A Randomized, Open-label, Phase 2 Trial of Ponatinib in Patients with Resistant Chronic Phase Chronic Myeloid Leukemia to Characterize the Efficacy and Safety of a Range of Doses

Phase 1

• Conditions: Therapeutic area: Diseases [C] - Blood and lymphatic diseases [C15]; MedDRA version: 19.0Level: LLTClassification code 10054352Term: Chronic phase chronic myeloid leukemiaSystem Organ Class: 100000004864; Chronic Phase Chronic Myeloid Leukemia

• Registration Number: EUCTR2014-001617-12-NL
• Lead Sponsor: ARIAD Pharmaceuticals, Inc.

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Study Start: 2015-09-08
• Last Update Posted: 7 November 2016

Recruitment & Eligibility

• Status: Authorised-recruitment may be ongoing or finished
• Sex: All
• Target Recruitment: 450

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.

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 330
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of

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 ant

Study & Design

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