The list of preferred terms included in grouped terms used for safety analysis in X2101 trial

Specific dose modification strategies for concomitant use of asciminib with other drug products

Select laboratory abnormalities (≥ 10%) that worsened from baseline in patients with Ph + CML in CP, previously treated with two or more tyrosine kinase inhibitors in ASCEMBL

The list of preferred terms included in grouped terms used for safety analysis in ASCEMBL

Supplementary Figure 1: Trends in Mortality by Leukemia Subtypes and Race Ethnicity. Total US 1992-2018. Results are shown for mortality trends for CML (panel A), ALL (panel B), and CLL (panel C), 1992-2018. For each panel, we show age-adjusted mortality rates by five mutually exclusive race-ethnicity categories: non-Hispanic White, non-Hispanic Black, non-Hispanic Asian Pacific Islander, non-Hispanic American Indian/Alaskan Natives, and Hispanic.

On June 6, 2024, the US Food and Drug Administration (FDA) approved imetelstat (RYTELO, Geron) for adults with low- to intermediate-1 risk myelodysplastic syndromes (MDS) with transfusion-dependent anemia requiring ≥4 red blood cell units over 8 weeks who have not responded to or have lost response to or are ineligible for erythropoiesis-stimulating agents. The approval was based on a randomized (2:1), double-blind, placebo-controlled multicenter trial, Study MDS3001. In the protocol-specified primary analysis, the ≥8-week RBC transfusion independence (RBC-TI) rate was 39.8% (95% CI, 30.9 to 49.3) in the imetelstat group versus 15% (95% CI, 7.1 to 26.6) in the placebo group (P < .001). This was supported by the rate of ≥24-week RBC-TI of 28% (95% CI, 20.1 to 37) in the imetelstat group versus 3.3% (95% CI, 0.4 to 11.5) in the placebo group (P < .001). However, there was no major difference between arms regarding the key secondary end point of erythroid response (HI-E) per International Working Group 2006 criteria or secondary end points reflective of a disease-modifying effect such as complete remission rate and overall survival. The most common adverse reactions were thrombocytopenia, leukopenia, neutropenia, increased liver enzymes, fatigue, prolonged partial thromboplastin time, arthralgia/myalgia, COVID-19, and headache. The rate of grade 3 to 4 neutropenia and thrombocytopenia were 72% and 65%, respectively, in the imetelstat arm compared with 7% and 8% in the placebo arm. Despite the high incidence of neutropenia and thrombocytopenia, the FDA determined that the benefits outweighed the risks in this patient population with high unmet need. Postmarketing requirements were issued to evaluate long-term safety and to conduct a randomized trial comparing at least two dosages of imetelstat to potentially minimize risks of imetelstat treatment and improve tolerability.

ABSTRACT:Myelodysplastic syndromes/neoplasms (MDSs) are heterogeneous stem cell malignancies characterized by poor prognosis and no curative therapies outside of allogeneic hematopoietic stem cell transplantation. Despite some recent approvals by the US Food and Drug Administration, (eg, luspatercept, ivosidenib, decitabine/cedazuridine, and imetelstat), there has been little progress in the development of truly transformative therapies for the treatment of patients with MDS. Challenges to advancing drug development in MDS are multifold but may be grouped into specific categories, including criteria for risk stratification and eligibility, response definitions, time-to-event end points, transfusion end points, functional assessments, and biomarker development. Strategies to address these challenges and optimize future clinical trial design for patients with MDS are presented here.

Abstract On October 29, 2021, FDA granted accelerated approval to asciminib (SCEMBLIX; Novartis), a tyrosine kinase inhibitor (TKI), for the treatment of adult patients with Philadelphia chromosome positive chronic myeloid leukemia (Ph+ CML) in chronic phase (CP), previously treated with two or more TKIs, and granted traditional approval to asciminib for adult patients with Ph+ CML in CP with the T315I mutation. The first indication was approved based on major molecular response (MMR) at 24 weeks in the ASCEMBL study, a randomized trial comparing asciminib with bosutinib in patients who had failed two or more TKIs. This indication was ultimately granted traditional approval on October 12, 2022, based on safety data and MMR rate at 96 weeks of 38% [95% confidence interval (CI), 30–46] in the asciminib arm versus 16% (95% CI, 8–26) in the bosutinib arm (P value: 0.001). The second indication was approved based on MMR rate by 96 weeks of 49% (95% CI, 34–64) in the single-arm CABL001X2101 study. The most common (≥20%) adverse reactions included upper respiratory tract infections, musculoskeletal pain, headache, fatigue, nausea, rash, and diarrhea. The most common (≥20%) laboratory abnormalities were thrombocytopenia, neutropenia, anemia, lymphopenia, hypertriglyceridemia, hyperuricemia, and increases in creatine kinase, alanine aminotransferase, aspartate aminotransferase, lipase, and amylase. This manuscript describes the basis for approval of these indications.

