A Phase II Study of Crenolanib in Relapsed/Refractory Acute Myeloid Leukemia Patients With FLT3 Activating Mutations
Condition: Acute Myeloid Leukemia With FLT3 Activating Mutations That Has Relapsed or Been Refractory After One or More Prior Therapies
MeSH terms: Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute
Intervention: Crenolanib besylate
Intervention description: Crenolanib besylate, 100 mg TID, 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.
Intervention MeSH terms: Crenolanib
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 56.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: FLT3; Crenolanib; Acute; Myeloid; AML

Summary:

      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).
    

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.