A Phase I Study Investigating Everolimus and Dovitinib in Metastatic Clear Cell Renal Cancer
Renal cell cancer, also referred to as kidney cancer, is diagnosed in approximately 170,000
people worldwide annually, resulting in 82,000 deaths. Treatment for metastatic kidney
cancer is difficult. Almost all of the patients die from their disease.
In 2006 a new drug called sunitinib, a tyrosine kinase inhibitor, transformed treatment
options. It targets the development of new blood vessels within the cancer. Although the
results with this drug are impressive, patients develop resistance a median after 11 months
to the drug, relapse and die of renal cancer. It is currently standard practice to switch to
everolimus when resistance to sunitinib occurs; this is associated with clear clinical
benefit. However the median time to progression with everolimus is 4 months in previously
treated patients, therefore further improvement in treating patients is required. The
optimal way of achieving this is to increase the efficacy of everolimus by adding agents
which directly target the cause of resistance to sunitinib.
dovitnib is a promising new drug the pharmacology data from a variety of in vitro and in
vivo studies with dovitnib provided preclinical rationale for clinical evaluation of
dovitinib in patients with metastatic clear cell renal cancer.
The combination of everolimus with dovitnib will target 3 major protagonists associated with
tumour growth The main risks and burdens to the patients participating in the study are the
potential for side effects of the trial medicines, these two drugs have not been used in
combination together and although there is safety data on each drug, there is no known
safety data on the drugs when used in combination. The first cohort of patients will receive
200mg of dovitnib and 5mg of everolimus. In previous studies these drugs have been
administered separately and at higher doses. The maximum tolerated dose (MTD) of dovitnib
for the 5-day on/ 2-day off dosing schedule has been defined as 500mg/day in a previous
Phase I studies. In the RECORD-1 study (a Phase III double blind randomised trial
investigating everolimus) a dose of 10mg was used.
Cohorts of three patients will be treated in each dose level. A minimum of 14 days will
elapse between the first patient being treated in each cohort and entering the next patient.
Further patients may be entered concurrently. Toxicity will be assessed according to NCI
CTCAE v4.0; if no dose limiting toxicity (DLT) occurs dose escalation will be undertaken for
the next cohort of patients.
In the event of DLT in 1out of the 3 patients the cohort will be expanded to a maximum of 6
patients. If more than or equal to 2 out of 6 patients experience DLT dose escalation will
be halted and the maximum administered dose (MAD) has been reached. If less than or equal
to 1 out of 6 patients had DLT dose escalation may continue.
Patients may not personally benefit from being in this study. However the information we
gain from this study might help to treat future patients who have metastatic kidney cancer.
Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
To determine and establish the safety profile of everolimus and dovitinib and define the dose limiting toxicity (DLT)
Determining causality of each adverse (AE) to everolimus and dovitinib and grading severity according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0
6 Months after all patients have come off study
Thomas Powles, MD
Queen Mary Unviersity of London, UK
United Kingdom: 'Ministry of Health and Regulatory Authority'