Gemtuzumab Ozogamicin With G-CSF, Cladribine, Cytarabine & Mitoxantrone for Untreated AML & High-Grade Myeloid Neoplasm

A two-stage design will be used to evaluate the EFS. Patients treated at the maximum tolerated dose (MTD) from the phase 1 portion of the trial will be used in the phase 2 analysis. If censoring occurs, secondary analyses analyzing 6-month or 1-year EFS accounting for censoring will be done, including estimating 6-month or 1-year EFS using the Kaplan-Meier method. The first stage of the two-stage phase 2 design will evaluate 30 patients. If 20 or more of the first 30 patients are alive without event at 6-months after study registration, an additional 30 patients will be enrolled. If 46 or more of the 60 patients treated at the MTD are alive and without event at 6-months after study registration, the study will consider the regimen of interest for further investigation. Patients last known to be alive in CR were censored at date of last contact.

Time frame: From the start of study treatment, assessed at 6 months and 1 year

Population: GO1 participants were treated in dose escalation. The primary endpoint per protocol is to assess the EFS rate at the MTD or RP2D and was not assessed at dose levels below the RP2D.

Defined as the highest dose studied in which the incidence of Dose Limiting Toxicity (DLT) is ≤33% (≤4 of 12 patients experiencing DLT), defined as any Grade 3 non-hematologic toxicity lasting \>48 hours that results in \>7-day delay of the subsequent treatment cycle, with the exception of febrile neutropenia or infection or toxicities secondary to febrile neutropenia or infection, or any Grade ≥4 non-hematologic toxicity except febrile neutropenia/infection (or toxicities secondary to febrile neutropenia or infection) unless felt to be a direct consequence of treatment-related toxicity (e.g. intestinal infection following mucosal barrier breakdown), and with the exception of constitutional symptoms if recovery to Grade ≤2 within 14 days. The National Cancer Institute Common Terminology Criteria for Adverse Events v5.0 will be used.

Time frame: At time of count recovery, second cycle of treatment, response assessment or removal from protocol (at approximately 1 month).

As a summary of adverse events (captured on trial using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0), 30-day all cause mortality is reported as a percent of patients treated at the MTD/RP2D. Will be estimated and 95% confidence intervals will be calculated. Regression models (logistic regression for binary endpoints, Cox regression for time-to-event endpoints \[Cox models for the hazard of the subdistribution for events with competing risks\]) will be used to compare outcomes with patients who have received GCLAM without GO at our institution, controlling for measured prognostic factors.

Time frame: Up to 5 years. 30-day all-cause mortality is reported

Population: 30-day mortality is reported among patients treated at the MTD/RP2D. There is no study-related reason to report survival data on the GO1 dose level. No efficacy assessments were evaluated during the GO1 phase 1 dose escalation study which focuses on DLT/toxicity assessments.

Will be estimated and 95% confidence intervals will be calculated. Regression models (logistic regression for binary endpoints, Cox regression for time-to-event endpoints \[Cox models for the hazard of the subdistribution for events with competing risks\]) will be used to compare outcomes with patients who have received GCLAM without GO at our institution, controlling for measured prognostic factors. o Aplasia rate is defined in this protocol as frequency of patients without blood count recovery after chemotherapy and bone marrow examination showing hypocellularity not meeting cellularity criteria for morphologic leukemia free state (MLFS). MRD negative (MRDneg) status is defined as negative for leukemic markers by multiparameter flow cytometry. Aplasia was defined as absence of tumoral cells but cellularity not meeting criteria for MLFS. Statistical significance tests were not performed.

Time frame: 90 days

Will be estimated and 95% confidence intervals will be calculated. Regression models (logistic regression for binary endpoints, Cox regression for time-to-event endpoints \[Cox models for the hazard of the subdistribution for events with competing risks\]) will be used to compare outcomes with patients who have received GCLAM without GO at our institution, controlling for measured prognostic factors. Complete response (CR) + complete response with incomplete hematologic recovery (CRi) rate is defined as the frequency of patients achieving CR or CRi per the European LeukemiaNet 2017 criteria as defined above. MRD negative (MRDneg) status is defined as negative for leukemic markers by multiparameter flow cytometry. Aplasia was defined as absence of tumoral cells but cellularity not meeting criteria for MLFS. Statistical significance tests were not performed.

