Eric X. Chen

Deintensification Candidate Subgroups in Human Papillomavirus-Related Oropharyngeal Cancer According to Minimal Risk of Distant Metastasis

PURPOSE To define human papillomavirus (HPV) -positive oropharyngeal cancers (OPC) suitable for treatment deintensification according to low risk of distant metastasis (DM). PATIENTS AND METHODS OPC treated with radiotherapy (RT) or chemoradiotherapy (CRT) from 2001 to 2009 were included. Outcomes were compared for HPV-positive versus HPV-negative patients. Univariate and multivariate analyses identified outcome predictors. Recursive partitioning analysis (RPA) stratified the DM risk. RESULTS HPV status was ascertained in 505 (56%) of 899 consecutive OPCs. Median follow-up was 3.9 years. HPV-positive patients (n = 382), compared with HPV-negative patients (n = 123), had higher local (94% v 80%, respectively, at 3 years; P < .01) and regional control (95% v 82%, respectively; P < .01) but similar distant control (DC; 90% v 86%, respectively; P = .53). Multivariate analysis identified that HPV negativity (hazard ratio [HR], 2.9; 95% CI, 2.0 to 5.0), N2b-N3 (HR, 2.9; 95% CI, 1.8 to 4.9), T4 (HR, 1.8; 95% CI, 1.2 to 2.9), and RT alone (HR, 1.8; 95% CI, 1.1 to 2.5) predicted a lower recurrence-free survival (RFS; all P < .01). Smoking pack-years > 10 reduced overall survival (HR, 1.72; 95% CI, 1.1 to 2.7; P = .03) but did not impact RFS (HR, 1.1; 95% CI, 0.7 to 1.9; P = .65). RPA segregated HPV-positive patients into low (T1-3N0-2c; DC, 93%) and high DM risk (N3 or T4; DC, 76%) groups and HPV-negative patients into different low (T1-2N0-2c; DC, 93%) and high DM risk (T3-4N3; DC, 72%) groups. The DC rates for HPV-positive, low-risk N0-2a or less than 10 pack-year N2b patients were similar for RT alone and CRT, but the rate was lower in the N2c subset managed by RT alone (73% v 92% for CRT; P = .02). CONCLUSION HPV-positive T1-3N0-2c patients have a low DM risk, but N2c patients from this group have a reduced DC when treated with RT alone and seem less suited for deintensification strategies that omit chemotherapy.

Combining Gemcitabine and Capecitabine in Patients With Advanced Biliary Cancer: A Phase II Trial

PURPOSE Biliary cancer has a poor prognosis, and chemotherapy has had little impact. The objectives of this trial were to determine the response rate, time to disease progression, survival, and safety profile of the combination of gemcitabine and capecitabine (GemCap) in patients with advanced biliary cancer. PATIENTS AND METHODS Eligible patients had pathologically proven, locally advanced or metastatic adenocarcinoma arising from the intra- and extrahepatic bile ducts or gallbladder with no prior chemotherapy. Patients were treated on a 3-week cycle consisting of capecitabine at 650 mg/m(2) orally twice a day for 14 days and gemcitabine at a fixed dose of 1,000 mg/m(2) intravenously over 30 minutes on days 1 and 8. RESULTS Forty-five patients were enrolled between July 2001 and January 2004. Fifty-three percent of patients had cholangiocarcinoma, 47% had gallbladder cancer, and 89% had metastatic disease. The overall objective response rate was 31%, with an additional 42% of patients with stable disease, for a disease control rate of 73%. The median overall survival time was 14 months (95% CI, 7.3 months to not available), and the median progression-free survival time was 7 months (95% CI, 4.6 to 11.8 months). This chemotherapy combination was generally well tolerated. Transient neutropenia, thrombocytopenia, fatigue, and hand-foot syndrome were commonly observed but were easily managed without discontinuing further treatment. CONCLUSION The significant antitumor activity combined with a mild toxicity profile seen in this study argue that GemCap chemotherapy may benefit patients with advanced biliary cancer. This regimen warrants further evaluation in a randomized study with survival and quality of life end points.

