LY3022855, an anti-colony stimulating factor-1 receptor (CSF-1R) monoclonal antibody, in patients with advanced solid tumors refractory to standard therapy: phase 1 dose-escalation trial.

Background Tumor-associated macrophages (TAMs) promote tumor growth, metastasis, and therapeutic resistance via colony-stimulating factor-1 (CSF-1), acting through CSF-1 receptor (CSF-1R) signaling. This phase 1 study determined the safety, tolerability, pharmacokinetics-pharmacodynamics, immunogenicity, and efficacy of the anti-CSF-1R antibody LY3022855 in solid tumors. Methods Patients with advanced solid tumors refractory to standard therapy were enrolled and treated in 2 dosing cohorts: weight-based (part A) and non-weight-based (part B). Part A patients were assigned to intravenous (IV) dose-escalation cohorts: 2.5 mg/kg once per week (QW), 0.3 mg/kg QW, 0.6 mg/kg QW, 1.25 mg/kg once every 2 weeks (Q2W) and 1.25 mg/kg QW doses of LY3022855. Non-weight-based doses in part B were 100 mg and 150 mg IV QW. Results Fifty-two patients (mean age 58.6 ± 10.4 years) were treated with ≥1 dose of LY3022855 (range: 4-6). Five dose-limiting toxicities (left ventricular dysfunction, anemia, pancreatitis, rhabdomyolysis, and acute kidney injury) occurred in 4 patients. The non-weight-based 100 mg QW dose was established as the RP2D. The most common treatment-emergent adverse events were increase in liver function variables, fatigue, nausea, vomiting, diarrhea, anorexia, pyrexia, increased lipase, amylase, and lactate dehydrogenase. Clearance decreased with increasing dose and weight-based dosing had minimal effect on pharmacokinetics. Serum CSF-1, and IL-34 levels increased at higher doses and more frequent dosing, whereas TAMs and CD14dimCD16bright levels decreased. Three patients achieved stable disease. No responses were seen. Conclusions LY3022855 was well tolerated and showed dose-dependent pharmacokinetics-pharmacodynamics and limited clinical activity in a heterogenous solid tumor population. ClinicalTrials.gov ID NCT01346358 (Registration Date: May 3, 2011).

Phase 2 study of treatment selection based on tumor thymidylate synthase expression in previously untreated patients with metastatic colorectal cancer: A trial of the ECOG-ACRIN Cancer Research Group (E4203).

BACKGROUND: The authors hypothesized that patients with metastatic colorectal cancer (mCRC) who had tumors with low thymidylate synthase (TS-L) expression would have a higher response rate to combined 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX) plus bevacizumab (FOLFOX/Bev) than those with high TS (TS-H) expression and that combined irinotecan and oxaliplatin (IROX) plus bevacizumab (IROX/Bev) would be more effective than FOLFOX/Bev in those with TS-H tumors. METHODS: TS protein expression was determined in mCRC tissue. Patients who had TS-L tumors received FOLFOX/Bev, and those who had TS-H tumors were randomly assigned to receive either FOLFOX/Bev or IROX/Bev. The primary endpoint was the response rate (complete plus partial responses). RESULTS: In total, 211 of 247 patients (70% TS-H) were registered to the treatment phase. Efficacy analyses included eligible patients who had started treatment (N = 186). The response rates for patients who received IROX/Bev (TS-H), FOLFOX/Bev (TS-H), and FOLFOX/Bev (TS-L) were 33%, 38%, and 49%, respectively (P = nonsignificant). The median progression-free survival (PFS) was 10 months (95% confidence interval [CI], 9-12 months; 10 months in the IROX/Bev TS-H group, 9 months in the FOLFOX/Bev TS-H group, and 13 months in the FOLFOX/Bev TS-L group). The TS-L group had improved PFS compared with the TS-H group that received FOLFOX/Bev (hazard ratio, 1.6; 95% CI, 1.0%-2.4%; P = .04; Cox regression). The median overall survival (OS) was 22 months (95% CI, 20 29 months; 18 months in the IROX/Bev TS-H group, 21 months in the FOLFOX/Bev TS-H group, and 32 months in the TS-L group). OS comparisons for the 2 TS-H arms and for the FOLFOX/Bev TS-H versus TS-L arms were not significantly different. CONCLUSIONS: TS expression was prognostic: Patients with TS-L tumors who received FOLFOX/Bev had a longer PFS than those with TS-H tumors, along with a trend toward longer OS. Patients with TS-H tumors did not benefit more from IROX/Bev than from FOLFOX/Bev. Cancer 2018;124:688-97. © 2017 American Cancer Society.

Randomized Phase II Study of Ramucirumab or Icrucumab in Combination with Capecitabine in Patients with Previously Treated Locally Advanced or Metastatic Breast Cancer.

