Joe Stephenson

An Open-Label Clinical Trial Evaluating Safety and Pharmacokinetics of Two Dosing Schedules of Panitumumab in Patients with Solid Tumors

PURPOSE This study evaluated safety, pharmacokinetics, and efficacy of 2 dose schedules and 2 infusion times of panitumumab in patients with advanced solid malignancies. PATIENTS AND METHODS This phase I multicenter, open-label study sequentially enrolled patients with advanced solid tumors refractory to standard therapy, or for which no standard therapy exists, to receive panitumumab 6 mg/kg every 2 weeks or 9 mg/kg every 3 weeks. Patients receiving panitumumab every 2 weeks received either all infusions over 60 minutes or a 60-minute infusion for the first dose followed by 30-minute infusions if the first infusion was well tolerated. Patients in the every-3-week cohort received 60-minute infusions. Safety outcomes included the incidence of adverse events and antipanitumumab antibody formation. Pharmacokinetic properties were determined. Efficacy endpoints included response rate and duration of response. RESULTS Eighty-six patients were enrolled; 84 (98%) received panitumumab. Treatment-related adverse events occurred in 90% of patients. Safety profiles were similar between patients receiving 30-minute (n = 20) and 60-minute (n = 43) infusions every 2 weeks and patients receiving panitumumab every 3 weeks (n = 21). Panitumumab exposure at steady state increased dose proportionally, and peak serum concentrations were similar in patients receiving either 30- or 60-minute infusions every 2 weeks. Objective responses were seen in 4 patients (5%) with colon, rectal, esophageal, and bladder cancers. CONCLUSION Similar drug exposures and safety profiles were observed in patients receiving panitumumab 6 mg/kg every 2 weeks with either 30- or 60-minute infusions and antitumor activity was seen in some patients. Exposure increased approximately dose proportionally at steady state.

Sequential ofatumumab and lenalidomide for the treatment of relapsed and refractory chronic lymphocytic leukemia and small lymphocytic lymphoma

Abstract Ofatumumab is a fully human anti-CD20 monoclonal antibody with enhanced antibody dependent and complement dependent cytotoxicity. Lenalidomide induces T cell and natural killer (NK) cell activation and in vitro enhances clearance of chronic lymphocytic leukemia (CLL) cells by monoclonal antibodies. We performed a multi-center, phase 2 trial of sequential treatment with ofatumumab and lenalidomide in patients with advanced, relapsed and refractory (R/R) CLL, consisting of ofatumumab 2000 mg intravenously on day 1 and lenalidomide 10 mg on days 8–28, for up to six cycles. Twenty-one subjects were included with median age of 63 years and two prior lines of therapy. The overall response rate was 47.6% and 23.8% had stable disease. Median overall survival was 21.5 months. Neutropenia and thrombocytopenia were the most frequent adverse events. Tumor flare reaction occurred in 43% of subjects. Intracycle sequential ofatumumab plus lenalidomide is active in high-risk R/R CLL and well tolerated except for frequent cytopenias.

Preliminary study of the specific endothelin a receptor antagonist zibotentan in combination with docetaxel in patients with metastatic castration-resistant prostate cancer†

This two‐part study assessed the safety and tolerability of combined treatment with zibotentan (ZD4054), a specific endothelin A receptor antagonist, plus docetaxel in patients with metastatic castration‐resistant prostate cancer.

Effects of Esomeprazole on the Pharmacokinetics of Lapatinib in Breast Cancer Patients

The aqueous solubility of lapatinib declines significantly at pH >4, suggesting that its bioavailability might be lowered by acid‐reducing drugs. A study was therefore conducted to assess the effects of esomeprazole on lapatinib pharmacokinetics (PK). Women with metastatic human epidermal growth factor receptor 2 positive (HER2+) breast cancer were enrolled. Patients received 1,250 mg lapatinib once daily (QD) in the morning on Days 1–7 (Period 1) and Days 8–14 (Period 2) with 40 mg esomeprazole QD at bedtime 3 hours after dinner on Days 8–14. Lapatinib PK sampling occurred during the 24‐hour steady‐state dosing intervals on Day 7 (lapatinib alone) and Day 14 (lapatinib with esomeprazole). Esomeprazole treatment resulted in decreased lapatinib bioavailability (mean 26%, range 6–49%) that was inversely associated with patient age as a significant covariate.

An open-label, phase II study of the polo-like kinase-1 (Plk-1) inhibitor, BI 2536, in patients with relapsed small cell lung cancer (SCLC)

OBJECTIVES This phase II, open-label study was designed to evaluate the response rate to the polo-like kinase 1 (Plk-1) inhibitor BI 2536 in patients with sensitive-relapsed small cell lung cancer (SCLC). Secondary endpoints included progression-free survival (PFS), overall survival (OS), duration of response, and safety. MATERIALS AND METHODS Patients were treated with the recommended phase II dose of 200mg of BI 2536 intravenously every 21days. This was a two-stage design with an early stopping rule in place if responses were not seen in at least 2 of the first 18 enrolled patients. RESULTS AND CONCLUSION Twenty-three patients were enrolled in the study and 21 patients were evaluable for response. No responses were observed and all 23 patients have progressed. The median PFS was 1.4 months. Treatment was generally well tolerated and the most frequent adverse events were neutropenia, fatigue, nausea, vomiting, and constipation. BI 2536 is not effective in the treatment of sensitive relapsed SCLC. The criteria for expanding the trial to the second stage were not achieved, and the study was terminated for a lack of efficacy.

