NCT06757855

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

• Status: Recruiting
• Phase: Phase 1 / Phase 2
• Study type: Interventional
• Enrollment: 29 (estimated)
• Sponsor: Institute of Hematology & Blood Diseases Hospital, China · Academic / Other
• Sex: All
• Age: 15 Years
• Healthy volunteers: Not accepted

Summary

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.

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.

Conditions

• CML,Blast Phase

Interventions

Type	Name	Description
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

Timeline

• Start date: 2025-01-26
• Primary completion: 2026-12-01
• Completion: 2028-12-01
• First posted: 2025-01-03
• Last updated: 2025-05-30

Locations

1 site across 1 country: China