Nintedanib + Azacitidine for Acute Myeloid Leukemia

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Northwestern University

Must not be taking: Anticoagulants, Antiplatelets, VEGFR inhibitors

Disqualifiers: Cardiovascular diseases, CNS leukemia, others

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

Compensation: Varies

Number of Visits: 9

Duration: 24 weeks

44 Participants Needed

Trial Summary

What is the purpose of this trial?

The purpose of this study is to find the appropriate dose of the study drug nintedanib when combined with azacitidine and the associated side effects of the combination in older adults with AML characterized by HOX gene overexpression who are not interested in or not considered fit for standard intensive chemotherapy. The use of the study drug nintedanib in this study is investigational. Investigational means that this medication has not yet been approved by the FDA to treat this type of cancer. Azacitidine received FDA Approval in 2004 for myelodysplastic syndrome (a blood cancer related to AML) and has a National Comprehensive Cancer Network (NCCN) guideline recommendation for treatment of older adults who are not candidates for or decline intensive remission induction therapy. We expect participation to continue in this study based on each participant's response to the drug, and ability to tolerate treatment. Participants may continue to receive study treatments for 6 cycles (one cycle is 28 days long). If the 6 cycles of treatment is completed, participants may be moved on to a maintenance phase of treatment. Treatment will continue until the participant's leukemia gets worse, or they experience serious side effects, have a break in treatment for more than 56 days or the study doctor feels it is best for study treatments to stop.

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop taking your current medications. However, you cannot have received certain treatments like chemotherapy, hormone therapy, or investigational drugs within 14 days before starting the trial, except for hydroxyurea and leukapheresis, which can continue during the study.

What data supports the effectiveness of the drug combination Nintedanib and Azacitidine for treating Acute Myeloid Leukemia?

Azacitidine has been shown to be effective in treating acute myeloid leukemia (AML) and other related blood disorders, improving survival and treatment response. Additionally, combining azacitidine with other drugs, like ivosidenib, has been shown to enhance effectiveness, suggesting potential benefits of combining it with Nintedanib. ^{1 2 3 4 5}

Is the combination of Nintedanib and Azacitidine safe for treating acute myeloid leukemia?

Azacitidine has been used safely in patients with acute myeloid leukemia and other blood disorders, with common side effects including low blood cell counts, fatigue, and fever. Serious side effects are rare, and the treatment is generally well-tolerated with proper management. ^{1 2 6 7 8}

What makes the drug Nintedanib + Azacitidine unique for treating acute myeloid leukemia?

The combination of Nintedanib and Azacitidine is unique because it combines two drugs with different mechanisms: Azacitidine, which is a hypomethylating agent that can prolong survival in certain blood cancers, and Nintedanib, which is typically used for other conditions like lung diseases, potentially offering a novel approach for treating acute myeloid leukemia. ^{1 4 7 8 9}

Research Team

Jessica Altman, MD

Principal Investigator

Northwestern University

Eligibility Criteria

This trial is for adults with Acute Myeloid Leukemia (AML) showing HOX gene overexpression, FLT3-ITD, or specific genetic changes. Suitable candidates are those unfit for intensive chemotherapy, have an ECOG performance status of 0-3, and acceptable organ function tests. Women must not be pregnant and participants should agree to use contraception.

Inclusion Criteria

Total bilirubin ? 1.5 x of institutional ULN within14 days prior to registration

Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SPGT]) 1.5 X institutional upper limit of normal (ULN) within14 days prior to registration

NOTE: A FOCBP is any woman (regardless of sexual orientation, having undergone a tubal ligation, or remaining celibate by choice) who meets the following criteria:

Exclusion Criteria

Exceptions for prior treatments are:

Patients with hypersensitivity to mannitol are not eligible; patients who have known hypersensitivity to peanut or soya, any other trial drug, or their excipients, or to contrast media are not eligible

I do not have active hepatitis, HIV, or a history of substance abuse.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive nintedanib orally twice daily on days 1-28 and azacitidine intravenously or subcutaneously on days 1-7. Treatment repeats every 28 days for up to 6 courses.

