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

Acute Myeloid Leukemia Clinical Trial

— 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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00780598
• Other study ID #: CHR-2797-038
• Status: Completed
• Phase: Phase 2
• First received: October 24, 2008
• Last updated: June 27, 2012
• Start date: October 2009
• Est. completion date: March 2011

Study information

• Verified date: March 2012
• Source: Chroma Therapeutics
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug AdministrationCanada: Canadian Institutes of Health ResearchNetherlands: The Central Committee on Research Involving Human Subjects (CCMO)
• Study type: Interventional

Clinical Trial Summary

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

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 76
• Est. completion date: March 2011
• Est. primary completion date: March 2011
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 60 Years and older

Eligibility

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 Design

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Acute Myeloid Leukemia
• AML
• Leukemia, Myeloid
• Leukemia, Myeloid, Acute

Intervention

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.

Locations

Country	Name	City	State
Canada	Royal Victoria Hospital	Montreal	Quebec
Canada	Princess Margaret Hopsital	Toronto	Ontario
Netherlands	VUMC	Amsterdam
Netherlands	Erasmus MC	Rotterdam
United States	University of Michigan Health System	Ann Arbor	Michigan
United States	Emory University Clinic	Atlanta	Georgia
United States	Montefiore Medical Center Weiler Division	Bronx	New York
United States	University of Chicago Medical Center	Chicago	Illinois
United States	Taussig Cancer Institute	Cleveland	Ohio
United States	Duke Univeristy Medical Center	Durham	North Carolina
United States	John Theurer Cancer Center, Hackensack University Medical Center,	Hackensack	New Jersey
United States	MD Anderson Cancer Center	Houston	Texas
United States	Monter Cancer Center	Lake Success	New York
United States	UCLA School of Medicine	Los Angeles	California
United States	Froedtert Hospital	Milwaukee	Wisconsin
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	M.D. Anderson Cancer Center Orlando	Orlando	Florida
United States	Washington University, Oncology/Bone Marrow Transplant	St Louis	Missouri
United States	Stony Brook University Medical Center	Stony Brook	New York
United States	Washington Cancer Institute	Washington	District of Columbia

Sponsors (2)

Lead Sponsor	Collaborator
Chroma Therapeutics	Quintiles, Inc.

Countries where clinical trial is conducted

United States,  Canada,  Netherlands, 

References & Publications (2)

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. — View 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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	No
Secondary	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	Yes
Secondary	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	No

External Links

•   A Multicentre Phase II Study of the Aminopeptidase Inhibitor, CHR- 2797, in the Treatment of Elderly and/or Previously Treated patients with Acute Myeloid Leukemia
•   A Phase I Study of CHR-2797, an Orally Active Aminopeptidase Inhibitor in Elderly and/or Treatment Refractory Patients with Acute Myeloid Leukemia or Multiple Myeloma.
•   Cellular Aminopeptidase Inhibition as a Target for the Therapy of AML by the Novel Agent CHR 2797.