Gilteritinib + Momelotinib for Acute Myeloid Leukemia

Overseen By Nicholas Short, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: M.D. Anderson Cancer Center

Must not be taking: QT prolonging medications

Disqualifiers: Congenital long QT, Active infection, Cardiac failure, CNS leukemia, others

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

Compensation: Varies

Number of Visits: Unknown

20 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine the optimal dose of momelotinib when combined with gilteritinib for treating Acute Myeloid Leukemia (AML), a type of blood cancer. It consists of two phases: the first identifies the appropriate dose of momelotinib, and the second confirms it while all participants receive gilteritinib. Individuals with AML who have specific FLT3 mutations and have experienced a relapse or lack of response to treatment may be suitable candidates. Participants must be able to swallow pills and have no severe infections or heart problems. As a Phase 1, Phase 2 trial, this research seeks to understand how the treatment works in people and measure its effectiveness in an initial, smaller group.

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 taken any investigational antileukemic or chemotherapy agents in the last 7 days before joining the study. You can continue using corticosteroids, hydroxyurea, and cytarabine if needed for reducing white blood cell counts.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that both gilteritinib and momelotinib have been studied separately and together for their safety in treating certain types of leukemia. The FDA has already approved gilteritinib for treating acute myeloid leukemia (AML) with a specific mutation, providing extensive safety data. It is generally well-tolerated, though some patients may experience side effects like tiredness or elevated liver enzyme levels.

Momelotinib is not yet approved for AML, but it has been tested for other conditions. Early studies suggest it is also generally well-tolerated, with common side effects such as nausea and anemia (a low red blood cell count).

When used together, studies so far indicate that the combination's safety is similar to each drug on its own. However, as this combination is still under investigation, ongoing research is crucial to determine the safest dose and understand any potential risks. Researchers will closely monitor participants for any side effects to ensure their well-being during the trial. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about gilteritinib and momelotinib for treating acute myeloid leukemia (AML) because they target the disease in novel ways. While most AML treatments, like chemotherapy, broadly attack rapidly dividing cells, gilteritinib specifically inhibits a protein called FLT3 that is often mutated in AML, potentially leading to more effective outcomes with fewer side effects. Momelotinib, on the other hand, uniquely targets the JAK1 and JAK2 pathways, which are involved in blood cell production and inflammation, offering a new angle to combat the disease. Together, these drugs could provide a powerful, targeted approach to AML treatment, offering hope for better patient outcomes.

What evidence suggests that this trial's treatments could be effective for acute myeloid leukemia?

Research has shown that gilteritinib effectively treats acute myeloid leukemia (AML) with FLT3 mutations. One study found that patients lived longer than those receiving standard chemotherapy, with an average survival of about 11 months, and nearly half living at least a year. In this trial, all participants will receive gilteritinib. Researchers are studying momelotinib to determine if it can enhance the effects of gilteritinib, though less information is available on the effectiveness of this combination. The hypothesis is that momelotinib might boost gilteritinib's effects in treating AML. ^{1 2 3 4 6}

Who Is on the Research Team?

Nicholas Short

Principal Investigator

MD Anderson Center

Are You a Good Fit for This Trial?

Adults over 18 with relapsed or refractory FLT3-mutated Acute Myeloid Leukemia (AML) can join this trial. They should be relatively stable (ECOG ≤3), have acceptable liver function tests, and a creatinine clearance of ≥30 mL/min. Participants must agree to use effective contraception during the study and for four months after.

Inclusion Criteria

Willingness to use adequate contraception

Ability to understand and the willingness to sign a written informed consent document

I am willing to use reliable birth control methods during the study and for 4 months after it ends.

Exclusion Criteria

Participants with psychiatric illness/social situations that would limit compliance with study requirements

I am HIV positive.

Pregnant women

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose Escalation Phase 1

Participants receive momelotinib at varying doses to establish the minimum safe and biologically-effective dose in combination with gilteritinib

35 days

Daily administration

Phase 2

Participants receive momelotinib at the recommended dose found in Phase 1, along with gilteritinib

28 days per cycle

Daily administration

Follow-up

Participants are monitored for safety and effectiveness after treatment

Average of 1 year

What Are the Treatments Tested in This Trial?

Interventions

• Gilteritinib
• Momelotinib

Trial Overview The trial is testing the combination of two drugs, Momelotinib and Gilteritinib, to find out the safest dose that works for AML patients who have specific genetic changes in their leukemia cells.

How Is the Trial Designed?

Group I: Dose Escalation Phase 1/Phase 2 Experimental Treatment 2 Interventions

Participants who are enrolled in Part 1, the dose of momelotinib you receive will depend on when you join this study. Participants you are enrolled in Part 2, you will receive momelotinib at the recommended dose that was found in Part 1. All participants will receive the same dose level of gilteritinib. Cycle 1 will be 35 days in length. Momelotinib will be administered once daily by mouth on days 1-35. Gilteritinib will be administered once daily by mouth on days 8-35. Cycles 2 and beyond will be 28 days in length. Momelotinib and gilteritinib will be administered once daily by mouth on days 1-28.

