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

Trial Summary

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.

What data supports the effectiveness of the drug Gilteritinib + Momelotinib for Acute Myeloid Leukemia?

Momelotinib has shown benefits in treating myelofibrosis, a different blood disorder, by improving anemia (low red blood cell count), symptoms, and spleen size. While this is not direct evidence for its use in Acute Myeloid Leukemia, it suggests potential benefits in blood-related conditions. ^{1 2 3 4 5}

What is known about the safety of Gilteritinib and Momelotinib in humans?

Gilteritinib, used for certain types of leukemia, has been associated with side effects like anemia, fever, and low platelet counts, and more serious issues like differentiation syndrome and pancreatitis, but these are generally manageable. Momelotinib's safety profile is not detailed in the provided research, so further information would be needed to assess its safety. ^{6 7 8 9 10}

How is the drug Gilteritinib + Momelotinib unique for treating acute myeloid leukemia?

Gilteritinib is a unique drug for treating acute myeloid leukemia because it specifically targets and inhibits the FLT3 mutation, which is present in about one-third of cases, and is effective as an oral medication, making it convenient for outpatient use. Momelotinib, when combined with Gilteritinib, may offer a novel approach by potentially addressing different pathways involved in the disease, although specific details on this combination's uniqueness are not provided in the research. ^{6 9 10 11 12}

What is the purpose of this trial?

To learn the recommended dose of momelotinib that can be given in combination with gilteritinib to participants with AML.

Research Team

Nicholas Short

Principal Investigator

MD Anderson Center

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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

Findings from Research

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]

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]

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]

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 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]

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 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, 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]

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 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]

References

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

Momelotinib: First Approval. [2023]

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

Overall survival in the SIMPLIFY-1 and SIMPLIFY-2 phase 3 trials of momelotinib in patients with myelofibrosis. [2022]

3. England 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. [2023]

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

Momelotinib long-term safety and survival in myelofibrosis: integrated analysis of phase 3 randomized controlled trials. [2023]

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

Momelotinib: an emerging treatment for myelofibrosis patients with anemia. [2022]

6. England 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. [2021]

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

Severe Gastrointestinal Toxicity Following the Use of Gilteritinib: A Case Series and Analysis of Postmarketing Surveillance Data. [2023]

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

Gilteritinib: First Global Approval. [2020]

9. France pubmed.ncbi.nlm.nih.gov

Gilteritinib: A Review in Relapsed or Refractory FLT3-Mutated Acute Myeloid Leukaemia. [2021]

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

FDA Approval Summary: Gilteritinib for Relapsed or Refractory Acute Myeloid Leukemia with a FLT3 Mutation. [2023]

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

Therapeutic Management of Patients with FLT3 + Acute Myeloid Leukemia: Case Reports and Focus on Gilteritinib Monotherapy. [2022]

12. Switzerland pubmed.ncbi.nlm.nih.gov

Pharmacokinetic Profile of Gilteritinib: A Novel FLT-3 Tyrosine Kinase Inhibitor. [2021]