Design of the VIALE-M phase III trial of venetoclax and oral azacitidine maintenance therapy in acute myeloid leukemia
Abstract
Prevention of relapse is a major therapeutic challenge and an unmet need for patients with acute myeloid leukemia (AML). Venetoclax is a highly selective, potent, oral BCL-2 inhibitor that induces apoptosis in AML cells. When combined with azacitidine, it leads to prolonged overall survival and rapid, durable remissions in treatment-naive AML patients ineligible for intensive chemotherapy. VIALE-M is a randomized, double-blind, two-arm study to evaluate the safety and efficacy of venetoclax in combination with oral azacitidine (CC-486) as maintenance therapy in patients in complete remission with incomplete blood count recovery after intensive induction and consolidation therapies. The primary end point is relapse-free survival. Secondary outcomes include overall survival, minimal residual disease conversion and improvement in quality-of-life.
Trial Registration Number: NCT04102020 (ClinicalTrials.gov)
Acute myeloid leukemia (AML) is an aggressive, rapidly fatal, heterogenous hematologic malignancy defined by the WHO as a myeloid neoplasm with 20% or more blasts in the peripheral blood or bone marrow [1]. AML can impair normal hematopoiesis, leading to severe cytopenia in one or more cell lineages that can result in symptoms such as extreme fatigue, infections and bleeding events [2]. It is one of the most common forms of acute leukemia in adults, has the lowest survival rate and accounts for the largest number of deaths [3]. An estimated 20,240 new cases of AML led to 11,400 deaths in the USA in 2021 [3].
With the exception of patients with acute promyelocytic leukemia (APL), where maintenance therapy with arsenic trioxide and retinoic acid has been shown to be beneficial, there was no established standard-of-care for maintenance therapy in non-APL AML [4–6]. Despite a longstanding interest in maintenance therapies such as IL-2 [7–9], low-dose cytarabine (LDAC) [10], hypomethylating drugs (HMAs) [11–19] and gemtuzumab ozogamicin [17] following intensive induction treatment, their clinical benefits have remained unclear [8].
CC-486 (developed by Celgene Corporation, a Bristol-Myers Squibb Company, NJ, USA), an oral formulation of azacitidine, has been approved for continued treatment of patients with AML who achieved first complete remission (CR) or incomplete count recovery (CRi) following intensive induction chemotherapy and were unable to complete intensive curative therapy [20]. The phase III, randomized, double-blind, placebo-controlled QUAZAR AML maintenance trial (CC-486-AML-001) showed oral azacitidine maintenance therapy to be the first maintenance therapy to provide statistically significant and clinically meaningful improvements in OS and relapse-free survival (RFS) relative to placebo in a broad range of patients with AML in remission following intensive induction and consolidation chemotherapy. The median OS and RFS were prolonged by 9.9 and 5.3 months, respectively. The safety and tolerability of oral azacitidine were manageable, with no unexpected adverse events [21,22].
Venetoclax (jointly being developed by AbbVie and Genentech/Roche) is a first-in-class, highly selective, potent, oral BCL-2 inhibitor that induces apoptosis in preclinical AML models. AML cells are co-dependent on other anti-apoptotic BCL-2 family members, so synergistic combinations with other therapeutic agents, such as HMAs or LDAC, are thought to enhance apoptosis. For AML patients who are eligible, standard-of-care treatment includes intensive chemotherapy with induction to achieve remission, followed by consolidation [23–27]. Induction chemotherapy typically results in CR in 60–80% of patients <60 years and 40–60% of older patients >60 years [28,29]. Consolidation therapy aims at eradicating residual leukemia and reducing the risk of disease relapse [6,30–32]. While patients who are fit to receive intensive treatment will often achieve remission, more than 50% of these patients will ultimately relapse [6,28,33,34]. Therefore, there is a critical and unmet need for strategies that decrease the risk of relapse and improve the survival of patients with AML.
