Biophysical and Immunological Characterization and Pharmacokinetics and Toxicology in Nonhuman Primates of the Anti-PD-1 Antibody Pembrolizumab.

The programmed cell death 1 (PD-1) pathway represents a major immune checkpoint, which may be engaged by cells in the tumor microenvironment to overcome active T-cell immune surveillance. Pembrolizumab (Keytruda®, MK-3475) is a potent and highly selective humanized mAb of the IgG4/kappa isotype designed to directly block the interaction between PD-1 and its ligands, PD-L1 and PD-L2. This blockade enhances the functional activity of T cells to facilitate tumor regression and ultimately immune rejection.

Optimal Dosing for Targeted Therapies in Oncology: Drug Development Cases Leading by Example.

One of the key objectives of oncology first-in-human trials has often been to establish the maximum tolerated dose (MTD). However, targeted therapies might not exhibit dose-limiting toxicities (DLT) at doses significantly higher than sufficiently active doses, and there is frequently a limited ability to objectively quantify adverse events. Thus, while MTD-based determination of recommended phase II dose may have yielded appropriate dosing for some cytotoxics, targeted therapeutics (including monoclonal antibodies and/or immunotherapies) sometimes need alternative or complementary strategies to help identify dose ranges for a randomized dose-ranging study.

Phase I dose-escalation trial of checkpoint kinase 1 inhibitor MK-8776 as monotherapy and in combination with gemcitabine in patients with advanced solid tumors.

Purpose: We determined the safety, pharmacokinetics, pharmacodynamics, and recommended phase II dose of MK-8776 (SCH 900776), a potent, selective checkpoint kinase 1 (Chk1) inhibitor, as monotherapy and in combination with gemcitabine in a first-in-human phase I clinical trial in patients with advanced solid tumor malignancies.

Patients And Methods: Forty-three patients were treated by intravenous infusion with MK-8776 at seven dose levels ranging from 10 to 150 mg/m(2) as monotherapy and then in combination with gemcitabine 800 mg/m(2) (part A, n = 26) or gemcitabine 1,000 mg/m(2) (part B, n = 17). Forty percent of patients had three or more prior treatment regimens, and one third of patients had previously received gemcitabine.

Ampullary and periampullary tumors: translational efforts to meet a challenge in diagnosis and treatment. Highlights from the "2011 ASCO Gastrointestinal Cancers Symposium". San Francisco, CA, USA. January 20-22, 2011.

Ampullary adenocarcinoma is a rare diagnosis and often managed as carcinomas of pancreatobiliary origin. However, there is accumulating evidence unveiling attributes of ampullary carcinomas that are distinct from that of pancreas or biliary cancers. Growing translational efforts in understanding this rare disease are exemplified by Abstracts #161 and #204 presented at the 2011 American Society of Clinical Oncology (ASCO) Gastrointestinal Cancers Symposium.

Inconsistent labeling of food effect for oral agents across therapeutic areas: differences between oncology and non-oncology products.

Purpose: Several recent oral oncology drugs were labeled for administration in fasted states despite the fact that food increases their bioavailability. Because this was inconsistent with the principles of oral drug delivery, we hypothesized that there were inconsistencies across therapeutic areas.

Experimental Design: Oral agents approved by the U.

A pharmacogenetic study of vorinostat glucuronidation.

High interindividual pharmacokinetic variability was observed in phase 1 studies of vorinostat (suberoylanilide hydroxamic acid), an oral histone deacetylase inhibitor. Thus, we hypothesized that the variability can be explained by genetic variants of the uridine 5'-diphosphate-glucuronosyltransferases (UGTs) involved in vorinostat metabolism. Baculosomes expressing human UGTs and 52 human liver microsomes were screened for vorinostat glucuronidation activity to identify the potential enzymes and functional variants.

Clinical outcome of pancreatic cancer patients with diabetes mellitus: is diabetes a poor prognostic factor? Highlights from the "2010 ASCO Annual Meeting". Chicago, IL, USA. June 4-8, 2010.

Diabetes mellitus and its related factors such as hyperinsulinemia have been linked to various cancer risks and outcomes. Previous research has offered inconsistent results in terms of relationship between diabetes and pancreatic cancers. Establishing clear association between these two entities may guide us in improving clinical outcomes of pancreatic cancer patients.

Circulating tumor cells in HER-2 positive metastatic breast cancer patients treated with trastuzumab and chemotherapy.

The detection of circulating tumor cells (CTCs) in peripheral blood may have important prognostic and predictive implications in breast cancer treatment. A limitation in this field has been the lack of a validated method of accurately measuring CTCs. While sensitivity has improved using RT-PCR, specificity remains a major challenge.

Global variation in CYP2C8-CYP2C9 functional haplotypes.

We have studied the global frequency distributions of 10 single nucleotide polymorphisms (SNPs) across 132 kb of CYP2C8 and CYP2C9 in approximately 2500 individuals representing 45 populations. Five of the SNPs were in noncoding sequences; the other five involved the more common missense variants (four in CYP2C8, one in CYP2C9) that change amino acids in the gene products. One haplotype containing two CYP2C8 coding variants and one CYP2C9 coding variant reaches an average frequency of 10% in Europe; a set of haplotypes with a different CYP2C8 coding variant reaches 17% in Africa.

Pharmacogenomics and pancreatic cancer treatment. Optimizing current therapy and individualizing future therapy.

Each year, more than 30,000 Americans are diagnosed with pancreatic cancer. We have only made incremental advancements in treatment of pancreatic cancer despite our best efforts. Research has revealed that pancreatic cancer is a genetic disease which is associated with various forms of cancer associated genetic alterations.

Pseudocirrhosis in a pancreatic cancer patient with liver metastases: a case report of complete resolution of pseudocirrhosis with an early recognition and management.

We report a case of pseudocirrhosis arising in the setting of regression of liver metastases from pancreatic cancer. A 55-year-old asymptomatic woman presented to our clinic with newly diagnosed metastatic pancreatic cancer with extensive liver metastases. She underwent systemic chemotherapy with gemcitabine and oxaliplatin (GEMOX).

Triple negative breast cancer: current understanding of biology and treatment options.

Purpose Of Review: We have made remarkable advances in treatment of breast cancer with combination chemotherapies, hormonal therapies, and modern targeted therapies. Triple negative breast cancers carry a poor prognosis, however, and they are insensitive to most available hormonal or targeted therapeutic agents thus far developed. A better understanding of pathophysiology, natural history, and currently available treatment options is necessary to improve outcomes of patients with triple negative breast cancer.

Long-term survival on capecitabine in two gemcitabine refractory pancreatic cancer patients. Is there a pharmacogenetic explanation?

Context: Capecitabine has shown efficacy in treatment of metastatic pancreatic cancer. Several researchers have identified thymidine phosphorylase, dihydropyrimidine dehydrogenase, or their ratio as indicators of response to capecitabine in various cancers.

Case Report: We report two patients with metastatic pancreatic carcinoma who had long-term survivals on capecitabine after gemcitabine failure.