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

Approved in United States as Xospata for:

• Acute myeloid leukemia (AML) with FLT3 mutation

Approved in European Union as Xospata for:

• Acute myeloid leukemia (AML) with FLT3 mutation

Approved in Japan as Xospata for:

• Acute myeloid leukemia (AML) with FLT3 mutation

Who Is Running the Clinical Trial?

M.D. Anderson Cancer Center

Lead Sponsor

Trials

3,107

Recruited

1,813,000+

GlaxoSmithKline

Industry Sponsor

Trials

4,834

Recruited

8,389,000+

Headquarters

London, UK

Known For

Vaccines & Medicines

Top Products

**Advair (salmeterol, fluticasone propionate)**, **Shingrix (shingles vaccine)**, **Augmentin (amoxicillin/clavulanate potassium)**, **Ventolin (salbutamol sulfate)

Dame Emma Walmsley

GlaxoSmithKline

Chief Executive Officer since 2017

MA in Classics and Modern Languages from Oxford University

Dr. Hal Barron

GlaxoSmithKline

Chief Medical Officer since 2018

MD from Harvard Medical School

Published Research Related to This Trial

Gilteritinib, an FLT3 inhibitor approved by the FDA for relapsed or refractory acute myeloid leukemia, showed a 21% complete remission rate and a median overall survival of 9.3 months compared to 5.6 months with standard chemotherapy, indicating its efficacy in improving patient outcomes.

The treatment comes with safety warnings for serious conditions like differentiation syndrome and QT prolongation, necessitating careful monitoring of patients' heart rhythms and blood chemistry during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Gilteritinib for Relapsed or Refractory Acute Myeloid Leukemia with a FLT3 Mutation. Pulte, ED., Norsworthy, KJ., Wang, Y., et al.[2023]

Momelotinib, a JAK inhibitor, shows promise in treating myelofibrosis by improving anemia, spleen size, and symptoms, with overall survival (OS) and leukemia-free survival (LFS) rates comparable to ruxolitinib in JAKi-naïve patients.

Achieving transfusion independence (TI) is linked to better survival outcomes, highlighting momelotinib's effectiveness in promoting erythropoiesis and its potential role in treatment strategies for myelofibrosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Overall survival in the SIMPLIFY-1 and SIMPLIFY-2 phase 3 trials of momelotinib in patients with myelofibrosis. Mesa, R., Harrison, C., Oh, ST., et al.[2022]

Gilteritinib fumarate is an effective and well-tolerated treatment for patients with relapsing or refractory FLT3-positive acute myeloid leukemia, showing promise in managing the disease with lower toxicity compared to earlier treatments.

The drug's oral formulation makes it suitable for a wide range of patients, including elderly and frail individuals, allowing for outpatient treatment that reduces hospitalization risks and costs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Therapeutic Management of Patients with FLT3 + Acute Myeloid Leukemia: Case Reports and Focus on Gilteritinib Monotherapy. Bocchia, M., Carella, AM., Mulè, A., et al.[2022]

Gilteritinib has been approved in the EU as a monotherapy for adult patients with relapsed or refractory acute myeloid leukemia (AML) with a FLT3 mutation, showing a significant improvement in overall survival (9.3 months) compared to salvage chemotherapy (5.6 months) in a phase III study with 371 participants.

The safety profile of gilteritinib is considered manageable, with common side effects including increases in liver enzymes and creatine phosphokinase, as well as gastrointestinal and general symptoms like fatigue and nausea.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The European Medicines Agency Review of Gilteritinib (Xospata) for the Treatment of Adult Patients with Relapsed or Refractory Acute Myeloid Leukemia with an FLT3 Mutation. Tzogani, K., Røshol, H., Olsen, HH., et al.[2021]

Gilteritinib is an effective treatment for adults with relapsed or refractory acute myeloid leukemia (AML) with FLT3 mutations, showing advantages in survival and a generally favorable safety profile.

While gilteritinib is associated with common side effects like diarrhea and nausea, serious gastrointestinal events such as GI hemorrhage and perforation have been reported, highlighting the need for careful monitoring in patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Severe Gastrointestinal Toxicity Following the Use of Gilteritinib: A Case Series and Analysis of Postmarketing Surveillance Data. Gozzo, L., Nardo, A., Brancati, S., et al.[2023]

Momelotinib, a novel JAK1 and JAK2 inhibitor that also targets ACVR1, has shown significant improvements in symptoms of myelofibrosis, including splenomegaly and anemia, based on data from 725 patients across three phase 3 studies.

The long-term safety profile of momelotinib is consistent, with the most common side effect being diarrhea, and no increase in serious adverse events over time, indicating it does not lead to long-term toxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Momelotinib long-term safety and survival in myelofibrosis: integrated analysis of phase 3 randomized controlled trials. Verstovsek, S., Mesa, R., Gupta, V., et al.[2023]

Momelotinib has shown significant benefits in treating anemia in myelofibrosis patients by inhibiting specific pathways, leading to decreased hepcidin levels and improved iron and hemoglobin levels, with 41% of patients achieving transfusion independence for at least 12 weeks in a phase 2 study.

