Faculty Bibliography

The TLR7/8 agonist, Resiquimod has been used as an immune adjuvant in cancer vaccines. We evaluated the safety and immunogenicity of the cancer testis antigen NY-ESO-1 given in combination with Montanide with or without Resiquimod in high risk melanoma patients. In Part I of the study, patients received 100ug full length NY-ESO-1 protein emulsified in 1.25mL Montanide (day 1) followed by topical application of 1000mg of 0.2% Resiquimod gel on days 1 and 3 (Cohort 1) versus days 1, 3, and 5 (Cohort 2) of a 21 day cycle. In Part II, patients were randomized to receive 100ug NY-ESO-1 protein plus Montanide (day 1) followed by topical application of placebo gel (Arm-A; N=8) or 1000mg of 0.2% Resiquimod gel (Arm-B; N=12) using the dosing regimen established in Part I. The vaccine regimens were generally well-tolerated. NY-ESO-1 specific humoral responses were induced or boosted in all patients, many with high titers. In Part II, 16 of 20 patients in both arms had NY-ESO-1-specific CD4+ T cell responses. CD8+ T cell responses were only seen in 3 of 12 patients in Arm B. Patients with TLR7 SNP rs179008 had a greater likelihood of developing NY-ESO-1-specific CD8+ responses. In conclusion, NY-ESO-1 protein in combination with Montanide with or without topical Resiquimod is safe and induces both antibody and CD4+ cell responses in the majority of patients; the small proportion of CD8+ cell responses suggests that the addition of topical Resiquimod to Montanide is not sufficient to induce consistent NY-ESO-1 specific CD8+ cell responses.

We performed a multicenter, investigator initiated, phase I dose escalation study of the oral multi-kinase inhibitor lestaurtinib in patients with JAK2V617F positive myelofibrosis, irrespective of baseline platelet count. A total of 34 patients were enrolled. Dose-limiting toxicities were observed in three patients overall, at the 100 mg (n = 1) and 160 mg (n = 2) twice-daily dose levels. The maximum tolerated dose was 140 mg twice daily. Gastrointestinal toxicity was the most common adverse event. Sixteen patients were evaluable for response at 12 weeks. Seven patients had clinical improvement by International Working Group - Myeloproliferative Neoplasms Research and Treatment criteria. Meaningful reductions in JAK2V617F allele burden were not observed. To measure JAK2 inhibition in vivo, plasma from treated patients was assayed for its ability to inhibit phosphorylation of signal transducer and activator of transcription 5 (STAT5): doses lower than 140 mg had variable and incomplete inhibition. In this phase I study, although gastrointestinal adverse events were common, significant clinical activity with lestaurtinib was observed (ClinicalTrials.gov identifier: NCT00668421).

BACKGROUND: In February 1999, the National Cancer Institute (NCI) issued a clinical alert based on five randomized trials that reported better overall survival (OS) with concurrent chemoradiotherapy (CCRT) than with surgery or radiation alone for locoregional cervical cancer. This study analyzes data from the surveillance epidemiology and end results (SEER) program to evaluate the improvement in survival in the era of CCRT. METHODS: The SEER database was queried for FIGO stages IB2-IVA cervical cancer patients treated with radiotherapy between 1995 and 2002. Patients diagnosed between 1999 and 2002 (CCRT era) were assumed to have received CCRT more frequently than patients diagnosed between 1995 and 1998 (RT era). Cases were stratified by period of diagnosis, age, and SEER region. OS and cause specific survival (CSS) were compared between the two time periods with chi-square log-rank tests. Multivariable Cox models were also used to compare OS and CSS between the two time periods, with adjustment for stratification variables and other covariates. RESULTS: The study included 3517 patients. Unadjusted OS and CSS were significantly improved in 1999-2002 compared with 1995-1998 (OS: p < 0.001, hazard ratio (HR): 0.81; CSS: p < 0.001, HR: 0.79). Significant improvements in OS and CSS were retained after adjustment for multiple variables (multivariable OS HR 0.78; CSS HR 0.76). CONCLUSION: Cervical cancer patients treated with radiotherapy after 1999 had improved OS and CSS compared with patients treated before 1999, likely reflecting increased usage of CCRT. This study adds to the population-level evidence supporting the adoption of CCRT as the standard of care for locoregional cervical cancer.

Senior housestaff and junior faculty are often expected to perform clinical research, yet may not always have the requisite knowledge and skills to do so successfully. Formal degree programs provide such knowledge, but require a significant commitment of time and money. Short-term training programs (days to weeks) provide alternative ways to accrue essential information and acquire fundamental methodological skills. Unfortunately, published information about short-term programs is sparse. To encourage discussion and exchange of ideas regarding such programs, we here share our experience developing and implementing INtensive Training in Research Statistics, Ethics, and Protocol Informatics and Design (INTREPID), a 24-day immersion training program in clinical research methodologies. Designing, planning, and offering INTREPID was feasible, and required significant faculty commitment, support personnel and infrastructure, as well as committed trainees. Clin Trans Sci 2014; Volume #: 1-7.

BACKGROUND: Activation of the RAS-RAF-MEK-ERK signaling pathway is thought to be the key driver of pediatric low-grade astrocytoma (PLGA) growth. Sorafenib is a multikinase inhibitor targeting BRAF, VEGFR, PDGFR, and c-kit. This multicenter phase II study was conducted to determine the response rate to sorafenib in patients with recurrent or progressive PLGA. METHODS: Key eligibility criteria included age >/=2 years, progressive PLGA evaluable on MRI, and at least one prior chemotherapy treatment. Sorafenib was administered twice daily at 200 mg/m2/dose (maximum of 400 mg/dose) in continuous 28-day cycles. MRI, including 3-dimensional volumetric tumor analysis, was performed every 12 weeks. BRAF molecular testing was performed on tumor tissue when available. RESULTS: Eleven patients, including 3 with neurofibromatosis type 1 (NF1), were evaluable for response; 5 tested positive for BRAF duplication. Nine patients (82%) came off trial due to radiological tumor progression after 2 or 3 cycles, including 3 patients with confirmed BRAF duplication. Median time to progression was 2.8 months (95% CI, 2.1-31.0 months). Enrollment was terminated early due to this rapid and unexpectedly high progression rate. Tumor tissue obtained from 4 patients after termination of the study showed viable pilocytic or pilomyxoid astrocytoma. CONCLUSIONS: Sorafenib produced unexpected and unprecedented acceleration of tumor growth in children with PLGA, irrespective of NF1 or tumor BRAF status. In vitro studies with sorafenib indicate that this effect is likely related to paradoxical ERK activation. Close monitoring for early tumor progression should be included in trials of novel agents that modulate signal transduction.