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

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).

Time frame: up to 4 years

Population: Intent to treat

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.

Time frame: Day 1 up to 9 months

Population: Intent to treat 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.

Time frame: Day 1 up to 6 months

Population: Intent to treat population

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.

Time frame: up to four years

Population: Intent to treat population of participants who had a 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.

Time frame: up to four years

Population: Intent to treat population of participants who had a response

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.

Time frame: up to 4 years

Population: Intent to treat

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.

Time frame: up to 4 years

Population: Intent to treat

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.

Time frame: Day 1 up to Month 9

Population: Intent to treat population.

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.

Time frame: Day 1 up to Month 6

Population: Intent to treat population.

Time frame: Day 1 up to Month 9

Population: Intent to treat population of participants who had a cytogenetic 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.

Time frame: Day 1 up to Month 6

Population: Intent to treat population of participants who had a response to treatment

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

Time frame: Day 1 up to Month 9

Population: Intent to treat

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.

Time frame: Day 1 up to Month 6

Population: Intent to treat

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).

Time frame: Day 1 up to Month 9

Population: Intent to treat population of study participants who had extramedullary disease at baseline

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.

Time frame: Day 1 up to Month 6

Population: Intent to treat population of participants who had evaluable samples. Participants with no data for these analyses either had degraded samples or the samples were missing.

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.

Time frame: Day 1 up to Month 6

Population: Intent to treat population of participants who had evaluable samples. Participants with no data for these analyses either had degraded samples or the samples were missing.

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).

Time frame: Day 1 up to Month 9

Population: Intent to treat population of participants with post-baseline assessment of T315I mutated BCR ABL