Clinical trial NCT00375219: Homoharringtonine (Omacetaxine Mepesuccinate) in Treating Patients With Chronic Myeloid Leukemia (CML) With the T315I BCR-ABL Gene Mutation
Official title: A Phase II Open-Label Study of the Subcutaneous Administration of Homoharringtonine. (Omacetaxine) (CGX-635) in the Treatment of Patients With Chronic Myeloid Leukemia. (CML) With the T315I BCR-ABL Gene Mutation
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Chronic Myeloid Leukemia
Keywords: Chronic Myeloid Leukemia
CML
HHT
Homoharringtonine
Omacetaxine
T315i
ChemGenex
ChemGenex Pharmaceuticals
Lead sponsor: Teva Branded Pharmaceutical Products R&D, Inc.
Sponsor class: INDUSTRY
Collaborators: name: Cephalon
name: ChemGenex Pharmaceuticals
First posted: 2006-09-12
Enrollment: 103
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: To evaluate the safety and efficacy of subcutaneous administration of omacetaxine mepesuccinate (HHT) in achieving a clinical response in CML patients in chronic, accelerated, or blast phase who have failed prior imatinib therapy and have the T315I kinase domain gene mutation.

Detailed description: Point mutations within the ABL kinase domain of the BCR-ABL gene are emerging as the most frequent mechanism for resistance to imatinib and resultant reactivation of kinase activity. The risk of mutation development is particularly high in patients who are beyond chronic phase, as well as those with a long duration of disease prior to imatinib therapy.

The T315I kinase domain (KD) point mutation has merited particular attention, as T315I expressing CML cells are markedly resistant to imatinib. CML patients with the T315I KD mutation, therefore, do not respond to continued treatment with imatinib, and preliminary clinical data indicate that neither of two newer tyrosine kinase inhibitors will have activity in patients with T315I KD mutation either.

Omacetaxine mepesuccinate (HHT) is a potent inducer of apoptosis (programmed cell death) in myeloid cells and inhibits angiogenesis (blood vessel formation). In Phase 2 studies, HHT has demonstrated clinical activity in patients with CML, both as a single agent and in-combination with other chemotherapeutic drugs. HHT works via a different mechanism than imatinib or other tyrosine kinase inhibitors (TKI's), and HHT has been shown to inhibit in vitro CML cell lines which harbor the T315I KD mutation and are highly resistant to imatinib. Therefore, CML patients who have the T315I KD mutation may still respond to treatment with HHT. HHT may therefore be an attractive therapeutic option for patients with the T315I KD mutation.

On this basis, a multicenter clinical trial is being conducted of HHT therapy for CML patients who have failed prior imatinib therapy and have the T315I KD mutation.

Patients will be treated with an induction course consisting of subcutaneous (SC) HHT twice daily for 14 consecutive days every 28 days. Patients who demonstrate a response, may receive maintenance therapy for up to 24 months, consisting of subcutaneous (SC) HHT twice daily for 7 days every 28 days.

Eligibility criteria: Inclusion Criteria:

* Male or female patients, age 18 years or older
* Philadelphia chromosome (Ph) positive chronic myelogenous leukemia in either chronic, accelerated, or blast phase
* The patient will have the T315I BCR-ABL gene mutation
* Patients will have failed prior imatinib therapy
* ECOG performance status 0-2

Exclusion Criteria:

* NYHA class III or IV heart disease, active ischemia or any other uncontrolled cardiac condition such as angina pectoris, clinically significant cardiac arrhythmia and requiring therapy, uncontrolled hypertension or congestive heart failure
* Myocardial infarction in the previous 12 weeks
* Lymphoid Ph+ blast crisis