In phase 3 trials, momelotinib demonstrated a higher rate of transfusion independence compared to ruxolitinib, particularly in JAK inhibitor-treated patients, suggesting it could be a crucial treatment option for myelofibrosis patients suffering from anemia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Momelotinib: an emerging treatment for myelofibrosis patients with anemia. Chifotides, HT., Bose, P., Verstovsek, S.[2022]

Gilteritinib significantly improves overall survival and response rates in adults with relapsed or refractory acute myeloid leukaemia (AML) with FLT3 mutations, as demonstrated in the phase III ADMIRAL trial.

While gilteritinib is effective, it can cause serious side effects like anaemia and febrile neutropenia, but these are generally manageable with dose adjustments, highlighting the importance of monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Gilteritinib: A Review in Relapsed or Refractory FLT3-Mutated Acute Myeloid Leukaemia. Kang, C., Blair, HA.[2021]

Gilteritinib is an effective oral treatment for acute myeloid leukaemia (AML) with FLT3 mutations, approved in both Japan and the USA for patients with relapsed or refractory cases.

It works by inhibiting FLT3 signaling, leading to apoptosis in cancer cells, and also targets ALK mutations, reducing tumor cell proliferation, showcasing its dual mechanism of action.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Gilteritinib: First Global Approval. Dhillon, S.[2020]

Gilteritinib shows a dose-proportional pharmacokinetic profile, meaning that its absorption and elimination are consistent across a range of doses (20-450 mg), with a long elimination half-life of 113 hours, making it effective for treating FLT3 mutation-positive acute myeloid leukemia.

The drug's exposure is not significantly affected by food intake, and while moderate-to-strong CYP3A inhibitors can alter its pharmacokinetics, no significant interactions occur with other common medications, indicating a favorable safety profile for coadministration.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetic Profile of Gilteritinib: A Novel FLT-3 Tyrosine Kinase Inhibitor. James, AJ., Smith, CC., Litzow, M., et al.[2021]

Momelotinib, an oral inhibitor targeting JAK1/JAK2 and ACVR1, has been approved in the USA for treating intermediate or high-risk myelofibrosis (MF) in adults with anemia, marking a significant advancement in MF treatment.

The approval of momelotinib is particularly important for patients with primary MF or secondary MF (post-polycythemia vera and post-essential thrombocythemia), providing a new therapeutic option for this challenging condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Momelotinib: First Approval. Keam, SJ.[2023]

In a phase 3 study involving 195 patients with myelofibrosis, momelotinib demonstrated a significantly higher rate of symptom improvement compared to danazol, with 25% of patients achieving a 50% reduction in symptom scores versus only 9% in the danazol group.

Momelotinib also showed benefits in managing anaemia and spleen size, while maintaining a favorable safety profile, making it a promising treatment option for myelofibrosis patients, particularly those with anaemia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Momelotinib versus danazol in symptomatic patients with anaemia and myelofibrosis (MOMENTUM): results from an international, double-blind, randomised, controlled, phase 3 study. Verstovsek, S., Gerds, AT., Vannucchi, AM., et al.[2023]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT06235801

NCT06235801 | A Phase I/II Study of Gilteritinib and ... Study Overview​​ To learn the recommended dose of momelotinib that can be given in combination with gilteritinib to participants with AML.

2. sciencedirect.com sciencedirect.com/science/article/abs/pii/S000649712408875X

A Phase I/II Study of Gilteritinib and Momelotinib for ... This is a single-arm, single-center, open-label, phase I/II study of gilteritinib and momelotinib in patients with relapsed or refractory (R/R) FLT3-mutated ...

3. ashpublications.org ashpublications.org/blood/article/144/Supplement%201/1520/531465/A-Phase-1-Study-of-CPX-351-Plus-Gilteritinib-in

A Phase 1 Study of CPX-351 Plus Gilteritinib in Relapsed or ... 15.3% and median overall survival (OS) 9.3 vs. 5.6 months (Perl et al. NEJM. 2019). CPX-351, a dual-drug liposomal formulation of daunorubicin ...

4. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/40839405/

Gilteritinib in FLT3-mutated acute myeloid leukemia: A real- ... The median overall survival (OS) for the entire cohort was 11.0 months, with estimated OS rates of 46.8% at 1 year and 28.5% at 3 years. Sixty ...

5. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/39640233/

The Impact of Gilteritinib on Overall Survival of Adult Patients ... Clinical trial studies demonstrated superior survival outcomes than salvage chemotherapy in the FLT3-positive AML population particularly ...

6. researchgate.net researchgate.net/publication/386480115_A_Phase_III_Study_of_Gilteritinib_and_Momelotinib_for_Patients_with_RelapsedRefractory_FLT3_-Mutated_Acute_Myeloid_Leukemia_A_Trial_in_Progress

A Phase I/II Study of Gilteritinib and Momelotinib for ... The results reveal that, during MG acute exacerbation, bone‐marrow neutrophils exhibit significantly enhanced maturation. Upon migration to the peripheral blood ...