Chronic Myeloid Leukemia
Conditions
Keywords
Chronic Myeloid Leukemia, CML, HHT, Homoharringtonine, Omacetaxine, T315i, ChemGenex, ChemGenex Pharmaceuticals
Brief summary
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.
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.
Interventions
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.
Sponsors
Cephalon
ChemGenex Pharmaceuticals
Teva Branded Pharmaceutical Products R&D, Inc.
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Achieving an Overall Hematologic Response by Subpopulation and Total Population | Day 1 up to 6 months | 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 | Day 1 up to 6 months | 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 | up to 3 years | 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
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants in Each Hematologic Response Category | Day 1 up to Month 6 | 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 | Day 1 up to Month 9 | 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 | Day 1 up to Month 9 | 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 | Day 1 up to Month 6 | 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 | Day 1 up to 22 months | — |
| Percentage of Participants in Each Cytogenetic Response Category Representing the Degree of Suppression of the Philadelphia Chromosome (Ph+) | Day 1 up to Month 9 | 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 |
| Kaplan-Meier Estimates for Time to Onset of Best Cytogenetic Response | up to 3 years | 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 | up to 4 years | 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 | up to 4 years | 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 | up to 4 years | 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 | up to 4 years | 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. |
| Kaplan-Meier Estimates for Time to Onset of Best Hematologic Response | Day 1 up to Month 6 | 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. |
| Percentage of Participants With Major Molecular Response (MMR) Representing the Degree of Suppression of BCR-ABL Transcript Levels Using the Housekeeping Gene GUS | Day 1 up to Month 6 | 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 | Day 1 up to Month 6 | 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. |
Countries
Canada, France, Germany, Hungary, India, Italy, Poland, Singapore, United Kingdom, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| CML: Chronic Phase Study participants with chronic myeloid leukemia (CML) in the chronic phase at the time of enrollment. 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. | 62 |
| CML: Accelerated Phase Study participants with chronic myeloid leukemia (CML) in the accelerated phase at the time of enrollment. 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. | 20 |
| CML: Blast Phase Study participants with chronic myeloid leukemia (CML) in the blast phase at the time of enrollment. 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. | 21 |
| Total | 103 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 8 | 2 | 1 |
| Overall Study | Allograft | 2 | 0 | 0 |
| Overall Study | Cord blood transplantation | 1 | 0 | 0 |
| Overall Study | Death | 4 | 3 | 7 |
| Overall Study | Disease progression | 18 | 9 | 12 |
| Overall Study | Failure to achieve a response | 16 | 2 | 0 |
| Overall Study | Hematologic resistance | 1 | 0 | 0 |
| Overall Study | Lost to Follow-up | 1 | 1 | 0 |
| Overall Study | Protocol Violation | 1 | 0 | 1 |
| Overall Study | Request of Patient, PI, Sponsor or RA | 5 | 3 | 0 |
| Overall Study | Specific tyrosine kinase inhibitor avail | 1 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | CML: Chronic Phase | CML: Accelerated Phase | CML: Blast Phase | Total |
|---|---|---|---|---|
| Age, Continuous | 59 years | 59 years | 50 years | 57 years |
| Body Surface Area (BSA) | 1.9 meters^2 | 1.8 meters^2 | 1.8 meters^2 | 1.9 meters^2 |
| Eastern Cooperative Oncology Group Performance Status Grade 0 | 41 participants | 6 participants | 6 participants | 53 participants |
| Eastern Cooperative Oncology Group Performance Status Grade 1 | 20 participants | 11 participants | 9 participants | 40 participants |
| Eastern Cooperative Oncology Group Performance Status Grade 2 | 1 participants | 2 participants | 5 participants | 8 participants |
| Eastern Cooperative Oncology Group Performance Status Grade 3 | 0 participants | 1 participants | 1 participants | 2 participants |
| Height | 171.5 centimeter | 172.0 centimeter | 170.2 centimeter | 171.0 centimeter |
| New York Heart Association (NYHA) Classification Class I | 61 participants | 18 participants | 18 participants | 97 participants |
| New York Heart Association (NYHA) Classification Class II | 1 participants | 2 participants | 3 participants | 6 participants |
| New York Heart Association (NYHA) Classification Class III | 0 participants | 0 participants | 0 participants | 0 participants |
| New York Heart Association (NYHA) Classification Class IV | 0 participants | 0 participants | 0 participants | 0 participants |
| Race/Ethnicity, Customized Asian | 8 participants | 2 participants | 2 participants | 12 participants |
| Race/Ethnicity, Customized Black | 4 participants | 6 participants | 6 participants | 16 participants |
| Race/Ethnicity, Customized Caucasian | 48 participants | 12 participants | 13 participants | 73 participants |
