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1.  Patients with pancreatic adenocarcinoma exhibit elevated levels of myeloid-derived suppressor cells upon progression of disease 
Elevated levels of myeloid-derived suppressor cells (MDSCs) induced by tumor-derived factors are associated with inhibition of immune responses in patients with gastrointestinal malignancies. We hypothesized that pro-MDSC cytokines and levels of MDSC in the peripheral blood would be elevated in pancreatic adenocarcinoma patients with progressive disease. Peripheral blood mononuclear cells (PBMCs) were isolated from 16 pancreatic cancer patients undergoing chemotherapy and phenotyped for MDSC using a five antigen panel (CD33, HLA-DR, CD11b, CD14, CD15). Patients with stable disease had significantly lower MDSC levels in the peripheral blood than those with progressive disease (1.41 ± 1.12 vs. 5.14 ± 4.58 %, p = 0.013, Wilcoxon test). A cutoff of 2.5 % MDSC identified patients with progressive disease. Patients with ECOG performance status ≥2 had a weaker association with increased levels of MDSC. Plasma was obtained from 15 chemonaive patients, 13 patients undergoing chemotherapy and 9 normal donors. Increases in the levels of pro-MDSC cytokines were observed for pancreatic cancer patients versus controls, and the pro-MDSC cytokine IL-6 was increased in those patients undergoing chemotherapy. This study suggests that MDSC in peripheral blood may be a predictive biomarker of chemotherapy failure in pancreatic cancer patients.
PMCID: PMC4504424  PMID: 25305035
MDSC; Pancreas cancer; Cytokines; Progression
2.  Baseline Serum Albumin Is a Predictive Biomarker for Patients With Advanced Pancreatic Cancer Treated With Bevacizumab 
Cancer  2014;120(12):1780-1786.
Phase 3 studies of bevacizumab in patients with advanced pancreatic cancer (APCA) demonstrated no improvement in outcome. To the authors’ knowledge, no validated predictive biomarkers for bevacizumab exist, although emerging data suggest that subsets of patients with APCA may benefit from treatment with bevacizumab. The authors evaluated baseline serum albumin (b-alb) as a predictive biomarker in a pooled analysis from 7 prospective clinical trials of gemcitabine-based therapy with or without bevacizumab.
Data were collected from individual databases from 7 prospective clinical trials. Patients were grouped by exposure to bevacizumab and by b-alb level (≥ 3.4 g/L or < 3.4 g/dL). Overall survival (OS), time to disease progression (TTP), overall response rate, and disease control rate (overall response rate plus stable disease lasting ≥ 16 weeks) were compared between groups. Univariate and multivariable analyses of prognostic factors were performed.
A total of 264 patients were included. The median age was 59 years (range, 31 years-85 years) and all patients had stage IV disease per TNM staging. Normal b-alb was associated with significantly improved median OS (10.2 months vs 4.1 months; P =.0001), median TTP (6.2 months vs 3.7 months; P = 0.0488), and disease control rate (71% vs 46%; P =.007) for patients receiving bevacizumab, but not for those treated without bevacizumab. Multivariable analysis revealed a significant influence of normal b-alb on OS (P =.0008) and TTP (P =.033).
Patients with APCA with normal b-alb derive benefit from treatment with bevacizumab. Future prospective investigations of bevacizumab in patients with APCA should consider selecting patients with normal b-alb to maximize potential benefit.
PMCID: PMC4265390  PMID: 24633933
pancreatic cancer; albumin; bevacizumab; predictive biomarker
3.  Caveolin-1 is Associated with Tumor Progression and Confers a Multi-Modality Resistance Phenotype in Pancreatic Cancer 
Scientific Reports  2015;5:10867.
Caveolin-1 (Cav-1) is a 21 kDa protein enriched in caveolae, and has been implicated in oncogenic cell transformation, tumorigenesis, and metastasis. We explored roles for Cav-1 in pancreatic cancer (PC) prognostication, tumor progression, resistance to therapy, and whether targeted downregulation could lead to therapeutic sensitization. Cav-1 expression was assessed in cell lines, mouse models, and patient samples, and knocked down in order to compare changes in proliferation, invasion, migration, response to chemotherapy and radiation, and tumor growth. We found Cav-1 is overexpressed in human PC cell lines, mouse models, and human pancreatic tumors, and is associated with worse tumor grade and clinical outcomes. In PC cell lines, disruption/depletion of caveolae/Cav-1 reduces proliferation, colony formation, and invasion. Radiation and chemotherapy up-regulate Cav-1 expression, while Cav-1 depletion induces both chemosensitization and radiosensitization through altered apoptotic and DNA repair signaling. In vivo, Cav-1 depletion significantly attenuates tumor initiation and growth. Finally, Cav-1 depletion leads to altered JAK/STAT, JNK, and Src signaling in PC cells. Together, higher Cav-1 expression is correlated with worse outcomes, is essential for tumor growth and invasion (both in vitro and in vivo), is responsible for promoting resistance to therapies, and may serve as a prognostic/predictive biomarker and target in PC.
PMCID: PMC4464260  PMID: 26065715
4.  A phase II study of biweekly pralatrexate and docetaxel in patients with advanced esophageal and gastroesophageal carcinoma that have failed first-line platinum-based therapy 
The appropriate second-line therapy for patients with advanced gastroesophageal (GE) or esophageal (E) cancer after failure of first-line platinum-based therapy is unclear. Pralatrexate and docetaxel have independently been shown to have efficacy in the treatment of these cancers. Thus, we performed a clinical trial examining the efficacy of the combination of these agents in the treatment of GE and E cancer.
