Homoharringtonine (Omacetaxine Mepesuccinate) in Treating Patients With Chronic Myeloid Leukemia (CML) With the T315I BCR-ABL Gene Mutation

This study has been completed.
Sponsor:
Collaborators:
Cephalon
ChemGenex Pharmaceuticals
Information provided by (Responsible Party):
Teva Pharmaceutical Industries
ClinicalTrials.gov Identifier:
NCT00375219
First received: September 8, 2006
Last updated: September 23, 2013
Last verified: September 2013
  Purpose

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.


Condition Intervention Phase
Chronic Myeloid Leukemia
Drug: Omacetaxine mepesuccinate
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase II Open-Label Study of the Subcutaneous Administration of Homoharringtonine (Omacetaxine Mepesuccinate) in the Treatment of Patients With Chronic Myeloid Leukemia (CML) With the T315I BCR-ABL Gene Mutation

Resource links provided by NLM:


Further study details as provided by Teva Pharmaceutical Industries:

Primary Outcome Measures:
  • Percentage of Participants Achieving a Clinical Response by Subpopulation [ Time Frame: up to 6 months ] [ Designated as safety issue: No ]
    Subpopulations reflect chronic myeloid leukemia (CML) phases: chronic, accelerated, and blast phase.

  • Participants with Adverse Events by Subpopulation [ Time Frame: up to 3 years ] [ Designated as safety issue: Yes ]
    Subpopulations reflect chronic myeloid leukemia (CML) phases: chronic, accelerated, and blast phase.


Secondary Outcome Measures:
  • Participants' Degree of Suppression of the Philadelphia Chromosome (Ph) [ Time Frame: up to 6 months ] [ Designated as safety issue: No ]
  • Participants' Degree of Suppression of BCR-ABL transcript levels [ Time Frame: up to 6 months ] [ Designated as safety issue: No ]
  • Percentage of Participants Who Showed a Hematological Improvement [ Time Frame: up to 6 months ] [ Designated as safety issue: No ]
  • Percentage of CML Participants with Accelerated or Blast Phase Who Return to Chronic Phase [ Time Frame: up to 3 years ] [ Designated as safety issue: No ]
  • Percentage of CML Participants with Accelerated or Blast Phase Who Show No Evidence of Leukemia [ Time Frame: up to 3 years ] [ Designated as safety issue: No ]
  • Percentage of Participants with Extramedullary Disease (EMD) at Baseline Who Achieve a Clinical Response [ Time Frame: up to 3 years ] [ Designated as safety issue: No ]
  • Percentage of Participants Who Had a Significant Reduction of the Proportion of T315I Mutated BCR-ABL [ Time Frame: up to 3 years ] [ Designated as safety issue: No ]
  • The Number of Induction Cycles to Achieve a Clinical Response [ Time Frame: up to 6 months ] [ Designated as safety issue: No ]
  • Time to Response [ Time Frame: up to 6 months ] [ Designated as safety issue: No ]
  • Duration of Response [ Time Frame: up to 3 years ] [ Designated as safety issue: No ]
  • Time to disease progression [ Time Frame: up to 3 years ] [ Designated as safety issue: No ]
  • Overall Survival [ Time Frame: up to 3 years ] [ Designated as safety issue: No ]

Enrollment: 103
Study Start Date: September 2006
Study Completion Date: September 2013
Primary Completion Date: December 2010 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: OMA

Omacetaxine mepesuccinate (OMA) Induction: 1.25 mg/m^2 subcutaneously, twice daily for 14 consecutive days every 28 days until response.

Maintenance: 1.25 mg/m^2 subcutaneously, twice daily for 7 consecutive days of every 28-day cycle for up to two years.

Drug: Omacetaxine mepesuccinate

Induction:

1.25 mg/m^2 subcutaneously, twice daily for 14 consecutive days every 28 days until response. Patients not demonstrating evidence of clinical response after 6 induction cycles will be considered for removal from the study.