| Race/Ethnicity, Customized Hispanic | 0 participants | 0 participants | 0 participants | 0 participants |
| Race/Ethnicity, Customized Other | 2 participants | 0 participants | 0 participants | 2 participants |
| Sex: Female, Male Female | 20 Participants | 5 Participants | 7 Participants | 32 Participants |
| Sex: Female, Male Male | 42 Participants | 15 Participants | 14 Participants | 71 Participants |
| Time from Initial Chronic Myeloid Leukemia (CML) Diagnosis | 50.0 months | 98.0 months | 46.6 months | 59.6 months |
| Weight | 77.7 kilograms | 69.1 kilograms | 68.8 kilograms | 76.0 kilograms |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 100 / 103 |
| serious Total, serious adverse events | 67 / 103 |
Outcome results
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).
Time frame: up to 3 years
Population: Intent to treat
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| CML: Chronic Phase | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) by Subpopulation and Total | Deaths during study or follow-up | 31 participants |
| CML: Chronic Phase | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) by Subpopulation and Total | Relation to drug: Possibly | 6 participants |
| CML: Chronic Phase | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) by Subpopulation and Total | Worst severity: Grade 5 | 9 participants |
| CML: Chronic Phase | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) by Subpopulation and Total | Worst severity: Grade 3 | 9 participants |
| CML: Chronic Phase | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) by Subpopulation and Total | >= 1 SAE | 36 participants |
| CML: Chronic Phase | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) by Subpopulation and Total | Relation to drug: Unrelated | 1 participants |
| CML: Chronic Phase | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) by Subpopulation and Total | Worst severity: Grade 4 | 37 participants |
| CML: Chronic Phase | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) by Subpopulation and Total | >=1 TEAE | 61 participants |
| CML: Chronic Phase | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) by Subpopulation and Total | Discontinued treatment due to AE | 18 participants |
| CML: Chronic Phase | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) by Subpopulation and Total | With hematologic toxicity | 55 participants |
| CML: Chronic Phase | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) by Subpopulation and Total | Worst severity: Grade 1 | 0 participants |
| CML: Chronic Phase | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) by Subpopulation and Total | Deaths during study (outcome of SAE) | 9 participants |
| CML: Chronic Phase | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) by Subpopulation and Total | Relation to drug: Unknown | 0 participants |
| CML: Chronic Phase | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) by Subpopulation and Total | Relation to drug: Probably | 54 participants |
| CML: Chronic Phase | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) by Subpopulation and Total | Worst severity: Grade 2 | 6 participants |
| CML: Accelerated Phase | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) by Subpopulation and Total | Relation to drug: Unrelated | 3 participants |
| CML: Accelerated Phase | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) by Subpopulation and Total | Deaths during study or follow-up | 14 participants |
| CML: Accelerated Phase | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) by Subpopulation and Total | >=1 TEAE | 20 participants |
| CML: Accelerated Phase | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) by Subpopulation and Total | >= 1 SAE | 12 participants |
| CML: Accelerated Phase | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) by Subpopulation and Total | Worst severity: Grade 1 | 1 participants |
| CML: Accelerated Phase | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) by Subpopulation and Total | Worst severity: Grade 2 | 2 participants |
| CML: Accelerated Phase | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) by Subpopulation and Total | Worst severity: Grade 3 | 4 participants |
| CML: Accelerated Phase | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) by Subpopulation and Total | Worst severity: Grade 4 | 9 participants |
| CML: Accelerated Phase | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) by Subpopulation and Total | Worst severity: Grade 5 | 4 participants |
| CML: Accelerated Phase | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) by Subpopulation and Total | Relation to drug: Possibly | 3 participants |
| CML: Accelerated Phase | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) by Subpopulation and Total | Relation to drug: Probably | 13 participants |
| CML: Accelerated Phase | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) by Subpopulation and Total | Relation to drug: Unknown | 1 participants |
| CML: Accelerated Phase | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) by Subpopulation and Total | With hematologic toxicity | 13 participants |
| CML: Accelerated Phase | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) by Subpopulation and Total | Discontinued treatment due to AE | 10 participants |
| CML: Accelerated Phase | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) by Subpopulation and Total | Deaths during study (outcome of SAE) | 4 participants |
