Acute Myeloid Leukemia
Conditions
Keywords
AML
Brief summary
This was a parallel, Phase 1/Phase 2, randomized, open label, multi-cohort, multi-center study assessing the safety, tolerability and preliminary efficacy of SAR443579 with different agents for treatment in adolescent and/or adult participants with CD123 expressing hematological malignancies. This protocol was structured as a master protocol (containing common protocol elements). Individual sub-studies would explore SAR443579 with combination partners, which might include approved or investigational agents. Experimental sub-studies would be tested through 3 parts: Part 1: dose finding (such as dose escalation/ safety run-in). Part 2: dose optimization (when applicable). Part 3: dose expansion. In each sub-study, a dose escalation would identify preliminary recommended dose for expansion (pRDE) of SAR443579 and its respective combination partner. Following the determination of the preliminary RDE, additional participants would be enrolled in the dose expansion part, or if dose optimization needs to be further evaluated, additional participants would be enrolled in the "dose optimization/expansion" part. Dose optimization and dose expansion part could involve randomization depending on specific sub-study design. Study consisted of a screening period, treatment period, and follow-up period. Participants would receive study treatment until documented disease progression, unacceptable adverse events, participant's decision to stop study treatment, or completion of the maximum cycles allowed in the sub-studies, or the participant met other criteria for discontinuation per study protocol (whichever occurred first).
Detailed description
Substudy 01: Title: A Phase 1/Phase 2, open-label, multi-center study, assessing the safety, tolerability and the preliminary efficacy of SAR443579 administered in combination with azacitidine + venetoclax in adult participants with CD123 expressing newly diagnosed Acute Myeloid Leukemia (ND-AML) that are ineligible for intensive chemotherapy Short title: A study to investigate natural killer cell engager (SAR443579) in combination with azacitidine + venetoclax in adult participants with newly diagnosed acute myeloid leukemia The expected duration of the study for a participant was approximately about 2.5 years. The study duration includes a screening period, an induction and maintenance. After the end of study treatment participants would enter the follow-up period for up to 2 years. Planned number of participants: 22 participants planned to be screened, 8 being adults and 14 being elderly; 9-18 participants planned to be enrolled (dose escalation part) Enrollment would be paused upon completion of Part 1: Dose Escalation. The available data would be reviewed and the recommended doses and schedule for optimization would be selected by the study board. Enrollment in the Part 2: Dose optimization and Part 3: Dose expansion would be provided in a future protocol amendment.
Interventions
BIOLOGICALSAR443579
Pharmaceutical form: Powder for solution for infusion Route of administration: intravenous infusion
DRUGvenetoclax
Pharmaceutical form :Film coated tablet Route of administration: oral
DRUGazacitidine
Pharmaceutical form: Lyophilized powder for suspension for injection Route of administration: intravenous or subcutaneous
Sponsors
Sanofi
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
\- Participants with CD123-expressing hematological neoplasm per the 5th edition of the WHO Classification of Hematolymphoid Tumors. Substudy 01: * Participants must be ≥18 years of age * Confirmed diagnosis of Acute Myeloid Leukemia * Ineligible for intensive chemotherapy. Ineligible for intensive chemotherapy was defined by the following criteria: A) ≥ 75 years of age, OR B) 18 to 74 years of age and meeting one or more of the following: 1. Eastern Cooperative Oncology Group (ECOG) performance status 2-3. 2. Cardiac history of congestive heart failure (CHF) requiring treatment or left ventricular ejection fraction (LVEF) ≤50% or symptomatic coronary heart disease confirmed by coronarography or cardiac imaging. 3. Diffusing capacity of the lungs for carbon monoxide (DLCO) ≤65% or forced expiratory volume (FEV1) ≤65%. 4. Creatinine clearance ≥30 to \<45 mL/min calculated by modification of diet in renal disease (MDRD) formula. 5. Moderate hepatic impairment with total bilirubin \>1.5 to ≤3.0x upper limit of normal (ULN). * Participant with an Eastern Cooperative Oncology Group (ECOG) performance status as follows: a) 0 to 2 for participants ≥75 years of age or b) 0 to 3 for participants 18 to 74 years of age. * For participants ≥75 years of age, adequate renal function demonstrated by a creatinine clearance ≥30 mL/min, calculated by modification of diet in renal disease (MDRD) * Participant with adequate liver function demonstrated by the following: 1. For participants 18 to 74 years of age, aspartate aminotransferase (AST) ≤3.0 × ULN, alanine aminotransferase (ALT) ≤3.0 × ULN and bilirubin ≤3.0 × ULN, unless considered due to leukemic organ involvement ˂5 × ULN. 2. For participants ≥75 years of age, aspartate aminotransferase (AST) ≤3.0 × ULN, alanine aminotransferase (ALT) ≤3.0 × ULN and bilirubin ≤1.5 × ULN, unless considered due to leukemic organ involvement ˂5 × ULN.
