Phase 1 dose escalation trial of TAS-102 (trifluridine/tipiracil) and temozolomide in the treatment of advanced neuroendocrine tumors.

Neuroendocrine tumors (NETs) are understudied and have limited systemic treatment options. Prior studies for patients with advanced NETs have demonstrated promising results when antimetabolite agents, including fluoropyrimidines, were combined with temozolomide TMZ. TAS-102 (trifluridine/tipiracil) is an antineoplastic agent that is non-cross resistant with 5-fluorouracil and capecitabine and that has a different toxicity profile. This study evaluated the safety of TAS-102 in combination with TMZ in patients in neuroendocrine tumors. Escalating doses of TMZ (100, 150 and 200 mg/m2) on days 8-12 were given in combination with TAS-102 (35 mg/m2 twice a day) on days 1-5 and 8-12 of a 28 day cycle in subjects with advanced NETs. Primary endpoints were safety and determination of maximum tolerated dose (MTD). Growth factor support was mandated starting with level 2 to avoid treatment delays. Fifteen evaluable subjects were enrolled in the phase 1 study. No dose limiting toxicities (DLTs) were observed on level 1. One DLT was observed on level 2 (grade 3 fatigue and inability to resume treatment), and 1 on level 3 (grade 4 thrombocytopenia). The most common grade ≥ 3 adverse events included neutropenia (33%), lymphopenia (27%), and thrombocytopenia (27%). Disease control rate of 92% and partial response rate of 8% were observed in 13 evaluable subjects. This study established MTD of TAS-102 (35 mg/m2 twice daily) and TMZ (200 mg/m2 daily). This regimen was well tolerated. Early signs of clinically meaningful activity were observed. Further evaluation of the efficacy of this regimen is warranted.

Metastatic Bulk Independently Predicts Outcomes for EGFR Precision Targeting in Colorectal Cancer.

Background: Molecular profiles guide the clinical management of metastatic colorectal cancer (mCRC), particularly related to the use of anti-epidermal growth factor receptor (EGFR) antibodies. Tumor sidedness has also been implicated in resistance to these therapies, but has largely been studied in the first-line setting. We examined the role of tumor sidedness and disease bulk in predicting clinical outcomes to anti-EGFR therapy in the treatment-refractory setting. Methods: We identified a retrospective cohort of 62 patients with KRAS wild-type mCRC who received anti-EGFR therapy in the late-line setting. Response was assessed per RECIST 1.1, with bulky disease defined as any single lesion >35 mm in longest cross-sectional diameter or nodal short axis. Primary sidedness was defined in relation to the splenic flexure. Results: Patients with right-sided primary tumors at time of late-line EGFR therapy presented with increased tumor bulk and worsened overall survival (OS) relative to left-sided primary tumors. Tumor bulk, defined as either a categorical or continuous variable, predicted worsened progression-free survival (PFS) and OS, which persisted when controlling for differences in the primary tumor location. Within the right-sided cohort, no objective responses were observed for bulky disease or during treatment with anti-EGFR monotherapy. The nonbulky cohort experienced clinical benefit with anti-EGFR monotherapy, showing similar PFS and an improved response rate compared with sequential chemotherapy. Conclusions: In an effort to expand understanding of the role of primary sidedness in clinical response to anti-EGFR therapy, we identified sidedness and tumor bulk as potential predictive biomarkers of clinical response in late-line mCRC. Future prospective studies of EGFR targeting should consider tumor bulk in addition to molecular profiling in the identification of populations most likely to achieve meaningful clinical benefit.

Effect of First-Line Chemotherapy Combined With Cetuximab or Bevacizumab on Overall Survival in Patients With KRAS Wild-Type Advanced or Metastatic Colorectal Cancer: A Randomized Clinical Trial.

