Ethical challenges related to the specialized role of clinical research nurses were identified. More research is warranted to fully understand their nature and frequency and to identify support systems for resolution.
Background: Molecular profiling of cancers is now routine at many cancer centers, and the number of precision cancer medicine clinical trials, which are informed by profiling, is steadily rising. Additionally, these trials are becoming increasingly complex, often having multiple arms and many genomic eligibility criteria. Currently, it is a challenging for physicians to match patients to relevant clinical trials using the patient's genomic profile, which can lead to missed opportunities. Automated matching against uniformly structured and encoded genomic eligibility criteria is essential to keep pace with the complex landscape of precision medicine clinical trials.Results: To meet these needs, we built and deployed an automated clinical trial matching platform called MatchMiner at the Dana-Farber Cancer Institute (DFCI). The platform has been integrated with Profile, DFCI's enterprise genomic profiling project, which contains tumor profile data for >20,000 patients, and has been made available to physicians across the Institute. As no current standard exists for encoding clinical trial eligibility criteria, a new language called Clinical Trial Markup Language (CTML) was developed, and over 158 genomically-driven clinical trials were encoded using this language. The platform is open source and freely available for adoption by other institutions. Conclusion:MatchMiner is the first open platform developed to enable computational matching of patient-specific genomic profiles to precision cancer medicine clinical trials. Creating MatchMiner required developing clinical trial eligibility standards to support genome-driven matching and developing intuitive interfaces to support practical use-cases. Given the complexity of tumor profiling and the rapidly changing multi-site nature of genome-driven clinical trials, open source software is the most efficient, scalable, and economical option for matching cancer patients to clinical trials.
A large group of patients with node‐positive breast cancer was divided into a training set (n = 851) and a validation set (n = 432) to demonstrate techniques for integrating steroid hormone receptor status, DNA flow cytometric findings, and other prognostic factors to predict patient survival. Multivariate analyses showed that estrogen receptor status, the number of involved axillary lymph nodes, patient age, S‐phase fraction, progesterone receptor status, and tumor size were significant predictors of survival in patients with node‐positive breast cancer. Techniques for optimizing and validating a cut point for a new prognostic factor and for examining alternative representations of prognostic factors were demonstrated. Prognostic indexes were created that could be used to identify patients with very good or very poor prognoses.
Background: CYC065 is a potent and selective inhibitor of CDK2 and CDK9. CDK2 drives cell cycle transition and activates major DNA double-strand break repair pathways; CDK9 regulates transcription of genes through phosphorylation of RNAP II. This first-in-human phase 1 study evaluates CYC065 administered by 4-hour infusion every 3 weeks in patients with advanced cancers. Methods: Dose escalation was 100% initially. Upon the occurrence of the first grade 2 drug-related toxicity, dose escalation decreased to 50% and then to 25% upon the occurrence of the first dose-limiting toxicity (DLT). Recommended phase 2 dose (RP2D) was MTD defined as highest dose level at which less than one-third of at least 6 patients experienced cycle 1 DLT. Blood samples were taken in at pre-dose and up to 24 hours after the first dose of cycle 1 to assess pharmacokinetic (PK) and pharmacodynamic (PD) effects. Biomarkers related to CYC065 target inhibition, e.g. phosphorylation of Ser2 RNA polymerase II - a direct substrate of CDK9, and protein levels of downstream targets, such as Mcl-1, were determined in patient's PBMCs. Results: 26 patients were treated. The MTD was 192 mg/m2. DLTs are reversible neutropenia, thrombocytopenia, febrile neutropenia, diarrhea, hypomagnesemia, white blood cell lysis syndrome and its associated electrolyte abnormalities and liver enzyme elevations. The most frequent adverse events (all cycles, regardless of causality) included constipation, diarrhea, decreased appetite, dehydration, fatigue, nausea, and vomiting, the majority mild to moderate in intensity. All patients participated in the PK/PD samplings. Exposure to CYC065 increased with dose. Average half-life ranged from 1.64 h to 3.9 h. Mcl-1 suppression, lasting at least 24 hours after a single dose, was observed in 11 out of 13 evaluable patients at the RP2D (192 mg/m2). Stable disease ≥ 6 cycles was observed in 6 patients, 5 of which treated at the RP2D: larynx neuroendocrine carcinoma (n=1), ovarian adenocarcinoma (n=2); uterine carcinosarcoma (1), parotid gland actinic cell carcinoma (n=1) and submandibular gland adenoid cystic carcinoma (n=1). Two patients with uterine and ovarian cancer are continuing on treatment having received 9 and 17 cycles respectively. Conclusion: CYC065 administered by 4-hour infusion is safe and demonstrated durable MCL-1 suppression at the RP2D. Durable stable diseases were observed. Additional dosing schedules to intensify dose density will be evaluated. Citation Format: Khanh T. Do, Nicole Chau, Andrew Wolanski, Brian Beardslee, Faith Hassinger, Ketki Bhushan, Solida Pruitt-Thompson, Amber Scotton, Sheelagh Frame, Daniella I. Zheleva, David Blake, Judy Chiao, Geoffrey I. Shapiro. Phase I safety, pharmacokinetic and pharmacodynamic study of CYC065, a cyclin dependent kinase inhibitor, in patients with advanced cancers (NCT02552953) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT037.