Exclusion criteria
* Any clinically significant, uncontrolled medical conditions (including any serious active systemic infection that was not controlled) * Known second malignancy either progressing or requiring active treatment within the last 3 years prior to first IMP administration * Known acquired immunodeficiency syndrome (AIDS-related illnesses) or HIV disease requiring antiretroviral treatment, or having active hepatitis B or C infection, or SARS-CoV-2 infection. With exception for: 1. HBV as determined by positive test for hepatitis B surface antigen (HBsAg) and/or HBV DNA. Participant who tested positive for anti-hepatitis B core (HBc) antigen IgG (with or without testing positive for anti-HBs), but tested negative for HBsAg and HBV DNA, was eligible. 2. A participant who tested positive for anti-HCV antibodies and had undetectable HCV RNA without receiving antiviral treatment for HCV was eligible. * Active, known, or suspected clinically significant autoimmune disease that had required systemic treatment in the past 2 years prior to first IMP administration, except controlled by replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc) * Predicted life expectancy ≤3 months. * Medical conditions requiring treatment with medications with narrow therapeutic index that were substrates of CYP enzymes and that could not be closely monitored to allow for dose adjustment. * Ongoing adverse event of NCI CTCAE \[Version 5.0\] Grade 2 or greater severity cause by any prior anti-cancer therapy Substudy 01: * Patient with Acute Promyelocytic Leukemia (APL) * Known active central nervous system involvement with AML at the time of enrollment as evidenced by cytology or pathology * Cardiovascular disease of New York Heart Association (NYHA) Class ≥2. * Malabsorption syndrome or other condition that precludes enteral route of administration * A baseline QTc interval of (using the Fridericia correction calculation) \>470 msec. * Participant had received treatment with at least one of the following: 1. A hypomethylating agent, venetoclax and/or chemo therapeutic agent for AML other than hydroxyurea used for disease control prior to the initiation of study therapy. 2. Experimental therapies for AML. 3. Concomitant medications of strong and moderate CYP3A inducers within 7 days prior to the initiation of study treatment. The above information was not intended to contain all considerations relevant to a participant's potential participation in a clinical trial.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Sub-study 1: Part 1: Dose Escalation: Number of Participants With Dose Limiting Toxicities (DLTs) | From Day 1 to Day 28 of Cycle 1 (each cycle was 28 days) | DLT=any of the following events during Cycle 1 (first 28 days) using NCI CTCAE v5.0 or ASTCT criteria, whether related or not to study treatment in absence of clear evidence to the contrary, and if not related to disease progression. Hematologic DLTs :toxicities, bone marrow hypocellularity, decreased neutrophils, febrile neutropenia, decreased platelets, anemia (all Grade 4) and Grade 3 thrombocytopenia. Non-hematologic DLTs: organ toxicities or infusion reaction (both Grade 4), Grade 3 infusion reaction lasting \>24 hours, Hy's law cases, Grade 3-4 infection, Grade 3 electrolyte abnormalities or transaminitis elevation, Grade \>=3 toxicities except alopecia, Grade 3 fatigue, asthenia, fever, anorexia, constipation, nausea, vomiting, diarrhea, infection, bleeding, Grade 3 cytokine release syndrome or laboratory abnormalities, Grade 3 or 4 tumor lysis syndrome. Any treatment related toxicity causing \>2-week delay in recovery to baseline/Grade \<=1 or requiring dose reduction/withdrawal. |
