A phase I study of AT-101 with cisplatin and etoposide in patients with advanced solid tumors with an expanded cohort in extensive-stage small cell lung cancer.

BACKGROUND: A phase I, dose-escalation study of AT-101 with cisplatin and etoposide was conducted to determine the maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D), safety and pharmacokinetics in patients with advanced solid tumors, with an expanded cohort in patients with extensive-stage small cell lung cancer (ES-SCLC) to assess preliminary activity. METHODS: In the dose escalation portion, increasing doses of AT-101 were administered orally BID on days 1-3 along with cisplatin on day 1 and etoposide on days 1-3 of a 21 day cycle. At the RP2D, an additional 7 patients with untreated ES-SCLC were enrolled. RESULTS: Twenty patients were enrolled in the dose-escalation cohort, and 7 patients with ES-SCLC were enrolled in the expanded cohort. The MTD/RP2D was established at AT-101 40 mg BID days 1-3 with cisplatin 60 mg/m2 and etoposide 120 mg/m2 on day 1 of a 21 day cycle with pegfilgrastim support. Two DLTs of neutropenic fever were seen at dose level 1. After the addition of pegfilgrastim, no additional DLTs were observed. Grade 3/4 treatment-related toxicities included: diarrhea, increased AST, neutropenia, hypophosphatemia, hyponatremia, myocardial infarction and pulmonary embolism. No apparent PK interactions were observed between the agents. Preliminary activity was observed with PRs in patients with ES-SCLC, high-grade neuroendocrine tumor, esophageal cancer and NSCLC. CONCLUSIONS: AT-101 with cisplatin and etoposide is well tolerated with growth factor support. Anti-tumor activity was observed in a variety of cancers including ES-SCLC, supporting further investigation with BH-3 mimetics in combination with standard chemotherapy for ES-SCLC.

BRAF V600 Mutation Detection in Plasma Cell-Free DNA: NCCTG N0879 (Alliance).

OBJECTIVE: To evaluate the prognostic significance of detectable circulating cell-free DNA (cfDNA) BRAF V600E/K mutations in patients with advanced melanoma enrolled in a clinical trial without BRAF-targeted therapy. PATIENTS AND METHODS: BRAF V600E/K mutation status was determined on archived tissue and pretreatment stored plasma from 149 patients with unresectable stage IV melanoma who were enrolled between May 5, 2010 and May 2, 2014 in the North Central Cancer Treatment Group/Alliance N0879 randomized phase 2 clinical trial. Results were reported as presence or absence of cfDNA BRAF V600E/K detection of assay vs tissue. Progression-free survival (PFS) and overall survival (OS) were assessed for patients with and without detectable BRAF mutation. RESULTS: In total, 63 of 149 (42.3%) patients had BRAF V600E/K results for tissue and blood, and 20 of 63 (31.7%) patients had tissue-diagnosed mutant BRAF. Of these, 11 of 20 (55.0%) patients had detectable plasma cfDNA BRAF. Among patients with tissue-mutant BRAF V600E/K, PFS and OS were shorter for those with corresponding cfDNA mutations (PFS, 5.8 vs 12.0 months; P=.051; OS, 9.2 vs 27.1 months; P=.054). Our assay demonstrated sensitivity of 55% (95% CI, 0.322 to 0.768), specificity of 97.7% (95% CI, 0.932 to 1.000), positive predictive value of 91.7% (95% CI, 0.760 to 1.000), and negative predictive value of 82.4% (95% CI, 0.719 to 0.928). CONCLUSION: In advanced melanoma, detectable cfDNA BRAF V600E/K mutation is present in about half the patients with stage IV with BRAF-mutant melanoma tumor tissue and appears to confer a poorer prognosis when detectable. Given the poorer prognosis, cfDNA can be used to risk-stratify patients with metastatic melanoma in practice or clinical trials.Trial Registration: clinicaltrials.gov Identifier: NCT00976573.

Implementation of a standardized approach to borderline resectable pancreatic cancer in a multisite community oncology program.

