| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Chronic Phase Chronic Myeloid Leukemia |
|
| E.1.1.1 | Medical condition in easily understood language |
| Chronic Phase Chronic Myeloid Leukemia |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Blood and lymphatic diseases [C15] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 19.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10054352 |
| E.1.2 | Term | Chronic phase chronic myeloid leukemia |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To characterize the efficacy of ponatinib administered in 3 starting doses (45 mg, 30 mg, and 15 mg daily) in patients with chronic phase CML who are resistant to at least two tyrosine kinase inhibitors (TKIs), as measured by major cytogenetic response by 12 months. |
|
| E.2.2 | Secondary objectives of the trial |
To characterize, according to ponatinib starting dose, the rates of Vascular Occlusive Events (VOEs), AEs (Adverse Events), and serious AEs (SAEs).
To evaluate safety differences according to ponatinib starting dose among the 3 starting dose cohorts, particularly for VOEs.
To characterize the exposure-response and exposure-toxicity relationships between PK parameters and selected safety and efficacy measures.
To characterize, according to ponatinib starting dose, the rates of cytogenetic responses and molecular responses; durability will be assessed by evaluating molecular response (MR2) and major molecular response (MMR) at 12, 18, and 24 months.
To characterize, according to ponatinib starting dose, the rate of discontinuation, dose reductions, and interruptions.
To characterize, according to ponatinib starting dose, the rates of hematologic responses.
To evaluate, according to ponatinib starting dose, time to response, duration of response, and survival outcomes. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
All patients must meet all of the following inclusion criteria for study entry:
1. Have chronic phase CML and are resistant to at least two prior tyrosine kinase inhibitors.
a. The diagnosis of CML will be made using standard hematopathologic and cytogenetic criteria. Chronic phase CML will be defined by all of the following:
i < 15% blasts in bone marrow
ii < 30% blasts plus promyelocytes in bone marrow
iii < 20% basophils in peripheral blood
iv ≥ 100 × 109/L platelets (≥ 100,000/mm3)
v No evidence of extramedullary disease except hepatosplenomegaly
vi No prior diagnosis of AP- or BP-CML
b. Cytogenetic assessment at screening must demonstrate the BCR-ABL fusion by presence of the t(9;22) Philadelphia chromosome.
i Variant translocations are only allowed provided they are assessable for cytogenetic response utilizing conventional cytogenetic techniques
ii Conventional chromosome banding must be performed
iii A minimum of 20 metaphases must be assessable at entry
c. Resistance to prior TKI therapy is defined as follows (patients must meet at least 1 criterion):
i Three months after the initiation of prior TKI therapy: No cytogenetic response (> 95% Ph+) or failure to achieve CHR or new mutation
ii Six months after the initiation of prior TKI therapy: BCR-ABLIS >10% and/or Ph+ >65% or new muation
iii Twelve months after the initiation of prior TKI therapy: BCR-ABLIS >10% and/or Ph+ >35% or new muation
iv At any time after the initiation of prior TKI therapy, the development of new BCR-ABL kinase domain mutations in the absence of CCyR or PCyR
v At any time after the initiation of prior TKI therapy, the development of new clonal evolution in the absence of CCyR or PCyR
vi At any time after the initiation of prior TKI therapy, the loss of of CHR, the loss of CCyR or PCyR, or the confirmed loss of MMR in 2 consecutive tests, one of which has a BCR-ABLIS transcript level of ≥1% or new mutation
2. Be male or female patients ≥ 18 years old.
3. Have an ECOG performance status of 0, 1, or 2.
4. Have adequate renal function as defined by the following criterion:
a. Serum creatinine ≤ 1.5 × ULN for institution
5. Have adequate hepatic function as defined by the following criteria:
a. Total serum bilirubin ≤ 1.5 × ULN, unless due to Gilbert’s syndrome
b. ALT ≤ 2.5 × ULN, or ≤ 5 × ULN if leukemic involvement of the liver is present
c. AST ≤ 2.5 × ULN, or ≤ 5 × ULN if leukemic involvement of the liver is present
6. Have normal pancreatic status as defined by the following criterion:
a. Serum lipase and amylase ≤ 1.5 × ULN
7. Have normal QT interval corrected (Frederica) (QTcF) interval on screening ECG evaluation, defined as QTcF of ≤ 450 ms in males or ≤ 470 ms in females.
8. Have a negative pregnancy test documented prior to enrollment (for females of childbearing potential).
9. Agree to use a highly effective form of contraception with sexual partners from randomization through at least 4 months after the end of treatment (for female and male patients who are fertile).
10. Provide written informed consent.
11. Be willing and able to comply with scheduled visits and study procedures.
12. Have fully recovered (≤ grade 1, returned to baseline, or deemed irreversible) from the acute effects of prior cancer therapy before initiation of study drug.
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|
| E.4 | Principal exclusion criteria |
Patients are not eligible for participation in the study if they meet any of the following exclusion criteria:
1. Have used any approved TKIs or investigational agents within 2 weeks or 6 half-lives of the agent, whichever is longer, prior to receiving study drug.