A Fleming phase II design with a single stage of 32 patients was planned. Pralatrexate 120 mg/m2 and docetaxel 35 mg/m2 were administered on day 1 of 14-day cycles. The primary end-point was to evaluate the overall response rate by Response Evaluation Criteria in Solid Tumors (RECIST) criteria, and secondary end-points were to evaluate for progression-free survival (PFS) and overall survival (OS).
The study was halted prematurely due to loss of funding after the accrual of six patients. Two patients had stable disease (SD) and four patients had disease progression per RECIST. When applying PERCIST criteria in four evaluable patients, two had a partial response (PR) and two had SD. Median PFS was 1.9 months (95% CI, 0.8-7.2) and median OS was 5.5 (0.8-11.7) months.
Pralatrexate and docetaxel as therapy in refractory esophageal and GE adenocarcinoma did not demonstrate meaningful preliminary activity. PERCIST may prove to better assess the meaningfulness of anatomic SD.
PMCID: PMC4397239  PMID: 26029462
Pralatrexate; docetaxel; gastrointestinal neoplasms; esophageal (E) cancer
5.  Should combination chemotherapy serve as the backbone in clinical trials of advanced pancreatic cancer?: A pooled analysis of phase II trials of gemcitabine-containing doublets plus bevacizumab 
Pancreas  2014;43(3):343-349.
To evaluate whether building upon multidrug chemotherapy regimens represents a viable strategy in pancreatic cancer clinical trial design.
We performed a pooled analysis of all single-arm phase II studies in which a specific targeted agent (the anti-VEGF monoclonal antibody bevacizumab) was added to gemcitabine-based cytotoxic doublets. The primary endpoint was overall survival (OS). Secondary endpoints included objective response rate, CA19-9 biomarker response rate, and adverse event frequencies. Kaplan-Meier methods estimated time-to-event endpoints, while the Cox proportional hazard model estimated univariate hazard ratios (HRs) of death.
For the 300 patients included in the pooled analysis, median OS was 9.1 months (95% CI 8.3 – 10.2). Differences in OS were observed according to patients’ baseline performance status (median OS 10.4 vs. 8.6 months for ECOG 0 vs. 1, respectively). Moreover, bevacizumab-related adverse events were not observed at increased frequency with gemcitabine-based doublets compared to historic data.
Recognizing the limitations of cross-study comparisons, these results compare favorably to those from CALGB 80303, a phase III trial testing bevacizumab in combination with gemcitabine alone. This is the largest dataset available to demonstrate the feasibility of building upon more intensive chemotherapy backbones in clinical trials of novel targeted agents in pancreatic cancer.
PMCID: PMC3955845  PMID: 24622062
pancreatic cancer; gemcitabine; clinical trial design; pooled analysis
6.  Neoadjuvant Modified (m) FOLFIRINOX for Locally Advanced Unresectable (LAPC) and Borderline Resectable (BRPC) Adenocarcinoma of the Pancreas 
Annals of surgical oncology  2014;22(4):1153-1159.
For patients with metastatic pancreatic cancer, FOLFIRINOX (fluorouracil [5-FU], leucovorin [LV], irinotecan [IRI], and oxaliplatin) has shown improved survival rates compared with gemcitabine but with significant toxicity, particularly in patients with a high tumor burden. Because of reported response rates exceeding 30 %, the authors began to use a modified (m) FOLFIRINOX regimen for patients with advanced nonmetastatic disease aimed at downstaging for resection. This report describes their experience with mFOLFIRINOX and aggressive surgical resection.
Between January 2011 and August of 2013, 43 patients with borderline resectable pancreatic cancer (BRPC, n = 18) or locally advanced pancreatic cancer (LAPC, n = 25) were treated with mFOLFIRINOX (no bolus 5-FU, no LV, and decreased IRI). Radiation was used based on response and intended surgery. Charts were retrospectively reviewed to assess response, toxicities, and extent of resection when possible.
The most common grade 3/4 toxicity was diarrhea in six patients (14 %) with no grade 3/4 neutropenia or thrombocytopenia. Resection was attempted in 31 cases (72 %) and accomplished in 22 cases (51.1 %) including 11 of 25 LAPC cases (44 %). Vascular resection was required in 4 cases (18 %), with R0 resection in 86.4 %of the resections. Complications occurred in 6 cases (27 %), with no perioperative deaths. The median progression-free survival period was 18 months if the resection was achieved compared with 8 months if no resection was performed (p < 0.001).
Neoadjuvant mFOLFIRINOX is an effective, well-tolerated regimen for patients with advanced nonmetastatic pancreatic cancer. When mFOLFIRINOX is coupled with aggressive surgery, high resection rates are possible even when the initial imaging shows locally advanced disease. Although data are still maturing, resection appears to offer at least a progression-free survival advantage.
