Sara Zaknoen

Infectious complications and immunodeficiency in patients with human T‐cell lymphotropic virus I‐associated adult T‐cell leukemia/lymphoma

Background. Adult T‐cell leukemia/lymphoma (ATL) is a malignancy of mature T‐cells occurring in patients infected with the human T‐cell lymphotropic virus‐I. These patients frequently develop a variety of infections throughout their disease course.

Biomarker‐based phase I dose‐escalation, pharmacokinetic, and pharmacodynamic study of oral apricoxib in combination with erlotinib in advanced nonsmall cell lung cancer

Apricoxib, a novel once‐daily selective cyclooxygenase‐2 inhibitor, was investigated in combination with erlotinib for recurrent stage IIIB/IV nonsmall cell lung cancer to determine the maximum tolerated dose, dose‐limiting toxicity, and recommended phase II dose (RP2D) based on changes in urinary prostaglandin E2 metabolite (PGE‐M).

A randomized, placebo-controlled, multicenter, biomarker-selected, phase 2 study of apricoxib in combination with erlotinib in patients with advanced non-small-cell lung cancer.

Cyclooxygenase-2 (COX-2) overexpression is associated with a poor prognosis in non–small-cell lung cancer (NSCLC) and may promote resistance to epidermal growth factor receptor inhibitors. This randomized phase 2 trial evaluated apricoxib, a novel COX-2 inhibitor, in combination with erlotinib in biomarker-selected patients. Patients with stage IIIB/IV NSCLC previously treated with platinum-based chemotherapy were randomized (2:1) to 400 mg/day apricoxib plus 150 mg/day erlotinib (AP/E) or placebo plus erlotinib (P/E) in 21-day cycles until disease progression or unacceptable toxicity. The primary endpoint was time to progression (TTP). A decrease of 50% or more from baseline urinary prostaglandin E2 metabolite after a 5-day, open-label, run-in period was used to select eligible patients. One hundred twenty patients (median age 64 years) were randomized (78 to AP/E and 42 to P/E). Overall median TTP was 1.8 months in the AP/E group and 2.1 months in the P/E group, with a 12% objective response rate in both groups (intent-to-treat analysis). A subgroup analysis in patients aged 65 years or younger demonstrated a statistically significant TTP benefit for AP/E (hazard ratio 0.5 [95% confidence interval: not applicable–0.9]; p=0.018) and overall survival advantage at minimum 1-year follow-up (median 12.2 versus 4.0 months; hazard ratio=0.5; p=0.021). The most common adverse events were rash, diarrhea, fatigue, and nausea. Toxicity contributed to early discontinuations in patients aged more than 65 years treated with AP/E. This is the first randomized placebo-controlled study of a COX-2 inhibitor in NSCLC to use a prospective patient-selection strategy. Although AP/E seemed to improve TTP and overall survival in a subset of patients aged 65 years or younger, the primary endpoint of the trial was not met.

The interleukin-2 receptor: a target for immunotherapy.

Immune intervention began almost two centuries ago when Jenner introduced vaccination with cowpox as a means of protecting against smallpox. This form of immune intervention plays a dominant role in the prevention of human disease. Furthermore, immunological approaches including radioimmunoassays, enzyme-linked immunoassays, microfluorometry, and modern molecular immunogenetics are critical in clinical diagnosis.

APRICoT-P: A phase II randomized placebo controlled study of apricoxib, a potent COX-2 inhibitor in combination with erlotinib and gemcitabine in pancreatic cancer patients.

TPS224 Background: Apricoxib is a once-daily, oral, potent and selective inhibitor of COX-2. The COX-2 pathway plays a key role in tumor growth, angiogenesis, and resistance to therapy. COX-2 and EGFR signaling regulate the dominant ERK/MAPK, AKT and b-catenin pathways in this disease, so combinations of COX-2 and EGFR inhibitors are of particular interest in pancreatic cancer. In addition, b-catenin activity is implicated in gemcitabine resistance, so combination of standard chemotherapy with apricoxib and erlotinib could have synergistic effects. In a previous phase I study in NSCLC the combination of apricoxib and erlotinib was found to be safe and demonstrated a tumor control rate of 60% in recurrent patients. In an ongoing phase II study in NSCLC patients are being selected based on a decrease in PGE-M a urinary marker of COX-2 activity. Because pancreatic cancer overwhelmingly overexpresses COX-2 in tumor cells, patients were not selected on the basis of decreases in PGE-M. However, baseline and pos...

TG01, a new potent COX-2 inhibitor in combination with erlotinib in metastatic or recurrent non-small cell lung cancer (NSCLC) patients: A phase 1 study

Objectives: Apricoxib is a once-daily oral, potent and selective inhibitor of COX-2. The COX-2 pathway plays a key role in tumor growth, angiogenesis and resistance to therapy. Preclinical studies of apricoxib show in vitro and in vivo activity in human lung cancer xenograft models. COX-2 signaling activates the Erk/MAPK pathway, thus combinations of COX-2 and EGFR inhibitors are of interest, particularly in NSCLC. The purpose of this study was to determine the safety and feasibility of combining apricoxib with erlotinib in NSCLC patients and to determine the recommended Phase II dose (RPIID) based on either the MTD or the optimum biologic dose (OBD). OBD was based on decreases in PGE-M, a urinary metabolite of PGE2. Methods: Pts with recurrent or metastatic NSCLC were treated with erlotinib (150 mg PO daily) and escalating doses of apricoxib (100-1200mg PO daily). Prior treatment with an EGFR TKI was allowed. PK for apricoxib and erlotinib were evaluated. PGE-M a urinary metabolite of PGE2, was collected at baseline and Day 15 of C1 and Day 1 of C2. The RPIID was to be based on > 75% inhibition of PGE-M and/or the MTD. DLT was defined as drug related G3 and G4 events. Results: 19 patients have been enrolled (3 at apricoxib 100mg; 3 at apricoxib 200mg, 12 at apricoxib 400mg). Characteristics: Sex: M/F: 7/12; Age range 54-81; The majority were ECOG PS 0 or 1. Number of prior therapies: 1-5. There were no DLTs; most common adverse events include G1 and G2 nausea, diarrhea and rash. 2 serious adverse events (gastric ulcer, SOB) and 2 deaths due to disease progression occurred. The RPIID selected was 400mg based on decline in urinary PGE-M and PK. Of 14 evaluable patients: 1 PR, 8 SD, and 5 PD as best response. SD was seen in pts having failed prior EGFR TKI therapy. Apricoxib pharmacokinetics revealed a median Tmax of 2 hours (range 1.5-4), mean (SD) T1/2 of 11.8 (5.3) hours, Cmax of 313.0 (99.6) ng/ml and AUC (0-t) of 2816 (1204) ng.h/ml. Conclusions: 1) Apricoxib and erlotinib have been safely administered in this Phase I study. 2) The RPIID of the combination is apricoxib 400mg and erlotinib 150mg. 3) The activity observed warrants further evaluation in a randomized Phase II study. That study is ongoing. TREATMENT SCHEDULE PATIENT DEMOGRAPHICS DISEASE CHARACTERISTICS