Renal Cell Carcinoma
Conditions
Brief summary
Adverse events (AEs) with Cabozantinib are frequent (about 40-67% of patients) and often lead to temporary treatment interruptions, dose reductions or permanent discontinuations, potentially reducing dose intensity and sustained exposure. Therefore, strategies are needed to improve tolerability without compromising antitumor activity. Therapeutic drug monitoring (TDM) is particularly suitable for drugs with high interpatient variability, narrow therapeutic windows and defined exposure-response relationships; real world data support this profile for Cabozantinib and suggest that pharmacokinetically guided dosing could help manage toxicity while maintaining efficacy. Based on this evidence, the study proposes a model of individualized pharmacological counselling integrating TDM, pharmacogenetic testing and structured evaluation of pharmacological interactions to optimize Cabozantinib exposure and minimize avoidable toxicity.
Interventions
OTHERIntensified Monitoring of Pharmacology
individualized pharmacological counselling integrating TDM, pharmacogenetic testing and structured evaluation of pharmacological interactions
Sponsors
Centro di Riferimento Oncologico - Aviano
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
OTHER
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
for the intervention group: * Patients diagnosed with histologically confirmed advanced/metastatic RCC with predominantly clear cell subtype. * Advanced (not amenable to curative surgery or radiation therapy) or metastatic (AJCC Stage IV) RCC, candidate to receive systemic treatment with nivolumab + Cabozantinib or Cabozantinib monotherapy as per clinical practice (investigators choice). * Signed Written Informed Consent. * Male or female subjects aged ≥18 years old. * Women of childbearing potential must avoid pregnancy while on Cabozantinib. Female partners of male patients taking Cabozantinib must also avoid pregnancy. Effective methods of contraception should be used by male and female patients and their partners during therapy, and for at least 4 months after completing therapy. Because oral contraceptives might possibly not be considered as "effective methods of contraception", due to factors such as missed doses, gastrointestinal disturbances, or potential drug interactions that could reduce their effectiveness, they should be used together with another method, such as a barrier method. * Previous nephrectomy is permitted. * All IMDC (International Metastatic RCC Database Consortium) risk (good, intermediate, poor). * Eastern Cooperative Oncology Group performance status 0 or 1 * Capable of understanding and complying with the protocol requirements. * patients will be included in the study regardless of their time of treatment start with Cabozantinib and regardless of their concomitant diseases or co-medication.
Exclusion criteria
for intervention group: * Patients with non-renal cell neoplasms of the kidney (e.g. urothelial, sarcoma, lymphoma). * Diagnosis of any non-RCC malignancy occurring within 2 years prior to the date of the start of treatment except for adequately treated basal cell or squamous cell skin cancer, or carcinoma in situ of the breast or of the cervix or low-grade prostate cancer (≤pT2, N0; Gleason 6) with no plans for treatment intervention. * Pregnancy status. * Refusal of informed consent. * Patients who could not attend periodic clinical check-ups. * Any condition that, in the investigator's judgment, could compromise appropriate participation in the study. Inclusion criteria for the historical control group: * Patients diagnosed with histologically confirmed advanced/metastatic RCC with predominantly clear cell subtype. * Advanced (not amenable to curative surgery or radiation therapy) or metastatic (AJCC Stage IV) RCC, candidate to receive systemic treatment with nivolumab + Cabozantinib or Cabozantinib monotherapy as per clinical practice (investigators choice).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Impact of the systematic pharmacological counseling activity intervention on Cabozantinib related toxicity | up to 48 months | The impact will be evaluated as the overall change of the frequency of treatment interruptions due to clinically relevant toxicity in RCC (Renal cell carcinoma) patients treated with Cabozantinib, compared to historical data. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Measure ctDNA levels via shallow whole-genome sequencing (liquid biopsy) as a tool for monitoring disease response. | up to 48 months | Mean/median values over time; Mean/median difference in ctDNA levels according to disease progression/response |
| Explore molecular biomarker expression patterns in patients starting Cabozantinib therapy for future stratification of toxicity risk. | up to 48 months | Absolute and relative frequencies |
| Assess the feasibility of model-based therapeutic drug monitoring and compare it to the traditional log-linear extrapolation method for estimating Cabozantinib Cmin. | up to 48 months | Predictive performance of model-based vs. log-linear extrapolation TDM approaches. |
| Evaluate influence of covariates (sex, inflammation, genetic polymorphisms) on Cabozantinib PK. | up to 48 months | Linear regression coefficient with relative 95% CI. |
| develop a PK/PD model describing the exposure-response and exposure-toxicity relationships for Cabozantinib. | up to 48 months | Linear regression coefficient with relative 95% CI. |
| Attitude Towards Pharmacological Counseling Among Oncologists | up to 48 months | Rate of adherence to pharmacological counseling recommendations. |
| Validate LC-MS/MS methods for Cabozantinib quantification in plasma and dried blood spot (Capitainer B and Hemaxis) in terms of accuracy | up to 48 months | Accuracy will be evaluated as difference between results obtained by the method to the nominal concentration of the analyte in the biological matrix |
| Validate LC-MS/MS methods for Cabozantinib quantification in plasma and dried blood spot (Capitainer B and Hemaxis) in terms of precision | up to 48 months | Precision will be evaluated as Coefficient of Variation (CV) calculated as standard deviation/mean values |
| Validate LC-MS/MS methods for Cabozantinib quantification in plasma and dried blood spot (Capitainer B and Hemaxis) in terms of linearity | up to 48 months | Linearity will be evaluated using squared R to assess the goodness of fit of the calibration curve |
| Explore accuracy of a point-of-care testing (POCT) device for Cabozantinib TDM. | up to 48 months | Accuracy will be evaluated as difference between results obtained by the method to the nominal concentration of the analyte in the biological matrix |
| Explore precision of a point-of-care testing (POCT) device for Cabozantinib TDM. | up to 48 months | Precision will be evaluated as Coefficient of Variation (CV) calculated as standard deviation/mean values |
| Explore the linearity of a point-of-care testing (POCT) device for Cabozantinib TDM. | up to 48 months | Linearity will be evaluated using squared R to assess the goodness of fit of the calibration curve |
| Explore comparability of a a point-of-care testing (POCT) device for Cabozantinib TDM with LC-MS method | up to 48 months | Comparability will be evalueted with Bland Altman analysis. |
| Characterization of the Exposure-Toxicity Relationship | up to 48 months | Sensitivity and specificity of Cmin cut-off values for predicting adverse events. |
| Assess associations between germline polymorphisms in genes related to Cabozantinib pharmacokinetics and drug exposure levels | up to 48 months | Mean/median Cmin difference according to genetic variants; |
| Assess associations between germline polymorphisms in genes related to Cabozantinib pharmacokinetics and treatment-related toxicities. | up to 48 months | Incidence/severity of treatment-related adverse events according to genetic variants. |
| Investigate the association between inflammatory biomarkers (CRP, IL-6, IL-1β, TNF-α, IFN-γ) and Cabozantinib adverse events. | up to 48 months | inflammatory marker levels according to incidence/severity of adverse events. |
| Investigate the association between inflammatory biomarkers (CRP, IL-6, IL-1β, TNF-α, IFN-γ) and Cabozantinib exposure | up to 48 months | Mean/median Cmin difference according to inflammatory marker levels; |
Countries
Italy
Contacts
CONTACTErika Cecchin, PhD, PharmD
Outcome results
None listed