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

What You Need to Know Before You Apply

What is the purpose of this trial?

The trial aims to determine the appropriate dose and assess the side effects of combining nintedanib and azacitidine for treating acute myeloid leukemia (AML) in older adults who cannot or choose not to undergo intensive chemotherapy. Nintedanib is an investigational drug, not yet FDA-approved for this cancer type, while azacitidine (also known as Vidaza or 5-azacytidine) is already used for related blood disorders. The study seeks participants with AML characterized by specific genetic changes, such as HOX gene overexpression, who are not interested in or suitable for intensive chemotherapy.

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 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.

Is there any evidence suggesting that this treatment is likely to be safe for humans?

Research has shown that azacitidine is generally well-tolerated and has been used since 2004 to treat certain blood cancers related to AML. Past studies have demonstrated a good safety record for azacitidine, with manageable side effects.

Research suggests that the combination of nintedanib and azacitidine is safe, although nintedanib remains under study. The combination is considered very safe, but like any treatment, it may have some side effects.

As this study is in its early stages, it primarily focuses on determining the right dose of nintedanib with azacitidine and monitoring for any side effects. The combination is still being tested for safety and effectiveness in people. Trial participants are closely monitored to assess their response to the treatment. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of nintedanib and azacitidine for treating Acute Myeloid Leukemia (AML) because it offers a novel approach compared to current treatments. While the standard care for AML typically involves chemotherapy drugs like cytarabine and anthracyclines, this combination uses nintedanib, a multi-kinase inhibitor, to target specific pathways involved in cancer cell growth and survival. Additionally, azacitidine is known for its role in altering DNA methylation, which can help reactivate tumor suppressor genes. This dual-action strategy could potentially enhance treatment effectiveness and offer new hope for patients with AML.

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

Research has shown that azacitidine effectively treats myelodysplastic syndrome, a condition related to acute myeloid leukemia (AML). It is often recommended for older adults who cannot tolerate strong chemotherapy. In this trial, participants will receive a combination of azacitidine and nintedanib. While researchers continue to study nintedanib for AML, it blocks certain processes that help cancer cells grow. Early studies suggest that combining nintedanib with azacitidine might enhance treatment effectiveness. This combination aims to more effectively target cancer in patients with specific genetic traits, offering hope for those unable to undergo intensive treatments. ^{2 3 6 7 8}

Who Is on the Research Team?

Jessica Altman, MD

Principal Investigator

Northwestern University

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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]

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]

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]

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]

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]

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]

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]

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