| Sub-study 1: Part 2: Dose Optimization: Number of Participants With Treatment-emergent Adverse Events (TEAEs), Treatment-emergent Serious Adverse Events (SAEs) and Treatment-emergent Adverse Events of Special Interest (AESIs) | AEs were planned to be collected from first dose of study treatment (Day 1) up to 30 days post last dose of study treatment | An AE was any untoward medical occurrence in participant or clinical study participant temporally associated with the use of study treatment, whether or not considered related to the study treatment. An SAE was any AE, that at any dose: resulted in death, was life-threatening, required inpatient hospitalization/prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, was a congenital anomaly/birth defect or was a medically important event. An AESI was an AE (serious or nonserious) of scientific and medical concern specific to the Sponsor's product or program, for which ongoing monitoring and immediate notification by the Investigator to the Sponsor was required. The TEAEs were defined as AEs that developed, worsened or became serious after the first administration of study treatment up to 30 days after the last administration of study treatment. |
| Sub-study 1: Part 2: Dose Optimization: Number of Participants With Potentially Clinically Significant Abnormalities (PCSA) in Hematology Parameters | Planned to be collected from first dose of study treatment (Day 1) up to 30 days post last dose of study treatment | Blood samples were planned to be collected to determine the PCSA in hematology. |
| Sub-study 1: Part 2: Dose Optimization: Number of Participants With Potentially Clinically Significant Abnormalities in Clinical Chemistry Parameters | Planned to be collected from first dose of study treatment (Day 1) up to 30 days post last dose of study treatment | Blood samples were planned to be collected to determine the PCSA in clinical chemistry. |
| Sub-study 1: Part 2: Dose Optimization: Complete Remission (CR) Rate | Tumor assessments were planned to be performed on Day 28 of each induction cycle and Day 56 of each maintenancecycle until relapsed disease, refractory disease, unacceptable AE, participant preference or death due to any cause,whichever occurred first | The CR rate was defined as percentage of participants who had a CR determined by the Investigator according to 2022European Leukemia Net (ELN) recommendations for diagnosis and management of AML. |
| Sub-study 1: Part 3: Dose Expansion: Complete Remission (CR) Rate | Tumor assessments were planned to be performed on Day 28 of each induction cycle and Day 56 of each maintenance cycle until relapsed disease, refractory disease, unacceptable AE, participant preference or death due to any cause, whichever occurred first | The CR rate was defined as percentage of participants who had a CR determined by the Investigator according to 2022 European Leukemia Net (ELN) recommendations for diagnosis and management of AML. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Sub-study 1: Part 1: Dose Escalation and Part 3: Dose Expansion: Number of Participants With Treatment-Emergent Adverse Events (TEAEs), TE Serious Adverse Events (TESAEs) and TE Adverse Events of Special Interest (TEAESIs) | From the first dose of study drug administration (Day 1) up to early termination of the study, maximum treatment duration was 31.3 weeks | An AE was any untoward medical occurrence in participant or clinical study participant temporally associated with the use of study treatment, whether or not considered related to the study treatment. An SAE was any AE, that at any dose: resulted in death, was life-threatening, required inpatient hospitalization/prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, was a congenital anomaly/birth defect or was a medically important event. An AESI was an AE (serious or nonserious) of scientific and medical concern specific to the Sponsor's product or program, for which ongoing monitoring and immediate notification by the Investigator to the Sponsor was required. TEAEs: AEs that developed, worsened/became serious after first administration of study treatment up to 30 days after last administration of study treatment. |
| Sub-study 1: Part 3: Dose Expansion: Percentage of Participants With Minimal Residual Disease | Tumor assessments were planned to be performed on Day 28 of each induction cycle and Day 56 of each maintenance cycle until relapsed disease, refractory disease, unacceptable AE, participant preference or death due to any cause, whichever occurred first | The minimal residual disease rate was defined as the percentage of participants with minimal residual disease as defined by 2022 ELN in participants achieving a CR, CR with partial hematologic recovery (CRh) or CR with incomplete hematologic recovery (CRi). |
