Olverembatinib Combined With Venetoclax and Azacitidine in Blast Phase Ph Chromosome-positive CML

A Multicenter, Single-arm I/II Clinical Study of Olverembatinib Combined With Venetoclax and Azacitidine in in Blast Phase Ph Chromosome- Chronic Myeloid Leukemia

Even in the TKI era, the outcoms of patients with blast phase is still poor.The response rate to conventional intensive chemotherapy is only 12.5% and the 5-year survival rate is 0 for patients with myeloid blast crsis. The response rate of TKI monotherapy is about 50% and the response rate is further improved when combined TKI and chemotherapy for patients with lymphoid blast crsis. The induction remission rate of chemotherapy alone for patients with Ph-positive acute lymphoblastic leukemia is 50-60%, and the remission rate increases to more than 95% when combined with TKI. Therefore, the application of TKI for patients in the blast crisis phase is of great significance. Olverembatinib is the only third-generation TKI drug approved in the Chinese mainland at present. Preclinical research data show that olverembatinib has a significant inhibitory effect on wild-type and mutant ABL resistant to the first and second-generation TKIs, as well as some complex mutations resistant to ponatinib. Phase I and II clinical studies have shown that for CML patients in the chronic and accelerated phases with resistance or intolerance to various TKIs, with or without T315I mutations, there are significant hematological and molecular responses and survival benefits. Olverembatinib can also inhibit many other kinases related to tumors. In vitro studies have shown that olverembatinib downregulates MCL-1 expression and acts synergistically with BCL-2 inhibitors to induce apoptosis of AML cells.

Preclinical studies have shown that venetoclax has a synergistic effect with TKIs. It upregulates apoptosis-inducing proteins, downregulates anti-apoptotic protein MCL1, inhibits the anti-apoptotic activity of BCL-XL, induces apoptosis of Ph+ cells, overcomes TKI resistance, and eliminates CML leukemia stem cells.

A large amount of evidence indicates that DNA hypermethylation plays an important role in the progression of CML, and abnormal DNA methylation is associated with progression to the accelerated and blast crisis phases and resistance to TKIs.Domestic scholars have reported successful cases of combined treatment with TKI, venetoclax, and demethylating agent azacitidine for CML patients with lymphoid blast crisis.

Therefore, we designed this study to explore the efficacy and safety of olverembatinib, venetoclax, and azacitidine in the treatment of CML patients in the blast crisis phase.

Study Overview

• Status: Recruiting
• Conditions: CML,Blast Phase
• Intervention / Treatment: Drug: Olverembatinib; Drug: Venetoclax; Drug: Azacitidine

Detailed Description

In patients with chronic myeloid leukemia (CML) in the blase crsis phase who are aged≥15 years, olverembatinib combined with venetoclax and azacitidine was applied for induction and consolidation therapy. After remission, allogeneic stem cell transplantation was performed or olverembatinib combined with venetoclax and azacitidine was continued for consolidation and maintenance therapy. The maximum tolerated dose of the combined chemotherapy of olverembatinib, venetoclax and azacitidine was determined, and the efficacy and safety of the combined chemotherapy were evaluated.

Primary Endpoints Phase I: Determine the maximum tolerated dose of the combined chemotherapy of olverembatinib, venetoclax and azacitidine.

Phase II: Determine the complete hematological response rate (CHR) after 2 courses of treatment.

• Study Type: Interventional
• Enrollment (Estimated): 29
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Hui Wei, MD; Phone Number: 13132507161; Email: weihui@ihcams.ac.cn

Study Locations

• China
  • Tianjin
    • Tianjin, Tianjin, China, 300020
      • Recruiting
      • Blood Diseases Hospital
      • Contact: hui wei, MD; Phone Number: 86-13132507161; Email: weihui@ihcams.ac.cn

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Patients with t(9;22)(q34;q11)/BCR::ABL1 positive blast-phase CML who are aged 15 years or older, whether initially in the blast phase or progressing from the chronic phase, with no gender restriction.

   Blast phase criteria: Conforming to the 2022 WHO criteria for CML Blast phase: bone marrow or peripheral blood blast cells ≥ 20%; for diagnosis of acute lymphoblastic transformation, if the immature lymphoblasts (determined by immunophenotype) ≥ 5% according to the ICC 2022 criteria; blast cell aggregation in bone marrow or extramedullary tissues.

2. ECOG performance status score ≤ 2.
3. Major organ function assessment criteria: Total bilirubin < 1.5×upper limit of normal (ULN), aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5×ULN; serum creatinine < 2×ULN; myocardial enzymes < 2×ULN; serum amylase ≤ 1.5×ULN; left ventricular ejection fraction (LEF) within the normal range on echocardiography.
4. Men and women of reproductive potential agree and adopt effective contraceptive measures.
5. The informed consent form is signed by the patient himself/herself or an immediate family member. Considering the patient's condition, if the patient's signature is not conducive to the control of the disease, the legal guardian or an immediate family member of the patient signs the informed consent form.

