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 ( Teva Branded Pharmaceutical Products, R&D Inc. )
ClinicalTrials.gov Identifier:
NCT00375219
First received: September 8, 2006
Last updated: May 5, 2014
Last verified: May 2014
  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 an Overall Hematologic Response by Subpopulation and Total Population [ Time Frame: Day 1 up to 6 months ] [ Designated as safety issue: No ]

    Subpopulations reflect chronic myeloid leukemia (CML) phases at the time of enrollment: chronic, accelerated, and blast phase. Primary endpoints as adjudicated by the Data Monitoring Committee were used for the primary analyses.

    Overall hematologic response for chronic phase participants includes confirmed complete hematologic response (CHR). Overall hematologic response for accelerated or blast phase participants includes confirmed complete hematologic response (CHR), no evidence of leukemia (NEL), or return to chronic phase (RCP). Hematologic response must last >= 8 weeks to be considered meaningful.

    Response rates by disease phase were examined relative to an a priori value of 2.5% using a one-sided lower 95% exact binomial confidence limit. If the lower limit from the one-sided lower 95% confidence limit exceeds 2.5%, the observed response rate will have exceeded the minimum threshold required to demonstrate efficacy.


  • Percentage of Participants Achieving a Major Cytogenetic Response by Subpopulation and Total Population [ Time Frame: Day 1 up to 6 months ] [ Designated as safety issue: No ]

    Subpopulations reflect chronic myeloid leukemia (CML) phases at the time of enrollment: chronic, accelerated, and blast phase. Primary endpoints as adjudicated by the Data Monitoring Committee were used for the primary analyses.

    Major cytogenetic response includes complete or partial response. Both confirmed and unconfirmed major cytogenetic response is considered meaningful.

    Unconfirmed response is based on a single bone marrow cytogenetic evaluation for participants where a confirmatory evaluation is not available.

    Complete response shows 0% Philadelphia chromosome positive (Ph+) cells. A partial response shows >0% - 35% Ph+ cells.

    Response rates by disease phase were examined relative to an a priori value of 2.5% using a one-sided lower 95% exact binomial confidence limit. If the lower limit from the one-sided lower 95% confidence limit exceeds 2.5%, the observed response rate will have exceeded the minimum threshold required to demonstrate efficacy.


  • Number of Participants With Treatment-Emergent Adverse Events (TEAEs) by Subpopulation and Total [ Time Frame: up to 3 years ] [ Designated as safety issue: Yes ]

    TEAE are any untoward events that were newly occurring or worsening from Baseline.

    Treatment related toxicity was considered by the investigator to be unrelated, possibly, probably or unknown related to study drug.

    Severity was graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v3.0 on the following scale: Grade 1 = mild, Grade 2 = moderate, Grade 3 = severe, Grade 4 = life-threatening, Grade 5 = death.

    A serious adverse event (SAE) is any untoward medical occurrence that is fatal or life-threatening; results in persistent or significant disability or incapacity; requires or prolongs in-patient hospitalization; is a congenital anomaly/birth defect in the offspring of a patient; and conditions not included in the above that may jeopardize the patient or may require intervention to prevent one of the outcomes listed above.

    A participant is only counted once in each category (at worst severity or strongest relationship).



Secondary Outcome Measures:
  • Percentage of Participants in Each Cytogenetic Response Category Representing the Degree of Suppression of the Philadelphia Chromosome (Ph+) [ Time Frame: Day 1 up to Month 9 ] [ Designated as safety issue: No ]

    Cytogenetic response categories:

    • Complete: 0% Ph+ cells
    • Partial: >0%-35% Ph+ cells
    • Minor: >35%-65% Ph+ cells
    • Minimal: >65%-95% Ph+ cells
    • No Response: >95% Ph+ cells
    • Unevaluable: <20 metaphases were examined and/or response could not be assigned

  • Percentage of Participants With Major Molecular Response (MMR) Representing the Degree of Suppression of BCR-ABL Transcript Levels Using the Housekeeping Gene GUS [ Time Frame: Day 1 up to Month 6 ] [ Designated as safety issue: No ]
    MMR is defined as a ratio of BCR-ABL/standard gene of less than 0.1% according to the international scale. BCR-ABL is a fusion gene of the breakpoint cluster region [BCR] gene and Abelson proto-oncogene [ABL] genes). This analysis used the standard gene GUS. Analysis was performed by quantitative reverse transcription polymerase chain reaction (qRT-PCR) of peripheral blood.

