A Safety and Tolerability Study of Crenolanib in Combination With Chemotherapy in Newly Diagnosed Acute Myeloid Leukemia Patients With FLT3 Mutations

Study Overview
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Brief Summary
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This pilot study is designed to evaluate the safety and tolerability of oral crenolanib besylate given sequentially during standard induction and consolidation chemotherapy in patients with newly diagnosed AML with FLT3 activating mutations.

Official Title
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A Safety and Tolerability Trial of Crenolanib and Chemotherapy With Cytarabine and Anthracyclines in Patients With Newly Diagnosed Acute Myeloid Leukemia With FLT3 Activating Mutations

Conditions
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Newly Diagnosed AML With FLT3 Activating Mutations

Intervention / Treatment
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* Drug: crenolanib
* Drug: cytarabine
* Drug: daunorubicin
* Drug: idarubicin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Unequivocal diagnosis of AML based on the WHO classification, excluding acute promyelocytic leukemia No prior therapy for AML, except for hydroxyurea, in this setting is allowed. Subjects with AML evolving from MDS may have received prior MDS therapy with demethylating agents Subjects must have tested positive for FLT3-ITD and/or other FLT3 activating mutations Age ≥18 years ECOG PS 0 - 2 Adequate liver function, defined as normal total bilirubin, ALT ≤2.0x ULN, and AST ≤2.0x ULN measured within 24 hours prior to crenolanib commencement Adequate renal function, defined as serum creatinine ≤1.5x ULN or GFR >50 mL/min Negative pregnancy test (serum or urine) for women of childbearing potential (WOCBP) • Women considered not of childbearing potential include any of the following: no menses for at least 2 years or menses within 2 years but amenorrheic for at least 2 months and luteinizing hormone (LH) and follicular stimulating hormone (FSH) values within normal range (according to definition of postmenopausal for laboratory used) or bilateral oophorectomy or radiation castration and amenorrheic for at least 3 months or with bilateral tubal ligation WOCBP must practice contraception. Acceptable methods of contraception are double barrier methods (condoms with spermicidal jelly or foam and diaphragm with spermicidal jelly or foam), oral, depo provera, or injectable contraceptives, intrauterine devices, tubal ligations, and abstention Male patients (except those with prior surgical contraceptive procedures) with female partners who are of childbearing potential: Recommendation is for male and partner to use effective contraceptive methods, such as latex condoms, during the study Able and willing to provide written informed consent Exclusion Criteria: Pre-existing liver diseases (i.e., cirrhosis, chronic hepatitis B or C, nonalcoholic steatohepatitis, and sclerosing cholangitis, etc.) Active CNS leukemia Subject with concurrent severe and/or uncontrolled medical conditions that in the opinion of the investigator may impair the participation in the study or the evaluation of safety and/or efficacy NYHA Class III-IV heart failure, myocardial infarction <6 months prior to study entry, and/or serious arrhythmia requiring anti-arrhythmic therapy Unable to swallow pills Major surgical procedures within 14 days of administration of crenolanib (does not include line placement as needed for chemotherapy administration). Unwillingness or inability to comply with protocol. Concurrent use of other investigational agents. Subjects who are not eligible for standard chemotherapy

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort A<br>Patients will be given cytarabine and daunorubicin during induction therapy plus crenolanib at 100 mg TID. | Drug: crenolanib<br> <br> * Other names: CP-868,596-26;Drug: cytarabine<br> <br> Drug: daunorubicin<br> <br> |
| Experimental: Cohort B<br>Patients will be given cytarabine and idarubicin during induction therapy plus crenolanib at 100 mg TID. | Drug: crenolanib<br> <br> * Other names: CP-868,596-26;Drug: cytarabine<br> <br> Drug: idarubicin<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The safety and tolerability of crenolanib in combination with chemotherapy will be determined by assessing the adverse events experienced by patients. |  | 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Patients' serum and plasma samples will be collected and pharmacokinetic parameters including Cmax and AUC will be measured. |  | day 4 and day 15 of induction 1; day 7 of consolidation 1 | 
| Response rate |  | day 14-28 of induction |