Nick DeVito and Ben Goldacre

Background

The US FDA Amendments Act (FDAAA 2007) requires certain clinical trials to report their results onto ClinicalTrials.gov within one year of completion. Our FDAAA TrialsTracker shows all individual trials that breach this legal requirement. Once a week, we write about one unreported clinical trial: you can read more background here and read past entries here.

Trials NCT02186301 & NCT02322281

This week’s unreported trials are the Tiger-1 and Tiger-3 studies of rocilentinib for epidermal growth factor receptor (EGFR) mutant NSCLC (NCT02186301 & NCT02322281). Tiger-1 enrolled 100 adult participants with EFRG-mutant non-small-cell lung cancer (NSCLC). The intervention group received daily treatment with rociletinib; erlotinib was the active comparator. The primary outcome was progression free survival up to 24 months. There were a number of secondary outcomes including overall survival, safety, various quality of life questionnaires, and tumor response rates. Tiger-3 enrolled 149 participants with EFRG-mutant NSCLC. The intervention groups received one of two different doses of rocilentinib; the active comparators were one of pemetrexed, gemcitabine, paclitaxel or docetaxel. The primary outcome was progression free survival assessed every 6 weeks until tumor progression. Secondary outcomes were tumor response rates, overall survival, safety outcomes, and plasma pharmacokinetics.

Clinical discussion

NSCLC is the most common form of primary lung cancer. Mutation of the EGFR is a cause of cancer, including NSCLC, that can be screened for, and potentially used to target therapies. The frequency of this mutation varies: for example a review found only 15% of all NSCLC patients in Europe had the EGFR mutation; while 47% in the Asia-Pacific region were affected. Drugs such as rocilentinib are part of a new group designed to target the EGFR (T790) mutation. This is important, as resistance to other therapies can develop over time. Another drug specifically targeting this mutation (osimertinib) has recently been approved by the FDA.

Development of rocilentinib was halted in 2016 following a negative vote for accelerated approval by an FDA advisory committee, and subsequent NDA rejection by the FDA. These rejections came on the heels of additional earlier trial data showing lower confirmed response rates than anticipated based on preliminary data. The Tiger-1 and Tiger-3 studies were subsequently terminated, having already recruited and collected data on 249 participants in total.

Legislative discussion

While it is unfortunate that rocilentinib does not currently appear to be viable as a treatment option for patients with NSCLC, this does not exempt sponsors and trialists from their obligations to report trial results. Commercial sponsors, when they are actively developing a product, can apply for a “certificate of delay” before the trial results would otherwise have been due: however no such certificate has been issued for these two trials; and in any case, rocilentinib has already been rejected by the FDA, and development halted over 2 years ago. These trials are therefore unlikely to have been eligible for such a certificate, had one been requested within the deadline for doing so.

Under the FDA Amendments Act 2007 these trials are required to report results within one year of their estimated or actual primary completion date. Currently the actual, non-estimated primary completion date given by the sponsor for Tiger-1 is 28 June 2017, with a recruitment status of “Terminated (Sponsor discontinued development of CO-1686 for NSCLC).” The registry entry for Tiger-3 contains an estimated primary completion date of June 2017 entered by the sponsor, but its status is currently “Unknown”, as the sponsors have not updated the trial’s record for over two years; note that sponsors are required to maintain their trial’s registry entry with current data.

As a general issue, it is important that trial results are shared when treatments are abandoned for commercial development, and this requirement is enshrined in the law on trial reporting. In the case of rocilentinib, while trials for this indication have terminated, it may eventually be tested for other diseases, or re-approached for use in specific populations suffering from NSCLC. Furthermore, some patients continue to receive this drug, despite it not being approved. In addition, other similar drugs may be developed in the future, in which case data collected on 249 patients for this treatment may contain valuable insights with regard to safety, effectiveness, or other issues such as mechanism or impact on surrogate outcomes.

Indeed Clovis Oncology, the developer of the drug and sponsor of these trials, recognises these issues on their website, describing rociletinib as follows: “an oral mutant-selective inhibitor of epidermal growth factor receptor (EGFR), for which we have terminated enrollment in all ongoing sponsored clinical studies, though we continue to provide drug to patients whose clinicians recommend continuing rociletinib therapy. We are continuing analyses of rociletinib data to determine whether certain populations of patients may represent an opportunity for a partner committed to investing in further clinical development. Clovis maintains global rights to rociletinib.”

While Tiger-3 reported limited results information in a 2017 conference abstract, there does not appear to be any public information available related to the results of Tiger-1. As previously discussed in this series on unreported trials, a conference abstract is not sufficient to meet the requirements of reporting a trial’s results. In addition, the conference abstract for Tiger-3 does not give quantitative data on outcomes: while low enrollment due to termination may compromise accurate hypothesis testing in these samples, having the data available could be valuable in the context of previous and future research.

Lastly, in addition to practical and legal issues, there is also an ethical case for reporting results in terminated trials: whether development of this drug in any context continues or not, the sacrifices made by 249 trial participants to contribute to our understanding of this drug should be honored by reporting the results of these trials in full, and according to the law.

Conclusion

Both of these unreported trials were sponsored by Clovis Oncology Inc. No PI is listed for either trial however both list numerous global study sites. As of 3 September 2018, Tiger-1 is 67 days and Tiger 3 is 65 days overdue to report. We hope the sponsor will report the results of these trials soon.

Ben Goldacre is a doctor, author, and director of the EBM DataLab at the University of Oxford. He co-founded the AllTrials campaign for trials transparency.

Competing interests: BG has received research funding from the Laura and John Arnold Foundation, the Wellcome Trust, the Oxford Biomedical Research Centre, the NHS National Institute for Health Research School of Primary Care Research, the Health Foundation, and the World Health Organization; he also receives personal income from speaking and writing for lay audiences on the misuse of science.

Nicholas J DeVito is a researcher at the EBM Datalab at the University of Oxford.

Competing interests: ND is employed on BG’s LJAF grant and is a Naji Foundation scholar at the University of Oxford.