Study of Crenolanib Combined With Chemotherapy in FLT3-mutated Acute Myeloid Leukemia Patients

Phase 1

Completed

• Conditions: Acute Myeloid Leukemia
• Interventions: Drug: Crenolanib besylate; Drug: Idarubicin; Drug: Azacytidine; Drug: Cytarabine; Drug: Mitoxantrone; Drug: Etoposide; Drug: Fludarabine; Drug: G-CSF

• Registration Number: NCT02400281
• Lead Sponsor: Arog Pharmaceuticals, Inc.

Brief Summary

This is an open label, two-arm, Phase I-II trial, non-randomized. Arm 1: crenolanib with standard chemotherapy (Idarubicin/Cytarabine, MEC;Mitoxantrone/Etoposide/Cytarabine, FLAG-Ida: Fludarabine/Cytarabine/G-CSF/Idarubicin) Arm 2: crenolanib with 5-azacitidine

Detailed Description

For each arm:

The phase I with dose-limiting toxicity (DLT) determination will use 3+3 design.

Phase II total of 52 patients (26 per arm) will be treated at established phase I dose.

Enrollment to be simultaneous to each arm.

Study Timeline

• Study First Submitted: 2015-03-18
• Study First Submitted QC: 2015-03-23
• Study First Posted: 2015-03-27
• Study Start: 2015-09
• Primary Completion: 2020-07-15
• Study Completion: 2020-07-15
• Results First Submitted: 2023-11-22
• Results First Submitted QC: 2024-02-21
• Results First Posted: 2024-03-20
• Status Verified: 2024-06
• Last Update Submitted: 2024-06-10
• Last Update Posted: 2024-07-03

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 28

Inclusion Criteria

1. Confirmed diagnosis of refractory/relapsed AML or high-risk MDS

   • Arm 1: Subjects must have received at least one prior therapy and a maximum of three prior therapies
   • Arm 2: Subjects must have received at least one prior therapy and a maximum of three prior therapies. No prior treatment with 5-Azacitidine is allowed in this arm.

2. FLT3 mutation positive (ITD, TKD or other)

3. ECOG PS 0-2

4. Adequate liver and renal function

5. Negative pregnancy test

6. Extramedullary leukemia allowed except CNS disease

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Exclusion Criteria

• Arm 1 and 2 Exclusion:

  1. <5% blasts in marrow or blood at time of screening
  2. Active HIV, hepatitis B or C
  3. CNS leukemia
  4. Clinically significant GVHD or organ dysfunction where chemotherapy specified by protocol cannot be given
  5. Patient with AML-M3 (APL)
  6. Pre-existing liver diseases (i.e. cirrhosis, chronic hepatitis B or C, nonalcoholic steatohepatitis, sclerosing cholangitis)

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Arm 1 crenolanib besylate combination	Crenolanib besylate	Arm 1 patients will receive crenolanib besylate, combined with standard chemotherapy (Idarubicin/Cytarabine, MEC;Mitoxantrone/Etoposide/Cytarabine, FLAG-Ida: Fludarabine/Cytarabine/G-CSF/Idarubicin
Arm 1 crenolanib besylate combination	Idarubicin	Arm 1 patients will receive crenolanib besylate, combined with standard chemotherapy (Idarubicin/Cytarabine, MEC;Mitoxantrone/Etoposide/Cytarabine, FLAG-Ida: Fludarabine/Cytarabine/G-CSF/Idarubicin
Arm 1 crenolanib besylate combination	Mitoxantrone	Arm 1 patients will receive crenolanib besylate, combined with standard chemotherapy (Idarubicin/Cytarabine, MEC;Mitoxantrone/Etoposide/Cytarabine, FLAG-Ida: Fludarabine/Cytarabine/G-CSF/Idarubicin
Arm 1 crenolanib besylate combination	G-CSF	Arm 1 patients will receive crenolanib besylate, combined with standard chemotherapy (Idarubicin/Cytarabine, MEC;Mitoxantrone/Etoposide/Cytarabine, FLAG-Ida: Fludarabine/Cytarabine/G-CSF/Idarubicin
Arm 2 crenolanib besylate combination	Crenolanib besylate	Arm 2 patients will receive crenolanib besylate and azacytidine.
Arm 2 crenolanib besylate combination	Azacytidine	Arm 2 patients will receive crenolanib besylate and azacytidine.
Arm 1 crenolanib besylate combination	Cytarabine	Arm 1 patients will receive crenolanib besylate, combined with standard chemotherapy (Idarubicin/Cytarabine, MEC;Mitoxantrone/Etoposide/Cytarabine, FLAG-Ida: Fludarabine/Cytarabine/G-CSF/Idarubicin
Arm 1 crenolanib besylate combination	Etoposide	Arm 1 patients will receive crenolanib besylate, combined with standard chemotherapy (Idarubicin/Cytarabine, MEC;Mitoxantrone/Etoposide/Cytarabine, FLAG-Ida: Fludarabine/Cytarabine/G-CSF/Idarubicin
Arm 1 crenolanib besylate combination	Fludarabine	Arm 1 patients will receive crenolanib besylate, combined with standard chemotherapy (Idarubicin/Cytarabine, MEC;Mitoxantrone/Etoposide/Cytarabine, FLAG-Ida: Fludarabine/Cytarabine/G-CSF/Idarubicin

Primary Outcome Measures

Name	Time	Method
Response Rate of Crenolanib Besylate Combination Therapy	Baseline up to first documented response, persistent disease, or death (whichever occurs first), 1 year.	To determine the response rate to crenolanib. CR Complete remission (CR) response criteria include a post-baseline bone marrow (BM) biopsy or aspiration % blasts \<5%, absolute neutrophil count (ANC) \>1×10\^9/L and platelet count \>100×10\^9/L. CRi response included all CR criteria met, except participant did not experience either platelet recovery or ANC recovery. Morphologic Leukemia-Free State (MLFS) response included ≤5% in % blasts in the BM aspirate or biopsy. Resistant Disease (RD) was defined as the absence of CR, CRi, CRp, PR or MLFS. Death in aplasia response include deaths occurring following chemotherapy while cytopenic with an aplastic or hypoplastic BM prior to death without evidence of persistent leukemia.

Trial Locations

Locations (1)

MD Anderson Cancer Center; 🇺🇸 Houston, Texas, United States