Myeloid blast-phase chronic myeloid leukemia (MBP-CML) is a rare disease with a dismal prognosis. It is twice as common as lymphoid blast-phase CML, and its prognosis is poorer. Despite the success with tyrosine kinase inhibitors in the treatment of chronic-phase CML, the same does not hold true for MBP-CML. In addition to the Philadelphia chromosome, other chromosomal and molecular changes characterize rapid progression. Although some progress in elucidating the biology of MBP-CML has been made, there is need to discover more in order to develop more satisfactory treatment options. Currently, most common treatment options include tyrosine kinase inhibitors (TKIs) as monotherapy or in combination with acute myeloid leukemia-based intensive chemotherapy regimens. Some patients may develop resistance to TKIs via BCR-ABL1-dependent or BCR-ABL1-independent mechanisms. In this paper, we provide an overview of the biology of MBP-CML, the current treatment approaches, and mechanisms of resistance to TKIs. In order to improve treatment responses in these patients, more emphasis should be placed on understanding the biology of myeloid blastic transformation in CML and mechanisms of resistance to TKIs. Although patient numbers are small, randomized clinical trials should be considered.

AbstractIntroduction: Molecularly targeted therapies such as tyrosine kinase inhibitors (TKI) are effective treatments for B-cell receptor (BCR)-ABL–bearing leukemias. We evaluated the impact of TKIs on historical chronic myeloid leukemia (CML) mortality trends compared with acute lymphoblastic leukemia (ALL) and chronic lymphoblastic leukemia (CLL). Methods: Because mortality trends reflect combined effects of leukemia incidence and survival, we also evaluated the contribution of incidence and survival trends to mortality trends by subtypes. We used data from 13 U.S. (SEER) registries (1992–2017) among U.S. adults. We utilized histology codes to identify cases of CML, ALL, and CLL and death certificate data to calculate mortality. We used Joinpoint to characterize incidence (1992–2017) and mortality (1992–2018) trends by subtype and diagnosis year. Results: For CML, mortality rates started declining in 1998 at an average rate of 12% annually. Imatinib was approved by the FDA for treating CML and ALL in 2001, leading to clear benefits for patients with CML. Five-year CML survival increased dramatically over time, especially between 1996 to 2011, 2.3% per year on average. ALL incidence increased 1.5% annually from 1992 to 2017. ALL mortality decreased 0.6% annually during 1992 to 2012 and then stopped declining. CLL incidence fluctuated during 1992 to 2017 while mortality decreased 1.1% annually during 1992 to 2011 and at a faster rate of 3.6% per year from 2011. Five-year survival increased 0.7% per year on average during 1992 to 2016. Conclusions: Survival benefit from TKIs and other novel therapies for treating leukemia subtypes has been demonstrated in clinical trials. Impact: Our study highlights the impact of molecularly targeted therapies at the population level.

The FDA has an accelerated approval program for drugs that have been identified as promising treatments for serious conditions when the available data suggest that the benefits outweigh the foreseeable risks. All of the currently available treatment options for chronic myeloid leukemia (CML) initially went through the accelerated approval program. Here, a group of academic CML experts, patient panelists, and members from the FDA convened to discuss the utility of the accelerated approval program as it pertains to CML, and the utility of this program in future drug development in this disease. The results of that discussion are summarized here.

Myelodysplastic syndromes (MDS) have historically been challenging diseases for drug development due to their biology, preclinical modeling, and the affected patient population. In April 2022, the FDA convened a panel of regulators and academic experts in MDS to discuss approaches to improve MDS drug development. The panel reviewed challenges in MDS clinical trial design and endpoints and outlined considerations for future trial design in MDS to facilitate drug development to meaningfully meet patient needs. Challenges for defining clinical benefit in patients with MDS include cumbersome response criteria, standardized transfusion thresholds, and application and validation of patient reported outcome instruments. Clinical trials should reflect the biology of disease evolution, the advanced age of patients with MDS, and how patients are treated in real-world settings to maximize the likelihood of identifying active drugs. In patients with lower-risk disease, response criteria for anemic patients should be based on baseline transfusion dependency, improvement in symptoms, and quality of life. For higher-risk patients with MDS, trials should include guidance to prevent dose reductions or delays that could limit efficacy, specify minimal durations of treatment (in the absence of toxicity or progression), and have endpoints focused on overall survival and durable responses. MDS trials should be designed from the outset to allow the practicable application of new therapies in this high-needs population, with drugs that can be administered and tolerated in community settings, and with endpoints that meaningfully improve patients’ lives over existing therapies.