Imatinib Mesylate in Patients With Adenoid Cystic Cancers of the Salivary Glands Expressing c-kit: A Princess Margaret Hospital Phase II Consortium Study

PURPOSE This study aimed to assess the antitumor activity of imatinib in adenoid cystic carcinoma (ACC) of the salivary gland expressing c-kit. A high level of c-kit expression has been identified in more than 90% of ACCs. Imatinib specifically inhibits autophosphorylation of the bcr-abl, platelet-derived growth factor receptor beta, and c-kit tyrosine kinases. PATIENTS AND METHODS In a single-arm, two-stage, phase II clinical trial, adult patients with unresectable or metastatic ACC measurable by Response Evaluation Criteria in Solid Tumors Group criteria and expressing c-kit by immunohistochemistry were treated with imatinib 400 mg orally bid. Response was assessed every 8 weeks. RESULTS Sixteen patients have been enrolled onto the study; 10 were female. Median age was 47 years (range, 31 to 69 years). Median Eastern Cooperative Oncology Group performance status was 1 (range, 0 to 2). Fourteen patients had lung metastases, 14 had prior radiotherapy, and six had prior chemotherapy. Toxicities occurring in at least 50% of patients included fatigue, nausea, vomiting, diarrhea, anorexia, edema, dyspnea, and/or headache, usually of mild to moderate severity. In 15 patients assessable for response, no objective responses have been observed. Nine patients had stable disease as best response. Six patients had progressive disease after two cycles. CONCLUSION Because of the lack of activity, the study has been stopped after the first stage and additional evaluation of imatinib in this population is not warranted. Overexpression of wild-type c-kit was not sufficient for clinical benefit from imatinib in ACC. Accrual to this study was rapid for a relatively rare cancer, encouraging additional efforts to identify more effective systemic therapy for these patients.

Surrogate End Points for Median Overall Survival in Metastatic Colorectal Cancer: Literature-Based Analysis From 39 Randomized Controlled Trials of First-Line Chemotherapy

PURPOSE Our aims were to determine the correlations between progression-free survival (PFS), time to progression (TTP), and response rate (RR) with overall survival (OS) in the first-line treatment of metastatic colorectal cancer (MCRC), and to identify a potential surrogate for OS. METHODS Randomized trials of first-line chemotherapy in MCRC were identified, and statistical analyses were undertaken to evaluate the correlations between the end points. RESULTS Thirty-nine randomized controlled trials were identified containing a total of 87 treatment arms. Among trials, the nonparametric Spearman rank correlation coefficient (r(s)) between differences (Delta) in surrogate end points (DeltaPFS, DeltaTTP, and DeltaRR) and DeltaOS were 0.74 (95% CI, 0.47 to 0.88), 0.52 (95% CI, 0.004 to 0.81), 0.39 (95% CI, 0.08 to 0.63), respectively. The r(s) for DeltaPFS was not significantly different from the r(s) DeltaTTP (P = .28). Linear regression analysis was performed using hazard ratios for PFS and OS. There was a strong relationship between hazard ratios for PFS and OS; the slope of the regression line was 0.54 +/- 0.10, indicating that a novel therapy producing a 10% risk reduction for PFS will yield an estimated 5.4% +/- 1% risk reduction for OS. CONCLUSION In first-line chemotherapy trials for MCRC, improvements in PFS are strongly associated with improvements in OS. In this patient population, PFS may be an appropriate surrogate for OS. As a clinical end point, PFS offers increased statistical power at a given time of analysis and a significant lead time advantage compared with OS.

Phase II Trial of Sorafenib in Patients With Recurrent or Metastatic Squamous Cell Carcinoma of the Head and Neck or Nasopharyngeal Carcinoma

PURPOSE To determine the efficacy and safety of single-agent sorafenib in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck (SCCHN) and nasopharyngeal carcinoma (NPC). PATIENTS AND METHODS In this single-arm phase II trial, oral continuous sorafenib was administered in 28-day cycles. Patients had <or= one line of chemotherapy for recurrent and/or metastatic disease, Eastern Cooperative Oncology Group performance status of <or= 2, and adequate organ function. At the end of stage 1, efficacy criteria for further accrual were not met, but the study was amended to enroll an additional five patients for paired tumor biopsies. RESULTS Twenty-seven and 26 patients were eligible for toxicity and efficacy evaluations, respectively. One patient (3.7%; 95% CI, 0.1% to 19.0%) achieved a partial response. Disease stabilization was maintained in 10 patients (37.0%; 95% CI, 22.4% to 61.2%). The median time to progression was 1.8 months (95% CI, 1.6 to 3.4 months), and median overall survival time was 4.2 months (95% CI, 3.6 to 8.7 months). Sorafenib was well tolerated with few grade 3 and no grade 4 toxicities. Biomarker analysis of paired tumor samples before and after treatment with sorafenib revealed a decrease of pERK in all five patients, with a decrease in Ki67 in four patients, consistent with a disruption of ERK signaling. The antiapoptotic protein Mcl-1 was downregulated in four patients, and there was also evidence of antiangiogenic activity. CONCLUSION Sorafenib was well tolerated and had modest anticancer activity comparable to monotherapy with other targeted agents in this group of patients. Further development in combination with radiation or other agents may be warranted.

