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1.  Phase II Trial of Erlotinib and Docetaxel in Advanced and Refractory Hepatocellular and Biliary Cancers: Hoosier Oncology Group GI06-101 
The Oncologist  2012;17(1):13.
Background
Patients with advanced hepatocellular (HCC) and biliary tract carcinomas (BTC) have poor prognosis. While the EGFR pathway is overactive in HCC and BTC, single agent anti-EGFR therapies confer modest activity. Preclinical data showed synergistic antiproliferative and proapoptotic effects between anti-EGFR therapies and taxanes. We conducted a phase I study of erlotinib and docetaxel in solid tumors, and noted good tolerability and sustained complete (5 years +) and partial responses in patients with HCC and BTC. This trial evaluated the efficacy of erlotinib with docetaxel in refractory hepatobiliary cancers.
Methods
Eligible patients were allowed to have two prior systemic therapies. Docetaxel 30 mg/m2 i.v. was administered on days 1, 8, 15, and erlotinib 150 mg was dosed orally on days 2–7, 9–14, 16–28 of each 28-day cycle. The primary endpoint was 16 weeks progression-free survival (PFS), and secondary endpoints included response, stable disease, and overall survival. Tumor samples were analyzed for KRAS gene mutations and E-cadherin expression by immunohistochemistry (IHC). Patients with BTC and HCC were accrued and assessed in separate strata for the efficacy endpoints, but for the two-stage initial design of the study, combined PFS was considered. A Simon optimal two-stage design tested the hypothesis that the 16-week PFS is ≤ 15% (clinically inactive) versus the alternative of ≥ 30% (warranting further study).
Results
Twenty-five patients, 14 with HCC and 11 with BTC, were enrolled. Common toxicities were rash (76%), diarrhea (56%), and fatigue (52%), mostly grade 1 or 2. No objective responses were seen. Seven BTC (64%) and 6 HCC patients (46%) had stable disease as best response, with a median duration of 16.1 weeks (95% CI 3.7–56.3) for BTC, and 17.6 weeks (95% CI 8.1–49.8) for HCC. The 16-week PFS was 64% for BTC (95% CI 29.7–84.5), and 38% for HCC (95% CI 14.1–62.8). Median overall survival was 5.7 and 6.7 months for BTC and HCC patients, respectively. BTC patients with grade ≥ 2 rash had higher median PFS (6.2 vs 2.2 months) and OS (14.2 vs 4.2 months). HCC patients with negative/low E-cadherin expression had higher median PFS (6.7 vs 2.1 months) and OS (14.5 vs 4 months).
Conclusion
Erlotinib with docetaxel met the 16-week PFS ≥ 30% endpoint, but overall survival was comparable to that seen with single-agent erlotinib. With the limitation of small numbers of patients, grade ≥ 2 rash (in BTC), and negative/low E-cadherin expression (HCC) were associated with higher PFS and OS.
Discussion
Refractory biliary tract and hepatocellular cancers are difficult to treat, and no chemotherapy or biologically targeted therapies have impacted survival. Based on preclinical synergism and prior phase I data, we conducted a multi-institutional study sequentially combining the EGFR-targeted agent erlotinib with docetaxel.
Results from this study show that the primary endpoint, 16-week PFS of ≥ 30%, was met for the combined group of BTC and HCC patients (as originally planned in the study design), as well as in each disease category: 63.6% for BTC and 38.5% for HCC patients. Nevertheless, no patients attained an objective response and the median survival of 5.7 months for BTC, and 6.7 months for HCC patients (while heavily pretreated), is comparable to that seen with single-agent EGFR-targeted therapies. Safety analysis shows that this regimen was generally well tolerated, and most adverse events were grade 1 or 2. Few patients had reversible grade 3 transaminase elevation (8%), and severe anorexia, fatigue, and rash were uncommon. As expected, patients with grade ≥ 2 rash experienced higher PFS and OS, but this was noted only among the BTC group, likely because too few HCC patients had grade ≥ 2 rash.
