Dose-escalation of second-line and first-line asciminib in chronic myeloid leukemia in chronic phase: the ASC2ESCALATE Phase II trial

Abstract

Up to 40% of newly diagnosed patients with chronic myeloid leukemia in chronic phase (CML-CP) discontinue treatment by 5 years, primarily due to resistance or intolerance. Rates of resistance to second-line (2L) treatment are also high. Some patients with resistance respond with dose escalation of tyrosine kinase inhibitors (TKIs). Asciminib demonstrated safety and efficacy across a broad dosage range. ASC2ESCALATE is an ongoing, Phase II, multicenter, single-arm, dose-escalation study of asciminib in 2L and first-line treatment of CML-CP. The primary end point is major molecular response at 12 months in 2L. Secondary end points include molecular responses at and by scheduled time points, survival, and safety. ASC2ESCALATE is the first study investigating asciminib in CML-CP following failure of one prior TKI.

Clinical Trial Registration: NCT05384587 (ClinicalTrials.gov)

Tweetable Abstract

ASC2ESCALATE is an ongoing, Phase II, multicenter, single-arm, #dose-escalation study of oral asciminib in first-line and second-line treatment for patients with #CML in chronic phase

Plain language summary

Article highlights.

Asciminib in the treatment of CML

• Asciminib is the first BCR::ABL1 inhibitor that works by Specifically Targeting the ABL1 Myristoyl Pocket (STAMP).

• Asciminib demonstrated favorable efficacy and safety in a Phase I study and in the Phase III ASCEMBL study.

• The Phase II ASCEND study suggested favorable efficacy and tolerability as first-line (1L) treatment for chronic myeloid leukemia in chronic phase (CML-CP).

The ASC2ESCALATE trial (NCT05384587)

• ASC2ESCALATE is a Novartis-sponsored, ongoing, Phase II, multicenter, single-arm, dose-escalation study of oral asciminib in second-line (2L) and 1L treatment of CML-CP.

• ASC2ESCALATE is the first study to assess asciminib in 2L and a dose-escalation strategy of asciminib in 2L and 1L for patients with CML-CP not meeting molecular milestones.

• The 2L cohort includes patients who have experienced treatment warning, resistance, or failure of or intolerance to their 1L TKI, and the 1L cohort includes newly diagnosed patients.

• All patients initiate treatment with asciminib at 80 mg QD and patients achieving BCR::ABL1^IS ≤1% at 6 months continue at the same dose, whereas patients not achieving this goal will escalate their dose to 200 mg QD.

• Patients not achieving major molecular response (MMR) at 12 months will undergo either dose escalation from 80 mg QD to 200 mg QD or from 200 mg QD to 200 mg BID. Additionally, if it is in the best interest of the patient based on the investigator's clinical judgement of prospective treatment benefit, the patient may be taken off the study and switched to the investigator's agent of choice.

Objectives & end points of the ASC2ESCALATE study

• The primary end point of this study is the proportion of patients receiving asciminib as their 2L TKI who achieve MMR at 12 months.

• Secondary end points include MMR rates at 3, 6, 18, and 24 months; MMR rates by all scheduled time points; MR² (BCR::ABL1^IS ≤1%), MR⁴ (BCR::ABL1^IS ≤0.01%) and MR^4.5 (BCR::ABL1^IS ≤0.0032%) at and by scheduled time points; time to and duration of MMR; time to treatment failure; progression-free survival; overall survival and safety/tolerability.

• All primary and secondary end points for the 2L cohort will be measured for the 1L cohort as secondary end points.

• Exploratory end points include assessment of BCR::ABL1 mutations, as well as healthcare resource utilization and impact of treatment on patient-reported outcomes.

Conclusion

• The ongoing ASC2ESCALATE trial is the first clinical trial designed to assess asciminib in patients with CML-CP requiring 2L therapy and will provide critical information on the efficacy and safety of dose escalation for patients not meeting response milestones in 1L and 2L.

