Safety and Anti-Disease Activity of Oral Tosedostat (CHR-2797) in Elderly Subjects With Refractory or Relapsed AML (OPAL)

The OPAL Study: A Phase II Study to Evaluate the Efficacy, Safety and Tolerability of Tosedostat (CHR-2797) in Elderly Subjects With Treatment Refractory or Relapsed Acute Myeloid Leukemia

The purpose of this study is to evaluate the efficacy and safety of tosedostat in elderly patients suffering from refractory or relapsed AML.

Study Overview

• Status: Completed
• Conditions: Acute Myeloid Leukemia; AML
• Intervention / Treatment: Drug: Tosedostat

Detailed Description

There is an urgent need for novel compounds and treatment strategies for elderly patients with AML, particularly those with refractory or relapsed disease for whom there are few effective treatment options. Treatment options for elderly patients are further limited by co-morbidity and tolerability constraints.

Tosedostat is a new aminopeptidase inhibitor, which in preclinical experiments has shown potent activity in both in vitro and in vivo cancer models as a single agent. In early clinical studies particularly good results have been observed in refractory and relapsed AML in older patients and these observations form the basis for the current study.

This multi-center, open label phase II study will enrol approximately 70 subjects in Part A and 130 subjects in Part B.

• Study Type: Interventional
• Enrollment (Actual): 76
• Phase: Phase 2

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Toronto, Ontario, Canada, M5G 2M9
      • Princess Margaret Hopsital
  • Quebec
    • Montreal, Quebec, Canada, H3A 1A1
      • Royal Victoria Hospital
• Netherlands
  • Amsterdam, Netherlands, 1081 HV
    • VUmc
  • Rotterdam, Netherlands, 3008 AE
    • Erasmus MC
• United States
  • California
    • Los Angeles, California, United States, 90095
      • UCLA School of Medicine
  • District of Columbia
    • Washington, District of Columbia, United States, 20010
      • Washington Cancer Institute
  • Florida
    • Orlando, Florida, United States, 32806
      • M.D. Anderson Cancer Center Orlando
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Emory University Clinic
  • Illinois
    • Chicago, Illinois, United States, 60637
      • University of Chicago Medical Center
  • Michigan
    • Ann Arbor, Michigan, United States, 48109-0008
      • University of Michigan Health System
  • Missouri
    • St Louis, Missouri, United States, 63110
      • Washington University, Oncology/Bone Marrow Transplant
  • New Jersey
    • Hackensack, New Jersey, United States, 07601
      • John Theurer Cancer Center, Hackensack University Medical Center,
  • New York
    • Bronx, New York, United States, 10461
      • Montefiore Medical Center Weiler Division
    • Lake Success, New York, United States, 11042
      • Monter Cancer Center
    • New York, New York, United States, 10065
      • Memorial Sloan-Kettering Cancer Center
    • New York, New York, United States, 10065
      • Weill Cornell Medical College - New York Presbyterian Hospital
    • Stony Brook, New York, United States, 11794-7007
      • Stony Brook University Medical Center
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke Univeristy Medical Center
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • Taussig Cancer Institute
  • Texas
    • Houston, Texas, United States, 77030
      • MD Anderson Cancer Center
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226-3596
      • Froedtert Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 60 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

INCLUSION:

1. Signed, informed consent prior to any study specific procedure

2. Subjects with a confirmed diagnosis of AML according to WHO classification (excluding APL) who have had either a first CR lasting less than 12 months, or have not had a first CR and who will receive their first salvage therapy in this study [6]. For the purposes of this study, the following considerations apply:

