Daniel, J.

AbstractBackgroundFactors predicting locoregional relapse after surgery for oropharyngeal squamous cell carcinoma (SCC) were identified in the pre‐human papillomavirus (HPV) era. We examined whether traditional indications for adjuvant radiotherapy (RT) or adjuvant chemoradiotherapy (CRT) still correlate with locoregional relapse in HPV‐positive patients after transoral robotic surgery (TORS).MethodsRetrospective review of oropharyngeal SCC cases identified patients with HPV‐positive tumors who did not receive adjuvant therapy after TORS despite intermediate or high‐risk features.ResultsMedian follow‐up was 26.7 months (range, 4.9–73.1 months). Five of 25 eligible patients (20%) relapsed at a median 4.8 months (range, 3.2–7.8 months). Two of 18 (11%) intermediate and 3 of 7 (43%) high‐risk patients relapsed. Kaplan–Meier 2‐year locoregional relapse‐free survival estimates for intermediate and high‐risk patients were 88% and 57% (p = .078), respectively.ConclusionTraditional indications for adjuvant RT or CRT were associated with high risk of locoregional relapse in HPV‐positive patients treated with TORS alone. © 2015 Wiley Periodicals, Inc. Head Neck 38: E1674–E1679, 2016

Abstract Background: Traditional adjuvant therapy for oropharyngeal squamous cell carcinoma (OPSCC) consists of 60-66 Gy of radiation therapy (XRT) given in 2 Gy daily fractions along with high dose cisplatin if the patient has high risk factors. Despite the excellent cure rates for HPV+ OPSCC, one in three patients treated with conventional treatment will develop grade >3 long-term sequelae from therapy. There is intense interest in de-intensifying adjuvant therapy for this patient population in order to maximize quality of life while maintaining excellent historical rates of disease control. Methods: MC1273 is a phase II non-randomized trial open at Mayo Clinic Rochester testing a novel course of aggressive therapy de-escalation following surgery for HPV+ OPSCC. The primary endpoint is local/regional control at 2 years while secondary endpoints include toxicity and quality of life (QOL). The eligibility criteria include all patients with p16-positive OPSCC with less than a ten pack-year smoking history who have had a complete surgical resection. Exclusion criteria include positive surgical margins, prior history of malignancy, and history of connective tissue disorders. Patients are divided into two prospective cohorts depending upon risk factors found at surgery. Patients with intermediate risk disease (≥T3, ≥N2, lymphovascular invasion, or perineural invasion) are enrolled in MC1273A while patients with extracapsular extension (ECE) are enrolled in MC1273B. Patients on MC1273A receive 30 Gy of radiation delivered in 1.5 Gy twice-daily fractions over the course of two weeks along with weekly docetaxel (15 mg/m2) given on day 1 and day 8. Patients on MC1273B receive a similar treatment regimen but also have the nodal level with positive ECE concurrently boosted to 36 Gy in 1.8 Gy twice-daily fractions. In addition to standard of care follow-up, patients receive a swallowing assessment with speech therapy immediately before XRT, one month post-XRT, and one year post-XRT. Patients also have QOL assessment consisting of the XeQOLS, Eq-5D, FACT H&N (Vers 4) and Dermatology Life Quality Index assessed at pre-XRT and 3, 12, and 24 months post-XRT. Results: Each cohort of MC1273 is powered to detect a 10% local/regional failure rate with 85% confidence. Each cohort will accrue 35 evaluable patients and 5 additional patients to account for ineligibilities and violations (40 patients total per cohort.) MC1273A began accrual in September 2013. The first five patients were monitored for grade ≥4 acute toxicities before proceeding to open accrual. MC1273B began accrual in May 2014 and has also proceeded to open accrual. Accrual will also begin in Mayo Clinic Scottsdale in the first quarter of 2015. Conclusions: MC1273 is meeting its accrual targets and should finish accrual by 2016. We anticipate that preliminary results for toxicity will be available by 2017 and local/regional data will be available by 2018. Citation Format: Daniel J. Ma, Katharine A. Price, Eric J. Moore, Joaquin J. Garcia, Scott H. Okuno, Daniel L. Price, Jeff A. Sloan, Nathan R. Foster, Robert L. Foote. MC1273: Phase II evaluation of aggressive dose de-escalation for adjuvant chemoradiation in HPV associated oropharynx cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr CT227. doi:10.1158/1538-7445.AM2015-CT227