KRAS is an important predictive marker for anti-EGFR therapies for lung and colorectal cancers, but for HCC or the heterogeneous group of BTC (with 10–50% KRAS mutations) no significant correlations have been established. We were not able to identify a correlation between KRAS and benefit from erlotinib-based therapy, as all but one HCC patient had KRAS wild type gene status. Preclinical data in multiple tumor types showed that E-cadherin, a signature marker for an “epithelial” tumor phenotype when overexpressed, predicts EGFR pathway activation and determines sensitivity to EGFR-targeted agents. E-cadherin is often seen as a poor prognostic marker when downregulated, as noted during cancer progression. Not all studies demonstrate beneficial effects from E-cadherin overexpression, possibly due to histological expression variability or tumor type specificity for this biomarker. Six BTC and 8 HCC patients had evaluable tumor samples for E-cadherin analysis. While the numbers were small and conclusions should be viewed with caution, negative/low E-cadherin expression was associated with improved PFS and OS for hepatobiliary cancers (most significant in HCC) in this refractory patient population where we expected lower expression levels.
In conclusion, the combination of erlotinib with docetaxel provided a 16-week PFS of ≥ 30% but showed no appreciable differences in overall survival from historical data with single-agent erlotinib. While EGFR represents an important target in this group of malignancies, it is clear that hepatobiliary cancers are heterogeneous, thus a meaningful improvement in survival most likely will require careful treatment selection based on patient tumor's molecular and genetic profiling.
doi:10.1634/theoncologist.2011-0253
PMCID: PMC3267812  PMID: 22210086
2.  A phase I study of an agonist CD40 monoclonal antibody (CP-870,893) in combination with gemcitabine in patients with advanced pancreatic ductal adenocarcinoma 
Purpose
This phase I study investigated the maximum-tolerated dose (MTD), safety, pharmacodynamics, immunological correlatives, and anti-tumor activity of CP-870,893, an agonist CD40 antibody, when administered in combination with gemcitabine in patients with advanced pancreatic ductal adenocarcinoma (PDA).
Experimental Design
Twenty-two patients with chemotherapy-naïve advanced PDA were treated with 1000 mg/m2 gemcitabine once weekly for 3 weeks with infusion of CP-870,893 at 0.1 mg/kg or 0.2 mg/kg on day 3 of each 28 day cycle.
Results
CP-870,893 was well-tolerated; one dose-limiting toxicity (grade 4 cerebrovascular accident) occurred at the 0.2 mg/kg dose level, which was estimated as MTD. The most common adverse event was cytokine release syndrome (grade 1 to 2). CP-870,893 infusion triggered immune activation marked by an increase in inflammatory cytokines, an increase in B cell expression of co-stimulatory molecules, and a transient depletion of B cells. Four patients achieved a partial response (PR). [18F]-fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT) demonstrated >25% decrease in FDG uptake within primary pancreatic lesions in 6 of 8 patients; however, responses observed in metastatic lesions were heterogeneous with some lesions responding with complete loss of FDG uptake while other lesions in the same patient failed to respond. Improved overall survival correlated with a decrease in FDG uptake in hepatic lesions (R = −0.929; p = 0.007).
Conclusions
CP-870,893 in combination with gemcitabine was well-tolerated and associated with anti-tumor activity in patients with PDA. Changes in FDG uptake detected on PET/CT imaging provide insight into therapeutic benefit. Phase II studies are warranted.
doi:10.1158/1078-0432.CCR-13-1320
PMCID: PMC3834036  PMID: 23983255
Pancreatic cancer; immunotherapy; CD40; CP-870,893; PET imaging; heterogeneity
3.  Combining hedgehog signaling inhibition with focal irradiation on reduction of pancreatic cancer metastasis 
Molecular cancer therapeutics  2013;12(6):1038-1048.