1. Introduction

1.1. Background & rationale

ATP-binding tyrosine kinase inhibitors (TKIs) have been markedly successful in allowing most patients with chronic myeloid leukemia in chronic phase (CML-CP) to have a life expectancy nearing that of the general population [1–5]. With the introduction of ATP-binding TKIs to clinical practice over 20 years ago, clinicians now have a broad range of options to choose from when treating CML [3,6]. For patients with newly diagnosed CML-CP, such options include the first-generation TKI imatinib and the second-generation (2G) TKIs bosutinib, dasatinib and nilotinib [6]. Based on long-term efficacy data from randomized Phase III trials of first-line (1L) TKIs, all options are highly effective treatment of newly diagnosed CML-CP, demonstrating major molecular response (MMR; BCR::ABL1^IS [International Scale] ≤0.1%) rates ranging from 60 to 65% for imatinib and 74 to 77% with 2G TKIs by 5 years in addition to 5-year overall survival (OS) rates of up to 96% [7–9].

Despite these advances, 28 to 40% of newly diagnosed patients with CML-CP discontinue 1L treatment by 5 years, primarily due to resistance or intolerance, prompting a switch to second-line (2L) therapy [7–10]. Although availability of several TKIs provides alternative options, switching is frequently not associated with an optimal clinical outcome [6,11,12]. Additionally, for patients who have experienced resistance with no specific BCR::ABL1 mutation, there is no clear recommendation for the optimal next TKI [6]. Patients with CML-CP are limited to alternative options with a similar mechanism of action [6,13]. When patients experience treatment failure of a 2G TKI in 1L, the estimated rate of treatment failure when using a 2G TKI in 2L is up to 60% [14]. In addition, discontinuation rates increase in 2L with observed overall discontinuation rates up to 86% [15]. OS also decreases with each subsequent line of therapy [16]. These limitations of approved ATP-binding TKIs for CML-CP underscore need for novel agents to treat the disease more optimally in the earliest lines of therapy.

Asciminib is the first BCR::ABL1 inhibitor that Specifically Targets the ABL Myristoyl Pocket (STAMP), differentiating it from the aforementioned ATP-binding TKIs [17]. Due to the unique binding site of asciminib, it can overcome mutations conferring resistance to ATP-binding TKIs. In addition, asciminib has improved specificity due to differing structures of myristate pocket binding sites in proteins other than BCR::ABL1. This is expected to reduce off-target effects occurring with ATP-binding TKIs [13]. These features provide asciminib with potential to overcome barriers to traditional ATP-binding TKIs.

A large Phase I dose-finding trial demonstrated asciminib can be effective and safe at doses up to 200 mg twice a day (BID) [18]. In this trial, MMR was achieved or maintained with asciminib by 12 months in approximately half of patients treated with ≥2 prior TKIs [18]. An observed flat exposure-safety relationship was demonstrated across doses of 80 to 200 mg once a day (QD) and 10 to 200 mg BID in patients with CML-CP/accelerated phase (AP) without and with the T315I mutation previously treated with ≥2 and ≥1 TKIs, respectively [18]. Importantly, no maximum tolerated dose was reached during this study [18]. In the Phase III ASCEMBL study, asciminib 40 mg BID showed superior efficacy compared with bosutinib 500 mg QD in patients with CML-CP after ≥2 prior TKIs with rates of MMR at week 24—the primary end point of the study—of 25.5 and 13.2%, respectively [19]. This effect was durable, and MMR rates remained consistently higher with asciminib compared with bosutinib. MMR rates at week 96, the key secondary end point of the study, were 37.6 and 15.8%, respectively [20–22]. Thus, ASCEMBL met primary and key secondary study objectives. Additionally, deep molecular responses (DMRs) were achieved in more patients treated with asciminib than with bosutinib. At week 96, DMR rates MR⁴ (BCR::ABL1^IS ≤0.01%) and MR^4.5 (BCR::ABL1^IS ≤0.0032%) were consistently higher with asciminib (17.2 and 10.8%, respectively) than with bosutinib (10.5 and 5.3%, respectively) [20–22]. Despite longer duration of exposure to asciminib compared with bosutinib in ASCEMBL, a lower proportion of patients receiving asciminib than bosutinib experienced all-grade and grade ≥3 adverse events (AEs), and fewer patients receiving asciminib discontinued due to AEs (7.7%) than with bosutinib (26.3%) by week 96 [20–22].