Exclusion Criteria:

1. Before group entry, other systemic anti-cancer treatments for acute transformation were received (excluding single-agent TKI, hormone, or hydroxyurea for reducing tumor burden before group entry, and single-agent olverembatinib ≤ 14 days)
2. Myocardial infarction occurred within 12 months before enrollment in this study; other clinically significant cardiac diseases (such as unstable angina, congestive heart failure, uncontrollable hypertension, uncontrollable arrhythmia, etc.)
3. Uncontrolled active severe infection
4. Known positive serum HIV
5. Acute pancreatitis occurred within 1 year before study screening, or a history of chronic pancreatitis
6. Uncontrolled hypertriglyceridemia (triglycerides > 450 mg/dL, i.e., 5.1 mmol/L) or hypercholesterolemia (total cholesterol (TC) ≥ 6.2 mmol/L)
7. Another malignancy diagnosed and treated within 5 years before diagnosis, or previously diagnosed with another malignancy with evidence of residual disease. Patients with non-melanoma skin cancer or any type of carcinoma in situ, if completely resected, should not be excluded
8. Pregnant or lactating women
9. Clinical manifestations of CNS leukemia or extramedullary infiltration
10. Uncontrolled diabetes, defined as glycated hemoglobin value > 7.5%. Patients with previously existing but well-controlled diabetes need not be excluded
11. Mental illness that may prevent the subject from completing treatment or providing informed consent
12. Other conditions considered unsuitable for this study by the investigator

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

Other: Olverembatinib Combined With Venetoclax and Azacitidine

Drug: Olverembatinib; induction therapy：40mg,QOD； consolidation maintenance therapy: If patients with CMR are reduced to 30mg.; Drug: Venetoclax; induction therapy：leverl 0: 100mg d-2; 200mg d-1; 400mg d1-14 leverl -1: 100mg d-2; 200mg d-1; 400mg d1-7 leverl 1: 100mg d-2; 200mg d-1; 400mg d1-21 consolidation maintenance therapy: 400mg d1-7; Drug: Azacitidine; induction therapy：75mg/m2/d, d1-7 consolidation maintenance therapy: 75mg/m2/d, d1-7

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
To determine the maximum tolerated dose of combination with olverembatinib, venetoclax and azacitidine	The standard "3+3" method is used to determine the maximum tolerated dose. There are 3 dose groups.	six weeks from day 1 of each course
Determine complete hematological response rate (CHR) after 2 courses	CHR is one of the evaluation criteria of treatment.	six weeks after day 1 of 2nd courses of the treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
overall survival (OS)	Used to evaluate all patients who enter clinical trials. From the date of entry into the trial until the date of patient death (including any cause) or last survival follow-up.	up to 2 years after the date of the last enrolled participants
Relapse-free survival (RFS)	Defined only for patients achieving CRc; measured from the date of achievement of remission until the date of hematologic relapse or death from any cause; patients not known to have relapsed or died at last follow-up are censored on the date they were last known to be alive	up to 2 years after the date of the last enrolled participants
Partial Cytogenetic Response（PCyR）	PCyR is an important clinical indicator for determining whether patients with CML are responding well to the treatment they are receiving.	up to 2 years
Complete Cytogenetic Response（CCyR）	It is another important indicator used to assess the response to treatment in patients with chronic myeloid leukemia (CML). In the CCyR state, the patient's bone marrow cells no longer detect any abnormal cells carrying the Philadelphia chromosome.	up to 2 years
Major Molecular Response（MMR）	When the test results show that the expression level of the BCR-ABL gene is reduced below a specific threshold, the patient is considered to have achieved MMR.	up to 2 years
Deep Molecular Response（DMR）	It is an advanced indicator to assess the response of patients with chronic myeloid leukemia (CML) to treatment. DMR indicates that the expression level of the BCR-ABL fusion gene has been reduced to a very low level, which usually indicates that the patient's disease is in a very stable controlled state with a low risk of recurrence.	up to 2 years
Therapeutic toxicity	This is a safety indicator and focuses on treatment-related toxicity.	up to 2 years after the date of the last enrolled participants

Collaborators and Investigators

• Sponsor: Institute of Hematology & Blood Diseases Hospital, China
• Investigators: Principal Investigator: Hui Wei, MD, Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College; Principal Investigator: Cheng Bing Liu, MD, Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College

Study record dates

Study Major Dates

• Study Start (Actual): January 26, 2025
• Primary Completion (Estimated): December 1, 2026
• Study Completion (Estimated): December 1, 2028

Study Registration Dates

• First Submitted: December 27, 2024
• First Submitted That Met QC Criteria: December 27, 2024
• First Posted (Actual): January 3, 2025

Study Record Updates

• Last Update Posted (Actual): May 30, 2025
• Last Update Submitted That Met QC Criteria: May 26, 2025
• Last Verified: December 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms; Chronic Disease; Disease Attributes; Neoplasms by Histologic Type; Hematologic Diseases; Neoplastic Processes; Leukemia, Myeloid; Bone Marrow Diseases; Leukemia; Myeloproliferative Disorders; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Cell Transformation, Neoplastic; Carcinogenesis; Blast Crisis; Antineoplastic Agents; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Venetoclax; Azacitidine
• Other Study ID Numbers: IIT2024090

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