Showing papers by "Eunice L. Kwak published in 2012"

ROS1 Rearrangements Define a Unique Molecular Class of Lung Cancers

Abstract: Purpose Chromosomal rearrangements involving the ROS1 receptor tyrosine kinase gene have recently been described in a subset of non‐small-cell lung cancers (NSCLCs). Because little is known about these tumors, we examined the clinical characteristics and treatment outcomes of patients with NSCLC with ROS1 rearrangement.

Activity and safety of crizotinib in patients with ALK-positive non-small-cell lung cancer: updated results from a phase 1 study.

Abstract: Summary Background ALK fusion genes occur in a subset of non-small-cell lung cancers (NSCLCs). We assessed the tolerability and activity of crizotinib in patients with NSCLC who were prospectively identified to have an ALK fusion within the first-in-man phase 1 crizotinib study. Methods In this phase 1 study, patients with ALK -positive stage III or IV NSCLC received oral crizotinib 250 mg twice daily in 28-day cycles. Endpoints included tumour responses, duration of response, time to tumour response, progression-free survival (PFS), overall survival at 6 and 12 months, and determination of the safety and tolerability and characterisation of the plasma pharmacokinetic profile of crizotinib after oral administration. Responses were analysed in evaluable patients and PFS and safety were analysed in all patients. This study is registered with ClinicalTrials.gov, number NCT00585195. Findings Between Aug 27, 2008, and June 1, 2011, 149 ALK -positive patients were enrolled, 143 of whom were included in the response-evaluable population. 87 of 143 patients had an objective response (60·8%, 95% CI 52·3–68·9), including three complete responses and 84 partial responses. Median time to first documented objective response was 7·9 weeks (range 2·1–39·6) and median duration of response was 49·1 weeks (95% CI 39·3–75·4). The response rate seemed to be largely independent of age, sex, performance status, or line of treatment. Median PFS was 9·7 months (95% CI 7·7–12·8). Median overall survival data are not yet mature, but estimated overall survival at 6 and 12 months was 87·9% (95% CI 81·3–92·3) and 74·8% (66·4–81·5), respectively. 39 patients continued to receive crizotinib for more than 2 weeks after progression because of perceived ongoing clinical benefit from the drug (12 for at least 6 months from the time of their initial investigator-defined disease progression). Overall, 144 (97%) of 149 patients experienced treatment-related adverse events, which were mostly grade 1 or 2. The most common adverse events were visual effects, nausea, diarrhoea, constipation, vomiting, and peripheral oedema. The most common treatment-related grade 3 or 4 adverse events were neutropenia (n=9), raised alanine aminotransferase (n=6), hypophosphataemia (n=6), and lymphopenia (n=6). Interpretation Crizotinib is well tolerated with rapid, durable responses in patients with ALK -positive NSCLC. There seems to be potential for ongoing benefit after initial disease progression in this population, but a more formal definition of ongoing benefit in this context is needed. Funding Pfizer.

Frequent Mutation of Isocitrate Dehydrogenase (IDH)1 and IDH2 in Cholangiocarcinoma Identified Through Broad-Based Tumor Genotyping