A Phase 1 Study of Mapatumumab (Fully Human Monoclonal Antibody to TRAIL-R1) in Patients with Advanced Solid Malignancies

Purpose: Mapatumumab (TRM-1, HGS-ETR1) is a fully human agonistic monoclonal antibody that targets and activates tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) receptor 1 (death receptor 4). Mapatumumab functions like the natural receptor ligand, TRAIL, a tumor necrosis factor superfamily member that is an important mediator of apoptosis in cancer cell lines. Promising preclinical activity with mapatumumab has been observed. Experimental Design: This phase I, open-label, dose-escalation study assessed the tolerability and toxicity profile of ≥2 doses of mapatumumab administered i.v. in patients with advanced solid tumors. Patients received mapatumumab every 28 days until progression or dose-limiting toxicity. Results: There were escalation levels from 0.01 to 20.0 mg/kg. Forty-one patients, 27 female, with a median age of 55 years (range, 23-81) were entered into the study and received 143 courses. The most common diagnoses were colorectal (10 patients) and ovarian cancer (9 patients). Patients received a median of two cycles (range, 1-33). Mapatumumab was well tolerated. Adverse events considered at least possibly related to mapatumumab that occurred most frequently included fatigue (36.2%), hypotension (34.1%), nausea (29.3%), and pyrexia (12.2%). The majority of adverse events were grade 1 or 2. The maximum tolerated dose was not reached. Linear pharmacokinetics was observed for doses up to 0.3 mg/kg and for the 20 mg/kg level, whereas exposure at 3 and 10 mg/kg increased less than proportionally. No objective responses were observed, but 12 patients had stable disease for 1.9 to 29.4 months. Conclusions: Mapatumumab is well tolerated and further evaluation of this TRAIL-R1 targeting agent is warranted.

Phase II study of erlotinib (OSI-774) in patients with metastatic colorectal cancer

Erlotinib (Tarceva™, OSI-774), a potent epidermal growth factor receptor tyrosine kinase inhibitor (EGFR), was evaluated in a phase II study to assess its activity in patients with metastatic colorectal cancer. In all, 38 patients with metastatic colorectal cancer were treated with erlotinib at a continuous daily oral dose of 150 mg. Radiological evaluation was carried out every 8 weeks and tumour biopsies were performed before treatment and on day 8. Of 31 evaluable patients, 19 (61%) had progressive disease and 12 (39%) had stable disease (s.d.). The median time to progression for those patients having s.d. was 123 days (range 108–329 days). The most common adverse events were rash in 34 patients and diarrhoea in 23 patients. Correlative studies were conducted to investigate the effect of erlotinib on downstream signalling. Tumour tissue correlations were based on usable tissue from eight match paired tumour samples pre- and on therapy, and showed a statistically significant decrease in the median intensity of both pEGFR (P=0.008) and phospho-extracellular signal-regulated kinase (ERK) (P=0.008) a week after commencement of treatment. No other statistically significant change in tumour markers was observed. Erlotinib was well tolerated with the most common toxicities being rash and diarrhoea. More than one-third of evaluable patients had s.d. for a minimum of 8 weeks. Correlative studies showed a reduction in phosphorylated EGFR and ERK in tumour tissue post-treatment.

Phase I/II Trial of Erlotinib and Cisplatin in Patients With Recurrent or Metastatic Squamous Cell Carcinoma of the Head and Neck: A Princess Margaret Hospital Phase II Consortium and National Cancer Institute of Canada Clinical Trials Group Study

PURPOSE To determine the phase II dose and objective response rate of erlotinib, a selective epidermal growth factor receptor tyrosine kinase inhibitor, in combination with cisplatin in patients with recurrent or metastatic squamous cell carcinoma of the head and neck (HNSCC). PATIENTS AND METHODS HNSCC patients with no prior chemotherapy and measurable disease were treated in three escalating-dose cohorts of daily continuous oral (PO) erlotinib and intermittent intravenous (IV) cisplatin given every 21 days. The recommended phase II dose (RPTD) was then evaluated in a two-stage trial with a primary end point of objective response rate. RESULTS A total of 51 patients were enrolled. The RPTD was identified as erlotinib 100 mg PO daily and cisplatin 75 mg/m2 IV every 21 days. Forty-five patients were treated at the RPTD, of which 44 and 43 were eligible for toxicity and efficacy evaluations, respectively. The intention-to-treat response rate was 21%, with one complete and eight partial responses (95% CI, 10% to 36%), and disease stabilization was achieved in 21 patients (49%; 95% CI, 33% to 65%). Median progression-free survival was 3.3 months (95% CI, 2.7 to 4.8 months) and median overall survival was 7.9 (95% CI, 5.6 to 9.5) months. The combination was well tolerated, with minimal grade 3 or higher toxicity. Subgroup analysis suggested that patients who developed higher grade skin rashes during cycle 1 had better survival outcomes (P = .034). CONCLUSION This schedule of erlotinib and cisplatin has a favorable toxicity profile and has antitumor activity in HNSCC comparable to standard combination chemotherapy regimens.