Based on the primary results from ASCEMBL, asciminib received accelerated approval by the US FDA for patients with CML-CP treated with ≥2 prior TKIs and full approval for patients with CML-CP with the T315I mutation based on results of the Phase I study in October 2021. Asciminib was later approved in August 2022 by the European Medicines Agency for patients treated with ≥2 prior TKIs [23–25]. Asciminib has also received worldwide approvals outside of the United States and Europe in countries such as Japan, Switzerland and the UK [26]. Additional approvals are underway in Latin American and Middle Eastern countries as well.

Asciminib has not been evaluated in 2L except for instances where patients have the T315I mutation [18,22]. Considering the encouraging efficacy and safety profile of asciminib demonstrated in heavily pretreated patients and high failure rates associated with currently approved TKIs in 2L, there is significant interest in evaluating asciminib as an additional treatment option for patients with CML-CP whose 1L TKI has been associated with treatment failure [18,20–22,27]. Dose-escalation studies with imatinib show patients experiencing resistance to therapy can achieve durable responses with higher doses of their TKI [28]. The IRIS study demonstrated that of patients with CML-CP not meeting molecular response milestones per previously published European LeukemiaNet (ELN) recommendations, 67% achieved or regained complete hematologic responses and 38% achieved or regained cytogenetic responses within 12 months of imatinib dose escalation [29]. An additional study of 84 patients demonstrated 40% of patients experienced long-lasting complete cytogenetic responses with imatinib dose escalation [28]. The ENESTxtnd study evaluated dose escalation of nilotinib in newly diagnosed patients with treatment failure or suboptimal responses on 300 mg BID. This study found most patients could achieve MMR by 12 months with 300 mg BID. Of patients with dose escalation to 400 mg BID, most were able to remain on this dose until end of treatment and of those who escalated due to lack of efficacy, most achieved MMR by 24 months [30]. Therefore, there is considerable interest in evaluating whether patients who do not meet molecular milestones can benefit from a dose-escalation approach with asciminib.

In 1L, asciminib has been undergoing ongoing evaluation in the Phase II ALLG CML13 ASCEND trial. With 23 months of follow-up, results of ASCEND demonstrated an early molecular response rate of 93% in newly diagnosed patients treated with asciminib. Rates of MMR and MR^4.5 were 78 and 32%, respectively, at 12 months. Asciminib was well tolerated with mostly low-grade AEs not resulting in treatment discontinuation [31].

Based on emergence of promising efficacy and safety data of asciminib in 1L, as well as the high efficacy and enduring long-term safety of asciminib in patients who have received ≥2 prior TKIs seen in the Phase I study and ASCEMBL, there is a strong rationale for further evaluation of asciminib in newly diagnosed patients with CML-CP aiming to improve the rates of DMR necessary for considering treatment-free remission [20–22,31,32]. Additionally, extensive exposure-safety and exposure-efficacy analyses performed on pooled data demonstrate no correlation between probability of a safety event and increased exposure and a positive exposure-efficacy relationship, suggesting a positive risk/benefit ratio with higher doses of asciminib [33]. Therefore, a dose-escalation approach with asciminib in 1L may allow for patients who do not achieve optimal milestones to remain on asciminib without the need to switch therapies, thereby increasing likelihood of DMR at later milestones without sacrificing safety.

1.2. Objectives

The primary objective of this study is to determine the efficacy of asciminib in the 2L cohort of patients with CML-CP. Secondary objectives include investigation of different molecular responses, progression-free survival (PFS), OS, and safety/tolerability. Exploratory objectives include assessing impact of treatment on patient-reported outcomes, evaluating healthcare resource utilization (HCRU) and characterizing BCR::ABL1 gene mutations. All primary and secondary analyses will be repeated for patients in the 1L cohort as secondary objectives (Table 1).

