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

NCT01657682

Description:

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).

Related Conditions:
  • Acute Myeloid Leukemia
Recruiting Status:

Active, not recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: A Phase II Study of Crenolanib in Relapsed/Refractory Acute Myeloid Leukemia Patients With FLT3 Activating Mutations
  • Official Title: A Phase II Study of Crenolanib in Relapsed/Refractory Acute Myeloid Leukemia Patients With FLT3 Activating Mutations

Clinical Trial IDs

  • ORG STUDY ID: ARO-005
  • NCT ID: NCT01657682

Conditions

  • Acute Myeloid Leukemia With FLT3 Activating Mutations That Has Relapsed or Been Refractory After One or More Prior Therapies

Interventions

DrugSynonymsArms
Crenolanib besylateCohort A - No prior FLT3 TKI exposure

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).

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 without a
      FLT3 TKI, and those whose AML has progressed after prior therapy with FLT3 TKIs. Subjects
      will take Crenolanib besylate at 100 mg TID until disease progression, death, or unacceptable
      toxicities. Concurrent hydroxyurea is permitted during the first 28 days of study therapy.
    

Trial Arms

NameTypeDescriptionInterventions
Cohort A - No prior FLT3 TKI exposureExperimentalWill enroll relapsed/refractory AML patients with FLT3 activating mutations who progressed on one or more prior chemotherapy regimens excluding any FLT3 TKI.
  • Crenolanib besylate
Cohort B - Prior therapy with FLT3 TKIExperimentalWill 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.
  • Crenolanib besylate

Eligibility 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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Response rate of patients receiving crenolanib therapy
Time Frame:1 year
Safety Issue:
Description: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.

Secondary Outcome Measures

Measure:Duration of response
Time Frame:1 year
Safety Issue:
Description:To determine the duration of clinical response in AML patients with FLT3 activating mutations treated with crenolanib.
Measure:Pharmacodynamic markers
Time Frame:1 year
Safety Issue:
Description:To analyze phospho-FLT3 and other pharmacodynamic markers from serially collected circulating leukemic blasts and/or marrow blast samples
Measure:Duration of progression-free survival and overall survival
Time Frame:1 year
Safety Issue:
Description:To determine the progression free survival and overall survival of AML patients with activating FLT3 mutations treated with crenolanib
Measure:Pharmacokinetic markers
Time Frame:1 year
Safety Issue:
Description: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)

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Active, not recruiting
Lead Sponsor:Arog Pharmaceuticals, Inc.

Trial Keywords

  • FLT3
  • Crenolanib
  • Acute
  • Myeloid
  • AML

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