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Basic Information about Clinical Trials
How do we think about trials for patients with sarcoma?
Obligatory—This is not medical advice
Clinical trials are made to answer specific questions. These can study medications or other interventions and how they affect any aspect of patient care. They exist in a number of phases (which we’ll talk about below). The first step is to determine whether a medication is even safe to administer. This is followed subsequently by preliminary tests of efficacy, as defined prior to the study, and then, finally, by comparison to some form of control (a medication that has been the standard). While there are many ways to bake a cake, this is the general thought process that propels hypothesis testing from Phase I through Phase III. In most sarcoma centers, there will be a variety of phases of clinical trials that are underway. Windows for trials open and close and there may even be temporary halts in recruitment depending upon safety, efficacy data, or supply chain issues. This is all to say that the modern clinical research process, while ostensibly simple from the outside, has a lot of variables that must be calibrated appropriately to function. Care is coordinated across sites, cities, states, nations, and oceans. It’s quite the system.
Indication for Clinical Trials
Clinical trials have been the modern bedrock of advancement in the care of patients. While there may at times be a sentiment that this might be a slow process, nonetheless, it is a means of imposing order onto chaos. Prior to wide acceptance of research principles over the prior century, medical experimentation was often performed without appropriate comparators, and even without consideration of methods of patient consent for procedures. To expand upon all of the developments here would probably involve a thousand-page treatise, but suffice to say that some of these references would be a good starting point.1234
Phases of Clinical Trials
The flow of trials is demonstrated as per above, but we’ll extrapolate more on each subtype here.
Phase I: trials designed to determine the maximum tolerated dose (MTD) of the medication under evaluation, which may or may not be the does that would be acceptable for the next phase study performed. These may have a relatively broad pool of inclusion criteria. Data can be collected with a few different statistical designs. Patients in phase I studies are followed very closely with serial laboratory draws and other physiologic testing. Often, these types of trials require the most frequent monitoring.
Phase II: trials with primary endpoints evaluating efficacy of the medication within a given context. Usually, again, this is a single arm design, however, there have been randomized Phase II trials as well. For patients with sarcoma, the endpoint under evaluation is generally the progression free survival, or some other equivalent such as progression free rate at a certain time point. Generally, this efficacy threshold is set based on historical controls. Remember that progression free survival is a surrogate endpoint that incorporates the following:
Time to growth of a lesion by 20% in the sum of target (eg chosen) lesions at any point, including after prior response5
Phase III: these are studies that usually randomize patients between the treatment under evaluation and a control arm. Within Leiomyosarcoma, recently, there was a phase III randomized study comparing doxorubicin to doxorubicin in the first line for advanced disease.6 (reference: ) . Older examples of randomized trials include the clinical trial of trabectedin or dacarbazine for patients with L-type sarcomas.7 Primary endpoints in these studies have also utilized progression free survival. It is in the best interest of patients that overall survival be measured as well, ideally as a primary endpoint, as that is what matters most to patients.
Looking at a clinical trial
Whenever one of these trials is performed, to answer its question more accurately, it must have constraints on the population that is studied. Sometimes this means a specific subtype of sarcoma. Other times this might mean that patients must have been failed by earlier lines of treatment such as doxorubicin. This allows for investigators to hone a more precise null hypothesis, or theory against which a trial is tested.
Let’s look at a clinical trial now enrolling patients with leiomyosarcoma to explore this further: Olaparib and Temozolomide Versus Usual Treatment for Uterine Leiomyosarcoma (NCT05633381)
This clinical trial is building on NCI protocol 10250 which was presented at ASCO in 2021. Within that study, patients with advanced uterine leiomyosarcoma who had progressed on more than one prior line of therapy received temozolomide and Olaparib. This trial was reviewed before in this substack (reference). The primary endpoint was response rate. Of 22 evaluable patients within that Phase II study, the response rate was 27% (6 of 22 patients), which exceeded the threshold set (5 of 22 patients). The progression free survival was 6.9 months for patients on that study.
Within this now recruiting trial, patients are of a similar population, although they must have progressed on two prior lines of systemic therapy, of which one must have been doxorubicin. The comparison arm of the Phase 3 portion is investigator’s choice between trabectedin and pazopanib. As an aside, these are standard of care options that will be received by most patients with leiomyosarcoma and therefore very reasonable control arms.
The primary outcome measures, or questions it is addressing, are progression free survival (for the phase II portion) and overall survival for the phase III portion. These are exactly what patients want to know—and the most common question asked of physicians today—how much longer will I live by taking these medications?
Enrolling in a clinical trial
If you’re interested in clinical trials for your sarcoma, the best step to better prepare yourself is to:
Have a conversation with your treating oncologist about what may or may not be available in your area
Visit your local academic center’s website, for instance in the bay area that would be UCSF
Consider reviewing clinicaltrials.gov
For studies on that site, it might be best to look through it and communicate with your oncologist. There can be some details in each study that are nuanced
Trials are a mechanism by which important questions are answered about an intervention—health related or otherwise. At their best, they are a means of clearly defining which intervention is superior. Within the realm of sarcoma, it is a process by which we determine which treatment is most effective for our patients. A clinical trial is only as good as the question that it answers. Within the cancer space, the most appropriate question at this this time is: does this treatment help patients live longer or better? Surrogate endpoints may approximate these answers, but it is important to understand their limitations. Patients interested in clinical trials should have a discussion with their treating oncologists and consider looking online at available trials in their area or nationally.