PMCID: PMC4373613  PMID: 25358667
7.  Peptide Vaccines and Peptidomimetics of EGFR (HER-1) Ligand Binding Domain Inhibit Cancer Cell Growth In Vitro and In Vivo 
Epidermal growth factor receptor (EGFR) is a validated target for several cancers including lung, colorectal, and certain subtypes of breast cancer. Cetuximab targets ligand binding of EGFR, but major problems like high cost, short t1/2, toxicity, and emergence of resistance are associated with the drug. Immunization with EGFR B cell epitopes will train the immune system to produce specific Abs that can kill cancer cells. Also, therapy with stable, less-expensive, and nontoxic EGFR peptide mimics will block EGFR signaling and inhibit cancer growth. We designed three peptides based on the contact sites between EGF and EGFR. The B cell epitopes were synthesized alone and also linked with the measles virus T cell epitope to produce a chimeric peptide vaccine. The peptide vaccines were immunogenic in both mice and rabbits and Abs raised against the vaccine specifically bound EGFR-expressing cells and recombinant human EGFR protein. The peptide mimics and the anti-peptide Abs were able to inhibit EGFR signaling pathways. Immunization with the peptide vaccine or treatment with the B cell epitopes significantly reduced tumor growth in both transplantable breast and lung cancer models. Immunohistochemical analysis also showed significant reductions in microvascular density and actively dividing cells in the tumor sections after treatment in the FVB/n breast cancer model. The 418–435 B cell epitope was the best candidate both as a vaccine or peptide mimic because it caused significant inhibition in the two mouse models. Our results show that this novel EGFR B cell epitope has great potential to be used as a vaccine or treatment option for EGFR-expressing cancers.
PMCID: PMC4324564  PMID: 23698748
8.  Carbohydrate Antigen 19-9 Is a Prognostic and Predictive Biomarker in Patients With Advanced Pancreatic Cancer Who Receive Gemcitabine-Containing Chemotherapy 
Cancer  2012;119(2):285-292.
Carbohydrate antigen 19-9 (CA19-9) is a widely used biomarker in pancreatic cancer. There is no consensus on the interpretation of the change in CA19-9 serum levels and its role in the clinical management of patients with pancreatic cancer.
Individual patient data from 6 prospective trials evaluating gemcitabine-containing regimens from 3 different institutions were pooled. CA19-9 values were obtained at baseline and after successive cycles of treatment. The objective of this study was to correlate a decline in CA19-9 with outcomes while undergoing treatment.
A total of 212 patients with locally advanced (n = 50) or metastatic (n = 162) adenocarcinoma of the pancreas were included. Median baseline CA19-9 level was 1077 ng/mL (range, 15–492,241 ng/mL). Groups were divided into those levels below (low) or above (high) the median. Median overall survival (mOS) was 8.7 versus 5.2 months (P = .0018) and median time to progression (mTTP) was 5.8 versus 3.7 months (P = .082) in the low versus high groups, respectively. After 2 cycles of chemotherapy, up to a 5% increase versus ≥ 5% increase in CA19-9 levels conferred an improved mOS (10.3 vs 5.1 months, P = .0022) and mTTP (7.5 vs 3.5 months, P = 0.0005).
In patients who have advanced pancreatic cancer treated with gemcitabine-containing regimens baseline CA19-9 is prognostic for outcome. A decline in CA19-9 after the second cycle of chemotherapy is not predictive of improved mOS or mTTP; thus, CA19-9 decline is not a useful surrogate endpoint in clinical trials. Clinically, a ≥ 5% rise in CA19-9 after 2 cycles of chemotherapy serves as a negative predictive marker.
PMCID: PMC4261189  PMID: 22786786
pancreatic; gemcitabine; carbohydrate antigen 19-9; outcomes; predictive; prognostic
9.  A phase I dose escalation study of a pharmacobiologically based scheduling of capecitabine and mitomycin C in patients with gastrointestinal malignancies 
Mitomycin C (MMC) produces significant upregulation of thymidine phosphorylase, a principal determinant of the therapeutic index of capecitabine-based treatment, starting 4–6 days after treatment. On the basis of the time-dependency of this upregulation, we performed a phase I dose escalation study of capecitabine and MMC in patients with gastrointestinal malignancies.
A total of 29 patients with advanced gastrointestinal malignancies received MMC at 6 mg/m2 on day 1 and capecitabine escalated in four successive patient cohorts of doses 500–1,000 mg/m2/day twice daily on days 8–21, every 28 days. MMC was capped at 36 mg/m2.
A total of 29 patients were enrolled and 90% had at least one prior treatment in the metastatic setting. There was one DLT, grade 3 hand and foot syndrome, at dose level four. The most common toxicity was fatigue (61%). No patients experienced grade 4 toxicities. Nine patients experienced prolonged stability of disease.
Capecitabine in combination with MMC in the proposed schedule is well-tolerated with evidence of preliminary activity. The recommended dose for phase II studies are MMC at 6 mg/m2 on day 1 of a 28-day cycle with the dose capped at 36 mg/m2, in combination with capecitabine at 1,000 mg/m2 twice daily on days 8–21.
PMCID: PMC4261191  PMID: 19657639
Capecitabine; Mitomycin C; Gastrointestinal malignancies
10.  Fractionated Radioimmunotherapy With 90Y-Clivatuzumab Tetraxetan and Low-Dose Gemcitabine Is Active in Advanced Pancreatic Cancer 
Cancer  2012;118(22):5497-5506.
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 (90Y-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.