BACKGROUND: Icrucumab (ICR) and ramucirumab (RAM) bind vascular endothelial growth factor (VEGF) receptors 1 and 2 (VEGFR-1 and -2), respectively. This open-label, randomized phase II study evaluated their efficacy and safety in combination with capecitabine (CAP) in patients with previously treated unresectable, locally advanced or metastatic breast cancer. METHODS: Patients were randomly assigned (1:1:1) to receive CAP (1,000 mg/m2 orally twice daily, days 1-14) alone or in combination with RAM (10 mg/kg intravenously [IV], days 1 and 8) (RAM + CAP) or ICR (12 mg/kg IV, days 1 and 8) (ICR + CAP) every 21 days. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), tumor response, safety, and pharmacokinetics. RESULTS: Of 153 patients randomized, 150 received treatment. Median PFS (95% confidence interval) was 22.1 (12.1-36.1) weeks on RAM + CAP, 7.3 (6.3-13.0) weeks on ICR + CAP, and 19.0 (12.1-24.3) weeks on CAP (hazard ratios [HRs]: 0.691, p = .1315, RAM + CAP versus CAP; 1.480, p = .0851, ICR + CAP versus CAP). Median OS was 67.4 weeks on RAM + CAP, 62.1 weeks on ICR + CAP, and 71.6 weeks on CAP (HRs: 1.833, p = .0283, RAM + CAP versus CAP; 1.468, p = .1550, ICR + CAP versus CAP). There was no statistically significant difference in PFS or OS between either combination arm and CAP. Treatment-related adverse events more frequent (by ≥10%) on RAM + CAP than on CAP were constipation, decreased appetite, headache, epistaxis, and hypertension. Those more frequent (by ≥10%) on ICR + CAP than CAP were anemia, increased lacrimation, periorbital edema, nausea, vomiting, peripheral edema, facial edema, dehydration, and dyspnea. CONCLUSION: Combining RAM or ICR with CAP did not improve PFS in the targeted study population. The Oncologist 2017;22:245-254 IMPLICATIONS FOR PRACTICE: Icrucumab and ramucirumab are recombinant human IgG1 monoclonal antibodies that bind vascular endothelial growth factor (VEGF) receptors 1 and 2 (VEGFR-1 and -2), respectively. VEGFR-1 activation on endothelial and tumor cell surfaces increases tumor vascularization and growth and supports tumor growth via multiple mechanisms, including contributions to angiogenesis and direct promotion of cancer cell proliferation. Strong preclinical and clinical evidence suggests key roles for VEGF and angiogenesis in breast cancer growth, invasion, and metastasis. This randomized phase II study evaluated the efficacy and safety of each antibody in combination with capecitabine in patients with previously treated unresectable, locally advanced or metastatic breast cancer.

Phase 1 study of narnatumab, an anti-RON receptor monoclonal antibody, in patients with advanced solid tumors.

Purpose Macrophage-stimulating 1-receptor (RON) is expressed on macrophages, epithelial cells, and a variety of tumors. Narnatumab (IMC-RON8; LY3012219) is a neutralizing monoclonal antibody that blocks RON binding to its ligand, macrophage-stimulating protein (MSP). This study assessed safety, maximum tolerated dose (MTD), pharmacokinetics, pharmacodynamics, and efficacy of narnatumab in patients with advanced solid tumors. Methods Narnatumab was administered intravenously weekly at 5, 10, 15, or 20 mg/kg or every 2 weeks at 15, 20, 30, or 40 mg/kg in 4-week cycles. Results Thirty-nine patients were treated, and 1 dose-limiting toxicity (DLT) (grade 3 hyponatremia, 5 mg/kg) was reported. The most common narnatumab-related adverse events (AEs) were fatigue (20.5%) and decreased appetite, diarrhea, nausea, and vomiting (10.3% each). Except for 2 treatment-related grade 3 AEs (hyponatremia, hypokalemia), all treatment-related AEs were grade 1 or 2. Narnatumab had a short half-life (<7 days). After Cycle 2, no patients had concentrations above 140 µg/mL (concentration that demonstrated antitumor activity in animal models), except for 1 patient receiving 30 mg/kg biweekly. Eleven patients had a best response of stable disease, ranging from 6 weeks to 11 months. Despite only 1 DLT, due to suboptimal drug exposure, the dose was not escalated beyond 40 mg/kg biweekly. This decision was based on published data reporting that mRNA splice variants of RON are highly prevalent in tumors, accumulate in cytoplasm, and are not accessible by large-molecule monoclonal antibodies. Conclusions Narnatumab was well tolerated and showed limited antitumor activity with this dosing regimen.

Safety and activity of anti-PD-L1 antibody in patients with advanced cancer.