   1. Subjects should have received only 1 induction course, but this may have consisted of more than one cycle of treatment, with different agents or doses in each cycle
   2. Induction courses should normally have consisted of agents and doses considered as standard of care for induction at the investigational site concerned
   3. Subjects may have received consolidation for any number of cycles. Consolidation will be considered as any regimens given while the subject was in remission
   4. Subjects who received hematopoietic stem cell transplant in first remission are eligible provided there has been no chemotherapy or other targeted therapies to treat a relapse, and there is no evidence of Graft Versus Host Disease (GVHD). Donor leukocyte infusion is allowed provided there is no evidence of hematologic relapse as defined by the International Working Group (IWG) [12]
3. Subject's peripheral blast count does not exceed 30,000/microlitre before randomization into the study. Hydroxyurea treatment or leukapheresis may be used prior to or during the screening period to achieve this - see Section 6.7.2.
4. Subject's life expectancy at randomization is judged to be at least 3 months
5. Subjects should have recovered from the adverse effects of prior therapies to grade ≤1 (according to CTCAE v3) (excluding alopecia and any adverse effects that are expected to be chronic and stable)
6. Subjects must have had a bone marrow aspiration performed within 28 days prior to randomization showing the subject has at least 5% blasts and is therefore neither in CR nor CRp. This may be done at the Screening Visit if appropriate and feasible

7. Subjects must have adequate hepatic and renal function including the following:

   1. Total bilirubin ≤ 1.5 x upper limit of normal (in the absence of Gilbert's syndrome)
   2. AST and ALT ≤ 2.5 x upper limit of normal
   3. Serum creatinine ≤ 1.5 x upper limit of normal
8. Age ≥ 60 years
9. Performance status ≤ 2 (ECOG scale)
10. Screening left ventricular ejection fraction (LVEF) ≥ 50%
11. Subject is able to comply with all study procedures during the study including all visits and tests
12. Male subjects with female partners of reproductive potential must use acceptable contraceptive methods for the duration of time on study and continue to do so for a further 3 months after the end of tosedostat treatment

Exclusion:

1. Subjects who have received prior therapy for first relapse or refractory disease (a second induction cycle within a single induction regimen is allowed as defined above in Inclusion criterion 2)
2. Anti-cancer therapy including chemotherapy, radiotherapy, endocrine therapy, immunotherapy or use of any other investigational agents within 2 weeks prior to randomization (with the exception of hydroxyurea which can be used in certain circumstances. Section 6.7.2)
3. Subjects with APL (FAB type M3) or CML in blast crisis
4. Any prior or co-existing medical condition that in the Investigator's judgment will substantially increase the risk associated with the subject's participation in the study
5. Psychiatric disorders or altered mental status precluding understanding of the informed consent process and/or completion of the necessary study procedures

6. Significant* cardiovascular disease defined as:

   1. Congestive heart failure NYHA class 4
   2. Unstable angina pectoris
   3. History of myocardial infarction within 6 months prior to study entry
   4. Presence of clinically significant valvular heart disease
   5. Uncontrolled or clinically significant ventricular arrhythmia
   6. Presence of clinically significant conduction defect on screening ECG
   7. Uncontrolled hypertension (i.e., systolic BP >160mmHg, diastolic >90 mmHg in repeated measurements) despite adequate therapy
   8. Clinically significant atrial fibrillation *Grade 3/4 in the CTCAE v3 grading would generally be considered clinically significant, although this remains a judgment for the Investigator to make.
7. Gastrointestinal disorders that may interfere with absorption of drug
8. Active serious infection or sepsis at randomization
9. Clinically significant interstitial lung disease

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Tosedostat; oral, once daily administration of tosedostat to evaluate its efficacy, safety and tolerability

Drug: Tosedostat; In Part A, approximately 70 subjects will be randomized to one of 2 dose regimens of tosedostat which will be administered orally, once daily. The dose regimens of tosedostat will be: 120 mg for 6 months once daily, OR; 240 mg (induction dose) once daily for 2 months, followed by 120 mg(maintenance dose) for 4 months In Part B a further 130 subjects will receive the dose regimen of tosedostat identified in Part A as being appropriate, based on the interim analysis during Part A.; Other Names: - CHR-2797; - Aminopeptidase inhibitor

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
The primary objective of the study is to evaluate the efficacy of tosedostat in elderly subjects with treatment refractory or relapsed AML by measuring CR and CRp.	Months 1, 2, 3 & 6

Secondary Outcome Measures

Outcome Measure	Time Frame
To evaluate the safety and tolerability of tosedostat in elderly subjects with treatment refractory or relapsed AML	Screening, Days 1, 2, 8, 15, 29, monthly thereafter + unschedulded visits when deemed necessary
To evaluate the efficacy of tosedostat in elderly subjects with treatment refractory or relapsed AML, as determined by measures other than CR and CRp for the type and duration of response	Months 1, 2, 3 & 6