Thirty-eight previously untreated patients (33 patients with stage IV disease and 5 patients with stage III disease) received gemcitabine 200 mg/m2 weekly for 4 weeks with 90Y-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 90Y doses of 6.5 mCi/m2, 9.0 mCi/m2, 12.0 mCi/m2, and 15.0 mCi/m2. In the second portion, 19 additional patients received weekly doses of 9.0 mCi/m2 or 12.0 mCi/m2.
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 90Y-hPAM4 was 12.0 mCi/m2 weekly for 3 weeks for cycle 1, with ≤9.0 mCi/m2 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.
Fractionated radioimmunotherapy with 90Y-hPAM4 and low-dose gemcitabine demonstrated promising therapeutic activity and manageable myelosuppression in patients with advanced pancreatic ductal carcinoma.
PMCID: PMC4215160  PMID: 22569804
combination therapy; gemcitabine; ductal pancreatic cancer; radioimmunotherapy; clivatuzumab tetraxetan; 90Y
11.  A Multi-Institutional Phase II Study of Neoadjuvant Gemcitabine and Oxaliplatin with Radiation Therapy in Patients with Pancreatic Cancer 
Cancer  2013;119(15):2692-2700.
The purpose of this study was to evaluate preoperative treatment with full-dose gemcitabine, oxaliplatin and radiation (RT) in localized pancreatic cancer.
Eligibility included confirmation of adenocarcinoma, resectable or borderline resectable disease, PS≤2, and adequate organ function. Treatment consisted of two, 28 day cycles of gemcitabine (1g/m2 over 30 minutes days 1, 8, 15) and oxaliplatin (85mg/m2 days 1, 15) with RT during cycle 1 (30Gy in 2Gy fractions). Patients were evaluated for surgery following cycle 2. Resected patients received 2 cycles of adjuvant chemotherapy.
Sixty-eight evaluable patients were treated at 4 centers. By central radiology review, 23 patients were resectable, 39 borderline resectable, and 6 unresectable. Sixty-six patients (97%) completed cycle 1/RT and 61 patients (90%) cycle 2. Adverse events ≥ grade 3 during preoperative therapy included neutropenia (32%), thrombocytopenia (25%), and biliary obstruction/cholangitis (14%). Forty-three patients were resected (63%) with R0 resection in 36 (84%). Median overall survival for all patients was 18.2 months (95%CI 13–26.9), those resected 27.1 months (95%CI 21.2–47.1) and those not resected 10.9 months (95%CI 6.1–12.6). A decrease in CA19-9 following neoadjuvant therapy was associated with R0 resection (p=0.02) which resulted in a median survival of 34.6 months (95% CI 20.3–47.1). Fourteen patients (21%) are alive and disease-free at a median follow-up time of 31.4 months (range, 24–47.6).
Preoperative therapy with full dose gemcitabine, oxaliplatin and RT was feasible and resulted in a high percentage of R0 resections. Results are particularly encouraging given a majority of patients with borderline resectable disease.
PMCID: PMC4174603  PMID: 23720019
pancreatic cancer; neoadjuvant; gemcitabine; oxaliplatin
12.  The Addition of Radiation to Chemotherapy does not Improve Outcome When Compared to Chemotherapy in the Treatment of Resected Pancreas Cancer: The Results of a Single-Institution Experience 
Annals of surgical oncology  2013;21(3):862-867.
Pancreas cancer is highly lethal even at early stages. Adjuvant therapy with chemotherapy (CT) or chemoradiation (CRT) is standard following surgery to delay recurrence and improve survival. There is no consensus on the added value of radiotherapy (RT). We conducted a retrospective analysis of clinical outcomes in pancreas cancer patients treated with CT or CRT following surgery.
Patients with resected pancreas adenocarcinoma were identified in our institutional database. Relevant clinicopathologic and demographic data were collected. Patients were grouped according to adjuvant treatment: group A: no treatment; group B: CT; group C: CRT. The primary endpoint of overall survival was compared between groups B vs. C. Univariate and multivariate analyses of potential prognostic factors were conducted including all patients.
A total of 146 evaluable patients were included (group A: n = 33; group B: n = 45; group C: n = 68). Demographics and pathologic characteristics were comparable. There was no significant survival benefit for CRT compared with CT (mOS 16.8 months vs. 21.5 months, respectively, p = 0.76). Local recurrence rates were similar in all three groups. Univariate analyses identified absence of lymph node involvement (hazards ratio [HR] 1.43, p = 0.0082) and administration of adjuvant therapy (HR 0.496, p = 0.0008) as significant predictors for improved survival. Multivariate analyses suggested that patients without nodal involvement derived the most benefit from adjuvant treatment.
The addition of RT to CT did not improve survival over CT. Lymph node involvement predicts inferior clinical outcome.
PMCID: PMC4041711  PMID: 24046122
13.  A phase I study of prolonged infusion of triapine in combination with fixed dose rate gemcitabine in patients with advanced solid tumors 
Investigational new drugs  2012;31(3):685-695.
Prolonged exposure of cancer cells to triapine, an inhibitor of ribonucleotide reductase, followed by gemcitabine enhances gemcitabine activity in vitro. Fixed-dose-rate gemcitabine (FDR-G) has improved efficacy compared to standard-dose. We conducted a phase I trial to determine the maximum tolerated dose (MTD), safety, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary efficacy of prolonged triapine infusion followed by FDR-G.