BACKGROUND: Programmed death 1 (PD-1) protein, a T-cell coinhibitory receptor, and one of its ligands, PD-L1, play a pivotal role in the ability of tumor cells to evade the host's immune system. Blockade of interactions between PD-1 and PD-L1 enhances immune function in vitro and mediates antitumor activity in preclinical models. METHODS: In this multicenter phase 1 trial, we administered intravenous anti-PD-L1 antibody (at escalating doses ranging from 0.3 to 10 mg per kilogram of body weight) to patients with selected advanced cancers. Anti-PD-L1 antibody was administered every 14 days in 6-week cycles for up to 16 cycles or until the patient had a complete response or confirmed disease progression. RESULTS: As of February 24, 2012, a total of 207 patients--75 with non-small-cell lung cancer, 55 with melanoma, 18 with colorectal cancer, 17 with renal-cell cancer, 17 with ovarian cancer, 14 with pancreatic cancer, 7 with gastric cancer, and 4 with breast cancer--had received anti-PD-L1 antibody. The median duration of therapy was 12 weeks (range, 2 to 111). Grade 3 or 4 toxic effects that investigators considered to be related to treatment occurred in 9% of patients. Among patients with a response that could be evaluated, an objective response (a complete or partial response) was observed in 9 of 52 patients with melanoma, 2 of 17 with renal-cell cancer, 5 of 49 with non-small-cell lung cancer, and 1 of 17 with ovarian cancer. Responses lasted for 1 year or more in 8 of 16 patients with at least 1 year of follow-up. CONCLUSIONS: Antibody-mediated blockade of PD-L1 induced durable tumor regression (objective response rate of 6 to 17%) and prolonged stabilization of disease (rates of 12 to 41% at 24 weeks) in patients with advanced cancers, including non-small-cell lung cancer, melanoma, and renal-cell cancer. (Funded by Bristol-Myers Squibb and others; ClinicalTrials.gov number, NCT00729664.).

Phase 1 study of ixazomib, an investigational proteasome inhibitor, in advanced non-hematologic malignancies.

PURPOSE: Ixazomib is an investigational proteasome inhibitor with demonstrated antitumor activity in xenograft models of multiple myeloma (MM), lymphoma, and solid tumors. This open-label, phase 1 study investigated intravenous (IV) ixazomib, in adult patients with advanced non-hematologic malignancies. METHODS: Patients received IV ixazomib twice-weekly for up to twelve 21-day cycles. The 0.125 mg/m(2) starting dose was doubled (one patient/dose) until 1.0 mg/m(2) based on dose-limiting toxicities (DLTs) in cycle 1. This was followed by 3 + 3 dose-escalation and expansion at the maximum tolerated dose (MTD). Primary objectives included safety and MTD assessment. Secondary objectives included assessment of pharmacokinetics, pharmacodynamics, and disease response. RESULTS: Ixazomib was escalated from 0.125 to 2.34 mg/m(2) to determine the MTD (n = 23); patients were then enrolled to MTD expansion (n = 73) and pharmacodynamic (n = 20) cohorts. Five patients experienced DLTs (1.0 and 1.76 mg/m(2): grade 3 pruritic rash; 2.34 mg/m(2): grade 3 and 4 thrombocytopenia, and grade 3 acute renal failure); thus, the MTD was 1.76 mg/m(2). Drug-related grade ≥3 adverse events (AEs) included thrombocytopenia (23 %), skin and subcutaneous (SC) tissue disorders (16 %), and fatigue (9 %). Among 92 evaluable patients, one (head and neck cancer) had a partial response and 30 had stable disease. Ixazomib terminal half-life was 3.8-7.2 days; plasma exposures increased dose-proportionally and drug was distributed to tumors. Inhibition of whole-blood 20S proteasome activity and upregulation of ATF-3 in tumor biopsies demonstrated target engagement. CONCLUSIONS: In patients with solid tumors, ixazomib was associated with a manageable safety profile, limited antitumor activity, and evidence of downstream proteasome inhibition effects.

Chemoradiation therapy sequencing for resected pancreatic adenocarcinoma in the National Cancer Data Base.

BACKGROUND: Pancreatic adenocarcinoma (PAC) has low overall survival (OS) rates and high recurrence rates following surgical resection. The role for preoperative radiation therapy (prRT) for PAC versus postoperative RT (poRT) remains uncertain. The authors used the National Cancer Data Base (NCDB) to report prRT outcomes for the largest multi-institutional patient cohort to date. METHODS: NCDB data were obtained for all patients who underwent resection and external beam radiation (RT) for PAC from 1998 to 2002. Patients with metastatic (M1) disease, intraoperative RT, RT both before and after surgery, missing OS, or missing RT variables were excluded. Univariate (UV) and multivariate (MV) analysis were run using treatment characteristics, tumor characteristics, and patient demographics. The difference in patients' known characteristics was described by a chi-square test or analysis of variance. RESULTS: A total of 5414 patients were identified. Of these, 277 received prRT and 5137 received poRT. Overall, 92.9% received chemotherapy and 7.1% received RT alone; 56% (2990 of 5307) of patients had stage III disease, according to American Joint Commission on Cancer (AJCC) staging manual, 5th edition. Median tumor size was 3 cm (range: 0-9.9 cm); 82% (199 of 244) of patients with prRT had negative surgical margins; 72% (3383 of 4699) of patients with poRT had negative margins. Forty-one percent (71 of 173) of patients with prRT were lymph node (LN)-positive; 65% (3159 of 4833) of patients with poRT were LN-positive. Median OS for patients with prRT was 18 months (95% CI = 18-19 months) and for patients with poRT, 19 months (95% CI = 17-22 months). CONCLUSIONS: Receipt of prRT was associated with lower stage, higher rates of negative margins, and lower rates of lymph node positivity at resection. However, there was no significant difference in median OS versus that of the poRT group.

