Open Label Study of Subcutaneous Homoharringtonine (Omacetaxine Mepesuccinate) in Patients With Advanced CML

Chronic Myeloid Leukemia Clinical Trial

Official title:

A Phase II Open-Label Study of the Subcutaneous Administration of Homoharringtonine. (Omacetaxine Mepesuccinate; OMA) in the Treatment of Patients With Chronic Myeloid. Leukemia (CML) Who Have Failed or Are Intolerant to Tyrosine Kinase Inhibitor Therapy

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00462943
• Other study ID #: CGX-635-CML-203
• Secondary ID: 2007-001286-15
• Status: Completed
• Phase: Phase 2
• Start date: March 7, 2007
• Est. completion date: June 27, 2013

Study information

• Verified date: December 2021
• Source: Teva Branded Pharmaceutical Products R&D, Inc.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

A Phase II open-label trial of subcutaneous HHT (omacetaxine mepesuccinate) in the treatment of patients who are resistant to or intolerant to Tyrosine Kinase Inhibitors.

Description:

This will be an open label, multicenter study of subcutaneous HHT (omacetaxine mepesuccinate) therapy of patients with chronic myeloid leukemia (CML) in chronic, accelerated, or blast phase who have failed or are intolerant to tyrosine kinase inhibitor therapy. Patients will be treated with induction course cycles consisting of subcutaneous (SC) HHT 1.25 mg/m² twice daily for 14 consecutive days every 28 days. Patients will be evaluated every 7 days with complete blood and platelet counts while undergoing induction therapy; the number of consecutive doses of HHT or intervals between subsequent cycles may be adjusted, as clinically indicated, according to guidelines provided in the treatment plan.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 100
• Est. completion date: June 27, 2013
• Est. primary completion date: August 4, 2009
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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
• Patients will have either failed, demonstrated intolerance, or a combination of prior failure and intolerance, to prior treatments with at least two tyrosine kinase inhibitors (TKI's). Failure of TKI treatment may either be primary (never achieved a response) or secondary resistance (loss of response).
• Acceptable Renal and Liver Function
• Eastern Cooperative Oncology Group (ECOG) performance status 0-2.
• Sexually active patients and their partners must use an effective double barrier method of contraception

Exclusion Criteria:

• New York Heart Association classification (NYHA) class III or IV heart disease, active ischemia or any other uncontrolled cardiac condition
• Myocardial infarction in the previous 12 weeks.
• Other concurrent illness which would preclude study conduct and assessment
• uncontrolled and active infection, and positive HIV or positive HTLV I/II status, whether on treatment or not.
• Pregnant or lactating.
• Any medical or psychiatric condition, which may compromise the ability to give written informed consent or to comply with the study protocol.
• Lymphoid Ph+ blast crisis
• Patient is enrolled in another clinical investigation within 30 days of enrollment or is receiving another investigational agent

Related Conditions & MeSH terms

• Chronic Myeloid Leukemia
• Leukemia
• Leukemia, Myelogenous, Chronic, BCR-ABL Positive

Intervention

Drug:
• Omacetaxine mepesuccinate
Induction: 1.25mg/m^2 subcutaneously twice daily for 14 consecutive days, every 28 days. Maintenance: 1.25mg/m^2 subcutaneously twice daily for 7 consecutive days, every 28 days. Response targets during induction vary by chronic myeloid leukemia (CML) subclass (chronic, accelerated, or blast phase). Participants will complete at least one cycle (14 days treatment of a 28 day cycle) of induction therapy before changing to maintenance therapy. Participants not demonstrating evidence of clinical response after 6 induction cycles will be considered for removal from the study.

