Rabia Khan

Risk Factors for Pancreatic Cancer: Case-Control Study

OBJECTIVES:Although cigarette smoking is the most well-established environmental risk factor for pancreatic cancer, the interaction between smoking and other risk factors has not been assessed. We evaluated the independent effects of multiple risk factors for pancreatic cancer and determined whether the magnitude of cigarette smoking was modified by other risk factors in men and women.METHODS:We conducted a hospital-based case-control study involving 808 patients with pathologically diagnosed pancreatic cancer and 808 healthy frequency-matched controls. Information on risk factors was collected by personal interview, and unconditional logistic regression was used to determine adjusted odds ratios (AORs) by the maximum-likelihood method.RESULTS:Cigarette smoking, family history of pancreatic cancer, heavy alcohol consumption (>60 mL ethanol/day), diabetes mellitus, and history of pancreatitis were significant risk factors for pancreatic cancer. We found synergistic interactions between cigarette smoking and family history of pancreatic cancer (AOR 12.8, 95% confidence interval [CI] 1.6–108.9) and diabetes mellitus (AOR 9.3, 95% CI 2.0–44.1) in women, according to an additive model. Approximately 23%, 9%, 3%, and 5% of pancreatic cancer cases in this study were related to cigarette smoking, diabetes mellitus, heavy alcohol consumption, and family history of pancreatic cancer, respectively.CONCLUSIONS:The significant synergy between these risk factors suggests a common pathway for carcinogenesis of the pancreas. Determining the underlying mechanisms for such synergies may lead to the development of pancreatic cancer prevention strategies for high-risk individuals.

Phase I Trial of a Combination of the Multikinase Inhibitor Sorafenib and the Farnesyltransferase Inhibitor Tipifarnib in Advanced Malignancies

Purpose: We evaluated the safety, maximum tolerated dose, pharmacokinetics, and biological effects of the combination of the Raf-1, RET, KIT, platelet-derived growth factor receptor, and vascular endothelial growth factor receptor 2 kinase inhibitor sorafenib and the farnesyltransferase inhibitor tipifarnib. Experimental Design: A standard 3 + 3 phase I dose-escalation design was used with a 28-day cycle (sorafenib daily and tipifarnib for 21 days, by mouth). Results: Fifty patients were treated; 43 reached restaging evaluation after cycle 2. The most common side effects were grade 1 to 2 rash, hyperglycemia, and diarrhea. Dose-limiting toxicity was rash, and the recommended phase II dose is sorafenib 400 mg p.o. qam/200 mg p.o. qpm and tipifarnib p.o. 100 mg bd. Despite the low doses of tipifarnib, one quarter of patients had 50 reduction in farnesyltransferase levels. Interestingly, six of eight patients with medullary thyroid cancer had durable stable disease (n = 3) or partial remissions (n = 3), lasting 12 to 26+ months. Five of the six responders had available tissue, and RET gene mutations were identified in them. Prolonged (6 months) stable disease was also seen in nine patients as follows: papillary thyroid cancer (n = 4; 18+ to 27+ months), adrenocortical cancer (n = 2; 7 and 11 months), and one each of melanoma (platelet-derived growth factor receptor mutation positive; 14 months), renal (6 months), and pancreatic cancer (6 months). Conclusions: Our study shows that the combination of tipifarnib and sorafenib is well tolerated. Activity was seen, especially in patients with medullary thyroid cancer, a tumor characterized by RET mutations. (Clin Cancer Res 2009;15(22):70618)

Passive smoking and the use of noncigarette tobacco products in association with risk for pancreatic cancer : A case-control study

The associations between passive smoking and the use of noncigarette tobacco products with pancreatic cancer are not clear.

Abstract A211: A phase I study of MABp1, a first-in-human, first-true human monoclonal antibody against the IL-1 in patients with advanced cancers.

