Trial Title:
Clinical Study Protocol for the Treatment of ND-AML and RR-AML With KMT2A Gene Abnormalities Using VHEA.
NCT ID:
NCT06328179
Condition:
Acute Myeloid Leukemia
Conditions: Official terms:
Leukemia
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Cytarabine
Etoposide
Venetoclax
Study type:
Interventional
Study phase:
N/A
Overall status:
Recruiting
Study design:
Allocation:
N/A
Intervention model:
Single Group Assignment
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Drug
Intervention name:
Venetoclax 100 mg d1,200 mg d2,400 mg d3-14;
Description:
VHEA -Induction Phase Regimen/Consolidation therapy after remission
Arm group label:
VHEA regimen in the treatment of ND-AML and RR-AML with MLL gene abnormalities.
Other name:
Homoharringtoine, HHT 2 mg/m2,qd,d1-7
Other name:
Etoposide 0.1 g,qd,d1-5
Other name:
Cytarabine 100 mg/m2,qd,d1-7
Summary:
This study is a clinical trial aimed at evaluating the efficacy and safety of the
VHEA(Venetoclax with Homoharringtonine,Etoposide,Cytarabine)regimen in the treatment of
newly diagnosed and relapsed/refractory acute myeloid leukemia (AML) with MLL gene
abnormalities.
This study includes the induction and consolidation phases of AML treatment.
Detailed description:
This study is a multicenter, single-arm, open-label clinical trial aimed at evaluating
the efficacy and safety of the VHEA(Venetoclax with
Homoharringtonine,Etoposide,Cytarabine)regimen in the treatment of newly diagnosed and
relapsed/refractory acute myeloid leukemia (AML) with MLL gene abnormalities.
Leukemia is a malignant tumor of the blood system that seriously endangers human health,
ranking among the top 10 in the mortality rate of malignant tumors in all age groups in
China. Acute myeloid leukemia (AML) is a malignant clonal blood system disease
originating from hematopoietic stem and progenitor cells, accounting for about 35% of
newly diagnosed leukemia cases each year and 80% of adult leukemia cases. The overall
prognosis is poor, with approximately 10-40% of newly diagnosed AML patients unable to
achieve CR, and over 50% of AML patients eventually relapse. Especially in AML with KMT2A
gene abnormalities, the conventional "3+7" chemotherapy regimen has a low remission rate
and a high relapse rate.
Chromosomal translocations include the Mixed Lineage Leukemia gene (MLL), also known as
the KMT2A gene, which produces various MLL fusion genes, including AF4, AF6, AF9, AF10,
ENL, ELL, and AF1q. Currently, more than 70 MLL fusion genes have been reported. MLL gene
abnormalities associated with leukemia account for 5% to 10% of all acute leukemias, and
MLL-related leukemia has a poor prognosis. There is currently no standard treatment
regimen for MLL-related AML with good efficacy. Current treatment options include
conventional chemotherapy, targeted epigenetic and DNA damage response therapies.
Conventional chemotherapy includes regimens composed of anthracyclines, cytarabine, and
etoposide, followed by consolidation therapy with allogeneic hematopoietic stem cell
transplantation, but the efficacy is still unsatisfactory.
Based on preliminary data from our institution, there have been a total of 30 cases of
AML with MLL gene abnormalities since 2016, accounting for approximately 12% of all AML
cases. Among these, 14 cases received initial induction chemotherapy using the standard
"3+7" regimen, with only 4 cases achieving complete remission (28.6%), 3 cases achieving
partial remission (21.4%), and 7 cases showing no response (50%). Five cases received
induction chemotherapy using a priming regimen, but none achieved remission.
Additionally, 11 patients either refused chemotherapy or sought treatment at other
hospitals, indicating that conventional chemotherapy regimens do not yield satisfactory
results in AML patients with MLL gene abnormalities. Therefore, it is of great clinical
significance to explore more effective chemotherapy regimens for MLL gene
abnormality-associated acute leukemia.
Venetoclax has demonstrated anti-tumor activity in various hematologic malignancies. In
November 2018, the U.S. Food and Drug Administration (FDA) approved the use of Venetoclax
in combination with hypomethylating agents (HMAs) or low-dose cytarabine for newly
diagnosed AML patients aged 75 years and older who are unfit for intensive chemotherapy.
According to the 2021 NCCN guidelines, Venetoclax in combination with HMAs or low-dose
cytarabine is an important treatment strategy for both newly diagnosed elderly AML
patients and relapsed/refractory AML patients who are not suitable for intensive
chemotherapy. Recent exploratory studies have also been conducted on the use of
Venetoclax in combination with hypomethylating therapy in newly diagnosed and
relapsed/refractory AML with KMT2A gene rearrangement. These studies found that
Venetoclax in combination with decitabine or azacitidine achieved an overall response
rate (ORR) of 83% and a complete response/complete response with incomplete hematologic
recovery (CR/CRi) of 75% in newly diagnosed AML with KMT2A gene rearrangement. However,
in relapsed/refractory AML with KMT2A rearrangement, the ORR and CR/CRi were only 17% and
8%, respectively.