24 weeks

6 cycles of treatment

Maintenance

After completion of 6 courses, participants may discontinue treatment, receive nintedanib every 4-8 weeks, or receive nintedanib and azacitidine every 4-8 weeks.

Variable, based on participant response

Follow-up

Participants are monitored for safety and effectiveness after treatment completion. Follow-up occurs every 3 months for 12 months and then every 6 months for up to 24 months.

24 months

Every 3 months for 12 months, then every 6 months

Treatment Details

Interventions

• Azacitidine
• Nintedanib

Trial Overview The study is testing the combination of Nintedanib (not yet FDA-approved for AML) with Azacitidine (approved for a related blood cancer). The goal is to determine the right dose and side effects over six 28-day cycles, possibly followed by maintenance treatment unless adverse events occur.

Participant Groups

Group I: Treatment (nintedanib, azacitidine) Experimental Treatment 3 Interventions

Participants receive nintedanib PO BID on days 1-28 and azacitidine IV or SC on days 1-7. Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. After completion of 6 courses, participants may discontinue treatment, receive nintedanib every 4-8 weeks, or receive nintedanib and azacitidine every 4-8 weeks.

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

Approved in European Union as Vidaza for:

• Acute myeloid leukemia
• Chronic myelomonocytic leukemia
• Myelodysplastic syndromes

Approved in United States as Vidaza for:

• Myelodysplastic syndromes
• Chronic myelomonocytic leukemia

Approved in Canada as Vidaza for:

• Myelodysplastic syndromes
• Acute myeloid leukemia

Approved in Japan as Vidaza for:

• Myelodysplastic syndromes
• Acute myeloid leukemia

Who Is Running the Clinical Trial?

Northwestern University

Lead Sponsor

Trials

1,674

Recruited

989,000+

Boehringer Ingelheim

Industry Sponsor

Trials

2,566

Recruited

16,150,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Robert H. Lurie Cancer Center

Collaborator

Trials

23

Recruited

1,800+

Findings from Research

The Vidaza Access Program in Belgium successfully facilitated access to azacitidine treatment for 175 patients with myelodysplastic syndromes (MDS), acute myeloid leukemia (AML), and chronic myelomonocytic leukemia (CMML) by streamlining the approval process for patient dossiers.

Out of the 175 patient dossiers submitted, 163 were approved by Celgene, demonstrating the program's effectiveness in ensuring timely treatment initiation without financial risk to hospitals, which is crucial for patient outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Azacitidine access program for Belgian patients with myelodysplastic syndromes, acute myeloid leukemia or chronic myelomonocytic leukemia. Meers, S., Selleslag, D., Potier, H., et al.[2018]

In a real-life study of 49 patients with myelodysplastic syndrome (MDS), acute myeloid leukaemia (AML), and chronic myelomonocytic leukaemia (CMML), azacitidine demonstrated a clinically acceptable safety profile, with 67.3% of patients experiencing treatment-related adverse events.

Efficacy results showed that 41.4% of MDS and CMML patients achieved a complete or partial response, and 43.8% of transfusion-dependent patients became transfusion-independent, with a median overall survival of 490 days.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and efficacy of azacitidine in Belgian patients with high-risk myelodysplastic syndromes, acute myeloid leukaemia, or chronic myelomonocytic leukaemia: results of a real-life, non-interventional post-marketing survey. Beguin, Y., Selleslag, D., Meers, S., et al.[2015]

In a study of 687 patients with higher-risk myelodysplastic syndromes (MDS) and oligoblastic acute myeloid leukemia (AML) treated with 5-azacytidine (5-AZA), factors such as the revised International Prognostic Scoring System (IPSS-R), Eastern Cooperative Oncology Group Performance Status (ECOG PS), and high baseline serum ferritin levels were found to independently predict response to treatment and overall survival.