Pancreatic cancer often presents in advanced stages and is unresponsive to conventional treatments. Thus, the need to develop novel treatment strategies for pancreatic cancer has never been greater. Here we report that combination of focal irradiation with hedgehog (Hh) signaling inhibition exerts better than additive effects on reducing metastases. In an orthotopic model, we found that focal irradiation alone effectively reduced primary tumor growth but did not significantly affect metastasis. We hypothesized that cancer stem cells (CSC) of pancreatic cancer are responsible for the residual tumors following irradiation, which may be regulated by Hh signaling. To test our hypothesis, we showed that tumor metastasis in our model was accompanied by increased expression of CSC cell surface markers as well as Hh target genes. We generated tumor spheres from orthotopic pancreatic and metastatic tumors, which have elevated levels of CSC markers relative to the parental cells and elevated expression of Hh target genes. Irradiation of tumor spheres further elevated CSC cell surface markers and increased Hh target gene expression. Combination of Hh signaling inhibition with radiation had more than additive effects on tumor sphere regeneration in vitro. This phenotype was observed in two independent cell lines. In our orthotopic animal model, focal radiation plus Hh inhibition had more than additive effects on reducing lymph node metastasis. We identified several potential molecules in mediating Hh signaling effects. Taken together, our data provide a rationale for combined use of Hh inhibition with irradiation for clinical treatment of pancreatic cancer patients.
doi:10.1158/1535-7163.MCT-12-1030
PMCID: PMC3681871  PMID: 23468532
4.  Contribution of Environment and Genetics to Pancreatic Cancer Susceptibility 
PLoS ONE  2014;9(3):e90052.
Several risk factors have been identified as potential contributors to pancreatic cancer development, including environmental and lifestyle factors, such as smoking, drinking and diet, and medical conditions such as diabetes and pancreatitis, all of which generate oxidative stress and DNA damage. Oxidative stress status can be modified by environmental factors and also by an individual's unique genetic makeup. Here we examined the contribution of environment and genetics to an individual's level of oxidative stress, DNA damage and susceptibility to pancreatic cancer in a pilot study using three groups of subjects: a newly diagnosed pancreatic cancer group, a healthy genetically-unrelated control group living with the case subject, and a healthy genetically-related control group which does not reside with the subject. Oxidative stress and DNA damage was evaluated by measuring total antioxidant capacity, direct and oxidative DNA damage by Comet assay, and malondialdehyde levels. Direct DNA damage was significantly elevated in pancreatic cancer patients (age and sex adjusted mean ± standard error: 1.00±0.05) versus both healthy unrelated and related controls (0.70±0.06, p<0.001 and 0.82±0.07, p = 0.046, respectively). Analysis of 22 selected SNPs in oxidative stress and DNA damage genes revealed that CYP2A6 L160H was associated with pancreatic cancer. In addition, DNA damage was found to be associated with TNFA −308G>A and ERCC4 R415Q polymorphisms. These results suggest that measurement of DNA damage, as well as select SNPs, may provide an important screening tool to identify individuals at risk for development of pancreatic cancer.
doi:10.1371/journal.pone.0090052
PMCID: PMC3961224  PMID: 24651674
5.  Phase 1 dose-escalation, pharmacokinetic, and cerebrospinal fluid distribution study of TAK-285, an investigational inhibitor of EGFR and HER2 
Investigational New Drugs  2013;32(1):160-170.
