The Study for CML Who Failed Prior TKIs or With T315I Mutation or Ph+ ALL Who Failed Prior TKIs or With T315I Mutation

Study Overview
=================
Brief Summary
-----------------
This protocol will allow ponatinib with refractory Chronic Myeloid Leukemia or Ph+ Acute Lymphoblastic Leukemia

Detailed Description
-----------------
The purpose of this study is to determine the safety and efficacy of ponatinib in patients with chronic myeloid leukemia (CML) in chronic phase (CP), accelerated phase (AP) or blast phase (BP) or with Ph positive (Ph+) acute lymphoblastic leukemia (ALL) who either are resistant or intolerant to either dasatinib or nilotinib, or have the T315I mutation.

Official Title
-----------------
A Phase II Multi-center, Randomized, Open-label Study of Ponatinib in Chinese Patients With Chronic Myeloid Leukemia Who Have Failed Prior TKIs or With T315I Mutation, or Ph+ALL Who Have Failed Prior TKIs or With T315I Mutation

Conditions
-----------------
Chronic Myeloid Leukemia, Acute Lymphoblastic Leukemia

Intervention / Treatment
-----------------
* Drug: Ponatinib


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: For CP-CML patients： Patients with CP-CML Patients must either meet criterion 2 or 3: Be previously treated with and resistant or intolerant to either Dasatinib or Nilotinib: Develop the T315I mutation after any TKI therapy; Must be ≥18 years old. Provide written informed consent. Eastern Cooperative Oncology Group performance status ≤ 2. Minimum life expectancy of 3 months or more. Adequate renal function Adequate hepatic function Normal pancreatic status Normal QTc interval on screening electrocardiogram (ECG) evaluation under resting state, defined as QTc of ≤ 450 ms in males or ≤ 470 ms in females. For AP/BP-CML and ALL patients： Patients with AP-CML and BP-CML or Ph+ ALL Other inclusions are the same with No.2-No.11 of CP-CML patients Exclusion Criteria: For CP-CML patients： Received TKI therapy within 7 days prior to receiving the first dose of Ponatinib, or have not recovered (> grade 2 by NCI CTCAE v5.0) from AEs (except alopecia) due to agents previously administered. Received other therapies (excluding hydroxyurea) as follows: 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. Underwent autologous or allogeneic stem cell transplant < 60 days prior to receiving the first dose of Ponatinib; Take medications that are known to be associated with Torsades de Pointes or QT interval prolongation. Require concurrent treatment with immunosuppressive agents, other than corticosteroids prescribed for a short course of therapy. Have previously been treated with Ponatinib or its analogues (including drug substance). Patients with CP-CML are excluded if they are in CCyR. Have active central nervous system (CNS) disease, as evidenced by cytology or pathology. Have significant, uncontrolled, or active heart/brain/peripheral vascular diseases Have a significant bleeding disorder unrelated to CML Have a history of pancreatitis or alcohol abuse Severely increased hypertriglyceridemia (triglycerides ≥ 5.6 mmol/L). Have malabsorption syndrome or other gastrointestinal illness that could affect absorption of orally administered Ponatinib. Have been diagnosed with another primary malignancy within the past 3 years (except for non-melanoma skin cancer, cervical cancer in situ, or controlled prostate cancer, which are allowed within 3 years). Are pregnant or lactating. Underwent major surgery (with the exception of minor surgical procedures, such as catheter placement or BM biopsy) within 14 days prior to first dose of Ponatinib. Infectious diseases test showed anti-HIV (+) or anti-HCV (+) or HbsAg (+) or TP (+). Suffer from any condition or illness that, in the opinion of the investigator, would compromise patient safety or interfere with the evaluation of the safety of the study drug. Have hypertension (diastolic blood pressure ≥ 90 mmHg and/or systolic blood pressure ≥ 140 mm Hg). Taken herbal preparations or related over-the-counter preparations containing Chinese herbal ingredients within 2 weeks prior to the first dose of Ponatinib. Any subject who is not suitable for the study in the opinion of the investigator. For AP/BP-CML and ALL patients： Received TKI therapy within 7 days prior to receiving the first dose of Ponatinib, or have not recovered (> grade 2 by NCI CTCAE v.5.0) from AEs (except alopecia) due to agents previously administered. Received other therapies (excluding hydroxyurea) as follows: For AP-CML patients, 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. For BP-CML patients, received chemotherapy within 7 days prior to the first dose of Ponatinib. Otherwise, 2a applies. For Ph+ ALL patients, received corticosteroids within 24 hours before the first dose of Ponatinib; otherwise, 2a applies. Underwent autologous or allogeneic stem cell transplant < 60 days prior to receiving the first dose of Ponatinib. Take medications that are known to be associated with Torsades de Pointes or QT interval prolongation. Require concurrent treatment with immunosuppressive agents, other than corticosteroids prescribed for a short course of therapy. Have previously been treated with Ponatinib or its analogues (including drug substance). Patients with AP-CML, BP-CML, or Ph+ ALL are excluded if they are in MaHR. Patients with AP-CML, BP-CML, or Ph+ ALL are excluded if a baseline BM aspirate adequate for cell count and differential report is not available. Have active central nervous system (CNS) disease as evidenced by cytology or pathology for AP-CML, BP-CML, or Ph+ ALL. Have significant, uncontrolled, or active cardiovascular disease. Have a significant bleeding disorder unrelated to CML or Ph+ ALL. Other exclusions are the same with No.11-No.21 of CP-CML.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ponatinib<br>CP-CML:Chronic Phase Chronic Myeloid Leukemia; AP-CML:Accelerated Phase Chronic Myeloid Leukemia; BP-CML:Blast Phase Chronic Myeloid Leukemia; Ph+ ALL:Ph+ Acute Lymphoblastic Leukemia; | Drug: Ponatinib<br>* CP-CML patients will be randomized into 30 mg and 45 mg dose groups at the ratio of 1:1,each group taken orally once daily. Other patients taken 45mg orally once daily.<br>* Other names: AP24534;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| MCyR(Major Cytogenetic Response) of CP-CML patients | To confirm the efficacy of Ponatinib in Chinese patients with CML who have failed Dasatinib or Nilotinib or with T315I mutation, or Ph+ ALL who have failed prior TKIs or with T315I mutation as evidenced by cytogenetic responses | 12 months | 
| MaHR(Major Hematologic Response) of AP-CML, BP-CML and Ph+ ALL patients by 6 months | To confirm the efficacy of Ponatinib in Chinese patients with CML who have failed Dasatinib or Nilotinib or with T315I mutation, or Ph+ ALL who have failed prior TKIs or with T315I mutation as evidenced by hematology responses | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of response | Assessment in the total patient population | Up to 5 years | 
| Progression-free survival (PFS) | Assessment in the total patient population | Up to 5 years | 
| Overall survival (OS) | Assessment in the total patient population | Up to 5 years | 
| Time to response (TTR) | Assessment in the total patient population | Up to 5 years | 
| Adverse events | Number of participants with adverse events as assessed by CTCAE v5.0 | Up to 5 years | 
| EORTC QLQ-C30 (version 3) | EORTC QLQ-C30 (version 3) score ranges from 1 to 4 or 1 to 7, A higher score represents a severer impressions or a best applies of patients. | Up to 5 years | 
| Maximum Plasma Concentration [Cmax] | Plasma concentration-time data for the population PK study | Up to 3 months |