Gilteritinib + Chemotherapy for Acute Myeloid Leukemia

Recruiting at 23 trial locations

Overseen By Astellas Pharma Global Development

Age: < 65

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Astellas Pharma Global Development, Inc.

Must not be taking: Strong CYP3A/P-gp inducers

Disqualifiers: Active CNS leukemia, Uncontrolled cardiovascular, Active infections, others

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

Compensation: Varies

Number of Visits: Unknown

9 Participants Needed

Trial Summary

What is the purpose of this trial?

The purpose of the phase 1 portion (dose escalation) of the study will be to establish an optimally safe and biologically active recommended phase 2 dose (RP2D) and/or to determine maximum tolerated dose (MTD) for gilteritinib in sequential combination with fludarabine, cytarabine and granulocyte colony-stimulating factor (FLAG). The purpose of the phase 2 portion (dose expansion) is to determine complete remission (CR) rates and composite complete remission (CRc) rates after two cycles of therapy. The study will also assess safety, tolerability and toxicities of gilteritinib in combination with FLAG, evaluate FLT3 inhibition, assess pharmacokinetics (PK), perform serial measurements of minimal residual disease, obtain preliminary estimates of 1-year event free survival (EFS) and overall survival (OS) rate and assess the acceptability as well as palatability of the formulation. One cycle is defined as 28 days of treatment. A participant completing 1 or 2 treatment cycles in phase 1 or 2 will have the option to participate in long term treatment (LTT) with gilteritinib (for up to 2 years).

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 take certain drugs like strong inducers of cytochrome P450 (CYP)3A/P-glycoprotein (P-gp) during the study. It's best to discuss your current medications with the study team.

What evidence supports the effectiveness of the drug combination including Gilteritinib, Cytarabine, and Fludarabine for treating acute myeloid leukemia?

Research shows that combinations of Cytarabine and Fludarabine are effective in treating acute myeloid leukemia (AML), with studies reporting complete remission rates of up to 71% in poor-risk AML cases. These findings suggest that combining these drugs with Gilteritinib could potentially enhance treatment effectiveness. ^{1 2 3 4 5}

Is the combination of Gilteritinib, Cytarabine, Fludarabine, and Granulocyte Colony-Stimulating Factor safe for treating acute myeloid leukemia?

The combination of Fludarabine, Cytarabine, and Granulocyte Colony-Stimulating Factor has been studied in various regimens for acute myeloid leukemia and is generally well-tolerated, though it can cause severe neutropenia (low white blood cell count), serious infections, and severe thrombocytopenia (low platelet count). Other side effects like severe diarrhea, alopecia (hair loss), and mucositis (inflammation of the mouth) were less common. Gilteritinib, another component, is generally considered safe but should be monitored for specific side effects. ^{4 5 6 7 8}

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

Gilteritinib is unique because it is an oral drug specifically targeting FLT3 mutations in acute myeloid leukemia, offering improved survival rates compared to standard chemotherapy, especially for patients with relapsed or refractory conditions. ^{9 10 11 12 13}

Research Team

Medical Director

Principal Investigator

Astellas Pharma Global Development

Eligibility Criteria

This trial is for children, adolescents, and young adults aged ≥6 months to <21 years with FLT3/ITD positive relapsed or refractory AML. They must have recovered from prior treatments, not be pregnant or breastfeeding, agree to use contraception, and not have active CNS leukemia or significant heart disease.

Inclusion Criteria

It's been over 90 days since my stem cell transplant and I don't have active GVHD.

My blood or bone marrow has a FLT3 mutation.

I will not donate eggs during and for 6 months after the study.

Exclusion Criteria

I have an ongoing infection that hasn't improved with treatment, but I've been off pressors and had negative blood cultures for 48 hours.

Subject has any significant concurrent disease, illness, psychiatric disorder or social issue that would compromise subject safety or compliance; interfere with consent, study participation, follow-up or interpretation of study results.

I need medication that strongly affects certain liver enzymes and proteins.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose Escalation

Establish an optimally safe and biologically active recommended phase 2 dose (RP2D) and/or determine maximum tolerated dose (MTD) for gilteritinib in combination with FLAG chemotherapy.