Safety, Pharmacokinetic, and Pharmacodynamic Phase I Dose-Escalation Trial of PF-00562271, an Inhibitor of Focal Adhesion Kinase, in Advanced Solid Tumors

PURPOSE PF-00562271 is a novel inhibitor of focal adhesion kinase (FAK). The objectives of this study were to identify the recommended phase II dose (RP2D) and assess safety and tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and antitumor activity of PF-00562271. PATIENTS AND METHODS Part 1 was a dose escalation without and with food. Part 2 enrolled specific tumor types in an expansion at the RP2D and also assessed the effect of PF-00562271 on single-dose midazolam PK in a subgroup of patients. RESULTS Ninety-nine patients (median age, 60 years; 98% with Eastern Cooperative Oncology Group performance status of 0 or 1) were treated in 12 fasting and three fed cohorts. The 125-mg twice-per-day fed dose was deemed the maximum-tolerated dose (MTD) and RP2D. Grade 3 dose-limiting toxicities included headache, nausea/vomiting, dehydration, and edema. Nausea was the most frequently observed toxicity (60% of patients, all grades 1 or 2 at RP2D). PF-00562271 exposure increased with increasing dose; serum concentration-time profiles showed characteristic nonlinear disposition. Steady-state exposures were reached within 1 week. On coadministration, geometric mean values of midazolam maximal observed serum concentration and area under the serum concentration-time curve increased by 60% and more than two-fold, respectively. Of 14 patients evaluable by [(18)F]fluorodeoxyglucose positron emission tomography in the expansion cohorts, seven metabolic responses were observed. With conventional imaging, 31 patients had stable disease at first restaging scans, and 15 of these remained stable for six or more cycles. CONCLUSION The MTD and RP2D of PF-00562271 is 125 mg twice per day with food. PF-00562271 displayed time- and dose-dependent nonlinear PK and is likely a potent CYP 3A inhibitor. This first-in-class study supports further investigation of FAK as a promising therapeutic target.

Phase I and Pharmacokinetic Study of Daily Oral AZD2171, an Inhibitor of Vascular Endothelial Growth Factor Tyrosine Kinases, in Combination With Carboplatin and Paclitaxel in Patients With Advanced Non–Small-Cell Lung Cancer: The National Cancer Institute of Canada Clinical Trials Group

PURPOSE AZD2171 is a potent inhibitor of vascular endothelial growth factor receptors that showed broad antitumor activity in preclinical models. Doses of up to 45 mg/d of AZD2171 are tolerable when administered alone. This study evaluated escalating doses of AZD2171 in combination with standard chemotherapy in patients with advanced non-small-cell lung cancer. PATIENTS AND METHODS Eligible patients received carboplatin targeted to an area under the concentration time curve of 6 mg . min/mL and paclitaxel 200 mg/m(2), both on day 1 of a 3-week cycle; daily oral AZD2171 at either 30 mg or 45 mg commenced day 2 of cycle 1. Pharmacokinetics of all drugs were performed, and tumor response was assessed by Response Evaluation Criteria in Solid Tumors (RECIST). RESULTS Twenty patients were enrolled. No dose-limiting toxicities were observed during cycle 1 at either dose. Fatigue, diarrhea, anorexia, and granulocytopenia were common; hypertension was manageable with a treatment algorithm designed for this protocol. No clinically significant drug-related bleeding was observed. At 45 mg/d, fatigue and diarrhea were increased, and headache and hoarseness were observed. Paclitaxel clearance decreased during cycle 2, but no other significant pharmacokinetic interactions were observed. After radiology review, confirmed responses were observed in nine patients (response rate, 45%; 95% CI, 23% to 68%); all but one enrolled patient showed evidence of tumor shrinkage, some with cavitation. CONCLUSION AZD2171 can be combined with standard doses of carboplatin/paclitaxel with encouraging antitumor activity. Toxicity is increased, but predictable and manageable.