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

Sponsor

Chroma Therapeutics (Industry)

Overall Status

Completed

CT.gov ID

NCT00780598

Collaborator

Quintiles, Inc. (Industry)

Enrollment

Locations

Arm

Duration (Months)

3.6

Patients Per Site

0.2

Patients Per Site Per Month

Study Details

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.

Condition or Disease	Intervention/Treatment	Phase
Acute Myeloid Leukemia AML	Drug: Tosedostat	Phase 2

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 Design

Study Type:

Interventional

Actual Enrollment :

76 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

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 Start Date :

Oct 1, 2009

Actual Primary Completion Date :

Mar 1, 2011

Actual Study Completion Date :

Mar 1, 2011

Arms and Interventions

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

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

Outcome Measures

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. [Months 1, 2, 3 & 6]

Secondary Outcome Measures

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]

Eligibility Criteria

Criteria

Ages Eligible for Study:

60 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Contacts and Locations

Locations

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

Sponsors and Collaborators

Chroma Therapeutics
Quintiles, Inc.

Investigators

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: 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
Principal Investigator: Gerrit J Ossenkoppele, MD, VUMC
Principal Investigator: Pieter Sonneveld, MD, Erasmus MC
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