| CML: Blast Phase | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) by Subpopulation and Total | Worst severity: Grade 2 | 1 participants |
| CML: Blast Phase | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) by Subpopulation and Total | Deaths during study or follow-up | 19 participants |
| CML: Blast Phase | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) by Subpopulation and Total | With hematologic toxicity | 13 participants |
| CML: Blast Phase | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) by Subpopulation and Total | Relation to drug: Probably | 13 participants |
| CML: Blast Phase | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) by Subpopulation and Total | >= 1 SAE | 19 participants |
| CML: Blast Phase | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) by Subpopulation and Total | Deaths during study (outcome of SAE) | 12 participants |
| CML: Blast Phase | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) by Subpopulation and Total | Discontinued treatment due to AE | 11 participants |
| CML: Blast Phase | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) by Subpopulation and Total | Relation to drug: Possibly | 5 participants |
| CML: Blast Phase | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) by Subpopulation and Total | Worst severity: Grade 1 | 0 participants |
| CML: Blast Phase | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) by Subpopulation and Total | Worst severity: Grade 4 | 4 participants |
| CML: Blast Phase | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) by Subpopulation and Total | >=1 TEAE | 21 participants |
| CML: Blast Phase | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) by Subpopulation and Total | Relation to drug: Unknown | 0 participants |
| CML: Blast Phase | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) by Subpopulation and Total | Worst severity: Grade 5 | 12 participants |
| CML: Blast Phase | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) by Subpopulation and Total | Relation to drug: Unrelated | 3 participants |
| CML: Blast Phase | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) by Subpopulation and Total | Worst severity: Grade 3 | 4 participants |
| Total Participants | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) by Subpopulation and Total | >= 1 SAE | 67 participants |
| Total Participants | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) by Subpopulation and Total | Relation to drug: Unrelated | 7 participants |
| Total Participants | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) by Subpopulation and Total | Relation to drug: Possibly | 14 participants |
| Total Participants | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) by Subpopulation and Total | Worst severity: Grade 1 | 1 participants |
| Total Participants | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) by Subpopulation and Total | Deaths during study or follow-up | 64 participants |
| Total Participants | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) by Subpopulation and Total | Relation to drug: Probably | 80 participants |
| Total Participants | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) by Subpopulation and Total | Relation to drug: Unknown | 1 participants |
| Total Participants | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) by Subpopulation and Total | Worst severity: Grade 2 | 9 participants |
| Total Participants | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) by Subpopulation and Total | Deaths during study (outcome of SAE) | 25 participants |
| Total Participants | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) by Subpopulation and Total | With hematologic toxicity | 81 participants |
| Total Participants | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) by Subpopulation and Total | Worst severity: Grade 3 | 17 participants |
| Total Participants | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) by Subpopulation and Total | Discontinued treatment due to AE | 39 participants |
| Total Participants | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) by Subpopulation and Total | Worst severity: Grade 4 | 50 participants |
| Total Participants | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) by Subpopulation and Total | >=1 TEAE | 102 participants |
| Total Participants | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) by Subpopulation and Total | Worst severity: Grade 5 | 25 participants |
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.
Time frame: Day 1 up to 6 months
Population: Intent to treat
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| CML: Chronic Phase | Percentage of Participants Achieving a Major Cytogenetic Response by Subpopulation and Total Population | 22.6 percentage of participants |
| CML: Accelerated Phase | Percentage of Participants Achieving a Major Cytogenetic Response by Subpopulation and Total Population | 5.0 percentage of participants |
| CML: Blast Phase | Percentage of Participants Achieving a Major Cytogenetic Response by Subpopulation and Total Population | 0 percentage of participants |
| Total Participants | Percentage of Participants Achieving a Major Cytogenetic Response by Subpopulation and Total Population | 14.6 percentage of participants |
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.
