Chronic Myeloid Leukemia
Conditions
Keywords
Leukemia, Leukemia, Myeloid, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, Neoplasms by Histologic Type, Neoplasms, Lymphoproliferative Disorders, Lymphatic Diseases, Immunoproliferative Disorders, Immune System Diseases, Myeloproliferative Disorders, Bone Marrow Diseases, Hematologic Diseases
Brief summary
The purpose of this study is to compare the efficacy of ponatinib and imatinib in patients with newly diagnosed chronic myeloid leukemia (CML) in the chronic phase.
Detailed description
This multicenter, international, phase 3 trial will test the hypothesis that ponatinib is an effective treatment for newly diagnosed CP-CML patients when compared with standard imatinib. Patients will be randomized in a 1:1 fashion, stratified by Sokal risk score at diagnosis (low, intermediate, high), to receive once daily oral administration of either ponatinib or imatinib. Efficacy measures include molecular, cytogenetic, and hematologic response rates at various timepoints; time to, duration of, and durability of responses; and survival follow-up. Safety measures include clinical laboratory testing, adverse event monitoring, vital signs, physical exams, ECGs, and ECHOs. Other measures include two patient-reported health outcomes questionnaires (FACT-Leu and EQ-5D-5L), determination of mutation status, and, for ponatinib only, measurement of steady-state plasma concentration. Accrual is expected to take approximately 2 years, and patients will be followed for survival for up to 8 years after the last patient's first dose; therefore, patient participation may last up to 10 years.
Interventions
DRUGponatinib
45 mg tablet, taken orally once daily
DRUGimatinib (Gleevec/ Glivec)
400 mg tablet, taken orally once daily
Sponsors
Ariad Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. CP CML within 6 months of diagnosis * CP-CML will be defined by (i) \<15% blasts in bone marrow; (ii) \<30% blasts plus promyelocytes in bone marrow; (iii) \<20% basophils in peripheral blood; (iv) ≥100 × 10\^9/L platelets (≥100,000/mm\^3); (v) No evidence of extramedullary disease except hepatosplenomegaly; AND (vi) No prior diagnosis of AP-CML or BP-CML 2. Cytogenetic assessment must demonstrate the BCR-ABL fusion by presence of the t(9;22) Philadelphia chromosome * (a)Variant translocations are only allowed provided they are assessable for cytogenetic response utilizing conventional cytogenetic techniques; (b) Conventional chromosome banding must be performed; AND (c) A minimum of 20 metaphases must be assessable at entry 3. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0, 1, or 2 4. Adequate hepatic function as defined by the following criteria: (a) Total serum bilirubin ≤1.5 x upper limit of normal (ULN), unless due to Gilbert's syndrome; (b) Alanine aminotransferase (ALT) ≤2.5 × ULN; AND (c) Aspartate aminotransferase (AST) ≤2.5 × ULN 5. Adequate renal function as defined as defined by serum creatinine \<1.5 x ULN 6. Adequate pancreatic function as defined by serum lipase and amylase ≤1.5 × ULN
Exclusion criteria
