Study of Azacitidine，Venetoclax，and Flumatinib in Newly Diagnosed Ph-positive Acute Leukemia and CML-AP/BP Patients

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to evaluate the efficacy and safety of azacitidine，venetoclax，and flumatinib in newly diagnosed Philadelphia chromosome-positive acute leukemia and accelerated phase or blast phase chronic myeloid leukemia patients.

Detailed Description
-----------------
This is a phase Ⅱ, open-label, single-arm, single-center study in newly diagnosed Ph-positive acute leukemia and CML-AP/BP patients. The patients will receive azacitidine, venetoclax, and flumatinib regimen in the induction treatment. The patients who respond to induction treatment will undergo consolidation treatment, and an optional allogeneic hematopoietic stem cell transplantation and post-transplantation maintenance treatment with induction therapy according to patient's wishes.

Official Title
-----------------
A Phase Ⅱ, Open Label, Single Arm, Single-Center Study to Evaluate the Efficacy and Safety of Azacitidine，Venetoclax，and Flumatinib in Newly Diagnosed Ph-positive Acute Leukemia and CML-AP/BP Patients

Conditions
-----------------
Philadelphia Chromosome, Acute Myeloid Leukemia, Acute Lymphoblastic Leukemia, Chronic Myeloid Leukemia, Mixed Phenotype Acute Leukemia

Intervention / Treatment
-----------------
* Drug: Azacitidine
* Drug: Venetoclax
* Drug: Flumatinib


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Newly diagnosed Ph-positive ALL/AML/MPAL and CML-AP/BP without the history of chemotherapy or target therapy. Age 18-65. Eastern Cooperative Oncology Group (ECOG) score: 0-3. Total serum bilirubin ≤ 2 x upper limit of normal (ULN), alanine aminotransferase (ALT) ≤ 1.5 x ULN, aspartate aminotransferase (AST) ≤ 1.5 x ULN. Creatinine clearance ≥ 30 mL/min. Serum lipase ≤ 1.5 x ULN, amylase =< 1.5 x ULN. No consumption of grapefruit, grapefruit products, Seville oranges, or star fruit within 3 days prior to starting venetoclax. Provide informed consent. Exclusion Criteria: Patients with another malignant disease. Patients has participated in or participating in other clinical trials. Patients with uncontrolled active infection. Patients with left ventricular ejection fraction < 0.5 by echocardiography or grade III/IV cardiovascular dysfunction according to the New York Heart Association Classification. Patients with HIV infection, active tuberculosis infection, or active hepatitis B or hepatitis C infection. Patients with uncontrolled active bleeding. Patients with history of previous chemotherapy or target therapy (except for oral hydroxyurea and/or leukopheresis for lowering white blood cell counts). Pregnant and lactating women; patients of childbearing potential should be willing to practice methods of contraception throughout the study period. Patients with other commodities that the investigators considered not suitable for the enrollment.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 65 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: Azacitidine，Venetoclax，and Flumatinib Regimen<br>See Detailed Description. | Drug: Azacitidine<br>* Azacitidine: 75mg/m2 qd, d1-d7, subcutaneous injection<br>Drug: Venetoclax<br>* Venetoclax: 100mg d1, 200mg d2, 300mg d3, 400mg d4-d14 or 21, oral (Adjusted according to the peripheral blood BCR/ABL1 results on day 14)<br>Drug: Flumatinib<br>* Flumatinib: 600mg qd, d4-d21, oral<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| CMR | Complete molecular remission (CMR) was defined as undetectable BCR/ABL transcript. | End of cycle 2 (each cycle is 28 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| CR/CRi, MRD-negative CR, CCyR, MMR | Complete remission (CR) was defined as < 5% bone marrow blasts in an aspirate with spicules and independent of transfusions. CR with incomplete hematologic recovery (CRi) was defined as <5% bone marrow blasts, either ANC<1×10^9/L or platelets < 100×10^9/L, transfusion independence but with persistence of cytopenia. Minimal residual disease (MRD)-negative CR was defined as a leukemic cell count below the sensitivity threshold of 1×10-4 (0.01%) bone marrow mononuclear cells (MNCs) by multiparameter flow cytometry. Complete cytogenetic response (CCyR) was defined as lack of Ph in ≥ 20 bone marrow metaphases. Major molecular response (MMR) was defined as a BCR-ABL/ABL transcript ratio of 0.1% (international scale). | End of cycle 1 and 2 (each cycle is 28 days) | 
| Number of adverse events | Adverse events are evaluated with CTCAE V5.0. | End of cycle 1 and 2 (each cycle is 28 days) | 
| RFS | Relapse-free survival (RFS) was the duration from the day of CR to leukemia relapse, death, or last follow-up. | 2 years | 
| OS | Overall survival (OS) was the time from enrollment to death for any reason. | 2 years | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Ph-positive AL, CML-AP/BP, Azacitidine+Venetoclax+Flumatinib