Phase II trial of bortezomib plus doxorubicin in hepatocellular carcinoma (E6202): a trial of the Eastern Cooperative Oncology Group.

PURPOSE: To evaluate the efficacy and tolerability of bortezomib in combination with doxorubicin in patients with advanced hepatocellular carcinoma, and to correlate pharmacodynamic markers of proteasome inhibition with response and survival. EXPERIMENTAL DESIGN: This phase II, open-label, multicenter study examined the efficacy of bortezomib (1.3 mg/m(2) IV on d1, 4, 8, 11) and doxorubicin (15 mg/m(2) IV on d1, 8) in 21-day cycles. The primary endpoint was objective response rate. RESULTS: Best responses in 38 treated patients were 1 partial response (2.6 %), 10 (26.3 %) stable disease, and 17 (44.7 %) progressive disease; 10 patients were unevaluable. Median PFS was 2.2 months. Median OS was 6.1 months. The most common grade 3 to 4 toxicities were hypertension, glucose intolerance, ascites, ALT elevation, hyperglycemia and thrombosis/embolism. Worse PFS was seen in patients with elevated IL-6, IL-8, MIP-1α and EMSA for NF-κB at the start of treatment. Worse OS was seen in patients with elevated IL-8 and VEGF at the start of treatment. Patients had improved OS if a change in the natural log of serum MIP-1α/CCL3 was seen after treatment. RANTES/CCL5 levels decreased significantly with treatment. CONCLUSIONS: The combination of doxorubicin and bortezomib was well-tolerated in patients with hepatocellular carcinoma, but the primary endpoint was not met. Exploratory analyses of markers of proteasome inhibition suggest a possible prognostic and predictive role and should be explored further in tumor types for which bortezomib is efficacious.

Treatment utilization and surgical outcome of ampullary and duodenal adenocarcinoma.

BACKGROUND: Ampullary (AMP-A) and duodenal adenocarcinomas (DA) are rare tumors. The literature regarding treatment and outcome is very limited. The objective of this project is to compare the outcomes of AMP-A and DA. METHODS: The records for AMP-A and DA patients between July 1995 and July 2012 at Emory University were reviewed for demographics, pathology, treatment, and survival. Survival rates were estimated by Kaplan-Meier method and compared with log-rank test. A Cox proportional hazard model was fitted to estimate the adjusted effect of AMP-A versus DA on overall survival (OS). RESULTS: Ninety-five AMP-A and 66 DA patients were identified. No significant difference between patients with DA and AMP-A was observed for age, gender, or grade. DA presented with larger tumors and higher stages. Treatment included surgery, surgery followed by adjuvant therapy or chemotherapy alone. No OS difference was observed when controlled for stage. AMP-A was sub-classified into intestinal (IAMP), pancreaticobiliary (PBAMP), and unspecified types. IAMP tended to present at a higher grade (P = 0.045) than PBAMP. No OS difference between the IAMP and PBAMP was observed. CONCLUSIONS: After accounting for stage, OS was not significantly different for AMP-A and DA patients. There was no OS difference comparing PBAMP with IAMP.

Survival, efficacy, and safety of small versus large doxorubicin drug-eluting beads TACE chemoembolization in patients with unresectable HCC.

OBJECTIVE: The purpose of this study was to investigate the overall survival, efficacy, and safety of small (100-300 µm) versus large (300-500 and 500-700 µm) doxorubicin drug-eluting beads transarterial chemoembolization (DEB TACE) in patients with unresectable hepatocellular carcinoma (HCC). MATERIALS AND METHODS: Ninety-four consecutive patients with unresectable HCC who underwent 269 DEB TACE procedures in 48 months were studied. DEB TACE procedures were performed using different DEB sizes: 100-300 µm (Group A, 59 patients) and with mixed 300-500 and 500-700 µm DEB (Group B, 35 patients). Survival rates were compared between the groups. RESULTS: The overall median survival in groups A and B were 15.1 and 11.1 months, respectively (p=0.005). Both groups were similar in demographics, tumor burden, and differential staging (p>0.5). Substratification of overall survival according to Child-Pugh class and Okuda, Cancer of the Liver Italian Program (CLIP), and Barcelona Clinic Liver Cancer (BCLC) staging were significantly higher in group A than in group B (p<0.05). Common terminology criteria for adverse events (CTCAE) grade III adverse events and 30-day mortality were significantly lower in group A than in group B (6.8% vs 20%; p=0.04, and 0% vs 14.3%; p=0.001, respectively). The particle size, Child-Pugh class, and serum α-fetoprotein level were significant prognostic indicators of survival on multivariate analysis. CONCLUSION: TACE with 100-300 µm sized DEB is associated with significantly higher survival rate and lower complications than TACE with 300-500 and 500-700 µm sized DEB.