Table 1.

Objectives and related end points.

Objectives	End points
Primary objectivea   • To determine efficacy of asciminib in patients with CML-CP in the 2L setting	End point for primary objectives   • Proportion of patients achieving MMR at 12 months in the 2L setting
Secondary objectivesa   • To investigate MR4.5 efficacy of asciminib   • To investigate MMR rate at time points other than 12 months   • To investigate MR2, MR4, and MR4.5 rate at visit   • To investigate MR2, MMR, MR4, and MR4.5 rate by visit   • To investigate the time to MMR   • To investigate the duration of MMR   • To investigate the TTF   • To investigate PFS   • To investigate OS   • To determine the safety and tolerability profile of asciminib in patients with CML-CP	End points for secondary objectives   • Proportion of patients who achieve MR4.5 at 24 months   • MMR rate at all scheduled data collection time points, including 3, 6, 18, and 24 months   • MR2, MR4, and MR4.5 at all scheduled data collection time points except for MR4.5 at 24 months   • MR2, MMR, MR4, and MR4.5 rates by all scheduled data collection time points, including 3, 6, 12, 18, and 24 months   • Time to MMR   • Duration of MMR   • TTF   • Time from the first dose of study treatment to the earliest occurrence of documented disease progression to AP/BP or the date of death from any cause, before the cutoff date   • Time from the first dose of study treatment to death due to any cause during the study   • Type, frequency, and severity of AEs; changes in laboratory values that fall outside the predetermined ranges; and clinically notable ECG and other safety data (vital signs, physical examination)
Exploratory objectives   • To characterize mutations in the BCR::ABL1 gene at baseline and during therapy and their association with molecular responses and clinical end points   • To assess the impact of treatment on PROs, including CML-specific symptoms and patient quality of life   • To evaluate the healthcare resource utilization during 24 months	• BCR::ABL1 gene mutations detected at baseline, during study treatment, and upon confirmed loss of response (per ELN 2020)/EOT   • Change in symptom burden and interference from baseline over time according to the MDASI-CML PRO instrument   • Change in health utility from baseline over time according to EQ-5D-5L   • Measurement of healthcare resource utilization with number and percentage of patients hospitalized, the total and average number of hospitalizations, reason for hospitalization, and type of hospital facility during 12 and 24 months

2L: Second line; AE: Adverse event; AP: Accelerated phase; BP: Blast phase; CML-CP: Chronic myeloid leukemia in chronic phase; ECG: Electrocardiogram; ELN: European LeukemiaNet; EOT: End of treatment; IS: International Scale; MDASI-CML: MD Anderson Symptom Inventory for Chronic Myelogenous Leukemia; MMR: Major molecular response; MR²: BCR::ABL1^IS ≤1%; MR⁴: BCR::ABL1^IS ≤0.01%; MR^4.5: BCR::ABL1^IS ≤0.0032%; OS: Overall survival; PFS: Progression-free survival; PRO: Patient-reported outcome; TTF: Time to treatment failure.

^aAll the primary and secondary analyses will be repeated for 1L patients with CML-CP, as secondary objectives of the study.

Data taken from [1,2].

1.3. ASC2ESCALATE trial design

ASC2ESCALATE is a Novartis-sponsored, ongoing, Phase II, multicenter, single-arm, dose-escalation study of oral asciminib in 2L and 1L treatment of CML-CP in the United States (Figure 1; ClinicalTrials.gov identifier: NCT05384587) [1,2,34,35].

Figure 1.

Study design for the Phase II ASC2ESCALATE trial (NCT05384587) [1,2].

1L: First line; 2L: Second line; BID: Twice a day; IS: International Scale; MMR: Major molecular response; NGS: Next-generation sequencing; QD: Once a day; TKI: Tyrosine kinase inhibitor.

