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

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

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.

Study Overview

• Status: Completed
• Conditions: Chronic Myeloid Leukemia
• Intervention / Treatment: Drug: Omacetaxine mepesuccinate

Detailed 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.

• Study Type: Interventional
• Enrollment (Actual): 100
• Phase: Phase 2

Contacts and Locations

Study Locations

• Canada
  • Montreal, Canada, H3a 1a1
    • Teva Investigational Site 313
  • Toronto, Canada, M5G 2M9
    • Teva Investigational Site 309
• France
  • Bordeaux, France, 33076
    • Teva Investigational Site 329
  • Le Chesnay Cedex, France, 78157
    • Teva Investigational Site 321
  • Lille, France, 59000
    • Teva Investigational Site 322
  • Lyon Cedex 03, France, 69437
    • Teva Investigational Site 320
  • Nice, France, 06202
    • Teva Investigational Site 324
  • Paris, France, 75475
    • Teva Investigational Site 328
  • Poitiers Cedex, France, 86021
    • Teva Investigational Site 323
  • Strasbourg, France, 67100
    • Teva Investigational Site 327
  • Toulouse, France, 31059
    • Teva Investigational Site 325
• Germany
  • Berlin, Germany, 10117
    • Teva Investigational Site 331
  • Mannheim, Germany, 68169
    • Teva Investigational Site 330
• Hungary
  • Budapest, Hungary, 1096
    • Teva Investigational Site 350
• India
  • Hyderabad, India, 500082
    • Teva Investigational Site 371
  • Mumbai, India, 400 014
    • Teva Investigational Site 370
• Italy
  • Bologna, Italy, 41038
    • Teva Investigational Site 390
• Poland
  • Gdansk, Poland, 80-952
    • Teva Investigational Site 360
  • Warszawa, Poland, 02776
    • Teva Investigational Site 361
• Singapore
  • Singapore, Singapore, 169608
    • Teva Investigational Site 380
• United Kingdom
  • London, United Kingdom, W12 0HS
    • Teva Investigational Site 340
• United States
  • California
    • Los Angeles, California, United States, 90033
      • Teva Investigational Site 303
  • Indiana
    • Beech Grove, Indiana, United States, 46107
      • Teva Investigational Site 308
  • Maryland
    • Baltimore, Maryland, United States, 21201
      • Teva Investigational Site 311
  • New York
    • Bronx, New York, United States, 10466
      • Teva Investigational Site 302
    • Buffalo, New York, United States, 14263
      • Teva Investigational Site 305
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19111
      • Teva Investigational Site 310
  • Texas
    • Houston, Texas, United States, 77030
      • Teva Investigational Site 301
  • Washington
    • Seattle, Washington, United States, 98109
      • Teva Investigational Site 314

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: OMA; Omacetaxine mepesuccinate (OMA) Induction: 1.25mg/m^2 subcutaneously twice daily for 14 consecutive days, every 28 days for up to six cycles. Omacetaxine mepesuccinate (OMA) Maintenance: 1.25mg/m^2 subcutaneously twice daily for 7 consecutive days, every 28 days for up to 24 months.

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.; Other Names: HHT; Homoharringtonine; CGX-635; Synribo; OMA

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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
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
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
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
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
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
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
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
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
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
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
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
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
Number of Treatment Cycles Needed to Achieve Best Cytogenetic Response		Day 1 up to Month 9
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
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
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

Collaborators and Investigators

• Sponsor: Teva Branded Pharmaceutical Products R&D, Inc.
• Collaborators: Cephalon; ChemGenex Pharmaceuticals

Publications and helpful links

General Publications

• Cortes J, Digumarti R, Parikh PM, Wetzler M, Lipton JH, Hochhaus A, Craig AR, Benichou AC, Nicolini FE, Kantarjian HM; Omacetaxine 203 Study Group. Phase 2 study of subcutaneous omacetaxine mepesuccinate for chronic-phase chronic myeloid leukemia patients resistant to or intolerant of tyrosine kinase inhibitors. Am J Hematol. 2013 May;88(5):350-4. doi: 10.1002/ajh.23408. Epub 2013 Mar 7.

Study record dates

Study Major Dates

• Study Start (Actual): March 7, 2007
• Primary Completion (Actual): August 4, 2009
• Study Completion (Actual): June 27, 2013

Study Registration Dates

• First Submitted: April 17, 2007
• First Submitted That Met QC Criteria: April 17, 2007
• First Posted (Estimate): April 19, 2007

Study Record Updates

• Last Update Posted (Actual): December 28, 2021
• Last Update Submitted That Met QC Criteria: December 1, 2021
• Last Verified: December 1, 2021

More Information

Terms related to this study

• Keywords: CML; Homoharringtonine; HHT; Omacetaxine
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Bone Marrow Diseases; Hematologic Diseases; Myeloproliferative Disorders; Leukemia, Myeloid; Leukemia; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Antineoplastic Agents, Phytogenic; Protein Synthesis Inhibitors; Homoharringtonine
• Other Study ID Numbers: CGX-635-CML-203; 2007-001286-15 (EudraCT Number)