Experimental Design
Triapine was given as a 24-hour infusion, immediately followed by FDR-G (1000 mg/m2 over 100-minute). Initially, this combination was administered days 1 and 8 of a 21-day cycle (Arm A, triapine starting dose 120 mg); but because of myelosuppression, it was changed to days 1 and 15 of a 28-day cycle (Arm B, starting dose of triapine 75 mg). Triapine steady-state concentrations (Css) and circulating ribonucleotide reductase M2-subunit (RRM2) were measured.
Thirty-six patients were enrolled. The MTD was determined to be triapine 90 mg (24-hour infusion) immediately followed by gemcitabine 1000 mg/m2 (100-minute infusion), every 2 weeks of a 4-week cycle. DLTs included grade 4 thrombocytopenia, leukopenia and neutropenia. The treatment was well tolerated with fatigue, nausea/vomiting, fever, transaminitis, and cytopenias being the most common toxicities. Among 30 evaluable patients, 1 had a partial response and 15 had stable disease. Triapine PK was similar, although more variable, compared to previous studies using doses normalized to body-surface-area. Steady decline in circulating levels of RRM2 may correlate with outcome.
This combination was well tolerated and showed evidence of preliminary activity in this heavily pretreated patient population, including prior gemcitabine failure.
PMCID: PMC3646991  PMID: 22847785
Triapine; Gemcitabine; Phase I; Clinical Trial
14.  Pancreatic Cancer-Associated Stellate Cells Promote Differentiation of Myeloid-Derived Suppressor Cells in a STAT3-Dependent Manner 
Cancer research  2013;73(10):3007-3018.
Pancreatic stellate cells (PSC) are a subset of pancreatic cancer-associated fibroblasts. These cells provide prosurvival signals to tumors; however, little is known regarding their interactions with immune cells within the tumor microenvironment. We hypothesized that factors produced by human PSC could enhance myeloid-derived suppressor cell (MDSC) differentiation and function, which promotes an immunosuppressive microenvironment. Primary PSC cell lines (n = 7) were generated from human specimens and phenotypically confirmed via expression of vimentin, α-smooth muscle actin (α-SMA), and glial fibrillary acidic protein (GFAP). Luminex analysis indicated that PSC but not human fetal primary pancreatic fibroblast cells (HPF; negative controls) produced MDSC-promoting cytokines [interleukin (IL-6), VEGF, macrophage colony-stimulating factor (M-CSF)] and chemokines (SDF-1, MCP-1). Culture of peripheral blood mononuclear cells [peripheral blood mononuclear cell (PBMC), n = 3 donors] with PSC supernatants or IL-6/granulocyte macrophage colony-stimulating factor (GM-CSF; positive control) for 7 days promoted PBMC differentiation into an MDSC (CD11b+CD33+) phenotype and a subpopulation of polymorphonuclear CD11b+CD33+CD15+ cells. The resulting CD11b+CD33+ cells functionally suppressed autologous T-lymphocyte proliferation. In contrast, supernatants from HPF did not induce an MDSC phenotype in PBMCs. Culture of normal PBMCs with PSC supernatants led to STAT3 but not STAT1 or STAT5 phosphorylation. IL-6 was an important mediator as its neutralization inhibited PSC supernatant-mediated STAT3 phosphorylation and MDSC differentiation. Finally, the FLLL32 STAT3 inhibitor abrogated PSC supernatant-mediated MDSC differentiation, PSC viability, and reduced autocrine IL-6 production indicating these processes are STAT3 dependent. These results identify a novel role for PSC in driving immune escape in pancreatic cancer and extend the evidence that STAT3 acts as a driver of stromal immunosuppression to enhance its interest as a therapeutic target.
PMCID: PMC3785672  PMID: 23514705
15.  FOLFIRINOX in Locally Advanced Pancreas Adenocarcinoma: Back to the Future? 
The Oncologist  2013;18(5):487-489.
PMCID: PMC3662837  PMID: 23704222
16.  A Phase II Study of Modulated-Capecitabine and Docetaxel in Chemonaive Patients with Advanced Non-Small Cell Lung Cancer (NSCLC) 
This phase II single-arm trial of docetaxel and capecitabine in previously untreated non-small cell lung cancer (NSCLC) patients was designed to evaluate response rate of this regimen based on promising efficacy data from phase II testing in pre-treated NSCLC patients. The trial also evaluated the correlation between peripheral blood dihydropyrimidine dehydrogenase (DPD) expression and efficacy/toxicity.
Patients with advanced NSCLC (metastatic, including malignant pleural effusion) without prior chemotherapy were enrolled. Baseline DPD screening was performed; patients with baseline DPD level < 0.07 nmol/min/mg protein were considered ineligible for the study. Treatment included a 28-day cycle of docetaxel 36 mg/m2 days 1, 8, 15 and capecitabine 1250 mg/m2/day in divided doses on days 5–18. Overall response rate (RR) was the primary endpoint with a target RR of 50%. Correlative studies included evaluation of DPD activity levels in peripheral blood and correlation with clinical responses.
Twenty-eight patients received 86 cycles of treatment (median 3 cycles) and were evaluable for response. The RR was 18% (5 patients); RR did not meet the pre-specified efficacy endpoint and the trial was stopped. 14 patients had stable disease (SD - 50%) and 4 pts had SD > 12 weeks. Median time to progression was 3.3 months (95% CI 1.5 – 4.6 months). Median overall survival was 10.5 months (95% CI: 3.2 – 15 months). Main toxicities included fatigue, stomatitis and leukopenia. DPD levels ranged from 0.06 to 0.26 nmol/min/mg. The majority of responders (4/5) had DPD levels ≤ 0.1 nmol/min/mg. Most of the responders (4/5) experienced grade 3 toxicities including leukopenia, dehydration, fatigue, and diarrhea. None of the patients (0/4) with higher DPD levels (>0.2 nmol/min/mg) had a response.