Importance: Combining biologic monoclonal antibodies with chemotherapeutic cytotoxic drugs provides clinical benefit to patients with advanced or metastatic colorectal cancer, but the optimal choice of the initial biologic therapy in previously untreated patients is unknown. Objective: To determine if the addition of cetuximab vs bevacizumab to the combination of leucovorin, fluorouracil, and oxaliplatin (mFOLFOX6) regimen or the combination of leucovorin, fluorouracil, and irinotecan (FOLFIRI) regimen is superior as first-line therapy in advanced or metastatic KRAS wild-type (wt) colorectal cancer. Design, Setting, and Participants: Patients (≥18 years) enrolled at community and academic centers throughout the National Clinical Trials Network in the United States and Canada (November 2005-March 2012) with previously untreated advanced or metastatic colorectal cancer whose tumors were KRAS wt chose to take either the mFOLFOX6 regimen or the FOLFIRI regimen as chemotherapy and were randomized to receive either cetuximab (n = 578) or bevacizumab (n = 559). The last date of follow-up was December 15, 2015. Interventions: Cetuximab vs bevacizumab combined with either mFOLFOX6 or FOLFIRI chemotherapy regimen chosen by the treating physician and patient. Main Outcomes and Measures: The primary end point was overall survival. Secondary objectives included progression-free survival and overall response rate, site-reported confirmed or unconfirmed complete or partial response. Results: Among 1137 patients (median age, 59 years; 440 [39%] women), 1074 (94%) of patients met eligibility criteria. As of December 15, 2015, median follow-up for 263 surviving patients was 47.4 months (range, 0-110.7 months), and 82% of patients (938 of 1137) experienced disease progression. The median overall survival was 30.0 months in the cetuximab-chemotherapy group and 29.0 months in the bevacizumab-chemotherapy group with a stratified hazard ratio (HR) of 0.88 (95% CI, 0.77-1.01; P = .08). The median progression-free survival was 10.5 months in the cetuximab-chemotherapy group and 10.6 months in the bevacizumab-chemotherapy group with a stratified HR of 0.95 (95% CI, 0.84-1.08; P = .45). Response rates were not significantly different, 59.6% vs 55.2% for cetuximab and bevacizumab, respectively (difference, 4.4%, 95% CI, 1.0%-9.0%, P = .13). Conclusions and Relevance: Among patients with KRAS wt untreated advanced or metastatic colorectal cancer, there was no significant difference in overall survival between the addition of cetuximab vs bevacizumab to chemotherapy as initial biologic treatment. Trial Registration: clinicaltrials.gov identifier: NCT00265850.

A Phase II Trial of a Histone Deacetylase Inhibitor Panobinostat in Patients With Low-Grade Neuroendocrine Tumors.

LESSONS LEARNED: Pancreatic neuroendocrine tumors versus carcinoid tumors should be examined separately in clinical trials.Progression-free survival is more clinically relevant as the primary endpoint (rather than response rate) in phase II trials for low-grade neuroendocrine tumors. BACKGROUND: The most common subtypes of neuroendocrine tumors (NETs) are pancreatic islet cell tumors and carcinoids, which represent only 2% of all gastrointestinal malignancies. Histone deacetylase (HDAC) inhibitors have already been shown to suppress tumor growth and induce apoptosis in various malignancies. In NET cells, HDAC inhibitors have resulted in increased Notch1 expression and subsequent inhibition of growth. We present here a phase II study of the novel HDAC inhibitor panobinostat in patients with low-grade NET. METHODS: Adult patients with histologically confirmed, metastatic, low-grade NETs and an Eastern Cooperative Oncology Group (ECOG) performance status of ≤2 were treated with oral panobinostat 20 mg once daily three times per week. Treatment was continued until patients experienced unacceptable toxicities or disease progression. The study was stopped at planned interim analysis based on a Simon two-stage design. RESULTS: Fifteen patients were accrued, and 13 were evaluable for response. No responses were seen, but the stable disease rate was 100%. The median progression-free survival (PFS) was 9.9 months, and the median overall survival was 47.3 months. Fatigue (27%), thrombocytopenia (20%), diarrhea (13%), and nausea (13%) were the most common related grade 3 toxicities. There was one grade 4 thrombocytopenia (7%). These results did not meet the prespecified criteria to open the study to full accrual. CONCLUSION: The HDAC inhibitor panobinostat has a high stable disease rate and reasonable PFS in low-grade NET, but has a low response rate.

A phase I study of selumetinib (AZD6244/ARRY-142866), a MEK1/2 inhibitor, in combination with cetuximab in refractory solid tumors and KRAS mutant colorectal cancer.

