| 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 | 21.0 |
| 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 CP-CML who are resistant to prior TKI therapy or have T315I mutation, as measured by ≤ 1% BCR-ABL1IS at 12 months. |
|
| E.2.2 | Secondary objectives of the trial |
•To characterize the rate of major molecular response (MMR) at 12 and 24 months and rate of major cytogenetic response (MCyR) by 12 months
•To evaluate duration of MMR
•To characterize the rates of AOEs, VTEs, AEs, and serious AEs (SAEs)
•To evaluate safety differences among the 3 starting dose cohorts, particularly for AOEs and VTEs
•To characterize the exposure-response and exposure-toxicity relationships between PK parameters and selected safety and efficacy measures
•To characterize the rates of cytogenetic responses and molecular responses; durability will be assessed by evaluating ≤ 1% BCR-ABL1IS response and major molecular response (MMR) at and by 6, 12, 18, and 24 months
•To characterize the rate of discontinuation, dose reductions, and interruptions
•To characterize the rates of hematologic responses
•To evaluate time to response, duration of response, and survival outcomes |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Have CP-CML and have received at least two prior TKI therapies and have demonstrated resistance to treatment
OR
Have documented history of presence of T315I mutation after receiving any number of prior TKI.
a. The diagnosis of CML will be made using standard hematopathologic and cytogenetic criteria; CP-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-ABL1 fusion by presence of the t(9;22) Philadelphia chromosome
i. Variant translocations are only allowed provided they meet inclusion criterion 1d
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-ABL1IS >10% and/or Ph+ >65% or new mutation
iii. Twelve months after the initiation of prior TKI therapy: BCR-ABL1IS >10% and/or Ph+ >35% or new mutation.
iv. At any time after the initiation of prior TKI therapy, the development of a new BCR-ABL1 kinase domain mutation(s).
v. At any time after the initiation of prior TKI therapy, the development of new clonal evolution
vi. At any time after the initiation of prior TKI therapy, the loss of CHR, or CCyR, or the confirmed loss of MMR in 2 consecutive tests, one of which has a BCR-ABL1IS transcript level of ≥1% or new mutation
d. > 1% of BCR-ABL1IS as shown by real-time polymerase chain reaction
2. Age ≥ 18 years old.
3. Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2.
4. Have adequate renal function as defined by the following criterion:
a. Serum creatinine ≤ 1.5 × upper limit of normal (ULN) for institution
b. Estimated creatinine clearance ≥ 30 mL/min (Cockcroft-Gault formula)
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. Alanine aminotransferase (ALT) ≤ 2.5 × ULN, or ≤ 5 × ULN if leukemic infiltration of the liver is present
c. Aspartate aminotransferase (AST) ≤ 2.5 × ULN, or ≤ 5 × ULN if leukemic infiltration 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 electrocardiogram (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 recovered from toxicities related to prior anticancer therapy to NCI CTCAE v 4.0 grade ≤1. |
|
| E.4 | Principal 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 the National Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE], v4.0) from AEs (except alopecia) due to agents previously administered.
3. Have undergone autologous or allogeneic stem cell transplant (SCT) < 60 days prior to receiving the first dose of ponatinib; have any evidence of ongoing graft versus-host disease (GVHD) or GVHD requiring immunosuppressive therapy.
4. Are being considered for hematopoietic SCT (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. Have active central nervous system (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.
8. Have clinically significant, uncontrolled, or active cardiovascular disease, specifically including, but not restricted to:
a. Any history of myocardial infarction (MI), unstable angina, cerebrovascular accident, or transient ischemic attack (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) (New York Heart Association [NYHA] class III or IV) within 6 months prior to enrollment, or left ventricular ejection fraction (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
9. Have uncontrolled hypertension (i.e., >150 and >90 for SBP and DBP, respectively). Patients with hypertension should be under treatment at study entry to ensure blood pressure control. Those requiring 3 or more antihypertensive medications should be discussed with the medical monitor.
10. Have poorly controlled diabetes defined as HbA1c values of > 7.5%. Patients with preexisting, well-controlled, diabetes are not excluded.
11. Have a significant bleeding disorder unrelated to CML.
12. Have a history of alcohol abuse.
13. Have a history of either acute pancreatitis within 1 year of study enrollment or of chronic pancreatitis.
14. Have malabsorption syndrome or other gastrointestinal illness that could affect oral absorption of study drug.
15. Have a history of another malignancy, other than cervical cancer in situ or 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.
16. Are pregnant or lactating.
17. Have undergone major surgery (with the exception of minor surgical procedures, such as catheter placement or BM biopsy) within 14 days prior to the first dose of ponatinib.
18. Have an active infection which requires intravenous antibiotics.
19. Have a known history of human immunodeficiency virus infection; testing is not required in the absence of prior documentation or known history.
20. Have any condition or illness that, in the opinion of the investigator, would compromise patient safety or interfere with the evaluation of the drug.
21. Have hypersensitivity to the ponatinib active substance or to any of its inactive ingredients listed in Section 14.7.1 of the protocol. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| At 12 months for each starting dose cohort. |
|
| E.5.2 | Secondary end point(s) |
•Molecular response rates: MMR at 12 and 24 months
•Cytogenetic response rates: MCyR by 12 months
•Duration of MMR
•Safety
a.Rate of AOEs and VTEs 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 ≤1% BCR-ABL1IS, MCyR and MMR) and on safety outcomes (including AOEs and VTEs)
•Cytogenetic response rates: CCyR at 12 months
•Molecular response rates: MR4, and MR4.5 by and at 3-month intervals and MR1 (≤ 10% BCR-ABL1IS) at 3 months
•Hematologic response rate: 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.Rate of ≤1% BCR-ABL1IS by 12 months and at and by 6, 18, and 24 months
b.MMR at and by 6 and 18 months; and by 12 and 24 months
•Duration of response in responders
•Time to response
•Rate of progression to accelerated phase (AP-) or blast phase (BP-) CML
•PFS
•OS |
|
| 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
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 9 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 49 |
| 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 |
| Australia |
| Canada |
| Chile |
| Hong Kong |
| Japan |
| Korea, Republic of |
| Russian Federation |
| Singapore |
| Taiwan |
| United States |
| Belgium |
| Denmark |
| Finland |
| France |
| Germany |
| Italy |
| Netherlands |
| Norway |
| Poland |
| Portugal |
| Spain |
| Sweden |
| United Kingdom |
| Czechia |
| Argentina |
|
| 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 | 6 |
| E.8.9.1 | In the Member State concerned months | 1 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 9 |
| E.8.9.2 | In all countries concerned by the trial months | 1 |
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