The influence of adjuvant radiotherapy dose on overall survival in patients with resected pancreatic adenocarcinoma.

BACKGROUND: Adjuvant radiotherapy (A-RT) for patients with resected pancreatic adenocarcinoma (PAC) is controversial. In the current study, the authors aim to determine whether there is an association between overall survival (OS) and A-RT dose. METHODS: National Cancer Data Base (NCDB) data were obtained for all patients who received A-RT for resected PAC from 1998 through 2002. Univariate and multivariate survival analyses were performed along with Kaplan-Meier estimates for A-RT levels < 40 grays (Gy), 40 Gy to < 50 Gy, 50 Gy to < 55 Gy, and ≥ 55 Gy. RESULTS: A total of 1385 patients met the inclusion criteria. The median age of the patients was 64 years (range, 29 years-87 years). All patients underwent surgical resection and A-RT with or without chemotherapy. A total of 231 patients were diagnosed with stage I disease, 273 were diagnosed with stage II disease, 734 were diagnosed with stage III disease, and 126 were diagnosed with stage IVA disease (according to the fifth edition of the American Joint Committee on Cancer); 21 were found to have an unknown stage of disease. The median A-RT dose was 45 Gy (range, 1.63 Gy-69 Gy). The median OS was 21 months (95% confidence interval [95% CI], 19 months-23 months). On multivariate analysis, an A-RT dose < 40 Gy (hazards ratio [HR], 1.30 [95% CI, 1.03-1.66]; P = .031), an A-RT dose of 40 Gy to < 50 Gy (HR, 1.17 [95% CI, 1.00-1.37]; P = .05), and an A-RT dose ≥ 55 Gy (HR, 1.44 [95% CI, 1.08-1.93]; P = .013) predicted worse OS compared with the reference category of 50 Gy to < 55 Gy. CONCLUSIONS: A-RT doses of < 40 Gy, 40 Gy to < 50 Gy, and ≥ 55 Gy were found to be associated with an inferior OS. The dose of A-RT delivered appears to influence OS and a prospective study evaluating the addition of optimally delivered A-RT for patients with resected PAC is needed.

Safety and efficacy of doxorubicin drug-eluting bead transarterial chemoembolization in patients with advanced hepatocellular carcinoma.

PURPOSE: To investigate the safety and efficacy of transarterial chemoembolization using doxorubicin drug-eluting beads (DEBs) in patients with Barcelona Clinic Liver Cancer (BCLC) C stage hepatocellular carcinoma (HCC). METHODS: Consecutive patients with initial staging of BCLC C HCC who received DEB transarterial chemoembolization over the last 5 years were studied. The study included 121 patients (mean age, 61.2 years old). Adverse events (AEs) after DEB transarterial chemoembolization were studied in detail and were recorded as per the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03 criteria. Survivals were analyzed according to parameters from the time of first DEB transarterial chemoembolization. Kaplan-Meier method by log-rank test and Cox proportional hazard model were used for survival analysis. RESULTS: AEs occurred in 30.2% of patients. No AEs were greater than Common Terminology Criteria for Adverse Events grade III. Grade I and II AEs included nausea and vomiting in 7.8% of patients and abdominal pain in 23.8% of patients. Grade III AEs were noted in 1.06% of patients. There were no gastrointestinal or hepatic complications. There were no deaths within 30 days after DEB transarterial chemoembolization. The overall median survival was 13.5 months. Among the Child-Pugh class A patients, those without PVT and metastasis (28.9%) had better survival when treated with DEB transarterial chemoembolization than those with PVT and metastases (9.9%) (18.8 mo versus 4.4 mo, P = .001). Ascites, performance status, Okuda stage HCC, serum alpha fetoprotein levels, and etiologic factor for chronic liver disease predicted survival. CONCLUSIONS: DEB transarterial chemoembolization appears to be a safe and effective treatment option for patients with BCLC C HCC. Patients with Child-Pugh class A without PVT and metastasis benefited most from DEB transarterial chemoembolization.

Fractionated radioimmunotherapy with (90) Y-clivatuzumab tetraxetan and low-dose gemcitabine is active in advanced pancreatic cancer: A phase 1 trial.

