Intensified Monitoring of PhArmacology of Cabozantinib as a tool for Toxicity management in patients with renal cell carcinoma

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Centro Di Riferimento Oncologico Di Aviano

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Decision date (initial)

2026-05-21

Transition trial

No

Low-intervention

Yes

Rare-disease indication

No

Vulnerable population

Yes

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacogenetic, Safety, Pharmacokinetic

To evaluate whether the implementation of a systematic pharmacological counseling activity based on TDM, pharmacogenetics and pharmacological interaction analysis, providing cabozantinib treatment-management suggestions to prescribing oncologists, results in a reduced frequency of treatment interruptions due to clinically relevant Cabozantinib-related toxicity in RCC patients compared with historical data.

Secondary objectives 11

1. Evaluate oncologists’ attitude toward pharmacological counseling by monitoring adherence to provided suggestions.
2. Validate LC-MS/MS methods for Cabozantinib quantification in plasma and DBS (Capitainer B and Hemaxis).
3. Explore feasibility of developing a point-of-care testing (POCT) device for Cabozantinib TDM.
4. Determine the Cabozantinib trough concentration (Cmin) that best differentiates patients experiencing clinically relevant toxicity from those who do not.
5. Assess associations between germline polymorphisms in genes related to Cabozantinib pharmacokinetics and both drug exposure levels and treatment-related toxicities.
6. Investigate the association between inflammatory biomarkers (CRP, IL-6, IL-1β, TNF-α, IFN-γ) and Cabozantinib exposure/adverse events.
7. Measure ctDNA levels via shallow whole-genome sequencing (liquid biopsy) as a tool for monitoring disease response.
8. Explore molecular biomarker expression patterns in patients starting Cabozantinib therapy for future stratification of toxicity risk.
9. Assess the feasibility of model-based therapeutic drug monitoring and compare it to the traditional log-linear extrapolation method for estimating Cabozantinib Cmin.
10. Evaluate influence of covariates (sex, inflammation, genetic polymorphisms) on Cabozantinib PK.
11. Develop a PK/PD model describing the exposure–response and exposure–toxicity relationships for Cabozantinib.

Conditions and MedDRA coding

Renal cell carcinoma

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 10

1. Patients diagnosed with histologically confirmed advanced/metastatic RCC with predominantly clear-cell subtype
2. 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).
3. Signed Written Informed Consent.
4. Male or female subjects aged ≥18 years old.
5. 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”, they should be used together with another method, such as a barrier method.
6. Previous nephrectomy is permitted.
7. All IMDC (International Metastatic RCC Database Consortium) risk (good, intermediate, poor).
8. Eastern Cooperative Oncology Group performance status 0 or 1
9. Capable of understanding and complying with the protocol requirements.
10. 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 6

1. Patients with non-renal cell neoplasms of the kidney (e.g. urothelial, sarcoma, lymphoma).
2. 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.
3. Pregnancy status.
4. Refusal of informed consent.
5. Patients who could not attend periodic clinical check-ups.
6. Any condition that, in the investigator’s judgment, could compromise appropriate participation in the study.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. The impact of the counseling intervention on Cabozantinib related toxicity will be evaluated as the overall reduction of the frequency of treatment interruptions due to clinically relevant toxicity in RCC patients treated with Cabozantinib, compared to historical data.

Secondary endpoints 14

1. Rate of adherence to pharmacological counseling recommendations.
2. Analytical performance parameters (accuracy, precision, linearity, LLOQ, stability).
3. Analytical performance parameters (accuracy, precision, linearity, LLOQ, stability). Comparability with LC-MS method.
4. Sensitivity and specificity of Cmin cut-off values for predicting adverse events.
5. Mean/median Cmin difference according to genetic variants.
6. Incidence/severity of treatment-related adverse events according to genetic variants.
7. Mean/median Cmin difference according to inflammatory marker levels.
8. Inflammatory marker levels according to incidence/severity of adverse events.
9. Mean/median values over time.
10. Mean/median difference in ctDNA levels according to disease progression/response.
11. Absolute and relative frequencies.
12. Predictive performance of model-based vs. log-linear extrapolation TDM approaches.
13. Linear regression coefficient with relative 95% CI.
14. Linear regression coefficient with relative 95% CI.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 4

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Centro Di Riferimento Oncologico Di Aviano

Sponsor organisation

Centro Di Riferimento Oncologico Di Aviano

Address

Via Franco Gallini 2

City

Aviano

Postcode

33081

Country

Italy

Scientific contact point

Organisation

Centro Di Riferimento Oncologico Di Aviano

Contact name

Erika Cecchin

Public contact point

Organisation

Centro Di Riferimento Oncologico Di Aviano

Contact name

Erika Cecchin

Locations

1 EU/EEA country · 2 investigational sites

By country

Investigational sites

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 20 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

1 submissions — initial application plus substantial / non-substantial modifications