| Sub-study 1: All 3 Parts: Concentrations Observed at the End of Dosing Period During Repeated Administration (Ctrough) of SAR443579 | Part 1:Dose escalation (dose levels 1 and 2): Pre-dose: At Days 1, 8, 15 and 22 of Cycle 1 and Days 8, 15, 22 and 28 of Cycle 2 (each cycle was 28 days) | Blood samples were collected just before treatment administration during repeated dosing to determine the Ctrough of SAR443579 during dose escalation part. Participants missed few scheduled site visits for sample collection and only participants with data collected at specified timepoints are reported. |
| Sub-study 1: All 3 Parts: Maximum Plasma Concentration Observed (Cmax) of Venetoclax | Part 1:Dose escalation (dose levels 1 and 2):Pre-dose and 2, 3, 4, 6, 11 and 24 hours post-dose on Cycle 1 Day 1; pre-dose and 2, 3, 4, 6, 9, 11 and 24 hours post-dose on Cycle 1 Day 8 | Blood samples were collected at specified timepoints to determine Cmax of venetoclax during dose escalation part. Participants missed few scheduled site visits for sample collection and only participants with data collected at specified timepoints are reported. |
| Sub-study 1: All 3 Parts: Area Under the Plasma Concentration Versus Time Curve Extrapolated to Infinity (AUC) of Venetoclax | Part 1:Dose escalation (dose levels 1 and 2):Pre-dose and 2, 3, 4, 6, 11 and 24 hours post-dose on Cycle 1 Day 1 | Blood samples were collected at specified timepoints to determine AUC of venetoclax during dose escalation part. Participants missed few scheduled site visits for sample collection and only participants with data collected at specified timepoints are reported. |
| Sub-study 1: All 3 Parts: Maximum Plasma Concentration Observed of Azacitidine | Part 1:Dose escalation (dose levels 1 and 2):Pre-dose, 0.5, 1.5, 2.5, 4.5 and 9.5 hours post-dose on Cycle 1 Day 1 | Blood samples were collected at specified timepoints to determine Cmax of azacitidine during dose escalation part. Participants missed few scheduled site visits for sample collection and only participants with data collected at specified timepoints are reported. The PK samples were not collected at the end of infusion and were therefore outside the protocol-defined time window; consequently, Cmax could not be estimated and N = 0 in IV category. No participants received Azacitidine by SC route, thus N=0 in SC category. |
| Sub-study 1: All 3 Parts: Area Under the Plasma Concentration Versus Time Curve Extrapolated to Infinity of Azacitidine | Part 1:Dose escalation (dose levels 1 and 2):Pre-dose, 0.5, 1.5, 2.5, 4.5 and 9.5 hours post-dose on Cycle 1 Day 1 | Blood samples were collected at specified timepoints to determine AUC of azacitidine during dose escalation part. Participants missed few scheduled site visits for sample collection and only participants with data collected at specified timepoints are reported. PK samples were not collected at the end of infusion; therefore, Cmax could not be estimated. In addition, PK samples collected outside the predefined time window resulted in insufficient data to calculate AUC, thus N=0 in IV category. No participants received Azacitidine by SC route, thus N=0 in SC category. |
| Sub-study 1: All 3 Parts: Number of Participants With Anti-Drug Antibodies (ADAs) Against SAR443579 | Part 1:Dose escalation (dose levels 1 and 2): first dose of study drug administration (Day 1) up to early termination of the study, maximum treatment duration was 31.3 weeks | Plasma samples were collected to assess the antibodies to SAR443579 during dose escalation part. Treatment-emergent ADA was defined as a participant with at least 1 treatment-induced or treatment-boosted ADA-positive sample at any time during the treatment or follow-up observation period. Non-treatment emergent ADA was defined as participant without any treatment-induced, treatment-boosted ADA-positive or ADA-inconclusive sample during the treatment or follow-up observation period. |
