Consolidating supplementary Phase I trials that assess new chemical entities (NCE) in combination with standard therapies could be a safe and efficient way of speeding up early clinical development, a study conducted by the US Oncology Research Network suggests.

Dr Daniel Von Hoff, the Network’s chief scientific officer, presented findings from the study in a poster session at the recent 43rd Annual Meeting of the American Society of Clinical Oncology (ASCO) in Chicago, US. The basic hypothesis was that several combination Phase I trials could be conducted simultaneously within a single protocol.

This is a departure from normal practice, in which additional Phase I studies evaluating a NCE in combination with standard therapies – on the basis that many new agents are eventually developed as combination treatments – are usually performed as individual and sequential Phase 1b trials.

In the protocol design described by Von Hoff, patients with advanced cancer were treated with the drug combination deemed most likely to help their condition, ie. the NCE (assuming it was compatible) plus an anthracycline, a tubulin interactive agent, an anti-metabolite, an angiogenesis inhibitor or an antibody to epidermal growth factor receptor.

The standard therapy was started at full dose, while three patients were given one-third of the full NCE dose, three received two-thirds of the NCE dose and three to six the full NCE dose in combination. The study then examined drug combinations with the different standard therapies applied. The additive properties of the drug combinations, rather than their minimal threshold, were evaluated to gauge the use of two drugs given together with no detrimental effects.


According to the research outlined by Von Hoff, this so-called Complete Phase 1b trial design offered a number of advantages over separate Phase 1b trials in assessing various drug combinations.

These included a very rapid follow-up on preclinical data in one study; time and cost savings in the trial start-up phase; rapid accrual, as the choice of standard therapies meant several patients in a practice were likely to be eligible for the trial (e.g., the standard therapy was the standard of care); patients were often less pretreated; and the trial outcomes made for more informed selection of follow-up randomised Phase II or Phase III clinical trials.

Initial experience with the Complete Phase 1b trial design suggested the approach was “safe and highly efficient,” said US Oncology, the company that administers the research network. “Our US Oncology research team is confident that the methodology described in our poster will significantly shorten the time it takes to bring new therapies into the daily care for patients with cancer,” Von Hoff commented.

Translational Oncology Program

This is also the rationale behind the US Oncology Research Network’s Translational Oncology Program (TOP), which is currently running trials using the new Phase 1b design. TOP is unique in that it carries out early-phase clinical trials in a community setting, whereas this type of study is usually conducted in academic medical centres, US Oncology points out.

The Translational Oncology Program was set up in 2004, at the request of physicians affiliated with US Oncology, and recruited its 200th patient this year. The programme comprises a select group of US Oncology physicians who address standard Phase I study designs and select Phase II studies. TOP’s goals include establishing a Phase I research infrastructure that will eventually incorporate targeted therapy.

“Early-stage trials conducted in a smaller, community setting can result in a speedier determination of a new agent’s viability, eventually bringing new therapies to patients quicker,” said Jeffery Nieves, director of the Translational Oncology Program.