Primary outcomes:
measure: Percentage of Participants Achieving an Overall Hematologic Response by Subpopulation and Total Population
timeFrame: Day 1 up to 6 months
measure: Percentage of Participants Achieving a Major Cytogenetic Response by Subpopulation and Total Population
timeFrame: Day 1 up to 6 months
measure: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) by Subpopulation and Total
timeFrame: up to 3 years
Secondary outcomes:
measure: Percentage of Participants in Each Cytogenetic Response Category Representing the Degree of Suppression of the Philadelphia Chromosome (Ph+)
timeFrame: Day 1 up to Month 9
measure: Percentage of Participants With Major Molecular Response (MMR) Representing the Degree of Suppression of BCR-ABL Transcript Levels Using the Housekeeping Gene GUS
timeFrame: Day 1 up to Month 6
measure: Percentage of Participants With Major Molecular Response (MMR) Representing the Degree of Suppression of BCR-ABL Transcript Levels Using the Housekeeping Gene ABL
timeFrame: Day 1 up to Month 6
measure: Percentage of Participants in Each Hematologic Response Category
timeFrame: Day 1 up to Month 6
measure: Percentage of Participants With Extramedullary Disease (EMD) at Baseline Achieving a Clinical Response
timeFrame: Day 1 up to Month 9
measure: Percentage of Participants With the Largest Percentage Reduction From Baseline of T315I Mutated BCR-ABL
timeFrame: Day 1 up to Month 9
measure: Number of Treatment Cycles Needed to Achieve Best Hematologic Response
timeFrame: Day 1 up to Month 6
measure: Number of Treatment Cycles Needed to Achieve Best Cytogenetic Response
timeFrame: Day 1 up to 22 months
measure: Kaplan-Meier Estimates for Time to Onset of Best Hematologic Response
timeFrame: Day 1 up to Month 6
measure: Kaplan-Meier Estimates for Time to Onset of Best Cytogenetic Response
timeFrame: up to 3 years
measure: Kaplan-Meier Estimates for Duration of Best Hematologic Response
timeFrame: up to 4 years
measure: Kaplan-Meier Estimates for Duration of Best Cytogenetic Response
timeFrame: up to 4 years
measure: Kaplan-Meier Estimates for Time to Disease Progression
timeFrame: up to 4 years
measure: Kaplan-Meier Estimates for Overall Survival
timeFrame: up to 4 years
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: Teva Investigational Site 003
state: California
city: Jacksonville
country: United States
facility: Teva Investigational Site 007
state: Florida
city: Atlanta
country: United States
facility: Teva Investigational Site 006
state: Georgia
city: Beech Grove
country: United States
facility: Teva Investigational Site 008
state: Indiana
city: Baltimore
country: United States
facility: Teva Investigational Site 011
state: Maryland
city: Boston
country: United States
facility: Teva Investigational Site 004
state: Massachusetts
city: Bronx
country: United States
facility: Teva Investigational Site 002
state: New York
city: Buffalo
country: United States
facility: Teva Investigational Site 005
state: New York
city: Philadelphia
country: United States
facility: Teva Investigational Site 010
state: Pennsylvania
city: Houston
country: United States
facility: Teva Investigational Site 001
state: Texas
city: Montreal
country: Canada
facility: Teva Investigational Site 013
city: Toronto
country: Canada
facility: Teva Investigational Site 009
city: Bordeaux
country: France
facility: Teva Investigational Site 029
city: Le Chesnay Cedex
country: France
facility: Teva Investigational Site 021
city: Lille
country: France
facility: Teva Investigational Site 022
city: Lyon Cedex 03
country: France
facility: Teva Investigational Site 020
city: Nice
country: France
facility: Teva Investigational Site 024
city: Paris
country: France
facility: Teva Investigational Site 028
city: Poitiers Cedex
country: France
facility: Teva Investigational Site 023
city: Strasbourg
country: France
facility: Teva Investigational Site 027
city: Toulouse
country: France
facility: Teva Investigational Site 025
city: Vandoeuvre-Les-Nancy CEDEX
country: France
facility: Teva Investigational Site 026
city: Berlin
country: Germany
facility: Teva Investigational Site 031
city: Mannheim
country: Germany
facility: Teva Investigational Site 030
city: Budapest
country: Hungary
facility: Teva Investigational Site 050
city: Hyderabad
country: India
facility: Teva Investigational Site 071
city: Mumbai
country: India
facility: Teva Investigational Site 070
city: Bologna
country: Italy
facility: Teva Investigational Site 090
city: Gdansk
country: Poland
facility: Teva Investigational Site 060
city: Warszawa
country: Poland
facility: Teva Investigational Site 061
city: Singapore
country: Singapore
facility: Teva Investigational Site 080
city: London
country: United Kingdom
facility: Teva Investigational Site 040
Study officials:
affiliation: Univ. of Texas M.D. Anderson Cancer Center
name: Jorge Cortes, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Mannheim der Universitat Heidelberg
name: Andreas Hochhaus, MD Prof Dr
role: PRINCIPAL_INVESTIGATOR
References:
citation: Cortes J, Lipton JH, Rea D, Digumarti R, Chuah C, Nanda N, Benichou AC, Craig AR, Michallet M, Nicolini FE, Kantarjian H; Omacetaxine 202 Study Group. Phase 2 study of subcutaneous omacetaxine mepesuccinate after TKI failure in patients with chronic-phase CML with T315I mutation. Blood. 2012 Sep 27;120(13):2573-80. doi: 10.1182/blood-2012-03-415307. Epub 2012 Aug 15.