BACKGROUND: KRAS mutations are clinically important predictors of resistance to EGFR-directed therapies in colorectal cancer (CRC). Oncogenic activation of the RAS/RAF/MEK/ERK signaling cascade mediates proliferation independent of growth factor signaling. We hypothesized that targeting MEK with selumetinib could overcome resistance to cetuximab in KRAS mutant CRC. METHODS: A phase I study (NCT01287130) was undertaken to determine the tolerability, and pharmacokinetic profiles of the combination of selumetinib and cetuximab, with an expanded cohort in KRAS-mutant CRC. RESULTS: 15 patients were treated in the dose escalation cohort and 18 patients were treated in the expansion cohort. Two dose-limiting toxicities were observed. One grade 3 acneiform rash and one grade 4 hypomagnesemia occurred. The most common grade 1 and 2 adverse events included rash, nausea/vomiting, diarrhea, and fatigue. The maximum tolerated dose was established at selumetinib 75 mg p.o. BID and cetuximab 250 mg/m(2) weekly following a 400 mg/m(2) load. Best clinical response in the dose escalation group included 1 unconfirmed partial response in a patient with CRC and stable disease (SD) in 5 patients (1 squamous cell carcinoma of the tonsil, 1 non-small cell lung cancer, and 3 CRC), and in the KRAS-mutant CRC dose expansion cohort, of the 14 patients who were evaluable for response, 5 patients had SD and 9 patients had progressive disease. CONCLUSIONS: The combination of selumetinib and cetuximab is safe and well tolerated. Minimal anti-tumor activity was observed in KRAS-mutant refractory metastatic CRC. Further investigations might be warranted in other cancer subtypes.

A multicenter phase 1 study of γ -secretase inhibitor RO4929097 in combination with capecitabine in refractory solid tumors.

BACKGROUND: RO4929097 is an oral inhibitor of γ -secretase that results in Notch signaling inhibition. Prior work has demonstrated that Notch signaling inhibition enhances chemotherapy sensitivity of cancer cells. This phase I study was conducted to determine maximum tolerated dose (MTD), toxicities and efficacy of RO4929097 and capecitabine in advanced solid tumors. METHODS: Patients with refractory solid tumors received capecitabine at a fixed dose of 1,000 mg/m(2) twice daily with escalating doses of RO4929097 on a 21-day cycle in a 3 + 3 design. Capecitabine was administered for 14 days and the RO49029097 once daily, 3 days per week, both for a 21 day cycle. RESULTS: Thirty patients were treated on six dose levels (20 to 150 mg). The maximally tolerated dose was not reached. One dose limiting toxicity was observed at each level 3 through 6 (hypophosphatemia, fatigue, and nausea/vomiting). Three confirmed partial responses were observed: two patients with fluoropyrimide-refractory colon cancer and one patient with cervical cancer. Autoinduction of RO4929097 was demonstrated with increasing dose levels and duration. CONCLUSIONS: The recommended phase 2 dose is capecitabine 1,000 mg/m(2) orally twice daily on days 1 through 14 with RO4929097 20 mg orally once daily on days 1-3, 8-10 and 15-17 with a 21 day cycle. Clinical benefit was observed in cervical and colon cancer. Autoinduction of RO4929097 was seen both with increasing cycle number and increasing dose. Plasma concentrations of RO4929097 were above those needed for Notch inhibition.

A phase I study of sorafenib, oxaliplatin and 2 days of high dose capecitabine in advanced pancreatic and biliary tract cancer: a Wisconsin oncology network study.