Abstract: Cancers of origin in the gallbladder and bile ducts are rarely curable with current modalities of cancer treatment. Our clinical application of broad-based mutational profiling for patients diagnosed with a gastrointestinal malignancy has led to the novel discovery of mutations in the gene encoding isocitrate dehydrogenase 1 (IDH1) in tumors from a subset of patients with cholangiocarcinoma. A total of 287 tumors from gastrointestinal cancer patients (biliary tract, colorectal, gastroesophageal, liver, pancreatic, and small intestine carcinoma) were tested during routine clinical evaluation for 130 site-specific mutations within 15 cancer genes. Mutations were identified within a number of genes, including KRAS (35%), TP53 (22%), PIK3CA (10%), BRAF (7%), APC (6%), NRAS (3%), AKT1 (1%), CTNNB1 (1%), and PTEN (1%). Although mutations in the metabolic enzyme IDH1 were rare in the other common gastrointestinal malignancies in this series (2%), they were found in three tumors (25%) of an initial series of 12 biliary tract carcinomas. To better define IDH1 and IDH2 mutational status, an additional 75 gallbladder and bile duct cancers were examined. Combining these cohorts of biliary cancers, mutations in IDH1 and IDH2 were found only in cholangiocarcinomas of intrahepatic origin (nine of 40, 23%) and in none of the 22 extrahepatic cholangiocarcinomas and none of the 25 gallbladder carcinomas. In an analysis of frozen tissue specimens, IDH1 mutation was associated with highly elevated tissue levels of the enzymatic product 2-hydroxyglutarate. Thus, IDH1 mutation is a molecular feature of cholangiocarcinomas of intrahepatic origin. These findings define a specific metabolic abnormality in this largely incurable type of gastrointestinal cancer and present a potentially new target for therapy.

Phase I Study of RO4929097, a Gamma Secretase Inhibitor of Notch Signaling, in Patients With Refractory Metastatic or Locally Advanced Solid Tumors

Abstract: Purpose To determine the maximum-tolerated dose (MTD) and assess safety, pharmacokinetics, pharmacodynamics, and evidence of antitumor activity of RO4929097, a gamma secretase inhibitor of Notch signaling in patients with advanced solid malignancies. Patients and Methods Patients received escalating doses of RO4929097 orally on two schedules: (A) 3 consecutive days per week for 2 weeks every 3 weeks; (B) 7 consecutive days every 3 weeks. To assess reversible CYP3A4 autoinduction, the expanded part of the study tested three dosing schedules: (B) as above; modified A, 3 consecutive d/wk for 3 weeks; and (C) continuous daily dosing. Positron emission tomography scans with [18F]fluorodeoxyglucose (FDG-PET) were used to assess tumor metabolic effects. Results Patients on schedule A (n = 58), B (n = 47), and C (n = 5; expanded cohort) received 302 cycles of RO4929097. Common grade 1 to 2 toxicities were fatigue, thrombocytopenia, fever, rash, chills, and anorexia. Transient grade 3 hypophosphatemia (dose-limiti...

Dose-painted intensity-modulated radiation therapy for anal cancer: a multi-institutional report of acute toxicity and response to therapy.

Abstract: Purpose Chemoradiation for anal cancer yields effective tumor control, but is associated with significant acute toxicity. We report our multi-institutional experience using dose-painted IMRT (DP-IMRT). Patients and Methods Between August 2005 and May 2009, 43 patients were treated with DP-IMRT and concurrent chemotherapy for biopsy-proven, squamous cell carcinoma of the anal canal at two academic medical centers. DP-IMRT was prescribed as follows: T2N0: 42 Gy, 1.5 Gy/fraction (fx) to elective nodal planning target volume (PTV) and 50.4 Gy, 1.8 Gy/fx to anal tumor PTV; T3-4N0-3: 45 Gy, 1.5 Gy/fx to elective nodal PTV, and 54 Gy, 1.8 Gy/fx to the anal tumor and metastatic nodal PTV >3 cm with 50.4 Gy, 1.68 Gy/fx to nodal PTVs ≤3 cm in size. Acute and late toxicity was reported by the treating physician. Actuarial analysis was performed using the Kaplan-Meier method. Results Median age was 58 years; 67% female; 16% Stage I, 37% II; 42% III; 5% IV. Fourteen patients were immunocompromised: 21% HIV-positive and 12% on chronic immunosuppression. Median follow-up was 24 months (range, 0.6–43.5 months). Sixty percent completed chemoradiation without treatment interruption; median duration of treatment interruption was 2 days (range, 2–24 days). Acute Grade 3+ toxicity included: hematologic 51%, dermatologic 10%, gastrointestinal 7%, and genitourinary 7%. Two-year local control, overall survival, colostomy-free survival, and metastasis-free survival were 95%, 94%, 90%, and 92%, respectively. Conclusions Dose-painted IMRT appears effective and well-tolerated as part of a chemoradiation therapy regimen for the treatment of anal canal cancer.