The study developed new modified risk classification systems (H-PSS and H-PSS-R) that better predict overall survival and leukemia-free survival in patients treated with 5-AZA, demonstrating improved predictive power compared to previous models.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Serum ferritin and ECOG performance status predict the response and improve the prognostic value of IPSS or IPSS-R in patients with high-risk myelodysplastic syndromes and oligoblastic acute myeloid leukemia treated with 5-azacytidine: a retrospective analysis of the Hellenic national registry of myelodysplastic and hypoplastic syndromes. Papageorgiou, SG., Kotsianidis, I., Bouchla, A., et al.[2022]

In a study of 149 patients with higher-risk myelodysplastic syndromes (MDS), chronic myelomonocytic leukemia (CMML), and acute myeloid leukemia (AML), azacitidine treatment resulted in a median progression-free survival (PFS) of 10.9 months and an overall survival (OS) of 14.1 months, demonstrating its effectiveness in a real-world clinical setting.

The safety profile of azacitidine was consistent with previous clinical trials, and factors such as Eastern Cooperative Oncology Group (ECOG) performance status and red blood cell transfusion prior to treatment were identified as predictive factors for better PFS.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Impact of performance status and transfusion dependency on outcome of patients with myelodysplastic syndrome, acute myeloid leukemia and chronic myelomonocytic leukemia treated with azacitidine (PIAZA study). Wehmeyer, J., Zaiss, M., Losem, C., et al.[2019]

A phase III study demonstrated that combining azacitidine with the IDH1 inhibitor ivosidenib significantly improves treatment outcomes for patients with acute myeloid leukemia who cannot undergo intensive chemotherapy.

The combination therapy tripled overall survival rates and enhanced complete remission and event-free survival compared to azacitidine alone, indicating a substantial efficacy boost from this drug pairing.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ivosidenib Boosts OS with Azacitidine in AML. [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 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 (Vidaza) is the only drug approved in the EU that significantly prolongs survival in adults with high-risk myelodysplastic syndromes (MDS) and acute myeloid leukaemia (AML), making it a crucial treatment option for patients not eligible for stem cell transplantation.

The treatment is associated with a lower risk of AML progression and higher rates of remission and blood transfusion independence, while maintaining an acceptable safety profile, with peripheral cytopenias being the most common side effect.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Azacitidine: a review of its use in higher-risk myelodysplastic syndromes/acute myeloid leukaemia. Keating, GM.[2021]

Azacitidine significantly improves response rates and overall survival in patients with myelodysplastic syndromes (MDS) and acute myeloid leukaemia (AML), with a median survival increase of 9.4 months compared to conventional care in higher-risk patients.

The treatment is generally well tolerated, with peripheral cytopenias being the most common side effect, along with gastrointestinal issues and injection-site reactions, making it a viable option for elderly patients as well.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Azacitidine: a review of its use in the management of myelodysplastic syndromes/acute myeloid leukaemia. Keating, GM.[2022]

References

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

Azacitidine access program for Belgian patients with myelodysplastic syndromes, acute myeloid leukemia or chronic myelomonocytic leukemia. [2018]

2. England pubmed.ncbi.nlm.nih.gov

Safety and efficacy of azacitidine in Belgian patients with high-risk myelodysplastic syndromes, acute myeloid leukaemia, or chronic myelomonocytic leukaemia: results of a real-life, non-interventional post-marketing survey. [2015]

3. England pubmed.ncbi.nlm.nih.gov

Serum ferritin and ECOG performance status predict the response and improve the prognostic value of IPSS or IPSS-R in patients with high-risk myelodysplastic syndromes and oligoblastic acute myeloid leukemia treated with 5-azacytidine: a retrospective analysis of the Hellenic national registry of myelodysplastic and hypoplastic syndromes. [2022]

4. England pubmed.ncbi.nlm.nih.gov

Impact of performance status and transfusion dependency on outcome of patients with myelodysplastic syndrome, acute myeloid leukemia and chronic myelomonocytic leukemia treated with azacitidine (PIAZA study). [2019]

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

Ivosidenib Boosts OS with Azacitidine in AML. [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. New Zealand pubmed.ncbi.nlm.nih.gov

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

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

Azacitidine: a review of its use in higher-risk myelodysplastic syndromes/acute myeloid leukaemia. [2021]

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

Azacitidine: a review of its use in the management of myelodysplastic syndromes/acute myeloid leukaemia. [2022]