Ignite Creation Date:
2024-10-26 @ 3:36 PM
Last Modification Date:
2024-10-26 @ 3:36 PM
Study NCT ID:
NCT06536010
Status:
RECRUITING
Last Update Posted:
None
First Post:
2024-07-29
Brief Title:
Clinical Trial Protocol for the Combined Use of VAG in the Treatment of ND-AML
Sponsor:
None
Organization:
None
Study Overview
Official Title:
Clinical Trial Protocol for the Combined Use of Azacitidine Venetoclax and Granulocyte Colony-Stimulating Factor in the Treatment of Newly Diagnosed Acute Myeloid Leukemia AML Phase IIb Single-arm Prospective Single-center Study
Status:
RECRUITING
Status Verified Date:
2024-07
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
No
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
This is a clinical efficacy study evaluating the VAG regimen in the treatment of newly diagnosed acute myeloid leukemia AML
The main objectives of the study are to assess the efficacy and safety of the VAG regimen and to explore the synergistic mechanisms of VAG in combating AML
The main objectives of the study are to assess the efficacy and safety of the VAG regimen and to explore the synergistic mechanisms of VAG in combating AML
Detailed Description:
This study is a single-arm prospective single-center phase IIb clinical efficacy study evaluating the therapeutic effects of azacitidine and venetoclax in combination with granulocyte colony-stimulating factor for the treatment of newly diagnosed acute myeloid leukemia AML
Acute myeloid leukemia AML is a malignant disease originating from myeloid hematopoietic stemprogenitor cells It is highly aggressive and patients have a very low survival rate The 5-year survival rate for diagnosed AML patients is approximately 29 with only 5-15 for patients aged 60 and above Currently the 37 regimen is the first-line induction chemotherapy for newly diagnosed AML patients with about 60-80 of young patients 60 years old and 40-60 of elderly patients 60 years old achieving complete remission CR However among AML patients receiving the 37 regimen those with poor physical condition or high-risk cytogenetics have a worse prognosis Therefore there is a need to explore new treatment regimens that are less intensive but still effective
Venetoclax is an oral selective Bcl-2 inhibitor Multiple studies and clinical trials have demonstrated that Venetoclax in combination with demethylating agents or low-dose cytarabine LDAC has synergistic anti-tumor effects and achieves higher treatment response and disease-free survival rates in AML patients The results of the VIALE-A study showed that the median overall survival OS time with Venetoclax plus Azacitidine AZA was 147 months compared to 96 months with Azacitidine alone P0001 The median duration of remission was 175 months with Venetoclax plus Azacitidine compared to 134 months with Azacitidine alone and the CRCRi rates were 664 and 283 respectively P0001 This combination significantly improves the overall survival of AML patients with high response rates and good safety profile In October 2020 the US Food and Drug Administration approved the use of Venetoclax in combination with Azacitidine Decitabine or LDAC for the treatment of newly diagnosed AML patients aged 75 years or older or those who are unfit for intensive induction chemotherapy due to comorbidities The Venetoclax plus Azacitidine regimen was also included in the AML NCCN guidelines in 2020 However while Venetoclax in combination with demethylating agents is recommended for the treatment of elderly AML patients there is currently a lack of research data for its use in young AML patients The results of a phase II clinical trial presented at the 2022 ASH Annual Meeting evaluating Venetoclax plus hypomethylating agents in young adults with newly diagnosed AML and adverse ELN risk showed a complete remission with incomplete hematologic recovery CRc rate of 78 after one cycle of treatment with a minimal residual disease MRD negativity rate of 77 After two cycles of treatment the CRc rate was 919 with an MRD negativity rate of 823 The CRc rates for favorable intermediate and adverse risk groups were 696 754 and 613 respectively Although the combination of Venetoclax and demethylating agents has shown promising efficacy there are still limitations such as adverse events including thrombocytopenia 46 nausea 44 constipation 43 neutropenia 42 febrile neutropenia 42 diarrhea 41 and tumor lysis syndrome TLS as well as suboptimal achievement of MRD negativity and depth of remission after induction therapy
Granulocyte colony-stimulating factor G-CSF is expressed by almost all AML cells and binds to its receptor G-CSFR In pre-activation regimens G-CSF induces tumor cells in the quiescent phase G0G1 to enter the proliferative phase S phase enhancing the cytotoxic effect of chemotherapy drugs on tumor cells improving the efficacy of chemotherapy and reducing adverse reactions A study conducted by Tang Xiaowens team at the First Affiliated Hospital of Soochow University on the efficacy and safety of decitabine DAC combined with HAAG in the treatment of newly diagnosed acute myeloid leukemia showed that after one cycle of DACHAAG induction therapy in 50 patients 48 patients 96 achieved complete remission CRCR with incomplete blood count recovery CRpCR with incomplete count recovery and incomplete marrow recovery CRi and 2 patients 4 achieved partial remission PR The median time to recovery of white blood cell count platelet count and hemoglobin was 175 days 190 days and 200 days respectively Only 16 850 and 6 350 of patients experienced grade 3-4 infections and bleeding while non-hematologic toxicities were mainly grade 1-2 and resolved after symptomatic treatment