This article provides a summary of discussions from the American Statistical Association (ASA) Biopharmaceutical (BIOP) Section Open Forum organized by the ASA BIOP Statistical Methods in Oncology Scientific Working Group in coordination with the US FDA Oncology Center of Excellence and LUNGevity Foundation on June 24, 2021, and January 13, 2022. Diverse stakeholders engaged in a discussion on how best to use various innovative clinical trial designs in designing future pediatric oncology trials. While standard randomized controlled trials are preferred to evaluate treatment effect in an unbiased manner, given the rarity of pediatric cancers, innovative strategies are needed to promote and assure timely cancer drug development in pediatric populations. The discussions highlighted the need to consider innovative designs with less stringent Type I error specification and Bayesian designs borrowing from external control data, or borrowing treatment effect information from adult data, or both. Such designs are available in the literature and some examples are summarized under the FDA Complex Innovative Trials Design Pilot Program (https://www.fda.gov/drugs/development-resources/complex-innovative-trial-design-meeting-program). Early consultation with global regulatory agencies for pediatric clinical trials can provide a better understanding of different features of the clinical trial design options for successful pediatric cancer drug development.

INTRODUCTION Molecularly targeted therapies such as tyrosine kinase inhibitors (TKIs) are effective treatments for BCR-ABL-bearing leukemias. We evaluated the impact of TKIs on historical chronic myeloid leukemia (CML) mortality trends compared to acute lymphoblastic leukemia (ALL) and chronic lymphoblastic leukemia (CLL). METHODS Since mortality trends reflect combined effects of leukemia incidence and survival, we also evaluated the contribution of incidence and survival trends to mortality trends by subtypes. We used data from 13 US SEER registries (1992-2017) among US adults. We utilized histology codes to identify cases of CML, ALL, and CLL and death certificate data to calculate mortality. We used Joinpoint to characterize incidence (1992-2017) and mortality (1992-2018) trends by subtype and diagnosis year. RESULTS For CML, mortality rates started declining in 1998 at an average rate of 12% annually. Imatinib was approved by the FDA for treating CML and ALL in 2001, leading to clear benefits for CML patients. Five-year CML survival increased dramatically over time, especially between 1996-2011, 2.3% per year on average. ALL incidence increased 1.5% annually from 1992-2017. ALL mortality decreased 0.6% annually during 1992-2012 and then stopped declining. CLL incidence fluctuated during 1992-2017 while mortality decreased 1.1% annually during 1992-2011 and at a faster rate of 3.6% per year from 2011. Five-year survival increased 0.7% per year on average during 1992-2016. CONCLUSIONS Survival benefit from TKIs and other novel therapies for treating leukemia subtypes has been demonstrated in clinical trials. IMPACT Our study highlights the impact of molecularly targeted therapies at the population level.

Although most of the legislation providing authority to the United States (US) Food and Drug Administration (FDA) to regulate the investigation and marketing of new drugs arose as a result of catastrophic events primarily affecting children, focused inclusion of children in clinical research activities investigating new drugs emerged much later in US regulations after it was finally recognized that they were being detrimentally affected by their exclusion. Specific legislative initiatives to promote the assessment of effectiveness and safety of drugs in children originated in the United States as a system of incentives and mandates that were followed nearly a decade later in the European Union (EU) by a single initiative that required and incentivized manufacturers to study drugs in children when there was a likelihood of pediatric use. Over time, recognition of the need for specific pediatric provisions has also emerged in Canada, Japan, Australia, and other parts of the world. Recent pediatric legislative initiatives to address the paradigm shift brought about by the advent of precision oncology have dramatically altered the global regulatory environment for pediatric cancer drug development and are reviewed here. Leveraging these recent changes offers the prospect for accelerating the development of novel agents for pediatric patients with cancer.

Supplementary Table from FDA Approval Summary: Decitabine and Cedazuridine Tablets for Myelodysplastic Syndromes

