Lia Gore

Phase I pharmacokinetic and pharmacodynamic study of the oral, small-molecule mitogen-activated protein kinase kinase 1/2 inhibitor AZD6244 (ARRY-142886) in patients with advanced cancers.

PURPOSE To assess the tolerability, pharmacokinetics (PKs), and pharmacodynamics (PDs) of the mitogen-activated protein kinase kinase (MEK) 1/2 inhibitor AZD6244 (ARRY-142886) in patients with advanced cancer. PATIENTS AND METHODS In part A, patients received escalating doses to determine the maximum-tolerated dose (MTD). In both parts, blood samples were collected to assess PK and PD parameters. In part B, patients were stratified by cancer type (melanoma v other) and randomly assigned to receive the MTD or 50% MTD. Biopsies were collected to determine inhibition of ERK phosphorylation, Ki-67 expression, and BRAF, KRAS, and NRAS mutations. RESULTS Fifty-seven patients were enrolled. MTD in part A was 200 mg bid, but this dose was discontinued in part B because of toxicity. The 50% MTD (100 mg bid) was well tolerated. Rash was the most frequent and dose-limiting toxicity. Most other adverse events were grade 1 or 2. The PKs were less than dose proportional, with a median half-life of approximately 8 hours and inhibition of ERK phosphorylation in peripheral-blood mononuclear cells at all dose levels. Paired tumor biopsies demonstrated reduced ERK phosphorylation (geometric mean, 79%). Five of 20 patients demonstrated >or= 50% inhibition of Ki-67 expression, and RAF or RAS mutations were detected in 10 of 26 assessable tumor samples. Nine patients had stable disease (SD) for >or= 5 months, including two patients with SD for 19 (thyroid cancer) and 22 (uveal melanoma plus renal cancer) 28-day cycles. CONCLUSION AZD6244 was well tolerated with target inhibition demonstrated at the recommended phase II dose. PK analyses supported twice-daily dosing. Prolonged SD was seen in a variety of advanced cancers. Phase II studies are ongoing.

Phase I Pharmacologic and Biologic Study of Ramucirumab (IMC-1121B), a Fully Human Immunoglobulin G1 Monoclonal Antibody Targeting the Vascular Endothelial Growth Factor Receptor-2

PURPOSE To evaluate the safety, maximum-tolerated dose (MTD), pharmacokinetics (PKs), pharmacodynamics, and preliminary anticancer activity of ramucirumab (IMC-1121B), a fully human immunoglobulin G(1) monoclonal antibody targeting the vascular endothelial growth factor receptor (VEGFR)-2. PATIENTS AND METHODS Patients with advanced solid malignancies were treated once weekly with escalating doses of ramucirumab. Blood was sampled for PK studies throughout treatment. The effects of ramucirumab on circulating vascular endothelial growth factor-A (VEGF-A), soluble VEGFR-1 and VEGFR-2, tumor perfusion, and vascularity using dynamic contrast-enhanced magnetic resonance imaging were assessed. Results Thirty-seven patients were treated with 2 to 16 mg/kg of ramucirumab. After one patient each developed dose-limiting hypertension and deep venous thrombosis at 16 mg/kg, the next lower dose (13 mg/kg) was considered the MTD. Nausea, vomiting, headache, fatigue, and proteinuria were also noted. Four (15%) of 27 patients with measurable disease had a partial response (PR), and 11 (30%) of 37 patients had either a PR or stable disease lasting at least 6 months. PKs were characterized by dose-dependent elimination and nonlinear exposure consistent with saturable clearance. Mean trough concentrations exceeded biologically relevant target levels throughout treatment at all dose levels. Serum VEGF-A increased 1.5 to 3.5 times above pretreatment values and remained in this range throughout treatment at all dose levels. Tumor perfusion and vascularity decreased in 69% of evaluable patients. CONCLUSION Objective antitumor activity and antiangiogenic effects were observed over a wide range of dose levels, suggesting that ramucirumab may have a favorable therapeutic index in treating malignancies amenable to VEGFR-2 inhibition.

Cytokine release syndrome after blinatumomab treatment related to abnormal macrophage activation and ameliorated with cytokine-directed therapy

Blinatumomab is a CD19/CD3-bispecific T-cell receptor-engaging (BiTE) antibody with efficacy in refractory B-precursor acute lymphoblastic leukemia. Some patients treated with blinatumomab and other T cell-activating therapies develop cytokine release syndrome (CRS). We hypothesized that patients with more severe toxicity may experience abnormal macrophage activation triggered by the release of cytokines by T-cell receptor-activated cytotoxic T cells engaged by BiTE antibodies and leading to hemophagocytic lymphohistiocytosis (HLH). We prospectively monitored a patient during blinatumomab treatment and observed that he developed HLH. He became ill 36 hours into the infusion with fever, respiratory failure, and circulatory collapse. He developed hyperferritinemia, cytopenias, hypofibrinogenemia, and a cytokine profile diagnostic for HLH. The HLH continued to progress after discontinuation of blinatumomab; however, he had rapid improvement after IL-6 receptor-directed therapy with tocilizumab. Patients treated with T cell-activating therapies, including blinatumomab, should be monitored for HLH, and cytokine-directed therapy may be considered in cases of life-threatening CRS. This trial was registered at www.clinicaltrials.gov as #NCT00103285.