In AML patients, venetoclax was evaluated as a single agent in a phase II, single-arm study in patients with high-risk relapsed or refractory AML or newly diagnosed patients with AML who were ineligible to receive intensive chemotherapy. The study achieved a 19% objective response rate with venetoclax monotherapy, with a tolerable safety profile [24]. A large phase Ib dose-escalation and expansion study evaluating the safety and efficacy of venetoclax in combination with decitabine or azacitidine in elderly patients with treatment naive AML ineligible for intensive chemotherapy reported that 67% of all patients achieved CR + CR with CRi, with a CR + CRi rate of 73% in the venetoclax 400 mg + HMA cohort. The median overall survival was 17.5 months [23,35]. Results from this study and those from a nonrandomized, open-label trial of venetoclax in combination with LDAC [25] led to the accelerated US FDA approval of venetoclax in combination with HMAs or LDAC for the treatment of newly diagnosed AML patients aged 75 years or older, or patients who were ineligible for intensive induction chemotherapy [36].
The VIALE-A phase III, randomized, double-blind, placebo-controlled study compared the safety and efficacy of venetoclax plus azacitidine with placebo plus azacitidine in newly diagnosed AML patients ineligible to receive intensive chemotherapy [37]. The study reported a median overall survival (OS) of 14.7 months in the venetoclax plus azacitidine arm versus 9.6 months in the placebo plus azacitidine control arm. The CR + CRi rate was 66.4% in the venetoclax plus azacitidine arm versus 28.3% in the control arm [35]. Moreover, the safety profile of patients in the venetoclax plus azacitidine arm was consistent with the known side effect profiles of both agents when administered independently [35]. Results from the VIALE-A study, taken together with those from the randomized, phase III, double-blind, placebo-controlled VIALE-C study on venetoclax in combination with LDAC in the same patient population [38], led to full FDA approval of the combination treatment on 16 October 2020 [39].
VIALE-M (M19-708) is a phase III randomized, double-blind, two-arm, multicenter clinical study of venetoclax plus oral azacitidine versus placebo plus oral azacitidine as maintenance therapy for patients 18 years and older with newly diagnosed AML in first CR or CRi following intensive induction and consolidation therapies. The study, which is registered on ClinicalTrials.gov (NCT04102020) and sponsored by AbbVie and Genentech, will evaluate the safety of venetoclax in combination with oral azacitidine as maintenance therapy for patients with AML in first CR or CRi and whether venetoclax in combination with oral azacitidine will improve RFS over oral azacitidine alone, which is the current standard-of-care in this maintenance setting.
Design
Objectives
The primary objective of this study is to determine if venetoclax plus oral azacitidine as maintenance therapy improves RFS compared with placebo plus oral azacitidine in patients aged ≥18 years with newly diagnosed AML who have achieved CR or CRi with conventional induction and consolidation chemotherapy and are not eligible for allogeneic stem cell transplantation. Secondary objectives include OS, minimal residual disease (MRD) conversion, and improvement in quality-of-life (QoL). Prior to randomization, the study includes a dose-finding portion to determine the recommended phase III dose (RPTD) of venetoclax in combination with oral azacitidine as maintenance therapy. Secondary objectives aim at characterizing safety, pharmacokinetic (PK) and toxicity profiles of venetoclax in combination with oral azacitidine as maintenance therapy in a subset of this patient population.
Eligibility criteria
Eligible patients must be 18 years or older with newly diagnosed AML per WHO 2016 classification [1], with confirmed CR or CRi following intensive induction chemotherapy and confirmed after consolidation therapy. Patients must have achieved first CR or CRi (after induction) within 120 days of first dose of study drug or be no more than 75 days since last dose of the last consolidation cycle. Within the screening period and prior to study drug administration, patients must have creatinine clearance ≥30 ml/min calculated by the Cockcroft Gault formula or measured by 24 h urine collection, bilirubin <2.0 × upper limit of normal, absolute neutrophil count ≥1500/μl and platelets ≥100,000/μl. They must also have an Eastern Cooperative Oncology Group performance status of ≤2, and AML with intermediate or poor risk cytogenetics per National Comprehensive Cancer Network (NCCN) 2016 criteria. Patients with a history of APL or active CNS involvement with AML will be excluded. Also, patients must not have any history of allogeneic stem cell transplantation or be candidates for allogeneic stem cell transplantation.
Study design & treatment
The VIALE-M study is an international, multicenter, randomized, double-blind, placebo-controlled, phase III study of maintenance therapy with venetoclax in combination with oral azacitidine and best supportive care (BSC) versus placebo plus oral azacitidine and BSC for patients aged ≥18 with AML who are in first CR or CRi. In VIALE-M, BSC is any supportive therapy that does not treat leukemia directly and will be determined by the investigator. This is a global study with approximately 300 study sites in 19 countries.
