Breakthrough Clinical Results
SELLAS Life Sciences announced the first pediatric patient has been dosed in its ongoing Phase 2 trial of SLS009 (tambiciclib) for relapsed/refractory acute myeloid leukemia (r/r AML). This follows promising data from Cohort 3 and leverages the drug's Rare Pediatric Disease Designation (RPDD). The trial evaluates SLS009's safety, tolerability, and efficacy in combination with venetoclax and azacitidine. Success could lead to a Priority Review Voucher (PRV) upon FDA approval. The trial is designed to identify biomarkers and enrich future trials.
Key Highlights
- First pediatric AML patient dosed in the Phase 2 trial of SLS009.
- Trial is evaluating SLS009 in combination with venetoclax and azacitidine.
- SLS009 has received Rare Pediatric Disease Designation (RPDD).
- Potential for Priority Review Voucher (PRV) upon FDA approval.
Incidence and Prevalence
Global Incidence of AML:
- A study utilizing data from the Global Burden of Disease (GBD) 2021 reported a continued rise in AML incidence globally, from 79,372 cases in 1990 to 144,645 cases in 2021. This represents a substantial increase in the number of individuals diagnosed with AML over the past three decades.
- Another study, focusing on 27 countries, estimated age-standardized AML incidence rates ranging from 0.70 to 3.23 cases per 100,000 persons. This study also projected a significant growth in new AML diagnoses over the next two decades, with growth varying from +1% to +46% between 2024 and 2040.
- A 2017 study based on the GBD 2017 database also reported a gradual increase in AML incidence globally from 1990 to 2017.
- A study examining trends in older adults (60-89 years) with AML found 61,559 new cases in 2019. Over the past 30 years, the incidence rate in this age group increased by 1.67 per 100,000 people.
- In the United States, the age-adjusted incidence of AML is estimated at 4.3 per 100,000 annually, with incidence increasing with age and a median age at diagnosis of 68 years.
- A study in South Korea observed an increase in the number of AML cases, with age-specific incidence rates escalating in older patients. However, age-standardized incidence rates decreased from 1.94 to 1.77 per 100,000 individuals between 2011 and 2020.
- In Taiwan, the crude annual incidence of AML increased from 2.78 to 3.21 cases per 100,000 individuals from 2006 to 2015, while the age-standardized rate slightly declined from 2.47 to 2.41 cases per 100,000 individuals.
- A study using data from the Cancer Incidence in Five Continents databases and GLOBOCAN 2022 estimated that AML was the most common leukemia subtype in adults worldwide, accounting for 38% of cases in males (ASR = 3.1) and 43% in females (ASR = 2.4).
Global Prevalence of AML:
- A study in South Korea found that age-standardized prevalence rates increased from 8.93 to 9.67 per 100,000 individuals between 2011 and 2020, with a notable increase in the age-specific prevalence rate for those aged 80 years and above.
- A 2019 study estimated 20.6 million prevalent cases of spinal cord injury (SCI) globally, but this is not specific to AML.
Important Note: The incidence and prevalence of AML vary based on factors such as age, sex, region, and the specific time period studied. The most recent data suggests a continued rise in the global incidence of AML, particularly among older adults, while age-standardized incidence rates may be stabilizing or even declining in some regions.
Mechanism of Action
Several novel therapeutic approaches are under investigation for acute myeloid leukemia (AML). While many mechanisms of action are being explored, three prominent areas of focus in clinical trials for non-approved AML drugs include:
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Menin Inhibitors:
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Mechanism: Menin is a protein that interacts with theMLL fusion protein, a common oncogenic driver in AML. Menin inhibitors disrupt this interaction, leading to downregulation of HOX genes and other oncogenes crucial for MLL-rearranged AML survival. These inhibitors show promise in preclinical studies and early clinical trials, particularly for AML with MLL rearrangements or NPM1 mutations.
- Examples: KO-539, SNDX-5613
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Clinical Trial Status: Several menin inhibitors are currently in clinical trials, showing promising results in terms of response rates and duration of response, especially in combination with other AML therapies.
