Pharmacokinetic Model of Abemaciclib: Correlation With Severe Diarrhea as the Primary Toxicity Endpoint in Patients With Localized Hormone Receptor-positive Breast Cancer
试验速览
- 阶段
- 4 期
- 状态
- 尚未招募
- 入组人数
- 235
- 主要终点
- Determine the relationship between the probability of occurrence of a severe diarrheal adverse event and plasma exposure to abemaciclib and its metabolites in patients with RH+HER2- breast cancer at high risk of recurrence receiving adjuvant abemaciclib
研究概览
简要总结
Remarkable progress has recently been made in the treatment of locally advanced, hormone receptor-positive, HER2-negative breast cancer with a high risk of recurrence, thanks to the addition of abemaciclib to endocrine therapy. This combination has led to a significant improvement in invasive disease-free survival. However, despite the combination's acceptable safety profile, 38% of patients experience grade 3 or higher diarrhea, and 23% experience grade 3 or higher neutropenia. This toxicity can lead to the premature discontinuation of treatment, limiting the benefits of this molecule. As with all oral therapies, the pharmacokinetics of abemaciclib lie at the intersection of efficacy and toxicity and can be modified by several external factors.
The hypothesis of the study is that abemaciclib's toxicity is correlated with its plasma levels and that its concentration is modified by certain patient characteristics. To this end, a pharmacokinetic model of abemaciclib could be developed using a prospective, multicenter, real-world blood dosage study. This study will describe the relationship between abemaciclib concentration and diarrhea and severe neutropenia, as classified by CTCAE, as well as potential clinical and drug interactions.
It is hoped that this model demonstrates the importance of monitoring abemaciclib concentrations. This could lead to a therapeutic trial in which the abemaciclib dose is adjusted according to concentration to limit toxicity while maintaining efficacy.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- Female
- 接受健康志愿者
- 否
入选标准
- •Women ≥ 18 years old
- •Having breast cancer of all histologies combined
- •Type Luminal A or B with positive hormone receptors (>10% expression for estrogen receptor and/or progesterone receptor) and HER2 negative or low epidermal growth receptor (according to GEFPICS1 definition)
- •Stage 2 or stage 3 according to the international classification, translated into the SENORIF recommendation
- •Having undergone complete excision surgery (R0 on the invasive tumor and/or on the ductal entity in situ) after neoadjuvant chemotherapy or not
- •Defined as high risk of recurrence according to the Monarch-E study, at initial diagnosis of the disease: either ≥ 4 affected axillary lymph nodes (≥N2 involvement), or 1-3 affected axillary lymph nodes (≥N1 involvement) associated with an Elston Ellis grade 3 or a tumor ≥ 5 cm
- •Initiation of adjuvant treatment with abemaciclib in combination with hormone therapy
- •Patient ECOG performance status between 0 and 2
- •Patients with a neutrophil count (NCC) defined as normal prior to the first dose of abemaciclib, i.e., an absolute NCC ≥ 1500/ mm3 (≥ 1.5 x 109/L) without granulocyte colony-stimulating factor (GCSF) injection within 15 days prior to laboratory testing, as well as a platelet count ≥ 100,000/mm3 and a hemoglobin level ≥ 8g/dL.
- •Patient with the psychological and mental capacity to understand the protocol and sign the consent form independently
- •Must be affiliated with the social security system or receive benefits through a third party
- •Have signed the study consent form after reading the information sheet
排除标准
- •Hypersensitivity to any of the excipients listed in section 6.1 of the abemaciclib (Verzenios) SPC
- •History of treatment with an anti-CDK4/6 (palbociclib, ribociclib, abemaciclib) for any indication
- •History of invasive cancer of any histology within the last 2 years, except for superficial skin tumors, not considered to be in complete remission
- •Presence of functional or inflammatory colorectal disease (Crohn's disease, ulcerative colitis) causing chronic diarrhea (as defined by the WHO as at least 3 bowel movements per day and/or liquid stools for at least 1 month)
- •Patient who has undergone total gastrectomy or suffers from short bowel syndrome
- •Patient unable to sign the consent form for societal reasons (illiteracy) or somatic reasons (central nervous system disease).
- •Persons benefiting from enhanced protection, namely minors, persons deprived of their liberty by judicial or administrative decision, persons staying in a health or social care institution, adults under legal protection, and finally patients in emergency situations.
- •Pregnant or breastfeeding women, women of childbearing age who are not using highly effective contraceptive methods (e.g., double-barrier contraception) during treatment and for at least 3 weeks after stopping treatment (The duration of contraception required for concomitant treatments, if any, should also be taken into account.)
研究组 & 干预措施
Patient treated with abemaciclib
All new patients who benefit from the addition of abemaciclib to adjuvant hormone therapy and who meet the inclusion criteria may be included in the study.
This single-arm study involves enrolled patients undergoing blood tests and completing self-administered questionnaires at various points during their treatment.
干预措施: Blood samples for PK (Biological)
Patient treated with abemaciclib
All new patients who benefit from the addition of abemaciclib to adjuvant hormone therapy and who meet the inclusion criteria may be included in the study.
This single-arm study involves enrolled patients undergoing blood tests and completing self-administered questionnaires at various points during their treatment.
干预措施: Questionnaire (Other)
结局指标
主要结局
Determine the relationship between the probability of occurrence of a severe diarrheal adverse event and plasma exposure to abemaciclib and its metabolites in patients with RH+HER2- breast cancer at high risk of recurrence receiving adjuvant abemaciclib
时间窗: From enrollment to 6 months of treatment
The probability of severe diarrhea (grades 2, 3, and 4 according to CTCAE v5.0) occurring based on exposure to abemaciclib and its metabolites (M2 and M20) will be characterized by a joint mixed-effects model combining longitudinal, pharmacokinetic (continuous type), and toxicity data (survival type).
次要结局
- Determine the relationship between the occurrence of severe neutropenic adverse events and plasma exposure to abemaciclib and its metabolites in patients with HR+, HER2- breast cancer at high risk of recurrence who are receiving adjuvant abemaciclib(From enrollment to 6 months of treatment)
- Develop a joint pharmacokinetic/pharmacodynamic (PK/PD) mixed-effects model that includes data on abemaciclib and metabolite concentrations, neutrophil counts, and severe diarrhea(From enrollment to 6 months of treatment)
- Evaluate the free fraction (fu) of abemaciclib concentrations at different protocol treatment times in the target population (only at Poitiers University Hospital)(From enrollment to 6 months of treatment)