  • Percentage of Participants With Major Molecular Response (MMR) Representing the Degree of Suppression of BCR-ABL Transcript Levels Using the Housekeeping Gene ABL [ Time Frame: Day 1 up to Month 6 ] [ Designated as safety issue: No ]
    MMR is defined as a ratio of BCR-ABL/standard gene of less than 0.1% according to the international scale. BCR-ABL is a fusion gene of the breakpoint cluster region [BCR] gene and Abelson proto-oncogene [ABL] genes). This analysis used the standard gene ABL. Analysis was performed by quantitative reverse transcription polymerase chain reaction (qRT-PCR) of peripheral blood.

  • Percentage of Participants in Each Hematologic Response Category [ Time Frame: Day 1 up to Month 6 ] [ Designated as safety issue: No ]

    Complete Response (CHR)

    • Chronic phase must last at least 8 weeks: WBC <10*10^9/liter, platelets <450*10^9/liter, myelocytes + metamyelocytes <5% in blood, no blasts or promyelocytes in blood, <20% basophils in peripheral blood, no extramedullary involvement.
    • Accelerated and Blast phase must last at least 4 weeks: absolute neutrophil count 1.5*10^9/liter, platelets 100*10^9/liter, no blood blasts, bone marrow blasts <5%, no extramedullary disease.

    Partial Response - CHR plus one or more of the following:

    • Persistence of splenomegaly with a reduction of ≥50% from pre-treatment
    • Platelets > 450*10^9/L
    • Presence of immature cells in the peripheral blood
    • 5% to 25% blasts in the bone marrow
    • If extra-medullary disease pre-treatment, reduction by ≥50% Hematologic Improvement - CHR, except allowing persistent thrombocytopenia (<100*10^9/L), and a few immature cells No evidence of leukemia: Morphologic leukemia-free state, defined as <5% bone marrow blasts.

  • Percentage of Participants With Extramedullary Disease (EMD) at Baseline Achieving a Clinical Response [ Time Frame: Day 1 up to Month 9 ] [ Designated as safety issue: No ]

    Clinical response was defined by disease phase and based on evaluations by the independent Data Monitoring Committee (DMC).

    Chronic Phase subgroup: achieving a complete hematologic response and/or major cytogenetic response (complete cytogenetic response or partial cytogenetic response, confirmed or unconfirmed).

    Accelerated Phase and Blast Phase subgroups: achieving complete hematologic response, no evidence of leukemia, return to chronic phase, and/or major cytogenetic response (complete cytogenetic response or partial cytogenetic response, confirmed or unconfirmed).

    The percentage of participants achieving response with extramedullary disease at Baseline was to be summarized, if the sample size was sufficient. This analysis was not done as the sample was ultimately insufficient


  • Percentage of Participants With the Largest Percentage Reduction From Baseline of T315I Mutated BCR-ABL [ Time Frame: Day 1 up to Month 9 ] [ Designated as safety issue: No ]
    Summarization is based on the best of the individual response assessments. Not assessable indicates that the participant either had no baseline assessment or the % mutation could not be determined in the post-baseline assessment(s).

  • Number of Treatment Cycles Needed to Achieve Best Hematologic Response [ Time Frame: Day 1 up to Month 6 ] [ Designated as safety issue: No ]
    Induction therapy was administered for 14 consecutive days for each 28 days cycle, for up to 6 cycles. All treatment arms were given omacetaxine mepesuccinate via subcutaneous (SC) administration at 1.25 mg/m^2 twice a day (BID) for the 14 consecutive days.