Chemotherapy has yielded minimal clinical benefit in pancreatic and biliary tract cancer. A high-dose, short course capecitabine schedule with oxaliplatin, has shown some efficacy with a lower incidence of palmar-plantar erythrodysesthesia. Achieving high exposures of the targeted agent sorafenib may be possible with this shorter schedule of capecitabine by avoiding dermatologic toxicity. All patients had pancreatic or biliary tract cancer. Patients in both cohorts received oxaliplatin 85 mg/m2 followed by capecitabine 2,250 mg/m2 PO every 8 h x 6 doses starting on days 1 and 15 of a 28 day cycle, or 2DOC (2 Day Oxaliplatin/Capecitabine). Cohort 1 used sorafenib 200 mg BID, and cohort 2 used sorafenib 400 mg BID. Sixteen patients were enrolled. Across all cycles the most common grade 1 or 2 adverse events were fatigue (10 pts), diarrhea (10 pts), nausea (9 pts), vomiting (8 pts), sensory neuropathy (8 pts), thrombocytopenia (7 pts), neutropenia (5 pts), and hand-foot syndrome (5 pts). Grade 3 toxicites included neutropenia, mucositis, fatigue, vomiting and diarrhea. Cohort 1 represented the MTD. Two partial responses were seen, one each in pancreatic and biliary tract cancers. The recommended phase II dose of sorafenib in combination with 2DOC is 200 mg BID. There were infrequent grade 3 toxicities, most evident with sorafenib at 400 mg BID.

A preclinical and clinical study of lithium in low-grade neuroendocrine tumors.

BACKGROUND: Low-grade neuroendocrine tumors (NETs) respond poorly to chemotherapy; effective, less toxic therapies are needed. Glycogen synthase kinase (GSK)-3ß has been shown to regulate growth and hormone production in NETs. Use of lithium chloride in murine models suppressed carcinoid cell growth, reduced GSK-3ß levels, and reduced expression of chromogranin A. This study assessed the efficacy of lithium chloride in patients with NETs. DESIGN: Eligible patients had low-grade NETs. A single-arm, open-label phase II design was used. Lithium was dosed at 300 mg orally three times daily, titrated to serum levels of 0.8-1.0 mmol/L. The primary endpoint was objective tumor response by the Response Evaluation Criteria in Solid Tumors. Secondary endpoints included overall survival, progression-free survival, GSK-3ß phosphorylation, and toxicity. RESULTS: Fifteen patients were enrolled between October 3, 2007 and July 17, 2008, six men and nine women. The median age was 58 years. Patient diagnoses were carcinoid tumor for eight patients, islet cell tumor for five patients, and two unknown primary sites. Eastern Cooperative Oncology Group performance status scores were 0 or 1. Two patients came off study because of side effects. The median progression-free survival interval was 4.50 months. There were no radiographic responses. Because of an early stopping rule requiring at least one objective response in the first 13 evaluable patients, the study was closed to further accrual. Patients had pre- and post-therapy biopsies. CONCLUSIONS: Lithium chloride was ineffective at obtaining radiographic responses in our 13 patients who were treated as part of this study. Based on the pre- and post-treatment tumor biopsies, lithium did not potently inhibit GSK-3ß at serum levels used to treat bipolar disorders.

A Phase 1 Dose Escalation Study of Neoadjuvant SBRT Plus Elective Nodal Radiation with Concurrent Capecitabine for Resectable Pancreatic Cancer.

PURPOSE: The role of neoadjuvant radiation for resectable pancreatic adenocarcinoma is controversial. We performed a prospective dose-escalation study of neoadjuvant stereotactic body radiation therapy (SBRT) with concurrent capecitabine and elective nodal irradiation (ENI) followed by surgical resection to explore the toxicity and feasibility of this approach. METHODS AND MATERIALS: Patients with biopsy proven, resectable cancers of the pancreatic head were enrolled. A 4 + 4 dose-escalation design was employed delivering 5 fractions of 5 to 7 Gy to primary tumor with concurrent capecitabine. The maximum tolerated dose level was expanded for an additional 4 patients. Patients at all dose levels were treated with ENI delivering 25 Gy in 5 fractions. Dose-limiting toxicity was defined as any grade ≥3 nonhematologic toxicity (National Cancer Institute Common Terminology Criteria for Adverse Events v4.0) attributable to chemoradiation occurring within 90 days of SBRT. RESULTS: A total of 17 patients were enrolled with 16 patients evaluable and 13 patients ultimately proceeding to surgery. The most common toxicity was nausea (56%). There were no dose-limiting toxicities, and SBRT was maximally dose escalated to 35 Gy in 5 fractions for 8 patients. All patients completing surgery had R0 resections. Seven patients (54%) had moderate treatment effect identified in pathologic specimens. Three patients (23%) developed locoregional recurrences, with 2 (15%) partially included within the treated volume. CONCLUSIONS: SBRT was safely dose escalated to 35 Gy in 5 fractions along with concurrent capecitabine and ENI. This regimen will be used in a future expansion cohort.

