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

This study is currently recruiting participants. (see Contacts and Locations)
Verified December 2013 by Arog Pharmaceuticals LLC
Sponsor:
Information provided by (Responsible Party):
Arog Pharmaceuticals LLC
ClinicalTrials.gov Identifier:
NCT01657682
First received: July 31, 2012
Last updated: December 31, 2013
Last verified: December 2013
  Purpose

This pilot Phase II study is designed to evaluate the efficacy and tolerability of crenolanib in two cohorts of AML patients with FLT3 activation mutations (patients whose leukemia has recurred after prior chemotherapy not including a FLT3 TKI and patients whose leukemia 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: Crenolanib besylate, 200mg/m2/day divided in three doses 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 FLT3 Activating Mutations

Resource links provided by NLM:


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) and at best response.

  • 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 and overall survival [ Time Frame: 1 year ] [ Designated as safety issue: No ]
    To determine the progression free survival and overall survival of AML patients with activating FLT3 mutations treated with crenolanib

  • 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 Primary Completion Date: December 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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: Crenolanib besylate, 200mg/m2/day divided in three doses daily

Crenolanib besylate, 200mg/m2/day divided in three doses daily (preferably every eight hours), taken orally at least 30 minutes pre or post meal. Patients will complete a daily diary to record the date, time and amount (number of tablets) of crenolanib taken and eating schedule.

Concurrent hydroxyurea (maximum 5g total daily dose x 14 days) is permitted during the first 28 days of study therapy.

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: Crenolanib besylate, 200mg/m2/day divided in three doses daily

Crenolanib besylate, 200mg/m2/day divided in three doses daily (preferably every eight hours), taken orally at least 30 minutes pre or post meal. Patients will complete a daily diary to record the date, time and amount (number of tablets) of crenolanib taken and eating schedule.

Concurrent hydroxyurea (maximum 5g total daily dose x 14 days) is permitted during the first 28 days of study therapy.


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 Crenolanib besylate, 200mg/m2/day divided in three doses daily until disease progression, death, or the patient discontinues treatment for adverse events, investigator's judgment, or other reasons.. Concurrent hydroxyurea is permitted during the first 28 days of study therapy.

  Eligibility

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

Inclusion Criteria:

  • Confirmed primary AML relapsed or refractory after prior therapy, AML secondary to antecedent chemotherapy or radiation therapy, or AML due to prior myelodysplastic syndrome (MDS)/ myeloproliferative neoplasm (MPN) as defined by WHO criteria with presence of either FLT3 ITD and/or other FLT3 activating mutations
  • Patients with secondary AML should have failed no more than two (2) prior regimens
  • Patients with antecedent MDS/MPN, defined by WHO criteria, without any prior therapy for AML, regardless of the number of therapies for MDS/ MPN
  • Patients with primary AML should have received no more than two (2) prior cytotoxic containing salvage regimens. Reinduction with the same regimen or stem cell transplant will not be considered a separate salvage regimen. Change of drugs will be considered a salvage regimen. Unlimited FLT3 TKI therapy (even in combination with cytotoxics/hypomethylating agents) is allowed for patients enrolled in cohort B
  • Patients must have tested positive for FLT3-ITD and /or other FLT3 activating mutations within 30 day screening period
  • 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)
  • 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 WOCBP
  • Able and willing to provide written informed consent.

Exclusion Criteria:

  • Absence of a FLT3 activating mutation
  • <5% blasts in blood or marrow at screening
  • Concurrent chemotherapy, 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 (defined as hepatitis B surface antigen positive) or C (defined as hepatitis C antibody positive)
  • Known clinically active central nervous system (CNS) leukemia
  • Patients less than 30 days post HSCT
  • Subjects who have clinically significant graft versus host disease requiring treatment and /or have >grade 2 persistent non hematological toxicity related to transplant
  • Prior crenolanib treatment for a non-leukemic indication
  • Major surgical procedures within 14 days of Day 1 administration of crenolanib.
  • Unwillingness or inability to comply with protocol.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

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

Contacts
Contact: Abhijit Ramachandran, MS 2145930515 aramachandran@arogpharma.com
Contact: Pritam Kambuj, MD 2145930509 pkambuj@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:
No publications provided by Arog Pharmaceuticals LLC

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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: December 31, 2013
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
Crenolanib
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions

ClinicalTrials.gov processed this record on August 28, 2014