Search

Purpose: This first-in-human study aimed to determine the MTD and safety of MEDI3617, a selective anti–angiopoietin-2 (Ang2) mAb, alone and combined with bevacizumab or cytotoxic chemotherapy. Patients and Methods: This phase I/Ib, multicenter, open-label, dose-escalation and dose-expansion study evaluated patients with advanced solid tumors. Patients received intravenous MEDI3617 as monotherapy [5–1,500 mg every 3 weeks (Q3W)] or with bevacizumab every 2 weeks (Q2W) or Q3W, weekly paclitaxel, or carboplatin plus paclitaxel Q3W. Dose expansions included a monotherapy cohort in platinum-resistant ovarian cancer and a bevacizumab combination cohort in bevacizumab-refractory malignant glioma. Safety/tolerability, pharmacokinetics, pharmacodynamics, and clinical activity were assessed. Results: We enrolled 116 patients. No formal MTD was identified (monotherapy or combination therapy). MEDI3617 demonstrated linear pharmacokinetics and maximal accumulation of peripheral Ang2 binding at doses above 300 mg Q3W. MEDI3617 monotherapy safety profile was acceptable, except in advanced ovarian cancer [prolonged grade 3 edema-associated adverse events (AE) occurred]. Otherwise, MEDI3617 combined with chemotherapy or bevacizumab was well tolerated. The AE profiles of MEDI3617 and bevacizumab were largely non-overlapping. Overall response rates in ovarian cancer and glioma monotherapy dose-expansion arms were 6% and 0%, respectively. Conclusions: Recommended MEDI3617 monotherapy dosage is 1,500 mg Q3W or 1,000 mg Q2W, except in ovarian cancer. Although peripheral edema has occurred with other Ang2 inhibitors, the severity and duration seen here in ovarian cancer potentially identifies a new, clinically significant safety signal for this class of agents. On the basis of limited clinical activity, MEDI3617 development was discontinued. Clin Cancer Res; 24(12); 2749–57. ©2018 AACR.

Purpose: Increased mitogenic signaling and angiogenesis, frequently facilitated by somatic activation of EGF receptor (EGFR; ErbB1) and/or loss of PTEN, and VEGF overexpression, respectively, drive malignant glioma growth. We hypothesized that patients with recurrent glioblastoma would exhibit differential antitumor benefit based on tumor PTEN/EGFRvIII status when treated with the antiangiogenic agent pazopanib and the ErbB inhibitor lapatinib. Experimental Design: A phase II study evaluated the antitumor activity of pazopanib 400 mg/d plus lapatinib 1,000 mg/d in patients with grade 4 malignant glioma and known PTEN/EGFRvIII status not receiving enzyme-inducing anticonvulsants (EIAC). The phase II study used a two-stage Green–Dahlberg design for futility. An independent, parallel phase I component determined the maximum-tolerated regimen (MTR) of pazopanib and lapatinib in patients with grade 3/4 glioma receiving EIACs. Results: The six-month progression-free survival (PFS) rates in phase II (n = 41) were 0% and 15% in the PTEN/EGFRvIII-positive and PTEN/EGFRvIII-negative cohorts, respectively, leading to early termination. Two patients (5%) had a partial response and 14 patients (34%) had stable disease lasting 8 or more weeks. In phase I (n = 34), the MTR was not reached. On the basis of pharmacokinetic and safety review, a regimen of pazopanib 600 mg plus lapatinib 1,000 mg, each twice daily, was considered safe. Concomitant EIACs reduced exposure to pazopanib and lapatinib. Conclusions: The antitumor activity of this combination at the phase II dose tested was limited. Pharmacokinetic data indicated that exposure to lapatinib was subtherapeutic in the phase II evaluation. Evaluation of intratumoral drug delivery and activity may be essential for hypothesis-testing trials with targeted agents in malignant glioma. Clin Cancer Res; 19(4); 900–8. ©2012 AACR.

Background: A phase I dose-escalating study of pazopanib was conducted to determine the maximum tolerated dose (MTD), pharmacokinetic/pharmacodynamic relationships, and clinical activity in patients with advanced hepatocellular carcinoma (HCC). Experimental Design: Asian patients (N = 28) were dose escalated on pazopanib (200–800 mg) once daily (QD) on 21-day cycles, with MTD as the primary endpoint using a modified 3 + 3 design. Changes in tumor vasculature were evaluated by dynamic contrast-enhanced MRI (DCE—MRI). Results: Two of five patients at the 800-mg dose level experienced dose-limiting toxicities [grade 3 aspartate aminotransferase (AST)/alanine aminotransferase (ALT) elevations and grade 3 malaise]. The MTD in patients with HCC (Child–Pugh class A) was 600 mg QD. Diarrhea, skin hypopigmentation, and AST elevation were the most commonly reported adverse events at the MTD. Mean Cmax and area under the concentration-time curve (AUC0–6) of pazopanib and its metabolites did not increase dose proportionally across the 200 to 800 mg range. Reductions in IAUGC and Ktrans were shown at all pazopanib doses evaluated, with the greatest reductions at 600 and 800 mg. Although larger DCE-MRI parameter decreases were associated with larger C24 and Cmax values, there was no constant relationship between tumor perfusion decreases measured by DCE-MRI and plasma pazopanib pharmacokinetic parameters. Overall, 19 patients (73%) had either partial response or stable disease. Conclusion: Pazopanib has a manageable safety profile in patients with advanced HCC, and 600 mg was chosen for further development of pazopanib in advanced HCCs. Moreover, pazopanib reduced tumor vessel leakage, as shown by DCE-MRI, indicating a direct effect on HCC vasculature that might be associated with its antitumor activity. Clin Cancer Res; 17(21); 6914–23. ©2011 AACR.

Purpose: Interleukin-18 (IL-18) is an immunostimulatory cytokine with antitumor activity in preclinical animal models. A phase I study of recombinant human IL-18 (rhIL-18) was done to determine the toxicity, pharmacokinetics, and biological activities of rhIL-18 in patients with advanced cancer.Experimental Design: Cohorts of patients were given escalating doses of rhIL-18, each administered as a 2-hour i.v. infusion on 5 consecutive days. Toxicities were graded using standard criteria. Serial blood samples were obtained for pharmacokinetic and pharmacodynamic measurements.Results: Twenty-eight patients (21 with renal cell cancer, 6 with melanoma, and 1 with Hodgkin's lymphoma) were given rhIL-18 in doses ranging from 3 to 1,000 μg/kg. Common side effects included chills, fever, nausea, headache, and hypotension. Common laboratory abnormalities included transient, asymptomatic grade 1 to 2 neutropenia, thrombocytopenia, anemia, hypoalbuminemia, hyponatremia, and elevations in liver transaminases. One patient in the 100 μg/kg cohort experienced transient grade 3 hypotension and grade 2 bradycardia during the first infusion of rhIL-18. No other dose-limiting toxicities were observed. Plasma concentrations of rhIL-18 increased with increasing dose, and 2.5-fold accumulation was observed with repeated dosing. Biological effects of rhIL-18 included transient lymphopenia and increased expression of activation antigens on lymphocytes and monocytes. Increases in serum concentrations of IFN-γ, granulocyte macrophage colony-stimulating factor, IL-18 binding protein, and soluble Fas ligand were observed. Two patients experienced unconfirmed partial responses after rhIL-18 treatment.Conclusions: rhIL-18 can be safely given in biologically active doses to patients with advanced cancer. A maximum tolerated dose of rhIL-18 was not determined. Further clinical studies of rhIL-18 are warranted.