^aThe patient will be taken off the study and switched to an investigator’s agent of choice if it is in the best interest of the patient.

2. Materials & methods

2.1. Eligibility criteria

2.1.1. Common to both 2L & 1L cohorts

Patients eligible to be included are ≥18 years of age and have diagnosed CML-CP (according to World Health Organization criteria) with no history of CML-AP or blast phase (BP). Additional inclusion criteria include an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2; adequate end-organ function within 14 days prior to the first dose of asciminib treatment; and written informed consent.

Patients are excluded if they have had prior treatment with asciminib, have known second CML-CP after prior progression to AP/BP, have had a hematopoietic stem cell transplant, or have a planned allogeneic hematopoietic stem cell transplant. Additional exclusion criteria include certain cardiac conditions, a history of pancreatitis, certain medications that may raise or lower levels of asciminib, pregnant or breast-feeding women, or women of childbearing potential unless on highly effective contraception. Patients will be tested for the T315I mutation and excluded if the mutation is found at screening.

2.1.2. Specific to the 2L cohort

Patients may be included if they meet the definition of warning, failure or intolerance to 1L TKI therapy at the time of screening. As per 2020 ELN recommendations, a warning response is defined in this trial as BCR::ABL1^IS >1%–10% or BCR::ABL1^IS >0.1%–1% at 6 and 12 months after start of treatment, respectively. Treatment failure is defined as BCR::ABL1^IS >10% with 6 to 12 months, BCR::ABL1^IS >1% with >12 months, or loss of MMR with >12 months of 1L treatment. Patients who experience intolerance to their 1L TKI may also be included if they have BCR::ABL1^IS >0.1% [6]. If patients are enrolling due to intolerance to their 1L TKI, there is no mandatory duration for which they must have received their 1L TKI. To be enrolled in the 2L cohort, patients need only to have experienced either warning, failure or intolerance to 1L therapy as defined above. Patients are excluded if they have been treated with ≥2 prior ATP-binding site TKIs.

2.1.3. Specific to the 1L cohort

Patients are allowed to be included in the 1L cohort even if treated with a prior TKI (imatinib, nilotinib, dasatinib or bosutinib) for ≤4 weeks prior to enrollment.

Figure 2 contains a complete list of eligibility criteria for both cohorts.

Figure 2.

Eligibility criteria [1,2].

1L: First line; 2L: Second line; AP: Accelerated phase; AV: Atrioventricular; BID: twice a day; BP: Blast phase; CML-CP: Chronic myeloid leukemia in chronic phase; ECOG: Eastern Cooperative Oncology Group; ELN: European LeukemiaNet; IS: International Scale; MMR: Major molecular response; QD: Once a day; QTcF: QTc interval corrected with the Fridericia formula; TKI: Tyrosine kinase inhibitor; ULN: Upper limit of normal.

^aPatients can have experienced treatment warning, resistance or failure of or intolerance to their 1L TKI to be eligible for the 2L cohort.

2.2. Interventions

All patients will initiate treatment with asciminib at 80 mg QD. Dose escalation may occur at 6 and 12 months of treatment depending on the patient's BCR::ABL1^IS results. Patients achieving BCR::ABL1^IS ≤1% at 6 months will continue at the same dose, whereas patients who do not achieve this will have their dose escalated to 200 mg QD. For patients not achieving MMR at 12 months, dose escalation to 200 mg QD if patients are on 80 mg QD or to 200 mg BID if patients are on 200 mg QD will occur. In addition, if MMR is not achieved at 12 months and if it is in the patient’s best interest based on the investigator's clinical judgement of prospective treatment benefit, the patient may be taken off the study and switched to the investigator's agent of choice (Figure 1). If patients have grade ≥3 or persistent grade 2 toxicity refractory to optimal management, no dose escalation will occur, and patients will remain on asciminib at their most current dosage.