BACKGROUND: It has been demonstrated that the humanized clivatuzumab tetraxetan (hPAM4) antibody targets pancreatic ductal carcinoma selectively. After a trial of radioimmunotherapy that determined the maximum tolerated dose of single-dose yttrium-90-labeled hPAM4 ((90) Y-hPAM4) and produced objective responses in patients with advanced pancreatic ductal carcinoma, the authors studied fractionated radioimmunotherapy combined with low-dose gemcitabine in this disease. METHODS: Thirty-eight previously untreated patients (33 patients with stage IV disease and 5 patients with stage III disease) received gemcitabine 200 mg/m(2) weekly for 4 weeks with (90) Y-hPAM4 given weekly in Weeks 2, 3, and 4 (cycle 1), and the same cycle was repeated in 13 patients (cycles 2-4). In the first part of the study, 19 patients received escalating weekly (90) Y doses of 6.5 mCi/m(2) , 9.0 mCi/m(2) , 12.0 mCi/m(2) , and 15.0 mCi/m(2) . In the second portion, 19 additional patients received weekly doses of 9.0 mCi/m(2) or 12.0 mCi/m(2) . RESULTS: Grade 3/4 thrombocytopenia or neutropenia (according to version 3.0 of the National Cancer Institute's Common Terminology Criteria for Adverse Events) developed in 28 of 38 patients after cycle 1 and in all retreated patients; no grade >3 nonhematologic toxicities occurred. Fractionated dosing of cycle 1 allowed almost twice the radiation dose compared with single-dose radioimmunotherapy. The maximum tolerated dose of (90) Y-hPAM4 was 12.0 mCi/m(2) weekly for 3 weeks for cycle 1, with ≤9.0 mCi/m(2) weekly for 3 weeks for subsequent cycles, and that dose will be used in future trials. Six patients (16%) had partial responses according to computed tomography-based Response Evaluation Criteria in Solid Tumors, and 16 patients (42%) had stabilization as their best response (58% disease control). The median overall survival was 7.7 months for all 38 patients, including 11.8 months for those who received repeated cycles (46% [6 of 13 patients] ≥1 year), with improved efficacy at the higher radioimmunotherapy doses. CONCLUSIONS: Fractionated radioimmunotherapy with (90) Y-hPAM4 and low-dose gemcitabine demonstrated promising therapeutic activity and manageable myelosuppression in patients with advanced pancreatic ductal carcinoma.

Safety and feasibility of same-day discharge of patients with unresectable hepatocellular carcinoma treated with doxorubicin drug-eluting bead transcatheter chemoembolization.

PURPOSE: The aim of this study was to investigate the safety and feasibility of same-day discharge of patients with unresectable hepatocellular carcinoma (HCC) after doxorubicin drug-eluting bead (DEB) transarterial chemoembolization and to elucidate the factors predisposing to overnight admission. MATERIALS AND METHODS: Consecutive patients with unresectable HCC who underwent superselective 100-300 µm DEB transarterial chemoembolization were included. The parameters of same-day therapy (group A) were compared with those of patients admitted overnight (group B). A χ2 test and a t test were used to compare categorical and continuous variables accordingly. RESULTS: Seventy-six patients (mean, 61 y) received 110 DEB transarterial chemoembolization treatments over an 8-month study period. In 84.5% (93/110) of DEB transarterial chemoembolization procedures, the patients were discharged on the same day (group A). The causes of hospitalization included the worsening of comorbidities in 41.1% (7/17), pain control in 29.4% (5/17), and groin and closure device-related complications in 29.4% (5/17) of patients. The mean Charlson comorbidity scores in groups A and B were 6.96 (standard deviation [SD] ± 1.98) and 8.47 (SD ± 2.18) (P = .0005), respectively. All of the patients in group B had Barcelona Clinic Liver Cancer (BCLC) stages C and D HCC (P = .024). There were no Common Terminology Criteria for Adverse Events (CTCAE) grade III or worse adverse events (AEs). There was no mortality or emergency visits within 30 days of discharge. CONCLUSIONS: Same-day discharge after superselective DEB transarterial chemoembolization for unresectable HCC is safe and feasible. BCLC C or D stage of disease, a higher Charlson comorbidity score, and groin or closure device complications are correlated with a greater likelihood for overnight admission.

Paediatric Strategy Forum for medicinal product development of multi-targeted kinase inhibitors in bone sarcomas: ACCELERATE in collaboration with the European Medicines Agency with participation of the Food and Drug Administration.

