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 | 19.1 |
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 |
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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 demonstrate the efficacy of ponatinib administered at 2 starting
doses (30 and 15 mg once daily [QD]) compared to nilotinib administered at 400 mg twice daily (BID) in patients with CP-CML who are resistant to imatinib, as measured by major molecular response (MMR) by 12 months. |
|
E.2.2 | Secondary objectives of the trial |
To characterize, according to each arm and ponatinib starting dose, the rate of VOEs, AEs, and serious adverse events (SAEs)
To characterize, according to each arm and ponatinib starting dose, the rate of cytogenetic responses and molecular responses other than MMR
To further characterize efficacy according to each arm and ponatinib starting dose, including time to response, duration of cytogenetic and molecular response, duration of therapy, progression free survival, overall survival, and impact of dose escalation after loss of response (ponatinib cohorts only)
To characterize, according to each arm and ponatinib starting dose, the rate of discontinuation, dose reductions, and interruptions
To characterize, according to each arm and ponatinib starting dose, the rate of hematologic responses |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Have CP-CML and are resistant to first-line imatinib treatment.
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 must demonstrate the BCR-ABL fusion by presence of the t(9;22) Philadelphia chromosome.
i Conventional chromosome banding must be performed
ii A minimum of 20 metaphases must be assessable at entry
iii Variant translocations are not allowed
c. BCR-ABL transcript levels must be assessable using the International
Scale.
i b2a2 or b3a2 transcript type
d. Resistance is defined as follows. Patients must meet at least 1 criterion.
i Three months after the initiation of therapy: No cytogenetic response (>95% Ph+) or failure to achieve CHR.
ii Six months after the initiation of therapy: BCR-ABLIS >10% and/or >35% Ph+.
iii Twelve months after the initiation of therapy: BCR-ABLIS >1% and/or Ph+ >0.
iv At any time after the initiation of therapy, the development of new BCR-ABL kinase domain mutations in the absence of MCyR.
v At any time after the initiation of therapy, the development of new clonal evolution in the absence of MCyR.
vi At any time after the initiation of therapy, the loss of CHR, the loss of CCyR, or the confirmed loss of MMR (in 2 consecutive tests, one of which has a BCR-ABLIS transcript level of ≥1%.
[NOTE: The above criteria were adapted from Baccarani et al, 2013.]
2. Be male or female ≥18 years old.
3. Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
4. Have adequate renal function as defined by the following criterion:
a. Serum creatinine ≤1.5 × upper limit of normal (ULN) for institution.
5. Have adequate hepatic function as defined by all of 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 a negative pregnancy test documented prior to enrollment (for females of childbearing potential).
8. Agree to use a highly effective form of contraception with sexual partners from the time of randomization through at least four (4) months after end of study treatment (for female and male patients who are fertile).
9. Provide written informed consent.
10. Be willing and able to comply with scheduled visits and study procedures.
11. Have fully recovered (≤ grade 1 or returned to baseline or deemed irreversible) from the acute effects of prior cancer therapy (ie, hydroxyurea or imatinib) before initiation of study drug. |
|
E.4 | Principal exclusion criteria |
1. Have previously been treated with any approved or investigational TKIs other than imatinib or treated with imatinib within 14 days prior to receiving study drug.
2. Have previously been treated with any anti-CML therapy other than hydroxyurea, including interferon, cytarabine, immunotherapy, or any cytotoxic chemotherapy, radiotherapy, or investigational therapy.
3. Underwent autologous or allogeneic stem cell transplant.
4. Are in CCyR or MMR.
5. 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 history of a revascularization procedure, including vascular surgery or the placement of a stent
d. History of venous thromboembolism, including deep venous thrombosis, superficial venous thrombosis, or pulmonary embolism, within 6 months prior to enrollment
e. Congestive heart failure (New York Heart Association [NYHA] class III or IV) within 6 months prior to enrollment or left ventricular ejection fraction (LVEF) less than 45% or less than the institutional lower limit of normal (whichever is higher) within 6 months prior to enrollment
6. Have cardiac conduction abnormalities as follows:
a. QTcF >450 msec on the average of 3 serial baseline ECGs (using the QTcF formula); congenital long QT syndrome, or a known family history of long QT syndrome; or inability to determine the QTcF
b. Presence of a complete left bundle branch block
c. Use of a ventricular pacemaker
d. History of clinically significant (as determined by the treating physician) atrial arrhythmia
e. Resting bradycardia <50 beats per minute
f. Any history of ventricular arrhythmia
7. Are taking medications with a known risk of Torsades de Pointes or that have the potential to prolong the QT interval (Appendix A), unless the medication can be discontinued or be substituted by another without the risk.
