Midostaurin + Chemotherapy for Acute Myeloid Leukemia

Recruiting at 26 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

24 Participants Needed

Trial Summary

What is the purpose of this trial?

This study will evaluate the safety, efficacy and pharmacokinetics of midostaurin in combination with standard chemotherapy in pediatrics patients with newly diagnosed FLT3-mutated Acute Myeloid Leukemia. The study has two parts: Part 1 to define the Recommended Phase 2 Dose, and Part 2 to evaluate safety and tolerability and efficacy of midostaurin. Both parts will consist of 2 induction blocks, 3 consolidation blocks, 12 cycles of post-consolidation consisting of continuous therapy with midostaurin, and a follow-up phase.

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.

What data supports the effectiveness of the drug Midostaurin in combination with chemotherapy for treating acute myeloid leukemia?

Research shows that Midostaurin, when combined with standard chemotherapy, can improve survival in patients with a specific genetic mutation (FLT3) in acute myeloid leukemia. It works by blocking certain proteins that help cancer cells grow, and has shown promise in both newly diagnosed and relapsed cases. ^{1 2 3 4 5}

Is midostaurin safe for humans when used with chemotherapy for acute myeloid leukemia?

Midostaurin, when used with chemotherapy for acute myeloid leukemia, has a manageable safety profile. Common side effects include fever with low white blood cell count, nausea, and diarrhea, but no new safety concerns were found in recent studies. ^{1 3 4 6 7}

What makes the drug midostaurin unique for treating acute myeloid leukemia?

Midostaurin is unique because it is an oral drug that targets multiple kinases, including FLT3, which is often mutated in acute myeloid leukemia (AML). This multikinase inhibition can directly affect cancer cells and also disrupt the supportive environment in the bone marrow, potentially improving outcomes when combined with standard chemotherapy. ^{1 2 4 6 8}

Research Team

Novartis Pharmaceuticals

Principal Investigator

Novartis Pharmaceuticals

Eligibility Criteria

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

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

My lab tests show a FLT3 mutation.

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

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

Treatment Details

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.

Participant Groups

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

Findings from Research

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, 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 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]

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]

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 (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 (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]

References

1. United States 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. [2019]

2. England 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. [2017]

3. Japan 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. [2022]

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

Midostaurin: an emerging treatment for acute myeloid leukemia patients. [2020]

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

Midostaurin, bortezomib and MEC in relapsed/refractory acute myeloid leukemia. [2022]

6. United States 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. [2021]

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

Midostaurin: First Global Approval. [2018]

8. Germany pubmed.ncbi.nlm.nih.gov

Cost-effectiveness of midostaurin in the treatment of newly diagnosed FLT3-mutated acute myeloid leukemia in France. [2021]