| Sub-study 1: Part 3: Dose Expansion: Composite Complete Remission (CRc) Rate | Tumor assessments were planned to be performed on Day 28 of each induction cycle and Day 56 of each maintenance cycle until relapsed disease, refractory disease, unacceptable AE, participant preference or death due to any cause, whichever occurred first | The CRc rate was defined as the percentage of participants who had a response of CR, CRh or CRi as best overall response as assessed by the Investigator according to 2022 ELN recommendations for diagnosis and management of AML. |
| Sub-study 1: Part 3: Dose Expansion: Overall Response Rate | Tumor assessments were planned to be performed on Day 28 of each induction cycle and Day 56 of each maintenance cycle until relapsed disease, refractory disease, unacceptable AE, participant preference or death due to any cause, whichever occurred first | The ORR was defined as the percentage of participants who had a response of CR or CRi or CRh or partial remission (PR) or MLFS (morphological leukemia-free state) as best overall response as assessed by the Investigator according to the 2022 ELN criteria. |
| Sub-study 1: Part 3: Dose Expansion: Duration of Complete Remission | Tumor assessments were planned to be performed on Day 28 of each induction cycle and Day 56 of each maintenance cycle until relapsed disease, refractory disease, unacceptable AE, participant preference or death due to any cause, whichever occurred first | Duration of CR was defined as the time interval from the first documented evidence of CR until disease relapse as determined by the Investigator as per 2022 ELN recommendations or death due to any cause, whichever occurred first. |
| Sub-study 1: Part 3: Dose Expansion: Duration of Composite Complete Remission | Tumor assessments were planned to be performed on Day 28 of each induction cycle and Day 56 of each maintenance cycle until relapsed disease, refractory disease, unacceptable AE, participant preference or death due to any cause, whichever occurred first | Duration of CRc was defined as the time interval from first documented evidence of CRc (CR, CRh or CRi) until disease relapse as determined by the Investigator as per 2022 ELN recommendations or death due to any cause, whichever occurred first. |
| Sub-study 1: Part 3: Dose Expansion: Duration of Overall Response Rate | Tumor assessments were planned to be performed on Day 28 of each induction cycle and Day 56 of each maintenance cycle until relapsed disease, refractory disease, unacceptable AE, participant preference or death due to any cause, whichever occurred first | Duration of overall response rate was defined as the time from the first documented evidence of CR or CRi or CRh or PR or MLFS until disease relapse as determined by the Investigator as per 2022 ELN recommendations or death due to any cause, whichever occurred first. |
| Sub-study 1: Part 3: Dose Expansion: Alternative Complete Remission Rate | Tumor assessments were planned to be performed on Day 28 of each induction cycle and Day 56 of each maintenance cycle until relapsed disease, refractory disease, unacceptable AE, participant preference or death due to any cause, whichever occurred first | Alternative CR rate was defined as percentage of participants with alternative CR or CRh as best overall response as assessed by the Investigator. |
| Sub-study 1: Part 3: Dose Expansion: Duration of Alternative Complete Remission | Tumor assessments were planned to be performed on Day 28 of each induction cycle and Day 56 of each maintenance cycle until relapsed disease, refractory disease, unacceptable AE, participant preference or death due to any cause, whichever occurred first | Duration of alternative CR was defined as the time from the first documented evidence of alternative CR or CRh until disease relapse as determined by the Investigator as per 2022 ELN recommendations or death due to any cause, whichever occurred first. |
