Cetuximab administered once every second week to patients with metastatic colorectal cancer: a two-part pharmacokinetic/pharmacodynamic phase I dose-escalation study
Abstract Background This phase I dose-escalation study was designed to determine the maximum tolerated dose (MTD) and recommended dose of cetuximab administered on an every-second-week schedule to patients with metastatic colorectal cancer, on the basis of safety, pharmacokinetic and pharmacodynamic evaluation. Patients and methods The study comprised two parts: a 6-week cetuximab monotherapy dose-escalation phase and a subsequent combination therapy phase, during which patients received cetuximab, at the same dose/schedule as in the monotherapy phase, followed by irinotecan plus infusional 5-fluorouracil/folinic acid (FOLFIRI). Patients in the control group received cetuximab as a 400 mg/m…
Phase I Pharmacokinetic/Pharmacodynamic Study of MLN8237, an Investigational, Oral, Selective Aurora A Kinase Inhibitor, in Patients with Advanced Solid Tumors
Abstract Purpose: Aurora A kinase (AAK) is a key regulator of mitosis and a target for anticancer drug development. This phase I study investigated the safety, pharmacokinetics, and pharmacodynamics of MLN8237 (alisertib), an investigational, oral, selective AAK inhibitor, in 59 adults with advanced solid tumors. Experimental Design: Patients received MLN8237 once daily or twice daily for 7, 14, or 21 consecutive days, followed by 14 days recovery, in 21-, 28-, or 35-day cycles. Dose-limiting toxicities (DLT) and the maximum-tolerated dose (MTD) for the 7- and 21-day schedules were determined. Pharmacokinetic parameters were derived from plasma concentration–time profiles. AAK inhibition in…
Phase I Assessment of New Mechanism-Based Pharmacodynamic Biomarkers for MLN8054, a Small-Molecule Inhibitor of Aurora A Kinase
Abstract The mitotic kinase Aurora A is an important therapeutic target for cancer therapy. This study evaluated new mechanism-based pharmacodynamic biomarkers in cancer patients in two phase I studies of MLN8054, a small-molecule inhibitor of Aurora A kinase. Patients with advanced solid tumors received MLN8054 orally for 7 consecutive days in escalating dose cohorts, with skin and tumor biopsies obtained before and after dosing. Skin biopsies were evaluated for increased mitotic cells within the basal epithelium. Tumor biopsies were assessed for accumulation of mitotic cells within proliferative tumor regions. Several patients in the highest dose cohorts showed marked increases in the ski…
FCGR polymorphisms and cetuximab efficacy in chemorefractory metastatic colorectal cancer: an international consortium study
OBJECTIVE: We aimed to better clarify the role of germline variants of the FCG2 receptor, FCGR2A-H131R and FCGR3A-V158F, on the therapeutic efficacy of cetuximab in metastatic colorectal cancer (mCRC). A large cohort with sufficient statistical power was assembled.DESIGN: To show a HR advantage of 0.6 in progression-free survival (PFS) for FCGR2A-HH versus the rest and FCGR3A-VV versus the rest, with an 80% power, 80 Kirsten Rat Sarcoma Viral Oncogene Homolog (KRAS) wild-type (KRAS-WT) and 52 KRAS-WT patients are required, respectively. This leads to a total sample size of 952 and 619 patients, respectively. Samples were collected from 1123 mCRC patients from 15 European centres treated wit…
PD-0024 Phase I/II Study of Folfiri Plus the MEK1/2 Inhibitor Pimasertib (MSC1936369B) as Second-Line Treatment for KRAS Mutated Metastatic Colorectal Cancer
ABSTRACT Introduction Pimasertib is a highly selective inhibitor of the MEK1/2 kinases of the MAPK pathway. It demonstrates potent antitumor activity in cell lines and xenograft models with activating (mainly BRAF and KRAS) mutations. A two-part study, comprising a safety run-in part followed by a randomized phase II part, was designed to investigate FOLFIRI plus pimasertib as second-line treatment for patients with KRAS mutated (mt) metastatic colorectal cancer (mCRC). The results of the safety run-in part, conducted primarily to determine the maximum tolerated dose (MTD) and the recommended phase II dose (RP2D), are reported here. Methods Patients with KRAS mt mCRC progressing on first-li…
A First-in-Human Phase I Study of the ATP-Competitive AKT Inhibitor Ipatasertib Demonstrates Robust and Safe Targeting of AKT in Patients with Solid Tumors.
Abstract Activation of AKT signaling by PTEN loss or PIK3CA mutations occurs frequently in human cancers, but targeting AKT has been difficult due to the mechanism-based toxicities of inhibitors that target the inactive conformation of AKT. Ipatasertib (GDC-0068) is a novel selective ATP-competitive small-molecule inhibitor of AKT that preferentially targets active phosphorylated AKT (pAKT) and is potent in cell lines with evidence of AKT activation. In this phase I study, ipatasertib was well tolerated; most adverse events were gastrointestinal and grade 1–2 in severity. The exposures of ipatasertib ≥200 mg daily in patients correlated with preclinical TGI90, and pharmacodynamic studies co…