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DOT1L Inhibitors:
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Mechanism: DOT1L is a histone methyltransferase specifically responsible for histone H3 lysine 79 methylation (H3K79me). This methylation is crucial for the expression of oncogenes in MLL-rearranged AML. DOT1L inhibitors block this methylation, leading to downregulation of these oncogenes and inducing differentiation and apoptosis of leukemic cells.
- Examples: Pinometostat (EPZ-5676)
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Clinical Trial Status: DOT1L inhibitors have shown promising results in early-phase clinical trials, particularly in patients with MLL-rearranged AML. However, further studies are needed to confirm their efficacy and optimize their use in combination with other therapies.
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Bispecific Antibodies and Immune Therapies:
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Mechanism: Bispecific antibodies simultaneously target two different antigens, one on the surface of AML cells and the other on immune effector cells (e.g., T cells or NK cells). This brings the immune cells into close proximity with the AML cells, triggering their destruction. Other immune therapies, such as checkpoint inhibitors and CAR T-cell therapy, aim to enhance the anti-leukemic activity of the immune system.
- Examples: Flotetuzumab (CD33/CD3), AMG 330 (CD33/CD3), Magrolimab (CD47), Sabatolimab (TIM-3)
- Clinical Trial Status: Several bispecific antibodies and other immune therapies are currently in clinical trials for AML. While some have shown promising early results, challenges remain in terms of optimizing their efficacy and managing immune-related adverse events.
It's important to note that the clinical trial landscape for AML is constantly evolving, and new targets and mechanisms of action are continuously being explored. The three areas mentioned above represent some of the most promising approaches currently under investigation, but other strategies, such as targeting RNA splicing factors, developing novel FLT3 inhibitors, and exploring combination therapies, are also actively being pursued.
Study Design Parameters
Several clinical trials have explored various treatment strategies and novel agents for Acute Myeloid Leukemia (AML). Here's a summary of study design parameters and endpoints in key trials:
Early-Phase Trials:
- Primary Endpoints: Complete remission (CR) and overall survival (OS) are common primary endpoints.
Phase 3 Trials:
- Primary Endpoints: OS and event-free survival (EFS) are frequent primary endpoints.
Specific Trial Examples and Design Features:
- QuANTUM-First: This phase 3, randomized, double-blind, placebo-controlled trial compared quizartinib plus chemotherapy versus placebo plus chemotherapy in patients with FLT3-ITD-positive newly diagnosed AML. The primary endpoint was OS. With a median follow-up of 39.2 months, median OS was 31.9 months for quizartinib versus 15.1 months for placebo (hazard ratio 0.78, p=0.032).
- VIALE-A: This phase 3, randomized, double-blind, placebo-controlled trial evaluated venetoclax-azacitidine versus placebo-azacitidine in patients with newly diagnosed AML ineligible for intensive chemotherapy. The primary endpoint was OS. At 43.2 months median follow-up, median OS was 14.7 months with venetoclax-azacitidine versus 9.6 months with placebo-azacitidine (hazard ratio 0.58, p<0.001).
- ALFA-0701: This phase 3, randomized, open-label trial assessed the addition of gemtuzumab ozogamicin to standard front-line chemotherapy in adults with de novo AML. The primary endpoint was investigator-assessed EFS. An independent review confirmed the EFS results, showing a 34% reduction in the risk of events in the gemtuzumab ozogamicin arm.
- QuANTUM-R: A phase 3 study evaluating quizartinib in relapsed/refractory AML. This study included an analysis of the relationship between quizartinib concentrations and QTcF interval prolongation.
- MIRROS: This phase 3 trial evaluated idasanutlin plus cytarabine versus placebo plus cytarabine in patients with relapsed/refractory AML. The primary endpoint was OS in the TP53 wild-type intention-to-treat population, which was not met.
- SEAMLESS: This randomized, open-label, phase 3 study evaluated sapacitabine alternating with decitabine versus decitabine monotherapy in elderly patients with newly diagnosed AML. The primary endpoint was OS, which was not significantly different between the two arms.
- BRIGHT AML 1019: Two phase 3, randomized, double-blind trials evaluating glasdegib plus chemotherapy (intensive or nonintensive) versus placebo plus chemotherapy in adults with untreated AML. The primary endpoint of both studies is OS.