Time frame: Day 1 up to 6 months
Population: Intent to treat population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| CML: Chronic Phase | Percentage of Participants Achieving an Overall Hematologic Response by Subpopulation and Total Population | 77.4 percentage of participants |
| CML: Accelerated Phase | Percentage of Participants Achieving an Overall Hematologic Response by Subpopulation and Total Population | 55.0 percentage of participants |
| CML: Blast Phase | Percentage of Participants Achieving an Overall Hematologic Response by Subpopulation and Total Population | 9.5 percentage of participants |
| Total Participants | Percentage of Participants Achieving an Overall Hematologic Response by Subpopulation and Total Population | 59.2 percentage of participants |
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.
Time frame: up to 4 years
Population: Intent to treat population of participants who had a response
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| CML: Chronic Phase | Kaplan-Meier Estimates for Duration of Best Cytogenetic Response | 6.64 months |
| CML: Accelerated Phase | Kaplan-Meier Estimates for Duration of Best Cytogenetic Response | 16.35 months |
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.
Time frame: up to 4 years
Population: Intent to treat population of participants who had a response
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| CML: Chronic Phase | Kaplan-Meier Estimates for Duration of Best Hematologic Response | 9.08 months |
| CML: Accelerated Phase | Kaplan-Meier Estimates for Duration of Best Hematologic Response | 3.59 months |
| CML: Blast Phase | Kaplan-Meier Estimates for Duration of Best Hematologic Response | 3.31 months |
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.
Time frame: up to 4 years
Population: Intent to treat
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| CML: Chronic Phase | Kaplan-Meier Estimates for Overall Survival | 49.31 months |
| CML: Accelerated Phase | Kaplan-Meier Estimates for Overall Survival | 18.72 months |
| CML: Blast Phase | Kaplan-Meier Estimates for Overall Survival | 3.45 months |
| Total Participants | Kaplan-Meier Estimates for Overall Survival | 21.51 months |
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.
Time frame: up to 4 years
Population: Intent to treat
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| CML: Chronic Phase | Kaplan-Meier Estimates for Time to Disease Progression | 7.73 months |
| CML: Accelerated Phase | Kaplan-Meier Estimates for Time to Disease Progression | 4.74 months |
| CML: Blast Phase | Kaplan-Meier Estimates for Time to Disease Progression | 2.20 months |
| Total Participants | Kaplan-Meier Estimates for Time to Disease Progression | 5.86 months |
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.
Time frame: up to 3 years
Population: Intent to treat
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| CML: Chronic Phase | Kaplan-Meier Estimates for Time to Onset of Best Cytogenetic Response | NA months |
| CML: Accelerated Phase | Kaplan-Meier Estimates for Time to Onset of Best Cytogenetic Response | NA months |
| CML: Blast Phase | Kaplan-Meier Estimates for Time to Onset of Best Cytogenetic Response | NA months |
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.
Time frame: Day 1 up to Month 6
Population: Intent to treat
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| CML: Chronic Phase | Kaplan-Meier Estimates for Time to Onset of Best Hematologic Response | 0.46 months |
| CML: Accelerated Phase | Kaplan-Meier Estimates for Time to Onset of Best Hematologic Response | 1.74 months |
| CML: Blast Phase | Kaplan-Meier Estimates for Time to Onset of Best Hematologic Response | NA months |
Secondary
Number of Treatment Cycles Needed to Achieve Best Cytogenetic Response
Time frame: Day 1 up to 22 months
Population: Intent to treat population of participants who had a cytogenetic response
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| CML: Chronic Phase | Number of Treatment Cycles Needed to Achieve Best Cytogenetic Response | 3.0 treatment cycles |
| CML: Accelerated Phase | Number of Treatment Cycles Needed to Achieve Best Cytogenetic Response | 2.5 treatment cycles |
| CML: Blast Phase | Number of Treatment Cycles Needed to Achieve Best Cytogenetic Response | 2.0 treatment cycles |
| Total Participants | Number of Treatment Cycles Needed to Achieve Best Cytogenetic Response | 3.0 treatment cycles |
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.