8. Are taking medicines that are strong CYP3A4 inhibitors, unless the medication can be discontinued or be substituted by another that is not an inhibitor (Appendix B)
9. Are taking medicines that are strong CYP3A4 inducers, unless the medication can be discontinued or be substituted by another that is not an inducer (Appendix B)
10. Have uncontrolled hypertension (diastolic blood pressure >90 mmHg and/or systolic >150 mmHg). Patients with hypertension should be under treatment at 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/mL) on more than 3 occasions. Patients with preexisting, well-controlled, diabetes are not excluded.
12. Have uncorrected hypokalemia or hypomagnesemia.
13. 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. A history of CNS involvement itself is not an exclusion if the CNS has been cleared of disease with a documented negative lumbar puncture.
14. Have a significant bleeding disorder unrelated to CML.
15. Have a history of thrombophilia (eg, Protein C deficiency)
16. Have a history of alcohol abuse.
17. Have a history of acute pancreatitis within 1 year of study entry or history of chronic pancreatitis.
18. Have history of malabsorption syndrome or other gastrointestinal condition that could affect oral absorption of study drug.
19. Have a history of a different malignancy, other than cervical cancer in situ or basal cell or squamous cell carcinoma of the skin, except if patient has been disease-free for at least 5 years, and are deemed by the investigator to be at low risk for recurrence of that malignancy.
20. Are pregnant or lactating.
21. Have undergone major surgery within 14 days prior to first dose of study treatment. Minor surgical procedures, such as catheter placement or bone marrow biopsy are allowed.
22. Have an ongoing or active infection. This includes but is not limited to the requirement for intravenous antibiotics.
23. Have any surgical or medical condition / illness that, in the opinion of the investigator, would compromise patient safety or interfere with the evaluation of the study drug.
24. Have hypersensitivity to the active substance in ponatinib and nilotinib or to any of the inactive ingredients listed in Section 14.9.1.1 for ponatinib and in Section 14.9.1.2 for nilotinib |
|
E.5 End points |
E.5.1 | Primary end point(s) |
Major molecular response (MMR) by 12 months for each cohort. |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
By 12 months of treatment. |
|
E.5.2 | Secondary end point(s) |
1. Cytogenetic response rates:
a. Major cytogenetic response (MCyR) by 12 months
b. Complete cytogenetic response (CCyR) at12 months
2. Molecular response rates: MR2, MR3/MMR, MR4, MR4.5 at 3-month intervals until end-of-treatment and MR1 (≤10% BCR-ABLIS) at 3 months
3. Safety
a. Vascular occlusive events in each cohort
b. AEs in each cohort
c. SAEs in each cohort
4. Time to response
5. Duration of response:
a. MR2 and MMR at 3, 6, 9, and 12 months, and then at 3-month intervals until completion of treatment
b. MCyR at 12 months, by cytogenetic analysis
c. Duration of response in responders
d. Duration of therapy
6. Progression-free survival
7. Overall survival
8. Hematologic response: complete hematologic response (CHR)
9. Tolerability:
a. Discontinuations due to AEs in each cohort
b. Dose reductions due to toxicity (prior to response) in each cohort
c. Dose interruptions in each cohort
10. Progression to accelerated phase (AP) or blast phase (BP) CML |
|
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 | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
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) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
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) | Yes |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
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 | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 63 |
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 |
Austria |
Belgium |
Canada |
Czech Republic |
Denmark |
France |
Germany |
Hong Kong |
Hungary |
Israel |
Italy |
Korea, Republic of |
Netherlands |
Poland |
Portugal |
Romania |
Russian Federation |
Singapore |
Spain |
Switzerland |
United Kingdom |
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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
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|
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 | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 7 |