplant, Immunotherapy, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: 36 months

72 Participants Needed

Trial Summary

What is the purpose of this trial?

The purpose of this study is to test the safety of an investigational drug called CFI-400945 alone and in combination with azacitidine.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot have had certain treatments like chemotherapy or immunotherapy within 14 days before starting the trial.

What data supports the effectiveness of the drug CFI-400945 + Azacitidine for Leukemia?

Azacitidine has shown effectiveness in treating acute myeloid leukemia (AML) by improving overall survival in older patients and those with specific risk factors. It is also approved for use in patients who cannot undergo intensive therapy, indicating its potential benefit in managing leukemia. ^{1 2 3 4 5}

What is known about the safety of Azacitidine and CFI-400945 for leukemia treatment?

Azacitidine has been used in treating leukemia and related conditions, with common side effects including low blood cell counts, fatigue, and infections. Serious but rare side effects like interstitial lung disease have been reported. The combination of glasdegib and azacitidine showed a safety profile consistent with each drug alone, suggesting it is generally safe for use in leukemia patients. ^{4 6 7 8 9}

What makes the drug CFI-400945 + Azacitidine unique for treating leukemia?

CFI-400945 is a novel drug that, when combined with azacitidine, may offer a new approach to treating leukemia by targeting specific pathways involved in cancer cell growth, potentially providing benefits over existing treatments that primarily focus on different mechanisms. ^{3 10 11 12 13}

Research Team

Gautam Borthakur, M.D.

Principal Investigator

The University of Texas MD Anderson Cancer Centre

Eligibility Criteria

This trial is for adults over 18 with certain blood cancers like AML, MDS, or CMML. It's open to those who have relapsed or didn't respond to previous treatments. Participants should be in good enough health as measured by lab tests and have a performance status of 0 or 1, meaning they are fully active or restricted in physically strenuous activity but can do light work.

Inclusion Criteria

I am older than 18 years.

My AML, MDS, or CMML has not improved after treatment with hypomethylating agents.

My disease has returned or didn't respond to treatment.

Exclusion Criteria

I haven't had any cancer treatments like chemotherapy or immunotherapy in the last 14 days.

I had a stem cell transplant for AML within the last 90 days or am on immunosuppressive therapy for GVHD.

I am on immunosuppressive therapy due to severe side effects from a bone marrow transplant.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive CFI-400945 alone or in combination with azacitidine, with dose escalation and expansion

36 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

4-8 weeks

Treatment Details

Interventions

• Azacitidine
• CFI-400945
• Decitabine

Trial Overview The study is testing the safety of CFI-400945 alone and combined with azacitidine. The participants will either receive just CFI-400945 or both drugs together to see how well they tolerate them and what effect they have on their cancer.

Participant Groups

Group I: 2A: Combination escalation and expansion Experimental Treatment 2 Interventions

Dose escalation and expansion arm with CFI-400945 and azacitidine

Group II: 1A: Monotherapy escalation and expansion Experimental Treatment 1 Intervention

Dose escalation and expansion arm with CFI-400945

Who Is Running the Clinical Trial?

Treadwell Therapeutics, Inc

Lead Sponsor

Trials

4

Recruited

300+

Findings from Research

In a trial involving 214 older patients with untreated acute myeloid leukemia (AML), adding azacitidine to standard chemotherapy did not improve event-free survival or overall survival compared to chemotherapy alone, with median overall survival being 15 months for the azacitidine group and 21 months for the chemotherapy-only group.

While the combination treatment resulted in higher toxicity, with more adverse events reported, it did not lead to a significant difference in early death rates, indicating that azacitidine may not be beneficial for unselected older patients with AML.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Azacitidine in combination with intensive induction chemotherapy in older patients with acute myeloid leukemia: The AML-AZA trial of the Study Alliance Leukemia. Müller-Tidow, C., Tschanter, P., Röllig, C., et al.[2018]

In a study of 149 previously untreated AML patients who were not eligible for intensive chemotherapy, azacitidine (AZA) treatment resulted in a response rate of 27.5% after a median of three cycles, with a best response rate of 33%.

The median overall survival for patients treated with AZA was 9.4 months, with significantly better outcomes for responders (51% two-year survival) compared to non-responders (10% two-year survival), highlighting the importance of cytogenetic factors in predicting treatment response.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Azacitidine in untreated acute myeloid leukemia: a report on 149 patients. Thépot, S., Itzykson, R., Seegers, V., et al.[2014]

Azacitidine is effective for treating adult patients with acute myeloid leukemia (AML) who have 20%-30% blasts and multilineage dysplasia, significantly prolonging median overall survival compared to conventional care, as shown in the AZA-001 phase III trial.

