Trial Title:
Venetoclax in Combination With Cladribine and Cytarabine Alternating With Azacitidine Plus Venetoclax for the Treatment of Newly Diagnosed Monocytic AML and Active Signaling Mutated AML
NCT ID:
NCT06504459
Condition:
Acute Monocytic Leukemia
Acute Myeloid Leukemia
Conditions: Official terms:
Leukemia
Leukemia, Monocytic, Acute
Cytarabine
Azacitidine
2-chloro-3'-deoxyadenosine
Venetoclax
Cladribine
Study type:
Interventional
Study phase:
Phase 2
Overall status:
Not yet recruiting
Study design:
Allocation:
N/A
Intervention model:
Single Group Assignment
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Drug
Intervention name:
Azacitidine
Description:
Given IV or SC
Arm group label:
Treatment (venetoclax, cladribine, cytarabine, azacitidine)
Other name:
5 AZC
Other name:
5-AC
Other name:
5-Azacitidine
Other name:
5-Azacytidine
Other name:
5-AZC
Other name:
Azacytidine
Other name:
Azacytidine, 5-
Other name:
Ladakamycin
Other name:
Mylosar
Other name:
U-18496
Other name:
Vidaza
Intervention type:
Procedure
Intervention name:
Biospecimen Collection
Description:
Undergo blood sample collection
Arm group label:
Treatment (venetoclax, cladribine, cytarabine, azacitidine)
Other name:
Biological Sample Collection
Other name:
Biospecimen Collected
Other name:
Specimen Collection
Intervention type:
Procedure
Intervention name:
Bone Marrow Aspiration
Description:
Undergo bone marrow aspiration and biopsy
Arm group label:
Treatment (venetoclax, cladribine, cytarabine, azacitidine)
Intervention type:
Procedure
Intervention name:
Bone Marrow Biopsy
Description:
Undergo bone marrow aspiration and biopsy
Arm group label:
Treatment (venetoclax, cladribine, cytarabine, azacitidine)
Other name:
Biopsy of Bone Marrow
Other name:
Biopsy, Bone Marrow
Intervention type:
Drug
Intervention name:
Cladribine
Description:
Given IV
Arm group label:
Treatment (venetoclax, cladribine, cytarabine, azacitidine)
Other name:
2-CdA
Other name:
2CDA
Other name:
CdA
Other name:
Cladribina
Other name:
Leustat
Other name:
Leustatin
Other name:
Leustatine
Other name:
RWJ-26251
Intervention type:
Drug
Intervention name:
Cytarabine
Description:
Given SC
Arm group label:
Treatment (venetoclax, cladribine, cytarabine, azacitidine)
Other name:
.beta.-Cytosine arabinoside
Other name:
1-.beta.-D-Arabinofuranosyl-4-amino-2(1H)pyrimidinone
Other name:
1-.beta.-D-Arabinofuranosylcytosine
Other name:
1-Beta-D-arabinofuranosyl-4-amino-2(1H)pyrimidinone
Other name:
1-Beta-D-arabinofuranosylcytosine
Other name:
1.beta.-D-Arabinofuranosylcytosine
Other name:
2(1H)-Pyrimidinone, 4-Amino-1-beta-D-arabinofuranosyl-
Other name:
2(1H)-Pyrimidinone, 4-amino-1.beta.-D-arabinofuranosyl-
Other name:
Alexan
Other name:
Ara-C
Other name:
ARA-cell
Other name:
Arabine
Other name:
Arabinofuranosylcytosine
Other name:
Arabinosylcytosine
Other name:
Aracytidine
Other name:
Aracytin
Other name:
Aracytine
Other name:
Beta-Cytosine Arabinoside
Other name:
CHX-3311
Other name:
Cytarabinum
Other name:
Cytarbel
Other name:
Cytosar
Other name:
Cytosine Arabinoside
Other name:
Cytosine-.beta.-arabinoside
Other name:
Cytosine-beta-arabinoside
Other name:
Erpalfa
Other name:
Starasid
Other name:
Tarabine PFS
Other name:
U 19920
Other name:
U-19920
Other name:
Udicil
Other name:
WR-28453
Intervention type:
Procedure
Intervention name:
Echocardiography
Description:
Undergo ECHO
Arm group label:
Treatment (venetoclax, cladribine, cytarabine, azacitidine)
Other name:
EC
Intervention type:
Procedure
Intervention name:
Lumbar Puncture
Description:
Undergo LP
Arm group label:
Treatment (venetoclax, cladribine, cytarabine, azacitidine)
Other name:
LP
Other name:
Spinal Tap
Intervention type:
Procedure
Intervention name:
Multigated Acquisition Scan
Description:
Undergo MUGA
Arm group label:
Treatment (venetoclax, cladribine, cytarabine, azacitidine)
Other name:
Blood Pool Scan
Other name:
Equilibrium Radionuclide Angiography
Other name:
Gated Blood Pool Imaging
Other name:
Gated Heart Pool Scan
Other name:
MUGA
Other name:
MUGA Scan
Other name:
Multi-Gated Acquisition Scan
Other name:
Radionuclide Ventriculogram Scan
Other name:
Radionuclide Ventriculography
Other name:
RNVG
Other name:
SYMA Scanning
Other name:
Synchronized Multigated Acquisition Scanning
Intervention type:
Other
Intervention name:
Questionnaire Administration
Description:
Ancillary studies
Arm group label:
Treatment (venetoclax, cladribine, cytarabine, azacitidine)
Intervention type:
Drug
Intervention name:
Venetoclax
Description:
Given PO
Arm group label:
Treatment (venetoclax, cladribine, cytarabine, azacitidine)
Other name:
ABT-0199
Other name:
ABT-199
Other name:
ABT199
Other name:
GDC-0199
Other name:
RG7601
Other name:
Venclexta
Other name:
Venclyxto
Summary:
This phase II trial tests how well venetoclax with cladribine and cytarabine alternating
with azacitidine and venetoclax works in treating patients with newly diagnosed monocytic
acute myeloid leukemia (AML) and active signaling mutated AML. Venetoclax is in a class
of medications called B-cell lymphoma-2 (BCL-2) inhibitors. It may stop the growth of
cancer cells by blocking BCL-2, a protein needed for cancer cell survival. Chemotherapy
drugs, such as cladribine, cytarabine and azacitidine, work in different ways to stop the
growth of cancer cells, either by killing the cells, by stopping them from dividing, or
by stopping them from spreading. Giving venetoclax with cladribine and cytarabine
alternating with azacitidine and venetoclax may kill more cancer cells in patients with
newly diagnosed monocytic AML and active signaling mutated AML.
Detailed description:
PRIMARY OBJECTIVE:
I. Assess efficacy of the investigational treatment based on disease remission.
SECONDARY OBJECTIVES:
I. Assess efficacy of the investigational treatment based on clinical response. II.
Assess any-cause survival after treatment. III. Assess survival in the absence of
treatment failure, hematologic relapse, or progressive disease.
IV. Assess duration of response, based on morphological assessments. V. Assess the safety
and tolerability of the regimen.
EXPLORATORY OBJECTIVES:
I. Assess response based on measurable residual disease (MRD). II. Identify markers of
clonal or clinical response and resistance to treatment.
III. Assess participant quality of life (QoL) using Patient Reported Outcomes Common
Terminology Criteria for Adverse Events (PRO CTCAE).
OUTLINE:
INDUCTION: Patients receive cladribine intravenously (IV) over 1-2 hours on days 1-5,
cytarabine subcutaneously (SC) twice daily (BID) on days 1-10, and venetoclax orally (PO)
once daily (QD) on days 1-21 of cycle 1.
RE-INDUCTION: Patients with > 5% blasts after cycle 1 receive cladribine IV over 1-2
hours on days 1-5, cytarabine SC BID on days 1-10, and venetoclax PO QD on days 1-21 of
cycle 2.