Clinical activity of crizotinib in advanced non-small cell lung cancer (NSCLC) harboring ROS1 gene rearrangement.

Abstract: 7508 Background: Chromosomal rearrangements of the ROS1 receptor tyrosine kinase gene define a new molecular subset of NSCLC. In cell lines, ROS1 rearrangements lead to expression of oncogenic ROS1...

Rapid Radiographic and Clinical Improvement After Treatment of a MET-Amplified Recurrent Glioblastoma With a Mesenchymal-Epithelial Transition Inhibitor

Abstract: Case Report A 62-year-old right-handed white woman presented with periodic motion-related nausea and vertigo. On physical examination, she had only mild high-frequency hearing loss on the right side. Cranial magnetic resonance imaging (MRI) revealed an unresectable contrast-enhancing lesion measuring 3.6 cm in maximal horizontal diameter within the genu of the corpus callosum, with surrounding abnormal T2/fluid-attenuated inversion recovery (FLAIR) hyperintensity. Stereotactic biopsy of the contrast-enhancing lesion established the diagnosis of glioblastoma (GBM), WHO grade 4. Her tumor tissue was tested for genetic abnormalities using a comprehensive panel that included screening for commonly mutated loci in 15 cancer-related genes using a multiplex polymerase chain reaction platform (SNaPshot, Version 3; Applied Biosystems, Carlsbad, CA); amplification of the mesenchymal-epithelial transition (MET), epidermal growth factor receptor (EGFR), and plateletderived growth factor receptor A (PDGFRA) genes using fluorescence in situ hybridization (FISH); status of chromosomes 1p and 19q by FISH; and O-6-methylguanine-DNA methyltransferase (MGMT) promoter DNA methylation status by methylationspecific polymerase chain reaction. Her tumor was found to have MET gene amplification by a dual-color FISH assay using probes for the MET locus (Fig 1, pink dots) and centromere 7 (Fig 1, aqua dots), which served as a copy-number control. In addition, the MGMT promoter was methylated. She was enrolled onto a clinical trial for patients with newly diagnosed GBM that combined the standard regimen of concurrent radiation and temozolomide followed by monthly temozolomide with cediranib, an oral small-molecule pan–vascular endothelial growth factor (VEGF) receptor tyrosine kinase inhibitor. After five postradiation cycles of temozolomide and cediranib, she developed headaches, fatigue, disorientation, and short-term memory loss. A cranial MRI examination demonstrated increased size of the contrast-enhancing lesion and significantly increased surrounding T2/FLAIR hyperintensity consistent with progressive disease. Administration of dexamethasone was started at 4 mg per day, and subsequently, her headache intensity mildly decreased. Her MET amplification status enabled her to enroll onto the MET-amplification/mutation enriched molecular cohort of a phase I trial of crizotinib (PF-02341066), an oral small-molecule inhibitor of the MET and anaplastic lymphoma kinase (ALK) tyrosine kinases, in patients with advanced cancer (A8081001). This cohort includes patients with tumors harboring specific genetic alterations in MET or ALK independent of tumor type, including MET gene amplification, kinase domain activating mutation, or other chromosomal translocations leading to altered transcriptional regulation of MET as well as ALK chromosomal translocation or gene amplification. She began receiving crizotinib 250 mg twice daily, and within 2 weeks, her headaches and short-term memory had significantly improved, and she was able to decrease her dexamethasone dose to 1 mg daily. Her first scheduled cranial MRI examination performed after two 28-day cycles of crizotinib demonstrated a 40% reduction (using two-dimensional measurements) of the contrast-enhancing lesion (Fig 2A) and decreased surrounding T2/FLAIR hyperintensity (Fig 2B). After four cycles, a restaging cranial MRI examination confirmed a stable 40% reduction in size of the contrast-enhancing lesion. She was neurologically stable, and dexamethasone was discontinued. One week before her sixth cycle, she developed increased disorientation, short-term memory loss, headaches, and nausea. At that time, a scheduled restaging cranial MRI examination demonstrated interval increase in size of the contrast-enhancing lesion consistent with progressive disease. Administration of crizotinib was stopped 6 months after initiation of treatment. The only adverse effects attributed to crizotinib were asymptomatic elevated ALT (grade 2) and hypophosphatemia (grade 2). During the third crizotinib cycle, she developed left popliteal venous thrombosis (grade 2) and began receiving enoxaparin. She subsequently developed small, asymptomatic peritumoral hemorrhages (grade 1) that were noted incidentally on her cranial MRI examination at the end of cycle four. The hemorrhages were attributed to enoxaparin therapy. Enoxaparin was then discontinued, and an inferior vena cava filter was placed. Crizotinib was postponed for 1 week and then restarted after a cranial computed tomography scan showed no extension of the hemorrhages. At the time of crizotinib discontinuation, a cranial MRI confirmed stability of the peritumoral hemorrhages since their discovery. Fig 1. JOURNAL OF CLINICAL ONCOLOGY D I A G N O S I S I N O N C O L O G Y VOLUME 30 NUMBER 3 JANUARY 2

