A study comparing three starting doses of Ponatinib tablets in patients with resistant chronic myeloid leukemia in the chronic phase.

Argentina, Australia, Belgium, Canada, Chile, China, Czech Republic, Czechia, Denmark, Finland, France, Germany, Hong Kong, Italy, Japan, Korea, Republic of, Norway, Poland, Portugal, Russian Federation, Singapore, Spain, Sweden, Switzerland, Taiwan, United Kingdom, United States (ICTRP)

ICTRP Trial ID
NCT02467270 (ICTRP)

Official title (approved by ethics committee)
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 (BASEC)

Academic title
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 (ICTRP)

Public title
Ponatinib in Participants With Resistant Chronic Phase Chronic Myeloid Leukemia (CP-CML) to Characterize the Efficacy and Safety of a Range of Doses (ICTRP)

Disease under investigation
Myeloid Leukemia, Chronic, Chronic Phase (ICTRP)

Intervention under investigation
Drug: Ponatinib (ICTRP)

Type of trial
Interventional (ICTRP)

Trial design
Allocation: Randomized. Intervention model: Parallel Assignment. Primary purpose: Treatment. Masking: None (Open Label). (ICTRP)

Inclusion/Exclusion criteria
Inclusion Criteria:

1. Have chronic phase-chronic myelogenous leukemia/chronic myeloid leukemia (CP-CML)
and have received at least two prior tyrosine kinase inhibitor (TKI) therapies and
have demonstrated resistance to treatment OR have documented history of presence of
T315I mutation after receiving any number of prior TKI.

o] The diagnosis of chronic myeloid leukemia (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*10^9/liter (L) platelets
(>=100,000/mm^3). v No evidence of extramedullary disease except hepatosplenomegaly
vi No prior diagnosis of AP-CML, and BP-CML o] Cytogenetic assessment at screening
must demonstrate the BCR-ABL1 fusion by presence of the t(922) Philadelphia
chromosome.

i Variant translocations are only allowed provided they meet inclusion criterion 1d.

o] Resistance to prior TKI therapy is defined as follows (participants 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 o] >1% of BCR-ABL1IS as shown by
real-time polymerase chain reaction

2. Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2.

3. Have adequate renal function as defined by the following criterion:

o] Serum creatinine <=1.5*ULN for institution o] Estimated creatinine clearance >=30
milliliter per minute (mL/min) (Cockcroft-Gault formula)

4. Have adequate hepatic function as defined by the following criteria:

o] Total serum bilirubin <=1.5*ULN, unless due to Gilbert's syndrome o] Alanine
transaminase (ALT) <=2.5*ULN, or <=5*ULN if leukemic infiltration of the liver is
present o] Aspartate transaminase (AST) <=2.5*ULN, or <=5*ULN if leukemic
infiltration of the liver is present

5. Have normal pancreatic status as defined by the following criterion:

o] Serum lipase and amylase <=1.5*ULN

6. Have normal QT interval corrected (Frederica) (QTcF) interval on screening
electrocardiogram (ECG) evaluation, defined as QTcF of <=450 milliseconds (ms) in
males or <=470 ms in females.

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
randomization through at least 4 months after the end of treatment (for female and
male participants who are fertile).

9. Provide written informed consent.

10. Be willing and able to comply with scheduled visits and study procedures.

11. Have recovered from toxicities related to prior anticancer therapy to National
Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v 4.0
grade <=1.

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, version 4.0) from AEs (except alopecia), due to agents previously
administered.

3. Have undergone autologous or allogeneic stem cell transplant <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 stem cell transplant (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 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:

o] Any history of myocardial infarction (MI), unstable angina, cerebrovascular
accident, or Transient Ischemic Attack (TIA) o] Any history of peripheral vascular
infarction, including visceral infarction o] Any revascularization procedure,
including the placement of a stent o] 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 o] History of
clinically significant (as determined by the treating physician) atrial arrhythmia
or any history of ventricular arrhythmia o] Venous thromboembolism, including deep
venous thrombosis or pulmonary embolism, within 6 months prior to enrollment

9. Have uncontrolled hypertension (that is, >150 and >90 for systolic blood pressure
(SBP) and diastolic blood pressure (DBP) respectively). Participants 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%. Participants 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 participants 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 first dose of pona (ICTRP)

not available

Primary and secondary end points
Percentage of Participants With Molecular Response (MR2: <=1% Breakpoint Cluster Region-Abelson Transcript Level) as Measured by the International Scale (BCR-ABL1IS) at Month 12 (ICTRP)

Percentage of Participants With Major Molecular Response (MMR/MR3);Percentage of Participants With Major Cytogenetic Response (MCyR);Duration of Major Molecular Response (MMR/MR3);Percentage of Participants With Adjusted Incidence Rates for Treatment Emergent Arterial Occlusive Events (AOEs), Venous Thrombotic Events (VTEs), Adverse Events (AEs), and Serious AEs (SAEs);Percentage of Participants With Complete Cytogenetic Response (CCyR);Percentage of Participants With Molecular Response 4 (MR4) and Molecular Response (MR4.5);Percentage of Participants With Molecular Response 1 (MR1);Percentage of Participants With Complete Hematologic Response (CHR);Percentage of Participants With Treatment Emergent AEs Leading to Treatment Discontinuation, Dose Reduction and Dose Interruption;Kaplan-Meier Estimate of Duration of Response (DOR) of <=1% BCR-ABL1 IS (MR2) at Months 12 and 24;Kaplan-Meier Estimate of Duration of Response (DOR) of Major Molecular Response (MMR/MR3);Duration of Response in Responders;Time to Response;Percentage of Participants With Progression to Accelerated Phase (AP)-Chronic Myeloid Leukemia (CML) or Blast Phase (BP)-CML;Progression-free Survival (PFS);Overall Survival (OS) (ICTRP)

Registration date
not available

Incorporation of the first participant
not available

Secondary sponsors
not available

Additional contacts
Study Director Clinical Science, Takeda (ICTRP)

Secondary trial IDs
2014-001617-12, 15/LO/1192, U1111-1238-0007, AP24534-14-203 (ICTRP)

Results-Individual Participant Data (IPD)
not available

Further information on the trial
https://clinicaltrials.gov/ct2/show/NCT02467270 (ICTRP)