Time frame: Day 1 up to Month 6
Population: Intent to treat population of participants who had a response to treatment
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| CML: Chronic Phase | Number of Treatment Cycles Needed to Achieve Best Hematologic Response | 1.0 treatment cycles |
| CML: Accelerated Phase | Number of Treatment Cycles Needed to Achieve Best Hematologic Response | 1.0 treatment cycles |
| CML: Blast Phase | Number of Treatment Cycles Needed to Achieve Best Hematologic Response | 1.0 treatment cycles |
| Total Participants | Number of Treatment Cycles Needed to Achieve Best Hematologic Response | 1.0 treatment cycles |
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
Time frame: Day 1 up to Month 9
Population: Intent to treat
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| CML: Chronic Phase | Percentage of Participants in Each Cytogenetic Response Category Representing the Degree of Suppression of the Philadelphia Chromosome (Ph+) | Complete | 16.1 percentage of participants |
| CML: Chronic Phase | Percentage of Participants in Each Cytogenetic Response Category Representing the Degree of Suppression of the Philadelphia Chromosome (Ph+) | Partial | 6.5 percentage of participants |
| CML: Chronic Phase | Percentage of Participants in Each Cytogenetic Response Category Representing the Degree of Suppression of the Philadelphia Chromosome (Ph+) | Minor | 4.8 percentage of participants |
| CML: Chronic Phase | Percentage of Participants in Each Cytogenetic Response Category Representing the Degree of Suppression of the Philadelphia Chromosome (Ph+) | Minimal | 16.1 percentage of participants |
| CML: Chronic Phase | Percentage of Participants in Each Cytogenetic Response Category Representing the Degree of Suppression of the Philadelphia Chromosome (Ph+) | No Response | 37.1 percentage of participants |
| CML: Chronic Phase | Percentage of Participants in Each Cytogenetic Response Category Representing the Degree of Suppression of the Philadelphia Chromosome (Ph+) | Unevaluable | 19.4 percentage of participants |
| CML: Accelerated Phase | Percentage of Participants in Each Cytogenetic Response Category Representing the Degree of Suppression of the Philadelphia Chromosome (Ph+) | Unevaluable | 60.0 percentage of participants |
| CML: Accelerated Phase | Percentage of Participants in Each Cytogenetic Response Category Representing the Degree of Suppression of the Philadelphia Chromosome (Ph+) | Minimal | 5.0 percentage of participants |
| CML: Accelerated Phase | Percentage of Participants in Each Cytogenetic Response Category Representing the Degree of Suppression of the Philadelphia Chromosome (Ph+) | Complete | 5.0 percentage of participants |
| CML: Accelerated Phase | Percentage of Participants in Each Cytogenetic Response Category Representing the Degree of Suppression of the Philadelphia Chromosome (Ph+) | Minor | 0 percentage of participants |
| CML: Accelerated Phase | Percentage of Participants in Each Cytogenetic Response Category Representing the Degree of Suppression of the Philadelphia Chromosome (Ph+) | Partial | 0 percentage of participants |
| CML: Accelerated Phase | Percentage of Participants in Each Cytogenetic Response Category Representing the Degree of Suppression of the Philadelphia Chromosome (Ph+) | No Response | 30.0 percentage of participants |
| CML: Blast Phase | Percentage of Participants in Each Cytogenetic Response Category Representing the Degree of Suppression of the Philadelphia Chromosome (Ph+) | Partial | 0 percentage of participants |
| CML: Blast Phase | Percentage of Participants in Each Cytogenetic Response Category Representing the Degree of Suppression of the Philadelphia Chromosome (Ph+) | Minor | 0 percentage of participants |
| CML: Blast Phase | Percentage of Participants in Each Cytogenetic Response Category Representing the Degree of Suppression of the Philadelphia Chromosome (Ph+) | Minimal | 9.5 percentage of participants |
| CML: Blast Phase | Percentage of Participants in Each Cytogenetic Response Category Representing the Degree of Suppression of the Philadelphia Chromosome (Ph+) | Unevaluable | 52.4 percentage of participants |
| CML: Blast Phase | Percentage of Participants in Each Cytogenetic Response Category Representing the Degree of Suppression of the Philadelphia Chromosome (Ph+) | No Response | 38.1 percentage of participants |
| CML: Blast Phase | Percentage of Participants in Each Cytogenetic Response Category Representing the Degree of Suppression of the Philadelphia Chromosome (Ph+) | Complete | 0 percentage of participants |
| Total Participants | Percentage of Participants in Each Cytogenetic Response Category Representing the Degree of Suppression of the Philadelphia Chromosome (Ph+) | No Response | 35.9 percentage of participants |
| Total Participants | Percentage of Participants in Each Cytogenetic Response Category Representing the Degree of Suppression of the Philadelphia Chromosome (Ph+) | Unevaluable | 34.0 percentage of participants |
| Total Participants | Percentage of Participants in Each Cytogenetic Response Category Representing the Degree of Suppression of the Philadelphia Chromosome (Ph+) | Partial | 3.9 percentage of participants |