Summary
Introduction This phase 1 study assessed safety, maximum tolerated dose (MTD), pharmacokinetics, cerebrospinal fluid (CSF) distribution, and preliminary clinical activity of the receptor tyrosine kinase inhibitor TAK-285. Methods Patients with advanced, histologically confirmed solid tumors and Eastern Cooperative Oncology Group performance status ≤2 received daily oral TAK-285; daily dose was escalated within defined cohorts until MTD and recommended phase 2 dose (RP2D) were determined. Eleven patients were enrolled into an RP2D cohort. Blood samples were collected from all cohorts; CSF was collected at pharmacokinetic steady-state from RP2D patients. Tumor responses were assessed every 8 weeks per Response Evaluation Criteria in Solid Tumors. Results Fifty-four patients were enrolled (median age 60; range, 35–76 years). The most common diagnoses were cancers of the colon (28 %), breast (17 %), and pancreas (9 %). Escalation cohorts evaluated doses from 50 mg daily to 500 mg twice daily; the MTD/RP2D was 400 mg twice daily. Dose-limiting toxicities included diarrhea, hypokalemia, and fatigue. Drug absorption was fast (median time of maximum concentration was 2–3 h), and mean half-life was 9 h. Steady-state average unbound CSF concentration (geometric mean 1.54 [range, 0.51–4.27] ng/mL; n = 5) at the RP2D was below the 50 % inhibitory concentration (9.3 ng/mL) for inhibition of tyrosine kinase activity in cells expressing recombinant HER2. Best response was stable disease (12 weeks of nonprogression) in 13 patients. Conclusions TAK-285 was generally well tolerated at the RP2D. Distribution in human CSF was confirmed, but the free concentration of the drug was below that associated with biologically relevant target inhibition.
doi:10.1007/s10637-013-9988-x
PMCID: PMC3913854  PMID: 23817974
Breast cancer; Brain metastases; EGFR; HER2; Pharmacokinetics
6.  A Phase I Study of Sunitinib Plus Capecitabine in Patients With Advanced Solid Tumors 
Journal of Clinical Oncology  2010;28(29):4513-4520.
Purpose
This open-label, phase I, dose-escalation study assessed the maximum-tolerated dose (MTD), safety, pharmacokinetics, and antitumor activity of sunitinib in combination with capecitabine in patients with advanced solid tumors.
Patients and Methods
Sunitinib (25, 37.5, or 50 mg) was administered orally once daily on three dosing schedules: 4 weeks on treatment, 2 weeks off treatment (Schedule 4/2); 2 weeks on treatment, 1 week off treatment (Schedule 2/1); and continuous daily dosing (CDD schedule). Capecitabine (825, 1,000, or 1,250 mg/m2) was administered orally twice daily on days 1 to 14 every 3 weeks for all patients. Sunitinib and capecitabine doses were escalated in serial patient cohorts.
Results
Seventy-three patients were treated. Grade 3 adverse events included abdominal pain, mucosal inflammation, fatigue, neutropenia, and hand-foot syndrome. The MTD for Schedule 4/2 and the CDD schedule was sunitinib 37.5 mg/d plus capecitabine 1,000 mg/m2 twice per day; the MTD for Schedule 2/1 was sunitinib 50 mg/d plus capecitabine 1,000 mg/m2 twice per day. There were no clinically significant pharmacokinetic drug-drug interactions. Nine partial responses were confirmed in patients with pancreatic cancer (n = 3) and breast, thyroid, neuroendocrine, bladder, and colorectal cancer, and cholangiocarcinoma (each n = 1).
Conclusion
The combination of sunitinib and capecitabine resulted in an acceptable safety profile in patients with advanced solid tumors. Further evaluation of sunitinib in combination with capecitabine may be undertaken using the MTD for any of the three treatment schedules.
doi:10.1200/JCO.2009.26.9696
PMCID: PMC2988641  PMID: 20837944
7.  Role of fatty acid synthase in gemcitabine and radiation resistance of pancreatic cancers 
Human fatty acid synthase (FASN) is a homo-dimeric protein with multi-enzymatic activity responsible for the synthesis of palmitate. FASN expression has been found to be up-regulated in multiple types of human cancers and its expression correlates with poor prognosis possibly by causing treatment resistance. In this study, we tested if FASN expression is up-regulated in human pancreatic cancers and if its higher expression level in pancreatic cancers causes intrinsic resistance to gemcitabine and radiation. We found that FASN expression is significantly up-regulated in human pancreatic cancer tissues without any correlation to age, sex, race, and tumor stage. Knocking down or over-expressing FASN significantly down- or up-regulate resistance of pancreatic cancer cell lines to both gemcitabine and radiation treatments. These findings imply that the elevated FASN expression in pancreatic cancers may contribute to unsuccessful treatments of pancreatic cancers by causing intrinsic resistance to both chemotherapy and radiation therapy.
