Safety Study of AKN-028 in Patients With Acute Myelogenous Leukemia

A Phase 1/2, Open-Label, Multi-Center Dose Escalation, Safety and Tolerability Study of AKN-028 in Patients With Acute Myelogenous Leukemia (AML)

This Phase 1/2 study consists of two parts. The purpose of Part 1 of the study is to examine the safety and tolerability of AKN-028 and to determine the recommended dose of AKN-028 for further evaluation in Part 2 of the study in patients with Acute Myelogenous Leukemia (AML). The purpose of Part 2 of the study is to determine safety and efficacy in patients with AML.

Inclusion Criteria:

• Provide written informed consent prior to Screening;

• Male or female patients, age ≥ 18 years;

• For females of childbearing potential, a negative urine pregnancy test must be obtained

• Confirmed diagnosis of AML (≥ 20% blasts in bone marrow and / or peripheral blood) according to World Health Organization (WHO) classification [2] and meeting at least one of the following:

  1. Newly diagnosed AML, but according to the clinical judgment of the principal investigator, patient is not a candidate for induction chemotherapy because of age, comorbidity, performance status, or other factors;
  2. AML in first relapse with WBC < 60,000/mm3 and ineligible for further intensive induction chemotherapy;
  3. AML in second relapse with low peripheral blast count (< 10,000/mm3) and with WBC < 60,000/mm3 and ineligible for intensive induction chemotherapy;
  4. Primary refractory disease, here defined as patients with AML not having achieved CR following up to 2 courses of chemotherapy for enrollment in Part 1 and patients with AML refractory following 1 course of chemotherapy for enrollment in Part 2;

Note: Severe neutropenia per se (up to Grade 4) should be accepted if it is likely to be related to the AML. However, the severe neutropenia may be due to the recently administered chemotherapy (e.g. cytarabin). It may be prudent to perform a new bone marrow examination. In case the marrow is hypoplastic (due to cytarabin) the screening should be postponed and G-CSF should be administered for a short period and then the patient should be re-evaluated. In case the bone marrow is not hypoplastic but rather infiltrated with AML cells the patient can be screened.

• Performance status of 0-3 on the Eastern Cooperative Oncology Group (ECOG) Performance Status Scale;

• Adequate organ function, including the following:

  • Serum creatinine ≤ 2.0 mg/dL (176.8 mMol/L) during screening;
  • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2x the upper limits of normal (ULN) during screening; and
  • Total bilirubin ≤1.5 x ULN during screening.

Exclusion Criteria:

• Patients who are candidates for induction chemotherapy for AML
• Total WBC count ≥ 60,000/mm3;
• Evidence of active central nervous system (CNS) leukemia;
• Evidence of blast-phase chronic myelogenous leukemia (CML);
• Histological or cytogenetic diagnosis of AML with M3 subtype (Acute Promyelocytic Leukemia);
• Lack of recovery of non-hematological toxicity from systemic therapy for the underlying hematologic condition;
• Previous or concurrent malignancy except non-invasive non-melanoma skin cancer, in situ carcinoma of the cervix, or other solid tumor treated curatively, and without evidence of recurrence for at least 2 years prior to study entry; this exclusion does not refer to the disease (AML) under study;
• Uncontrolled systemic infection (viral, bacterial, or fungal);
• Uncontrolled disseminated intravascular coagulation;
• Known positive serology for human immunodeficiency virus;
• Clinically significant cardiac dysfunction (New York Heart Association Class 3 or 4) at the time of screening, or a history of myocardial infarction or heart failure within 3 months preceding the first dose of AKN-028;
• Chronic Graft versus Host Disease (GVHD) with the exception of mild (Grade 1) skin or oral GVHD;
• Major surgery within the 28 days preceding the first dose of AKN-028;
• Concomitant administration of any other anti-leukemia or anti-neoplastic therapy (during the screening period, hydroxyurea is allowed for ≤ 7 days before Cycle 1, as well as for ≤ 7 days between cycles);
• Concomitant treatment with immunotherapy, or any investigational agent within 28 days preceding the first dose of AKN-028, or lack of recovery from toxicity of such treatment;
• Active autoimmune disease requiring immunosuppressive therapy;
• Radiotherapy, or lack of recovery of any radiotherapy-related acute toxicity, within the 28 days preceding the first dose of AKN-028;
• Previous treatment in any clinical study with AKN-028, any other FLT-3 inhibitor, or any other c-Kit inhibitor;
• Female patients who are pregnant or breast-feeding;
• Male, or female patients of childbearing potential, unwilling to use an approved, effective means of contraception (e.g., oral contraception, barrier contraception, intrauterine device) in accordance with the investigator's standards;
• Known current drug or alcohol abuse;
• Active viral Hepatitis B and /or C;
• Other severe, acute, or chronic medical or psychiatric condition, or laboratory abnormality that, in the opinion of the investigator, may compromise the safety of the patient during the study, affect the patient's ability to complete the study, or interfere with interpretation of study results;
• Any condition, which is judged by the Investigator to be inappropriate for study participation, including an inability to communicate or cooperate with the Investigator and the requirements of this study.