A Randomized, Open-label Study of Ponatinib Versus Nilotinib in Patients with Chronic Myeloid Leukemia in Chronic Phase Following Resistance to Imatinib

Phase 1

• Conditions: Chronic Phase Chronic Myeloid Leukemia; MedDRA version: 19.1Level: LLTClassification code 10054352Term: Chronic phase chronic myeloid leukemiaSystem Organ Class: 100000004864; Therapeutic area: Diseases [C] - Blood and lymphatic diseases [C15]

• Registration Number: EUCTR2015-001318-92-PL
• Lead Sponsor: ARIAD Pharmaceuticals, Inc.

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Results First Posted: 1900-01-01
• Study Start: 2016-06-22
• Study Completion: 2021-01-19
• Last Update Posted: 6 December 2021

Recruitment & Eligibility

• Status: ot Recruiting
• Sex: All
• Target Recruitment: 44

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.
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 384
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 216

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 syndro

Study & Design

• Study Type: Interventional clinical trial of medicinal product
• Study Design: Not specified