1. Received prior imatinib therapy 2. Received prior dasatinib therapy 3. Received prior nilotinib therapy 4. Received, for CML, any other systemic anticancer therapy, experimental therapy, or radiation therapy with the exception of anagrelide or hydroxyurea 5. Major surgery within 28 days prior to initiating therapy 6. History of bleeding disorder unrelated to CML 7. History of acute pancreatitis within 1 year of study or history of chronic pancreatitis 8. History of alcohol abuse 9. Have uncontrolled hypertriglyceridemia (triglycerides \>450 mg/dL) 10. Clinically significant, uncontrolled, or active cardiovascular disease, specifically including, but not restricted to: 1. Myocardial infarction, within 6 months prior to randomization 2. Unstable angina within 6 months prior to randomization 3. Congestive heart failure within 6 months prior to randomization 4. History of clinically significant (as determined by the treating physician) atrial arrhythmia or any ventricular arrhythmia 5. Any history of ventricular arrhythmia 6. Cerebrovascular accident or transient ischemic attack within 6 months prior to randomization 7. Any history of peripheral arterial occlusive disease requiring revascularization 8. Any history of venous thromboembolism including deep venous thrombosis or pulmonary embolism 11. Uncontrolled hypertension (diastolic blood pressure \>90 mm Hg; systolic \>140 mm Hg). Patients with hypertension should be under treatment on study entry to effect blood pressure control 12. Taking medications that are known to be associated with Torsades de Pointes 13. Ongoing or active infection. The requirement for intravenous (IV) antibiotics is considered active infection 14. Known history of human immunodeficiency virus (HIV). Testing is not required in the absence of history 15. Pregnant or breastfeeding 16. Malabsorption syndrome or other gastrointestinal illness that could affect oral absorption of study drugs 17. Diagnosed with or received anticancer therapy for another primary malignancy within 3 years prior to entry (except for non-melanoma skin cancer or cervical cancer in situ) 18. Any condition or illness that, in the opinion of the Investigator, would compromise patient safety or interfere with the evaluation of the drug
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Major Molecular Response (MMR) Rate at 12 Months | 12 months after first dose | A ratio of reverse transcribed transcript of BCR-ABL to ABL ≤ 0.1% on the international scale, measured by real-time quantitative polymerase chain reaction. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| MMR Rate | 5 years after first dose | To compare the efficacy of ponatinib with imatinib, as measured by MMR rate, at 5 years |
| <10% BCR-ABL^IS Rate | 3 months after first dose | To compare the proportion of patients achieving a ratio of \<10% BCR-ABL to ABL transcript levels at 3 months, as measured by the international scale (\<10% BCR-ABL\^IS), in patients administered ponatinib versus those administered imatinib |
| Complete Cytogenetic Response (CCyR) Rate | 12 months after first dose | The percentage of Ph+ metaphases in bone marrow (peripheral blood may not be used), with a review of a minimum of 20 metaphases. Responses are defined as follows: Complete (CCyR): 0% Ph+ metaphases. |
| Progression-free Survival | Up to 8 years after the last patient's first dose | To compare, according to treatment with ponatinib versus imatinib, progression-free survival |
| Overall Survival | Up to 8 years after the last patient's first dose | To compare, according to treatment with ponatinib versus imatinib, overall survival |
Countries
Australia, Austria, Belgium, Canada, Czechia, Finland, France, Germany, Hong Kong, Italy, Netherlands, New Zealand, Poland, Portugal, Puerto Rico, Singapore, Slovakia, South Korea, Spain, Sweden, Switzerland, Taiwan, United Kingdom, United States
Participant flow
Pre-assignment details
A total of 307 subjects were enrolled (ponatinib patients: 155; imatinib patients: 152). Patients were randomized in a 1:1 fashion to receive either ponatinib or imatinib.