Abstract The BBB can critically limit the delivery of several molecularly-targeted agents into the brain. The discovery of focal BRAF mutations in melanoma has stimulated the development of specific BRAF inhibitors. MEK is downstream of BRAF in the MAPK pathway, and has been targeted for combination therapy with BRAF inhibition. Trametinib is a MEK1/2 inhibitor that has improved survival in combination with dabrafenib in clinical trials for metastatic melanoma. We have recently shown that BRAF inhibitors (vemurafenib and dabrafenib) have limited brain distribution due to active efflux at the blood-brain barrier (BBB). Melanoma metastasizes to the brain and effective treatments require adequate CNS exposure of all drugs used in combination therapy. The study purpose was to investigate mechanisms that influence the CNS distribution of trametinib, particularly focusing on the active efflux transport proteins P-gp and Bcrp in the BBB. Intracellular accumulation and bidirectional flux studies were conducted in polarized MDCKII cells that overexpress human P-gp (MDR1) or murine Bcrp (Bcrp1). The brain and plasma AUCs of trametinib were determined after an intravenous dose of 5 mg/kg in WT, Mdr1a/b (-/-), Bcrp1 (-/-) and Mdr1a/b (-/-) Bcrp1 (-/-) (TKO) mice. The steady-state brain distribution of trametinib was determined using osmotic pumps in WT and Mdr1a/b (-/-) (P-gp KO), Bcrp1 (-/-) (Bcrp KO), and Mdr1a/b (-/-) Bcrp1 (-/-) (TKO) mice. The steady-state brain distribution of a combination of trametinib and dabrafenib were determined in WT and TKO mice. IC50s were determined in patient-derived melanoma cell lines (WT and V600E mutant) using the MTT assay. Intracellular accumulation of trametinib was 45% lower in the MDCKII-MDR1 cells and 81% lower in the MDCKII-Bcrp1 cells as compared to WT. Trametinib permeability was ∼ 2.5 and 3.7-fold greater in the basolateral-to-apical direction as compared to apical-to-basolateral direction in the MDR1 and Bcrp1 cells, respectively. Following a single intravenous dose, the brain-to-plasma AUC ratios were approximately 5-fold greater in P-gp KO and TKO mice as compared to the WT. Interestingly, the brain distribution of trametinib in Bcrp KO mice was no different from WT mice. The steady-state brain to plasma (B/P) ratio of trametinib was 5-fold greater in the TKO mice when compared to the wild-type mice. The B/P ratio of both dabrafenib and trametinib were significantly greater in the TKO mice as compared to WT when dosed simultaneously. The IC50 for trametinib alone was > 10 μM in both the WT (M15) and V600E (M12) mutant cells, while a combination of dabrafenib and trametinib had an IC50 of 2.04 μM in the M12 cells. This study shows that P-gp and BCRP restrict the brain distribution of trametinib with P-gp playing a dominant role in the efflux of trametinib at the blood-brain barrier. These findings are clinically relevant to the efficacy of trametinib in mono or combination therapy for the treatment of melanoma brain metastases. Citation Format: Shruthi Vaidhyanathan, Rajendar K. Mittapalli, Daniel J. Ma, Mark A. Schroeder, Jann N. Sarkaria, William F. Elmquist. Trametinib (Mekinist TM) has limited brain distribution in the mouse model. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3714. doi:10.1158/1538-7445.AM2014-3714