BACKGROUND: Treatment paradigms for borderline resectable pancreatic cancer are evolving with increasing use of neoadjuvant chemotherapy and neoadjuvant chemoradiation. Variations in the definition of borderline resectable pancreatic cancer and neoadjuvant approaches have made standardizing care for borderline resectable pancreatic cancer difficult. We report an effort to standardize management of borderline resectable pancreatic cancer throughout Sanford Health, a large community oncology network. METHODS: Starting in October 2013, cases of pancreatic adenocarcinoma without known metastatic disease were categorized as borderline resectable pancreatic cancer if they met ≥ 1 of the following criteria: (1) abutment of superior mesenteric, common hepatic, or celiac arteries with < 180° involvement, (2) venous involvement deemed potentially suitable for reconstruction, and/or (3) biopsy-proven lymph node involvement. Patients with borderline resectable pancreatic cancer were treated with neoadjuvant chemotherapy followed by reimaging and surgery if venous involvement had improved; if disease remained borderline resectable, patients underwent neoadjuvant chemoradiation and surgical exploration as long as reimaging did not reveal evidence of progressive disease. RESULTS: Forty-three patients from October 2013 to April 2017 were diagnosed with borderline resectable pancreatic cancer. Twelve of 42 (29%) patients proceeded to surgical exploration directly after neoadjuvant chemotherapy; 23 (55%) received neoadjuvant chemoradiation. Overall, 28/43 (65%) underwent exploration with 19 (44%) able to undergo resection. Of those, 14/19 (74%) attained R0 resection and 11/19 (58%) were pathologic N0. No pretreatment or treatment variables were associated with resection rates; resection was the only variable associated with survival. CONCLUSION: This report demonstrates the feasibility of implementing a standardized approach to borderline resectable pancreatic cancer across multiple sites over a wide geographic area. Adherence to protocol therapies was good and surgical outcomes are similar to many reported series.

Delivering Precision Oncology in a Community Cancer Program: Results From a Prospective Observational Study.

INTRODUCTION: Precision oncology (PO) is a growing treatment approach in the era of next-generation sequencing (NGS) and matched therapies. Effective delivery of PO in the community has not been extensively studied. Our program developed a virtual molecular tumor board (MTB) strategy to help guide PO care. MATERIALS AND METHODS: Over 18 months, eligible adult patients with advanced, incurable solid tumor malignancies were enrolled in a molecular profiling (MP) study using the Foundation Medicine NGS panel. Results were reviewed through a weekly, videoconferenced MTB conducted across our largely rural integrated health system. Recommendations from the MTB were used to identify actionable alterations (AAs). Feasibility of PO care delivery was assessed as the primary outcome. Secondary outcomes included the frequency of AAs, genomic matched treatments, genomic matched clinical trial enrollment, and clinical outcomes. RESULTS: A total of 120 participants with a variety of advanced tumor types were enrolled. Of these, 109 (90.8%) had successful MP. Treatment on the basis of an AA was recommended by the MTB in 58% of patients (63 of 109) who had a successful MP result. For those completing MP, treatments included enrollment in a genomic matched clinical trial (n = 16; 14.6%) and genomic matched treatment with a Food and Drug Administration-approved agent (n = 23; 21.1%). Response and survival data were similar regardless of the matched treatment option chosen. CONCLUSION: A video-conferenced MTB-facilitated NGS testing and treatment delivery system was implemented in our integrated community oncology program. Continued use of this model aims to increase understanding of the impact of PO in this setting.

A phase I study of radiation therapy and twice-weekly gemcitabine and cisplatin in patients with locally advanced pancreatic cancer.

PURPOSE: In vitro studies suggest that low-dose gemcitabine sensitizes cells to radiation therapy and that this effect persists for 48 h after drug exposure. Cisplatin is a radiation sensitizer and is also synergistic with gemcitabine in some in vitro tumor systems. Gemcitabine's radiosensitizing properties can theoretically be exploited by twice-weekly administration. This study assessed toxicity in patients with pancreatic cancer treated with radiation therapy, gemcitabine, and cisplatin. METHODS AND MATERIALS: Patients with locally advanced pancreatic or gastric cancer were eligible. Gemcitabine and cisplatin were given twice weekly for 3 weeks during radiation therapy (50.4 Gy in 28 fractions). The starting dose of gemcitabine was 5 mg/m(2) i.v. The starting dose for cisplatin was 5 mg/m(2). Chemotherapy doses escalated every 3 to 6 patients according to a standard Phase I study design. RESULTS: Twenty-four evaluable patients, all with pancreatic cancer, were treated on this protocol. Grade 3 neutropenia occurred in 2 patients, Grade 3 thrombocytopenia occurred in 2, and Grade 4 lymphopenia occurred in 1. There was no clear relationship between chemotherapy dose and hematologic toxicity. The most common Grade 3-4 nonhematologic toxic responses were vomiting (7 patients) and nausea (7 patients). Dose-limiting toxicity consisting of Grade 4 nausea and vomiting occurred in 2 of 3 patients at dose Level 6 (gemcitabine 45 mg/m(2) i.v. and cisplatin 10 mg/m(2) i.v.). Six patients were treated at dose Level 5 (gemcitabine 30 mg/m(2) i.v. and cisplatin 10 mg/m(2) i.v.) without dose-limiting toxicity. CONCLUSION: Gemcitabine 30 mg/m(2) i.v. twice weekly and cisplatin 10 mg/m(2) i.v. twice weekly may be given concurrently with radiation therapy (50.4 Gy in 28 fractions) with acceptable toxicity.