Microwave ablation for colorectal cancer metastasis to the liver: a single-center retrospective analysis.

BACKGROUND: The purpose of this study is to evaluate the safety and intermediate-term efficacy of percutaneous microwave (MW) ablation for the treatment of colorectal liver metastases (CRLM) at a single institution. METHODS: A retrospective review was performed of all CRLM treated with MW ablation from 3/2011 to 7/2020 (102 tumors; 72 procedures; 57 patients). Mean age was 60 years (range, 36-88) and mean tumor size was 1.8 cm (range, 0.5-5.0 cm). The patient population included 19 patients with extra-hepatic disease. Chemotherapy (pre- and/or post-ablation) was given in 98% of patients. Forty-five sessions were preceded by other focal CRLM treatments including resection, ablation, radiation, and radioembolization. Kaplan-Meier curves were used to estimate local tumor progression-free survival (LTPFS), disease-free survival (DFS), and overall survival (OS) and multivariate analysis (Cox Proportional Hazards model) was used to test predictors of OS. RESULTS: Technical success (complete ablation) was 100% and median follow-up was 42 months (range, 1-112). There was a 4% major complication rate and an overall complication rate of 8%. Local tumor progression (LTP) rate during the entire study period was 4/98 (4%), in which 2 were retreated with MW ablation for a secondary LTP-rate of 2%. LTP-free survival at 1, 3, and 5 years was 93%, 58%, and 39% and median LTP-free survival was 48 months. OS at 1, 3, and 5 years was 96%, 66%, 47% and median OS was 52 months. There were no statistically significant predictors of OS. CONCLUSIONS: MW ablation of hepatic colorectal liver metastases appears safe with excellent local tumor control and prolonged survival compared to historical controls in selected patients. Further comparative studies with other local treatment strategies appear indicated.

National Comprehensive Cancer Network Infusion Efficiency Workgroup Study: Optimizing Patient Flow in Infusion Centers.

PURPOSE: The National Comprehensive Cancer Network (NCCN) formed an Infusion Efficiency Workgroup to determine best practices for operating efficient and effective infusion centers. METHODS: The Workgroup conducted three surveys that were distributed to NCCN member institutions regarding average patient wait time, chemotherapy premixing practices, infusion chair use, and premedication protocols. To assess chair use, the Workgroup identified and defined five components of chair time. RESULTS: The average patient wait time in infusion centers ranged from 25 to 102 minutes (n = 23; mean, 58 minutes). Five of 26 cancer centers (19%) routinely mix chemotherapy drugs before patient arrival for patients meeting specified criteria. Total planned chair time for subsequent doses of the same drug regimens for the same diseases varied greatly among centers, as follows: Administration of doxorubicin and cyclophosphamide ranged from 85 to 240 minutes (n = 22); of FOLFIRINOX (folinic acid, fluorouracil, irinotecan hydrochloride, and oxaliplation) ranged from 270 to 420 minutes (n = 22); of rituximab ranged from 120 to 350 minutes (n = 21); of paclitaxel plus carboplatin ranged from 255 to 380 minutes (n = 21); and of zoledronic acid ranged from 30 to 150 minutes (n = 22) for planned total chair time. Cancer centers were found to use different premedication regimens with varying administration routes that ranged in administration times from zero to 60 minutes. CONCLUSION: There is a high degree of variation among cancer centers in regard to planned chair time for the same chemotherapy regimens, providing opportunities for improved efficiency, increased revenue, and more standardization across centers. The NCCN Workgroup demonstrates potential revenue impact and provides recommendations for cancer centers to move toward more efficient and more standard practices.

Phase I trial of weekly paclitaxel and BMS-214662 in patients with advanced solid tumors.