The dose-escalation strategy described above will be the same for the 1L cohort. Patients who derive clinical benefit from asciminib as per investigator’s assessment may receive post-trial access in accordance with applicable local and US laws. Patients may also discontinue at any time due to unacceptable toxicity or progression at the discretion of investigator or patient.

2.3. Outcomes

To assess the primary objective, the proportion of patients achieving MMR at 12 months in the 2L setting will be measured as the primary end point. Secondary efficacy end points are the same for 2L and 1L cohorts and include MMR rates at 3, 6, 18 and 24 months (MMR at 12 months for patients in the 1L cohort as a secondary end point); MMR rates by all scheduled time points; MR² (BCR::ABL1^IS ≤1%), MR⁴, and MR^4.5 at and by scheduled time points; time to and duration of MMR; time to treatment failure (TTF) and time from first dose of study treatment to disease progression or death due to any cause (Table 1).

2.4. Participant timeline

Patients in both 2L and 1L cohorts will be treated up to the end of their study treatment period, defined as ≤104 weeks after the patient receives their first dose. The end of the study will occur when the last patient enrolled completes 104 weeks of treatment or experiences treatment failure.

2.5. Planned sample size

Approximately 92 patients will be enrolled for the 2L patient cohort in order to obtain ≥83 evaluable patients in the study. For the 1L cohort, enrollment will be stopped when a maximum of 90 patients have been enrolled or when approximately 60 patients have been enrolled and the 2L cohort is fully recruited, whichever is first.

2.6. Data collection & monitoring

All screening assessments will occur within 28 days before week 1 (day 1), and written informed consent will be obtained before any study-specific procedures. Patients will undergo baseline laboratory assessments in addition to medical evaluation to include history and physical, as well as electrocardiogram. Mutational analysis for T315I will be performed by Sanger sequencing at a Novartis designated laboratory at screening.

Pharmacokinetics will be assessed using blood samples from all patients receiving asciminib. Serial blood samples will be collected at several time points, and additional pharmacokinetic blood sample collections will occur for patients proceeding with dose escalation (weeks 28 and 40 only for patients with dose escalation at 6 months and weeks 52 and 64 only for patients with dose escalation at 12 months).

For molecular response assessments, BCR::ABL1 transcripts will be determined by real-time quantitative polymerase chain reaction centrally at screening and weeks 4, 12, 24, 36, 48, 60, 72, 84, 96 and 104. A sample will be obtained at screening and at weeks 24, 48, 72, 96 and 104 to assess for BCR::ABL1 mutations via next-generation sequencing.

2.7. Harms

Safety will be assessed at scheduled intervals and laboratory measures will be analyzed at each scheduled visit. AEs will be assessed using the Common Terminology Criteria for Adverse Events (CTCAE) version 5, and serious AEs should be reported to Novartis within 24 h of learning of their occurrence. An additional 30-day safety follow-up should be conducted after the end of the study treatment.

Patients should be discontinued from the study if the investigator believes continuation would be detrimental to them. Given potential risks related to dose escalation, specific details regarding dose modification and discontinuation are included within the study protocol, which also includes recommendations for supportive care of expected toxicities. Patients should also be discontinued if they experience treatment failure as defined by the ELN [6]. Patients who discontinue study treatment due to an AE should be followed up at least weekly for 4 weeks, until event resolution or stabilization, whichever comes first. If new mutations such as T315I are detected by exploratory next-generation sequencing in the absence of treatment failure, the patient may continue on study at the same dose unless they meet the criteria for dose escalation.

2.8. Auditing

Investigator sites, vendors and Novartis systems are audited by auditors separate from those conducting, monitoring, or performing quality control of the trial and are conducted to ensure compliance with global and local requirements, protocols and internal standard operating procedures.

2.9. Data management

Data entered by the investigational staff will be reviewed by Novartis personnel to ensure accuracy and completeness. Designated investigator site staff will respond promptly to queries and make data changes upon receipt. Once the required actions have been performed and the data are declared complete and accurate, it will be locked and ready for data analysis.