The review also highlights the potential benefits of combining azacitidine with other treatments for AML, suggesting it may enhance patient outcomes further.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Azacitidine for the treatment of patients with acute myeloid leukemia with 20%-30% blasts and multilineage dysplasia. Font, P.[2017]

Oral azacitidine (Onureg, CC-486) has been approved by the FDA for the continued treatment of adult patients with acute myeloid leukemia (AML) who are in complete remission but cannot undergo intensive curative therapy, showing a significant improvement in overall survival compared to placebo in a trial with older adults (≥ 55 years).

While CC-486 is effective, it is associated with gastrointestinal toxicities, fatigue, and pneumonia, and caution is advised regarding dosing, especially in patients with liver issues, as its pharmacokinetics differ from other azacitidine formulations, which could lead to serious risks if substituted incorrectly.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Oral Azacitidine for Continued Treatment of Adults with Acute Myeloid Leukemia Unable to Complete Intensive Curative Therapy. Jen, EY., Wang, X., Li, M., et al.[2023]

In a phase 3 trial involving 488 patients aged 65 and older with newly diagnosed acute myeloid leukemia (AML), azacitidine significantly improved median overall survival to 10.4 months compared to 6.5 months with conventional care regimens (CCRs).

The one-year survival rate was also higher for azacitidine at 46.5% versus 34.2% for CCR, indicating that azacitidine is a promising treatment option for older patients with AML, while maintaining a safety profile consistent with previous studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

International phase 3 study of azacitidine vs conventional care regimens in older patients with newly diagnosed AML with >30% blasts. Dombret, H., Seymour, JF., Butrym, A., et al.[2022]

In a study of 1406 patients receiving azacitidine, the most common severe adverse events were hematologic, with grade 3-4 anemia occurring in 43.4% of patients, which was higher than reported in clinical trials.

Despite the high frequency of adverse events, treatment discontinuation due to these events was low (5.1%), indicating that with proper management, azacitidine can be safely administered to most patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adverse Events in 1406 Patients Receiving 13,780 Cycles of Azacitidine within the Austrian Registry of Hypomethylating Agents-A Prospective Cohort Study of the AGMT Study-Group. Leisch, M., Pfeilstöcker, M., Stauder, R., et al.[2022]

Azacitidine (AZA) was found to be more effective than conventional care in treating patients with higher-risk myelodysplastic syndromes (MDS), chronic myelomonocytic leukemia (CMML), and acute myeloid leukemia (AML), with overall response rates of 27% for MDS, 20% for AML, and 20% for CMML among 83 patients studied.

The treatment showed a median overall survival of 75% at 12 months for MDS and CMML patients, and 60% for AML patients, indicating a promising efficacy, although the most common side effects included myelosuppression and infections.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Real Life Data on Efficacy and Safety of Azacitidine Therapy for Myelodysplastic Syndrome, Chronic Myelomonocytic Leukemia and Acute Myeloid Leukemia. Helbig, G., Chromik, K., Woźniczka, K., et al.[2021]

In a phase 1b study involving 72 patients with newly diagnosed acute myeloid leukemia (AML) and higher-risk myelodysplastic syndromes (MDS), the combination of glasdegib and azacitidine showed an acceptable safety profile, with no significant drug-drug interactions and consistent safety with the individual drugs.

The treatment resulted in overall response rates of 30.0% for AML and 33.3% for MDS, with notable improvements in transfusion independence and a median overall survival of 9.2 months for AML and 15.8 months for MDS, indicating preliminary clinical benefits.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase 1b study of glasdegib + azacitidine in patients with untreated acute myeloid leukemia and higher-risk myelodysplastic syndromes. Sekeres, MA., Schuster, M., Joris, M., et al.[2023]

Azacitidine is an effective treatment for adult patients with myelodysplastic syndromes, chronic myelomonocytic leukemia, and acute myeloid leukemia who cannot undergo standard treatments, but it carries risks of significant adverse events like hematotoxicity and infections.

This report highlights a rare but serious potential side effect of azacitidine: interstitial pneumonitis, as demonstrated in a case involving an 86-year-old woman, suggesting that healthcare providers should monitor for this condition in patients receiving the drug.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Azacitidine-Induced Interstitial Pneumonitis. Verriere, B., Ferreira, V., Denis, E., et al.[2017]

In a phase 3 trial involving 123 patients with FLT3-mutated acute myeloid leukemia (AML) who were ineligible for intensive chemotherapy, the combination of gilteritinib and azacitidine (GIL + AZA) showed significantly higher rates of composite complete remission (CRc) at 58.1% compared to 26.5% for azacitidine alone (P < 0.001).