The seventh multi-stakeholder Paediatric Strategy Forum focused on chimeric antigen receptor (CAR) T-cells for children and adolescents with cancer. The development of CAR T-cells for patients with haematological malignancies, especially B-cell precursor acute lymphoblastic leukaemia (BCP-ALL), has been spectacular. However, currently, there are scientific, clinical and logistical challenges for use of CAR T-cells in BCP-ALL and other paediatric malignancies, particularly in acute myeloid leukaemia (AML), lymphomas and solid tumours. The aims of the Forum were to summarise the current landscape of CAR T-cell therapy development in paediatrics, too identify current challenges and future directions, with consideration of other immune effector modalities and ascertain the best strategies to accelerate their development and availability to children. Although the effect is of limited duration in about half of the patients, anti-CD19 CAR T-cells produce high response rates in relapsed/refractory BCP-ALL and this has highlighted previously unknown mechanisms of relapse. CAR T-cell treatment as first- or second-line therapy could also potentially benefit patients whose disease has high-risk features associated with relapse and failure of conventional therapies. Identifying patients with very early and early relapse in whom CAR T-cell therapy may replace haematopoietic stem cell transplantation and be definitive therapy versus those in whom it provides a more effective bridge to haematopoietic stem cell transplantation is a very high priority. Development of approaches to improve persistence, either by improving T cell fitness or using more humanised/fully humanised products and co-targeting of multiple antigens to prevent antigen escape, could potentially further optimise therapy. Many differences exist between paediatric B-cell non-Hodgkin lymphomas (B-NHL) and BCP-ALL. In view of the very small patient numbers with relapsed lymphoma, careful prioritisation is needed to evaluate CAR T-cells in children with Burkitt lymphoma, primary mediastinal B cell lymphoma and other NHL subtypes. Combination trials of alternative targets to CD19 (CD20 or CD22) should also be explored as a priority to improve efficacy in this population. Development of CD30 CAR T-cell immunotherapy strategies in patients with relapsed/refractory Hodgkin lymphoma will likely be most efficiently accomplished by joint paediatric and adult trials. CAR T-cell approaches are early in development for AML and T-ALL, given the unique challenges of successful immunotherapy actualisation in these diseases. At this time, CD33 and CD123 appear to be the most universal targets in AML and CD7 in T-ALL. The results of ongoing or planned first-in-human studies are required to facilitate further understanding. There are promising early results in solid tumours, particularly with GD2 targeting cell therapies in neuroblastoma and central nervous system gliomas that represent significant unmet clinical needs. Further understanding of biology is critical to success. The comparative benefits of autologous versus allogeneic CAR T-cells, T-cells engineered with T cell receptors T-cells engineered with T cell receptor fusion constructs, CAR Natural Killer (NK)-cell products, bispecific T-cell engager antibodies and antibody-drug conjugates require evaluation in paediatric malignancies. Early and proactive academia and multi-company engagement are mandatory to advance cellular immunotherapies in paediatric oncology. Regulatory advice should be sought very early in the design and preparation of clinical trials of innovative medicines, for which regulatory approval may ultimately be sought. Aligning strategic, scientific, regulatory, health technology and funding requirements from the inception of a clinical trial is especially important as these are very expensive therapies. The model for drug development for cell therapy in paediatric oncology could also involve a 'later stage handoff' to industry after early development in academic hands. Finally, and very importantly, strategies must evolve to ensure appropriate ease of access for children who need and could potentially benefit from these therapies.

2541 Background: There is considerable interest in the use of minimal residual disease (MRD) in clinical trials of hematologic malignancies, especially as a potential surrogate endpoint to expedite drug approval. Although surrogacy has not yet been established in most hematologic malignancies (except CML), MRD data has been submitted in applications to the agency to allow for further characterization of the product’s activity. Here we describe the new drug applications (NDA) or biologics licensing applications (BLA) that included MRD data and provide an analysis of the MRD data and the Agency’s decisions. Methods: The authors reviewed internal databases for all original and supplemental NDA and BLA applications submitted to the Division of Hematology Products (DHP) between 2014 and 2016 that pertained to malignant hematologic conditions. The applications were reviewed for inclusion of MRD data. The clinical reviews and prescribing information (PI) of the identified applications were reviewed for assessment of MRD data and FDA’s findings. Results: There were 34 NDAs or BLAs submitted between 2014-2016. Of these, 13 (38%) included MRD data, in the following diseases: CML, CLL, ALL, and MM. MRD data was added to the PI in 6 cases (46%), not included in 4 (31%), and was not proposed for inclusion in 3 (23%). Among the 6 cases in which MRD data was included in the PI, 5 used PCR testing and 1 used flow cytometry. Among the 4 in which MRD data was not included in the PI, the identified issues included: missing data among those in CR, incomplete test performance characteristics data (e.g.-limit of detection), disparate sample sources (blood, bone marrow), high amount of test failure rates (i.e.-inability to identify a clonal rearrangement), lack of test validation in the proposed disease setting, and inappropriate planned statistical analyses. Conclusions: Nearly 40% of applications submitted to DHP between 2014 and 2016 included MRD data. While the data submitted was deemed adequate for inclusion in the PI in 46% of cases, 31% of applications contained MRD data that the Agency deemed un-interpretable. Data collection and assay performance characteristics should be of significant rigor and completeness to allow for comprehensive review.

The U.S. Food and Drug Administration (FDA) approved eltrombopag for pediatric patients with chronic immune (idiopathic) thrombocytopenia (ITP) ages ≥6 on June 11, 2015, and ages ≥1 on August 24, 2015. Approval was based on the FDA review of two randomized trials that included 159 pediatric patients with chronic ITP who had an insufficient response to corticosteroids, immunoglobulins, or splenectomy. This manuscript describes the basis for approval of these applications. The FDA concluded that eltrombopag has shown efficacy and a favorable benefit to risk profile for pediatric patients with chronic ITP.