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

NCT01573247 | Terminated Phase 1 DMC

• 2 other identifiers: AKN0012011-003285-33
• Study Type: interventional
• Target: 25
• Locations: 4 countries
• Sites: 8

Brief Summary

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.

Conditions

Acute Myeloid Leukemia

Keywords

Acute myeloid leukemia; Refractory Acute myeloid leukemia; FLT3 inhibitor; kinase inhibitor

Outcome Measures

Primary Outcomes (2)

• Plasma pharmacokinetic profiles

  up to 3 months

• Adverse Events

  Safety follow up

  up to 3 months

Secondary Outcomes (1)

• Response

  participants will be followed for the duration of up to 3 months

Study Arms (1)

AKN-028

EXPERIMENTAL

Drug: AKN-028

Interventions

AKN-028 DRUG

Part 1 of the study is a sequential dose-escalation evaluation of AKN-028. Part 1 started as an accelerated intra-patient dose escalation design in one patient at a time (the N=1 portion), and has switched to standard 3 + 3 design with inter-cohort dose escalation when AUC of 12 μM\*hrs has been reached. Starting dose of AKN-028 was 60 mg twice a day. During Part 2 of the study AKN-028 will be administered at the dose level selected in Part 1. Patients will be treated for a maximum of 3 cycles (first cycle of 14 days followed by 2 cycles of 21 days), with at least a 7-day treatment-free period between cycles. Patients with significant benefit after 3rd cycle may continue treatment at discretion of the investigator for as long as the patient continues to show significant benefit.

AKN-028

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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:
• 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;
• AML in first relapse with WBC \< 60,000/mm3 and ineligible for further intensive induction chemotherapy;
• AML in second relapse with low peripheral blast count (\< 10,000/mm3) and with WBC \< 60,000/mm3 and ineligible for intensive induction chemotherapy;
• 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.

You may not qualify if:

• 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;
• 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;

Sponsors & Collaborators

• Akinion Pharmaceuticals AB: lead

Study Sites (8)

University Hospital Brno

Brno, 625 00, Czechia

Location

University Hospital Kralovske Vinohrady

Prague, 100 34, Czechia

Location

MTZ Clinical Research Inc.

Warsaw, 02-106, Poland

Location

Institute of Hematology and Transfusion Medicine

Warsaw, 02-776, Poland

Location

Sahlgrenska University Hospital

Gothenburg, Sweden

Location

Orebro University Hospital

Örebro, Sweden

Location

Uppsala University Hospital

Uppsala, SE-751 85, Sweden

Location

St.Bartholomew's Hospital

West Smithfield, EC1A 7BE, United Kingdom

Location

Related Publications (1)

• Eriksson A, Kalushkova A, Jarvius M, Hilhorst R, Rickardson L, Kultima HG, de Wijn R, Hovestad L, Fryknas M, Oberg F, Larsson R, Parrow V, Hoglund M. AKN-028 induces cell cycle arrest, downregulation of Myc associated genes and dose dependent reduction of tyrosine kinase activity in acute myeloid leukemia. Biochem Pharmacol. 2014 Jan 15;87(2):284-91. doi: 10.1016/j.bcp.2013.10.022. Epub 2013 Nov 4.

  PMID: 24200998 DERIVED

MeSH Terms

Conditions

Leukemia, Myeloid, Acute

Interventions

N-3-(1H-indol-5-yl)-5-pyridin-4-yl-pyrazine-2,3-diamine

Condition Hierarchy (Ancestors)

Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases

Study Officials

• Martin Höglund, MD, PhD

  Dept of Hematology, Uppsala University Hospital

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 28, 2012
• First Posted: April 9, 2012
• Study Start: December 1, 2011
• Primary Completion: March 1, 2016
• Study Completion: March 1, 2016
• Last Updated: March 25, 2016

Record last verified: 2016-03

Locations

PL (2); SE (3); CZ (2); GB (1)