Dose Escalation Study Investigating Everolimus and Dovitinib in Metastatic Clear Cell Renal Cancer (DEVELOP)
When kidney cancer spreads beyond the kidney, it is known as metastatic kidney cancer. This is very difficult to treat and almost all patients will die of their disease within 3 years.
Sunitinib has become standard therapy for untreated patients with metastatic clear cell renal (kidney) cancer. It targets a growth factor known as VEGF which is important in treating renal cancer. Although the results with this drug are impressive, patients develop resistance to the drug, relapse and die of renal cancer. It is currently standard practice is to treat patients with everolimus when resistance to sunitinib occurs; this is associated with clear clinical benefit. However the median time to progression with everolimus is 4.9 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.
Dovitinib is a promising new drug in renal cancer. Dovitinib blocks cellular functions such as activation of downstream signalling molecules, cell proliferation and survival. Combining dovitinib and everolimus is very attractive.
This trial is aimed to establish the maximum tolerated dose for the combination of dovitinib and everolimus in clear call renal cancer, which can then be taken into a randomised phase II study.
A maximum of 30 patients will be recruited into this multi centre national trial.
The study has established the MAD and the MTD. The MTD was Cohort 0 (Everolimus 5mg and Dovitinib 200mg). 6 patients were recruited in this cohort with only 1 patient experiencing a DLT. A further 3 patients were recruited into Cohort 1 (Everolimus 5mg and Dovitinib 300mg), where 2 patients experienced a DLT.
A total of 7 assessable patients will be recruited during the expansion phase at the MTD (Cohort 0: Everolimus 5mg and Dovitinib 200mg) to further define the safety, tolerability, efficacy, PK and biological end points.
Assessable patients for the expansion cohort are defined as being on the study for a minimum of 6 weeks. Any patients enrolled who are not assessable will be replaced.
Metastatic Clear Cell Renal Cancer
|Study Design:||Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||A Phase I Study Investigating Everolimus and Dovitinib in Metastatic Clear Cell Renal Cancer|
- To determine and establish the safety profile of everolimus and dovitinib and define the dose limiting toxicity (DLT) [ Time Frame: 6 Months after all patients have come off study ] [ Designated as safety issue: Yes ]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
- To determine the maximum tolerated dose (MTD) of everolimus and dovitinib given orally in patients with VEGF resistant renal cancer [ Time Frame: 1 month after each cohort is closed to recruitment ] [ Designated as safety issue: Yes ]Determining the maximal dose at which no more than one patient out of up to six at that dose level experiences an almost certainly or probably drug related DLT, as defined in 3.1.4 of the protocol.
- To evaluate clinical benefit at 6 months (Stable disease, partial response and complete response ) in the 13 assessable patients who received the maximum tolerated dose (n=13). [ Time Frame: 6 months after all patients have come off study ] [ Designated as safety issue: No ]Response assessment (stable disease (SD), partial response (PR) or complete response (CR)) determined according to Response Evaluation Criteria in Solid Tumours (RECIST v1.1). 50% or more clinical benefit at 6 months would be of interest
- To evaluate tumour response in the 13 patients who received the maximum tolerated dose (n=13). This includes the 7 additional assessable patients in the expansion cohort. [ Time Frame: 6 months after all patients have come off study ] [ Designated as safety issue: No ]Response assessment will be measured by RECIST v1.1 at 6 and 14 weeks. 2 or more responses (15%) would be of interest
- To determine plasma pharmacokinetic (PK) parameters following administration of everolimus and dovitinib [ Time Frame: 6 months after all patients have come off study ] [ Designated as safety issue: No ]Measurement of PK parameter values for both drugs on day 5 of the 1st cycle and (pre dose, and 3 hour sample).
|Study Start Date:||April 2011|
|Study Completion Date:||October 2012|
|Primary Completion Date:||October 2012 (Final data collection date for primary outcome measure)|
Dovitinib and Everolimus
Cohort 0: 200mg, Cohort 1: 300mg, Cohort 2: 300mg, Cohort 3: 400mg, Cohort 4: 500mg. Cohort -1: 100mgDrug: Everolimus
Cohort 0: 5mg, Cohort 1: 5mg, Cohort 2: 10mg, Cohort 3: 10mg, Cohort 4: 10mg, Cohort -1: 5mg.
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.
|Barts Health NHS Trust|
|London, United Kingdom, EC1M 7BE|
|Principal Investigator:||Thomas Powles, MD||Queen Mary Unviersity of London, UK|