Young Oncologists: Master Class in Trial Design

ESMO’s Young Oncologist Programme began on Friday afternoon with a master class exploring the development of clinical trial protocols.The presenters reviewed issues around trial design in the era of targeted agents and biomarkers.

The importance of accelerating drug development from bench to bedside was addressed by Professor Luis Costa from Hospital de Santa Maria, Lisbon, Portugal. The reality is that only 8% of tested products entering phase 1 trials and subsequently phase 2-3 trials, said Professor Costa, eventually clear the hurdle of gaining FDA approval and entering the market. This has had the consequence of pharmaceutical development costs reaching unprecedented levels. Citing the example of BCRABL inhibition, he said that imatinib took 41 years from discovery to approval.

Translational medicine needs to be ‘bi-directional’, he said, with information shared between industries, laboratories and clinics. The fundamental ‘bottleneck’ for oncology, he said, is not the validation of targets but validation of the disease model itself with good correlation now needed between the observed model disease phenotype and human disease condition. Biology driven phase 2 trials using high throughput technologies or dedicate bioassays for each molecular alteration are needed to speed drug development. But it is sometimes undesirable, he cautioned, to restrict entry to phase 2 trials based on what are thought to be the drug targets, at least in cases where knowledge is uncertain. Translational research requires a ‘bi-directional’ sharing of knowledge and ideas by the scientific and clinical community to develop biomarkers that reliably select mechanisms that can lead to breakthrough therapeutics.

Professor Heinz Zwierzina from Innsbruck Medical University, Austria, said that biomarker dependent therapy represents the way forward for personalised cancer treatment. The importance of biomarker patient selection, he said, has been well demonstrated by the example of trastuzumab in breast cancer were the response rose from 10% in all breast cancer patients to 35 to 50% in a selected HER2 positive population. There is now a need, said Professor Zwierzina, to achieve similar success stories with other targeted therapies. With the short-comings of single biomarkers and the complexity of cancer biology, he said, multiple/ composite biomarkers will be increasingly relied on to assess safety and efficacy of the new generation of anti-cancer drugs.

The transition from phase 2 to phase 3 trials has the highest rate of attrition, said Mrs Sarah Brown, from the University of Leeds, UK. This, she said, emphasises the importance of good design in the development for phase 2 trials. “In the design of phase 2 trials close collaboration between clinicians and statisticians is key. We need to appreciate that no one-size fits all and that early discussions equal optimal design,” said Mrs Brown.

A fascinating insight into the celebrated Flims workshops was provided by Mrs Brown. The Flims workshops, which run as a joint initiative by ECCO, AACR, EORTC and ESMO, have been introducing young oncologists to the principles of good clinical trial design since 1999.

The workshop helped Mrs Brown and colleagues to develop their trial idea for a randomised phase 2 study of docetaxel plus oxalipatin versus docetaxel alone in previously treated non-small cell lung cancer (NSCLC) patients into a full clinical trial protocol. Describing the valuable experience, of the week long workshop, where she benefited from the advice and expertise of Flims faculty members, she said, “You’re the chief investigator responsible for ensuring that an investigation is conducted according to the study protocol, ethics requirements and for obeying all the applicable national and institutional regulations.”

Additionally, she added, the workshop teaches delegates how to obtain ethics and site approvals, manage grants and develop databases. The successful outcome of Mrs Brown’s trial was publication of the study in the European Journal of Cancer. Mrs Brown ended her presentation urging people to apply to Flims. “If you’re interested in clinical research and haven’t been to Flims, then apply, and if you’re not selected apply again! If you’re a senior oncologist encourage your young colleagues to apply and support them with their applications.”

In the last presentation Professor Luis Paz-Ares from Seville University Hospital, Spain, reviewed the impact that targeted agents are having on Clinical trial design. Change is needed, he argued in clinical trial design with earlier phase studies considering selecting patients whose tumours express the ‘target being targeted’.

The questions that need to be considered include whether separate trials should be performed for each drug or genotype, the relevance of prior treatment with chemotherapy, whether a placebo or chemo comparator is needed, and that historical comparators may not be appropriate. “Overall survival should be used as an endpoint where possible, but surrogate endpoints could include progression free survival and response rate,” said Professor Paz-Ares.