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

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

This protocol will allow ponatinib with refractory Chronic Myeloid Leukemia or Ph+ Acute Lymphoblastic Leukemia

Study Overview

• Status: Active, not recruiting
• Conditions: Acute Lymphoblastic Leukemia; Chronic Myeloid Leukemia
• Intervention / Treatment: Drug: Ponatinib

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.

• Study Type: Interventional
• Enrollment (Estimated): 90
• Phase: Phase 2

Contacts and Locations

Study Locations

• China
  • Beijing, China
    • 1st affiliated hospital, Peking University
  • Tianjin, China
    • Hematology Hospital, Chinese Academy of Medical Sciences
  • Anhui
    • Hefei, Anhui, China
      • Anhui Provincial Hospital
    • Hefei, Anhui, China
      • The First Affiliated Hospital of Anhui Medical University
  • Guangdong
    • Guangzhou, Guangdong, China
      • Nanfang Hospital of Southern Medical University
  • Hubei
    • Wuhan, Hubei, China
      • Tongji Hospital affiliated to Tongji Medical College, Huazhong University of Science and Technology
  • Hunan
    • Changsha, Hunan, China
      • Xiangya Hospital Central South University
  • Jiangsu
    • Suzhou, Jiangsu, China
      • The First Affiliated Hospital of Soochow University
  • Liaoning
    • Shenyang, Liaoning, China
      • Shengjing Hospital Of China Medical University
  • Shandong
    • Jinan, Shandong, China
      • Qilu Hospital of Shandong University
  • Shanxi
    • Taiyuan, Shanxi, China
      • Second Hospital of Shanxi Medical University
  • Shenzhen
    • Shenzhen, Shenzhen, China
      • Shenzhen Second People's Hospital
  • Sichuan
    • Chengdu, Sichuan, China
      • West China Hospital, Sichuan University
  • Zhejiang
    • Hangzhou, Zhejiang, China
      • The First Affiliated Hospital of Medical School of Zhejiang University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Ponatinib; 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; 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.; Other Names: Iclusig; 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

Collaborators and Investigators

• Sponsor: Otsuka Beijing Research Institute
• Investigators: Study Director: Juma Paty, Director, OBRI

Study record dates

Study Major Dates

• Study Start (Actual): July 9, 2020
• Primary Completion (Actual): July 22, 2022
• Study Completion (Estimated): December 31, 2025

Study Registration Dates

• First Submitted: December 31, 2019
• First Submitted That Met QC Criteria: January 15, 2020
• First Posted (Actual): January 18, 2020

Study Record Updates

• Last Update Posted (Actual): November 1, 2023
• Last Update Submitted That Met QC Criteria: October 30, 2023
• Last Verified: October 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Disease Attributes; Bone Marrow Diseases; Hematologic Diseases; Myeloproliferative Disorders; Leukemia, Lymphoid; Chronic Disease; Leukemia; Leukemia, Myeloid; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Protein Kinase Inhibitors; Ponatinib
• Other Study ID Numbers: 297-403-00003

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No