The response rate for the regimen did not demonstrate sufficient activity and further study of this regimen in this setting is not indicated. Interestingly, the results suggest that low DPD expression may be associated with response to capecitabine but also with increased toxicity.
PMCID: PMC3549571  PMID: 23079156
non-small cell lung cancer; dihydropyrimidine deficiency; capecitabine
17.  Treatment Patterns and Clinical Outcomes in Patients With Metastatic Colorectal Cancer Initially Treated with FOLFOX–Bevacizumab or FOLFIRI–Bevacizumab: Results From ARIES, a Bevacizumab Observational Cohort Study 
The Oncologist  2012;17(12):1486-1495.
Results of a first-line analysis of the Avastin® Registry: Investigation of Effectiveness and Safety (ARIES) study, a prospective, community-based observational cohort study assessing the impact of chemotherapy choice and treatment duration on outcomes in patients with metastatic colorectal cancer, are reported.
The Avastin® Registry: Investigation of Effectiveness and Safety (ARIES) study is a prospective, community-based observational cohort study that evaluated the effectiveness and safety of first-line treatment patterns, assessing the impact of chemotherapy choice and treatment duration.
The ARIES study enrolled patients with metastatic colorectal cancer (mCRC) receiving first-line chemotherapy with bevacizumab and followed them longitudinally. The protocol did not specify treatment regimens or assessments. Analyses included all patients who initiated bevacizumab in combination with either first-line oxaliplatin with infusional 5-fluorouracil and leucovorin (FOLFOX) or irinotecan with infusional 5-fluorouracil and leucovorin (FOLFIRI). Progression-free survival (PFS) and overall survival (OS) times were estimated using Kaplan–Meier methods. Hazard ratios (HRs) were estimated with multivariate Cox regression analysis, adjusting for potential confounding factors.
In total, 1,550 patients with first-line mCRC were enrolled (median follow-up, 21 months) and most received FOLFOX–bevacizumab (n = 968) or FOLFIRI–bevacizumab (n = 243) as first-line therapy. The baseline characteristics and median treatment duration were generally similar between subgroups. There were no significant differences in the median PFS (10.3 months vs. 10.2 months) or OS (23.7 months vs. 25.5 months) time between the FOLFOX–bevacizumab and FOLFIRI–bevacizumab subgroups, respectively, by unadjusted analyses. Multivariate analyses showed FOLFIRI–bevacizumab resulted in a similar PFS (HR, 1.03; 95% confidence interval [CI], 0.88–1.21) and OS (HR, 0.95; 95% CI, 0.78–1.16) outcome as with FOLFOX–bevacizumab. The incidence proportions of bevacizumab-associated adverse events were similar for FOLFOX- and FOLFIRI-based therapies.
In first-line mCRC patients, the FOLFOX–bevacizumab and FOLFIRI–bevacizumab regimens were associated with similar treatment patterns and clinical outcomes.
PMCID: PMC3528380  PMID: 23015662
Bevacizumab; FOLFOX protocol; FOLFIRI protocol; Safety; Treatment outcome
18.  Elevated baseline CA19-9 levels correlate with adverse prognosis in patients with early- or advanced-stage pancreas cancer 
Medical oncology (Northwood, London, England)  2012;29(5):10.1007/s12032-012-0278-9.
CA19-9 is the most specific biomarker for pancreas cancer. We investigated the prognostic significance of normal (≤37 U/mL) versus elevated (>37 U/mL) CA19-9 levels in patients with resected and advanced pancreas cancer. Relevant data were obtained from patients treated for early-stage or advanced pancreatic adenocarcinoma at our institution. Log-rank tests were used to evaluate relationship between CA19-9 and clinical outcomes of interest for both early- and advanced-stage patients. A total of 123 patients were included (Group A: N = 30 stage I/II; Group B: N = 93 stage III/IV). In group A, elevated preoperative CA19-9 was significantly associated with lymph node involvement (p = 0.031), tumor ≥3 cm (p = 0.011), and lack of tumor differentiation (p = 0.048). Failure of postoperative CA19-9 to normalize predicted significantly worse DFS (p = 0.021). For group B, elevated baseline CA19-9 was associated with shorter OS on chemotherapy (p = 0.0008) and decline in CA19-9 >25 % with treatment was a significant predictor of improved OS (p = 0.0099). Higher than normal CA19-9 level is an adverse prognostic factor in both early and advanced settings and may prove to be useful in the selection of patients for more aggressive therapy in future trials. CA19-9 level decrease of >25 % predicts improved survival in advanced disease on chemotherapy.
PMCID: PMC3839283  PMID: 22729400
CA19-9; Pancreas cancer; Prognostic; Biomarker
19.  Yttrium-90 Radioembolization as Salvage Therapy for Colorectal Cancer With Liver Metastases 
Clinical colorectal cancer  2012;11(3):10.1016/j.clcc.2011.12.002.