Panitumumab in Patients with KRAS Wild-Type Colorectal Cancer after Progression on Cetuximab

Abstract: Purpose Cetuximab and panitumumab are monoclonal antibodies that target the epidermal growth factor receptor (EGFR) and are approved for the treatment of patients with KRAS wild-type metastatic colorectal cancer. There are no data that describe the activity of panitumumab in patients with progressive disease on cetuximab. We performed a single-arm phase II trial of panitumumab in patients with KRAS wild-type metastatic colorectal cancer that had progressed on prior cetuximab. Patients and Methods We used a two-stage study design to treat patients with panitumumab at 6 mg/kg every 14 days (cycle length = 28 days). Treatment was continued until disease progression, death, inability to tolerate panitumumab, or study withdrawal. The primary endpoint was response rate; secondary endpoints included progression-free survival and overall survival. Twenty patients were treated in the first stage, with plans to treat an additional twelve pa tients if there was at least one objective response. We collected blood samples at baseline and prior to cycles 2 and 3 to evaluate for the presence of anti-cetuximab and anti-panitumumab antibodies. Results We treated twenty patients for a median of two cycles (range 1–4). No patients responded, and 45% had a best response of stable disease (no progression for at least two cycles). Median progression-free survival was 1.7 months and median overall survival was 5.2 months. Panitumumab was well tolerated. Thirteen patients (65%) had grade 1–2 dry skin or rash, and three patients had treatment-related grade 3 toxicities (one each with hyperglycemia, hyperbilirubinemia, and hypokalemia). No patients had detectable anti-cetuximab antibodies at any time point; one patient developed anti-panitumumab antibodies. Conclusions Panitumumab has minimal benefit in patients with KRAS wild-type metastatic colorectal cancer that has progressed on prior cetuximab. Discussion Both cetuximab and panitumumab competitively inhibit ligand binding to EGFR, thereby promoting receptor internalization and blocking receptor-mediated signaling. Although the two agents have never been compared directly in a randomized clinical trial, they produce similar response rates when used alone as well as in combination with cytotoxic agents. Cetuximab is a chimeric antibody with approximately 30% murine protein, while panitumumab is a fully human monoclonal antibody. Correspondingly, rates of severe hypersensitivity reactions are somewhat increased with cetuximab (3%) compared to panitumumab (1%). However, the potential efficacy of panitumumab in patients who have developed disease progression on cetuximab has been an open question. Metges et al. (PANERB trial) prospectively treated 32 KRAS wild-type metastatic colorectal cancer patients with cetuximab and irinotecan followed by panitumumab monotherapy after progression. Remarkably, the authors reported an objective response rate of 22% to panitumumab, including a disease control rate (objective response plus stable disease) of 73% in 11 patients who had previously responded to cetuximab and irinotecan. In contrast, we found no responders and a stable disease rate of 45% with a median duration of only 1.7 months in our trial of 20 patients. Moreover, no patients had detectable anticetuximab antibodies at baseline. It is not clear to what extent the PANERB trial included patients without objective disease progression on cetuximab or for whom cetuximab-containing regimens may have been ceased due to toxicity in the absence of disease progression. In both circumstances, retreatment with panitumumab may be expected to demonstrate some degree of clinical activity. In our study, disease progression after at least 4 weeks of cetuximab documented radiographically or by increased carcinoembryonic antigen (CEA) levels was required for inclusion in order to ensure that the study population demonstrated unequivocal evidence of progression on cetuximab. While it remains possible that a small subset of patients may benefit from panitumumab after progression on cetuximab, our results suggest that this approach should not be adopted until predictive biomarkers for panitumumab response in this setting have been discovered and validated. Until then, patients who develop progression on cetuximab should be enrolled in trials of novel agents.

