Phase II Study of Crenolanib in Subjects With Relapsed/Refractory AML With FLT3 Activating Mutations

A Phase II Study of Crenolanib Besylate in Subjects With Relapsed/Refractory Acute Myeloid Leukemia With FLT3 Activating Mutations

This is a Phase II open label study of crenolanib besylate. This study will enroll subjects with relapsed or refractory AML with FLT3 activating mutations. Prior treatment with other FLT3 TKIs is allowed. Subjects will take crenolanib 200mg/m2/day divided in three doses daily (preferably every eight hours), taken orally at least 30 minutes pre or post meal until disease progression, death, or the patient discontinues treatment for adverse events, investigator's judgment, or other reasons. Patients who are able to proceed to allogeneic stem cell transplant will be able to resume crenolanib therapy post-transplant in an attempt to maintain remission.

Study Overview

• Status: Completed
• Conditions: Relapsed or Refractory Acute Myeloid Leukemia With FLT3 Activating Mutations
• Intervention / Treatment: Drug: Crenolanib Besylate (CP-868,596-26)

• Study Type: Interventional
• Enrollment (Actual): 14
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Texas
    • Dallas, Texas, United States, 75390
      • University of Texas Southwestern Medical Center

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Relapsed/refractory primary AML or AML secondary to antecedent hematologic disorder with an expected survival of 3 months or greater
• Patients must have tested positive for FLT3-ITD and /or other FLT3 activating mutations within < 60 days of the screening period.
• Age ≥18 years
• ECOG PS 0 - 2
• Adequate liver function, defined as total or direct bilirubin ≤1.5x ULN, ALT ≤3.0x ULN,AST ≤3.0x ULN. Exceptions for ALT and AST restrictions will be made in the setting of documented liver involvement with leukemia
• Adequate renal function, defined as serum creatinine ≤1.5x ULN
• Recovery from non-hematological toxicities of prior therapy (including HSCT) to no more than grade 1 (except alopecia)
• Subjects should have received no anti-leukemic therapy (except hydroxyurea) prior to the first dose of crenolanib as follows: for 14 days for classical cytotoxic agents and for five times the t1/2 (half-life) for FLT3 inhibitors and antineoplastic agents that are neither cytotoxic nor FLT3 inhibitors (e.g. hypomethylating agent or MEK inhibitor)
• Negative pregnancy test for women of childbearing potential
• Able and willing to provide written informed consent
• Subjects who received crenolanib prior to and are within 30-90 days of an allogeneic stem cell transplant (HSCT) and have either no active GVHD where therapy has been initiated or GVHD where therapy has not been escalated within 14 days prior to start of study drug

Exclusion Criteria:

• Absence of FLT3 activating mutation
• <5% blasts in blood or marrow at screening
• Concurrent chemotherapy, systemic immunosuppressants, or targeted anti-cancer agents,other than hydroxyurea
• Patient 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
• HIV infection or active hepatitis B manifested as hepatitis surface antigen positive (HepBsAg) or hepatitis C manifested as hepatitis C antibody positive
• For post HSCT, subjects who are within 29 days of an allogeneic transplant, and/or are on an unstable dose of immunosuppressive drugs for management or prophylaxis of GVHD or have escalated therapy for GVHD within 14 days of starting study drug and/or have >/=Grade 2 persistent non hematological toxicity related to the transplant or did not receive crenolanib prior to HSCT
• Evidence of lack of engraftment if post allogeneic transplant
• Unable to swallow pills
• Major surgical procedures within 14 days of Cycle 1 Day 1 administration of crenolanib
• Unwillingness or inability to comply with protocol.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Crenolanib Besylate

Drug: Crenolanib Besylate (CP-868,596-26); Subjects will take crenolanib 200mg/m2/day divided in three doses daily (preferably every eight hours), taken orally at least 30 minutes pre or post meal until disease progression, death, or the patient discontinues treatment for adverse events, investigator's judgment, or other reasons. Patients who are able to proceed to allogeneic stem cell transplant will be able to resume crenolanib therapy post-transplant in an attempt to maintain remission.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Response Rate	To determine the response rate to crenolanib.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. Partial Response (PR) response included a decrease of ≥50% in % blasts in the BM aspirate or biopsy from baseline but >5%. Hematologic improvement (HI) response included erythroid response where Hgb increased ≥ 1.5 g/dL, platelet response where platelets increased ≥ 30 x 10^9/L for patient starting with >20 x 10^9/L platelets or increase from <20 x 10^9/L to >20 x 10^9/L and by at least 100% and neutrophil response where at least 100% increase and an increase >0.5 x 10^9/L. Resistant Disease (RD) was defined as the absence of CR, CRi, CRp, PR or HI.	From the date of first dose to the end of protocol treatment, 1 year.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Impact of crenolanib on patient experience	The impact of crenolanib on patient experience will be determined by measuring patient hematological improvement, bridge to transplant, duration of leukemia control, blood and platelet transfusions, infections, days of hospitalization, and performance status	3 years
Safety of crenolanib	The safety and tolerability of crenolanib will be determined by assessing the adverse events experienced by patients	3 years
Pharmacokinetic analysis of crenolanib in patients with AML	The bioavailability of crenolanib will be assessed by performing pharmacokinetic analysis of patients' serum samples	3 years
Analysis of pharmacodynamic markers	Analysis of phospho-FLT3 and other pharmacodynamic markers from serially collected circulating leukemic blasts and/or marrow blast samples	3 years
Analysis of Pharmacogenetics	Pharmacogenetic analyses, correlation of remission with genomic abnormalities including but not limited to mutant FLT3 allelic ratio	3 years

Collaborators and Investigators

• Sponsor: Arog Pharmaceuticals, Inc.

Publications and helpful links

Helpful Links

• AROG Pharmaceuticals, LLC

Study record dates

Study Major Dates

• Study Start: July 1, 2012
• Primary Completion (Actual): August 1, 2014
• Study Completion (Actual): November 1, 2014

Study Registration Dates

• First Submitted: January 30, 2012
• First Submitted That Met QC Criteria: January 30, 2012
• First Posted (Estimated): January 31, 2012

Study Record Updates

• Last Update Posted (Actual): January 30, 2024
• Last Update Submitted That Met QC Criteria: January 3, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Keywords: relapsed; refractory; leukemia; FLT3; Crenolanib; Acute; myeloid
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Antineoplastic Agents; Crenolanib
• Other Study ID Numbers: ARO-004