The eighth Paediatric Strategy Forum focused on multi-targeted kinase inhibitors (mTKIs) in osteosarcoma and Ewing sarcoma. The development of curative, innovative products in these tumours is a high priority and addresses unmet needs in children, adolescents and adults. Despite clinical and investigational use of mTKIs, efficacy in patients with bone tumours has not been definitively demonstrated. Randomised studies, currently being planned or in progress, in front-line and relapse settings will inform the further development of this class of product. It is crucial that these are rapidly initiated to generate robust data to support international collaborative efforts. The experience to date has generally indicated that the safety profile of mTKIs as monotherapy, and in combination with chemotherapy or other targeted therapy, is consistent with that of adults and that toxicity is manageable. Increasing understanding of relevant predictive biomarkers and tumour biology is absolutely critical to further develop this class of products. Biospecimen samples for correlative studies and biomarker development should be shared, and a joint academic-industry consortium created. This would result in an integrated collection of serial tumour tissues and a systematic retrospective and prospective analyses of these samples to ensure robust assessment of biologic effect of mTKIs. To support access for children to benefit from these novel therapies, clinical trials should be designed with sufficient scientific rationale to support regulatory and payer requirements. To achieve this, early dialogue between academia, industry, regulators, and patient advocates is essential. Evaluating feasibility of combination strategies and then undertaking a randomised trial in the same protocol accelerates drug development. Where possible, clinical trials and development should include children, adolescents, and adults less than 40 years. To respond to emerging science, in approximately 12 months, a multi-stakeholder group will meet and review available data to determine future directions and priorities.

Farnesyl transferase expression determines clinical response to the docetaxel-lonafarnib combination in patients with advanced malignancies.

BACKGROUND: Lonafarnib (LNF) is a protein farnesyl transferase (FTase) inhibitor that has shown synergistic activity with taxanes in preclinical models and early stage clinical trials. Preclinical findings suggested tubulin acetylation and FTase expression levels may be important determinants of drug sensitivity that would help identify patient populations more likely to benefit from this regimen. This pilot study evaluated the biological effects of LNF and docetaxel (DTX) combination therapy in refractory solid tumors by comparing pretreatment and post-treatment tumor biopsies. METHODS: Patients with histologically confirmed locally advanced or metastatic solid malignancies refractory to standard therapies or with no effective therapies available were eligible. Patients were randomized to 1 of 4 dosing cohorts: 1) 30 mg/m², 100 mg; 2) 36 mg/m², 100 mg; 3) 30 mg/m², 150 mg; or 4) 36 mg/m², 150 mg of DTX intravenously weekly, LNF orally twice daily, respectively. RESULTS: Of the 38 patients enrolled, 36 were treated, and 29 were evaluable for toxicity and response assessment. The combination of LNF and DTX was tolerated in all cohorts with the exception of a 28% incidence of grade 3/4 diarrhea, which was manageable with aggressive antidiarrheal regimens. Seven patients derived clinically meaningful benefit from this combination treatment; these patients had significantly lower basal FTase-beta mRNA expression levels than the mean study population level (P < .05). Correlation of clinical benefit with tubulin acetylation content as well as basal acetyl-tubulin content were evaluated. However, no significant correlation was found. CONCLUSIONS: Despite the small number of patients, these findings support our preclinical mechanistic studies and warrant further clinical investigations using FTase-beta mRNA expression as a potential predictive biomarker to select for an enriched patient population to study the effects of taxane and FTase inhibitor combination therapies.

Differential expression of ERCC1 in pancreas adenocarcinoma: high tumor expression is associated with earlier recurrence and shortened survival after resection.

BACKGROUND: Increased tumor expression of excision repair cross-complementing gene-1 (ERCC1) is associated with decreased survival in patients with various cancers. Its effect in pancreatic adenocarcinoma (PAC) is not defined. METHODS: Ninety-five patients were selected from a prospective database of all patients (n = 220) who underwent pancreaticoduodenectomy for PAC between January 2000 and October 2008. Tumor was isolated to perform immunohistochemistry for ERCC1 expression and was graded by a single pathologist. Main outcomes were recurrence-free survival (RFS) and overall survival (OS). RESULTS: Median age was 63 years; 50 patients (53%) were male and 73 (77%) received adjuvant chemotherapy. Median follow-up was 25 months. Median RFS and OS was 9 and 16 months. Median tumor size was 3 cm; 26% had a positive resection margin, 34% had poorly differentiated tumors, 61% had positive lymph nodes, 88% had perineural invasion, and 45% had lymphovascular invasion. Tumors exhibited differential ERCC1 expression in terms of intensity staining [none-weak: 61%; moderate-strong: 39%], percentage staining [0: 39%; 1-10: 29%; 11-50: 20%; 51-100: 12%], and overall expression [low: 84%; high: 16%]. High ERCC1 expression was associated with reduced RFS (6 vs. 10 months; P = 0.03) and decreased OS (9 vs. 18 months; P = 0.019). After accounting for adverse tumor factors, high ERCC1 expression persisted as a negative prognostic factor on multivariate Cox regression for both RFS and OS [hazards ratio (HR), 2.1; 95% confidence interval (CI), 1.1-3.9; P = 0.02; HR, 3; 95% CI, 1.6-6; P = 0.001, respectively]. A subset analysis of only those 73 patients who received adjuvant therapy revealed the same negative effect of high ERCC1 expression on RFS (4 vs. 15 months; P = 0.001) and OS (9 vs. 20 months; P < 0.001). CONCLUSIONS: Pancreas cancer exhibits differential expression of ERCC1. High ERCC1 expression is associated with both reduced RFS and OS after resection. ERCC1 expression levels may help to predict patient outcome with adjuvant chemotherapy.

