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

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia

Intervention / Treatment
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* Drug: Olverembatinib
* Drug: Venetoclax
* Drug: prednisone
* Drug: Vincristine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female patients aged 14 years or older 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 Eastern Cooperative Oncology Group (ECOG) Performance status 0-2 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%; Subject has provided written informed consent prior to any screening procedure Exclusion Criteria: Lymphoid blast crisis of chronic myelocytic leukemia (CML) Previous or ongoing systemic anti-ALL therapy (including but not restricted to TKI and/or radiotherapy, except for appropriate pre-treatment) Clinical manifestations of CNS or extramedullary involvement with ALL 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.) Uncontrolled active serious infections that could, in the investigator's opinion, potentially interfere with the completion of treatment Known HIV seropositivity History of acute pancreatitis within 1 year of study screening or history of chronic pancreatitis Uncontrolled hypertriglyceridemia (triglycerides >450 mg/dL) Female patients who are pregnant or breast feeding Poorly controlled diabetes, defined as glycosylated hemoglobin (HbA1c) values of >7.5%. Patients with preexisting, well-controlled diabetes are not excluded Any serious psychiatric illness that could, in the investigator's opinion, potentially interfere with the completion of treatment

Ages Eligible for Study
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Minimum Age: 14 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Olverembatinib Combined With Reduced-Intensity Chemotherapy and Venetoclax<br>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<br>* a third-generation TKI<br>Drug: Venetoclax<br>* a selective inhibitor of B-cell lymphoma 2 (Bcl-2)<br>Drug: prednisone<br>* Glucocorticoids<br>Drug: Vincristine<br>* Anti-tumor alkaloids<br>|

What is the study measuring?
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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 |