Up to 56 days

Multiple visits for dose administration and monitoring

Dose Expansion

Determine complete remission (CR) rates and composite complete remission (CRc) rates after two cycles of therapy.

Up to 56 days

Multiple visits for dose administration and monitoring

Long Term Treatment (LTT)

Participants completing 1 or 2 treatment cycles may opt into long term treatment with gilteritinib for up to 2 years.

Up to 2 years

Follow-up

Participants are monitored for safety and effectiveness after treatment.

4 weeks

Treatment Details

Interventions

• Cytarabine
• Fludarabine
• Gilteritinib
• Granulocyte Colony-Stimulating Factor

Trial Overview The study tests gilteritinib combined with chemotherapy (fludarabine, cytarabine, G-CSF) in two phases: Phase 1 finds the safest dose; Phase 2 checks how well it works. It measures remission rates after two cycles and monitors safety over a potential two-year treatment period.

Participant Groups

Group I: Dose Expansion Experimental Treatment 4 Interventions

Participants will be administered fludarabine, cytarabine and granulocyte colony-stimulating factor (FLAG) chemotherapy on days -1 to 5 and gilteritinib will be administered once per day on days 8 to 21 at the dose determined in dose escalation portion. Participants may receive prophylactic intrathecal cytarabine at the start of the cycle, as per institutional standards. A participant completing 2 cycles (cycle is defined as 28 days) will have the option to participate in long term treatment (LTT) with gilteritinib (for up to 2 years).

Group II: Dose Escalation - 6 months to less than 1 year of age Experimental Treatment 4 Interventions

Participants will be administered fludarabine, cytarabine and granulocyte colony-stimulating factor (FLAG) chemotherapy on days -1 to 5 and gilteritinib will be administered once per day on days 8 to 21 at the assigned dose. Participants may receive prophylactic intrathecal cytarabine at the start of the cycle, as per institutional standards. A participant completing 2 cycles (cycle is defined as 28 days) will have the option to participate in long term treatment (LTT) with gilteritinib (for up to 2 years).

Group III: Dose Escalation - 2 years to less than 21 years of age Experimental Treatment 4 Interventions

Participants will be administered fludarabine, cytarabine and granulocyte colony-stimulating factor (FLAG) chemotherapy on days -1 to 5 and gilteritinib will be administered once per day on days 8 to 21 at the assigned dose. Participants may receive prophylactic intrathecal cytarabine at the start of the cycle, as per institutional standards. A participant completing 2 cycles (cycle is defined as 28 days) will have the option to participate in long term treatment (LTT) with gilteritinib (for up to 2 years).

Group IV: Dose Escalation - 1 year to less than 2 years of age Experimental Treatment 4 Interventions

Participants will be administered fludarabine, cytarabine and granulocyte colony-stimulating factor (FLAG) chemotherapy on days -1 to 5 and gilteritinib will be administered once per day on days 8 to 21 at the assigned dose. Participants may receive prophylactic intrathecal cytarabine at the start of the cycle, as per institutional standards. A participant completing 2 cycles (cycle is defined as 28 days) will have the option to participate in long term treatment (LTT) with gilteritinib (for up to 2 years).

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

Approved in United States as Cytosar-U for:

• Acute myeloid leukemia
• Acute lymphocytic leukemia
• Chronic myeloid leukemia
• Meningeal leukemia

Approved in European Union as Depocyt for:

• Lymphomatous meningitis

Approved in Canada as Cytosar-U for:

• Acute myeloid leukemia
• Acute lymphocytic leukemia
• Chronic myeloid leukemia

Who Is Running the Clinical Trial?

Astellas Pharma Global Development, Inc.

Lead Sponsor

Trials

204

Recruited

123,000+

Tadaaki Taniguchi

Astellas Pharma Global Development, Inc.

Chief Medical Officer

M.D., Ph.D.

Naoki Okamura

Astellas Pharma Global Development, Inc.

Chief Executive Officer

Not available

Findings from Research

In a multicenter, randomized phase III study involving 326 patients with relapsed or refractory acute myeloid leukemia (AML), adding fludarabine to high-dose cytarabine and idarubicin (F-SHAI) improved the time to treatment failure from 2.04 to 3.38 months, indicating a moderate enhancement in treatment efficacy.