Long-term outcomes of neoadjuvant chemotherapy before chemoradiation for locally advanced pancreatic cancer.

Abstract: BACKGROUND: Neoadjuvant chemotherapy before chemoradiation therapy (CRT) may improve outcomes for patients with locally advanced pancreatic cancer, but optimal management remains controversial, and prior reports have limited follow-up. METHODS: Seventy consecutive patients with unresectable (n = 46) or borderline resectable (n = 24) locally advanced pancreatic cancer were treated with CRT from 2005 to 2009. Patients typically received 50.4 grays in 28 fractions (91%) with concurrent 5-fluorouracil (84%) or capecitabine (14%). Forty patients received CRT alone, and 30 patients received neoadjuvant chemotherapy before CRT for a median of 4 months, typically gemcitabine (93%). All patients without progression after neoadjuvant chemotherapy were offered CRT. RESULTS: Median follow-up was 14.2 months (range, 3-57 months). Fifty-three percent of patients in the CRT group versus 83% in the neoadjuvant chemotherapy before CRT group had unresectable tumors at diagnosis; after completion of CRT, 20% of patients in both groups underwent resection. Compared with CRT alone, the neoadjuvant chemotherapy before CRT group demonstrated improved median overall survival (OS; 18.7 vs 12.4 months; P = .02) and progression-free survival (11.4 vs 6.7 months; P = .02). On multivariate analysis, receipt of neoadjuvant chemotherapy (adjusted hazard ratio [HR], 0.49; 95% CI, 0.28-0.87; P = .02) and surgical resection (adjusted HR, 0.38; 95% CI, 0.17-0.85; P = .02) were associated with increased OS. CONCLUSIONS: Gemcitabine-based neoadjuvant chemotherapy confers a significant OS advantage by allowing the selection of patients who will derive greatest benefit from CRT. Median survival with this approach was similar to that seen with surgical resection. Cancer 2012;118: 3026–35. © 2011 American Cancer Society.

A first-in-human phase Ib study to evaluate the MEK inhibitor GDC-0973, combined with the pan-PI3K inhibitor GDC-0941, in patients with advanced solid tumors.

Abstract: 2566 Background: Both RAS/RAF/MEK and PI3K/Akt signaling pathways are deregulated in many tumor types. Targeting both pathways may be more efficacious than targeting either pathway alone. In precli...

Pancreatic neuroendocrine tumors with involved surgical margins: prognostic factors and the role of adjuvant radiotherapy.

