A Phase II Study of Crenolanib in Relapsed/Refractory Acute Myeloid Leukemia Patients With FLT3 Activating Mutations - Full Text View

Purpose

This is a Phase II open label study of crenolanib besylate. This study will enroll subjects with relapsed Acute Myeloid Leukemia (AML) with FLT3 activating mutations. Two cohorts of patients will be enrolled: those whose AML has recurred after prior chemotherapy (not including a FLT3 TKI), and those whose AML has progressed after prior therapy with a FLT3 TKI.

Condition	Intervention	Phase
Acute Myeloid Leukemia With FLT3 Activating Mutations That Has Relapsed or Been Refractory After One or More Prior Therapies	Drug: 100mg Crenolanib besylate, given three times daily	Phase 2

Study Type:	Interventional
Study Design:	Allocation: Non-Randomized Endpoint Classification: Safety/Efficacy Study Intervention Model: Parallel Assignment Masking: Open Label Primary Purpose: Treatment
Official Title:	A Phase II Study of Crenolanib in Relapsed/Refractory Acute Myeloid Leukemia Patients With Activating FLT3 Mutations

Resource links provided by NLM:

Genetics Home Reference related topics: familial acute myeloid leukemia with mutated CEBPA

MedlinePlus related topics: Acute Myeloid Leukemia Leukemia

U.S. FDA Resources

Further study details as provided by Arog Pharmaceuticals LLC:

Primary Outcome Measures:

Response rate of patients receiving crenolanib therapy [ Time Frame: 1 year ] [ Designated as safety issue: No ]
To determine the response rate to crenolanib, including the rates of complete remission (CR), CR with incomplete blood count recovery (CRi), and partial remission (PR), in relapsed/refractory AML patients with FLT3 activating mutations after first cycle (28-days).
Toxicity rate associated with crenolanib therapy [ Time Frame: 1 year ] [ Designated as safety issue: Yes ]
To determine the safety and tolerability of crenolanib in AML patients with FLT3 activating mutations. The two cohorts of patients will be jointly monitored for the safety. The toxicity is defined as any grade 4 or greater non-hematologic toxicities attributed to the study drug. Targeting a 30% toxicity rate as a trade-off, the trial will be stopped early according to the following monitoring rule. If at any time during the study we determine that there is more than a 95% chance that the toxicity rate is more than 30% we will stop the study. Crenolanib has been well tolerated in studies including over 100 patients and toxicity patterns are relatively well understood.

Secondary Outcome Measures:

Duration of response [ Time Frame: 1 year ] [ Designated as safety issue: No ]
To determine the duration of clinical response in AML patients with FLT3 activating mutations treated with crenolanib.
Pharmacodynamic markers [ Time Frame: 1 year ] [ Designated as safety issue: No ]
To analyze phospho-FLT3 and other pharmacodynamic markers from serially collected circulating leukemic blasts and/or marrow blast samples
Duration of progression-free survival [ Time Frame: 1 year ] [ Designated as safety issue: No ]
To determine the length of time that passes between start of crenolanib therapy and progression of disease in patients who receive crenolanib therapy
Pharmacokinetic markers [ Time Frame: 1 year ] [ Designated as safety issue: No ]
To characterize the pharmacokinetics of crenolanib in adult patients and relate drug disposition to outcome or pharmacodynamic markers (i.e. toxicity and/or FLT3 inhibition)

Estimated Enrollment:	41
Study Start Date:	October 2012
Estimated Study Completion Date:	December 2013
Estimated Primary Completion Date:	August 2013 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Experimental: Cohort B - Prior therapy with FLT3 TKI Will enroll relapsed/refractory AML patients with FLT3 activating mutations whose leukemia has progressed and have history of prior therapy with one or more FLT3 TKIs.	Drug: 100mg Crenolanib besylate, given three times daily Crenolanib besylate given 100 mg, three times a day (preferably every eight hours) continuously until one of the criteria for study discontinuation is fulfilled
Experimental: Cohort A - Prior chemotherapy, without prior FLT3 TKI Will enroll relapsed/refractory AML patients with FLT3 activating mutations who progressed on one or more prior chemotherapy regimens excluding a FLT3 TKI.	Drug: 100mg Crenolanib besylate, given three times daily Crenolanib besylate given 100 mg, three times a day (preferably every eight hours) continuously until one of the criteria for study discontinuation is fulfilled

Detailed Description:

This is a Phase II open label study of crenolanib besylate. This study will enroll subjects with relapsed Acute Myeloid Leukemia (AML) with FLT3 activating mutations. Two cohorts of patients will be enrolled: those whose AML has recurred after prior chemotherapy (not including a FLT3 TKI), and those whose AML has progressed after prior therapy with a FLT3 TKI. Subjects will take 100mg (one tablet) of crenolanib three times a day until disease progression, death, or the patient discontinues treatment for adverse events, investigator's judgment, or other reasons.

Eligibility

Ages Eligible for Study:	18 Years and older
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

Confirmed primary AML diagnosis with presence of either FLT3 ITD and/or other FLT3 activating mutations
Males and females age ≥ 18 years
ECOG PS 0-2
Adequate liver function, defined as bilirubin ≤ 1.5x ULN, ALT ≤ 3.0x ULN, and AST ≤ 3.0x ULN.
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)
In the absence of rapidly progressing leukemia, subjects should have received no anti-leukemic therapy (except hydroxyurea) prior to the first dose of crenolanib for 2 weeks (for classical cytotoxic agents and FLT3 inhibitors; 4 weeks for radiation).
Negative serum pregnancy test for WOCBP.
Able and willing to provide written informed consent.

Exclusion Criteria:

Absence of a FLT3 activating mutation
Secondary AML or AML in the setting of antecedent hematological disorders
< 5% blasts in blood or marrow at screening
Concurrent chemotherapy, systemic immuno-suppressants, 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 or C
Known clinically active central nervous system (CNS) leukemia
Patients who have had HSCT and are within 180 days of an allogeneic transplant or 90 days of an autologous transplant, and/or have received immunosuppressive drugs for management or prophylaxis of GVHD within 30 days of enrollment, and/or have clinically significant graft-versus-host disease requiring treatment, and/or have > Grade 1 persistent non hematological toxicity related to the transplant
Major surgical procedures within 14 days of Day 1 administration of crenolanib.
Unwillingness or inability to comply with protocol.

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT01657682

Contacts

Contact: Abhijit Ramachandran, MS	2145930515	aramachandran@arogpharma.com
Contact: Morgan Grant	2145930588	mgrant@arogpharma.com

Locations

United States, Texas
MD Anderson Cancer Center	Recruiting
Houston, Texas, United States
Contact: Jorge Cortes, MD jcortes@mdanderson.edu

Sponsors and Collaborators

Arog Pharmaceuticals LLC

More Information

Additional Information:

AROG Pharmaceuticals This link exits the ClinicalTrials.gov site

No publications provided

Responsible Party:	Arog Pharmaceuticals LLC
ClinicalTrials.gov Identifier:	NCT01657682 History of Changes
Other Study ID Numbers:	ARO-005
Study First Received:	July 31, 2012
Last Updated:	October 16, 2012
Health Authority:	United States: Food and Drug Administration

Keywords provided by Arog Pharmaceuticals LLC:

FLT3
Crenolanib
Acute
Myeloid
AML

Additional relevant MeSH terms:

Leukemia
Leukemia, Myeloid, Acute
Leukemia, Myeloid
Neoplasms by Histologic Type
Neoplasms

ClinicalTrials.gov processed this record on June 18, 2013