The dose-finding portion of the study includes dose-escalation where patients will receive venetoclax plus oral azacitidine at pre-proposed study dose levels. This part of the study will follow a Bayesian optimal interval design to guide de-escalation decisions based on the cumulative number of patients experiencing dose-limiting toxicities (DLTs) at the administered dose level. In the dose-escalation portion, each dose level will initially enroll at least six DLT-evaluable patients. Approximately 12 patients will be assigned to receive the preliminary RPTD identified during dose escalation. DLTs will be observed during cycle 1. When the RPTD has been reached, the safety expansion phase will enroll a different cohort of at least 12 additional patients who will receive venetoclax plus oral azacitidine at the preliminary RPTD identified from the dose-escalation portion.
In the randomization portion of the study, patients will be randomized 1:1 to receive placebo or venetoclax once daily and oral azacitidine once daily on the first 14 days at the RTPD of each 28-day treatment cycle for 24 cycles (Figure 1).
*BSC, excluding any AML-directed therapy, will be determined for each patient by the investigator and institutional guidelines.
†Dose-finding will follow a BOIN design to guide dose-escalation and de-escalation decisions.
AML: Acute myeloid leukemia; BOIN: Bayesian optimal interval; BSC: Best supportive care; RPTD: Recommended phase II dose.
Patients will be stratified by age (<60 or ≥60 years), 2016 NCCN cytogenetic risk at diagnosis (poor, intermediate), and MRD status at screening (MRD-positive [≥10-3] or missing; MRD-negative [<10-3]). All patients who complete at least one cycle will be assessed for relapse using a modified International Working Group criteria for AML [40], based on their most recent physical examination, bone marrow aspirate/biopsy results and hematology values. Patients will be assessed as having relapsed with the reappearance of ≥5% blasts after CR or CRi in peripheral blood or in the bone marrow, or the development of extramedullary disease. Patients will have a final visit performed at relapse or when the study drug is discontinued. For all parts of the study presented here, patients who discontinue the study drug(s) but have not had an event of documented relapse will return for post-treatment follow-up visits every 3 months for 1 year and every 6 months; thereafter, starting from study drug discontinuation until documented relapse. Following relapse, survival information will be collected every 3 months or more frequently for up to 2 years after relapse or until the sponsor’s decision to stop follow-up. In all parts, treatment may discontinue due to relapse/unacceptable toxicity, or continue beyond 24 cycles under investigator’s discretion.
The VIALE-M trial will be conducted in accordance with guidelines established by the International Conference on Harmonization (ICH) and those governing clinical study conduct and the ethical principles that have their origin in the Declaration of Helsinki. The trial will also adhere to the appropriate Institutional Review Board (IRB)/Independent Ethics Committee (IEC) study protocol approvals at each study site.
Study assessments
Efficacy assessments
The primary end point of RFS is the time from randomization to the date of relapse or the date of death from any cause, whichever comes first. Bone marrow will be assessed at screening, cycles 3, 6, 9 and every three cycles thereafter day 1 until cycle 24 or until the final visit, or whenever clinically indicated as per routine care.
Secondary objectives include OS, MRD conversion, and improvement in QoL. The key secondary efficacy analysis of OS is defined as time from randomization to death from any cause. OS data from patients who have not died will be censored at the last known date when the patient was alive.
The MRD conversion rate is defined as the proportion of patients deemed MRD positive (≥10-3) at screening who convert to MRD <10-3 after randomization. Patients who are MRD <10-3 at screening will be excluded from this analysis. For MRD testing, bone marrow aspirate samples will be collected for multiparametric flow cytometry assessments to be performed at a central laboratory [41]. Sample will be collected from patients at baseline, on day 1 of cycles 3, 6, 9 and every three cycles thereafter until cycle 24, or until relapse/the final visit, or whenever clinically indicated as per routine care. MRD negative response will be defined as <1 residual blast per 1000 leukocytes (<10-3 or 0.1%) [41]. Additional exploratory analyses are planned to evaluate molecular-based MRD and may include but is not limited to NPM1.
