Cabozantinib Dose Skipping as an Alternative to Dose Reductions

Standard regimens: 20 or 40mg once daily with standard breakfast

Experimental regimens:

* Instead of 20mg once daily: 60mg for one day, followed by two skipping days (60-0-0). Also taken with standard breakfast.
* Instead of 40mg once daily: 60mg for two days, followed by one skipping day (60-60-0). Also taken with standard breakfast.

• Cabozantinib (Drug): For patients using 40mg the experimental regimen consists of 60mg once daily for 2 days followed by 1 skipping day (60-60-0 mg). For patients using 20mg the experimental regimen consists of 60mg once daily for 1 day followed by 2 skipping days (60-0-0 mg). In both cases cabozantinib is also taken with standard breakfast.

Primary outcomes

• Comparison of the AUC0-72h of the experimental and the standard regimen. [From enrollment to the end of the study at approximately 2 months]: AUC is calculated by modeliing a PK curve from plasma concentrations. AUCs are compared between the standard and experimental regimen.
• Comparison of blood trough concentration (Ctrough) [From enrollment to the end of the study at approximately 2 months]: Comparison of Ctrough, which is the plasma concentration of cabozantinib before ingestion of a dose cabozantinib, between the standard and experimental regimen.

Secondary outcomes

• Health-economic cost-consequences [From enrollment to the end of the study at approximately 2 months]: Calculating the cost-savings of the alternative dosing regimens
• Patients preference [From enrollment to the end of the study at 2 months]: Patients preference of one of the dosing regimens.
• Quality of life score [From enrollment to the end of the study at approximately 2 months]: Fill in a questionnaires (EQ-5D-5L) about the quality of life. Which looks into two things: 1. Five dimensions of health: mobility, self-care, daily activities, pain/disconfomrt and anxiety/some feelings. It uses a five point scale with 1 equally to no problem and 5 equally to extreme problems. It results in a score with 0 equally to dead and 1 equally to perfect health. 2. Subjective assessment of one's own health on a scale from 0 to 100. Where 0 equals worst imaginable health and 100 equals best imaginable health.
• Quality of life score [From enrollment to the end of the study at approximately 2 months]: Fill in a questionnaire (FKSI-19) with questions reflecting quality of life in patients with RCC. A question is answered using a 5-point scale where zero equals not at all and 4 equals very much. The higher the score the better the quality of life.
• Side effects: nausea and/or diarrhea [From enrollment to the end of the study at approximately 2 months]: Total number of patients experiencing nausea and/or diarrhea

Sex: All, ages: 18 Years to any

Inclusion Criteria:

* Willing and able to provide informed consent;
* Aged 18 years or older;
* Histologically confirmed advanced renal cell carcinoma;
* At least 4 weeks on a stable dosage of cabozantinib of 40 mg or 20 mg once daily as single-agent treatment or in combination with nivolumab;
* Acceptable tolerability and the need for dose reductions or treatment interruptions has been estimated as low;
* Eastern Cooperative Oncology Group (ECOG) performance status of 0-2;
* Estimated life expectancy of ≥6 months;
* No response evaluation planned during the study period.

Exclusion Criteria:

* Inability to follow the recommended standard breakfast;
* Gastrointestinal abnormalities influencing the absorption of cabozantinib, including active inflammatory bowel disease, malabsorption syndrome, and prior major surgery of the stomach, pancreas, liver or small bowel.
* Use of moderate or strong inhibitor of cytochrome P450 enzymes within 1 month of start of treatment with cabozantinib, including ketoconazole, grapefruit juice, clarithromycin, erythromycin, itraconazole and ritonavir.
* Use of moderate or strong inducer of cytochrome P450 enzymes within 1 month of start of treatment with cabozantinib, including rifampicin, phenytoin, carbamazepine, phenobarbital and herbal preparations containing St. John's Wort.
* Use of inhibitor of multidrug resistance-associated protein 2 within 1 month of start of treatment with cabozantinib, including cyclosporine, delavirdine, efavirenz, emtricitabine, benzbromarone and probenecid.

• Results publication: Tan Z, Voller S, Yin A, Rieborn A, Gelderblom AJ, van der Hulle T, Knibbe CAJ, Moes DJAR. Population Pharmacokinetics of Cabozantinib in Metastatic Renal Cell Carcinoma Patients: Towards Drug Expenses Saving Regimens. Clin Pharmacokinet. 2024 Jun;63(6):857-869. doi: 10.1007/s40262-024-01379-y. Epub 2024 Jun 14. PMID 38874883

• Tom van der Hulle, MD PhD, Principal investigator, Leiden University Medical Center

NIH grants: 2025