REMISSION AFTER INDUCTION: Patients who achieve complete remission (CR)/CR with partial
hematologic recovery/CR with incomplete blood count recovery/morphologic leukemia-free
state (MLFS) after cycle 1 of induction, receive cladribine IV over 1-2 hours on days
1-3, cytarabine SC BID on days 1-10 and venetoclax PO QD on days 1-21 of cycle 2.
CONTINUING THERAPY: Patients who achieve MLFS receive venetoclax PO QD on days 1-21 and
azacitidine IV or SC QD on days 1-7 for 2 cycles then cladribine IV over 1-2 hours on
days 1-3, cytarabine SQ BID on days 1-10 and venetoclax PO QD on days 1-21 for 2 cycles.
Cycles repeat every 28 days and continue to alternate every 2 cycles for up to cycle 18
in the absence of disease progression or unacceptable toxicity.
Additionally, patients undergo echocardiography (ECHO) or multigated acquisition scan
(MUGA) and lumbar puncture (LP) during screening and as clinically indicated on study.
Patients also undergo bone marrow aspiration and biopsy and blood sample collection
throughout the study.
At completion of study treatment, patients are followed up for 2 years.
Criteria for eligibility:
Criteria:
Inclusion Criteria:
- Ability to comprehend the investigational nature of the study and provide informed
consent (i.e., participant or legally authorized representative [LAR]). Written
informed consent must be obtained prior to any study-specific procedures or
interventions
- Eligible AML patients of all races and ethnic groups will be considered for
participation, irrespective of gender identity
- Newly diagnosed, histologically confirmed monocytic AML, as defined by World Health
Organization (WHO), or active signaling mutated AML defined as AML with mutation(s)
to N/KRAS, FLT3 ITD/TKD, NF1, PTPN11 or CBL
- Ineligible for standard of care induction therapy using intensive chemotherapy (IC)
or unwilling to undergo IC induction therapy. Ineligible for IC is defined as
- ≥ 75 yrs of age; OR
- 18-74 yrs of age with one of the following:
- Eastern Cooperative Oncology Group (ECOG) performance status of ≥ 2 at
screening
- Severe cardiac disorder (e.g., congestive heart failure requiring
treatment, ejection fraction ≤ 50%, or chronic stable angina)
- Severe pulmonary disorder (e.g., diffuse capacity of the lung for carbon
monoxide [DLCO] ≤ 65% or forced expiratory volume in 1 second [FEV1] ≤
65%)
- Creatinine clearance < 45 ml/min (calculated by the Cockcroft-Gault
equation)
- Hepatic disorder with total bilirubin > 1.5 x upper limit of normal (ULN)
- Any other comorbidity that the treating physician judges to be
incompatible with IC
- If ≥ 75 yrs of age, the following organ function values must be met and ECOG must be
0 to 2 at screening:
- Creatinine clearance (calculated with the Cockcroft-Gault equation) ≥ 30 ml/min
- Total bilirubin ≤ 1.5 x upper limit of normal (ULN) (Unless due to leukemic
infiltration)
- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
[SGOT]) or alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase
[SGPT]) ≤ 3 x ULN (Unless due to leukemic infiltration) (With the exception of
documented Gilbert's syndrome or similar conditions. Liver function testing
(LFT) and timepoints may be added, as clinically indicated, in such cases)
- Note: In cases of confirmed leukemic organ involvement, exceptions may be
made
- Willing and able to provide bone marrow (BM) samples, including BM samples for
research use only analysis
- Willing and able to accept supportive and prophylactic care for hematologic
toxicities, infection, and immediate sequalae
- Willingness to adhere to (a) study schedule of activities; (b) requirements for bio
samples collections; and (b) lifestyle restrictions while on-treatment
- Negative urine pregnancy test at screening and within 24 hours of cycle 1 day 1
(C1D1) for persons of childbearing potential (PCBP). Serum pregnancy testing will be
used for confirmation in cases of equivocal results. Pregnancy is exclusionary
because the agents used in this study have the potential for teratogenic or
abortifacient effects
- Willingness to comply with study requirements for contraception within the specified
timeframe, as follows:
