Midostaurin + Chemotherapy for Acute Myeloid Leukemia

Not currently recruiting at 31 trial locations

Overseen By Novartis Pharmaceuticals

Age: < 18

Sex: Any

Trial Phase: Phase 2

Sponsor: Novartis Pharmaceuticals

Must not be taking: FLT3 inhibitors

Disqualifiers: Concurrent malignancy, CNS involvement, others

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

Prior Safety Data This treatment has passed at least one previous human trial

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 3

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests the safety and effectiveness of midostaurin (Rydapt) combined with standard chemotherapy for children newly diagnosed with FLT3-mutated Acute Myeloid Leukemia (AML), a type of blood cancer. The study examines the treatment's efficacy and side effects. It consists of two main parts: determining the optimal dose and assessing the treatment's safety and effectiveness. Children recently diagnosed with AML and possessing the FLT3 genetic mutation may qualify for this trial. As a Phase 2 trial, the research focuses on evaluating the treatment's effectiveness in an initial, smaller group.

Will I have to stop taking my current medications?

The trial information does not specify if you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

Is there any evidence suggesting that midostaurin in combination with chemotherapy is likely to be safe for pediatric patients with Acute Myeloid Leukemia?

Research shows that midostaurin, when combined with chemotherapy, is generally well-tolerated by patients with Acute Myeloid Leukemia (AML) who have the FLT3 mutation. Studies indicate that while some side effects can occur, they usually do not require stopping treatment.

One study found that patients taking midostaurin had a lower risk of death compared to those who did not, suggesting the treatment might be effective and not overly harmful. Another study confirmed that midostaurin worked well with various chemotherapy drugs, regardless of the patient's age or gender.

Overall, midostaurin has been tested in many people with AML and is already approved by the FDA for another condition, supporting its safety. While side effects can occur, the available data suggest that midostaurin is generally safe for people with this specific type of leukemia. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for Acute Myeloid Leukemia?

Most treatments for acute myeloid leukemia (AML) involve chemotherapy drugs like cytarabine and daunorubicin. However, midostaurin is unique because it targets specific proteins involved in cancer cell growth, offering a more precise attack against the disease. Researchers are excited about midostaurin because it can be used after traditional chemotherapy to help prevent the cancer from coming back, potentially improving long-term outcomes. This combination approach may enhance the effectiveness of treatment by leveraging both broad and targeted strategies against AML.

What evidence suggests that midostaurin combined with chemotherapy could be effective for Acute Myeloid Leukemia?

Research has shown that midostaurin, administered to participants in this trial following chemotherapy, extends the lives of patients with Acute Myeloid Leukemia (AML), particularly those with FLT3 mutations. One study found that after four years, 51.4% of patients taking midostaurin remained alive, compared to 44.3% of those who received a placebo. Another study demonstrated that 73% of patients had no detectable cancer after treatment with midostaurin and chemotherapy. Although some patients may experience a return of cancer, these findings suggest that midostaurin can improve outcomes for AML patients with FLT3 mutations. ^{1 6 7 8 9}

Who Is on the Research Team?

Novartis Pharmaceuticals

Principal Investigator

Novartis Pharmaceuticals

Are You a Good Fit for This Trial?

This trial is for pediatric patients with newly diagnosed FLT3-mutated Acute Myeloid Leukemia. They must have a certain level of physical function, normal liver and kidney tests, and no prior treatment with FLT3 inhibitors or other cancers. Patients with specific types of AML or leukemia in the brain are excluded.

Inclusion Criteria

My lab tests show a FLT3 mutation.

I have a new diagnosis of AML according to the latest standards.

My kidneys are working well enough (creatinine clearance ≥ 30 ml/min).

Exclusion Criteria

I have been treated with a FLT3 inhibitor, but not for more than a week before joining this study.

I do not have any other cancer types or specific leukemia conditions.

My condition is a type of leukemia that affects areas outside the bone marrow, or I have secondary AML or MDS.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Induction

Participants receive induction chemotherapy and midostaurin to achieve remission

Up to 6 weeks per block

Multiple visits for chemotherapy administration and monitoring

Consolidation

Participants receive consolidation chemotherapy and midostaurin to maintain remission

Up to 6 weeks per block

Multiple visits for chemotherapy administration and monitoring

Post-consolidation

Participants receive continuous midostaurin therapy for maintenance

12 cycles (28 days per cycle)

Monthly visits for drug administration and monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 5 years

Every 3 months after last follow-up visit

What Are the Treatments Tested in This Trial?

Interventions

• Midostaurin

Trial Overview The study tests Midostaurin combined with standard chemotherapy to see its safety, how well it works, and how the body processes it in children with AML. It includes two phases: one to find the best dose and another to assess long-term effects over several treatment cycles followed by continuous therapy.