  • Number of Treatment Cycles Needed to Achieve Best Cytogenetic Response [ Time Frame: Day 1 up to 22 months ] [ Designated as safety issue: No ]
  • Kaplan-Meier Estimates for Time to Onset of Best Hematologic Response [ Time Frame: Day 1 up to Month 6 ] [ Designated as safety issue: No ]

    Time to onset was analyzed using Kaplan-Meier estimates. Participants who did not achieve a response are censored at their last visit day.

    Overall hematologic response for chronic phase participants includes confirmed complete hematologic response (CHR). Overall hematologic response for accelerated or blast phase participants includes confirmed complete hematologic response (CHR), no evidence of leukemia (NEL), or return to chronic phase (RCP). Hematologic response must last >= 8 weeks to be considered meaningful.


  • Kaplan-Meier Estimates for Time to Onset of Best Cytogenetic Response [ Time Frame: up to 3 years ] [ Designated as safety issue: No ]

    Time to onset was analyzed using Kaplan-Meier estimates. Participants who did not achieve a response are censored at their last visit day.

    Major cytogenetic response includes complete or partial response. Both confirmed and unconfirmed major cytogenetic response is considered meaningful.

    Unconfirmed response is based on a single bone marrow cytogenetic evaluation for participants where a confirmatory evaluation is not available.

    Complete response shows 0% Philadelphia chromosome positive (Ph+) cells. A partial response shows >0% - 35% Ph+ cells.


  • Kaplan-Meier Estimates for Duration of Best Hematologic Response [ Time Frame: up to 4 years ] [ Designated as safety issue: No ]
    Duration of response is defined as the time from first reported date of hematologic response until the earliest date of objective evidence of disease progression, relapse or death. Data was censored at the last examination date for participants with ongoing response or participants who discontinued treatment for reasons other than adverse event, disease progression or death.

  • Kaplan-Meier Estimates for Duration of Best Cytogenetic Response [ Time Frame: up to 4 years ] [ Designated as safety issue: No ]
    Duration of response is defined as the time from first reported date of cytogenetic response until the earliest date of objective evidence of disease progression, relapse or death. Data was censored at the last examination date for participants with ongoing response or participants who discontinued treatment for reasons other than adverse event, disease progression or death.

  • Kaplan-Meier Estimates for Time to Disease Progression [ Time Frame: up to 4 years ] [ Designated as safety issue: No ]
    Time to disease progression is defined as the time from the initiation of treatment until the onset date of death, the development of CML accelerated phase or blast phase, or the loss of complete hematologic response or major cytogenetic response, whichever came first. Participants were censored only if they did not have progression or if they discontinued treatment for reasons other than AE, progression or death.

  • Kaplan-Meier Estimates for Overall Survival [ Time Frame: up to 4 years ] [ Designated as safety issue: No ]
    Overall survival is defined as the time from the initiation of treatment until death from any cause or the last day of participant contact or evaluation for participants that were lost to follow-up. Participants were censored t the last recorded contract or evaluation when a participant was alive at time of analysis. A quarterly phone survey was conducted to collect survival data for participants who discontinued from the study.


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: omacetaxine
Treatment was the same for all cohorts: induction therapy was subcutaneous (SC) administration of omacetaxine at 1.25 mg/m^2 twice a day (BID), administered for 14 consecutive days every 28 (±3) days for up to 6 cycles. Maintenance therapy was subcutaneous (SC) administration of omacetaxine at 1.25 mg/m^2 twice a day (BID), administered for 7 consecutive days every 28 (±3) days for up to 3 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 3 years.

Other Names:
  • Homoharringtonine
  • OMA
  • Synribo
  • HHT
  • CGX-635

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
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

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 Branded Pharmaceutical Products, R&D Inc.
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 ( Teva Branded Pharmaceutical Products, R&D Inc. )
ClinicalTrials.gov Identifier: NCT00375219     History of Changes
Other Study ID Numbers: CGX-635-CML-202, 2006-000176-32
Study First Received: September 8, 2006
Results First Received: May 5, 2014
Last Updated: May 5, 2014
Health Authority: United States: Food and Drug Administration
Canada: Health Canada
European Union: European Medicines Agency
United Kingdom: Medicines and Healthcare Products Regulatory Agency
Australia: Department of Health and Ageing 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 August 25, 2014