Safety, pharmacokinetics, and pharmacodynamics of AMG 102, a fully human hepatocyte growth factor-neutralizing monoclonal antibody, in a first-in-human study of patients with advanced solid tumors.

Purpose: The aims were to assess the safety, pharmacokinetics, maximum tolerated dose, and antitumor activity of AMG 102, a fully human hepatocyte growth factor/scatter factor (HGF/SF)–neutralizing monoclonal antibody, in patients with solid tumors. Experimental Design: Patients (N = 40) with refractory advanced solid tumors were enrolled into six sequential dose-escalation cohorts (0.5, 1, 3, 5, 10, or 20 mg/kg AMG 102 i.v. every 2 weeks) and a dose-expansion cohort (20 mg/kg AMG 102 every 2 weeks). Safety, anti–AMG 102 antibody formation, pharmacokinetics, tumor response, and exploratory biomarkers were assessed. Results: AMG 102 was well tolerated up to the planned maximum dose of 20 mg/kg, and the maximum tolerated dose was not reached. Treatment-related adverse events were generally mild and included fatigue (13%), constipation (8%), nausea (8%), vomiting (5%), anorexia (5%), myalgia (5%), and hypertension (5%). Two patients experienced dose-limiting toxicities: one patient (0.5 mg/kg cohort) experienced grade 3 hypoxia and grade 3 dyspnea and one patient (1 mg/kg cohort) experienced grade 3 upper gastrointestinal hemorrhage. No anti–AMG 102 antibodies were detected, and AMG 102 had linear pharmacokinetics within the dose range investigated. Sixteen of 23 (70%) evaluable patients had a best response of stable disease with progression-free survival ranging from 7.9 to 40 weeks. Circulating levels of the biomarker HGF/SF (bound and unbound) increased in a dose-dependent manner, whereas soluble c-Met concentrations were generally similar across doses. Conclusions: AMG 102 is safe and well tolerated, has a favorable pharmacokinetic profile, and will be further investigated as a monotherapy and in combination with other agents. Clin Cancer Res; 16(2); 699–710

MGMT promoter methylation correlates with survival benefit and sensitivity to temozolomide in pediatric glioblastoma.

Methylation of the DNA‐repair gene O6‐methylguanine‐DNA methyltransferase (MGMT) causes gene silencing. This epigenetic modification has been associated with a favorable prognosis in adult patients with glioblastoma (GBM) who receive temozolomide and other alkylating agents. We explored MGMT promoter methylation in pediatric GBM and its relationship to survival and temozolomide sensitivity.

A phase I study of weekly R1507, a human monoclonal antibody insulin-like growth factor-I receptor antagonist, in patients with advanced solid tumors.

Purpose: A phase I study was conducted to evaluate the pharmacokinetics, pharmacodynamics, safety, and tolerability of R1507—a fully human IgG1 type monoclonal antibody directed against the human insulin-like growth factor-I receptor. Experimental design: Patients with advanced solid tumors were assigned to receive i.v. R1507 weekly (qW), starting with 1 mg/kg. Subsequent cohorts were dosed at 3 and then 9 mg/kg. An additional 12 patients received 9 mg/kg R1507 qW. Patients remained on the study until the development of a dose-limiting toxicity or progressive disease. Results: In total, 37 patients were treated with R1507 qW. No dose-limiting toxicities were identified and the maximum tolerated dose was not reached. The pharmacokinetics of R1507 were characterized by a slow clearance and limited volume of distribution, with an estimated elimination half-life justifying weekly administration. Serum IGF-I ligand levels increased proportionally to dose during the first 72 hours in all cohorts. R1507 was well tolerated. Two patients diagnosed with Ewings sarcoma had partial responses of 11.5 and >26 months (ongoing at time of submission); 13 patients had stable disease; and 16 had progressive disease as best response by the Response Evaluation Criteria in Solid Tumors. Conclusion: R1507 is well tolerated and shows antitumor activity in patients with solid neoplasms, in particular Ewings sarcoma. The recommended dose for the weekly schedule is 9 mg/kg qW. Clin Cancer Res; 16(8); 2458–65. ©2010 AACR.

A phase I and pharmacokinetic study of the oral histone deacetylase inhibitor, MS-275, in patients with refractory solid tumors and lymphomas.

