ABSTRACT
Ruxolitinib, a small molecule JAK-1/2 inhibitor, was approved by the U.S. Food and Drug Administration (FDA) in November 2011, as the first therapeutic for the treatment of intermediate and high-risk myelofibrosis. The Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway is one of the most well-studied intracellular signaling networks. Recent advances in our understanding of the complexities of signal activation and regulation of gene expression has provided opportunities for targeted therapeutic interventions. Although numerous inhibitors of the JAK/STAT pathway are currently being evaluated in clinical trials, ruxolitinib represents the first FDA approved in-class JAK inhibitor. We report a drug eruption associated with ruxolitinib.
Subject(s)
Drug Eruptions/etiology , Erythema/chemically induced , Janus Kinases/antagonists & inhibitors , Primary Myelofibrosis/drug therapy , Pyrazoles/adverse effects , Drug Eruptions/pathology , Erythema/pathology , Humans , Male , Middle Aged , Nitriles , PyrimidinesABSTRACT
PURPOSE: This study reports a phase I immunotherapy trial in 23 women with metastatic breast cancer consisting of eight infusions of anti-CD3 × anti-HER2 bispecific antibody (HER2Bi) armed anti-CD3-activated T cells (ATC) in combination with low-dose IL-2 and granulocyte-macrophage colony-stimulating factor to determine safety, maximum tolerated dose (MTD), technical feasibility, T-cell trafficking, immune responses, time to progression, and overall survival (OS). EXPERIMENTAL DESIGN: ATC were expanded from leukapheresis product using IL2 and anti-CD3 monoclonal antibody and armed with HER2Bi. In 3+3 dose escalation design, groups of 3 patients received 5, 10, 20, or 40 × 10(9) armed ATC (aATC) per infusion. RESULTS: There were no dose-limiting toxicities and the MTD was not defined. It was technically feasible to grow 160 × 10(9) ATC from a single leukapheresis. aATC persisted in the blood for weeks and trafficked to tumors. Infusions of aATC induced anti-breast cancer responses and increases in immunokines. At 14.5 weeks after enrollment, 13 of 22 (59.1%) evaluable patients had stable disease and 9 of 22 (40.9%) had progressive disease. The median OS was 36.2 months for all patients, 57.4 months for HER2 3+ patients, and 27.4 months for HER2 0-2+ patients. CONCLUSIONS: Targeting HER2(+) and HER2(-) tumors with aATC infusions induced antitumor responses, increases in Th1 cytokines, and IL12 serum levels that suggest that aATC infusions vaccinated patients against their own tumors. These results provide a strong rationale for conducting phase II trials.