Clinical Trial 18406

Cancer Type: Malignant Hematology
Interventions:AZD1775; Belinostat; MK-1775 (AZD1775); PXD101 (Belinostat)

Study Type: Treatment
Phase of Study: Phase I
Investigators:

  • Jeffrey Lancet

Overview

Study Title

A Phase 1 Study of AZD1775 in Combination with Belinostat in Relapsed and Refractory Myeloid Malignancies and Selected Untreated Patients with Acute Myeloid Leukemia

Summary

The purpose of this study is to test the safety of giving belinostat with AZD1775.

Objective

To identify the maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D) for a regimen combining AZD1775 with belinostat in patients with refractory/relapsed acute myeloid leukemia (AML), chronic myeloid leukemia in blast crisis (CML-BC), or intermediate-2 or high-risk myelodysplastic syndrome (MDS), and selected previously untreated poor-prognosis patients with AML.

Inclusion Criteria

  • Participants must have one of the following, histologically or cytologically confirmed: Acute Myeloid Leukemia (AML) [non- acute promyelocytic leukemia (APL) AML]; Chronic Myeloid Leukemia Blast Crisis (CML-BC); Myelodysplastic Syndrome (MDS)
  • Eastern Cooperative Oncology Group (ECOG) performance status == 50%)
  • Total bilirubin => Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) => Creatinine within normal limits for the laboratory OR creatinine clearance >= 60 mL/min/1.73 m^2 (estimated glomerular filtration rate [eGFR]) for patients with creatinine levels above the ULN for the laboratory
  • Human immunodeficiency virus (HIV)-infected persons are eligible if they meet other related eligibility criteria
  • Women of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and 4 months after completion of AZD1775 and belinostat administration
  • Ability to swallow medication
  • Ability to understand and the willingness to sign a written informed consent document

  • Exclusion Criteria

  • Clinical picture indicative of leukostasis or evidence of disseminated intravascular coagulopathy
  • Other investigational agent within 3 weeks prior to initiation of study therapy
  • Ongoing toxicities >= grade 2 from prior therapy
  • Acute promyelocytic leukemia (APL, M3)
  • Active central nervous system (CNS) leukemia
  • History of allergic reactions attributed to compounds of similar chemical or biologic composition to AZD1775 or belinostat
  • Stem cell transplant within previous 3 months prior to initiation of study therapy
  • Major surgical procedures => Uncontrolled infection
  • Women who are pregnant or breastfeeding
  • Circulating blast count >= 50,000/uL within the week preceding enrollment
  • Current candidacy for a potentially curative allogeneic stem cell transplant, unless declined
  • Corrected QT (QTc) interval >= 450 ms (i.e., grade 1 or higher) on electrocardiogram (ECG) prior to initiation of study treatment
  • History of sustained ventricular tachycardia (VT), ventricular fibrillation (VF), torsades de pointes, or resuscitated cardiac arrest unless currently addressed with an implanted cardiac defibrillator
  • Concomitant treatment with an anti-arrhythmic agent to prevent or control arrhythmia; agents used for rate-control of atrial fibrillation are permitted provided that they are not prohibited due to potential drug interactions
  • Known congenital long QT syndrome
  • Second degree atrioventricular (AV) block type II, third degree AV block, or ventricular rate 120 bpm
  • Unstable angina, myocardial infarction or New York Heart Association (NYHA) class III/IV congestive heart failure within 30 days preceding study enrollment
  • Ongoing or planned treatment with any of the following: Ongoing or planned treatment with any of the following: Atorvastatin; Metformin; Inhibitors of uridine diphosphate (UDP) glucuronosyltransferase 1 family, polypeptide A complex locus (UGT1A). Strong inhibitors or inducers of cytochrome P450 family 3, subfamily A, polypeptide 4 (CYP3A4); as part of the enrollment/informed consent procedures, the patient will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the patient is considering a new over-the-counter medicine or herbal product. If any of these agents have been used, patients must be off them for >= 2 weeks before starting study treatment.
  • Any known UGT1A polymorphism, heterozygous or homozygous
  • History of prior therapy with belinostat or AZD1775
  • Active gastrointestinal (GI) conditions that might predispose to drug intolerance or poor drug absorption
  • Receiving any other therapies for cancer treatment (with the exception of gonadotropin-releasing hormone [GnRH] agonists for prostate cancer); Note: hydroxyurea is allowed before initiation of study treatment and for the first 5 days of study treatment
  • Diagnosis or treatment for another malignancy within 3 years of enrollment, with the exception of complete resection of basal cell carcinoma or squamous cell carcinoma of the skin, any in situ malignancy, or low-risk prostate cancer after curative therapy