Despite the higher CRc rates, there was no significant difference in overall survival between the GIL + AZA group (median OS of 9.82 months) and the azacitidine group (median OS of 8.87 months), leading to the study's closure for futility.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase 3 trial of gilteritinib plus azacitidine vs azacitidine for newly diagnosed FLT3mut+ AML ineligible for intensive chemotherapy. Wang, ES., Montesinos, P., Minden, MD., et al.[2023]

In a study of 43 acute myeloid leukemia (AML) patients, the combination of 5-azacytidine (AZA) and sorafenib resulted in a 46% overall response rate, with 27% achieving complete response with incomplete count recovery (CRi) and 16% achieving complete response (CR).

The treatment demonstrated significant FLT3 inhibition, with 64% of patients achieving over 85% inhibition during the first cycle, indicating that the efficacy of the therapy is linked to the plasma concentrations of sorafenib.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase 2 study of azacytidine plus sorafenib in patients with acute myeloid leukemia and FLT-3 internal tandem duplication mutation. Ravandi, F., Alattar, ML., Grunwald, MR., et al.[2021]

Azacitidine is an effective and well-tolerated treatment for patients with higher-risk myelodysplastic syndromes (MDS) and acute myeloid leukaemia (AML), including older patients who are ineligible for stem cell transplants, as demonstrated in pivotal phase 3 trials.

It is the only approved hypomethylating agent that has been shown to prolong overall survival compared to conventional care, making it the recommended first-line treatment for most patients with higher-risk MDS.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Azacitidine: A Review in Myelodysplastic Syndromes and Acute Myeloid Leukaemia. Scott, LJ.[2022]

Azacitidine is an approved treatment for myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML), showing benefits even in patients with higher blast counts, as demonstrated in recent phase III trials.

Oral azacitidine (CC-486) has shown promising biological activity and tolerability in early studies, potentially offering a more convenient treatment option for patients with MDS and AML, with ongoing investigations into extended dosing schedules.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Oral Azacitidine (CC-486) for the Treatment of Myelodysplastic Syndromes and Acute Myeloid Leukemia. Cogle, CR., Scott, BL., Boyd, T., et al.[2023]

References

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

Azacitidine in combination with intensive induction chemotherapy in older patients with acute myeloid leukemia: The AML-AZA trial of the Study Alliance Leukemia. [2018]

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

Azacitidine in untreated acute myeloid leukemia: a report on 149 patients. [2014]

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

Azacitidine for the treatment of patients with acute myeloid leukemia with 20%-30% blasts and multilineage dysplasia. [2017]

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

FDA Approval Summary: Oral Azacitidine for Continued Treatment of Adults with Acute Myeloid Leukemia Unable to Complete Intensive Curative Therapy. [2023]

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

International phase 3 study of azacitidine vs conventional care regimens in older patients with newly diagnosed AML with >30% blasts. [2022]

6. Switzerland pubmed.ncbi.nlm.nih.gov

Adverse Events in 1406 Patients Receiving 13,780 Cycles of Azacitidine within the Austrian Registry of Hypomethylating Agents-A Prospective Cohort Study of the AGMT Study-Group. [2022]

7. Switzerland pubmed.ncbi.nlm.nih.gov

Real Life Data on Efficacy and Safety of Azacitidine Therapy for Myelodysplastic Syndrome, Chronic Myelomonocytic Leukemia and Acute Myeloid Leukemia. [2021]

8. Germany pubmed.ncbi.nlm.nih.gov

A phase 1b study of glasdegib + azacitidine in patients with untreated acute myeloid leukemia and higher-risk myelodysplastic syndromes. [2023]

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

Azacitidine-Induced Interstitial Pneumonitis. [2017]

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

Phase 3 trial of gilteritinib plus azacitidine vs azacitidine for newly diagnosed FLT3mut+ AML ineligible for intensive chemotherapy. [2023]

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

Phase 2 study of azacytidine plus sorafenib in patients with acute myeloid leukemia and FLT-3 internal tandem duplication mutation. [2021]

12. New Zealand pubmed.ncbi.nlm.nih.gov

Azacitidine: A Review in Myelodysplastic Syndromes and Acute Myeloid Leukaemia. [2022]

13. England pubmed.ncbi.nlm.nih.gov

Oral Azacitidine (CC-486) for the Treatment of Myelodysplastic Syndromes and Acute Myeloid Leukemia. [2023]