Maintenance:

1.25 mg/m^2 subcutaneously, twice daily for 7 consecutive days in a 28-day cycle, for up to 2 years.

Other Names:
  • Homoharringtonine
  • OMA
  • SynriboTM
  • HHT

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

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT00375219

  Hide Study Locations
Locations
United States, California
Teva Investigational Site 003
Los Angeles, California, United States
United States, Florida
Teva Investigational Site 007
Jacksonville, Florida, United States
United States, Georgia
Teva Investigational Site 006
Atlanta, Georgia, United States
United States, Indiana
Teva Investigational Site 008
Beech Grove, Indiana, United States
United States, Maryland
Teva Investigational Site 011
Baltimore, Maryland, United States
United States, Massachusetts
Teva Investigational Site 004
Boston, Massachusetts, United States
United States, New York
Teva Investigational Site 002
Bronx, New York, United States
Teva Investigational Site 005
Buffalo, New York, United States
United States, Pennsylvania
Teva Investigational Site 010
Philadelphia, Pennsylvania, United States
United States, Texas
Teva Investigational Site 001
Houston, Texas, United States
Canada
Teva Investigational Site 013
Montreal, Canada
Teva Investigational Site 009
Toronto, Canada
France
Teva Investigational Site 029
Bordeaux, France
Teva Investigational Site 021
Le Chesnay Cedex, France
Teva Investigational Site 022
Lille, France
Teva Investigational Site 020
Lyon Cedex 03, France
Teva Investigational Site 024
Nice, France
Teva Investigational Site 028
Paris, France
Teva Investigational Site 023
Poitiers Cedex, France
Teva Investigational Site 027
Strasbourg, France
Teva Investigational Site 025
Toulouse, France
Teva Investigational Site 026
Vandoeuvre-Les-Nancy, France
Germany
Teva Investigational Site 031
Berlin, Germany
Teva Investigational Site 030
Mannheim, Germany
Hungary
Teva Investigational Site 050
Budapest, Hungary
India
Teva Investigational Site 071
Hyderabad, India
Teva Investigational Site 070
Mumbai, India
Italy
Teva Investigational Site 090
Bologna, Italy
Poland
Teva Investigational Site 060
Gdansk, Poland
Singapore
Teva Investigational Site 080
Singapore, Singapore
United Kingdom
Teva Investigational Site 040
London, United Kingdom
Sponsors and Collaborators
Teva Pharmaceutical Industries
Cephalon
ChemGenex Pharmaceuticals
Investigators
Principal Investigator: Jorge Cortes, MD Univ. of Texas M.D. Anderson Cancer Center
Principal Investigator: Andreas Hochhaus, MD Prof Dr Mannheim der Universitat Heidelberg
  More Information

Additional Information:
No publications provided by Teva Pharmaceutical Industries

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Teva Pharmaceutical Industries
ClinicalTrials.gov Identifier: NCT00375219     History of Changes
Other Study ID Numbers: CGX-635-CML-202, 2006-000176-32
Study First Received: September 8, 2006
Last Updated: September 23, 2013
Health Authority: United States: Food and Drug Administration
Canada: Health Canada
Europe: European Medicines Evaluation Agency
United Kingdom: Medicines Control Agency
Australia: Therapeutic Goods Administration
India: Drugs Controller General of India
Singapore: Health Sciences Authority

Keywords provided by Teva Pharmaceutical Industries:
Chronic Myeloid Leukemia
CML
HHT
Homoharringtonine
Omacetaxine
T315i
ChemGenex
ChemGenex Pharmaceuticals

Additional relevant MeSH terms:
Leukemia
Leukemia, Myeloid
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Neoplasms by Histologic Type
Neoplasms
Myeloproliferative Disorders
Bone Marrow Diseases
Hematologic Diseases
Homoharringtonine
Harringtonines
Antineoplastic Agents, Phytogenic
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Growth Substances
Physiological Effects of Drugs
Growth Inhibitors

ClinicalTrials.gov processed this record on April 17, 2014