Trial Title:
Comparison of VA (Venetoclax, Azacitidine), VACl (VA, Cladribine), VACh (VA, Chidamide), and Alternating VACl/VACh in Newly Diagnosed Acute Myeloid Leukemia
NCT ID:
NCT06532552
Condition:
Acute Myeloid Leukemia, Adult
Newly Diagnosed
Conditions: Official terms:
Leukemia
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Azacitidine
Venetoclax
Cladribine
Conditions: Keywords:
Venetoclax
Azacitidine
Cladribine
Chidamide
Study type:
Interventional
Study phase:
Phase 2
Overall status:
Recruiting
Study design:
Allocation:
Randomized
Intervention model:
Parallel Assignment
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Drug
Intervention name:
VACl
Description:
Azacitidine:75mg/m2 Subcutaneous daily for 7 days Venetoclax: orally once daily (100 mg
d1, 200mg d2, 400mg d3-21) Cladribine: 5mg/m2 IV over approximately 1 to 2 hours, daily
on days 1-3.
Arm group label:
VACl group
Other name:
Venetoclax+Azacitidine+Cladribine
Intervention type:
Drug
Intervention name:
VACh
Description:
Azacitidine: 75mg/m2 Subcutaneous daily for 7 days Venetoclax: orally once daily (100mg
d1, 200mg d2, 400mg d3-28) Chidamide: 10mg orally daily for 12 days
Arm group label:
VACh group
Other name:
Venetoclax+Azacitidine+Chidamide
Intervention type:
Drug
Intervention name:
VACl Alternating With VACh
Description:
VACl:
Azacitidine:75mg/m2 Subcutaneous daily for 7 days Venetoclax: orally once daily (100 mg
d1, 200mg d2, 400mg d3-21) Cladribine: 5mg/m2 IV over approximately 1 to 2 hours, daily
on days 1-3.
VACh:
Azacitidine: 75mg/m2 Subcutaneous daily for 7 days Venetoclax: orally once daily (100mg
d1, 200mg d2, 400mg d3-28) Chidamide: 10mg orally daily for 12 days
Arm group label:
VACl Alternating With VACh group
Other name:
Venetoclax+Azacitidine+Cladribine alternating with Venetoclax+Azacitidine+Chidamide
Intervention type:
Drug
Intervention name:
VA
Description:
Azacitidine: 75mg/m2 Subcutaneous (SC) daily for 7 days Venetoclax: orally once daily
(100mg d1, 200mg d2, 400mg d3-28).
Arm group label:
VA group
Other name:
Venetoclax+Azacitidine
Summary:
This prospective, multi-center, randomized, controlled Phase II study is to compare the
therapeutic efficacy and side effect of VACl (Venetoclax,Azacitidine,Cladribine)
alternating with VACh (Venetoclax,Azacitidine,Chidamide), VACl, VACh and VA in newly
diagnosed adult acute myeloid leukemia (AML) patients ineligible for intensive therapy or
declining. Cladribine is a purine analogue widely used in hematologic malignancies. The
monocytic leukemia stem cell is selective sensitivity to Cladribine. Chidamide, a newly
designed selective histone deacetylase inhibitor, could down regulate myeloid cell
leukaemia 1 (MCL1) expression in Venetoclax resistant AML cells. Chidamide or Cladribine
have synergistic anti-leukemia effects with VA through their unique mechanisms, which can
eradicate leukemia stem cells and prevent the occurrence of drug resistance.
Detailed description:
AML is a clonal myelopoietic stem cell disorder characterized by the accumulation of
neoplastic cells in the bone marrow and in the peripheral circulation. The median age of
AML patients is 68 years. Although intensive chemotherapy and allogeneic stem cell
transplant (allo-HSCT) are standard approaches for newly diagnosed patients, they are
associated with higher rates of treatment related complications and inferior outcomes in
older patients. Venetoclax, a newly orally available and selective B cell lymphoma-2
(BCL2) inhibitor, Venetoclax in combination with hypomethylation agents or cytarabine has
been approved by the Food and Drug Administration (FDA) for the treatment of patients
with newly diagnosed AML unfit for intensive chemotherapy. However, the emergence of
resistance to Venetoclax based combinations has become an important clinical dilemma.
Resistance to Venetoclax can be acquired through the up regulation of anti-apoptotic
proteins, such as myeloid cell leukaemia 1 (MCL1). Chidamide, a newly designed selective
histone deacetylase inhibitor, Chidamide could down Bregulate MCL1 expression in
Venetoclax resistant AML cells. Our experience showed that the Chidamide+VA could improve
the condition of R/R AML patients who are resistant to VA. Cladribine is a purine
analogue widely used in hematologic malignancies. It was demonstrated that addition of
Cladribine to the VA regimen increases eradication of primary AML containing monocytic
leukemia stem cell activity in both in vitro and in vivo preclinical models. Chidamide or
Cladribine have synergistic anti-leukemia effects with VA through their unique
mechanisms, which can eradicate leukemia stem cells and prevent the occurrence of drug
resistance, thereby increasing response rate, prolonging patient survival, reducing
recurrence, and improving prognosis without increasing treatment-related complications.
Therefore, this prospective, multi-center, randomized, controlled Phase II study is to
compare the therapeutic efficacy and side effect of VACl
(Venetoclax,Azacitidine,Cladribine) alternating with VACh
(Venetoclax,Azacitidine,Chidamide), VACl, VACh and VA in newly diagnosed adult AML
patients ineligible for intensive therapy or declining.