Abstract: Purpose: Pancreatic neuroendocrine tumors (pNET) are rare neoplasms associated with poor outcomes without resection, and involved surgical margins are associated with a worse prognosis. The role of adjuvant radiotherapy (RT) in these patients has not been characterized. Methods and Materials: We retrospectively evaluated 46 consecutive patients with positive or close (<1 mm) margins after pNET resection, treated from 1983 to 2010, 16 of whom received adjuvant RT. Median RT dose was 50.4 Gy in 1.8-Gy fractions; half the patients received concurrent chemotherapy with 5-fluorouracil or capecitabine. No patients received adjuvant chemotherapy. Cox multivariate analysis (MVA) was used to analyze factors associated with overall survival (OS). Results: Median age at diagnosis was 56 years, and 52% of patients were female. Median tumor size was 38 mm, 57% of patients were node-positive, and 11% had a resected solitary liver metastasis. Patients who received RT were more likely to have larger tumors (median, 54 mm vs. 30 mm, respectively, p = 0.002) and node positivity (81% vs. 33%, respectively, p = 0.002) than those not receiving RT. Median follow-up was 39 months. Actuarial 5-year OS was 62% (95% confidence interval [CI], 41%-77%). In the group that did not receive RT, 3 patients (10%)more » experienced local recurrence (LR) and 5 patients (18%) developed new distant metastases, while in the RT group, 1 patient (6%) experienced LR and 5 patients (38%) developed distant metastases. Of all recurrences, 29% were LR. On MVA, male gender (adjusted hazard ratio [AHR] = 3.81; 95% CI, 1.21-11.92; p = 0.02) and increasing tumor size (AHR = 1.02; 95% CI, 1.01-1.04; p = 0.007) were associated with decreased OS. Conclusions: Long-term survival is common among patients with involved-margin pNET. Despite significantly worse pathologic features among patients receiving adjuvant RT, rates of LR between groups were similar, suggesting that RT might aid local control, and merits further evaluation.« less

BRAF V600 mutant colorectal cancer (CRC) expansion cohort from the phase I/II clinical trial of BRAF inhibitor dabrafenib (GSK2118436) plus MEK inhibitor trametinib (GSK1120212).

Abstract: 3528 Background: BRAF V600 mutations occur in 10-15% of CRC and may predict lack of response to standard chemotherapy and anti-EGFR treatment. There have been no significant recent changes in the t...

Multicenter phase Ib/II study of everolimus (RAD001) and tivozanib (AV-951) in patients with refractory, metastatic colorectal cancer.

Abstract: 560 Background: Everolimus (E) is an oral inhibitor of mTOR. Tivozanib (T) is a highly potent, selective, oral inhibitor of VEGF receptors-1, -2, and -3. Preclinical data suggest antitumor activity for this combination in colorectal cancer. We therefore performed a multicenter Phase Ib trial of E + T in patients (pts) with any refractory gastrointestinal (GI) malignancy, followed by a Phase II trial of E + T in pts with refractory, metastatic colorectal cancer (mCRC). Methods: Eligibility criteria: histologically confirmed, measurable disease; ECOG PS≤2; blood pressure ≤150/100; no venous thromboembolism within prior 6 months. Pts with mCRC must have received prior fluoropyrimidine, irinotecan, oxaliplatin, bevacizumab and anti-EGFR antibody (if KRAS wt). E was administered once daily continuously. T was administered once daily for 3 out of every 4 weeks. The Phase Ib study in pts with any GI malignancy followed a standard 3+3 design with 3 dose levels: (1) E 5 mg/d + T 1 mg/d; (2) E 10 mg/d + T 1 mg/d; (...

FOLFIRINOX in locally advanced and metastatic pancreatic cancer.

