Phase 1/2 Safety and Efficacy of PLX3397 in Adults With Relapsed or Refractory Acute Myeloid Leukemia (AML)

• Safety-Subject incidence of adverse events [ Time Frame: 1 year ] [ Designated as safety issue: Yes ]
  Subjects will take oral doses of PLX3397 twice a day. Physical examinations, vital signs, 12-lead electrocardiograms (ECG), adverse events, hematology and serum chemistry will be used to assess safety throughout the study. Adverse events will be monitored and reviewed for safety issues/abnormal changes in the above mentioned tests.
• Complete Remission (CR) Rate including complete remission with incomplete blood count recovery (CRi) [ Time Frame: 1 year ] [ Designated as safety issue: No ]
  Evaluated by bone marrow assessments at a minimum of once every month. Evaluated using the International Working Group Response Criteria (Cheson 2003).

The purpose of this study is to evaluate the safety of study drug PLX3397 at 3 dose levels (800 mg/day, 1000 mg/day, and 1200 mg/day) and explore the efficacy in patients with relapsed or refractory acute myeloid leukemia (AML). Additional dose levels beyond 1200 mg/day may be considered based on safety and efficacy observations.

Protocol PLX108-05 is a Phase 1/2 open-label, sequential dose escalation (Part 1) followed by cohort expansion (Part 2) design at the recommended phase 2 dose established in Part 1. Treatment with PLX3397 will consist of continuous oral administration in 28-day cycles until unacceptable or dose-limiting toxicity, elective allogeneic hematopoietic stem cell transplantation, disease progression or relapse, patient death, Investigator decision, or voluntary withdrawal.

• Drug: PLX3397
  Maximum Tolerated Dose of PLX3397 will be administered orally, twice daily.
• Drug: PLX3397
  The drug product is available in capsule form, to be taken orally.

• Experimental: PLX3397
  Subjects will be dosed at the maximum tolerated dose.
  Intervention: Drug: PLX3397
• Experimental: oral dose of 800 mg/day of PLX3397
  Intervention: Drug: PLX3397
• Experimental: oral dose of 1000 mg/day PLX3397
  Intervention: Drug: PLX3397
• Experimental: oral dose of 1200 mg PLX3397
  Intervention: Drug: PLX3397

Inclusion Criteria:

• Male or female patients ≥18 years old
• Morphologically documented primary Acute Myeloid Leukemia (AML), prior chemotherapy-related AML, or AML secondary to an antecedent hematologic disorder (e.g. MDS), as defined by World Health Organization (WHO) criteria, confirmed by pathology review at the treating institution. Bone marrow involvement is required for Cohort Expansion Phase (Part 2)only.
• In at least first relapse or refractory AML; patients ≥ 60 years old can be included if unable or unwilling to undergo induction chemotherapy for hematopoietic stem cell transplantation (HSCT)
• Positive for Flt3-ITD activating mutation during Screening
• ECOG performance status of 0, 1, or 2

• Adequate recovery (to at least Grade 1) from toxicity of prior therapy as follows:

  • ≥2 weeks prior to C1D1 for cytotoxic therapy (excluding hydroxyurea, which is permitted at doses less than or equal to 5 g/day during first 2 weeks of cycle 1)

  • ≥4 half-lives for non-cytotoxic therapy prior to C1D1; washout period from last chemotherapy of at least 2 weeks OR at least 4 half-lives prior to C1D1.

    • Adequate renal and hepatic function
  • Adequate renal function, defined as Creatinine Clearance > 60 ml/min.
  • Adequate hepatic function, defined as AST and ALT < 3.0X ULN and serum direct bilirubin < 1.5X ULN. Exceptions may be made for patients with elevated liver transaminases secondary to AML.
• Life expectancy of at least 1 month
• Willing and able to provide written informed consent prior to any study related procedures and to comply with all study requirements

• Women of child-bearing potential must have a negative serum pregnancy test within 7 days of initiation of dosing and must agree to use two acceptable methods of birth control while on study drug and for 3 months after the last dose. Women of non-childbearing potential may be included if they meet at least one of the following criteria:

  • Surgically sterile
  • Have been postmenopausal for ≥ 1 year
  • Have follicle stimulation hormone (FSH) levels indicative of postmenopausal state (i.e. 30-120 IU/L) Sexually active men must also agree to use an acceptable method of birth control while on study drug and for 3 months after last dose.

Exclusion Criteria:

• Diagnosis of acute promyelocytic leukemia
• Diagnosis of chronic myelogenous leukemia in blast crisis
• Presence of CNS involvement of leukemia [discuss with Medical Monitor]

• Eligible for hematopoietic stell cell transplant (HSCT) at time of screening. However, patients who meet both of the following criteria may be eligible for study participation:

  1. eligible for HSCT but with non-optimal AML disease control (i.e., blasts greater than 5 percent) may be enrolled as bridge-to-transplant.
  2. relapsed disease following prior HSCT may be enrolled as alternative to second HSCT or as bridge-to-transplant regimen.
• Receipt of HSCT within 60 days of the first dose of PLX3397, on immunosuppressive therapy post HSCT at the time of Screening, or with clinically significant graft-versus-host disease. [Use of topical steroids for ongoing skin (Graft versus Host Disease) (GVHD) is permitted)
• Investigational drug use within 28 days of the first dose of PLX3397
• For Cohort Expansion Phase (Part 2) only: Relapse or refractory disease following treatment with another FLT3 tyrosine kinase inhibitor (TKI). This does NOT include patients who discontinued AC220 or other TKI due to poor tolerability or to undergo HSCT.
• Disease positive for D835 mutation at Screening
• A concurrent active cancer that requires non-surgical therapy (e.g. chemotherapy, radiation, adjuvant therapy). Prior history of other cancer is allowed, as long as there was no active disease within 1 year.
• Refractory nausea and vomiting, malabsorption, biliary shunt, or significant bowel resection that would preclude adequate absorption
• Patients with serious illnesses, uncontrolled infection, medical conditions, or other medical history including abnormal laboratory results, which in the investigator's opinion would be likely to interfere with a patient's participation in the study, or with the interpretation of the results
• Women of child-bearing potential who are pregnant or breast feeding
• QTcF ≥ 450 msec