Locations

Country	Name	City	State
Canada	Teva Investigational Site 313	Montreal
Canada	Teva Investigational Site 309	Toronto
France	Teva Investigational Site 329	Bordeaux
France	Teva Investigational Site 321	Le Chesnay Cedex
France	Teva Investigational Site 322	Lille
France	Teva Investigational Site 320	Lyon Cedex 03
France	Teva Investigational Site 324	Nice
France	Teva Investigational Site 328	Paris
France	Teva Investigational Site 323	Poitiers Cedex
France	Teva Investigational Site 327	Strasbourg
France	Teva Investigational Site 325	Toulouse
Germany	Teva Investigational Site 331	Berlin
Germany	Teva Investigational Site 330	Mannheim
Hungary	Teva Investigational Site 350	Budapest
India	Teva Investigational Site 371	Hyderabad
India	Teva Investigational Site 370	Mumbai
Italy	Teva Investigational Site 390	Bologna
Poland	Teva Investigational Site 360	Gdansk
Poland	Teva Investigational Site 361	Warszawa
Singapore	Teva Investigational Site 380	Singapore
United Kingdom	Teva Investigational Site 340	London
United States	Teva Investigational Site 311	Baltimore	Maryland
United States	Teva Investigational Site 308	Beech Grove	Indiana
United States	Teva Investigational Site 302	Bronx	New York
United States	Teva Investigational Site 305	Buffalo	New York
United States	Teva Investigational Site 301	Houston	Texas
United States	Teva Investigational Site 303	Los Angeles	California
United States	Teva Investigational Site 310	Philadelphia	Pennsylvania
United States	Teva Investigational Site 314	Seattle	Washington

Sponsors (3)

Lead Sponsor	Collaborator
Teva Branded Pharmaceutical Products R&D, Inc.	Cephalon, ChemGenex Pharmaceuticals

Countries where clinical trial is conducted

United States,  Canada,  France,  Germany,  Hungary,  India,  Italy,  Poland,  Singapore,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Percentage of Participants Achieving an Overall Hematologic Response by Subpopulation and Total Population	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.	Day 1 up to 6 months
Primary	Percentage of Participants Achieving a Major Cytogenetic Response by Subpopulation and Total Population	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.	Day 1 up to 9 months
Primary	Number of Participants With Treatment-Emergent Adverse Events (TEAEs) by Subpopulation and Total	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).	up to 4 years
Secondary	Percentage of Participants in Each Cytogenetic Response Category Representing the Degree of Suppression of the Philadelphia Chromosome (Ph+)	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	Day 1 up to Month 9
Secondary	Percentage of Participants With Major Molecular Response (MMR) Representing the Degree of Suppression of BCR-ABL Transcript Levels Using the Housekeeping Gene GUS	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.	Day 1 up to Month 6
Secondary	Percentage of Participants With Major Molecular Response (MMR) Representing the Degree of Suppression of BCR-ABL Transcript Levels Using the Housekeeping Gene ABL	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.	Day 1 up to Month 6
Secondary	Percentage of Participants in Each Hematologic Response Category	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.	Day 1 up to Month 6
Secondary	Percentage of Participants With Extramedullary Disease (EMD) at Baseline Achieving a Clinical Response	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).	Day 1 up to Month 9
Secondary	Percentage of Participants With the Largest Percentage Reduction From Baseline of T315I Mutated BCR-ABL	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).	Day 1 up to Month 9
Secondary	Number of Treatment Cycles Needed to Achieve Best Hematologic Response	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.	Day 1 up to Month 6
Secondary	Number of Treatment Cycles Needed to Achieve Best Cytogenetic Response		Day 1 up to Month 9
Secondary	Kaplan-Meier Estimates for Time to Onset of Best Hematologic Response	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.	Day 1 up to Month 6
Secondary	Kaplan-Meier Estimates for Time to Onset of Best Cytogenetic Response	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.	Day 1 up to Month 9
Secondary	Kaplan-Meier Estimates for Duration of Best Hematologic Response	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.	up to four years
Secondary	Kaplan-Meier Estimates for Duration of Best Cytogenetic Response	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.	up to four years
Secondary	Kaplan-Meier Estimates for Time to Disease Progression	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.	up to 4 years
Secondary	Kaplan-Meier Estimates for Overall Survival	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.	up to 4 years