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

NCT ID: NCT00780598

Last Updated: 2012-06-28

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 76 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2009-10-31
• Study Completion Date: 2011-03-31

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.

Conditions

Acute Myeloid Leukemia; AML

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Tosedostat

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

Group Type: EXPERIMENTAL

Tosedostat

Intervention Type: DRUG

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.

Interventions

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.

Intervention Type: DRUG

Other Intervention Names

- CHR-2797; - Aminopeptidase inhibitor

Eligibility Criteria

Inclusion Criteria

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

• Minimum Eligible Age: 60 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Quintiles, Inc.

INDUSTRY

Sponsor Role: collaborator

Chroma Therapeutics

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Jorge E Cortes, MD

Role: PRINCIPAL_INVESTIGATOR

M.D. Anderson Cancer Center

Karen Yee, MD

Role: PRINCIPAL_INVESTIGATOR

Princess Margaret Hospital, Canada

Eric Feldman, MD

Role: PRINCIPAL_INVESTIGATOR

Weill Cornell Medical College - New York Presbyterian Hospital

David Rizzieri, MD

Role: PRINCIPAL_INVESTIGATOR

Duke University

Joseph Jurcic, MD

Role: PRINCIPAL_INVESTIGATOR

Memorial Sloan Kettering Cancer Center

Richard Larson, MD

Role: PRINCIPAL_INVESTIGATOR

University of Chicago

Hanna J Khoury, MD

Role: PRINCIPAL_INVESTIGATOR

Emory University Clinic

Harry Erba, MD

Role: PRINCIPAL_INVESTIGATOR

University of Michigan

Samir Parekh, MD

Role: PRINCIPAL_INVESTIGATOR

Montefiore Medical Center

Aarthi Shenoy, MD

Role: PRINCIPAL_INVESTIGATOR

Medstar Health Research Institute

Anjali Advani, MD

Role: PRINCIPAL_INVESTIGATOR

Taussig Cancer Institute

Shambavi Richard, MD

Role: PRINCIPAL_INVESTIGATOR

Stony Brook University Medical Center

Steven Allen, MD

Role: PRINCIPAL_INVESTIGATOR

Monter Cancer Center

Ehab Attalah, MD

Role: PRINCIPAL_INVESTIGATOR

Froedtert Hospital

John Storring, MD

Role: PRINCIPAL_INVESTIGATOR

Royal Victoria Hospital, Belfast

Gerrit J Ossenkoppele, MD

Role: PRINCIPAL_INVESTIGATOR

VUMC

Pieter Sonneveld, MD

Role: PRINCIPAL_INVESTIGATOR

Erasmus Medical Center

Gary Schiller, MD

Role: PRINCIPAL_INVESTIGATOR

UCLA Division of Hematology/oncology, Los Angeles

Peter Westervelt, MD

Role: PRINCIPAL_INVESTIGATOR

Washington University School of Medicine

Julio Hajdenberg, MD

Role: PRINCIPAL_INVESTIGATOR

MD Anderson Cancer centre, Orlando, FL

Stuart Goldberg, MD

Role: PRINCIPAL_INVESTIGATOR

John Theurer Cancer Center, Hackensack NJ

Locations

UCLA School of Medicine

Los Angeles, California, United States

Washington Cancer Institute

Washington D.C., District of Columbia, United States

M.D. Anderson Cancer Center Orlando

Orlando, Florida, United States

Emory University Clinic

Atlanta, Georgia, United States

University of Chicago Medical Center

Chicago, Illinois, United States

University of Michigan Health System

Ann Arbor, Michigan, United States

Washington University, Oncology/Bone Marrow Transplant

St Louis, Missouri, United States

John Theurer Cancer Center, Hackensack University Medical Center,

Hackensack, New Jersey, United States

Monter Cancer Center

Lake Success, New York, United States

Memorial Sloan-Kettering Cancer Center

New York, New York, United States

Weill Cornell Medical College - New York Presbyterian Hospital

New York, New York, United States

Stony Brook University Medical Center

Stony Brook, New York, United States

Montefiore Medical Center Weiler Division

The Bronx, New York, United States

Duke Univeristy Medical Center

Durham, North Carolina, United States

Taussig Cancer Institute

Cleveland, Ohio, United States

MD Anderson Cancer Center

Houston, Texas, United States

Froedtert Hospital

Milwaukee, Wisconsin, United States

Princess Margaret Hopsital

Toronto, Ontario, Canada

Royal Victoria Hospital

Montreal, Quebec, Canada

VUMC

Amsterdam, , Netherlands

Erasmus MC

Rotterdam, , Netherlands

Countries

United States; Canada; Netherlands

References

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.

Reference Type: BACKGROUND

PMID: 18701491 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 8695828 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 23453583 (View on PubMed)

Other Identifiers

CHR-2797-038

Identifier Type: -

Identifier Source: org_study_id