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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

IRB ARIA2915

CC 15-875

Hospital Main Campus

Phase Phase 2

Disease Leukemia - Chronic Myeloid (CML)

Drug Ponatinib

Description

Primary Objectives

• To characterize the efficacy of ponatinib administered in 3 starting doses (45 mg, 30 mg, and 15 mg daily) in patients with CP-CML who are resistant to at least two TKIs, as measured by MCyR by 12 months.

Key Secondary Objectives

• To characterize, according to ponatinib starting dose, the rates of VOEs, AEs, and SAEs.
• To evaluate safety differences, according to ponatinib starting dose, between the 3 starting dose cohorts-particularly for VOEs.
• To characterize the exposure-response and exposure-toxicity relationships between PK parameters and selected safety and efficacy measures.

Other Secondary Objectives

• To characterize, according to ponatinib starting dose, the rates of cytogenetic responses and molecular responses; durability will be assessed by evaluating MR2 and MMR at 12, 18, and 24 months.
• To characterize, according to ponatinib starting dose, the rates of discontinuation, dose reductions, and dose interruptions.
• To characterize, according to ponatinib starting dose, the rates of hematologic responses.
• To evaluate, according to ponatinib starting dose, time to response, duration of response, and survival outcomes.

Exploratory Objectives

• Correlation of tumor cell and plasma biomarkers with ponatinib efficacy and safety
• QoL and health outcomes

Inclusion Criteria

1. Have CP-CML and are resistant to at least two prior TKIs.
   • The diagnosis of CML will be made using standard hematopathologic and cytogenetic criteria. CP-CML will be defined by all of the following:
     • < 15% blasts in bone marrow
     • < 30% blasts plus promyelocytes in bone marrow
     • < 20% basophils in peripheral blood
     • ≥ 100 x 10⁹/L platelets (≥ 100,000/mm³)
     • No evidence of extramedullary disease except hepatosplenomegaly
     • No prior diagnosis of AP- or BP-CML
   • Cytogenetic assessment at screening must demonstrate the BCR-ABL fusion by presence of the t(9;22) Philadelphia chromosome.
     • Variant translocations are only allowed provided they are assessable for cytogenetic response utilizing conventional cytogenetic techniques
     • Conventional chromosome banding must be performed
     • A minimum of 20 metaphases must be assessable at entry
     • Resistance to prior TKI therapy is defined as follows (patients must meet at least 1 criterion):
       • Three months after the initiation of prior TKI therapy: No cytogenetic response (> 95% Ph+) or failure to achieve CHR or new mutation
       • Six months after the initiation of prior TKI therapy: BCR-ABLIS >10% and/or Ph+ >65% or new mutation
       • Twelve months after the initiation of prior TKI therapy: BCR-ABLIS >10% and/or Ph+ >35% or new mutation
       • 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
       • At any time after the initiation of prior TKI therapy, the development of new clonal evolution in the absence of CCyR or PCyR
       • At any time after the initiation of prior TKI therapy, the loss of CHR, 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
     • Be male or female patients ≥ 18 years old.
     • Have an ECOG performance status of 0, 1, or 2.
     • Have adequate renal function as defined by the following criterion:
       • Serum creatinine ≤ 1.5 x ULN for institution
     • Have adequate hepatic function as defined by the following criteria:
       • Total serum bilirubin ≤ 1.5 x ULN, unless due to Gilbert's syndrome
       • ALT ≤ 2.5 x ULN, or ≤ 5 x ULN if leukemic involvement of the liver is present
       • AST ≤ 2.5 x ULN, or ≤ 5 x ULN if leukemic involvement of the liver is present
     • Have normal pancreatic status as defined by the following criterion:
       • Serum lipase and amylase ≤ 1.5 x ULN
     • Have normal QTcF interval on screening ECG evaluation, defined as QTcF of ≤ 450 ms in males or ≤ 470 ms in females.
     • Have a negative pregnancy test documented prior to enrollment (for females of childbearing potential).
     • 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).
     • Provide written informed consent.
     • Be willing and able to comply with scheduled visits and study procedures.
     • Have fully recovered (≤ grade 1, returned to baseline, or deemed irreversible) from the acute effects of prior cancer therapy before initiation of study drug.

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 (Appendix A).
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:
   • Any history of MI, unstable angina, cerebrovascular accident, or TIA
   • Any history of peripheral vascular infarction, including visceral infarction
   • Any revascularization procedure, including the placement of a stent
   • Congestive heart failure (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
   • History of clinically significant (as determined by the treating physician) atrial arrhythmia or any history of ventricular arrhythmia
   • 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 antibiotics.
20. Have a known history of human immunodeficiency virus infection; testing is not required in the absence of prior documentation or known history.
21. Have any condition or illness that, in the opinion of the investigator, would compromise patient safety or interfere with the evaluation of the drug.
22. Have hypersensitivity to the ponatinib active substance or to any of its inactive ingredients listed in Section 14.7.1.