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

NCT00780598 | Completed Phase 2 DMC

• 1 other identifier: CHR-2797-038
• Study Type: interventional
• Target: 76
• Locations: 3 countries
• Sites: 21

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.

Conditions

Acute Myeloid Leukemia; AML

Keywords

Acute Myeloid Leukemia; AML; Cancer; Hematological malignancies; Elderly; Refractory; Relapsed; Blood disorder

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (2)

• 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

Study Arms (1)

Tosedostat

EXPERIMENTAL

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

Drug: Tosedostat

Interventions

Tosedostat 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.

Also known as: - CHR-2797, - Aminopeptidase inhibitor

Tosedostat

Eligibility Criteria

• Age: 60 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Chroma Therapeutics: lead
• Quintiles, Inc.: collaborator

Study Sites (21)

UCLA School of Medicine

Los Angeles, California, 90095, United States

Location

Washington Cancer Institute

Washington D.C., District of Columbia, 20010, United States

Location

M.D. Anderson Cancer Center Orlando

Orlando, Florida, 32806, United States

Location

Emory University Clinic

Atlanta, Georgia, 30322, United States

Location

University of Chicago Medical Center

Chicago, Illinois, 60637, United States

Location

University of Michigan Health System

Ann Arbor, Michigan, 48109-0008, United States

Location

Washington University, Oncology/Bone Marrow Transplant

St Louis, Missouri, 63110, United States

Location

John Theurer Cancer Center, Hackensack University Medical Center,

Hackensack, New Jersey, 07601, United States

Location

Monter Cancer Center

Lake Success, New York, 11042, United States

Location

Memorial Sloan-Kettering Cancer Center

New York, New York, 10065, United States

Location

Weill Cornell Medical College - New York Presbyterian Hospital

New York, New York, 10065, United States

Location

Stony Brook University Medical Center

Stony Brook, New York, 11794-7007, United States

Location

Montefiore Medical Center Weiler Division

The Bronx, New York, 10461, United States

Location

Duke Univeristy Medical Center

Durham, North Carolina, 27710, United States

Location

Taussig Cancer Institute

Cleveland, Ohio, 44195, United States

Location

MD Anderson Cancer Center

Houston, Texas, 77030, United States

Location

Froedtert Hospital

Milwaukee, Wisconsin, 53226-3596, United States

Location

Princess Margaret Hopsital

Toronto, Ontario, M5G 2M9, Canada

Location

Royal Victoria Hospital

Montreal, Quebec, H3A 1A1, Canada

Location

VUMC

Amsterdam, 1081 HV, Netherlands

Location

Erasmus MC

Rotterdam, 3008 AE, Netherlands

Location

Related Publications (3)

• 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.

  PMID: 18701491 BACKGROUND

• 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.

  PMID: 8695828 BACKGROUND

• 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.

  PMID: 23453583 DERIVED

MeSH Terms

Conditions

Leukemia, Myeloid, Acute; Neoplasms; Hematologic Neoplasms; Recurrence; Hematologic Diseases

Interventions

tosedostat

Condition Hierarchy (Ancestors)

Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Hemic and Lymphatic Diseases; Neoplasms by Site; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Study Officials

• 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

• David Rizzieri, MD

  Duke University

  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

• Samir Parekh, MD

  Montefiore Medical Center

  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, Belfast

  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

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 24, 2008
• First Posted: October 27, 2008
• Study Start: October 1, 2009
• Primary Completion: March 1, 2011
• Study Completion: March 1, 2011
• Last Updated: June 28, 2012

Record last verified: 2012-03

Locations

NL (2); CA (2); US (17)