Time to deterioration in Global Health Status (GHS)/QoL score is defined as time from randomization to death from any cause, or the first-time decrease of ≥5 points from baseline, whichever occurs first. Patients without any of the specified events will be censored at their last European Organization for Research and Treatment of Cancer QoL questionnaire – Core 30 item (EORTC QLQ-C30) assessment.
Safety assessments
Safety evaluations include adverse event monitoring, physical examinations, vital sign measurements and clinical laboratory testing (hematology and chemistry) as measures of safety and tolerability. These assessments will be performed in all randomized patients who receive at least one dose of venetoclax/placebo and oral azacitidine and continue for the entire study duration, which includes all follow-up visits.
Blood samples for PK profiling will be collected and analyzed for plasma concentrations of venetoclax and oral azacitidine at baseline and on day 5 of cycles 1, 2, 4 and 6. PK samples will also be collected on days 14 and 21 of the first cycle, for levels 1 and 2 of the dose-escalation portion.
Health-related QoL assessments
The patient-reported outcome (PRO) measures chosen for this study have been validated in cancer patients and include a generic health-related QoL measure (EQ-5D-5L), a cancer-specific health-related QoL measure that includes functional and symptom scales as well as a GHS scale (EORTC QLQ-C30), and a symptom-based measure to assess fatigue, Patient Reported Outcomes Measurement Information System (PROMIS) Fatigue Short Form 7a.
Correlative assessments
Exploratory correlative analyses will be performed to explore biomarkers predictive of venetoclax activity. Medical resource utilization and cost-effectiveness/cost utility analyses will be conducted to evaluate if venetoclax plus oral azacitidine as maintenance therapy reduces healthcare resource utilization in comparison to placebo plus oral azacitidine.
Statistical analyses
Analysis methods
The primary efficacy analyses will compare RFS distributions with venetoclax plus oral azacitidine versus placebo plus oral azacitidine. The distribution of RFS will be estimated for each study arm using Kaplan–Meier methodology [42] and compared between the two study arms using the log-rank test, stratified by age (<60, ≥60 years), NCCN cytogenetic risk at diagnosis (poor, intermediate) and MRD status at screening (MRD-positive [≥10-3] or missing, MRD-negative [<10-3]). The RFS hazard ratio (HR) and corresponding 95% CI between the two study arms will be estimated using the Cox proportional hazards model, stratified by the same parameters as above.
The distribution of OS will be estimated for each study arm using Kaplan–Meier methodology and compared between the two study arms using the log-rank test, stratified by the same parameters as for primary efficacy analyses. The OS HR and corresponding 95% CI between the two study arms will be estimated using the Cox proportional hazards model.
The MRD conversion rate (95% CI) will be estimated for each study arm using binomial distribution (Clopper–Pearson exact method) [43] and compared between the two study arms using the Cochran–Mantel–Haenszel test stratified by age (<60, ≥60 years) and NCCN cytogenetic risk at diagnosis (poor, intermediate).
The distribution of time to deterioration in GHS/QoL will be estimated for each study arm using Kaplan–Meier methodology [42] and compared between the two study arms using the log-rank test, stratified by age (<60, ≥60 years), NCCN cytogenetic risk at diagnosis (poor, intermediate) and MRD status at screening (MRD positive [≥10-3] or missing, MRD negative [<10-3]). The HR and corresponding 95% CI between the two study arms will be estimated using the Cox proportional hazards model. Fatigue will be assessed using the global fatigue score as measured by PROMIS Fatigue Short Form 7a and scores will be computed according to the PROMIS fatigue scoring manual. Changes from baseline to post baseline visits in fatigue scores will be analyzed to compare the two arms using a linear mixed-effect regression model with stratification factors of age (<60, ≥60 years), NCCN cytogenetic risk at diagnosis (poor risk, intermediate) and MRD status at screening (MRD positive or missing, MRD negative) and treatment arm as fixed factors. Time and treatment-by-time interaction will also be included in the model as random factors. Patients without a baseline score or any post baseline scores will be excluded from the analysis.