Background: IL-1 is associated with pathological inflammatory responses, including inflammation that supports a malignant phenotype in the tumor microenvironment. Targeting IL-1α may reduce tumor potential by undermining one or more aspects of tumor-driven angiogenesis, tissue matrix remodeling and metastasis. MABp1 is a true human therapeutic antibody generated by a natural human immune response and was cloned directly from a human peripheral B lymphocyte. MABp1 binds IL-1α with high-affinity and is a potent blocker of IL-1α biological activity. Blocking IL-1α activity using MABp1 may be a safe and effective means of interrupting the chronic inflammatory response that supports tumor growth and invasiveness. Methods: This is an open label, first-in-man, phase I trial of MABp1 in patients with advanced cancers both metastatic and refractory to standard of care treatment. The trial included two dosing arms: arm A (4 levels of MABp1, administered once every 3 weeks); arm B consisted of the highest dose concentration in arm A administered once every 2 weeks. The trial followed a 3+3 design. Pharmacokinetics was measured at pre-screening and on days 1 (post-infusion), 8 and 15 during each cycle for the first 3 cycles and on day 1 of each subsequent cycle post-infusion. Pharmacodynamic sampling of CRP, IL-6 and IL-1 receptor antagonist (IL-1RA) occurred at screening and on days 1, 8 and 15 of each cycle. Results: Thirty-six patients were enrolled in arm A. Enrollment in arm B, the biweekly dosing cohort, is still ongoing. Pharmacokinetic investigation of patients in the highest dosing cohort of arm A showed an average peak serum concentration of 80 micrograms per milliliter, with a half-life of approximately 3 days. The most common possibly drug related adverse events (AEs) included 7 patients with grade I-II proteinuria (19%), 5 patients with grade I nausea (14%), and 4 patients with grade I-II fatigue (11%). A maximum dose of 3.75 mg/kg was reached on arm A, the highest dose concentration, with one dose-limiting toxicity (DLT) of a possibly drug-related infection. Of the 36 patients enrolled in arm A, 6 patients had (17%) had stable disease for >6 months (colorectal (CRC), Castleman9s lymphoma, rectal, non-small cell lung (NSCLC), neuroendocrine, pseudomyxoma peritonei. One patient with KRAS+ CRC had a PR (−33% by RECIST) and continued on study for 18 months. Low IL-1RA at baseline ( 6 months. Conclusions: MABp1 was well tolerated with minimal AEs at the 3.75 mg/kg dose given every 3 weeks. MABp1 showed evidence of anti-tumor activity and altered disease progression in CRC, NSCLC, and other tumor subtypes. Reducing tumor-driven inflammation through IL-1α antagonism may be an effective disease modifying anti-cancer agent in advanced stage disease. Patient responses and an association of positive outcomes with low baseline IL1-RA levels support this finding. Further study is warranted in advanced cancers with MABp1. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A211.

First-in-human study of AMG 208, an oral MET inhibitor, in adult patients (pts) with advanced solid tumors.

41 Background: AMG 208 is a small molecule MET inhibitor that suppresses proliferation and induces apoptosis in human tumor xenografts. This first-in-human study evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of AMG 208. We report data from the dose escalation part of the study. METHODS Key eligibility criteria: ≥ 18 yr, advanced solid tumors, ECOG ≤ 2, and evaluable/measurable disease. Using a modified Fibonacci design, 3-9 pts were enrolled into 1 of 7 sequential dose cohorts (25, 50, 100, 150, 200, 300, and 400 mg) of AMG 208. Pts received AMG 208 orally on days 1 and 4-28 once daily. If no dose limiting toxicity (DLT) was seen on days 1-28, pts received AMG 208 once daily starting at day 36 provided pts showed no evident disease progression. In cohorts 1-3, a standard 3+3 design was followed. In cohorts 4-7, a modified 3+3+3 design was followed. RESULTS As of July 16 2012, 54 pts (25 mg [n=6], 50 mg [n=4], 100 mg [n=4], 150 mg [n=3], 200 mg [n=16], 300 mg [n=10], and 400 mg [n =11]) had received ≥ 1 dose of AMG 208. 67% were men; 19% had prostate cancer (PC). Median (range) age: 61 (39-80) yr. ECOG 0/1: 52%/48%. 6 DLTs were seen: a grade (G) 3 increased AST (200 mg), a G3 thrombocytopenia (200 mg), a G4 acute myocardial infarction (300 mg), a G3 prolonged QT (300 mg), and two G3 hypertensions (400 mg). The maximum tolerated dose was not reached. 83% of pts had tx-related adverse events (AE). Tx-related AE occurring in > 10 pts: fatigue (n=24), nausea (n=18), hypertension (n=12), and diarrhea (n=11). 24% of pts had grade ≥ 3 tx-related AE. AMG 208 was orally bioavailable with a 30-35 hr mean half-life in plasma. Exposure increased linearly with dose; accumulation at day 28 was 2.7-fold across cohorts. Of the 42 pts with available tumor response data for site reads, 1 had complete response on bone scan (PC 300 mg) while 2 had partial responses (PR; PC 400 mg and kidney cancer 200 mg; both had -33% tumor shrinkage), and 29 had stable disease (SD); 1 other PC pt had PR after data cutoff. Of the 35 pts with available tumor response data for central reads, 26 had SD. FLT and biomarker data will be presented. CONCLUSIONS AMG 208 up to 400 mg daily had manageable toxicities and showed evidence of antitumor activity, especially in prostate cancer. CLINICAL TRIAL INFORMATION NCT00813384.