Clinical Research in Oncology

One of my interests in oncology (and the real reason I went in to oncology) is clinical research. I believe that oncology affords a real opportunity for me, as a doctor, to make an impact on any woman's life and via clinical trials, to make gains in the treatment options for women with cancer. Clinical trials are the only way we can meet the high expectations of patients and of society to offer only those therapies that are proven to be effective. Needless to say, I am a huge proponent of clinical trials in oncology, and whenever a trial option is available, I offer it to my patients. In the next posts at the beginning of each month, I will be highlighting some important trials in both breast and gynecologic cancers. I think knowing what's going on now is as important as commenting on what's already been done, and what's just been published.

As a refresher, there are three types of treatment trials that are done in oncology: phase I, phase II, and phase III trials. By far, the most important trial design is the phase III trial. These are randomized, controlled trials where an experimental treatment is compared to the current standard of care (or in the case of breast cancer, for example, a standard of care). In the adjuvant setting, the objective is to improve overall survival and in the metastatic setting, the objective is generally progression-free survival and overall response rates. In the latter case, trials in advanced or metastatic disease are also reporting the rate of "clinical benefit," which takes the overall response rate and adds to that the proportion of patients who achieved stable disease for a predetermined period of time. Positive phase III trials have the capability of changing standards of care and in women's cancers, and have led to the adoption of intraperitoneal chemotherapy as an adjuvant treatment for stage III-IV optimally cytoreduced ovarian cancer, the use of Trastuzumab in the adjuvant setting in HER2 positive breast cancer, and the use of Bevacizumab and paclitaxel as a first-line treatment in metastatic breast cancer.

For women who do not meet criteria for phase III trials, phase II trials are options. These are novel treatments looking at response rates in specifically defined populations. For example, novel drug X may be in a phase II trial in women with recurrent ovarian cancer; however, eligibility might be limited to women with a certain type of ovarian cancer (say, serous histologies), only with measurable disease (CT-defined lesions >1cm), and previously untreated for metastatic or recurrent cancer. By selecting the specific population, trial designers can then estimate the expected response rate for available treatments and the effect of change they are interested in showing- all of which will drive the number of patients required. However, given the inclusion/exclusion criterias, women may not be eligible even for phase II trials.

For those who are still interested in novel therapies, phase I trials are available, usually at specialized centers. These are typically "first in human" studies—either the first time the drug is being tried in oncology (or in specific disease settings like breast or ovarian cancers) or the schedule being tried has not been done before. Unlike phase II or phase III trials, phase I trials do not test for how active a drug is; instead, the objective is to determine the safest allowable dose of the drug by defining the side effects seen at each dose evaluated. When a dose causes too much side effects as defined in the study, this dose is generally termed the maximally tolerated dose. Phase I trials also give us the opportunity to see how a body handles this new agent, by performing pharmacokinetic studies.

For now, I'll focus on what I consider priority studies in breast oncology, and I reference the trial number (NCT) that will give you more information on www.clinicaltrials.gov. These are trials that are underway nationally, and for us here in New England, ones that we are running locally. For women with advanced tumors at diagnosis, an option to downsize the tumor using first-line chemotherapy (termed neoadjuvant treatment) is a popular one. We know that by shrinking down tumors, women whose only option is a mastectomy can become candidates for breast conservation. Neoadjuvant trials are underway. Through Brown University Oncology Group, the combination of carboplatin and nAb-paclitaxel is being used in a phase II trial. In women with HER2 negative disease, the drug bevacizumab is being used with this combination, after which women will also get doxorubicin and cyclophosphamide (AC) (NCT00723125). For women with HER2 positive disease, carboplatin and nAb-paclitaxel is being combined with trastuzumab (NCT00617942). For women deemed ineligible for chemotherapy, neoadjuvant endocrine therapy is also being evaluated. Letrozole +/- Zoledronic acid is currently in a randomized phase II trial (NCT00375752). If after neoadjuvant chemotherapy women are found with residual breast cancer, clinical trials are underway to evaluate the role of further treatment. At Brown, we are performing a phase II trial of gemcitabine, capecitabine, and bevacizumab for women with residual disease following treatment with an anthracycline- and taxane- based neoadjuvant regimen (NCT00462865).

For women who have undergone surgery and require adjuvant treatment several high priority national trials are recruiting. For the HER2 negative patient, the Eastern Cooperative Group (ECOG) is running ECOG 1503, a randomized trial of chemotherapy +/- bevacizumab for women with node-positive or high risk node-negative breast cancer (NCT00433511). For HER2 positive women, the National Surgical Breast and Bowel Project (NSABP) is performing B-41, a trial of doxorubicin/cyclophosphamide followed by trastuzumab or lapatanib or both (NCT00486668). Also being performed in this population is a trial conducted internationally with the Breast International Group (BIG), the North Central Cancer Treatment Group (NCCTG), National Cancer Institutes of both the US and Canada. Theirs is a randomized study of adjuvant Lapatinib, Trastuzumab, Their Sequence or Their Combination (NCT00490139).

Finally, for women with metastatic breast cancer, multiple options abound for both phase I and phase II trials. This link will take you to clinicaltrials.gov for a listing of actively recruiting trials in this setting: http://clinicaltrials.gov/ct2/results?term=metastatic+breast+cancer&recr=Open. More to come, as we shift focus to trial options in gynecologic tumors.