Homoharringtonine (HHT) is widely used for the treatment of myeloid leukemia. HHT
promotes apoptosis and inhibits autophagy in CML cells by activating ERK phosphorylation
and inhibiting Akt phosphorylation. Bcl-2 protein is an apoptosis inhibitor that plays an
important regulatory role in cell apoptosis. NFκB is a nuclear transcription factor
present in cells that regulates κ immunoglobulin and has anti-apoptotic effects. HHT
significantly inhibits the expression of NFκB and Bcl-2 protein, ultimately leading to
cell apoptosis.
Venetoclax has been widely used in various hematological malignancies, but the short
duration of sustained remission and the occurrence of resistance are the main problems
currently. The mechanisms of Venetoclax resistance mainly include the activation of
selective dependence on the Bcl-2 anti-apoptotic protein family and kinase mutations,
among which other members of the Bcl-2 family, including BCL2-A1, MCL-1, and BCL-XL, have
been proven to be key factors leading to primary or acquired resistance to Venetoclax.
Recent studies have shown that Venetoclax has synergistic inhibition of AML cell
proliferation with Homoharringtonine, reduces mitochondrial membrane potential, promotes
AML cell apoptosis, and exhibits time-dependent and concentration-dependent effects.
Venetoclax with Homoharringtonine can synergistically promote apoptosis of AML cell lines
and primary cells by inhibiting the activation of the MAPK/ERK, PI3K/AKT, and P53
signaling pathways. Therefore, based on this, we propose that Venetoclax with
Homoharringtonine, Etoposide, and Cytarabine may be an effective treatment option for
newly diagnosed and relapsed/refractory AML with MLL gene abnormalities.
This study will include AML patients with newly diagnosed or relapsed refractory MALL
gene abnormalities. The VHEA regimen will be used for induction, followed by one
consolidation cycle after achieving CRh/CRi/MLFS. If patients have a PR/NR, VHEA will be
continued for induction therapy until disease remission. After achieving remission,
patients who are willing and meet the criteria will undergo transplantation. If
transplantation is not performed, consolidation chemotherapy will be continued until
disease progression.
Specific treatment plan: VHEA Venetoclax 100 mg d1,200 mg d2,400 mg d3-14;
homoharringtoine, HHT 2 mg/m2,qd,d1-7; Etoposide 0.1 g,qd,d1-5; Cytarabine 100
mg/m2,qd,d1-7
Criteria for eligibility:
Criteria:
Inclusion Criteria:
- Age between 18 and 60 years old;Eastern Cooperative Oncology Group (ECOG)
performance status score of 0 or 1.
- Expected survival time of at least 3 months.
- Does not meet any of the following criteria for severe heart, lung, liver, or kidney
disease:A) History of congestive heart failure requiring treatment, or ejection
fraction ≤ 50%, or presence of chronic stable angina;B) Lung diffusing capacity for
carbon monoxide (DLCO) ≤ 65%, or forced expiratory volume in one second (FEV1) ≤
65%;C) Moderate liver dysfunction, total bilirubin > 1.5 to ≤ 3.0 × upper limit of
normal (ULN);D) Creatinine clearance ≥ 30 mL/min to < 45 mL/min.
- No other significant contraindications to chemotherapy as determined by the
physician;
- Capable of understanding and willing to sign the informed consent form for this
study.
Exclusion Criteria:
- Presence of other malignancies;
- Underwent cardiac vascular intervention or stent placement within 12 months prior to
signing the informed consent, or history of myocardial infarction, unstable angina,
or other clinically significant cardiac disease;
- Uncontrolled active infection (including bacterial, fungal, or viral infection) and
visceral bleeding;
- Pregnant or lactating women;
- Participation in any other clinical study within 3 months prior to signing the
informed consent;
- Any other condition deemed unsuitable for participation in this study by the
investigator.
Gender:
All
Minimum age:
18 Years
Maximum age:
60 Years
Healthy volunteers:
No
Locations:
Facility:
Name:
The Affiliated Huaian No.1 People's Hospital of Nanjing Medical University(Huai'an First People's Hospital)
Address:
City:
Huai'an
Zip:
210000
Country:
China
Status:
Recruiting
Contact:
Last name:
Shandong Tao
Phone:
15252393900
Email:
TSD8884@126.com
Start date:
May 24, 2022
Completion date:
December 30, 2027
Lead sponsor:
Agency:
Huai'an First People's Hospital
Agency class:
Other
Collaborator:
Agency:
Zhenjiang First People's Hospital
Agency class:
Other
Collaborator:
Agency:
The First People's Hospital of Changzhou
Agency class:
Other
Collaborator:
Agency:
The Affiliated Hospital of Xuzhou Medical University
Agency class:
Other
Source:
Huai'an First People's Hospital
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT06328179