PMCID: PMC3039422  PMID: 21331354
Human fatty acid synthase (FASN); palmitate; gemcitabine; radiation treatments; treatment resistance; pancreatic cancers
8.  Phase I Pharmacologic and Biologic Study of Ramucirumab (IMC-1121B), a Fully Human Immunoglobulin G1 Monoclonal Antibody Targeting the Vascular Endothelial Growth Factor Receptor-2 
Journal of Clinical Oncology  2010;28(5):780-787.
Purpose
To evaluate the safety, maximum-tolerated dose (MTD), pharmacokinetics (PKs), pharmacodynamics, and preliminary anticancer activity of ramucirumab (IMC-1121B), a fully human immunoglobulin G1 monoclonal antibody targeting the vascular endothelial growth factor receptor (VEGFR)-2.
Patients and Methods
Patients with advanced solid malignancies were treated once weekly with escalating doses of ramucirumab. Blood was sampled for PK studies throughout treatment. The effects of ramucirumab on circulating vascular endothelial growth factor-A (VEGF-A), soluble VEGFR-1 and VEGFR-2, tumor perfusion, and vascularity using dynamic contrast-enhanced magnetic resonance imaging were assessed.
Results
Thirty-seven patients were treated with 2 to 16 mg/kg of ramucirumab. After one patient each developed dose-limiting hypertension and deep venous thrombosis at 16 mg/kg, the next lower dose (13 mg/kg) was considered the MTD. Nausea, vomiting, headache, fatigue, and proteinuria were also noted. Four (15%) of 27 patients with measurable disease had a partial response (PR), and 11 (30%) of 37 patients had either a PR or stable disease lasting at least 6 months. PKs were characterized by dose-dependent elimination and nonlinear exposure consistent with saturable clearance. Mean trough concentrations exceeded biologically relevant target levels throughout treatment at all dose levels. Serum VEGF-A increased 1.5 to 3.5 times above pretreatment values and remained in this range throughout treatment at all dose levels. Tumor perfusion and vascularity decreased in 69% of evaluable patients.
Conclusion
Objective antitumor activity and antiangiogenic effects were observed over a wide range of dose levels, suggesting that ramucirumab may have a favorable therapeutic index in treating malignancies amenable to VEGFR-2 inhibition.
doi:10.1200/JCO.2009.23.7537
PMCID: PMC2834394  PMID: 20048182
9.  Role of fatty acid synthase in gemcitabine and radiation resistance of pancreatic cancers 
Human fatty acid synthase (FASN) is a homo-dimeric protein with multi-enzymatic activity responsible for the synthesis of palmitate. FASN expression has been found to be up-regulated in multiple types of human cancers and its expression correlates with poor prognosis possibly by causing treatment resistance. In this study, we tested if FASN expression is up-regulated in human pancreatic cancers and if its higher expression level in pancreatic cancers causes intrinsic resistance to gemcitabine and radiation. We found that FASN expression is significantly up-regulated in human pancreatic cancer tissues without any correlation to age, sex, race, and tumor stage. Knocking down or over-expressing FASN significantly down- or up-regulate resistance of pancreatic cancer cell lines to both gemcitabine and radiation treatments. These findings imply that the elevated FASN expression in pancreatic cancers may contribute to unsuccessful treatments of pancreatic cancers by causing intrinsic resistance to both chemotherapy and radiation therapy.
PMCID: PMC3039422  PMID: 21331354
Human fatty acid synthase (FASN); palmitate; gemcitabine; radiation treatments; treatment resistance; pancreatic cancers

Results 1-9 (9)