2.10. Statistical methods

Data will be analyzed by Novartis and/or a designated contract research organization. Data from all participating sites for this protocol will be combined. Categorical data will be presented in frequencies and percentages, and descriptive statistics will be provided for continuous data; 95% CIs will also be reported as appropriate, along with Kaplan–Meier estimates for time-to-event variables. All safety parameters will be summarized, and no inferential tests for safety analyses will be performed.

2.10.1. Analysis sets

The full analysis set (FAS) comprises all patients to whom study treatment has been assigned. Patients will be analyzed according to the assigned treatment regimen. The FAS will be used for all efficacy analyses and for analyzing patient-reported outcomes data and HCRU data. All patients with evaluable biomarker measurements in the FAS will be included in the biomarker analysis. The FAS will also be used to list and summarize demographic and other baseline data, including disease characteristics. The safety set will be used for all safety analysis and includes all patients who received ≥1 dose of study treatment.

2.10.2. Primary objective

To measure the primary objective of this study, measurement of MMR achieved at 12 months in the 2L cohort will be performed. This objective will be assessed using the FAS.

The proportion of patients achieving MMR at 12 months will be presented together with an exact 95% Clopper–Pearson CI at the one-sided 2.5% level of significance. The null hypothesis is that the proportion of patients achieving MMR is ≤0.30. The alternative hypothesis is that the proportion of patients achieving MMR is >0.30. Successful achievement of MMR at 12 months will be demonstrated and the null hypothesis rejected if the lower limit of the 95% CI is >0.30. The 0.30 cutoff was chosen based on the observed MMR of 29.3% at week 48 and cumulative incidence of MMR of 33.2% by week 48 in the ASCEMBL trial in patients with ≥2 prior TKIs and the expectation that MMR rates will be higher in earlier lines of treatment [34].

2.10.3. Secondary objectives

To measure secondary efficacy objectives of this study, the FAS will be used for analysis of all secondary efficacy end points and no statistical analysis of secondary efficacy end points will be performed. Time-to-event variables such as duration of MMR, TTF, PFS and OS will be analyzed by the Kaplan–Meier method. Since the number of patients undergoing dose escalation is expected to be small, end points of MR⁴ and MR^4.5 will be evaluated for all patients regardless of dose escalation. In 1L, there will be no formal testing of DMR after dose escalation.

Safety analysis will be conducted on the safety set, and data will be presented using summary statistics only. Incidence of treatment-emergent AEs will be summarized by system organ class and/or preferred term, severity as per CTCAE version 5, type, and relation to study treatment. In addition, all deaths will be summarized. Serious and non-serious AEs during the treatment period will be tabulated. All deaths, serious AEs, AEs of special interest, AEs leading to discontinuation, and grade ≥3 AEs will be summarized for those patients who undergo dose escalation. Shift tables will be used to summarize changes in laboratory values, and all vital signs and 12-lead electrocardiogram data will be summarized by visit/time.

2.10.4. Exploratory objectives

The exploratory biomarker objective is to characterize mutations in the BCR::ABL1 gene at baseline and during therapy and to assess their association with molecular responses to therapy and clinical end points. As the study is not powered to assess specific biomarker-related hypotheses, statistical analyses of these data should be considered exploratory.

The MD Anderson Symptom Inventory for Chronic Myelogenous Leukemia (MDASI-CML) and EQ-5D-5L will be used to compare data on the patient’s disease-related symptoms and health-related quality of life from baseline to end of treatment. Descriptive statistics will be provided for the MDASI-CML symptom and interference scores and the change in scores from baseline to all available time points to the end of study. Descriptive statistics will be provided for EQ-5D-5L health index scores and for the EQ visual analogue scale at each scheduled assessment time point.

Measures of HCRU include hospital, emergency room, general practitioner, specialist and urgent care visits. Frequency and duration of hospitalizations, as well as the frequency of visits, will be measured from baseline to end of treatment. At each HCRU occurrence collected, the reason (i.e., related to CML, AE related to CML) will also be collected to quantify impact of treatment on healthcare resources. HCRU data will be summarized with descriptive statistics for quantitative variables and with count and percentage for qualitative variables. Summary statistics will include additional data around hospitalizations (i.e., number of patients hospitalized and reason for hospitalization).

