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Ensuring Success in Early Phase Oncology Clinical Trials

Ensuring Success in Early Phase Oncology Clinical Trials

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Published by: bellamaj on Jan 14, 2013
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Ensuring Success in Early PhaseOncology Clinical Trials
The numbers of oncology drugs in clinical development is more than twice thenumber in any other therapeutic area (PharmaLive.com). Yet despite being themost commonly tested therapies, oncology drugs have the worst approval rates.Only 5% of agents with anticancer activity in preclinical development arelicensed (Hutchison and Kirk, 2011).The main reason for failure is that preclinical strategies to evaluate noveloncology agents are suboptimal. In addition, conducting clinical trials in cancerpatients is challenging because of the number and type of prior treatmentspatients have undergone and because novel agents are tested in patients withlate-stage malignancies, which are inherently more difficult to treat than earliermalignancies.The current landscape of cancer therapeutics is evolving as the genetic andmolecular mechanisms involved in cancer are increasingly understood. Moretargeted and individualized therapy has presented exciting possibilities tocombat disease, but the new approaches have also added complexity to clinicaldevelopment.In any disease state, conducting successful Phase 1 trials is a key component of ushering a novel therapy through clinical development. Although Phase 1studies in most therapeutic areas consist of healthy patients, Phase 1 studies inoncology consist of patients with active disease. This creates unique challengesand potential opportunities. Understanding these challenges and opportunitiesis paramount for designing Phase 1 oncology studies and keeping them on track.
Unique Aspects of Phase 1 Oncology Studies
Oncology trials are bound to enrolling patients with later-stage disease whohave already been treated with standard of care. The reason for thisdistinctiveness is an ethical one; any new investigational agent bears thepotential of failure or suboptimal therapeutic efficacy, and the inclusion of earlystage patients who do have proven treatments would be regarded as unethicalunless the new agent has shown activity.
Late-stage patients tend to be less responsive to medications, and they tend tobe more confounded by co-morbities or potential for interaction with otherdrugs. Their response to an investigational therapy may not represent theresponse in early stage disease. This is a particular concern for immunological
treatment approaches like tumor vaccines, in which the patient’s immune
system defends against the tumor, because in late stage disease, the immunesystem is less able to mount a response. In patients with late-stage disease, itcan be difficult to discern whether adverse events are caused by theinvestigational agent, some other anti-cancer agent being taken as standard of care, or by the disease itself.The main benefit of conducting trials in patients with disease is that efficacydata may be obtained. However, gathering meaningful data can be difficult andtake a long time. For many non-oncology indications, such as high bloodpressure or diabetes, objective results can be seen within days to weeks.Evaluating meaningful clinical efficacy in patients with tumors takes months toyears. Although tumor responses can sometimes be evaluated after a short timeof 1 to 3 months, endpoints like disease-free survival or time to progression canonly be learned if patients are followed beyond the median time to progressionof their tumor, which can easily reach 1 year or longer. Given the timeenrollment takes, a Phase 1 oncology trial can take 1.5 to 2 years. Enrollmenttimes can be especially long because oncology trials usually need to beconducted over a number of dose escalation levels before any anti-tumorefficacy can be identified.Before a trial is conducted, careful consideration needs to be given to whetherand how a drug might be beneficial or harmful to patients. Early phase oncologytrials enroll patients who have been dealing with disease for a long time and are
facing a difficult prognosis. “Patients can get really sick really fast,” according to
Catherine Holloway, MS, global project director at Clinipace Worldwide. Evenpatients who meet all inclusion criteria for a study can have a rapid worseningof malignancy shortly after enrolling. Having patients get very sick or die duringa trial takes an emotional toll on all members of the study team.In general, oncology patients are committed to supporting progress in scienceand medicine. Therefore, patients tend to be compliant with the treatmentregimen and evaluations.
Evolution in Trial Design
The goal of Phase 1 studies is to find the optimal dose of therapy, meaning onethat is high enough to be effective but not so high as to cause intolerability.Historically, Phase 1 trial designs involved conservative methods of findingmaximum tolerated doses. Doses were started at 0. 1 mouse-equivalents, whichmeans
10% of dose that 10% of mice would die from. “Slow
go” 3 + 3
designs were common. Each dose level would have 3 patients. If patients at onedose level had no dose-limiting toxicity, the next cohort was initiated at a higherdose level. If a cohort met predefined criteria for a dose-limiting toxicity, 3 morepatients would be added to the cohort to determine if the event was an outlieror represented a trend. If a drug continued to Phase 2, it would be at the doselevel just prior to the one where a dose-limiting toxicity was seen.Having an approach that is too conservative can lead to trials in which patientsare treated with doses too low to be effective (Eisenhauer et al, 2000). Thismeans diseased and sometimes terminally ill patients would be treated with adrug unlikely to be effective. This can be unsettling to the physicians treatingpatients, and it has raised concern among ethicists. As more targeted therapiesare being developed, the focus of Phase 1 trials is shifting toward findingwhether a drug is reaching its target tissue or is the optimal biologically activedose. For example, the right dose of a biological like a monoclonal antibody isnot necessarily the maximally tolerated dose of this monoclonal but the dosewith a saturation of its target.
Keys for Setting up Phase I Oncology Studies
The major challenge in entering clinical development is translating in vitro and
preclinical data into a clinical regimen,”
according to Jurgen Frisch, MD, chief medical officer of European operations at Clinipace Worldwide. Knowing a clearscientific profile from preclinical data is crucial to design an adequate first trial.Preclinical models include tumor models, transgenic models, tissue data, andcell investigations. The goal is to know how a drug is acting: what are theprimary targets and what may be secondary targets that could become safetyconcerns or produce inadvertent effects.
Develop a solid trial design.
In a Phase 1 study, the primary endpoint will besafety. Secondary endpoints might include measures to evaluate effectivenessor narrow an indication or target population.

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