Yttrium-90 (90Y) radioembolization is a treatment option for patients with metastatic colorectal cancer with unresectable liver metastases. We conducted a retrospective analysis to evaluate outcomes in 24 such patients who underwent 90Y radioembolization. We concluded that 90Y radioembolization is reasonable for select patients with unresectable hepatic metastases in the absence of other metastatic sites.
Few patients with metastatic colorectal cancer (mCRC) are candidates for resection of their hepatic disease. Yttrium-90 (90Y) radioembolization has promise in the treatment of unresectable mCRC. We conducted retrospective study to assess the efficacy in patients with refractory mCRC who underwent 90Y radioembolization.
Materials and methods
Patients with unresectable mCRC with liver metastases treated at The Ohio State University were included in this analysis. Demographic data, carcinoembryonic antigen (CEA) values, observed toxicities, and information on prior therapies were collected. Response was assessed by RECIST (Response Evaluation Criteria in Solid Tumors) 1.1 criteria. Overall survival (OS) and progression-free survival (PFS) were estimated by the Kaplan-Meier method.
Twenty-four patients (median age, 63 years) were included. Of the patients, 54% had extrahepatic disease; 67% had bilobar involvement. The patients had received a median of 3 prior therapies. No objective responses were observed. Five patients had a CEA response. Median PFS and OS were 3.9 months (95% CI, 2.4–4.8 months) and 8.9 months (95% CI, 4.2–16.7 months), respectively. Patients older than 65 years had improved PFS (4.6 vs. 2.4 months) and OS (14 vs. 5.5 months) vs. younger patients, likely due to receipt of 90Y treatment earlier in their disease course. The presence of extrahepatic disease and the absence of CEA response appeared negatively predictive of efficacy. Toxicities were expected and manageable.
90Y radioembolization is active in select patients with refractory mCRC and with liver metastases, and is safe and well tolerated in the elderly. In patients with extensive extrahepatic disease, 90Y should be used in combination with chemotherapy. CEA may be a predictor of efficacy.
PMCID: PMC3839284  PMID: 22277350
Hepatic; Locoregional; Colorectal cancer; Y-90; Radioembolization
20.  Influence of KRAS Mutation Status in Metachronous and Synchronous Metastatic Colorectal Adenocarcinoma 
Cancer  2012;118(24):10.1002/cncr.27666.
Mutations in the v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) are present in approximately 30% to 40% of colorectal adenocarcinomas. Wild-type (WT) KRAS mutation status is predictive of tumor response with epidermal growth factor receptor-directed therapies, but the results from studies evaluating the prognostic value of KRAS status in localized disease have been contradictory. The prognostic value of KRAS in metastatic disease, specifically according to whether patients have synchronous or metachronous disease at presentation, is less understood.
One-hundred ten consecutive patients with metastatic colorectal adenocarcinoma underwent testing for KRAS exon 2 mutations by polymerase chain reaction amplification and direct nucleotide sequencing. The clinical characteristics, treatments, and outcomes of these patients were then analyzed retrospectively, stratified according to whether patients presented with synchronous or metachronous metastasis and according to KRAS mutation status (WT or mutated).
For the entire cohort, the median overall survival from the date of diagnosis of metastatic disease was 34.3 months (95% confidence interval, 28.3–49.4 months) for patients with WT KRAS (n = 70). The median overall survival for patients with mutated KRAS (n = 40) was 40.3 months (95% confidence interval, 27.9–51.1 months; log-rank P = .91). Kaplan-Meier survival analysis indicated that 3-year overall survival and 5-year overall survival were not statistically different. Within the subgroups of patients with synchronous and metachronous metastatic disease, no significant differences were observed in median overall survival, 3-year overall survival, or 5-year overall survival between the WT KRAS and mutated KRAS groups.
In this study, KRAS mutation status did not influence overall survival in either synchronous or metachronous metastatic colorectal adenocarcinoma and, as such, had no prognostic role in this disease setting.
PMCID: PMC3839285  PMID: 22674181
metastatic colorectal adenocarcinoma; KRAS; mutation; prognosis
21.  Phase I Dose-Escalation Study of EZN-2208 (PEG-SN38), a Novel Conjugate of Poly(ethylene) Glycol and SN38, Administered Weekly in Patients With Advanced Cancer 
Cancer chemotherapy and pharmacology  2013;71(6):10.1007/s00280-013-2149-2.
This study evaluated the tolerability, pharmacokinetics (PK), and preliminary antitumor activity of EZN-2208, a water-soluble, poly(ethylene) glycol conjugate of SN38.
Patients with advanced malignancies were enrolled in dose-escalating cohorts (3 + 3 design). EZN-2208 was administered as a 1-hour intravenous infusion given weekly for 3 weeks per each 4-week cycle. Doses ranged from 1 to 12 mg/m2.
Forty-one patients received EZN-2208. All patients had received prior cancer therapy (median = 2, range = 1–11). Twenty patients (49%) had received prior irinotecan, and one patient had received prior topotecan. One patient in the 9-mg/m2 cohort had dose-limiting toxicity (grade 3 febrile neutropenia), and one patient in the 12-mg/m2 cohort had grade 3 neutropenia that resulted in the inability to deliver the third dose of EZN-2208. The most commonly reported drug-related adverse events were nausea (51%), diarrhea (46%), fatigue (41%), alopecia (29%), neutropenia (24%), and vomiting (22%). Administration of EZN-2208 results in prolonged exposure to SN38. Stable disease, sometimes prolonged and associated with tumor shrinkage, was observed as best response.
