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

Phase 2

Completed

• Conditions: Newly Diagnosed AML With FLT3 Activating Mutations
• Interventions: Drug: crenolanib; Drug: cytarabine; Drug: daunorubicin; Drug: idarubicin

• Registration Number: NCT02283177
• Lead Sponsor: Arog Pharmaceuticals, Inc.

Brief Summary

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.

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2014-10-29
• Study First Submitted QC: 2014-11-03
• Study First Posted: 2014-11-05
• Study Start: 2015-01
• Primary Completion: 2019-12
• Study Completion: 2019-12
• Status Verified: 2024-01
• Results First Submitted: 2024-01-09
• Results First Submitted QC: 2024-01-09
• Last Update Submitted: 2024-01-09
• Results First Posted: 2024-02-02
• Last Update Posted: 2024-02-02

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 44

Inclusion Criteria

1. Unequivocal diagnosis of AML based on the WHO classification, excluding acute promyelocytic leukemia

2. No prior therapy for AML, except for hydroxyurea, in this setting is allowed.

3. Subjects with AML evolving from MDS may have received prior MDS therapy with demethylating agents

4. Subjects must have tested positive for FLT3-ITD and/or other FLT3 activating mutations

5. Age ≥18 years

6. ECOG PS 0 - 2

7. 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

8. Adequate renal function, defined as serum creatinine ≤1.5x ULN or GFR >50 mL/min

9. 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

10. 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

11. 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

12. Able and willing to provide written informed consent

Exclusion Criteria

1. Pre-existing liver diseases (i.e., cirrhosis, chronic hepatitis B or C, nonalcoholic steatohepatitis, and sclerosing cholangitis, etc.)
2. Active CNS leukemia
3. 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
4. NYHA Class III-IV heart failure, myocardial infarction <6 months prior to study entry, and/or serious arrhythmia requiring anti-arrhythmic therapy
5. Unable to swallow pills
6. Major surgical procedures within 14 days of administration of crenolanib (does not include line placement as needed for chemotherapy administration).
7. Unwillingness or inability to comply with protocol.
8. Concurrent use of other investigational agents.
9. Subjects who are not eligible for standard chemotherapy

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Cohort B	cytarabine	Patients will be given cytarabine and idarubicin during induction therapy plus crenolanib at 100 mg TID.
Cohort A	crenolanib	Patients will be given cytarabine and daunorubicin during induction therapy plus crenolanib at 100 mg TID.
Cohort A	cytarabine	Patients will be given cytarabine and daunorubicin during induction therapy plus crenolanib at 100 mg TID.
Cohort A	daunorubicin	Patients will be given cytarabine and daunorubicin during induction therapy plus crenolanib at 100 mg TID.
Cohort B	crenolanib	Patients will be given cytarabine and idarubicin during induction therapy plus crenolanib at 100 mg TID.
Cohort B	idarubicin	Patients will be given cytarabine and idarubicin during induction therapy plus crenolanib at 100 mg TID.

Primary Outcome Measures

Name	Time	Method
Clinical Response to Crenolanib With Standard Induction Chemotherapy	2 years	To determine the response rate to crenolanib. Complete remission (CR) response criteria includes a post-baseline bone marrow (BM) biopsy or aspiration % blasts \<5%, the absence of Auer rods and extramedullary leukemia, absolute neutrophil count (ANC) \>1×10\^9/L and platelet count \>100×10\^9/L. Complete remission with incomplete blood count recovery (CRi) response includes all CR criteria met, except participant do not achieve either platelet or ANC recovery. Composite Complete CR response includes all subjects who achieve a CR and CRi. Partial Response (PR) response includes all CR criteria met except a decrease of ≥50% in % blasts in the BM aspirate or biopsy from baseline but within 5-25% or bone marrow blasts \<5% with persistent Auer rods. Refractory Disease response includes subjects who do not satisfy the criteria for CR, CRi or PR.

Secondary Outcome Measures

Name	Time	Method
3-Year Overall Survival	3 years	Overall survival (OS) was measured from the date of the first dose of treatment to the date of death from any cause or to the last date that the patient was known to be alive. OS at 3-years is presented.

Trial Locations

Locations (9)

Cleveland Clinic; 🇺🇸 Cleveland, Ohio, United States

University of Iowa Hospitals and Clinics; 🇺🇸 Iowa City, Iowa, United States

Roswell Park Cancer Institute; 🇺🇸 Buffalo, New York, United States

University of Texas Southwestern Medical Center; 🇺🇸 Dallas, Texas, United States

City of Hope Medical Center; 🇺🇸 Duarte, California, United States

Memorial Sloan Kettering Cancer Center; 🇺🇸 New York, New York, United States

Fred Hutchinson Cancer Research Center; 🇺🇸 Seattle, Washington, United States

Dana-Farber Cancer Institute; 🇺🇸 Boston, Massachusetts, United States

Weill Cornell Medical College; 🇺🇸 New York, New York, United States