2. Received interferon, cytarabine, or immunotherapy within 14 days, or any other cytotoxic chemotherapy, radiotherapy, or investigational therapy within 28 days prior to receiving the
first dose of ponatinib, or have not recovered (> grade 1 by NCI CTCAE, v4.0) from AEs (except alopecia), due to agents previously administered.
3. Have undergone autologous or allogeneic SCT < 60 days prior to receiving the first dose of ponatinib; have any evidence of ongoing GVHD or GVHD requiring immunosuppressive therapy.
4. Are being considered for HSCT within 6-12 months of enrollment (note: ponatinib is not to be used as a bridge to HSCT in this trial).
5. Are taking medications with a known risk of Torsades de Pointes
6. Have previously been treated with ponatinib.
7. Are in MCyR, defined as CCyR, PCyR, or MR2, which is ≤1% BCR-ABLIS.
8. Have active CNS disease as evidenced by cytology or pathology; in the absence of clinical CNS disease, lumbar puncture is not required. History itself of CNS involvement is not exclusionary if CNS has been cleared with a documented negative lumbar puncture.
9. Have clinically significant, uncontrolled, or active cardiovascular disease, specifically including, but not restricted to:
a. Any history of MI, unstable angina, cerebrovascular accident, or TIA
b. Any history of peripheral vascular infarction, including visceral infarction
c. Any revascularization procedure, including the placement of a stent
d. Congestive heart failure (CHF) (NYHA class III or IV) within 6 months prior to enrollment, or LVEF less than lower limit of normal, per local institutional standards, within 6 months prior to enrollment
e. History of clinically significant (as determined by the treating physician) atrial arrhythmia or any history of ventricular arrhythmia
f. Venous thromboembolism, including deep venous thrombosis or pulmonary embolism, within 6 months prior to enrollment
10. Have uncontrolled hypertension (diastolic blood pressure > 90 mmHg; systolic > 150 mmHg). Patients with hypertension should be under treatment on study entry to effect blood pressure control.
11. Have poorly controlled diabetes, defined as HbA1c values over the previous year of > 7.5% (59 mmol/mol) on more than 3 occasions; patients with preexisting, well-controlled, diabetes are not excluded.
12. Have a significant bleeding disorder unrelated to CML.
13. Have a history of alcohol abuse.
14. Have a history of either acute pancreatitis within 1 year of study or of chronic pancreatitis.
15. Have malabsorption syndrome or other gastrointestinal illness that could affect oral absorption of study drug.
16. Have a history of another malignancy, other than cervical cancer in situ or nonmetastatic basal cell or squamous cell carcinoma of the skin; the exception is if patients have been
disease-free for at least 5 years, and are deemed by the investigator to be at low risk for recurrence of that malignancy.
17. Are pregnant or lactating.
18. Have undergone major surgery (with the exception of minor surgical procedures, such as catheter placement) within 14 days prior to first dose of ponatinib.
19. Have an ongoing or active infection; this includes, but is not limited to, the requirement for intravenous antibiotics.
20. Have a known history of human immunodeficiency virus infection; testing is not required in the absence of prior documentation or known history.
21. Have any condition or illness that, in the opinion of the investigator, would compromise patient safety or interfere with the evaluation of the drug.
22. Have hypersensitivity to the ponatinib active substance or to any of its inactive ingredients listed in [protocol] Section 14.7.1.
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|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| MCyR by 12 months for each dose cohort (MCyR is defined as PCyR, CCyR, or ≤ 1% BCR-ABLIS (eg, MR2), which is equivalent to CCyR) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| After 12 months of treatment and the final analysis will be done at the end of the study |
|
| E.5.2 | Secondary end point(s) |
Safety:
a. Rate of VOEs in each dose cohort
b. Rate of AEs in each dose cohort
c. Rate of SAEs in each dose cohort
Exposure-response and exposure-toxicity relationships of area under the curve (AUC) and maximum plasma concentration (Cmax) at steady state on efficacy outcomes (including MCyR, MR2, and MMR) and safety outcomes (VOEs and AEs that occur in at least 30 patients)
Cytogenetic response rate: CCyR by and at 12 months
Molecular response rates: MR2, MR3/MMR, MR4, and MR4.5 at 3-month intervals and MR1 (≤ 10% BCR-ABLIS) at 3 months
Hematologic response rates: Complete hematologic response (CHR) at 3 months
Tolerability:
a. Rate of discontinuation due to AEs in each dose cohort
b. Dose reductions due to AE in each dose cohort
c. Dose interruptions in each dose cohort
Duration of response:
a. Rates of MR2 and MMR at 12, 18, and 24 months
b. Rate of MCyR at 12, 18, and 24 months
Duration of response in responders
Time to response
Rate of progression to accelerated phase (AP-) or blast phase (BP-) CML
Progression Free Survival
Overall Survival |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| At each visit and the final analysis will be done at the end of the study. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
| This is a controlled study of ponatinib at three different starting doses. |
|
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 46 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Argentina |
| Australia |
| Belgium |
| Canada |
| Chile |
| Czech Republic |
| Denmark |
| Finland |
| France |
| Germany |
| Hong Kong |
| Italy |
| Japan |
| Korea, Republic of |
| Netherlands |
| Norway |
| Poland |
| Portugal |
| Russian Federation |
| Singapore |
| Spain |
| Sweden |
| Taiwan |
| United Kingdom |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
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