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The numbers of oncology drugs in clinical development is more than twice the number in any other therapeutic area (PharmaLive.com). Yet despite being the most commonly tested therapies, oncology drugs have the worst approval rates. Only 5% of agents with anticancer activity in preclinical development are licensed (Hutchison and Kirk, 2011). The main reason for failure is that preclinical strategies to evaluate novel oncology agents are suboptimal. In addition, conducting clinical trials in cancer patients is challenging because of the number and type of prior treatments patients have undergone and because novel agents are tested in patients with late-stage malignancies, which are inherently more difficult to treat than earlier malignancies. The current landscape of cancer therapeutics is evolving as the genetic and molecular mechanisms involved in cancer are increasingly understood. More targeted and individualized therapy has presented exciting possibilities to combat disease, but the new approaches have also added complexity to clinical development. In any disease state, conducting successful Phase 1 trials is a key component of ushering a novel therapy through clinical development. Although Phase 1 studies in most therapeutic areas consist of healthy patients, Phase 1 studies in oncology consist of patients with active disease. This creates unique challenges and potential opportunities. Understanding these challenges and opportunities is 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 who have already been treated with standard of care. The reason for this distinctiveness is an ethical one; any new investigational agent bears the potential of failure or suboptimal therapeutic efficacy, and the inclusion of early stage patients who do have proven treatments would be regarded as unethical unless the new agent has shown activity.
Late-stage patients tend to be less responsive to medications, and they tend to be more confounded by co-morbities or potential for interaction with other drugs. Their response to an investigational therapy may not represent the response 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 immune system is less able to mount a response. In patients with late-stage disease, it can be difficult to discern whether adverse events are caused by the investigational 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 efficacy data may be obtained. However, gathering meaningful data can be difficult and take a long time. For many non-oncology indications, such as high blood pressure or diabetes, objective results can be seen within days to weeks. Evaluating meaningful clinical efficacy in patients with tumors takes months to years. Although tumor responses can sometimes be evaluated after a short time of 1 to 3 months, endpoints like disease-free survival or time to progression can only be learned if patients are followed beyond the median time to progression of their tumor, which can easily reach 1 year or longer. Given the time enrollment takes, a Phase 1 oncology trial can take 1.5 to 2 years. Enrollment times can be especially long because oncology trials usually need to be conducted over a number of dose escalation levels before any anti-tumor efficacy can be identified. Before a trial is conducted, careful consideration needs to be given to whether and how a drug might be beneficial or harmful to patients. Early phase oncology trials 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. Even patients who meet all inclusion criteria for a study can have a rapid worsening of malignancy shortly after enrolling. Having patients get very sick or die during a trial takes an emotional toll on all members of the study team. In general, oncology patients are committed to supporting progress in science and medicine. Therefore, patients tend to be compliant with the treatment regimen and evaluations.
Evolution in Trial Design
The goal of Phase 1 studies is to find the optimal dose of therapy, meaning one that is high enough to be effective but not so high as to cause intolerability. Historically, Phase 1 trial designs involved conservative methods of finding maximum tolerated doses. Doses were started at 0. 1 mouse-equivalents, which means 10% of dose that 10% of mice would die from. “Slow-as-you-go” 3 + 3 designs were common. Each dose level would have 3 patients. If patients at one dose level had no dose-limiting toxicity, the next cohort was initiated at a higher dose level. If a cohort met predefined criteria for a dose-limiting toxicity, 3 more patients would be added to the cohort to determine if the event was an outlier or represented a trend. If a drug continued to Phase 2, it would be at the dose level 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 patients are treated with doses too low to be effective (Eisenhauer et al, 2000). This means diseased and sometimes terminally ill patients would be treated with a drug unlikely to be effective. This can be unsettling to the physicians treating patients, and it has raised concern among ethicists. As more targeted therapies are being developed, the focus of Phase 1 trials is shifting toward finding whether a drug is reaching its target tissue or is the optimal biologically active dose. For example, the right dose of a biological like a monoclonal antibody is not necessarily the maximally tolerated dose of this monoclonal but the dose with 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 clear scientific profile from preclinical data is crucial to design an adequate first trial. Preclinical models include tumor models, transgenic models, tissue data, and cell investigations. The goal is to know how a drug is acting: what are the primary targets and what may be secondary targets that could become safety concerns or produce inadvertent effects.