Collaborators and Investigators

• Sponsor: Chroma Therapeutics
• Collaborators: Quintiles, Inc.
• Investigators: Principal Investigator: Samir Parekh, MD, Montefiore Medical Center; Principal Investigator: David Rizzieri, MD, Duke University; Principal Investigator: Jorge E Cortes, MD, M.D. Anderson Cancer Center; Principal Investigator: Karen Yee, MD, Princess Margaret Hospital, Canada; Principal Investigator: Eric Feldman, MD, Weill Cornell Medical College - New York Presbyterian Hospital; Principal Investigator: Joseph Jurcic, MD, Memorial Sloan Kettering Cancer Center; Principal Investigator: Richard Larson, MD, University of Chicago; Principal Investigator: Hanna J Khoury, MD, Emory University Clinic; Principal Investigator: Harry Erba, MD, University of Michigan; Principal Investigator: Aarthi Shenoy, MD, MedStar Health Research Institute; Principal Investigator: Anjali Advani, MD, Taussig Cancer Institute; Principal Investigator: Shambavi Richard, MD, Stony Brook University Medical Center; Principal Investigator: Steven Allen, MD, Monter Cancer Center; Principal Investigator: Ehab Attalah, MD, Froedtert Hospital; Principal Investigator: John Storring, MD, Royal Victoria Hospital; Principal Investigator: Gerrit J Ossenkoppele, MD, VUmc; Principal Investigator: Pieter Sonneveld, MD, Erasmus Medical Center; Principal Investigator: Gary Schiller, MD, UCLA Division of Hematology/oncology, Los Angeles; Principal Investigator: Peter Westervelt, MD, Washington University School of Medicine; Principal Investigator: Julio Hajdenberg, MD, MD Anderson Cancer centre, Orlando, FL; Principal Investigator: Stuart Goldberg, MD, John Theurer Cancer Center, Hackensack NJ

Publications and helpful links

General Publications

• Krige D, Needham LA, Bawden LJ, Flores N, Farmer H, Miles LE, Stone E, Callaghan J, Chandler S, Clark VL, Kirwin-Jones P, Legris V, Owen J, Patel T, Wood S, Box G, Laber D, Odedra R, Wright A, Wood LM, Eccles SA, Bone EA, Ayscough A, Drummond AH. CHR-2797: an antiproliferative aminopeptidase inhibitor that leads to amino acid deprivation in human leukemic cells. Cancer Res. 2008 Aug 15;68(16):6669-79. doi: 10.1158/0008-5472.CAN-07-6627.
• Estey E, Kornblau S, Pierce S, Kantarjian H, Beran M, Keating M. A stratification system for evaluating and selecting therapies in patients with relapsed or primary refractory acute myelogenous leukemia. Blood. 1996 Jul 15;88(2):756. No abstract available.
• Cortes J, Feldman E, Yee K, Rizzieri D, Advani AS, Charman A, Spruyt R, Toal M, Kantarjian H. Two dosing regimens of tosedostat in elderly patients with relapsed or refractory acute myeloid leukaemia (OPAL): a randomised open-label phase 2 study. Lancet Oncol. 2013 Apr;14(4):354-62. doi: 10.1016/S1470-2045(13)70037-8. Epub 2013 Feb 28.

Study record dates

Study Major Dates

• Study Start: October 1, 2009
• Primary Completion (Actual): March 1, 2011
• Study Completion (Actual): March 1, 2011

Study Registration Dates

• First Submitted: October 24, 2008
• First Submitted That Met QC Criteria: October 24, 2008
• First Posted (Estimate): October 27, 2008

Study Record Updates

• Last Update Posted (Estimate): June 28, 2012
• Last Update Submitted That Met QC Criteria: June 27, 2012
• Last Verified: March 1, 2012

More Information

Terms related to this study

• Keywords: Elderly; Cancer; Acute Myeloid Leukemia; Relapsed; Refractory; AML; Hematological malignancies; Blood disorder
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Tosedostat
• Other Study ID Numbers: CHR-2797-038