| Total Participants | Percentage of Participants in Each Cytogenetic Response Category Representing the Degree of Suppression of the Philadelphia Chromosome (Ph+) | Minimal | 12.6 percentage of participants |
| Total Participants | Percentage of Participants in Each Cytogenetic Response Category Representing the Degree of Suppression of the Philadelphia Chromosome (Ph+) | Complete | 10.7 percentage of participants |
| Total Participants | Percentage of Participants in Each Cytogenetic Response Category Representing the Degree of Suppression of the Philadelphia Chromosome (Ph+) | Minor | 2.9 percentage of participants |
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.
Time frame: Day 1 up to Month 6
Population: Intent to treat
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| CML: Chronic Phase | Percentage of Participants in Each Hematologic Response Category | Return to chronic phase | NA percentage of participants |
| CML: Chronic Phase | Percentage of Participants in Each Hematologic Response Category | Complete response | 77.4 percentage of participants |
| CML: Chronic Phase | Percentage of Participants in Each Hematologic Response Category | No response | 19.4 percentage of participants |
| CML: Chronic Phase | Percentage of Participants in Each Hematologic Response Category | No evidence of leukemia | NA percentage of participants |
| CML: Chronic Phase | Percentage of Participants in Each Hematologic Response Category | Hematologic improvement | 0 percentage of participants |
| CML: Chronic Phase | Percentage of Participants in Each Hematologic Response Category | Partial response | 0 percentage of participants |
| CML: Chronic Phase | Percentage of Participants in Each Hematologic Response Category | Unevaluable | 3.2 percentage of participants |
| CML: Accelerated Phase | Percentage of Participants in Each Hematologic Response Category | No evidence of leukemia | 5.0 percentage of participants |
| CML: Accelerated Phase | Percentage of Participants in Each Hematologic Response Category | No response | 25.0 percentage of participants |
| CML: Accelerated Phase | Percentage of Participants in Each Hematologic Response Category | Unevaluable | 20.0 percentage of participants |
| CML: Accelerated Phase | Percentage of Participants in Each Hematologic Response Category | Complete response | 45.0 percentage of participants |
| CML: Accelerated Phase | Percentage of Participants in Each Hematologic Response Category | Partial response | 0 percentage of participants |
| CML: Accelerated Phase | Percentage of Participants in Each Hematologic Response Category | Hematologic improvement | 0 percentage of participants |
| CML: Accelerated Phase | Percentage of Participants in Each Hematologic Response Category | Return to chronic phase | 5.0 percentage of participants |
| CML: Blast Phase | Percentage of Participants in Each Hematologic Response Category | Complete response | 4.8 percentage of participants |
| CML: Blast Phase | Percentage of Participants in Each Hematologic Response Category | Return to chronic phase | 4.8 percentage of participants |
| CML: Blast Phase | Percentage of Participants in Each Hematologic Response Category | Partial response | 0 percentage of participants |
| CML: Blast Phase | Percentage of Participants in Each Hematologic Response Category | No response | 81.0 percentage of participants |
| CML: Blast Phase | Percentage of Participants in Each Hematologic Response Category | Hematologic improvement | 4.8 percentage of participants |
| CML: Blast Phase | Percentage of Participants in Each Hematologic Response Category | Unevaluable | 4.8 percentage of participants |
| CML: Blast Phase | Percentage of Participants in Each Hematologic Response Category | No evidence of leukemia | 0 percentage of participants |
| Total Participants | Percentage of Participants in Each Hematologic Response Category | Complete response | 56.3 percentage of participants |
| Total Participants | Percentage of Participants in Each Hematologic Response Category | No response | 33.0 percentage of participants |
| Total Participants | Percentage of Participants in Each Hematologic Response Category | Hematologic improvement | 1.0 percentage of participants |
| Total Participants | Percentage of Participants in Each Hematologic Response Category | No evidence of leukemia | 1.0 percentage of participants |
| Total Participants | Percentage of Participants in Each Hematologic Response Category | Partial response | 0 percentage of participants |
| Total Participants | Percentage of Participants in Each Hematologic Response Category | Unevaluable | 6.8 percentage of participants |
| Total Participants | Percentage of Participants in Each Hematologic Response Category | Return to chronic phase | 1.9 percentage of participants |
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). 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
Time frame: Day 1 up to Month 9
Population: Intent to treat population of study participants who had extramedullary disease at baseline. Analysis not performed due to insufficient sample size.