| Sub-study 1: Part 3: Dose Expansion: Event-Free Survival (EFS) | Tumor assessments were planned to be performed on Day 28 of each induction cycle and Day 56 of each maintenance cycle until relapsed disease, refractory disease, unacceptable AE, participant preference or death due to any cause, whichever occurred first | The EFS was defined as the time interval from the first day of treatment assignment until treatment failure, relapse from remission, or death from any cause, whichever occurred first. |
| Sub-study 1: Part 3: Dose Expansion: Overall Survival (OS) | Tumor assessments were planned to be performed on Day 28 of each induction cycle and Day 56 of each maintenance cycle until relapsed disease, refractory disease, unacceptable AE, participant preference or death due to any cause, whichever occurred first | The OS was defined as time interval from the day of treatment assignment to death from any cause. |
| Sub-study 1: Part 3: Dose Expansion: Percentage of Participants With Hematopoietic Stem Cell Transplantation (HSCT) | Tumor assessments were planned to be performed on Day 28 of each induction cycle and Day 56 of each maintenance cycle until relapsed disease, refractory disease, unacceptable AE, participant preference or death due to any cause, whichever occurred first | The HSCT rate was defined as the percentage of such participants who underwent HSCT through study treatment but before subsequent therapy, among the safety/exposed population. |
| Sub-study 1: Part 3: Dose Expansion: Time to Treatment Failure (TTF) | Tumor assessments were planned to be performed on Day 28 of each induction cycle and Day 56 of each maintenance cycle until relapsed disease, refractory disease, unacceptable AE, participant preference or death due to any cause, whichever occurred first | The TTF was defined as the time from first day of treatment assignment to the first discontinuation for any reason excluding remission, that is, relapsed disease, refractory disease, unacceptable AE, participant preference or death, whichever occurred first. |
| Sub-study 1: All 3 Parts: Transfusion Independence (TI) Rate | Part 1:Dose escalation (dose levels 1 and 2): From Baseline (Day 1, before 1st dose of study treatment administration) to 56 days post-baseline during treatment period (Maximum exposure duration: 31.3 weeks) | The TI rate was defined differently for participants who were transfusion dependent (TD) at baseline and participants who were transfusion independent (TI) at baseline. For subgroup of participants with TD at baseline, the TI rate was defined as the percentage of participants who converted from baseline TD to TI during on treatment period; For subgroup of participants with TI at baseline, the TI rate was defined as the percentage of participants who remained TI during 56-day post baseline period during treatment. |
Countries
Australia, United States
Participant flow
Recruitment details
The study was conducted at 7 sites in 2 countries. A total of 10 participants were screened from 13-Aug-2024 to 03-Apr-2025, of which 3 were screen failures mainly due to not meeting eligibility criteria. A total of 7 participants with CD123-expressing newly diagnosed acute myeloid leukemia (NDAML) who were ineligible for intensive chemotherapy were enrolled. Two sub-studies 1 and 2 were planned with 3 parts in each (Part 1: Dose escalation, Part 2: Dose optimization, Part 3: Dose expansion).
Pre-assignment details
The study was prematurely terminated by the sponsor for non-safety related reasons. Thereby no participants were enrolled in the following parts of sub-study 1: Part 1: Dose escalation-dose level 3 (1.5 mg/kg), Parts 2 and 3; and sub-study 2 (all 3 parts) and these sub-studies parts were not conducted. Thus, related data are not reported in any section of this record. Only results of completed part (sub-study 1: Part 1: Dose escalation-dose level 1 \[0.6 mg/kg\] and 2 \[1 mg/kg\]) are reported.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 78.3 years STANDARD_DEVIATION 3.9 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 5 Participants |
| Sex: Female, Male Female | 1 Participants |
| Sex: Female, Male Male | 3 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 1 / 4 | 2 / 3 |
| other Total, other adverse events | 4 / 4 | 3 / 3 |
| serious Total, serious adverse events | 3 / 4 | 2 / 3 |
Outcome results
None listed