Develop a solid trial design. In a Phase 1 study, the primary endpoint will be
safety. Secondary endpoints might include measures to evaluate effectiveness or narrow an indication or target population.
Clinically meaningful endpoints such as progression-free survival take a long time to measure and are rarely used in Phase 1 studies. Shorter-term endpoints can include surrogate parameters of efficacy, such as activity of a kinase or amount of drug binding to excised tumor cells. Other diagnostic variables may indicate something about the activity of the drug before clinical effects are seen. For example, in the case of tumor vaccines, immune responses deemed to be a mandatory response for any later clinical response can be detected as a valid surrogate endpoint far before an effect on a tumor can be discerned. Although later phase trials must have strong power analysis to scientifically prove the value of a therapy, early phase trials, especially phase 1 studies, do not have such a consistent need for power analysis or justification of sample size. Dosing is an important consideration in study design. The goal is to start at lowest therapeutic dose possible to avoid having cohorts that will not yield useful information. Furthermore, because of regulatory and scientific considerations it is useful to determine the minimal effective dose of a new agent. If possible, preclinical data should be used to determine whether dosing should be daily or twice daily. Multiple dosing schedules within various cohorts may be needed. Dose escalation procedures should be clearly detailed in the protocol to avoid errors in treatment assignment. If patients are not assigned to correct cohorts and doses, they will be unenrolled from the study, which increases the cost of the trial and is disappointing to patients and the enrolling sites. If the experimental therapy is a targeted one, diagnostic tools will be needed to identify patients with specific disease characteristics. For example, if a therapy targets tumor cells carrying a mutation in a tyrosine kinase receptor protein, such as EGFR in lung cancer or B-Raf kinase in skin cancer, patient tumors will need to be screened for those that carry the mutation. Using biomarkers (Box 1, Table 1) for inclusion criteria in a study can slow enrollment and add costs. Also, having complex study designs and novel biomarkers can slow the process of regulatory approval. It can be challenging to write a clear protocol, especially when a treatment is being tested for the first time in humans. Getting feedback from key opinion leaders and principal investigators can be especially helpful in crafting inclusion and exclusion criteria to maximize the population of enrollable patients.
The following are important enrollment-related questions to consider: What is the tumor type or cell type being targeted? What is the age of the population (pediatric, geriatric, or anyone over the age of 18)? How healthy do patients have to be to enter the study? Do patients have to have a certain level of functioning of a specific organ? What comorbidities are allowed? What should patient life expectancy be? What prior treatments are acceptable? What should the length of any wash-out periods be? Are there any lab value cut-offs?
Also important is developing a clear schedule of events and a calendar for labs, tests, and scans. Assessments and procedures need to be described clearly to avoid site personnel from having confusion on the timing or process of collecting pharmacokinetic and other laboratory samples.
Use technology. Technology-based tools such as electronic data capture and
clinical trial management have improved many aspects of the research process. Having a platform for sharing information and documents can lead to better communication and faster site activation. Electronic data capture can provide a lot of support for the investigator and the study personnel and thus has big advantages over paper forms in monitoring enrollment, patient outcomes, and data quality.
Select high-performing sites and personnel. Most Phase 1 oncology studies
have only 2-3 study sites. Start-up at each site is costly, and if the study only needs a few cohorts, resources should not be put into starting up more sites than necessary. In oncology, “the earlier your development stage is, the more important it is to have experienced investigators and sites,” according to Dr. Frisch. Ideally, investigators and site personnel should be familiar with challenges and requirements of oncology clinical trials, the risks of investigational drugs, and how to handle them. Later trials, such as Phase 3 studies, may seem larger and more complex, but the therapies evaluated in them are much closer to standard treatments than those in Phase 1 studies. Early phase studies have different requirements for special diagnostics, treatment actions, and documentation.
