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

Study Overview
=================
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.

Official Title
-----------------
Phase I-II Study of Crenolanib Combined With Standard Salvage Chemotherapy, and Crenolanib Combined With 5-Azacitidine in Acute Myeloid Leukemia Patients With FLT3 Activating Mutations

Conditions
-----------------
Acute Myeloid Leukemia

Intervention / Treatment
-----------------
* Drug: Crenolanib besylate
* Drug: Idarubicin
* Drug: Cytarabine
* Drug: Azacytidine
* Drug: Mitoxantrone
* Drug: Etoposide
* Drug: Fludarabine
* Drug: G-CSF


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: 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. FLT3 mutation positive (ITD, TKD or other) ECOG PS 0-2 Adequate liver and renal function Negative pregnancy test Extramedullary leukemia allowed except CNS disease Exclusion Criteria: Arm 1 and 2 Exclusion: <5% blasts in marrow or blood at time of screening Active HIV, hepatitis B or C CNS leukemia Clinically significant GVHD or organ dysfunction where chemotherapy specified by protocol cannot be given Patient with AML-M3 (APL) Pre-existing liver diseases (i.e. cirrhosis, chronic hepatitis B or C, nonalcoholic steatohepatitis, sclerosing cholangitis)

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm 1 crenolanib besylate combination<br>Arm 1 patients will receive crenolanib besylate, combined with standard chemotherapy (Idarubicin/Cytarabine, MEC;Mitoxantrone/Etoposide/Cytarabine, FLAG-Ida: Fludarabine/Cytarabine/G-CSF/Idarubicin | Drug: Crenolanib besylate<br> <br> * Other names: CP-868,596-26;Drug: Idarubicin<br> <br> * Other names: 4-demethoxydaunorubicin;Drug: Cytarabine<br> <br> * Other names: cytosine arabinoside;Drug: Mitoxantrone<br> <br> * Other names: Novantrone;Drug: Etoposide<br> <br> * Other names: etoposide phosphate;Drug: Fludarabine<br> <br> * Other names: Fludarabine phosphate;Drug: G-CSF<br> <br> |
| Experimental: Arm 2 crenolanib besylate combination<br>Arm 2 patients will receive crenolanib besylate and azacytidine. | Drug: Crenolanib besylate<br> <br> * Other names: CP-868,596-26;Drug: Azacytidine<br> <br> * Other names: 5-azacytidine;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose-limiting toxicities of crenolanib besylate combination therapy |  | 6 months | 
| Response rate of crenolanib besylate combination therapy |  | 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of response |  | 2 years | 
| Progression free survival |  | 2 years | 
| Overall survival |  | 2 years |