A study of Iclusig (ponatinib), an oral kinase-inhibitor treatment administered, by standard dose or reduced doses, for patients with Philadelphia chromosome positive chronic myeloid leukemia (Ph+CML) who no longer benefit from, or who have an abnormal gene (T315I positive) marker for resistance to other kinase-inhibitor treatments.

Phase 1

• Conditions: Chronic Phase Chronic Myeloid Leukemia; MedDRA version: 20.0Level: LLTClassification code 10054352Term: Chronic phase chronic myeloid leukemiaSystem Organ Class: 100000004864; Therapeutic area: Diseases [C] - Blood and lymphatic diseases [C15]

• Registration Number: EUCTR2014-001617-12-CZ
• Lead Sponsor: ARIAD Pharmaceuticals, Inc. ( a wholly-owned subsidiary of Takeda Pharmaceutical Company Limited)

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Study Start: 2015-07-13
• Last Update Posted: 20 August 2018

Recruitment & Eligibility

• Status: ot Recruiting
• Sex: All
• Target Recruitment: 276

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 are assessable
for cytogenetic response utilizing conventional cytogenetic techniques
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.
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 202

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

Study & Design

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