The combination of venetoclax and hypomethylating agents is the most common approach which synergistically induces cell apoptosis and reduces MCL-1 levels thereby overcoming resistance to BCL-2 inhibitors Additionally the combination interferes with the energy metabolism of leukemia cells and targets leukemia stem cells However there is currently no research on the combination of azacitidine venetoclax and G-CSF The investigators has conducted a preliminary clinical study on the VAG regimen azacitidine venetoclax and granulocyte colony-stimulating factor for newly diagnosed AML which has shown promising results We plan to expand the sample size and further investigate its mechanism of tumor cell killing
Acute myeloid leukemia AML is a malignant disease originating from myeloid hematopoietic stemprogenitor cells It is highly aggressive and patients have a very low survival rate The 5-year survival rate for diagnosed AML patients is approximately 29 with only 5-15 for patients aged 60 and above Currently the 37 regimen is the first-line induction chemotherapy for newly diagnosed AML patients with about 60-80 of young patients 60 years old and 40-60 of elderly patients 60 years old achieving complete remission CR However among AML patients receiving the 37 regimen those with poor physical condition or high-risk cytogenetics have a worse prognosis Therefore there is a need to explore new treatment regimens that are less intensive but still effective
Venetoclax is an oral selective Bcl-2 inhibitor Multiple studies and clinical trials have demonstrated that Venetoclax in combination with demethylating agents or low-dose cytarabine LDAC has synergistic anti-tumor effects and achieves higher treatment response and disease-free survival rates in AML patients The results of the VIALE-A study showed that the median overall survival OS time with Venetoclax plus Azacitidine AZA was 147 months compared to 96 months with Azacitidine alone P0001 The median duration of remission was 175 months with Venetoclax plus Azacitidine compared to 134 months with Azacitidine alone and the CRCRi rates were 664 and 283 respectively P0001 This combination significantly improves the overall survival of AML patients with high response rates and good safety profile In October 2020 the US Food and Drug Administration approved the use of Venetoclax in combination with Azacitidine Decitabine or LDAC for the treatment of newly diagnosed AML patients aged 75 years or older or those who are unfit for intensive induction chemotherapy due to comorbidities The Venetoclax plus Azacitidine regimen was also included in the AML NCCN guidelines in 2020 However while Venetoclax in combination with demethylating agents is recommended for the treatment of elderly AML patients there is currently a lack of research data for its use in young AML patients The results of a phase II clinical trial presented at the 2022 ASH Annual Meeting evaluating Venetoclax plus hypomethylating agents in young adults with newly diagnosed AML and adverse ELN risk showed a complete remission with incomplete hematologic recovery CRc rate of 78 after one cycle of treatment with a minimal residual disease MRD negativity rate of 77 After two cycles of treatment the CRc rate was 919 with an MRD negativity rate of 823 The CRc rates for favorable intermediate and adverse risk groups were 696 754 and 613 respectively Although the combination of Venetoclax and demethylating agents has shown promising efficacy there are still limitations such as adverse events including thrombocytopenia 46 nausea 44 constipation 43 neutropenia 42 febrile neutropenia 42 diarrhea 41 and tumor lysis syndrome TLS as well as suboptimal achievement of MRD negativity and depth of remission after induction therapy
Granulocyte colony-stimulating factor G-CSF is expressed by almost all AML cells and binds to its receptor G-CSFR In pre-activation regimens G-CSF induces tumor cells in the quiescent phase G0G1 to enter the proliferative phase S phase enhancing the cytotoxic effect of chemotherapy drugs on tumor cells improving the efficacy of chemotherapy and reducing adverse reactions A study conducted by Tang Xiaowens team at the First Affiliated Hospital of Soochow University on the efficacy and safety of decitabine DAC combined with HAAG in the treatment of newly diagnosed acute myeloid leukemia showed that after one cycle of DACHAAG induction therapy in 50 patients 48 patients 96 achieved complete remission CRCR with incomplete blood count recovery CRpCR with incomplete count recovery and incomplete marrow recovery CRi and 2 patients 4 achieved partial remission PR The median time to recovery of white blood cell count platelet count and hemoglobin was 175 days 190 days and 200 days respectively Only 16 850 and 6 350 of patients experienced grade 3-4 infections and bleeding while non-hematologic toxicities were mainly grade 1-2 and resolved after symptomatic treatment
The combination of venetoclax and hypomethylating agents is the most common approach which synergistically induces cell apoptosis and reduces MCL-1 levels thereby overcoming resistance to BCL-2 inhibitors Additionally the combination interferes with the energy metabolism of leukemia cells and targets leukemia stem cells However there is currently no research on the combination of azacitidine venetoclax and G-CSF The investigators has conducted a preliminary clinical study on the VAG regimen azacitidine venetoclax and granulocyte colony-stimulating factor for newly diagnosed AML which has shown promising results We plan to expand the sample size and further investigate its mechanism of tumor cell killing
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None