Olverembatinib Combined With Reduced-Intensity Chemotherapy and Venetoclax for de Novo Ph+ ALL

Olverembatinib Combined With Reduced-Intensity Chemotherapy and Venetoclax for Newly Diagnosed Philadelphia Chromosome-positive Acute Lymphoblastic Leukemia: A Prospective, Single-arm, Single-center Clinical Trial

The introduction of TKIs has greatly improved the prognosis of Ph+ ALL patients. The third-generation TKI ponatinib in combination with chemotherapy has demonstrated superior efficacy to first- and second-generation TKIs. However, unfortunately, ponatinib is not available in mainland China. Olverembatinib is the only third-generation TKI drug currently approved in mainland China. Venetoclax is an oral selective inhibitor of Bcl-2, and small exploratory clinical studies have demonstrated that venetoclax in combination with ponatinib showed high rates of CR as well as molecular response in relapsed/refractory Ph+ ALL. This study will explore the safety and efficacy of olverembatinib in combination with reduced-intensity chemotherapy and venetoclax in patients with newly diagnosed Ph+ ALL.

Study Overview

• Status: Recruiting
• Conditions: Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia
• Intervention / Treatment: Drug: Olverembatinib; Drug: Venetoclax; Drug: prednisone; Drug: Vincristine

• Study Type: Interventional
• Enrollment (Estimated): 60
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Jianxiang Wang, Dr; Phone Number: 86-22-23909120; Email: wangjx@ihcams.ac.cn

Study Locations

• China
  • Tianjin, China, 300020
    • Recruiting
    • Institute of Hematology & Blood Diseases Hospital
    • Contact: Jianxiang Wang, Dr.; Phone Number: 86-22-23909120; Email: wangjx@medmail.com.cn
    • Principal Investigator: Jianxiang Wang, Dr.
    • Sub-Investigator: Ying Wang, Dr.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 12 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Male or female patients aged 14 years or older
2. Newly diagnosed Philadelphia chromosome positive(either t(9;22) and/or BCR-ABL positive and/ or FISH positive) acute lymphoblastic leukemia; Patients will be diagnosed according to morphologic,immunologic, cytogenetic and molecular(MICM) criteria, including bone marrow morphology, immunophenotype, cytogenetic and molecular genetic (BCR/ABL gene, qualitative and quantitative analysis) examination
3. Eastern Cooperative Oncology Group (ECOG) Performance status 0-2
4. Adequate end organ function as defined by: Total bilirubin ≤ 1.5 x upper limit of normal（ULN）; serum alanine aminotransferase (ALT) and serum aspartate aminotransferase (AST) ≤ 2.5 x ULN or ≤5 x ULN if leukemic involvement of the liver is present; Creatinine ≤ 1.5 x ULN; Serum amylase and lipase ≤ 1.5 x ULN; Alkaline phosphatase ≤ 2.5 x ULN unless considered tumor related; normal electrolytes: Potassium ≥ LLN; Magnesium ≥ LLN; Phosphorus ≥ LLN; Cardiac color Doppler ultrasound ejection fraction ≥ 45%;
5. Subject has provided written informed consent prior to any screening procedure

Exclusion Criteria:

1. Lymphoid blast crisis of chronic myelocytic leukemia (CML)
2. Previous or ongoing systemic anti-ALL therapy (including but not restricted to TKI and/or radiotherapy, except for appropriate pre-treatment)
3. Clinical manifestations of CNS or extramedullary involvement with ALL
4. Patients with a history of myocardial infarction within 12 months or clinically significant cardiac disorders disease (e.g., unstable angina, congestive heart failure, uncontrollable hypertension, uncontrollable arrhythmia, etc.)
5. Uncontrolled active serious infections that could, in the investigator's opinion, potentially interfere with the completion of treatment
6. Known HIV seropositivity
7. History of acute pancreatitis within 1 year of study screening or history of chronic pancreatitis
8. Uncontrolled hypertriglyceridemia (triglycerides >450 mg/dL)
9. Female patients who are pregnant or breast feeding
10. Poorly controlled diabetes, defined as glycosylated hemoglobin (HbA1c) values of >7.5%. Patients with preexisting, well-controlled diabetes are not excluded
11. Any serious psychiatric illness that could, in the investigator's opinion, potentially interfere with the completion of treatment

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: Olverembatinib Combined With Reduced-Intensity Chemotherapy and Venetoclax; For Induction cycle, olverembatinib will be given orally 40mg every other day. Patients with CMR, olverembatinib will be reduced to 30 mg every other day. Induction and consolidation cycles combined with a certain period of venetoclax. Reduced-intensity chemotherapy regimens consist mainly of vincristine and prednisone. Patients can receive allogeneic hematopoietic stem cell transplantation (HSCT),or patients who keep BCR/ABL negative can receive autologous HSCT whenever possible during their first CR. Otherwise, they will finish the consolidation chemotherapy.

Drug: Olverembatinib; a third-generation TKI; Drug: Venetoclax; a selective inhibitor of B-cell lymphoma 2 (Bcl-2); Drug: prednisone; Glucocorticoids; Drug: Vincristine; Anti-tumor alkaloids

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
CMR rate	Complete molecular remission rate (CMR rate) at 3 months of treatment (90 days)	At 3 months of treatment (90 days)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall survival(OS)	From the date of registration to the date of death resulting from any cause	up to 60 months
Relapse free survival	From the date of complete remission(CR) until the date of documented relapse or death due to any cause or the last follow-up day	up to 60 months
The rate of adverse events		an expected average of 24 months
complete remission (CR) rate		an expected average of 3 months
The duration of CR		up to 60 months
The duration of molecular CR		up to 60 months

Collaborators and Investigators

• Sponsor: Institute of Hematology & Blood Diseases Hospital, China
• Investigators: Principal Investigator: Jianxiang Wang, Dr, Institute of Hematology & Blood Diseases Hospital, China

Study record dates

Study Major Dates

• Study Start (Actual): October 8, 2022
• Primary Completion (Estimated): October 25, 2024
• Study Completion (Estimated): March 1, 2025

Study Registration Dates

• First Submitted: October 21, 2022
• First Submitted That Met QC Criteria: October 21, 2022
• First Posted (Actual): October 26, 2022

Study Record Updates

• Last Update Posted (Actual): October 5, 2023
• Last Update Submitted That Met QC Criteria: October 3, 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; Chromosome Aberrations; Translocation, Genetic; Leukemia; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Lymphoid; Philadelphia Chromosome; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Inflammatory Agents; Antineoplastic Agents; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Antineoplastic Agents, Phytogenic; Venetoclax; Prednisone; Vincristine
• Other Study ID Numbers: IIT2022040-EC-1

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

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