First-in-Human Study of AMG 820, a Monoclonal Anti-Colony-Stimulating Factor 1 Receptor Antibody, in Patients with Advanced Solid Tumors

Purpose: Binding of colony-stimulating factor 1 (CSF1) ligand to the CSF1 receptor (CSF1R) regulates survival of tumor-associated macrophages, which generally promote an immunosuppressive tumor microenvironment. AMG 820 is an investigational, fully human CSF1R antibody that inhibits binding of the ligands CSF1 and IL34 and subsequent ligand-mediated receptor activation. This first-in-human phase I study evaluated the safety, pharmacokinetics, pharmacodynamics, and antitumor activity of AMG 820. Experimental Design: Adult patients with relapsed or refractory advanced solid tumors received intravenous AMG 820 0.5 mg/kg once weekly or 1.5 to 20 mg/kg every 2 weeks until disease progression, adverse event (AE), or consent withdrawal. Results: Twenty-five patients received ≥1 dose of AMG 820. AMG 820 was tolerated up to 20 mg/kg; the MTD was not reached. One dose-limiting toxicity was observed (20 mg/kg; nonreversible grade 3 deafness). Most patients (76%) had treatment-related AEs; the most common were periorbital edema (44%), increased aspartate aminotransferase (AST; 28%), fatigue (24%), nausea (16%), increased blood alkaline phosphatase (12%), and blurred vision (12%). No patients had serious or fatal treatment-related AEs; 28% had grade ≥3 treatment-related AEs. Grade 3 AST elevations resolved when treatment was withheld. AMG 820 showed linear pharmacokinetics, with minimal accumulation (<2-fold) after repeated dosing. Pharmacodynamic increases in serum CSF1 concentrations and reduced numbers of skin macrophages were observed. Best response was stable disease in 8 patients (32%). Conclusions: AMG 820 was tolerated with manageable toxicities up to 20 mg/kg every 2 weeks. Pharmacodynamic response was demonstrated, and limited antitumor activity was observed. Clin Cancer Res; 23(19); 5703–10. ©2017 AACR.

Abstract CT137: First-in-human study of AMG 820, a monoclonal anti-CSF-1R (c-fms) antibody, in patients (pts) with advanced solid tumors

Background: Tumor-associated macrophages (TAMs) may contribute to tumor growth and invasion and promote an immunosuppressive tumor microenvironment, making them an attractive target for cancer immunotherapy. TAMs can be activated by the binding of colony stimulating factor-1 (CSF-1) to its receptor CSF-1R (c-fms). AMG 820 is an investigational, fully human antagonistic antibody to CSF-1R that inhibits ligand-induced receptor activation. In this open-label, sequential dose-escalation study, we evaluated the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and efficacy of AMG 820. Methods: Key eligibility criteria: age ? 18 years, advanced solid tumors relapsed or refractory to standard treatment, measurable disease per RECIST 1.1, ECOG performance status ? 2, and no primary central nervous system tumors/metastases. AMG 820 was administered by IV infusion once weekly at a starting dose of 0.5 mg/kg (cohort 1). Dosing frequency was later amended to once every 2 weeks (Q2W) with planned escalation to 1.5, 3, 6, 10, 20, and 30 mg/kg (cohorts 2–7), following a 3 + 3 design until a maximum tolerated dose (MTD, highest dose at which Results: A total of 25 pts received ? 1 dose of AMG 820: 3 pts at 0.5, 1.5, and 6 mg/kg; 4 pts at 3 and 10 mg/kg; 8 pts at 20 mg/kg. Median (range) age: 63 (48–80) years. Women: 56%. ECOG 0/1/2: 20%/76%/4%. MTD was not reached. One DLT was observed (20 mg/kg): nonreversible grade 3 hearing impairment in a female pt with anal cancer with confounding factors (prior treatment [tx] with cisplatin). Most pts (76%) had tx-related adverse events (TRAEs). Most common TRAEs (in > 10% of pts overall) were periorbital edema (11, 44%), increased aspartate aminotransferase (7, 28%), fatigue (6, 24%), nausea (4, 16%), increased blood alkaline phosphatase (3, 12%), and blurred vision (3, 12%). Grade ? 3 TRAEs were observed in 28% of pts. There were no serious or fatal TRAEs. After the first dose of AMG 820 at 20 mg/kg, mean estimates of Cmax and AUClast (AUC from time 0 to time of last sample) were 619 μg/mL and 89,200 μg•hr/mL, respectively. Both AMG 820 AUClast and Cmax increased linearly with dose, with minimal accumulation ( Conclusions: AMG 820 was tolerated with manageable toxicities up to 20 mg/kg Q2W and showed linear PK, with PD response in CSF-1 serum levels and tx-related changes in skin macrophages. These results and an increasing understanding of the role of TAMs in tumor immunosuppression provide the rationale for combining AMG 820 with other immunotherapies. Citation Format: Kyriakos Papadopoulos, Larry Gluck, Lainie P. Martin, Anthony J. Olszanski, Gateree Ngarmchamnanrith, Erik Rasmussen, Benny Amore, Dirk Nagorsen, John S. Hill, Joe Stephenson. First-in-human study of AMG 820, a monoclonal anti-CSF-1R (c-fms) antibody, in patients (pts) with advanced solid tumors. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT137.