How Is the Trial Designed?

Group I: Chemotherapy followed by Midostaurin Experimental Treatment 6 Interventions

In Part 1, midostaurin with standard induction (Block 1 induction according to local practice, Block 2 induction containing fludarabine, cytarabine, daunorubicin/idarubicin) and consolidation (Block 3: cytarabine + mitoxantrone, Block 4: cytarabine + etoposide, Block 5: cytarabine) followed by single agent midostaurin post-consolidation therapy. In Part 2, midostaurin with standard induction (Block 1 induction according to local practice, Block 2 induction containing cytarabine + mitoxantrone) and consolidation (Block 3: cytarabine + etoposide, Block 4: cytarabine + mitoxantrone, Block 5: cytarabine) followed by single agent midostaurin post-consolidation therapy.

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

Approved in United States as Rydapt for:

• Acute Myeloid Leukemia (AML) with FLT3 mutation
• Aggressive Systemic Mastocytosis

Approved in European Union as Rydapt for:

• Acute Myeloid Leukemia (AML) with FLT3 mutation
• Aggressive Systemic Mastocytosis

Who Is Running the Clinical Trial?

Novartis Pharmaceuticals

Lead Sponsor

Trials

2,963

Recruited

4,275,000+

Founded

1996

Headquarters

Basel, Switzerland

Known For

Precision medicine

Top Products

Gleevec, Cosentyx, Entresto, Kisqali

Dr. Vas Narasimhan

Novartis Pharmaceuticals

Chief Executive Officer since 2018

MD from Harvard Medical School

Dr. Shreeram Aradhye

Novartis Pharmaceuticals

Chief Medical Officer since 2021

MD

Published Research Related to This Trial

Midostaurin, a multikinase inhibitor, was found to have a manageable safety profile in a study of 103 patients with FLT3 mutation-positive acute myeloid leukemia, with no new safety events reported during treatment.

The treatment showed promising outcomes, including high rates of transplant success and low relapse rates during maintenance therapy, indicating its efficacy when combined with chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Updated safety of midostaurin plus chemotherapy in newly diagnosed FLT3 mutation-positive acute myeloid leukemia: the RADIUS-X expanded access program. Roboz, GJ., Strickland, SA., Litzow, MR., et al.[2021]

Midostaurin, a multikinase inhibitor, has been shown to improve survival in acute myeloid leukemia (AML) patients with Flt3 mutations when combined with conventional chemotherapy, followed by a year of maintenance therapy.

While midostaurin is generally well tolerated as a monotherapy, its combination with chemotherapy can increase gastrointestinal toxicity, and its antileukemic effects may involve multiple mechanisms beyond just Flt3 inhibition, including effects on the bone marrow microenvironment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antileukemic effects of midostaurin in acute myeloid leukemia - the possible importance of multikinase inhibition in leukemic as well as nonleukemic stromal cells. Tvedt, TH., Nepstad, I., Bruserud, Ø.[2017]

In a phase I study involving 10 patients with relapsed/refractory acute myeloid leukemia (AML), the combination of midostaurin, all-trans retinoic acid (ATRA), and CLAG chemotherapy showed promising results with no dose-limiting toxicities observed.

The treatment led to a 22% complete remission rate and a 11% rate of complete remission with incomplete count recovery, indicating potential efficacy, especially in specific genetic subtypes of AML.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I study of cladribine, cytarabine, granulocyte colony stimulating factor (CLAG regimen) and midostaurin and all-trans retinoic acid in relapsed/refractory AML. Ramsingh, G., Westervelt, P., McBride, A., et al.[2022]

Midostaurin, when combined with standard chemotherapy (cytarabine and daunorubicin), significantly improves event-free survival, disease-free survival, and overall survival in patients with newly diagnosed FLT3-mutated acute myeloid leukemia (AML), based on a phase III trial.

The treatment with midostaurin is considered safe, showing no significant difference in overall toxicity compared to placebo, although it was associated with a higher incidence of grade 3 to 5 anemia and rash.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Midostaurin in Combination With Standard Chemotherapy for Treatment of Newly Diagnosed FMS-Like Tyrosine Kinase 3 (FLT3) Mutation-Positive Acute Myeloid Leukemia. Kim, M., Williams, S.[2019]

Midostaurin (Rydapt®) is a multikinase inhibitor that received FDA approval in April 2017 for treating adult patients with newly diagnosed FLT3 mutation-positive acute myeloid leukaemia (AML) when used alongside standard chemotherapy.

