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Dose escalation for gilteritinib will be conducted according to a BOIN design. Gilteritinib 40 mg/day will be given orally starting day 6 until day 19. CLAG-M chemotherapy will be administered at a fixed dose and schedule as following:

* Cladribine (CL) 5 mg/m2 I.V. over 2 hours once per day on days 1 to 5, given first.
* Cytarabine (A) 2,000 mg/m2 I.V. over 4 hours once per day on days 1 to 5, given second, 2 hours after cladribine.
* Filgrastim (GCSF) 300 mcg S.C. once per day on days 0 to 5, started 24 hours prior to chemotherapy. If WBC is \> 20 × 109/L on day 0, the filgrastim dose on day 0 will be omitted.
* Mitoxantrone (M) 10 mg/m2 I.V. once per day on days 1 to 3

Dose escalation for gilteritinib will be conducted according to a BOIN design. Gilteritinib 80 mg/day will be given orally starting day 6 until day 19. CLAG-M chemotherapy will be administered at a fixed dose and schedule as following:

* Cladribine (CL) 5 mg/m2 I.V. over 2 hours once per day on days 1 to 5, given first.
* Cytarabine (A) 2,000 mg/m2 I.V. over 4 hours once per day on days 1 to 5, given second, 2 hours after cladribine.
* Filgrastim (GCSF) 300 mcg S.C. once per day on days 0 to 5, started 24 hours prior to chemotherapy. If WBC is \> 20 × 109/L on day 0, the filgrastim dose on day 0 will be omitted.
* Mitoxantrone (M) 10 mg/m2 I.V. once per day on days 1 to 3

Dose escalation for gilteritinib will be conducted according to a BOIN design. Gilteritinib 120 mg/day will be given orally starting day 6 until day 19. CLAG-M chemotherapy will be administered at a fixed dose and schedule as following:

* Cladribine (CL) 5 mg/m2 I.V. over 2 hours once per day on days 1 to 5, given first.
* Cytarabine (A) 2,000 mg/m2 I.V. over 4 hours once per day on days 1 to 5, given second, 2 hours after cladribine.
* Filgrastim (GCSF) 300 mcg S.C. once per day on days 0 to 5, started 24 hours prior to chemotherapy. If WBC is \> 20 × 109/L on day 0, the filgrastim dose on day 0 will be omitted.
* Mitoxantrone (M) 10 mg/m2 I.V. once per day on days 1 to 3

Gilteritinib is an oral FLT3 inhibitor, and is active against both FLT3-ITD and FLT3-TKD mutations. Gilteritinib will be given orally according to the assigned phase I dose cohort starting day 6 until day 19. Participants will be given the daily dose with water as at the same time each morning. Gilteritinib should be taken at least 2 hours after or 1 hour before consuming food.

Gilteritinib 40 MG Oral Tablet

Cladribine is given intravenously at a dose of 5 mg/m2 I.V. over 2 hours once per day on days 1 to 5.

Cytarabine is given intravenously at a dose of 2,000 mg/m2 I.V. over 4 hours once per day on days 1 to 5, given second, 2 hours after cladribine.

Filgrastim (GCSF) or biosimilar, will be given at a dose of 300 mcg S.C. once per day on days 0 to 5, started 24 hours prior to chemotherapy. If WBC is \> 20 × 109/L on day 0, the filgrastim dose on day 0 will be omitted.

Filgrastim

Mitoxantrone is given intravenously at a dose of 10 mg/m2 I.V. over 2 hours once per day on days 1 to 3.

Ayman Qasrawi, MD

The purpose of this study is to evaluate the dose-limiting toxicities (DLT) and define the maximum tolerated dose (MTD) and the recommended phase II study dose of gilteritinib when combined with mitoxantrone, cladribine, cytarabine and filgrastim (GM-CLAG) in participants with FLT3- mutated relapsed or refractory (R/R) acute myeloid leukemia (AML).

The treatment of FLT3- mutated relapsed or refractory (R/R) is challenging. Gilteritinib, as a single agent, is the first FLT3 inhibitor to be FDA approved in the R/R setting. This phase I clinical trial will evaluate DLT/MTD and the recommended phase II study dose of gilteritinib when combined with mitoxantrone, cladribine, cytarabine and filgrastim (CLAG-M) in patients with FLT3- mutated R/R AML. This study will also evaluate the pharmacodynamics and pharmacokinetics of gilteritinib when combined with CLAG-M at specific time points. Although this combination has not been established to have superior clinical benefit in comparison to single-agent gilteritinib, the objective of this trial is to provide a possible therapeutic benefit in addition to safety and tolerability.

GM-CLAG in Relapsed/Refractory FLT3-mutated AML

Phase Ib Trial of Gilteritinib in Combination With Mitoxantrone, Cladribine, Cytarabine and Filgrastim (GM-CLAG) for Relapsed/Refractory FLT3-mutated Acute Myeloid Leukemia

DLT is defined as:

* Any treatment-related death
* Grade 4 neutropenia or thrombocytopenia lasting \> 42 days from start of cycle in the absence of active AML

  * Any Grade 4 or greater ANC lasting past cycle day 42
  * Any Grade 4 or greater platelets lasting past cycle day 42
* Grade ≥ 4 organ toxicity (i.e., adverse reactions involving neurologic, pulmonary, cardiac, gastrointestinal, genitourinary, renal, hepatic, or cutaneous systems.)
* Confirmed Hy's law cases

The MTD will be defined as the highest dose of Gilteritinib estimated to have less than 20% hematologic or non-hematologic DLT rates. Enrollment of next patient will be allowed only after prior cohort has completed Cycle 1 and recovered or failure of response has been documented by Day 42.

All the following criteria should be met:

1. bone marrow blasts \<5%
2. absence of circulating blasts and blasts with Auer roda
3. absence of extramedullary disease
4. ANC ≥ 1.0 × 109 /L (1000/µL)
5. platelet count ≥ 100 × 109 /L (100,000/µL).

All CR criteria should be met except for residual neutropenia ANC ≤ 1.0 × 109 /L (1000/µL) or thrombocytopenia ≤ 100 × 109 /L (100,000 /µL).

All CR criteria should be met except for residual neutropenia and thrombocytopenia with at least partial recovery as evidenced by: ANC ≥ 0.5 × 109 /L (500/µL) and platelet count ≥ 50 × 109 /L (100,000/µL).

This is a composite rate of subjects who achieve a CR and those who achieve CRi.

All hematologic criteria of CR; decrease of bone marrow blast percentage to 5% to 25%; MRD status will be determined by FLT3 polymerase chain reaction (PCR) testing of bone marrow aspirates obtained at the end of each cycle of induction.

Best response is defined as the best measured response (CR, CRp, CRi, or PR) post-treatment.

Two best responses, up to the time of 2 cycles of treatment period will be defined.

To evaluate percentage of patients proceeding to transplantation at anytime during study period

Defined for all patients of the trial; measured from the date of registration to the date of death from any cause; patients not known to have died at last follow-up are censored on the date they were last known to be alive.

Defined only for patients achieving CR, or CRi; measured from the date of achievement of a remission until the date of relapse or death from any cause.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
GM-CLAG in Relapsed/Refractory FLT3-mutated AML	NCT05330377	Acute Myeloid L...	Gilteritinib 40... Cladribine Cytarabine Filgrastim Mitoxantrone	18 Years -	University of Kentucky
GM-CLAG in Relapsed/Refractory FLT3-mutated AML	NCT05330377	Acute Myeloid L...	Gilteritinib 40... Cladribine Cytarabine Filgrastim Mitoxantrone	18 Years -	University of Kentucky

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