PURPOSE: To assess the maximum tolerated dose (MTD), dose-limiting toxicity (DLT), pharmacodynamics, and antitumor activity of continuous weekly-administered paclitaxel and BMS-214662, a novel farnesyl transferase inhibitor. EXPERIMENTAL DESIGN: Patients were treated every week as tolerated with i.v. paclitaxel (fixed dose, 80 mg/m(2)/wk) administered over 1 h followed by i.v. BMS-214662 (escalating doses, 80-245 mg/m(2)/wk) over 1 h starting 30 min after completion of paclitaxel. RESULTS: Twenty-six patients received 94 courses (one course, 21 days) of study treatment. Two patients received five courses of BMS-214662 as a weekly 24-h infusion (209 mg/m(2)/wk). The most common toxicities were grade 1 to 2 nausea/vomiting and/or diarrhea. DLTs observed at or near the MTD (200 mg/m(2)/wk) were grade 4 febrile neutropenia with sepsis occurring on day 2 of course 1 (245 mg/m(2)/wk), reversible grade 3 to 4 serum transaminase increases on day 2, and grade 3 diarrhea (200 and 245 mg/m(2)/wk). Objective partial responses were observed in patients with pretreated head and neck, ovarian, and hormone-refractory prostate carcinomas, and leiomyosarcoma. The observed pharmacokinetics of paclitaxel and BMS-214662 imply no interaction between the two. Significant inhibition (>80%) of farnesyl transferase activity in peripheral mononuclear cells was observed at the end of BMS-214662 infusion. CONCLUSIONS: Pretreated patients with advanced malignancies can tolerate weekly paclitaxel and BMS-214662 at doses that achieve objective clinical benefit. Due to multiple DLTs occurring at the expanded MTD, the recommended phase 2 dose and schedule is paclitaxel (80 mg/m(2) over 1 h) and BMS-214662 (160 mg/m(2) over 1 h) administered weekly.

Dose-escalating and pharmacologic study of oxaliplatin in adult cancer patients with impaired hepatic function: a National Cancer Institute Organ Dysfunction Working Group study.

PURPOSE: To determine the toxicities, pharmacokinetics, and maximally tolerated doses of oxaliplatin in patients with hepatic impairment and to develop formal guidelines for oxaliplatin dosing in this patient population. EXPERIMENTAL DESIGN: Sixty adult cancer patients with variable hepatic function received i.v. oxaliplatin ranging from 60 to 130 mg/m(2) every 3 weeks. Patients were stratified by levels of total bilirubin, aspartate aminotransferase (AST), and alkaline phosphatase (AP) into five cohorts based on the degree of hepatic dysfunction: control group A [bilirubin, AST, and AP < or = upper limit of normal (ULN)], mild dysfunction group B (bilirubin < or = ULN, ULN < AST < or = 2.5 x ULN, or ULN < AP < or = 5 x ULN), moderate dysfunction group C (ULN < bilirubin < or = 3.0 mg/dL, AST > 2.5 x ULN, or AP > 5 x ULN), severe dysfunction group D (bilirubin > 3.0 mg/dL, any AST, and any AP), and liver transplantation group E (any bilirubin, any AST, and any AP). Doses were escalated in cohorts of three patients, and urine and plasma ultrafiltrates were assayed for platinum concentrations. RESULTS: Dose escalation of single-agent oxaliplatin to 130 mg/m(2) was well tolerated in all cohorts. Platinum clearance did not correlate with any liver function test. Two of 56 assessable patients with a diagnosis of laryngeal carcinoma and cervical adenocarcinoma experienced partial responses lasting 3 and 5.5 months. CONCLUSIONS: Oxaliplatin at 130 mg/m(2) every 3 weeks was well tolerated in all patients with impaired liver function. Dose reductions of single-agent oxaliplatin are not indicated in patients with hepatic dysfunction.

Oxaliplatin pharmacokinetics and pharmacodynamics in adult cancer patients with impaired renal function.