While the complete remission rates and overall survival were similar between the standard SHAI and F-SHAI regimens, a significantly higher percentage of patients in the F-SHAI group achieved complete or incomplete remission, which may facilitate more patients proceeding to allogeneic stem cell transplantation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chemomodulation of sequential high-dose cytarabine by fludarabine in relapsed or refractory acute myeloid leukemia: a randomized trial of the AMLCG. Fiegl, M., Unterhalt, M., Kern, W., et al.[2021]

Clofarabine-based treatment can be a feasible salvage therapy for patients with refractory acute myeloid leukemia after failed fludarabine attempts, with 29% achieving complete remission and 21% successfully undergoing transplantation.

No deaths related to the clofarabine treatment were reported, indicating a favorable safety profile in this small cohort of 14 patients, although the overall success rate remains low.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clofarabine-based chemotherapy as a bridge to transplant in the setting of refractory or relapsed acute myeloid leukemia, after at least one previous unsuccessful salvage treatment containing fludarabine: a single institution experience. Molteni, A., Riva, M., Ravano, E., et al.[2022]

A combination treatment of high-dose arabinosyl cytosine, fludarabine, and idarubicin resulted in a high complete remission rate of 71% after the first course and 82% overall in 45 patients with poor-risk acute myeloid leukemia (AML).

The treatment showed limited non-hematologic toxicity, which is beneficial for elderly patients, but significant hematologic toxicity was observed, with a recovery time of 3 to 4 weeks and challenges in mobilizing peripheral blood stem cells after treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fludarabine, arabinosyl cytosine and idarubicin (FLAI) for remission induction in poor-risk acute myeloid leukemia. Russo, D., Pricolo, G., Michieli, M., et al.[2019]

In a pilot study involving 17 patients with acute myeloid leukemia (AML), the combination of fludarabine, topotecan, and cytarabine (FTA) resulted in a 35% complete remission rate, indicating its potential efficacy in treating this condition.

However, the treatment was associated with significant side effects, as 41% of patients experienced severe diarrhea, highlighting the need for careful monitoring and further investigation of FTA's safety and effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A fludarabine, topotecan, and cytarabine regimen is active in patients with refractory acute myelogenous leukemia. Giles, FJ., Cortes, JE., Kantarjian, HM., et al.[2013]

In a phase III trial involving 112 newly diagnosed AML patients under 60 years, the FLAI regimen (fludarabine, cytarabine, and idarubicin) resulted in a significantly higher complete remission (CR) rate of 74% compared to 51% for the ICE regimen (idarubicin, Ara-C, and etoposide).

FLAI was associated with lower rates of both hematological and non-hematological toxicities, particularly gastrointestinal issues, making it a safer option for induction treatment in AML patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Multicentre phase III trial on fludarabine, cytarabine (Ara-C), and idarubicin versus idarubicin, Ara-C and etoposide for induction treatment of younger, newly diagnosed acute myeloid leukaemia patients. Russo, D., Malagola, M., de Vivo, A., et al.[2013]

The FLAG-IDA chemotherapy regimen was administered to seven children with refractory acute myeloid leukemia (AML), and while it was tolerable with no early deaths, the efficacy remains uncertain due to high relapse rates and limited patient numbers.

Hematological toxicity was common among patients, with one case of severe non-hematological toxicity (bacterial meningitis), highlighting the need for careful monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fludarabine, cytarabine, granulocyte colony-stimulating factor and idarubicin for relapsed childhood acute myeloid leukemia. Nakayama, H., Tomizawa, D., Tanaka, S., et al.[2018]

In a study of 42 adult patients with relapsed or refractory acute myeloid leukemia (AML) treated with the FLAG ± Ida chemotherapy regimen, the complete remission (CR) rate was 47.6%, which aligns with historical rates of 52% to 63%.

The median overall survival (OS) for patients achieving CR was not reached, with an estimated 48-month survival rate of 56%, indicating that FLAG ± Ida remains an effective salvage treatment for R/R AML, despite common adverse effects like pancytopenia and infection.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Retrospective Analysis of Adult Patients With Relapsed/Refractory Acute Myeloid Leukemia Treated with FLAG at a Comprehensive Cancer Center. Tenold, ME., Moskoff, BN., Krishnan, R., et al.[2022]

The DAF regimen, which includes daunorubicin, fludarabine, and cytarabine, showed a 56% overall response rate in 34 patients with relapsed or refractory acute myeloid leukemia (AML), with 15 out of 16 patients achieving complete remission after the first course.

