NCI-sponsored Trials in Papillary Renal Cell
Following are some of the trials for metastatic papillary renal cell carcinoma (prcc) that the NCI is working on or planning for. The trial ids, if given, are referenced on www.clinicaltrials.gov.
- A few years ago, in a Phase II trial sponsored by the NCI using the GlaxoSmithKline (GSK) molecule foretinib, a c-Met inhibitor, papillary Type I patients who had a germline mutation in c-Met, showed a dramatic response to foretinib. Unfortunately, GSK chose not to continue development of foretinib. Nevertheless, the NCI has not given up on c-Met inhibitors, and is now testing a Novartis compound called INC-280 in a Phase II trial in familial Type I papillary patients. INC-280, which targets the c-MET gene, was used in a Phase I trial in Europe. The Phase II trial is for 22 people and is currently recruiting. People are eligible even if they don’t have a germline c-Met Trial id NCT02019693.
- The NCI is running another Phase II trial, NCT01130519, using Genentech’s drugs bevacizumab and erlotinib in pRCC Type I and Type II patients. The trial enrollment calls for a cohort of 41 patients, but they may not been currently recruiting. In interim results, half the current trial participants have a mutation in the FH gene (Type II). Of those patients, 60% have had a response and the other 40% are stable. Fort eh other half, without an FH mutation, the response rate has been 29%.
- In preclinical testing, the NCI has been studying the effects inhibiting Hsp90 (heat shock protein 90) when c-Met is mutated. Heat shock proteins stabilize proteins against heat stress but also stabilize those proteins that are required for tumor growth so researchers have looked into inhibiting them in metastatic cancer patients. The NCI, again in the pre-clinical setting, a synergistic effect when employing both c-Met inhibitors and Hsp90 inhibitors. The are speaking with pharmaceutical companies about conducting a clinical trial using these inhibitors in prcc Type I patients. Stay tuned.
- Papillary Type II can result from a mutation in the fumarate hydratase (FH) gene. Based on the NCI’s work in The Cancer Genome Atlas (TCGA) project, a new gene called ABL1 is upregulated in FH-deficient tumors. ABL1, when upregulated, promotes glycolysis via the mTOR pathway, in other words, it acts as a proto-oncogene (a gene that induces cancer, in this case prcc Type II). The mechanism of action is described in the December 8, 2014 article in Cancer Cell entitled Targeting ABL1-Mediated Oxidative Stress Adaptation in Fumarate Hydratase-Deficient Cancer http://www.cell.com/cancer-cell/abstract/S1535-6108(14)00409, written by NCI staff.
The preceding is a prelude to the fact that the NCI will sponsor a Phase I-II trial, in prcc Type II patients, using the AstraZeneca drug vandetanib to inhibit the activity of ABL1 and combine it with the diabetes medication metformin to allow them to reduce the dosage of vandetanib and thus reduce the side effects of the drug. The NCI would like to initiate this trial by the summer of 2015.