PURPOSE: To characterize the pharmacokinetics and pharmacodynamics of oxaliplatin in cancer patients with impaired renal function. EXPERIMENTAL DESIGN: Thirty-four patients were stratified by 24-h urinary creatinine clearance (CrCL) into four renal dysfunction groups: group A (control, CrCL, >or=60 mL/min), B (mild, CrCL, 40-59 mL/min), C (moderate, CrCL, 20-39 mL/min), and D (severe, CrCL, <20 mL/min). Patients were treated with 60 to 130 mg/m2 oxaliplatin infused over 2 h every 3 weeks. Pharmacokinetic monitoring of platinum in plasma, plasma ultrafiltrates, and urine was done during cycles 1 and 2. RESULTS: Plasma ultrafiltrate platinum clearance strongly correlated with CrCL (r2 = 0.712). Platinum elimination from plasma was triphasic, and maximal platinum concentrations (Cmax) were consistent across all renal impairment groups. However, only the beta-half-life was significantly prolonged by renal impairment, with values of 14.0 +/- 4.3, 20.3 +/- 17.7, 29.2 +/- 29.6, and 68.1 h in groups A, B, C, and D, respectively (P = 0.002). At a dose level of 130 mg/m2, the area under the concentration time curve increased in with the degree of renal impairment, with values of 16.4 +/- 5.03, 39.7 +/- 11.5, and 44.6 +/- 14.6 mug.h/mL, in groups A, B, and C, respectively. However, there was no increase in pharmacodynamic drug-related toxicities. Estimated CrCL using the Cockcroft-Gault method approximated the measured 24-h urinary CrCL (mean prediction error, -5.0 mL/min). CONCLUSIONS: Oxaliplatin pharmacokinetics are altered in patients with renal impairment, but a corresponding increase in oxaliplatin-related toxicities is not observed.

Multidisciplinary Optimization of Oral Chemotherapy Delivery at the University of Wisconsin Carbone Cancer Center.

PURPOSE: Use of oral chemotherapy is expanding and offers advantages while posing unique safety challenges. ASCO and the Oncology Nursing Society jointly published safety standards for administering chemotherapy that offer a framework for improving oral chemotherapy practice at the University of Wisconsin Carbone Cancer Center. METHODS: With the goal of improving safety, quality, and uniformity within our oral chemotherapy practice, we conducted a gap analysis comparing our practice against ASCO/Oncology Nursing Society guidelines. Areas for improvement were addressed by multidisciplinary workgroups that focused on education, workflows, and information technology. Recommendations and process changes included defining chemotherapy, standardizing patient and caregiver education, mandating the use of comprehensive electronic order sets, and standardizing documentation for dose modification. Revised processes allow pharmacists to review all orders for oral chemotherapy, and they support monitoring adherence and toxicity by using a library of scripted materials. RESULTS: Between August 2015 and January 2016, revised processes were implemented across the University of Wisconsin Carbone Cancer Center clinics. The following are key performance indicators: 92.5% of oral chemotherapy orders (n = 1,216) were initiated within comprehensive electronic order sets (N = 1,315), 89.2% compliance with informed consent was achieved, 14.7% of orders (n = 193) required an average of 4.4 minutes review time by the pharmacist, and 100% compliance with first-cycle monitoring of adherence and toxicity was achieved. CONCLUSION: We closed significant gaps between institutional practice and published standards for our oral chemotherapy practice and experienced steady improvement and sustainable performance in key metrics. We created an electronic definition of oral chemotherapies that allowed us to leverage our electronic health records. We believe our tools are broadly applicable.

Precision medicine in colorectal cancer: the molecular profile alters treatment strategies.

When considering treatment options for patients with metastatic colorectal cancer (mCRC), molecular profiling has become a pivotal component in guiding clinical decisions. FOLFOX and FOLFIRI (fluorouracuil, leucovorin plus oxaliplatin or ininotecan, respectively) are the standard base regimens used for the treatment of mCRC. Biologic agents, such as the epidermal growth factor receptor (EGFR) targeted therapies, cetuximab and panitumumab and the vascular endothelial growth factor monoclonal antibody, bevacizumab, are safe and effective in the first-line setting. The most efficacious use of these agents in terms of timing and selection of the right patient population continues to be debated. Here we review multiple investigations into the effectiveness of treatment options as a function of the mutations present in colon cancers. Early studies have reported that KRAS mutations at exon 2 predict resistance to EGFR targeted therapies. More recently the data have expanded to include KRAS mutations at exons 3 and 4 and NRAS mutations at exons 2, 3 and 4 as well as other biomarkers including BRAF and PIK3CA, leading to the evolution of the treatment of mCRC to a more precision-based approach. As our understanding of relevant biomarkers increases, and data from both molecular profiling and treatment response become more readily available, treatment options will become more precise and their outcomes more effective.