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.
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.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| CML: Chronic Phase | Percentage of Participants With Major Molecular Response (MMR) Representing the Degree of Suppression of BCR-ABL Transcript Levels Using the Housekeeping Gene ABL | 19.2 percentage of participants |
| CML: Accelerated Phase | Percentage of Participants With Major Molecular Response (MMR) Representing the Degree of Suppression of BCR-ABL Transcript Levels Using the Housekeeping Gene ABL | 15.4 percentage of participants |
| CML: Blast Phase | Percentage of Participants With Major Molecular Response (MMR) Representing the Degree of Suppression of BCR-ABL Transcript Levels Using the Housekeeping Gene ABL | 0 percentage of participants |
| Total Participants | Percentage of Participants With Major Molecular Response (MMR) Representing the Degree of Suppression of BCR-ABL Transcript Levels Using the Housekeeping Gene ABL | 16.4 percentage of participants |
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.
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.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| CML: Chronic Phase | Percentage of Participants With Major Molecular Response (MMR) Representing the Degree of Suppression of BCR-ABL Transcript Levels Using the Housekeeping Gene GUS | 8.1 percentage of participants |
| CML: Accelerated Phase | Percentage of Participants With Major Molecular Response (MMR) Representing the Degree of Suppression of BCR-ABL Transcript Levels Using the Housekeeping Gene GUS | 12.5 percentage of participants |
| CML: Blast Phase | Percentage of Participants With Major Molecular Response (MMR) Representing the Degree of Suppression of BCR-ABL Transcript Levels Using the Housekeeping Gene GUS | 0 percentage of participants |
| Total Participants | Percentage of Participants With Major Molecular Response (MMR) Representing the Degree of Suppression of BCR-ABL Transcript Levels Using the Housekeeping Gene GUS | 8.2 percentage of participants |
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).