Background: Although PARP inhibition is effective against HR repair-deficient cancers, efficacy is limited by HR proficiency, whether present de novo or as a result of acquired resistance, prompting HR disrupting strategies to sensitize tumor cells. Inhibition of CDK1 and CDK12 compromise HR by blocking BRCA1 phosphorylation, affecting recruitment to sites of DNA damage, and by reducing HR gene expression, respectively. Dinaciclib is a pan-CDK inhibitor that inhibits both CDK1 and CDK12 at nanomolar potency. We conducted a Phase 1 study combining dinaciclib and veliparib in patients with advanced solid tumors who are not germline BRCA carriers. Methods: A 3+3 design was utilized. Veliparib was administered twice daily continuously in 28-day cycles. Dinaciclib was administered intravenously on days 8 and 22. In part 1A, escalation followed a two-dimensional schema, utilizing doses of dinaciclib between 10 - 45 mg/m2 and veliparib between 20 - 120 mg. In part 1B, veliparib was escalated between 200 mg - 400 mg with dinaciclib maintained at 30 mg/m2. PK and PD assessments were performed at baseline, after veliparib, and after the combination. Preliminary Results: Sixty-three heavily pretreated patients were enrolled in part 1A (n = 39) and 1B (n = 24). Thirty-four patients had breast or gynecologic malignancies. The MTD was 400 mg twice-daily veliparib with dinaciclib at 30 mg/m2. DLTs included G4 neutropenia > 7 days (n =1), febrile neutropenia (n = 1), mucositis (n = 1) and fatigue (n = 1). Common drug-related toxicities were neutropenia (78%), nausea (75%), fatigue (67%), electrolyte abnormalities (59%), elevated liver function tests (57%), diarrhea (52%), lymphopenia (52%), anemia (43%), dehydration (37%), anorexia (30%), vomiting (29%), hypoalbuminemia (29%), dizziness (29%), headache (22%), mucositis (18%), elevated creatinine (16%), alopecia (16%), thrombocytopenia (14%), abdominal pain (13%), insomnia (13%), and dysgeusia (11%). The median number of cycles completed was 2 (r: 1 - 10). One patient with TNBC achieved complete resolution of axillary adenopathy lasting > 8 months. Twenty-four patients (38%) had stable disease as the best response, with 9 progression-free > 4 months (TNBC, gynecologic and thymic ca). Paired tumor biopsies from one patient demonstrated reduced Ki-67 and increased gamma-H2AX staining after combination treatment compared to after veliparib alone. Conclusions: Dinaciclib administered at doses known to produce PD effects is tolerable with full dose veliparib. Anti-tumor activity is limited in non-BRCA carriers, possibly related to intermittent administration of a CDK inhibitor with known short half-life. Additional patients are being enrolled utilizing dinaciclib in more dose-intense schedules. Citation Format: Geoffrey I. Shapiro, Khanh T. Do, Sara M. Tolaney, John F. Hilton, James M. Cleary, Andrew Wolanski, Brian Beardslee, Faith Hassinger, Ketki Bhushan, Dongpo Cai, Elizabeth Downey, Solida Pruitt-Thompson, Suzanne M. Barry, Bose Kochupurakkal, Joseph Geradts, Christine Unitt, Alan D. D'Andrea, Alona Muzikansky, Richard Piekarz, L. Austin Doyle, Jeffrey Supko. Phase 1 dose-escalation study of the CDK inhibitor dinaciclib in combination with the PARP inhibitor veliparib in patients with advanced solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT047. doi:10.1158/1538-7445.AM2017-CT047
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