Abstract: 313 Background: The recently published Phase III trial of 5-FU, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) demonstrated improved survival compared to gemcitabine in good performance status (PS) patients with metastatic pancreatic cancer (Conroy et al, NEJM 2011). Less is known about the efficacy and tolerability with FOLFIRINOX in the non-clinical trial setting. In this retrospective analysis, we report our institutional experience with FOLFIRINOX. Methods: 29 patients with locally advanced or metastatic pancreatic cancer treated with FOLFIRINOX between July 2010 and April 2011 were used for this analysis. Clinical characteristics, and gradeable toxicities were tabulated, and formal radiographic review performed to determine best overall response rates (ORR). Results: 17 patients received FOLFIRINOX for metastatic disease and 12 patients for locally advanced disease. The median age of patients was 60 (range 39-76). 22/29 patients were men. 18/29 patients had received no prior chemotherapy. There...

A phase 2 study of oral MKC-1, an inhibitor of importin-β, tubulin, and the mTOR pathway in patients with unresectable or metastatic pancreatic cancer

Abstract: Background MKC-1 is an orally available cell cycle inhibitor with downstream targets that include tubulin and the importin-β family. We conducted an open-label Phase II study with MKC-1 in patients with advanced pancreatic cancer. Methods Eligibility criteria included unresectable or metastatic pancreatic cancer, performance status of 1 or better, and failure of at least one prior regimen of chemotherapy. MKC-1 was administered orally, twice daily, initially at 100 mg/m2 dosing for 14 consecutive days of a 28-day cycle. This schedule was modified during the trial to fixed and continuous dosing of 150 mg per day. Results 20 of an original target of 33 patients were accrued, with a median age of 61 (range 44–81). No objective responses were observed, with one patient demonstrating stable disease. Overall survival was 101 days from the start of MKC-1 administration, and median time to progression was 42 days. The most common adverse events listed as related or possibly related to MKC-1 administration were hematologic toxicities and fatigue. One patient developed grade 5 (fatal) pancytopenia. Grade 3 and 4 events included cytopenias (lymphopenia, anemia), hyperbilirubinemia, pneumonia, mucositis, fatigue, infusion reaction, anorexia, and hypoalbuminemia. Conclusions MKC-1 administration was associated with substantial toxicity and did not demonstrate sufficient activity in patients with advanced pancreatic cancer to justify further exploration in this patient population.

A phase I study of temsirolimus in combination with gemcitabine in previously untreated metastatic pancreatic cancer.

Abstract: 296 Background: The PI3K/mTOR/Akt pathway has been demonstrated to be active in pancreatic cancer, and preclinical data in mouse xenograft models has suggested possible synergy between gemcitabine and temsirolimus, an inhibitor of the mTOR pathway. The objective of this Phase I study was to assess toxicity and tolerability of gemcitabine and temsirolimus combination therapy in patients with newly diagnosed metastatic pancreatic cancer. Methods: The study was conducted with a modified, 3+3 phase I design for dose escalation. Patients in cohort 1 received temsirolimus at a fixed dose of 10mg IV on days 1,8,15, and 22, while gemcitabine was administered at 800mg/m2 IV on days 1 and 15 of each 28 day cycle. Results: Between November 2007 and September 2008, 9 patients were enrolled in the trial, with a median age of 56. 6/9 patients were male, and all enrolled patients had a performance status of 1. One patient discontinued prior to starting treatment. 5 of the 8 patients receiving at least one infusion of ge...

Multicenter randomized phase II trial of cisplatin, irinotecan plus bevacizumab (PCA) versus docetaxel, cisplatin, irinotecan plus bevacizumab (TPCA) in patients (pts) with metastatic esophagogastric cancer (MEGCA).

Abstract: 4027 Background: In MEGCA, PCA has a 65% response rate (RR) and 8.3 mos time to progression (Shah. JCO 2006); TPCA has a 66% RR and 8.9 mos progression-free survival (PFS) (Enzinger. ESMO 2008 upda...

Phase I study of sequential sapacitabine and seliciclib in patients with advanced solid tumors.

Abstract: 3053 Background: Sapacitabine is an orally administered nucleoside analogue; the active metabolite CNDAC generates ss DNA breaks that are converted to ds DNA breaks (DSB) during subsequent replicat...