Criteria for eligibility:
Criteria:
Inclusion Criteria:
1. Subject must have confirmation of previously untreated AML by World Health
Organization (WHO) criteria. Prior therapy with hydroxyurea or a total dose of
cytarabine no more than 0.5g (for emergency use for stabilization) is allowed.
2. Subject must be≥18 years of age with at least one of the following conditions:
A)≥60 years of age; B) Congestive heart failure or documented cardiomyopathy with an
ejection fractions (EF)≤50%; C) Documented pulmonary disease with Diffusion Lung
capacity for CO (DLCO)≤65% or Forced Expiratory Volume in the first second
（FEV1）≤65%, or dyspnea at rest or requiring oxygen, or any pleural neoplasm or
uncontrolled lung neoplasm; D) On dialysis and age older than 60 years or
uncontrolled renal carcinoma; E) Liver cirrhosis Child B or C, or documented liver
disease with marked elevation of transaminases (>3 times normal values) and an age
older than 60 years, or any biliary tree carcinoma or uncontrolled liver carcinoma
or acute viral hepatitis; F) Active infection resistant to anti-infective therapy;
G) Current mental illness requiring psychiatric hospitalization,
institutionalization or intensive outpatient management, or current cognitive status
that produces dependence (as confirmed by the specialist) not controlled by the
caregiver; H) ECOG performance status≥3 not related to leukemia; I)Any other
comorbidity that the physician judges to be incompatible with conventional intensive
chemotherapy; J) The patient refused the conventional intensive chemotherapy.
3. Adequate organ function as defined below:
A)liver function (bilirubin≤2mg/dL, aspartate transaminase (AST) and/or alanine
transaminase (ALT)≤3 x ULN).
Unless liver enzyme abnormalities are determined by the treating MD and PI to be due
to leukemic infiltration.
B)kidney function (creatinine≤1.5xULN ).
4. A negative urine pregnancy test is required within 1 week for all women of
childbearing potential prior to enrolling on this trial.
5. Patient must have the ability to understand the requirements of the study and signed
informed consent. A signed informed consent by the patient or his legally authorized
representative is required prior to their enrollment on the protocol.
6. Patient must have a projected life expectancy of at least 12 weeks.
Exclusion Criteria:
1. Subject has a history of other malignancies prior to study entry, with the exception
of:
A) Adequately treated in situ carcinoma of the cervix uteri or carcinoma in situ of
breast; B) Basal cell carcinoma of the skin or localized squamous cell carcinoma of
the skin; C) Previous malignancy confined and surgically resected (or treated with
other modalities) with curative intent.
2. Subject has acute promyelocytic leukemia
3. Patient has known active central nervous syster (CNS) involvement with AML.
4. Subject has a white blood cell count> 25×10^9/L. (Hydroxyurea is permitted to meet
this criterion.)
5. Prior therapy with venetoclax, Cladribine, hypomethylating agents (HMAs), Chidamide
or Chimeric Antigen Receptor T cell therapy.
6. Subject has a malabsorption syndrome or other condition that precludes enteral route
of administration.
7. Subject is known to be positive for human immunodeficiency virus (HIV) (HIV testing
is not required.)
8. Subject has received strong and/or moderate CYP3A inducers within 7 days prior to
the initiation of study treatment.
9. Subject has consumed grapefruit, grapefruit products, Seville oranges (including
marmalade containing Seville oranges) or Starfruit within 3 days prior to the
initiation of study treatment.
10. Subject has a cardiovascular disability status of New York Heart Association
Class≥2. Class 2 is defined as cardiac disease in which patients are comfortable at
rest but ordinary physical activity results in fatigue, palpitations, dyspnea, or
anginal pain.
11. Subject has chronic respiratory disease that requires continuous oxygen, or
significant history of renal, neurologic, psychiatric, endocrinologic, metabolic,
immunologic, hepatic, cardiovascular disease, or any other medical condition that in
the opinion of the investigator would adversely affect his/her participating in this
study.
12. Subject exhibits evidence of other clinically significant uncontrolled systemic
infection requiring therapy (viral, bacterial or fungal).
13. Subject is known to be positive for hepatitis B or C infection with the exception of
those with an undetectable viral load within 3 months (Hepatitis B or C testing is
not required). Subjects with serologic evidence of prior vaccination to HBV [i.e.,
HBs Ag-, and anti-HBs+-] may participate)
Gender:
All
Minimum age:
18 Years
Maximum age:
N/A
Healthy volunteers:
No
Locations:
Facility:
Name:
The First Affliated Hospital of Soochow University
Address:
City:
Suzhou
Zip:
215006
Country:
China
Status:
Recruiting
Contact:
Last name:
Sheng-Li Xue, M.D.
Phone:
+8651267781139
Email:
slxue@suda.edu.cn
Start date:
July 29, 2024
Completion date:
August 1, 2028
Lead sponsor:
Agency:
The First Affiliated Hospital of Soochow University
Agency class:
Other
Collaborator:
Agency:
Jining Medical University
Agency class:
Other
Collaborator:
Agency:
Qilu Hospital of Shandong University
Agency class:
Other
Collaborator:
Agency:
The Affiliated Hospital of Qingdao University
Agency class:
Other
Collaborator:
Agency:
The First Affiliated Hospital of Anhui Medical University
Agency class:
Other
Collaborator:
Agency:
Tongji Hospital
Agency class:
Other
Collaborator:
Agency:
First Affiliated Hospital Bengbu Medical College
Agency class:
Other
Source:
The First Affiliated Hospital of Soochow University
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT06532552