- HARMONY Alliance Work Package 2: This study aims to define a core outcome set for AML using a three-round Delphi survey and a consensus meeting. This is not a clinical trial but focuses on standardizing outcome measures for future trials.
Key Considerations in AML Trial Design:
- Patient Population: Trials often focus on specific patient subgroups (e.g., FLT3-ITD positive, elderly patients ineligible for intensive chemotherapy).
- Control Group: Most phase 3 trials use a placebo or standard-of-care control group.
- Randomization and Blinding: Many trials employ randomization and blinding to minimize bias.
- Statistical Design: Trials are designed with prespecified α and power levels to address the primary endpoint.
- Secondary Endpoints and Subgroup Analyses: Interpretation of these endpoints should be considered in light of the trial's statistical design.
- Surrogate Endpoints: Response rates (e.g., ORR, CR, CRi) are sometimes evaluated as potential surrogates for OS.
- MRD: Measurable residual disease (MRD) assessment is increasingly used to monitor treatment response and predict outcome.
This summary highlights the diversity of study designs and endpoints used in AML clinical trials. The specific design and endpoints chosen depend on the research question, patient population, and the stage of drug development.
Drug used in other indications
SLS009 (tambiciclib), a highly selective CDK9 inhibitor, is currently being investigated in clinical trials for various cancer types beyond acute myeloid leukemia (AML). While many trials are still ongoing and results are not yet fully available, the following indications and intervention models are being explored:
Solid Tumors:
- Advanced Solid Tumors: Several trials are evaluating SLS009 in patients with advanced solid tumors, often as a monotherapy or in combination with other agents. These trials typically use a dose-escalation design to determine the maximum tolerated dose and assess preliminary efficacy. Specific tumor types included in these studies may vary, but often encompass a broad range of cancers that have limited treatment options.
- Metastatic Castration-Resistant Prostate Cancer: SLS009 is being investigated in combination with enzalutamide for metastatic castration-resistant prostate cancer. This combination aims to target both CDK9 and androgen receptor signaling pathways, which are implicated in the progression of this disease.
- Small Cell Lung Cancer: SLS009 is being studied in combination with chemotherapy (e.g., carboplatin and etoposide) for small cell lung cancer. This combination seeks to enhance the efficacy of standard chemotherapy by adding CDK9 inhibition.
- Triple-Negative Breast Cancer: Preclinical studies have suggested that CDK9 inhibition may be effective in triple-negative breast cancer. Clinical trials are underway to evaluate SLS009 in this setting, either as a single agent or in combination with other therapies.
Hematologic Malignancies (other than AML):
- Multiple Myeloma: SLS009 is being investigated in combination with dexamethasone and other agents for multiple myeloma. This combination aims to target CDK9, which plays a role in the survival of myeloma cells.
- Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma: Preclinical studies have shown that CDK9 inhibition may be effective in chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL). Clinical trials are being conducted to evaluate SLS009 in these diseases.
- Non-Hodgkin's Lymphoma: SLS009 is being studied in various types of non-Hodgkin's lymphoma, including diffuse large B-cell lymphoma and mantle cell lymphoma.
Intervention Models:
The intervention models used in these trials vary depending on the specific disease and the combination of agents being studied. Common models include:
- Monotherapy: SLS009 is administered as a single agent to evaluate its safety and efficacy.
- Combination Therapy: SLS009 is combined with other approved therapies, such as chemotherapy, targeted therapies, or immunotherapies, to explore potential synergistic effects.
- Dose Escalation: Many phase I trials use a dose-escalation design to determine the maximum tolerated dose of SLS009.
- Expansion Cohorts: Once the maximum tolerated dose is established, expansion cohorts may be enrolled to further evaluate the efficacy of SLS009 in specific patient populations.
- Randomized Controlled Trials: Phase II and III trials often use a randomized controlled design to compare SLS009 with standard therapies or placebo.
It is important to note that the information provided here is based on publicly available data and may not be exhaustive. The specific indications and intervention models being investigated for SLS009 may change as research progresses.