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.
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
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
Single group
Azacitidine
DrugGiven IV or SC
Biospecimen Collection
Procedure/SurgeryUndergo blood sample collection
Bone Marrow Aspiration
Procedure/SurgeryUndergo bone marrow aspiration and biopsy
Bone Marrow Biopsy
Procedure/SurgeryUndergo bone marrow aspiration and biopsy
Cladribine
DrugGiven IV
Cytarabine
DrugGiven SC
Echocardiography
Procedure/SurgeryUndergo ECHO
Lumbar Puncture
Procedure/SurgeryUndergo LP
Multigated Acquisition Scan
Procedure/SurgeryUndergo MUGA
Questionnaire Administration
Other interventionAncillary studies
Venetoclax
DrugGiven PO
Composite complete remission (CRc) rate
CRc is defined as achievement of complete remission (CR), CR with partial hematologic recovery (CRh) or CR with incomplete blood count recovery (CRi) after induction (or re-induction). The CRc rate will be computed on the safety set and presented with a point-estimate and exact binomial 95% confidence interval (CI). CRc will also be modeled with univariable logistic regressions, applied to the efficacy set, to determine if any baseline patient or disease feature is correlated with clinical response.
Overall response rate (ORR)
ORR will be defined as the proportion of evaluable participants who attain a partial remission (PR) or better (i.e., CR, CRh, CRi, morphologic leukemia-free state \[MLFS\], or PR) while on investigational treatment. ORR will be computed for both the safety set and the efficacy set and presented with a point estimate and exact binomial CI. ORR will also be modeled with univariable logistic regressions with baseline patient and disease features as predictors and results considered hypothesis-generating.
Overall survival (OS)
OS will be computed for both the safety set and the efficacy set, and estimated with the Kaplan-Meier method. Median OS and OS rates at common landmark times (e.g., 1 year, 2 years) will be estimated with 95% log-log CIs. For both sets, univariable Cox models will be fit to OS to assess the impact of baseline patient and disease features with results (i.e., unadjusted hazard ratios and Wald test p-values) considered hypothesis-generating. Median follow-up will utilize a patient's OS measurement and censoring status and be estimated using the reverse Kaplan-Meier method.
Event-free survival (EFS)
EFS will be measured from start of treatment to the earliest date of treatment failure, progressive disease, or death from any cause. EFS will be estimated for the efficacy set using the Kaplan-Meier method, with median EFS and EFS rates at common landmark times presented with 05% log-log CIs. EFS will be alternatively estimated upon assigning 1-day event times to participants who never achieve MLFS or better. Univariable Cox models will be fit to EFS to assess the impact of baseline patient and disease features with model results considered hypothesis-generating.
Duration of response (DOR)
DOR will be measured from the first date of documented hematologic response to the earliest of the following occurrences: hematologic relapse, disease progression (clinical or morphologic), or any-cause death. DOR will be estimated by the Kaplan-Meier method. Median DOR will be presented with a 95% log-log CI.
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OHSU Knight Cancer Institute
Lead sponsor
Oregon Health and Science University
Collaborator
AbbVie
Collaborator
