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

Primary Purpose

Acute Myeloid Leukemia, AML

Status
Completed
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
Tosedostat
Sponsored by
Chroma Therapeutics
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Acute Myeloid Leukemia focused on measuring Acute Myeloid Leukemia, AML, Cancer, Hematological malignancies, Elderly, Refractory, Relapsed, Blood disorder

Eligibility Criteria

60 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • UCLA School of Medicine
  • Washington Cancer Institute
  • M.D. Anderson Cancer Center Orlando
  • Emory University Clinic
  • University of Chicago Medical Center
  • University of Michigan Health System
  • Washington University, Oncology/Bone Marrow Transplant
  • John Theurer Cancer Center, Hackensack University Medical Center,
  • Montefiore Medical Center Weiler Division
  • Monter Cancer Center
  • Memorial Sloan-Kettering Cancer Center
  • Weill Cornell Medical College - New York Presbyterian Hospital
  • Stony Brook University Medical Center
  • Duke Univeristy Medical Center
  • Taussig Cancer Institute
  • MD Anderson Cancer Center
  • Froedtert Hospital
  • Princess Margaret Hopsital
  • Royal Victoria Hospital
  • VUMC
  • Erasmus MC

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Tosedostat

Arm Description

oral, once daily administration of tosedostat to evaluate its efficacy, safety and tolerability

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

To evaluate the safety and tolerability of tosedostat in elderly subjects with treatment refractory or relapsed AML
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

Full Information

First Posted
October 24, 2008
Last Updated
June 27, 2012
Sponsor
Chroma Therapeutics
Collaborators
Quintiles, Inc.
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1. Study Identification

Unique Protocol Identification Number
NCT00780598
Brief Title
Safety and Anti-Disease Activity of Oral Tosedostat (CHR-2797) in Elderly Subjects With Refractory or Relapsed AML
Acronym
OPAL
Official Title
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
Study Type
Interventional

2. Study Status

Record Verification Date
March 2012
Overall Recruitment Status
Completed
Study Start Date
October 2009 (undefined)
Primary Completion Date
March 2011 (Actual)
Study Completion Date
March 2011 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Chroma Therapeutics
Collaborators
Quintiles, Inc.

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

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

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Acute Myeloid Leukemia, AML
Keywords
Acute Myeloid Leukemia, AML, Cancer, Hematological malignancies, Elderly, Refractory, Relapsed, Blood disorder

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
76 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Tosedostat
Arm Type
Experimental
Arm Description
oral, once daily administration of tosedostat to evaluate its efficacy, safety and tolerability
Intervention Type
Drug
Intervention Name(s)
Tosedostat
Other Intervention Name(s)
- CHR-2797, - Aminopeptidase inhibitor
Intervention Description
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.
Primary Outcome Measure Information:
Title
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.
Time Frame
Months 1, 2, 3 & 6
Secondary Outcome Measure Information:
Title
To evaluate the safety and tolerability of tosedostat in elderly subjects with treatment refractory or relapsed AML
Time Frame
Screening, Days 1, 2, 8, 15, 29, monthly thereafter + unschedulded visits when deemed necessary
Title
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
Time Frame
Months 1, 2, 3 & 6

