A Phase II Study of Durvalumab in Combination with Tremelimumab in Patients with Rare Cancers.

LESSONS LEARNED: Disease control with signals of response were demonstrated, which should lead to future validating clinical trials using checkpoint inhibitors in this underserved rare malignancy population. Although the study of single types of rare cancers is practically challenging, clinical trial designs that aggregate such patients into cohorts treated similarly are feasible, even in the community setting. BACKGROUND: Patients with rare cancers are an underserved population with limited access to clinical trials aside from phase I trials in the refractory setting. Treatment of these patients is often based on collections of anecdotes and small denominator review articles. Despite broad evidence of efficacy of combined immune checkpoint blockade across multiple tumor types, patients with rare tumors have not been afforded the opportunity for these therapies. METHODS: A phase II, investigator-initiated, single institution trial using durvalumab (1,500 mg every [Q]4 weeks × 13) and tremelimumab (75 mg Q4 weeks × 7, then Q12 weeks × 2) is reported. The population included 50 patients with advanced rare solid tumors (incidence <6/100,000 per year). The phase II dose and safety profile were defined in prior phase I trials. All patients had exhausted standard therapy options and all had received at least one prior line of systemic therapy (n = 49) unless a standard treatment option did not exist (n = 1). RESULTS: A complete response was demonstrated in one patient with anal cancer. Striking partial responses were seen in four patients. Prolonged disease stability was noted in 18 patients. Thirteen patients experienced disease progression. Patients were considered unevaluable if unable to initiate therapy (n = 6) or unable to complete two cycles of therapy (n = 8). In all cases, patients were unevaluable because of clinical deterioration. The toxicity profile paralleled prior published studies. Toxicities were manageable and without new signals. There were two events of grade 4 immune-mediated hepatitis and one death from pneumonitis. CONCLUSION: This single-cohort basket trial demonstrated clinical activity from combined checkpoint blockade in 23 of the 36 evaluable patients. Patients with rare cancers, not eligible for immunotherapy via conventional clinical trial mechanisms, should be considered for this therapy through compassionate use, further clinical trials, and national registry programs.

The Competency of Clinical Research Coordinators: The Importance of Education and Experience.

BACKGROUND: The organization and operation of clinical trials have become increasingly complex requiring the coordination of a well-trained workforce to ensure that complicated protocols yield valid results that will advance human health. We hypothesized that formal education in clinical research is equivalent to a number of years of work experience as a clinical research professional in terms of self-perceived clinical research competence. METHODS: Using REDCap, we conducted a survey of students and recent graduates from academic programs in clinical research in the USA using the CICRP index that consists of 20 clinical research core competencies. We compared the responses of recent graduates to CRCs wording in the USA and Canada in various research settings who responded to a similar survey conducted by the Joint Task Force and to experienced CRCs working at research-intensive CTSA hubs and their affiliated hospitals who were surveyed as part of the NIH funded DIAMOND project. RESULTS: We found that the degree of self-perceived competence to perform advanced core competencies such as those related to regulatory affairs among new graduates of formal academic programs without research experience to be equivalent to as many as five years of on-the-job-training in a research-intensive CTSA setting and more than ten years of experience in less research-intensive community settings. CONCLUSIONS: These findings suggest that scores on both forms of the CICRP differentiate CRCs according to formal education in clinical research, years of experience as a CRC and type of research setting in which they work. Further, the self-perceived competency assessed by CICRP acquired by completing an academic program in clinical research is equivalent to years of work experience.

Leveling the Joint Task Force Core Competencies for Clinical Research Professionals.

Competency standards for clinical research professionals are being developed across the enterprise, based largely on the Core Competency Framework put forth by the Joint Task Force for Clinical Trial Competency (JTF). In late 2016, representatives from organizations around the world convened at a workshop hosted by the Multi-Regional Clinical Trial Center of Brigham and Women's Hospital and Harvard (MRCT Center) to discuss their use of the standards. A number of modifications were suggested that resulted in the publication of JTF Framework 2.0. Another suggested evolution of the Framework was to consider "leveling" the competencies, to reflect the increase in competency that occurs as individuals progress in their careers. This paper describes the process utilized and final outcome of this work. The leveled competencies, defined as the Fundamental, Skilled, and Advanced levels, and the included examples are expected to provide better-defined tools and resources to organizations that are creating educational and training programs, standardized role descriptions, or professional progression planning for clinical research professionals.

Phase I studies of interleukin (IL)-2 and rituximab in B-cell non-hodgkin's lymphoma: IL-2 mediated natural killer cell expansion correlations with clinical response.

PURPOSE: Expansion and activation of natural killer (NK) cells with interleukin-2 (IL-2) may enhance antibody-dependent cellular cytotoxicity (ADCC), an important mechanism of rituximab activity. Two parallel Phase I studies evaluated combination therapy with rituximab and IL-2 in relapsed or refractory B-cell non-Hodgkin's lymphoma (NHL). EXPERIMENTAL DESIGN: Thirty-four patients with advanced NHL received rituximab (375 mg/m(2) i.v. weekly, weeks 1-4) and escalating doses of s.c. IL-2 [2-7.5 MIU daily (n = 19) or 4.5-14 million international units three times weekly (n = 15), weeks 2-5]. Safety, tolerability, clinical responses, NK cell counts, and ADCC activity were evaluated. RESULTS: Maximally tolerated doses (MTD) of IL-2 were 6 MIU daily and 14 million international units thrice weekly. The most common adverse events were fever, chills, and injection site reactions. Dose-limiting toxicities were fatigue and reversible liver enzyme test elevations. Of the 9 patients enrolled at the daily schedule MTD, 5 showed clinical response. On the thrice-weekly schedule at the MTD, 4 of 5 patients responded. Responders showed median time to progression of 14.9 and 16.1 months, respectively, for the two studies. For the same total weekly dose, thrice-weekly IL-2 administration induced greater increases in NK cell counts than daily dosing, and NK cells correlated with clinical response on the thrice-weekly regimen. ADCC activity was increased and maintained after IL-2 therapy in responding and stable disease patients. CONCLUSIONS: Addition of IL-2 to rituximab therapy is safe and, using thrice-weekly IL-2 dosing, results in NK cell expansion that correlates with response. This combination treatment regimen merits additional evaluation in a randomized clinical trial.