Clinically relevant biomarkers to select patients for targeted inhibitor therapy after resection of hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is a vascular tumor that proliferates through angiogenic pathways mediated, in part, by vascular endothelial growth factor receptor 2 (VEGFR2), and platelet-derived growth factor receptor (PDGFR) α and ß. We hypothesized that overexpression of these proteins is associated with decreased survival after resection. METHODS: A total of 57 patients, with available tissue for analysis, who underwent liver resection for HCC between August 2000 and March 2008 at a single institution were identified from a prospectively maintained database. Tumor specimens were assessed with immunohistochemistry for VEGFR2, PDGFR-α, and PDGFR-ß expression and were graded by an experienced pathologist. Primary outcome was overall survival (OS). RESULTS: Median patient age was 64 years; 65% (n=37) were male. Median follow-up was 24.5 months, and median OS was 25.5 months. Median tumor size and number were 7 cm and 1, respectively. Macro and microvascular invasion was present in 9% (n=5) and 42% (n=24) of patients, respectively. Seventy-five percent of patients had tumors exceeding Milan criteria. 9% had positive resection margins. Thirty-five percent of patients had cirrhosis and the median nonadjusted Model for End-Stage Liver Disease (MELD) score was 7.5. Tumors exhibited differential expression of VEGFR2 (low: 79%, high: 21%), PDGFR-α (low: 93%, high: 7%), and PDGFR-ß (low: 96%, high: 4%). After excluding all 30-day deaths (n=7), high PDGFR-α and PDGFR-ß expression were independently associated with decreased OS (8.7 vs 29.1 months, P=0.01; 2.8 vs 28.8 months, P<0.001; respectively). High VEGFR2 expression displayed a trend toward decreased OS (20.8 vs 27.5 months, P=0.2). When adjusted for tumor burden, vascular invasion, margin status, and MELD score on independent multivariate analyses, both PDGFR-α and -ß high expression were independently associated with decreased survival. CONCLUSIONS: High expression of PDGFR-α and PDGFR-ß may be independently associated with decreased OS irrespective of margin status, MELD score, and tumor extent. This finding may help to select patients who would benefit from targeted inhibitor therapy in the adjuvant setting.

Chemotherapy in the treatment of metastatic gastric cancer: is there a global standard?

Gastric cancer remains one of the leading causes of cancer mortality worldwide even though its incidence has been decreasing in recent years. Despite remarkable advancements in chemotherapy, advanced gastric cancer has remained a therapeutic challenge for physicians as well as for patients. While early chemotherapeutic regimens succeeded in showing a modest but definite improvement over best supportive care, no single regimen stood out as superior. Most early trials failed to show survival benefit of combination regimens over single agent fluorouracil, but combination regimens were shown to have better response rates. Based on these data, the Japanese adopted single agent fluorouracil as a reference standard for further investigations, while the rest of the world used a doublet containing fluorouracil and platinum. As more clinical trials were conducted, the Japanese standard evolved into a doublet, while the Western countries adopted triplet combinations. There is no established global standard as yet, but with the introduction of newer targeted agents based on molecular assays and personalized approaches combined with conventional chemotherapy, multiple regimens are likely to emerge as global standards rather than one standard treatment for all.

Comparison of yttrium-90 radioembolization and transcatheter arterial chemoembolization for the treatment of unresectable hepatocellular carcinoma.

PURPOSE: To compare the effectiveness and toxicity of transcatheter arterial chemoembolization (chemoembolization) and yttrium-90-labeled microspheres (radioembolization) in patients with unresectable hepatocellular carcinoma (HCC). MATERIALS AND METHODS: Outcomes from patients who underwent radioembolization or chemoembolization as the only treatment for unresectable HCC from 1996 to 2006 were compared. Response was assessed with Response Evaluation Criteria in Solid Tumors, survival was assessed with the Kaplan-Meier method, and toxicity was graded with National Cancer Institute criteria. Multivariate analysis for factors affecting survival was performed. RESULTS: Seventy-one patients were treated with either chemoembolization (n = 44, 62%) or radioembolization (n = 27, 38%). Treatment groups were similar in age, sex, Child class, Model for End-Stage Liver Disease score, tumor size, and vascular invasion. Progressive disease at 3 months was observed in 16 (36%) of the 44 patients treated with chemoembolization and nine (33%) of the 27 patients treated with radioembolization (P = not statistically significant). The median overall survival was similar for both groups (6 months with chemoembolization vs 6 months with radioembolization, P= .7). Grade 3 or higher toxicity was observed in 24 of the 71 patients (34%). Tumor multifocality, vascular invasion, and hepatitis C seropositivity were independently associated with worse survival, whereas method of treatment was not. CONCLUSIONS: In this single-center study, preliminary evidence suggests that chemoembolization and radioembolization provided similar effectiveness and toxicity in patients with unresectable HCC.