10. Eligibility

Sex
All
Minimum Age & Unit of Time
60 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
INCLUSION: Signed, informed consent prior to any study specific procedure 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: 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 Induction courses should normally have consisted of agents and doses considered as standard of care for induction at the investigational site concerned Subjects may have received consolidation for any number of cycles. Consolidation will be considered as any regimens given while the subject was in remission 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] 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. Subject's life expectancy at randomization is judged to be at least 3 months 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) 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 Subjects must have adequate hepatic and renal function including the following: Total bilirubin ≤ 1.5 x upper limit of normal (in the absence of Gilbert's syndrome) AST and ALT ≤ 2.5 x upper limit of normal Serum creatinine ≤ 1.5 x upper limit of normal Age ≥ 60 years Performance status ≤ 2 (ECOG scale) Screening left ventricular ejection fraction (LVEF) ≥ 50% Subject is able to comply with all study procedures during the study including all visits and tests 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: 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) 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) Subjects with APL (FAB type M3) or CML in blast crisis 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 Psychiatric disorders or altered mental status precluding understanding of the informed consent process and/or completion of the necessary study procedures Significant* cardiovascular disease defined as: Congestive heart failure NYHA class 4 Unstable angina pectoris History of myocardial infarction within 6 months prior to study entry Presence of clinically significant valvular heart disease Uncontrolled or clinically significant ventricular arrhythmia Presence of clinically significant conduction defect on screening ECG Uncontrolled hypertension (i.e., systolic BP >160mmHg, diastolic >90 mmHg in repeated measurements) despite adequate therapy 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. Gastrointestinal disorders that may interfere with absorption of drug Active serious infection or sepsis at randomization Clinically significant interstitial lung disease
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Jorge E Cortes, MD
Organizational Affiliation
M.D. Anderson Cancer Center
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Karen Yee, MD
Organizational Affiliation
Princess Margaret Hospital, Canada
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Eric Feldman, MD
Organizational Affiliation
Weill Cornell Medical College - New York Presbyterian Hospital
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
David Rizzieri, MD
Organizational Affiliation
Duke University
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Joseph Jurcic, MD
Organizational Affiliation
Memorial Sloan Kettering Cancer Center
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Richard Larson, MD
Organizational Affiliation
University of Chicago
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Hanna J Khoury, MD
Organizational Affiliation
Emory University Clinic
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Harry Erba, MD
Organizational Affiliation
University of Michigan
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Samir Parekh, MD
Organizational Affiliation
Montefiore Medical Center
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Aarthi Shenoy, MD
Organizational Affiliation
Medstar Health Research Institute
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Anjali Advani, MD
Organizational Affiliation
Taussig Cancer Institute
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Shambavi Richard, MD
Organizational Affiliation
Stony Brook University Medical Center
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Steven Allen, MD
Organizational Affiliation
Monter Cancer Center
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Ehab Attalah, MD
Organizational Affiliation
Froedtert Hospital
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
John Storring, MD
Organizational Affiliation
Royal Victoria Hospital
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Gerrit J Ossenkoppele, MD
Organizational Affiliation
VUMC
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Pieter Sonneveld, MD
Organizational Affiliation
Erasmus Medical Center
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Gary Schiller, MD
Organizational Affiliation
UCLA Division of Hematology/oncology, Los Angeles
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Peter Westervelt, MD
Organizational Affiliation
Washington University School of Medicine
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Julio Hajdenberg, MD
Organizational Affiliation
MD Anderson Cancer centre, Orlando, FL
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Stuart Goldberg, MD
Organizational Affiliation
John Theurer Cancer Center, Hackensack NJ
Official's Role
Principal Investigator
Facility Information:
Facility Name
UCLA School of Medicine
City
Los Angeles
State/Province
California
ZIP/Postal Code
90095
Country
United States
Facility Name
Washington Cancer Institute
City
Washington
State/Province
District of Columbia
ZIP/Postal Code
20010
Country
United States
Facility Name
M.D. Anderson Cancer Center Orlando
City
Orlando
State/Province
Florida
ZIP/Postal Code
32806
Country
United States
Facility Name
Emory University Clinic
City
Atlanta
State/Province
Georgia
ZIP/Postal Code
30322
Country
United States
Facility Name
University of Chicago Medical Center
City
Chicago
State/Province
Illinois
ZIP/Postal Code
60637
Country
United States
Facility Name
University of Michigan Health System
City
Ann Arbor
State/Province
Michigan
ZIP/Postal Code
48109-0008
Country
United States
Facility Name
Washington University, Oncology/Bone Marrow Transplant
City
St Louis
State/Province
Missouri
ZIP/Postal Code
63110
Country
United States
Facility Name
John Theurer Cancer Center, Hackensack University Medical Center,
City
Hackensack
State/Province
New Jersey
ZIP/Postal Code
07601
Country
United States
Facility Name
Montefiore Medical Center Weiler Division
City
Bronx
State/Province
New York
ZIP/Postal Code
10461
Country
United States
Facility Name
Monter Cancer Center
City
Lake Success
State/Province
New York
ZIP/Postal Code
11042
Country
United States
Facility Name
Memorial Sloan-Kettering Cancer Center
City
New York
State/Province
New York
ZIP/Postal Code
10065
Country
United States
Facility Name
Weill Cornell Medical College - New York Presbyterian Hospital
City
New York
State/Province
New York
ZIP/Postal Code
10065
Country
United States
Facility Name
Stony Brook University Medical Center
City
Stony Brook
State/Province
New York
ZIP/Postal Code
11794-7007
Country
United States
Facility Name
Duke Univeristy Medical Center
City
Durham
State/Province
North Carolina
ZIP/Postal Code
27710
Country
United States
Facility Name
Taussig Cancer Institute
City
Cleveland
State/Province
Ohio
ZIP/Postal Code
44195
Country
United States
Facility Name
MD Anderson Cancer Center
City
Houston
State/Province
Texas
ZIP/Postal Code
77030
Country
United States
Facility Name
Froedtert Hospital
City
Milwaukee
State/Province
Wisconsin
ZIP/Postal Code
53226-3596
Country
United States
Facility Name
Princess Margaret Hopsital
City
Toronto
State/Province
Ontario
ZIP/Postal Code
M5G 2M9
Country
Canada
Facility Name
Royal Victoria Hospital
City
Montreal
State/Province
Quebec
ZIP/Postal Code
H3A 1A1
Country
Canada
Facility Name
VUMC
City
Amsterdam
ZIP/Postal Code
1081 HV
Country
Netherlands
Facility Name
Erasmus MC
City
Rotterdam
ZIP/Postal Code
3008 AE
Country
Netherlands

12. IPD Sharing Statement

Citations:
PubMed Identifier
18701491
Citation
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.
Results Reference
background
PubMed Identifier
8695828
Citation
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.
Results Reference
background
PubMed Identifier
23453583
Citation
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.
Results Reference
derived

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

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