For the intensive PK sampling days in the dose-finding portion, values for the PK parameters of venetoclax and oral azacitidine including the maximum observed plasma concentration (Cmax), the time to Cmax (Tmax), the area under the plasma concentration versus time curve (AUC) from time 0 to the time of the last measurable concentration (AUCt) for azacitidine, and AUC from time 0 to 24 h post dose (AUC0-24) for venetoclax will be determined using noncompartmental methods.
Sample size
Approximately 426 patients will be enrolled for the randomization portion of the VIALE-M study, based on calculations for the primary end point of RFS that assume median RFS in the oral azacitidine arm as 11.4 months, HR of 0.65, interim efficacy analysis of RFS at 82% of RFS events with O'Brien-Fleming boundary, 1:1 randomization ratio for the venetoclax plus oral azacitidine arm (arm A) and the placebo plus oral azacitidine arm (arm B), and drop-out rate of 3% by month 12 for each arm. A total of 233 RFS events will provide approximately 90% power to detect a statistically significant difference between the two arms for RFS at one-sided alpha level of 0.025 using the log-rank test. The planned sample size will also provide approximately 80% power to detect a statistically significant improvement in OS assuming an increase in median OS from 26.7 months in the placebo with oral azacitidine arm to 39.9 months in the venetoclax plus oral azacitidine arm with approximately 200 deaths. The assumption of median RFS and median OS for placebo plus oral azacitidine are based on the QUAZAR study [21,22], and adjusted for the difference between the QUAZAR study and VIALE-M eligibility criteria. This results in an expected median RFS of 11.4 months with oral azacitidine in the VIALE-M study population compared with 10.2 months noted in the QUAZAR study.
Conclusion
The majority of patients with AML who achieve remission following induction chemotherapy will go on to relapse. The prevention of relapse is a critical and unmet need for patients with AML who are in remission. The authorization of oral azacitidine for patients with AML who achieve first CR or CRi following intensive induction chemotherapy and were not able to complete intensive curative therapy provides the first approved strategy for maintenance therapy in AML. Oral azacitidine provides statistically significant and clinically meaningful improvements in survival relative to placebo.
Venetoclax is a BCL-2 inhibitor that inhibits the mitochondrial anti-apoptotic pathway, resulting in rapid cell death. BCL-2 dependence is common in AML cells; however, AML cells can be co-dependent on other BCL-2 family members for survival [44–48]. Sensitivity to venetoclax can be increased through potentially synergistic combination with other therapeutic agents such as HMAs or LDAC [49–51]. Previous studies evaluating the combination of venetoclax plus azacitidine have shown the safety and efficacy of this combination in newly diagnosed AML patients [23,35,52].
Leukemia stem cells, which overexpress the BCL-2 family of proteins and often persist after conventional chemotherapy, cause perpetuation of AML, worse clinical outcomes and contribute to relapse. Curative therapy in AML must incorporate agents with activity against these cells either during induction and consolidation and/or during maintenance [53]. The analysis of leukemic stem cells from patients undergoing treatment with venetoclax in combination with azacitidine showed a disruption of the tricarboxylic acid cycle, as manifested by decreased α-ketoglutarate and increased succinate levels. Inhibition of the electron transport chain complex II leads to suppression of oxidative phosphorylation, which efficiently and selectively targets leukemic stem cells. These findings suggest that a therapeutic intervention that disrupts the metabolic machinery can eradicate leukemic stem cells and offer clinical activity in a patient population with historically poor outcomes [53].
Moreover, given the high relapse rates, limited strategies for relapse prevention and the safety of venetoclax and azacitidine to date, the patient population selected for this study is suitable for treatment with venetoclax in combination with oral azacitidine as maintenance therapy.
This study differs from the QUAZAR study in patient eligibility criteria, including age (≥18 vs ≥55 years), enrollment after induction and consolidation versus after induction with or without consolidation, and CR or CRi with full count recovery (absolute neutrophil count ≥1500/μl; platelets ≥100,000/μl) at enrollment versus CR or CRi with or without full count recovery. The rationale for this criterion derives from the fact that this study will evaluate the combination of venetoclax and oral azacitidine for the first time, and it is known that both drugs have an overlapping safety profile, mainly for hematologic and gastrointestinal toxicities [22,35].