A phase II study of sorafenib, oxaliplatin, and 2 days of high-dose capecitabine in advanced pancreas cancer.

PURPOSE: Fluoropyrimidines and oxaliplatin have demonstrated some efficacy against pancreatic adenocarcinoma, but survival remains brief. Sorafenib is an oral multikinase inhibitor which we sought to combine with a unique capecitabine and oxaliplatin regimen for pancreatic adenocarcinoma. METHODS: We performed a multicenter phase II study of sorafenib 200 mg orally twice daily along with oxaliplatin 85 mg/m(2) IV on days 1 and 15, followed by capecitabine 2250 mg/m(2) orally every 8 h for six doses starting on days 1 and 15 of a 28-day cycle in patients who had no more than one previous chemotherapy regimen for their pancreatic adenocarcinoma. The primary objective was response rate; secondary objectives were progression-free survival (PFS), overall survival (OS), and safety. RESULTS: Twenty-four patients were enrolled; median age was 63 years (range 48-83). The most common related toxicities were fatigue, neuropathy, anemia, thrombocytopenia, diarrhea, nausea, leukopenia, and hand-foot syndrome. Grade 3 hand-foot syndrome was rare (4 %). Other grade 4 toxicities included abdominal pain (8 %), pulmonary embolism (4 %), and anemia (4 %). Three partial responses were seen (13 %), and 11 patients had stable disease (46 %) as their best response. Median PFS was 6.0 months (range 1.5-13 months). Median OS was 8.1 months (range 1.5-13.6 months). CONCLUSIONS: Sorafenib, oxaliplatin, and capecitabine produced partial responses in patients with advanced pancreatic cancer including previously treated patients and demonstrated a PFS of 6 months with few grade 3/4 toxicities.

Capecitabine-related neurotoxicity presenting as trismus.

Capecitabine is an oral fluoropyrimidine used for cancer treatment. It is generally well tolerated. A patient who had previously received adjuvant 5-fluorouracil without neurotoxicity had a severe adverse reaction when later given capecitabine in the metastatic setting. She presented with the acute onset of neuromuscular symptoms, the most prominent being trismus but also including slurred speech, confusion, gait abnormalities, and ocular changes. Her symptoms completely resolved with discontinuation of capecitabine.

Phase I study of pazopanib in patients with advanced solid tumors and hepatic dysfunction: a National Cancer Institute Organ Dysfunction Working Group study.

PURPOSE: Pazopanib is a potent, multitargeted receptor tyrosine kinase inhibitor; however, there is limited information regarding the effects of liver function on pazopanib metabolism and pharmacokinetics. The objective of this study was to establish the maximum-tolerated dose (MTD) and pharmacokinetic profile of pazopanib in patients with varying degrees of hepatic dysfunction. EXPERIMENTAL DESIGN: Patients with any solid tumors or lymphoma were stratified into four groups based on the degree of hepatic dysfunction according to the National Cancer Institute Organ Dysfunction Working Group (NCI-ODWG) criteria. Pazopanib was given orally once a day on a 21-day cycle. A modified 3+3 design was used. RESULTS: Ninety-eight patients were enrolled. Patients in the mild group tolerated 800 mg per day. The moderate and severe groups tolerated 200 mg per day. Pharmacokinetic data in the mild group were similar to the data in the normal group. Comparison of the median Cmax and area under the curve [AUC(0-24)] in the moderate or severe groups at 200 mg per day to the values in the normal and mild groups at 800 mg per day indicated less than dose-proportional systemic exposures in patients with moderate and severe hepatic impairment. This suggests that the lower maximum-tolerated dose in the moderate and severe group is not due to a decrease in drug clearance or alteration in the proportion of metabolites. CONCLUSIONS: In patients with mild liver dysfunction, pazopanib is well tolerated at the Food and Drug Administration (FDA)-approved dose of 800 mg per day. Patients with moderate and severe liver dysfunction tolerated 200 mg per day.