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

• Register: ClinicalTrials.gov
• Last refreshed on: 19 February 2024
• Main ID: NCT02467270
• Date of registration: 02/06/2015
• Prospective Registration: Yes
• Primary sponsor: Takeda
• 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 OPTIC
• Scientific 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
• Date of first enrolment: June 30, 2015
• Target sample size: 283
• Recruitment status: Active, not recruiting
• URL: https://clinicaltrials.gov/ct2/show/NCT02467270
• Study type: Interventional
• Study design: Allocation: Randomized. Intervention model: Parallel Assignment. Primary purpose: Treatment. Masking: None (Open Label).
• Phase: Phase 2

Countries of recruitment

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

Contacts

• Name: Study Director Clinical Science
• Affiliation: Takeda

Key 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(9;22) 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 pancreatit


Age minimum: 18 Years
Age maximum: N/A
Gender: All

Health Condition(s) or Problem(s) studied

Myeloid Leukemia, Chronic, Chronic Phase

Intervention(s)

Drug: Ponatinib

Primary Outcome(s)

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 [Time Frame: 12 months after the first dose of study treatment]

Secondary Outcome(s)

Percentage of Participants With Progression to Accelerated Phase (AP)-Chronic Myeloid Leukemia (CML) or Blast Phase (BP)-CML [Time Frame: From first dose date of study treatment up to data cut-off: 31 May 2020 (Approximately 5 years)]

Duration of Response in Responders [Time Frame: Baseline up to data cut-off: 31 May 2020 (Approximately 5 years)]

Overall Survival (OS) [Time Frame: Up to data cut-off: 31 May 2020 (Up to approximately 5 years)]

Percentage of Participants With Complete Hematologic Response (CHR) [Time Frame: 3 months after the first dose of study treatment]

Duration of Major Molecular Response (MMR/MR3) [Time Frame: Baseline up to approximately 8 years]

Percentage of Participants With Molecular Response 1 (MR1) [Time Frame: 3 months after the first dose of study treatment]

Percentage of Participants With Treatment Emergent AEs Leading to Treatment Discontinuation, Dose Reduction and Dose Interruption [Time Frame: Up to data cut-off: 31 May 2020 (Approximately 5 years)]

Kaplan-Meier Estimate of Duration of Response (DOR) of Major Molecular Response (MMR/MR3) [Time Frame: 12 and 24 months after the first dose of study treatment]

Kaplan-Meier Estimate of Duration of Response (DOR) of <=1% BCR-ABL1 IS (MR2) at Months 12 and 24 [Time Frame: 12 and 24 months after the first dose of study treatment]

Percentage of Participants With Molecular Response 4 (MR4) and Molecular Response (MR4.5) [Time Frame: Up to approximately 8 years]

Progression-free Survival (PFS) [Time Frame: Up to data cut-off: 31 May 2020 (Up to approximately 5 years)]

Time to Response [Time Frame: Baseline up to data cut-off: 31 May 2020 (Approximately 5 years)]

Percentage of Participants With Major Cytogenetic Response (MCyR) [Time Frame: 12 months after the first dose of study treatment]

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) [Time Frame: From first dose up to 30 days after last dose of the study drug up to data cut-off date: 31 May 2020 (Up to approximately 5 years)]

Percentage of Participants With Complete Cytogenetic Response (CCyR) [Time Frame: Month 12]

Percentage of Participants With Major Molecular Response (MMR/MR3) [Time Frame: 12 months after the first dose of study treatment]

Secondary ID(s)

2014-001617-12

AP24534-14-203

U1111-1238-0007

15/LO/1192

Source(s) of Monetary Support

Please refer to primary and secondary sponsors

Results

• Results available: Yes
• Date Posted: 14/06/2021
• URL: https://clinicaltrials.gov/ct2/show/results/NCT02467270