For the patient population eligible for this study – newly diagnosed AML patients who have achieved CR or CRi after receiving standard induction and consolidation therapies – the prolongation of RFS is considered to have clinical significance, because it includes the clinical outcome of duration of time to relapse after remission. RFS has been used as the primary end point in recent and ongoing studies intended to confirm the usefulness of other agents in AML maintenance therapy [54–56]. RFS provides several advantages in the assessment of clinical benefit, making it a preferred surrogate end point to OS in the AML patient population; it is an end point attributable to the most recent maintenance therapy, and unlike OS, is not influenced by subsequent therapies that may include venetoclax. Patients with symptoms or findings of detectable disease are expected to withdraw consent from the study and move to a different treatment regimen. Such potential withdrawal of consent would be higher in the BSC arm (without AML maintenance therapy) and could result in a predictable bias in OS assessment. Moreover, age is associated with a high variability in life expectancy in newly diagnosed AML patients, which complicates interpretation of treatment effects for OS when death is unrelated to AML or treatment toxicity.
While RFS is set as the primary end point, OS is a key secondary end point. A fixed sequence testing procedure is planned for the primary and secondary end points, and no formal statistical testing will be performed for the secondary efficacy end points if the primary RFS treatment comparisons are not statistically significant. Secondary end points for the study are devised to evaluate if venetoclax in combination with oral azacitidine as maintenance therapy improves OS in comparison to placebo with oral azacitidine, and to evaluate if venetoclax in combination with oral azacitidine as maintenance therapy improves the MRD conversion rate among patients who are MRD positive at screening in comparison to placebo with oral azacitidine.
Health-realted QoL can play a significant role in patients with AML as a prognostic factor and as a factor influencing treatment decisions [57]. For patients with AML, health-related QoL is generally poor. Baseline measures of fatigue and physical functioning have been identified as independent prognostic factors for OS, with several studies reporting improvements in outcomes following treatment [58]. The specific symptoms and functional aspects assessed by the PRO measures chosen for this study are among the most impactful to AML patients [59,60]. The study will also collect biospecimens (peripheral blood and/or bone marrow aspirate) to support the exploratory biomarker research objectives of the study. Assessments will include biomarkers related to the pathway(s) targeted by the study drug, or those believed to be related to the disease(s) being studied. The information learned from analyzing these samples may be used to investigate factors influencing response to treatment, scientific questions related to AML and/or the development of new therapies and diagnostic tests.
The VIALE-M trial is the first to evaluate the safety and efficacy of venetoclax in combination with the oral formulation of azacitidine compared with placebo plus oral azacitidine in patients with AML who have achieved CR or CRi after induction and consolidation therapies. The findings from this study may support the use of this combination as an improved strategy for maintenance therapy in patients with AML in first remission.
The VIALE-M maintenance trial is currently enrolling eligible patients. For additional information, please visit the National Clinical Trial website [61].
Venetoclax-azacitidine combination regimen
Previously reported studies have shown the safety and increased efficacy of the venetoclax plus azacitidine combination regimen compared with the control treatment of placebo plus azacitidine in newly diagnosed patients with acute myeloid leukemia (AML) who were ineligible to receive intensive chemotherapy. Combined therapy with venetoclax and azacitidine has also been shown to eradicate leukemic stem cells through disruption of the metabolic machinery in AML.
The VIALE-M trial
The phase III randomized, double-blind, two-arm, multicenter VIALE-M (M19-708 Study) clinical trial was initiated to determine the recommended phase III dose of venetoclax in combination with oral azacitidine (CC-486) that can be safely administered as maintenance therapy, and to evaluate the safety and efficacy of venetoclax in combination with oral azacitidine versus placebo plus oral azacitidine as maintenance therapy for patients aged ≥18 years with newly diagnosed AML in first complete remission (CR) or incomplete count recovery (CRi) following intensive induction and consolidation therapies.
Following the dose-finding part of the study, approximately 426 patients will be randomized 1:1 to either placebo or venetoclax once a day for 24 cycles and oral azacitidine once a day for the first 14 days of each 28 day cycle for 24 cycles.
Patients aged 18 years and older with newly diagnosed AML per WHO 2016 classification must have achieved first CR or CRi (after induction) ≤120 days of first dose of study drug or ≤75 days past last dose of last consolidation cycle, have intermediate or poor risk cytogenetics per NCCN 2016 categorization, have Eastern Cooperative Oncology Group status ≤2, and have no history of acute promyelocytic leukemia or active CNS involvement with AML.