- Sperm producing participants who are active with PCBP must use approved
contraception from C1D1 to 30 days, 3 months, or 6 months, after the last dose
of venetoclax (30 days), azacitidine (3 months), cladribine (6 months), or
cytarabine (6 months), whichever is later in time
- PCBP who are sexually active with sperm-producing persons must use
contraception from C1D1 to 30 days after the last dose of venetoclax or to 6
months after the last dose of azacitidine, cladribine, or cytarabine, whichever
is later in time
Exclusion Criteria:
- Symptomatic central nervous system involvement with AML
- Prior treatment for AML, with the exception of cytoreduction for proliferative
disease (per institutional protocol) with any of the following: Hydroxyurea,
hematopoietic growth factors, leukapheresis
- Another active malignancy within the previous 5 years of C1D1
- Investigational therapy within 28 days of C1D1, or within 5 half-lives or longer, if
known
- Recent and significant medical interventions, such as major surgery within 28 days
or stem cell transplant within 100 days (and without active treatment for graft
versus host disease [GVHD]) of C1D1. Standard of care procedures for patients with
hematologic malignancies, such as biopsies and lumbar punctures, are not
exclusionary
- Hypersensitivity to any of the components of the investigational regimen (i.e.,
cladribine, cytarabine, venetoclax, azacitidine) or any excipients in the
formulations
- Treatment based on agents targeting or inhibiting BCL-2 (for other, prior
indication/malignancy) within the previous 5 years
- History of dysphagia, short-gut syndrome, gastroparesis, or other conditions that
limit the ingestion or gastrointestinal absorption of drugs administered orally
- Use of drugs with documented drug-drug interaction toxicities with the study drugs
- Strong or moderate CYP3A4 inducers or inhibitors within 2 days or 3 half lives
whichever is longer, prior to C1D1 are exclusionary. Dose adjustments and other
modifications may be considered if the wash-out period has not been met, with
the approval of the investigator and the research pharmacy
- Uncontrolled infection. Participants with controlled infection must be afebrile and
hemodynamically stable for at least 72 hours prior to C1D1 and must be amenable to
alternate treatment if current treatment will interact with investigational regimen
- Active infection with hepatitis B virus (HBV) or hepatitis C virus (HCV). Enrollment
of individuals with evidence of chronic HBV or HCV infection will be considered on a
case-by-case basis by the principal investigator
- Individuals with serology positive for human immunodeficiency virus (HIV) and under
active treatment with highly active antiretroviral therapy (HAART) (or another
therapy that may interfere with metabolism of study agents)
- Pregnancy at enrollment or unwillingness to stop breastfeeding. Because there is a
potential risk for adverse events in nursing infants secondary to treatment of the
mother with the chemotherapy agents, breastfeeding be discontinued from start of
treatment until 1 week after the final dose of any study drug
- Uncontrolled intercurrent illness including, but not limited to ongoing or active
uncontrolled infection, unstable cardiac or pulmonary function or acute
insufficiency (e.g., symptomatic congestive heart failure, unstable angina pectoris,
cardiac arrhythmia), or psychiatric illness or social situation that could limit
compliance with study requirements
Gender:
All
Minimum age:
18 Years
Maximum age:
N/A
Healthy volunteers:
No
Locations:
Facility:
Name:
OHSU Knight Cancer Institute
Address:
City:
Portland
Zip:
97239
Country:
United States
Contact:
Last name:
Curtis A. Lachowiez
Phone:
503-494-6157
Email:
lachowie@ohsu.edu
Investigator:
Last name:
Curtis A. Lachowiez
Email:
Principal Investigator
Start date:
October 31, 2024
Completion date:
May 1, 2028
Lead sponsor:
Agency:
OHSU Knight Cancer Institute
Agency class:
Other
Collaborator:
Agency:
Oregon Health and Science University
Agency class:
Other
Collaborator:
Agency:
AbbVie
Agency class:
Industry
Source:
OHSU Knight Cancer Institute
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT06504459