Purpose: To evaluate the toxicity profile, pharmacologic, and biological properties of 3-pyridylmethyl N-{4-[(2-aminophenyl)carbamoyl]benzyl}carbamate (MS-275), a histone deacetylase inhibitor, when administered orally on three different dosing schedules. Experimental Design: Patients with advanced solid malignancies and lymphomas were treated on three dose schedules: once every other week, twice weekly for 3 weeks every 28 days, and once weekly for 3 weeks every 28 days. First-cycle plasma pharmacokinetics and peripheral blood mononuclear cell histone acetylation were determined. Results: Twenty-seven patients received ≥149 courses of treatment. Hypophosphatemia and asthenia were dose limiting on the weekly and twice-weekly dosing schedules; there was no dose-limiting toxicity on the every other week schedule. Pharmacokinetic variables revealed dose-dependent and dose-proportional increases. Two of 27 patients showed partial remissions, including one patient with metastatic melanoma who had a partial response and has remained on study for >5 years. Six patients showed prolonged disease stabilization. Levels of histone H3 and H4 acetylation in peripheral blood mononuclear cells increased qualitatively but with a high degree of interpatient variation. Conclusions: MS-275 is well tolerated at doses up to 6 mg/m2 every other week or 4 mg/m2 weekly for 3 weeks followed by 1 week of rest and results in biologically relevant plasma concentrations and antitumor activity. Twice-weekly dosing was not tolerable due to asthenia, and further evaluation of this schedule was halted. The recommended dose for further disease-focused studies is 4 mg/m2 given weekly for 3 weeks every 28 days or 2 to 6 mg/m2 given once every other week.

Mapatumumab, an Antibody Targeting TRAIL-R1, in Combination With Paclitaxel and Carboplatin in Patients With Advanced Solid Malignancies: Results of a Phase I and Pharmacokinetic Study

PURPOSE A phase I study assessed the safety, tolerability, pharmacokinetics, and preliminary antitumor effect of mapatumumab, a fully-human agonist monoclonal antibody to the tumor necrosis factor-related apoptosis-inducing ligand receptor 1 (TRAIL-R1, DR4), in combination with paclitaxel and carboplatin. PATIENTS AND METHODS Patients with advanced solid malignancies received 3, 10, or 20 mg/kg of mapatumumab with standard doses of paclitaxel and carboplatin every 21 days for up to six cycles in the absence of disease progression. Additional cycles of paclitaxel and/or mapatumumab were permissible in selected cases. RESULTS Twenty-seven patients (21 males), with a median age of 54 years, received mapatumumab in the following three cohorts: 3 mg/kg (n = 4), 10 mg/kg (n = 11), and 20 mg/kg (n = 12). The median number of cycles was four. Dose-limiting toxicities (DLTs) were grade 3 hypersensitivity reaction (n = 1) and neutropenic fever (n = 1), both at 10 mg/kg. Non-DLT treatment-related adverse events occurring in more than 10% of administered doses included alopecia, neutropenia, fatigue, nausea, anemia, thrombocytopenia, anorexia, and neuropathy. Paclitaxel and carboplatin exposures were similar in the presence or absence of mapatumumab. Plasma mapatumumab concentrations seemed similar to data from previous phase I monotherapy studies. Five patients (19%) achieved a confirmed radiologic partial response (including one pathologic complete response), and 12 patients (44%) had stable disease as their best response. CONCLUSION Mapatumumab is well-tolerated up to 20 mg/kg in combination with paclitaxel and carboplatin. There are no apparent pharmacokinetic interactions among the drugs. Preliminary anticancer activity demonstrated clinical benefit for the majority of these patients.

Small cell undifferentiated variant of hepatoblastoma: adverse clinical and molecular features similar to rhabdoid tumors.

Small cell undifferentiated (SCU) histology in patients with stage I hepatoblastoma (HB) predicts an increased risk of relapse. We sought to determine the significance of SCU histology in patients with unresectable HB.

E2F1 and E2F2 Determine Thresholds for Antigen-Induced T-Cell Proliferation and Suppress Tumorigenesis

ABSTRACT E2F activity is critical for the control of the G1 to S phase transition. We show that the combined loss of E2F1 and E2F2 results in profound effects on hematopoietic cell proliferation and differentiation, as well as increased tumorigenesis and decreased lymphocyte tolerance. The loss of E2F1 and E2F2 impedes B-cell differentiation, and hematopoietic progenitor cells in the bone marrow of mice lacking E2F1 and E2F2 exhibit increased cell cycling. Importantly, we show that E2F1 and E2F2 double-knockout T cells exhibit more rapid entry into S phase following antigenic stimulation. Furthermore, T cells lacking E2F1 and E2F2 proliferate much more extensively in response to subthreshold antigenic stimulation. Consistent with these observations, E2F1/E2F2 mutant mice are highly predisposed to the development of tumors, and some mice exhibit signs of autoimmunity.