Time frame: Day 1 up to Month 9
Population: Intent to treat population of participants with post-baseline assessment of T315I mutated BCR ABL
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| CML: Chronic Phase | Percentage of Participants With the Largest Percentage Reduction From Baseline of T315I Mutated BCR-ABL | Not assessable | 36.0 percentage of participants |
| CML: Chronic Phase | Percentage of Participants With the Largest Percentage Reduction From Baseline of T315I Mutated BCR-ABL | 1-24% reduction | 8.0 percentage of participants |
| CML: Chronic Phase | Percentage of Participants With the Largest Percentage Reduction From Baseline of T315I Mutated BCR-ABL | 0% reduction | 14.0 percentage of participants |
| CML: Chronic Phase | Percentage of Participants With the Largest Percentage Reduction From Baseline of T315I Mutated BCR-ABL | 75-99% reduction | 4.0 percentage of participants |
| CML: Chronic Phase | Percentage of Participants With the Largest Percentage Reduction From Baseline of T315I Mutated BCR-ABL | 50-74% reduction | 14.0 percentage of participants |
| CML: Chronic Phase | Percentage of Participants With the Largest Percentage Reduction From Baseline of T315I Mutated BCR-ABL | 100% reduction | 6.0 percentage of participants |
| CML: Chronic Phase | Percentage of Participants With the Largest Percentage Reduction From Baseline of T315I Mutated BCR-ABL | 25-49% reduction | 18.0 percentage of participants |
| CML: Accelerated Phase | Percentage of Participants With the Largest Percentage Reduction From Baseline of T315I Mutated BCR-ABL | 75-99% reduction | 0 percentage of participants |
| CML: Accelerated Phase | Percentage of Participants With the Largest Percentage Reduction From Baseline of T315I Mutated BCR-ABL | 50-74% reduction | 0 percentage of participants |
| CML: Accelerated Phase | Percentage of Participants With the Largest Percentage Reduction From Baseline of T315I Mutated BCR-ABL | 1-24% reduction | 38.5 percentage of participants |
| CML: Accelerated Phase | Percentage of Participants With the Largest Percentage Reduction From Baseline of T315I Mutated BCR-ABL | 100% reduction | 0 percentage of participants |
| CML: Accelerated Phase | Percentage of Participants With the Largest Percentage Reduction From Baseline of T315I Mutated BCR-ABL | 0% reduction | 15.4 percentage of participants |
| CML: Accelerated Phase | Percentage of Participants With the Largest Percentage Reduction From Baseline of T315I Mutated BCR-ABL | 25-49% reduction | 15.4 percentage of participants |
| CML: Accelerated Phase | Percentage of Participants With the Largest Percentage Reduction From Baseline of T315I Mutated BCR-ABL | Not assessable | 30.8 percentage of participants |
| CML: Blast Phase | Percentage of Participants With the Largest Percentage Reduction From Baseline of T315I Mutated BCR-ABL | Not assessable | 25.0 percentage of participants |
| CML: Blast Phase | Percentage of Participants With the Largest Percentage Reduction From Baseline of T315I Mutated BCR-ABL | 100% reduction | 0 percentage of participants |
| CML: Blast Phase | Percentage of Participants With the Largest Percentage Reduction From Baseline of T315I Mutated BCR-ABL | 75-99% reduction | 25.0 percentage of participants |
| CML: Blast Phase | Percentage of Participants With the Largest Percentage Reduction From Baseline of T315I Mutated BCR-ABL | 50-74% reduction | 12.5 percentage of participants |
| CML: Blast Phase | Percentage of Participants With the Largest Percentage Reduction From Baseline of T315I Mutated BCR-ABL | 25-49% reduction | 0 percentage of participants |
| CML: Blast Phase | Percentage of Participants With the Largest Percentage Reduction From Baseline of T315I Mutated BCR-ABL | 1-24% reduction | 12.5 percentage of participants |
| CML: Blast Phase | Percentage of Participants With the Largest Percentage Reduction From Baseline of T315I Mutated BCR-ABL | 0% reduction | 25.0 percentage of participants |
| Total Participants | Percentage of Participants With the Largest Percentage Reduction From Baseline of T315I Mutated BCR-ABL | 100% reduction | 4.2 percentage of participants |
| Total Participants | Percentage of Participants With the Largest Percentage Reduction From Baseline of T315I Mutated BCR-ABL | 25-49% reduction | 15.5 percentage of participants |
| Total Participants | Percentage of Participants With the Largest Percentage Reduction From Baseline of T315I Mutated BCR-ABL | 50-74% reduction | 11.3 percentage of participants |
| Total Participants | Percentage of Participants With the Largest Percentage Reduction From Baseline of T315I Mutated BCR-ABL | Not assessable | 33.8 percentage of participants |
| Total Participants | Percentage of Participants With the Largest Percentage Reduction From Baseline of T315I Mutated BCR-ABL | 75-99% reduction | 5.6 percentage of participants |
| Total Participants | Percentage of Participants With the Largest Percentage Reduction From Baseline of T315I Mutated BCR-ABL | 0% reduction | 15.5 percentage of participants |
| Total Participants | Percentage of Participants With the Largest Percentage Reduction From Baseline of T315I Mutated BCR-ABL | 1-24% reduction | 14.1 percentage of participants |