Time frame: 90 days

Population: GO1: remission rates for 6 patients: CR rate was 4/6, CR+CRi rate was 5/6 (all MRDneg)

Will be estimated and 95% confidence intervals will be calculated. Regression models (logistic regression for binary endpoints, Cox regression for time-to-event endpoints \[Cox models for the hazard of the subdistribution for events with competing risks\]) will be used to compare outcomes with patients who have received GCLAM without GO at our institution, controlling for measured prognostic factors. Complete response with incomplete hematologic recovery (CRi) rate is defined as the frequency of patients achieving CRi, which is defined by the European LeukemiaNet 2017 guidelines as all CR criteria except for residual neutropenia (ANC \<1.0 x 109/L \[1000/mL\]) or thrombocytopenia (platelet count \<100 x 109/L \[100,000/mL\]). MRD negative (MRDneg) status is defined as negative for leukemic markers by multiparameter flow cytometry. Aplasia was defined as absence of tumoral cells but cellularity not meeting criteria for MLFS. Statistical significance tests were not performed.

Time frame: 90 days

Will be estimated and 95% confidence intervals will be calculated. Regression models (logistic regression for binary endpoints, Cox regression for time-to-event endpoints \[Cox models for the hazard of the subdistribution for events with competing risks\]) will be used to compare outcomes with patients who have received GCLAM without GO at our institution, controlling for measured prognostic factors. Morphologic leukemia free state (MLFS) rate is defined as the frequency of patients achieving MLFS, which is defined by the European LeukemiaNet guidelines as bone marrow blasts \<5%; absence of blasts with Auer rods; absence of extramedullary disease; no hematologic recovery required. At least 200 cells should be enumerated or cellularity should be at least 10%. MRD negative (MRDneg) status is defined as negative for leukemic markers by multiparameter flow cytometry. Aplasia was defined as absence of tumoral cells but cellularity not meeting criteria for MLFS. Statistical significance

Time frame: 90 days

Will be estimated and 95% confidence intervals will be calculated. Regression models (logistic regression for binary endpoints, Cox regression for time-to-event endpoints \[Cox models for the hazard of the subdistribution for events with competing risks\]) will be used to compare outcomes with patients who have received GCLAM without GO at our institution, controlling for measured prognostic factors. Complete response (CR) rate is defined as the frequency of patients achieving CR, which is defined by the European LeukemiaNet 2017 guidelines as bone marrow blasts \<5%; absence of circulating blasts and blasts with Auer rods; absence of extramedullary disease; ANC ≥1.0 x 109/L (1000/mL); platelet count ≥100 x 109/L. (100 000/mL). MRD negative (MRDneg) status is defined as negative for leukemic markers by multiparameter flow cytometry. Aplasia was defined as absence of tumoral cells but cellularity not meeting criteria for MLFS. Statistical significance tests were not performed.

Time frame: 90 days

OS was calculated for all participants and measured from initial trial therapy to death from any cause. Patients last known ot be alive were censored at date of last contact. Will be estimated using the Kaplan-Meier method. Regression models (logistic regression for binary endpoints, Cox regression for time-to-event endpoints \[Cox models for the hazard of the subdistribution for events with competing risks\]) will be used to compare outcomes with patients who have received GCLAM without GO at our institution, controlling for measured prognostic factors.

Time frame: 3 years and 1 month

Population: RFS is reported among patients treated at the MTD/RP2D. There is no study-related reason to report survival data on the GO1 dose level. No efficacy assessments were evaluated during the GO1 phase 1 dose escalation study which focuses on DLT/toxicity assessments.

RFS was calculated for participants who achieved a complete remission (with or without count recovery; CR or CRi) and measured from the date remission to the first of relapse from CR/CRi or death from any cause. Patients last known to be alive in CR /CRi were censored at date of last contact. Will be estimated using the Kaplan-Meier method. Time to relapse will be estimated using non-parametric estimates of the cumulative incidence curve with death analyzed as a competing event. Regression models (logistic regression for binary endpoints, Cox regression for time-to-event endpoints \[Cox models for the hazard of the subdistribution for events with competing risks\]) will be used to compare outcomes with patients who have received GCLAM without GO at our institution, controlling for measured prognostic factors.

Time frame: Up to 5 years. 2-year RFS reported.

Population: RFS is reported among patients treated at the MTD/RP2D. There is no study-related reason to report survival data on the GO1 dose level. No efficacy assessments were evaluated during the GO 1 phase 1 dose escalation study which focuses on DLT/toxicity assessments.