The treatment was well tolerated, with severe neutropenia and serious infections occurring in a significant number of patients, but no severe long-term complications like liver or kidney failure were observed, indicating a favorable safety profile for this regimen.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Daunorubicin, cytarabine and fludarabine (DAF) for remission induction in relapsed or refractory acute myeloid leukemia. Evaluation of safety, tolerance and early outcome--Polish Adult Leukemia Group (PALG) pilot study. Hołowiecki, J., Grosicki, S., Kyrcz-Krzemien, S., et al.[2013]

In a phase 3 trial involving 371 patients with relapsed or refractory FLT3-mutated acute myeloid leukemia (AML), gilteritinib significantly improved overall survival compared to salvage chemotherapy, with a median survival of 9.3 months versus 5.6 months.

Gilteritinib also led to higher rates of complete remission (21.1% vs. 10.5%) and had fewer severe adverse events compared to chemotherapy, indicating it is a safer and more effective treatment option for this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Gilteritinib or Chemotherapy for Relapsed or Refractory FLT3-Mutated AML. Perl, AE., Martinelli, G., Cortes, JE., et al.[2023]

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]

In a phase IB study involving 80 participants with newly diagnosed FLT3-mutated acute myeloid leukemia (AML), gilteritinib combined with intensive chemotherapy achieved a high composite complete response rate of 89%, indicating strong efficacy in this patient population.

Gilteritinib was well-tolerated as both part of the chemotherapy regimen and as maintenance therapy, with a median overall survival time of 46.1 months, suggesting it is a safe and effective treatment option for patients with FLT3-mutant AML.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Gilteritinib in Combination With Induction and Consolidation Chemotherapy and as Maintenance Therapy: A Phase IB Study in Patients With Newly Diagnosed AML. Pratz, KW., Cherry, M., Altman, JK., et al.[2023]

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 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]

References

1. England pubmed.ncbi.nlm.nih.gov

Chemomodulation of sequential high-dose cytarabine by fludarabine in relapsed or refractory acute myeloid leukemia: a randomized trial of the AMLCG. [2021]

2. Japan pubmed.ncbi.nlm.nih.gov

Clofarabine-based chemotherapy as a bridge to transplant in the setting of refractory or relapsed acute myeloid leukemia, after at least one previous unsuccessful salvage treatment containing fludarabine: a single institution experience. [2022]

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

Fludarabine, arabinosyl cytosine and idarubicin (FLAI) for remission induction in poor-risk acute myeloid leukemia. [2019]

4. England pubmed.ncbi.nlm.nih.gov

A fludarabine, topotecan, and cytarabine regimen is active in patients with refractory acute myelogenous leukemia. [2013]

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

Multicentre phase III trial on fludarabine, cytarabine (Ara-C), and idarubicin versus idarubicin, Ara-C and etoposide for induction treatment of younger, newly diagnosed acute myeloid leukaemia patients. [2013]

6. Australia pubmed.ncbi.nlm.nih.gov

Fludarabine, cytarabine, granulocyte colony-stimulating factor and idarubicin for relapsed childhood acute myeloid leukemia. [2018]

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

Retrospective Analysis of Adult Patients With Relapsed/Refractory Acute Myeloid Leukemia Treated with FLAG at a Comprehensive Cancer Center. [2022]

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

Daunorubicin, cytarabine and fludarabine (DAF) for remission induction in relapsed or refractory acute myeloid leukemia. Evaluation of safety, tolerance and early outcome--Polish Adult Leukemia Group (PALG) pilot study. [2013]

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

Gilteritinib or Chemotherapy for Relapsed or Refractory FLT3-Mutated AML. [2023]

10. France pubmed.ncbi.nlm.nih.gov

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

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

Gilteritinib in Combination With Induction and Consolidation Chemotherapy and as Maintenance Therapy: A Phase IB Study in Patients With Newly Diagnosed AML. [2023]

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

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

13. 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]