It is also approved for advanced systemic mastocytosis conditions, including aggressive systemic mastocytosis and mast cell leukaemia, highlighting its efficacy in targeting multiple hematological malignancies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Midostaurin: First Global Approval. Kim, ES.[2018]

Midostaurin is an oral Type III receptor tyrosine kinase inhibitor that effectively targets FLT3 mutations in acute myeloid leukemia (AML), showing robust anti-blast responses in relapsed/refractory patients and potentially bridging them to transplant.

While generally well tolerated as a single agent, midostaurin's hematologic toxicity increases when combined with standard chemotherapy, but it may prolong survival in patients with FLT3-ITD mutations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Midostaurin: an emerging treatment for acute myeloid leukemia patients. Gallogly, MM., Lazarus, HM.[2020]

Midostaurin (MIDO) combined with standard chemotherapy significantly improves survival in adults with newly diagnosed FLT3-mutated acute myeloid leukemia (AML), providing an additional 1.12 life years and 1.23 quality-adjusted life years compared to standard-of-care alone.

The cost-effectiveness analysis indicates that MIDO is a viable treatment option, with an incremental cost-effectiveness ratio of €62,305 per quality-adjusted life year, making it a cost-effective choice under the €100,000 per QALY threshold for end-of-life treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cost-effectiveness of midostaurin in the treatment of newly diagnosed FLT3-mutated acute myeloid leukemia in France. Tremblay, G., Cariou, C., Recher, C., et al.[2021]

In a phase I study involving patients with acute myeloid leukemia (AML), the combination of the tyrosine kinase inhibitor midostaurin with bortezomib and chemotherapy showed a 56.5% complete response (CR) rate and an 82.5% overall response rate, indicating significant efficacy in treating refractory or relapsed AML.

While the treatment was effective, it was also associated with expected drug-related toxicities, including peripheral neuropathy, decreased ejection fraction, and diarrhea, particularly at higher dose levels.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Midostaurin, bortezomib and MEC in relapsed/refractory acute myeloid leukemia. Walker, AR., Wang, H., Walsh, K., et al.[2022]

Citations

1. nejm.org nejm.org/doi/full/10.1056/NEJMoa1614359

Midostaurin plus Chemotherapy for Acute Myeloid ... The 4-year overall survival rate was 51.4% in the midostaurin group and 44.3% in the placebo group. Analyses of subgroups according to FLT3 ...

2. ashpublications.org ashpublications.org/blood/article/144/Supplement%201/4282/534025/Real-World-Treatment-Patterns-and-Effectiveness-of

Real-World Treatment Patterns and Effectiveness of ... Median OS was not reached in both. In the midostaurin cohort, 32% of patients relapsed, with median time to relapse of 8.3 months. No patients ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC4848023/

Midostaurin: an emerging treatment for acute myeloid ... Despite good initial response to conventional induction therapy, relapse is common, contributing to 5-year remission rates of only 40% in patients under 60 ...

4. sciencedirect.com sciencedirect.com/science/article/abs/pii/S000649712407040X

Real-World Treatment Patterns and Effectiveness of ... Of the patients who died, 22 had relapsed AML. Median OS was not reached in both. In the midostaurin cohort, 32% of patients relapsed, with ...

5. haematologica.org haematologica.org/article/view/haematol.2022.281967

Efficacy and toxicity of midostaurin with idarubicin and ... Complete remission (CR) was attained in 83 of 114 patients (73%) receiving midostaurin and IDA-based 7+3 induction. Event-free survival (EFS) ...

6. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/39800921/

A Multicenter Retrospective Analysis This study aimed to evaluate the safety and efficacy of the combination of midostaurin with CLAG-M versus midostaurin plus 7+3 in FLT3-mutated AML patients.

7. sciencedirect.com sciencedirect.com/science/article/pii/S0006497119401389

Midostaurin in Adults with Newly Diagnosed FLT3-Mutation ... Conclusions: Midostaurin continued to demonstrate a manageable safety profile with longer follow-up and was associated with high transplant and low relapse ...

8. clinicaltrials.gov clinicaltrials.gov/study/NCT03280030

A Study of Midostaurin Efficacy and Safety in Newly ... This study evaluated the efficacy and safety of midostaurin in combination with daunorubicin/cytarabine induction, high dose cytarabine consolidation and ...

9. jhoponline.com jhoponline.com/special-issues/2020-year-in-review-aml/safety-and-efficacy-of-midostaurin-in-younger-and-older-patients-with-newly-diagnosed-flt3-mutated-aml

Safety and Efficacy of Midostaurin in Younger and Older ... Midostaurin + chemotherapy resulted in high response rates regardless of patient age, sex, induction drug, or alternative chemotherapy regimen.