Participants by arm
| Arm | Count |
|---|---|
| Ponatinib ponatinib: 45 mg tablet, taken orally once daily | 155 |
| Imatinib imatinib (Gleevec/ Glivec): 400 mg tablet, taken orally once daily | 152 |
| Total | 307 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | Ponatinib | Imatinib | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 36 Participants | 36 Participants | 72 Participants |
| Age, Categorical Between 18 and 65 years | 119 Participants | 116 Participants | 235 Participants |
| Age, Continuous | 51.9 years STANDARD_DEVIATION 15.66 | 51.2 years STANDARD_DEVIATION 15.19 | 51.5 years STANDARD_DEVIATION 15.41 |
| Region of Enrollment Australia | 1 participants | 6 participants | 7 participants |
| Region of Enrollment Belgium | 3 participants | 2 participants | 5 participants |
| Region of Enrollment Canada | 16 participants | 13 participants | 29 participants |
| Region of Enrollment Czech Republic | 1 participants | 3 participants | 4 participants |
| Region of Enrollment Finland | 1 participants | 0 participants | 1 participants |
| Region of Enrollment France | 14 participants | 21 participants | 35 participants |
| Region of Enrollment Germany | 11 participants | 12 participants | 23 participants |
| Region of Enrollment Hong Kong | 4 participants | 1 participants | 5 participants |
| Region of Enrollment Italy | 15 participants | 14 participants | 29 participants |
| Region of Enrollment Korea, Republic of | 3 participants | 2 participants | 5 participants |
| Region of Enrollment Netherlands | 1 participants | 1 participants | 2 participants |
| Region of Enrollment New Zealand | 4 participants | 4 participants | 8 participants |
| Region of Enrollment Poland | 0 participants | 1 participants | 1 participants |
| Region of Enrollment Portugal | 0 participants | 2 participants | 2 participants |
| Region of Enrollment Singapore | 1 participants | 11 participants | 12 participants |
| Region of Enrollment Spain | 16 participants | 9 participants | 25 participants |
| Region of Enrollment Sweden | 6 participants | 2 participants | 8 participants |
| Region of Enrollment Switzerland | 1 participants | 0 participants | 1 participants |
| Region of Enrollment Taiwan | 3 participants | 2 participants | 5 participants |
| Region of Enrollment United Kingdom | 6 participants | 12 participants | 18 participants |
| Region of Enrollment United States | 48 participants | 34 participants | 82 participants |
| Sex: Female, Male Female | 58 Participants | 60 Participants | 118 Participants |
| Sex: Female, Male Male | 97 Participants | 92 Participants | 189 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 145 / 154 | 144 / 152 |
| serious Total, serious adverse events | 49 / 154 | 13 / 152 |
Outcome results
Primary
Major Molecular Response (MMR) Rate at 12 Months
A ratio of reverse transcribed transcript of BCR-ABL to ABL ≤ 0.1% on the international scale, measured by real-time quantitative polymerase chain reaction.
Time frame: 12 months after first dose
Population: Patients with 12 month assessment (due to early termination of the study, none of the endpoints could be evaluated as planned).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ponatinib | Major Molecular Response (MMR) Rate at 12 Months | 8 participants |
| Imatinib | Major Molecular Response (MMR) Rate at 12 Months | 5 participants |
p-value: 0.074Cochran-Mantel-Haenszel
Secondary
<10% BCR-ABL^IS Rate
To compare the proportion of patients achieving a ratio of \<10% BCR-ABL to ABL transcript levels at 3 months, as measured by the international scale (\<10% BCR-ABL\^IS), in patients administered ponatinib versus those administered imatinib
Time frame: 3 months after first dose
Population: Patients with 3 month assessment
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ponatinib | <10% BCR-ABL^IS Rate | 103 participants |
| Imatinib | <10% BCR-ABL^IS Rate | 77 participants |
p-value: <0.001Cochran-Mantel-Haenszel
Secondary
Complete Cytogenetic Response (CCyR) Rate
The percentage of Ph+ metaphases in bone marrow (peripheral blood may not be used), with a review of a minimum of 20 metaphases. Responses are defined as follows: Complete (CCyR): 0% Ph+ metaphases.
Time frame: 12 months after first dose
Population: Patients with 12 month assessment
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ponatinib | Complete Cytogenetic Response (CCyR) Rate | 5 participants |
| Imatinib | Complete Cytogenetic Response (CCyR) Rate | 6 participants |
p-value: 0.317Cochran-Mantel-Haenszel
Secondary
MMR Rate
To compare the efficacy of ponatinib with imatinib, as measured by MMR rate, at 5 years
Time frame: 5 years after first dose
Secondary
Overall Survival
To compare, according to treatment with ponatinib versus imatinib, overall survival
Time frame: Up to 8 years after the last patient's first dose
Secondary
Progression-free Survival
To compare, according to treatment with ponatinib versus imatinib, progression-free survival
Time frame: Up to 8 years after the last patient's first dose