Immediate versus delayed adjuvant chemoradiation for resected pancreatic cancer: An analysis of local control and survival.

Abstract: 301 Background: Patients with resected pancreatic cancer have a significant risk of both local and distant failures. Because of the importance of chemotherapy (CT) highlighted by recent trials, the...

A matter of timing: is there a role for radiation in locally advanced pancreatic cancer, and if so, when?

Abstract: Overview:The role of radiation therapy in the management of locally advanced pancreatic cancer is controversial. Despite its localized presentation, locally advanced pancreatic cancer is characteri...

Phase I/II study of preoperative (pre-op) short course chemoradiation (CRT) with proton beam therapy (PBT) and capecitabine (cape) followed by early surgery for resectable pancreatic ductal adenocarcinoma (PDAC) of the head.

Abstract: 4021 Background: Standard adjuvant 6 week CRT may delay and reduce tolerability of adjuvant gemcitabine-based chemotherapy. We explore the safety and efficacy of a one-week course of pre-op CRT with PBT and cape followed by early pancreaticoduodenectomy (PD). Methods: Patients with radiographically resectable, biopsy-proven PDAC of the head were enrolled from May 2007-December 2010 on this prospective, NCI-sponsored clinical trial. Eligibility included no CT involvement of SMA or celiac artery; No metastatic disease. Dose level 1 consisted of PBT delivered 3 Gy x 10. Pts in subsequent dose levels received 5 Gy x 5 in progressively shortened schedules: level 2 (wk 1 M W F, wk 2 T Th), level 3 (wk 1 M T Th F, wk 2 M), level 4 (wk 1 M-F). PBT was targeted at pancreatic mass with elective nodal coverage. Pts received Cape 825 mg/m2 BID wk 1 and 2 M-F. Surgery was performed 1-6 wks after completion of cape. Patients were recommended to receive 6 mo of gemcitabine after surgery. Genotyping of 15 genes (includin...

Pancreatic Neuroendocrine Tumors With Involved Surgical Margins: Prognostic Factors and the Role of Adjuvant

Abstract: Purpose: Pancreatic neuroendocrine tumors (pNET) are rare neoplasms associated with poor outcomes without resection, and involved surgical margins are associated with a worse prognosis. The role of adjuvant radiotherapy (RT) in these patients has not been characterized. Methods and Materials: We retrospectively evaluated 46 consecutive patients with positive or close (<1 mm) margins after pNET resection, treated from 1983 to 2010, 16 of whom received adjuvant RT. Median RT dose was 50.4 Gy in 1.8-Gy fractions; half the patients received concurrent chemotherapy with 5-fluorouracil or capecitabine. No patients received adjuvant chemotherapy. Cox multivariate analysis (MVA) was used to analyze factors associated with overall survival (OS). Results: Median age at diagnosis was 56 years, and 52% of patients were female. Median tumor size was 38 mm, 57% of patients were node-positive, and 11% had a resected solitary liver metastasis. Patients who received RT were more likely to have larger tumors (median, 54 mm vs. 30 mm, respectively, p Z 0.002) and node positivity (81% vs. 33%, respectively, p Z 0.002) than those not receiving RT. Median follow-up was 39 months. Actuarial 5-year OS was 62% (95% confidence interval [CI], 41%e77%). In the group that did not receive RT, 3 patients (10%) experienced local recurrence (LR) and 5 patients (18%) developed new distant metastases, while in the RT group, 1 patient (6%) experienced LR and 5 patients (38%) developed distant metastases. Of all recurrences, 29% were LR. On MVA, male gender (adjusted hazard ratio [AHR] Z 3.81; 95% CI, 1.21e11.92; p Z 0.02) and increasing tumor size (AHR Z 1.02; 95% CI, 1.01e1.04; p Z 0.007) were associated with decreased OS.