Investigators and site personnel who are familiar with these things are more likely to deliver quality data. To maintain patient safety, investigators need to be able to discern whether adverse events were likely caused by the investigational drug, the disease itself, or other therapies. Less experienced investigators can be misled by events or overlook them. If possible, clinical research associates (CRAs) should have experience in early stage oncology trials. As the liaison between the clinical research organization and study sites, CRAs are key in communicating trial conduct to both parties. An understanding of clinical oncology is important for interacting with study sites and recognizing the significance of certain toxicities. Oncology is one of the more global and internationally harmonized therapeutic areas, but there are regional standards and differences in how to handle medicine, treat patients, and do clinical investigations. Service providers should have regional knowledge of these areas so they can specifically address them in training investigators. This helps set up the framework for a trial and helps avoid mistakes and misunderstandings. In the US and Europe, many oncology studies are done in large universities or independent commercial Phase 1 units. Both have access to patients and have staffing to handle the types of collections that need to be done for Phase 1 studies, such as 12-hour pharmacokinetic samples. An advantage of university sites is that they have key opinion leaders, but start-up can take a long time and overhead costs are often high. Emerging locales, such as Latin America, have large cancer centers with investigators who may be good candidates for taking part in Phase 1 trials. Investigators should have extensive experience in oncology and clinical investigation before participating in Phase 1 studies.
Staying on Pace Throughout Phase I Studies
Phase 1 studies require daily monitoring. This population of patients can have rapid changes in the course of their disease or response to therapy. Frequent communication between investigators and patients as well as investigators and the sponsor is critical for maintaining patient safety in case toxicities arise. CRAs must monitor screening and enrollment at each site. They also need to have frequent contact with sites to make sure data are logged in a timely manner.
Electronic data capture can facilitate quality control of data and dissemination of data to the sponsor, investigators, and safety boards; monitoring for protocol compliance; and recognizing trends in toxicity. Having a sophisticated technology platform can be used for quickly updating, obtaining, and reacting to information so individual parties can communicate and interact with each other without complicated exchanges of data. Being able to assess reliability of data is a significant advantage of electronic data capture. Data can either be monitored manually, or comparison functions can be automatically programmed to check, for example, whether data fits with inclusion/exclusion criteria specified in the protocol. Having access to data provides an immediate chance to correct or clarify uncertain data points.
Advances in biotechnology will continue to expand the potential for new therapeutics in oncology. Translating in vitro data into an approved clinical regimen will continue to be challenging, especially as targeted therapies add complexity to designing studies and assessing effectiveness. However, several strategies, including developing a solid study design, choosing the right study team, and using technology, can help streamline the conduct of trials and improve quality of data.
PharmaLive.com. Top 15 Therapeutic Areas. Available at: www.pharmalive.com/special_reports/sample.cfm?reportID=327. Accessed 12 March 2012. Hutchison L, Kirk R. High drug attrition rates—where are we going wrong? Nature Reviews Clinical Oncology. 2011;8:189-190. Eisenhauer EA, O’Dwyer PJ, Christian M, Humphrey JS. Phase 1 clinical trial design in cancer drug development. J Clin Oncol. 2000;18(3):684-92. Caris Life Sciences. Biomarker Appendix. Available at: http://www.mycancer.com/cancer-diagnosis. Accessed 27 March 2012.
About Clinipace Worldwide
Clinipace Worldwide, a global digital clinical research organization (dCRO), specializes in fully-integrated clinical research services for biopharmaceutical and medical device firms. Optimized by TEMPO™, its proprietary eClinical platform, the Clinipace team of experts brings extensive knowledge and insight into site selection, patient recruitment, clinical operations, data management, medical monitoring, biostatistics, and regulatory affairs to ensure a successful clinical development program through proactive clinical trial management. With specific expertise in oncology, among other therapeutic areas, Clinipace Worldwide has managed over 600 global contract research and regulatory projects. Clinipace Worldwide is headquartered in Research Triangle Park, North Carolina with offices in Overland Park, Kansas, Boulder, Colorado, Zurich, Switzerland, Munich, Germany, Tel-Aviv, Israel, New Delhi, India, Sao Paulo, Brazil, Buenos Aires, Argentina, and Lima, Peru. For more information visit our website at www.clinipace.com. Corporate Headquarters 3800 Paramount Pkwy, Suite 100 Morrisville, North Carolina 27560 919.224.8800 email@example.com www.clinipace.com