Clinical trial NCT04233346: The Study for CML Who Failed Prior TKIs or With T315I Mutation or Ph+ ALL Who Failed Prior TKIs or With 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
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
Conditions: Chronic Myeloid Leukemia
Acute Lymphoblastic Leukemia
Keywords: Acute Lymphoblastic Leukemia
Chronic Myeloid Leukemia
ponatinib
Lead sponsor: Otsuka Beijing Research Institute
Sponsor class: INDUSTRY
First posted: 2020-01-18
Enrollment: 93
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

Eligibility criteria: Inclusion Criteria:

For CP-CML patients：

1. Patients with CP-CML

   Patients must either meet criterion 2 or 3:
2. Be previously treated with and resistant or intolerant to either Dasatinib or Nilotinib:
3. Develop the T315I mutation after any TKI therapy;
4. Must be ≥18 years old.
5. Provide written informed consent.
6. Eastern Cooperative Oncology Group performance status ≤ 2.
7. Minimum life expectancy of 3 months or more.
8. Adequate renal function
9. Adequate hepatic function
10. Normal pancreatic status
11. 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：

1. Patients with AP-CML and BP-CML or Ph+ ALL
2. Other inclusions are the same with No.2-No.11 of CP-CML patients

Exclusion Criteria:

For CP-CML patients：

1. 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.
2. 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.
3. Underwent autologous or allogeneic stem cell transplant \< 60 days prior to receiving the first dose of Ponatinib;
4. Take medications that are known to be associated with Torsades de Pointes or QT interval prolongation.
5. Require concurrent treatment with immunosuppressive agents, other than corticosteroids prescribed for a short course of therapy.
6. Have previously been treated with Ponatinib or its analogues (including drug substance).
7. Patients with CP-CML are excluded if they are in CCyR.
8. Have active central nervous system (CNS) disease, as evidenced by cytology or pathology.
9. Have significant, uncontrolled, or active heart/brain/peripheral vascular diseases
10. Have a significant bleeding disorder unrelated to CML
11. Have a history of pancreatitis or alcohol abuse
12. Severely increased hypertriglyceridemia (triglycerides ≥ 5.6 mmol/L).
13. Have malabsorption syndrome or other gastrointestinal illness that could affect absorption of orally administered Ponatinib.
14. 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).
15. Are pregnant or lactating.
16. 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.
17. Infectious diseases test showed anti-HIV (+) or anti-HCV (+) or HbsAg (+) or TP (+).
18. 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.
19. Have hypertension (diastolic blood pressure ≥ 90 mmHg and/or systolic blood pressure ≥ 140 mm Hg).
20. Taken herbal preparations or related over-the-counter preparations containing Chinese herbal ingredients within 2 weeks prior to the first dose of Ponatinib.
21. Any subject who is not suitable for the study in the opinion of the investigator.

For AP/BP-CML and ALL patients：

1. 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.
2. 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.
3. Underwent autologous or allogeneic stem cell transplant \< 60 days prior to receiving the first dose of Ponatinib.
4. Take medications that are known to be associated with Torsades de Pointes or QT interval prolongation.
5. Require concurrent treatment with immunosuppressive agents, other than corticosteroids prescribed for a short course of therapy.
6. Have previously been treated with Ponatinib or its analogues (including drug substance).
7. Patients with AP-CML, BP-CML, or Ph+ ALL are excluded if they are in MaHR.
8. 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.
9. Have active central nervous system (CNS) disease as evidenced by cytology or pathology for AP-CML, BP-CML, or Ph+ ALL.
10. Have significant, uncontrolled, or active cardiovascular disease.
11. Have a significant bleeding disorder unrelated to CML or Ph+ ALL.
12. Other exclusions are the same with No.11-No.21 of CP-CML.

Primary outcomes:
measure: MCyR(Major Cytogenetic Response) of CP-CML patients
timeFrame: 12 months
measure: MaHR(Major Hematologic Response) of AP-CML, BP-CML and Ph+ ALL patients by 6 months
timeFrame: 6 months
Secondary outcomes:
measure: Duration of response
timeFrame: Up to 5 years
measure: Progression-free survival (PFS)
timeFrame: Up to 5 years
measure: Overall survival (OS)
timeFrame: Up to 5 years
measure: Time to response (TTR)
timeFrame: Up to 5 years
measure: Adverse events
timeFrame: Up to 5 years
measure: EORTC QLQ-C30 (version 3)
timeFrame: Up to 5 years
measure: Maximum Plasma Concentration [Cmax]
timeFrame: Up to 3 months
Other outcomes:
Locations:
city: Hefei
country: China
facility: Anhui Provincial Hospital
state: Anhui
city: Hefei
country: China
facility: The First Affiliated Hospital of Anhui Medical University
state: Anhui
city: Guangzhou
country: China
facility: Nanfang Hospital of Southern Medical University
state: Guangdong
city: Wuhan
country: China
facility: Tongji Hospital Affiliated to Tongji Medical College, Huazhong University of Science and Technology
state: Hubei
city: Changsha
country: China
facility: Xiangya Hospital Central South University
state: Hunan
city: Suzhou
country: China
facility: The First Affiliated Hospital of Soochow University
state: Jiangsu
city: Shenyang
country: China
facility: Shengjing Hospital of China Medical University
state: Liaoning
city: Jinan
country: China
facility: Qilu Hospital of Shandong University
state: Shandong
city: Taiyuan
country: China
facility: Second hospital of Shanxi Medical University
state: Shanxi
city: Shenzhen
country: China
facility: Shenzhen Second People's Hospital
state: Shenzhen
city: Chengdu
country: China
facility: West China Hospital, Sichuan University
state: Sichuan
city: Hangzhou
country: China
facility: The First Affiliated Hospital of Medical School of Zhejiang University
state: Zhejiang
city: Beijing
country: China
facility: 1st affiliated hospital, Peking University
city: Tianjin
country: China
facility: Hematology Hospital, Chinese Academy of Medical Sciences
Study officials:
affiliation: OBRI
name: Juma Paty, Director
role: STUDY_DIRECTOR
References: