Clinical trial NCT00780598: Safety and Anti-Disease Activity of Oral Tosedostat (CHR-2797) in Elderly Subjects With Refractory or Relapsed AML
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
Overall status: COMPLETED
Phase: PHASE2
Conditions: Acute Myeloid Leukemia
AML
Keywords: Acute Myeloid Leukemia
AML
Cancer
Hematological malignancies
Elderly
Refractory
Relapsed
Blood disorder
Lead sponsor: Chroma Therapeutics
Sponsor class: INDUSTRY
Collaborators: name: Quintiles, Inc.
First posted: 2008-10-27
Enrollment: 76
Sex: ALL
Minimum age (years): 60
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

Eligibility criteria: 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

Primary outcomes:
measure: 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.
timeFrame: Months 1, 2, 3 & 6
Secondary outcomes:
measure: To evaluate the safety and tolerability of tosedostat in elderly subjects with treatment refractory or relapsed AML
timeFrame: Screening, Days 1, 2, 8, 15, 29, monthly thereafter + unschedulded visits when deemed necessary
measure: 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
timeFrame: Months 1, 2, 3 & 6
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: UCLA School of Medicine
state: California
city: Washington
country: United States
facility: Washington Cancer Institute
state: District of Columbia
city: Orlando
country: United States
facility: M.D. Anderson Cancer Center Orlando
state: Florida
city: Atlanta
country: United States
facility: Emory University Clinic
state: Georgia
city: Chicago
country: United States
facility: University of Chicago Medical Center
state: Illinois
city: Ann Arbor
country: United States
facility: University of Michigan Health System
state: Michigan
city: St Louis
country: United States
facility: Washington University, Oncology/Bone Marrow Transplant
state: Missouri
city: Hackensack
country: United States
facility: John Theurer Cancer Center, Hackensack University Medical Center,
state: New Jersey
city: Bronx
country: United States
facility: Montefiore Medical Center Weiler Division
state: New York
city: Lake Success
country: United States
facility: Monter Cancer Center
state: New York
city: New York
country: United States
facility: Memorial Sloan-Kettering Cancer Center
state: New York
city: New York
country: United States
facility: Weill Cornell Medical College - New York Presbyterian Hospital
state: New York
city: Stony Brook
country: United States
facility: Stony Brook University Medical Center
state: New York
city: Durham
country: United States
facility: Duke Univeristy Medical Center
state: North Carolina
city: Cleveland
country: United States
facility: Taussig Cancer Institute
state: Ohio
city: Houston
country: United States
facility: MD Anderson Cancer Center
state: Texas
city: Milwaukee
country: United States
facility: Froedtert Hospital
state: Wisconsin
city: Toronto
country: Canada
facility: Princess Margaret Hopsital
state: Ontario
city: Montreal
country: Canada
facility: Royal Victoria Hospital
state: Quebec
city: Amsterdam
country: Netherlands
facility: VUMC
city: Rotterdam
country: Netherlands
facility: Erasmus MC
Study officials:
affiliation: M.D. Anderson Cancer Center
name: Jorge E Cortes, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Princess Margaret Hospital, Canada
name: Karen Yee, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Weill Cornell Medical College - New York Presbyterian Hospital
name: Eric Feldman, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Duke University
name: David Rizzieri, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Memorial Sloan Kettering Cancer Center
name: Joseph Jurcic, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Chicago
name: Richard Larson, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Emory University Clinic
name: Hanna J Khoury, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Michigan
name: Harry Erba, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Montefiore Medical Center
name: Samir Parekh, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Medstar Health Research Institute
name: Aarthi Shenoy, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Taussig Cancer Institute
name: Anjali Advani, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Stony Brook University Medical Center
name: Shambavi Richard, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Monter Cancer Center
name: Steven Allen, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Froedtert Hospital
name: Ehab Attalah, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Royal Victoria Hospital, Belfast
name: John Storring, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: VUMC
name: Gerrit J Ossenkoppele, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Erasmus Medical Center
name: Pieter Sonneveld, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: UCLA Division of Hematology/oncology, Los Angeles
name: Gary Schiller, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Washington University School of Medicine
name: Peter Westervelt, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: MD Anderson Cancer centre, Orlando, FL
name: Julio Hajdenberg, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: John Theurer Cancer Center, Hackensack NJ
name: Stuart Goldberg, MD
role: PRINCIPAL_INVESTIGATOR
References:
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.
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.
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.