EZN-2208 has an acceptable safety profile in previously treated patients with advanced malignancies. The recommended phase II dose of EZN-2208 administered according to this schedule was 9 mg/m2.
PMCID: PMC3839288  PMID: 23543270
topoisomerase-1 inhibitors; SN-38; polyethylene glycol; Phase 1 clinical trials
22.  A dose escalation and pharmacodynamic study of triapine and radiation in patients with locally advanced pancreas cancer 
Triapine (Vion Pharmaceuticals), a novel inhibitor of the M2 subunit of ribonucleotide reductase (RR), is a potent radiosensitizer. This NCI/CTEP-sponsored phase I study assessed the safety/tolerability of triapine in combination with radiation (RT) in patients with locally advanced pancreas cancer (LAPCA).
We evaluated 3 dose levels of triapine (24 mg/m2, 48 mg/m2, 72 mg/m2) administered with 50.4 Gy of RT in 28 fractions. Patients with LAPCA received triapine thrice weekly, every other week during the course of RT. Dose-limiting toxicity (DLT) was assessed during and for 4 weeks following completion of RT. Dynamic contrast enhanced (DCE)-MRI and serum RR levels were evaluated as potential predictors for early response.
Twelve patients were treated. Four patients (1 non-evaluable [NE]) were enrolled at dose level 1 (DL1), three patients at DL2, and five patients (2NE) at DL3. No DLTs were observed and the MTD was not reached. Two patients (17%) achieved PR and 6 patients (50%) had SD. One patient underwent R0 resection following therapy. 92% of patients (100% on DL3) experienced freedom from local tumor progression. 75% of patients who eventually progressed developed metastases without local progression. RR levels did not appear to predict outcome. In 4 patients with available data, DCE-MRI may predict early response or resistance to therapy.
The combination of triapine at 72 mg/m2 three times weekly every other week and standard RT is tolerable with interesting activity in patients with LAPCA.
PMCID: PMC3477302  PMID: 22818416
Triapine; radiation; pancreas cancer
24.  Integrating anti-EGFR therapies in metastatic colorectal cancer 
Colorectal cancer remains one of the most common causes of cancer diagnoses and mortality in the United States. The treatment of metastatic colorectal cancer has evolved significantly over the last decade with near-tripling of patient survival rate. A significant contribution to this outcome was the advent of novel targeted agents, such as the epidermal growth factor (EGFR) inhibitors. In an era of emphasis on refining therapy, the presence of KRAS mutation will predict for resistance and limit exposure to patients who are more likely to benefit. In contrast, the presence of BRAF mutations does not seem to have a predictive value. Agents that are thought to reverse resistance to EGFR inhibitors such as those targeting PI3K, c-MET or IGF-1R are currently under study.
EGFR inhibitors have exhibited single agent activity, and seem to synergize very well with standard chemotherapy except for cetuximab and 5-fluorouracil, leucovorin, oxaliplatin (FOLFOX). Preliminary data suggests that EGFR inhibitors have similar effectiveness to vascular endothelial growth factor (VEGF) inhibitors in the first line setting. Skin toxicity remains the main limiting factor for the utilization of EGFR inhibitors, but strategies including the use of agents such as minocycline or doxycycline added to topical care seem to limit the severity of the rash.
PMCID: PMC3712294  PMID: 23997940
Epidermal growth factor inhibitors (EGFR inhibitor); metastatic colorectal cancer (mCRC); cetuximab; panitumumab; KRAS; targeted therapy
25.  A dose-finding, pharmacokinetic and pharmacodynamic study of a novel schedule of flavopiridol in patients with advanced solid tumors 
Investigational new drugs  2010;30(2):629-638.
Based on the promising activity and tolerability of flavopiridol administered with a pharmacokinetically-derived dosing schedule in chronic lymphocytic leukemia (CLL), we conducted a phase I study using this schedule in patients with advanced solid tumors.
Experimental Design
Flavopiridol was given IV as a 30-min loading dose followed by a 4-hr infusion weekly for 4 weeks repeated every 6 weeks. Dose-escalation was in cohorts of three patients using the standard 3+3 phase I study design. Blood samples were obtained for pharmacokinetic and pharmacodynamic studies.
Thirty-four eligible patients with advanced solid tumors received a total of 208 doses (median 7, range 1–24). Total doses ranged from 40 – 105 mg/m2. The primary dose limiting toxicity was cytokine release syndrome (CKRS). No antitumor responses were observed. The mean peak plasma concentration across all doses was 1.65 ± 0.86 µM. Area under the concentration-versus-time curve (AUC0–∞) ranged from 4.31 to 32.2 µM·hr with an overall mean of 13.6 ± 7.0 µM·hr. Plasma flavopiridol concentrations and AUC increased proportionally with dose. There was no correlation between cytokine levels and clinical outcomes.
The maximum-tolerated dose of flavopiridol is 20 mg/m2 bolus followed by 20 mg/m2 infusion over 4 hours given weekly for 4 weeks on a 6-week cycle in patients with advanced solid tumors. Flavopiridol PK was notably different, and there was a higher frequency of CKRS, despite prophylactic steroids, seen in this patient group compared to previous studies with CLL using a similar dosing schedule.
PMCID: PMC3486515  PMID: 20938713
Flavopiridol; CDK inhibitor; Phase I trial; Solid tumors

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