3. Ethics & dissemination

ASC2ESCALATE was designed in accordance with the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use Harmonized Tripartite Guidelines for Good Clinical Practice (ICH/GCP), with applicable local regulations and with the ethical principles described in the Declaration of Helsinki. Approval from the Institutional Review Board/Independent Ethics Committee for the trial protocol, written informed consent form, consent form updates, patient recruitment procedures, and any other written information to be provided to patients will be obtained from each study site. Written informed consent is to be obtained from all study participants involved via a separate document provided to investigators by the study sponsor complying with ICH/GCP guidelines and regulatory requirements.

4. Conclusion

In this first clinical trial to assess asciminib in patients with CML-CP who require 2L therapy (ASC2ESCALATE), both efficacy and safety of dose escalation in patients not meeting certain response milestones in 2L and 1L will be assessed. By employing a dose-escalation strategy with asciminib treatment in 2L and 1L, ASC2ESCALATE will provide critical information on whether increasing asciminib dose might enable a greater proportion of patients with CML-CP to meet milestones in achieving molecular responses, thereby providing another option for those experiencing intolerance of or resistance to ATP-binding TKIs.

Funding Statement

The ASC2ESCALATE study presented here is sponsored and funded by Novartis Pharmaceuticals Corporation.

Author contributions

All authors were involved in the development and approval of this manuscript. Authors had full control of the content and made the final decision on all aspects of this publication.

Financial disclosure

The ASC2ESCALATE study presented here is sponsored and funded by Novartis Pharmaceuticals Corporation. All authors received nonfinancial support (assistance with manuscript preparation) from Nucleus Global, which received funding from Novartis Pharmaceuticals Corporation.

Competing interests disclosure

EL Atallah is a member of the speakers' bureau for Bristol Myers Squibb, AbbVie, and Blueprint and received consulting fees from Novartis, Bristol Myers Squibb, and AbbVie and research funding from Novartis, Takeda, and AbbVie. MJ Mauro received personal fees from Bristol Myers Squibb, Takeda, and Pfizer. K Sasaki received research funding and honoraria for advisory boards from Novartis. MY Levy received honoraria from and is a member of the speakers’ bureau for TG Therapeutics, Epizyme, GSK, Novartis, Dova, AbbVie, Amgen, Bristol Myers Squibb, Janssen, Karyopharm, Morphosys, Seagen, Takeda, AstraZeneca, BeiGene, Gilead, Jazz Pharmaceuticals and Sanofi and is a member of the board of directors/advisory committees for Sellas. P Koller received consulting fees and honoraria for speakers' bureau from Novartis and Takeda, consulting fees from Bristol Myers Squibb, Daiichi Sankyo, and Ascentage, and safety review committee for Treadwell Therapeutics. D Yang is an employee of Novartis. D Laine is an employee of Novartis. J Sabo is an employee of Novartis. E Gu is an employee of Novartis. JE Cortes received grants and consulting fees from Novartis and Pfizer and grants from Bristol Myers Squibb. 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.

Writing disclosure

Medical writing support was provided by Christopher DiMaio, MD (Nucleus Global). Writing support was funded by Novartis Pharmaceuticals Corporation.

Data availability statement

This is a clinical trial protocol manuscript and no data is being reported. After the primary study results have been accepted for publication, de-identified individual participant data and supporting documents may be available upon request.

Ethical conduct of research

The authors state that this clinical study was designed and shall be implemented, executed, and reported in accordance with the ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable local regulations (including European Directive 2001/20/EC, US CFR 21), and following the principles outlined in the Declaration of Helsinki. Approval from the Institutional Review Board/Independent Ethics Committee shall be obtained from each study site. Additionally, signed informed consent will be obtained from each participant in the study.