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

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

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.

Study Overview

• Status: Completed
• Conditions: Newly Diagnosed AML With FLT3 Activating Mutations
• Intervention / Treatment: Drug: cytarabine; Drug: idarubicin; Drug: daunorubicin; Drug: crenolanib

• Study Type: Interventional
• Enrollment (Actual): 44
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • California
    • Duarte, California, United States, 91010
      • City of Hope Medical Center
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • University of Iowa Hospitals and Clinics
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Dana-Farber Cancer Institute
  • New York
    • Buffalo, New York, United States, 14263
      • Roswell Park Cancer Institute
    • New York, New York, United States, 10065
      • Weill Cornell Medical College
    • New York, New York, United States, 10065
      • Memorial Sloan Kettering Cancer Center
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic
  • Texas
    • Dallas, Texas, United States, 75390
      • University of Texas Southwestern Medical Center
  • Washington
    • Seattle, Washington, United States, 98195
      • Fred Hutchinson Cancer Research Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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 Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Clinical Response to Crenolanib With Standard Induction Chemotherapy	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.	2 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
3-Year Overall Survival	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.	3 years

Collaborators and Investigators

• Sponsor: Arog Pharmaceuticals, Inc.
• Investigators: Principal Investigator: Richard Stone, MD, Dana-Farber Cancer Institute

Study record dates

Study Major Dates

• Study Start: January 1, 2015
• Primary Completion (Actual): December 1, 2019
• Study Completion (Actual): December 1, 2019

Study Registration Dates

• First Submitted: October 29, 2014
• First Submitted That Met QC Criteria: November 3, 2014
• First Posted (Estimated): November 5, 2014

Study Record Updates

• Last Update Posted (Actual): February 2, 2024
• Last Update Submitted That Met QC Criteria: January 9, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Antibiotics, Antineoplastic; Cytarabine; Daunorubicin; Idarubicin; Crenolanib
• Other Study ID Numbers: ARO-006