Objectives
The primary objective of the randomization portion of this study is to evaluate if venetoclax in combination with oral azacitidine as maintenance therapy improves relapse-free survival compared with placebo plus oral azacitidine in patients with AML who have achieved CR or CRi with conventional induction and consolidation chemotherapy.
Secondary objectives include OS, MRD conversion and improvement in quality-of-life.
Supplementary data
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Author contributions
V Ivanov, S-P Yeh, J Mayer, L Saini, A Unal and AT Fathi contributed to the manuscript draft; provided critical review for important intellectual content; approved the final version to be published, and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. M Boyiadzis contributed to the design of the study and to the manuscript draft; provided critical review for important intellectual content; approved the final version to be published and agrees to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. K Kang and SN Addo contributed to the design of the study; contributed to the manuscript draft and provided critical review for important intellectual content; provided final approval of the version to be published, and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. DM Hoffman and WL Mendes made substantial contributions to the conception and design of the study; contributed to the manuscript draft and provided critical review for important intellectual content; provided final approval of the version to be published, and agree to be accountable for all aspects of the manuscript ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.
Acknowledgments
The authors would like to thank all the patients and their families, the study investigators, study coordinators and support staff of the M19-708 study.
Financial & competing interests disclosure
Venetoclax is being developed in collaboration between AbbVie and Genentech. AbbVie and Genentech provided financial support for the study and participated in the design, study conduct, as well as the writing, review and approval of the manuscript. No honoraria or payments were made for authorship. V Ivanov: investigator in AbbVie-funded clinical trials. Research funding from AbbVie, Novartis, Astellas, MSD, Ascentage Pharma and Takeda. SP Yeh: advisory board member for AbbVie, Amgen, Janssen, Astellas, Astex and Takeda. J Mayer: research funding from AbbVie. L Saini: advisory board for AbbVie, AMGEN, Astellas, Astex, Roche, Takeda, Gilead, Jazz Pharma, BMS, Novartis and Servier. A Unal: investigator in AbbVie-funded clinical trial. A Fathi: consulting with Genentech, AbbVie, Agios/Servier, Celgene/BMS, Forma, Ipsen, Astellas, Takeda, Morphosys, Novartis, Amgen. Clinical trial support from AbbVie, Celgene/BMS, Agios/Servier. M Boyiadzis: genentech employee and may own stock. DM Hoffman, K Kang, SN Addo and WL Mendes: abbVie employees and may own stock or stock options. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
Medical writing support was provided by A Balachandran and editorial support was provided by AT Hadsell, employees of AbbVie.
Ethical conduct of research
The study protocol, informed consent form(s), recruitment materials and all patient materials will be submitted to the IEC/IRB for review and approval. Approval of both the protocol and the informed consent form(s) will be obtained before any patient is enrolled. Any amendment to the protocol will require review and approval by the IEC/IRB before the changes are implemented to the study. In addition, all changes to the consent form(s) will be IEC/IRB approved. The study will be conducted in accordance with ICH guidelines, applicable regulations and guidelines governing clinical study conduct and the ethical principles that have their origin in the Declaration of Helsinki.
Data sharing statement
Included in trial registration: https://clinicaltrials.gov/ct2/show/NCT04102020?term=VIALE-M
AbbVie is committed to responsible data sharing regarding the clinical trials we sponsor. This includes access to anonymized, individual and trial-level data (analysis data sets), as well as other information (e.g., protocols, clinical study reports or analysis plans), as long as the trials are not part of an ongoing or planned regulatory submission. This includes requests for clinical trial data for unlicensed products and indications.
These clinical trial data can be requested by any qualified researchers who engage in rigorous, independent, scientific research and will be provided following review and approval of a research proposal, statistical analysis plan and execution of a data sharing agreement. Data requests can be submitted at any time after approval in the USA and Europe and after acceptance of this manuscript for publication. The data will be accessible for 12 months, with possible extensions considered. For more information on the process or to submit a request, visit the following link: https://www.abbvie.com/our-science/clinical-trials/clinical-trials-data-and-information-sharing/data-and-information-sharing-with-qualified-researchers.html
Open access
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Papers of special note have been highlighted as: • of interest; •• of considerable interest
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