Talimogene laherparepvec upregulates immune-cell populations in non-injected lesions: findings from a phase II, multicenter, open-label study in patients with stage IIIB-IVM1c melanoma.

Background: Talimogene laherparepvec (T-VEC), an oncolytic virus, was designed to selectively replicate in and lyse tumor cells, releasing tumor-derived antigen to stimulate a tumor-specific immune response.

Methods: In this phase II study in patients with unresectable stage IIIB-IV melanoma, we evaluated non-injected lesions to establish whether baseline or change in intratumoral CD8 T-cell density (determined using immunohistochemistry) correlated with T-VEC clinical response.

Results: Of 112 enrolled patients, 111 received ≥1 dose of T-VEC.

Biodistribution, shedding, and transmissibility of the oncolytic virus talimogene laherparepvec in patients with melanoma.

Background: Talimogene laherparepvec (T-VEC) is an intralesionally delivered, modified herpes simplex virus type-1 oncolytic immunotherapy. The biodistribution, shedding, and potential transmission of T-VEC was systematically evaluated during and after completion of therapy in adults with advanced melanoma.

Methods: In this phase 2, single-arm, open-label study, T-VEC was administered into injectable lesions initially at 10 plaque-forming units (PFU)/mL, 10 PFU/mL 21 days later, and 10 PFU/mL every 14 (±3) days thereafter.

Trebananib or placebo plus carboplatin and paclitaxel as first-line treatment for advanced ovarian cancer (TRINOVA-3/ENGOT-ov2/GOG-3001): a randomised, double-blind, phase 3 trial.

Background: Angiopoietin 1 and 2 regulate angiogenesis and vascular remodelling by interacting with the tyrosine kinase receptor Tie2, and inhibition of angiogenesis has shown promise in the treatment of ovarian cancer. We aimed to assess whether trebananib, a peptibody that inhibits binding of angiopoietin 1 and 2 to Tie2, improved progression-free survival when added to carboplatin and paclitaxel as first-line therapy in advanced epithelial ovarian, primary fallopian tube, or peritoneal cancer in a phase 3 clinical trial.

Methods: TRINOVA-3, a multicentre, multinational, phase 3, double-blind study, was done at 206 investigational sites (hospitals and cancer centres) in 14 countries.

Phase 1b Study of Trebananib Plus Paclitaxel and Trastuzumab in Patients With HER2-Positive Locally Recurrent or Metastatic Breast Cancer.

Introduction: Trebananib, a peptide-Fc fusion protein, blocks angiogenesis by inhibiting binding of angiopoietin-1/2 to the receptor tyrosine kinase Tie2. Trebananib plus trastuzumab and paclitaxel was evaluated in human epidermal growth factor receptor 2-positive breast cancer in an open-label phase 1b clinical study.

Patients And Methods: Women with human epidermal growth factor receptor 2-positive breast cancer received weekly paclitaxel (80 mg/m), trastuzumab (8 mg/m then 6 mg/kg every 3 weeks), and intravenous trebananib (10 mg/kg or 30 mg/kg weekly) beginning week 2.

A Phase I, First-in-Human Study of AMG 780, an Angiopoietin-1 and -2 Inhibitor, in Patients with Advanced Solid Tumors.

Purpose: To assess the toxicity, pharmacokinetics, tumor vascular response, tumor response, and pharmacodynamics of AMG 780, a mAb designed to inhibit the interaction between angiopoietin-1 and -2 and the Tie2 receptor.

Experimental Design: This was a phase I dose-escalation study of patients with advanced solid tumors refractory to standard treatment without previous antiangiogenic treatment. AMG 780 was administered by intravenous infusion every 2 weeks in doses from 0.

A phase I study of MK-5108, an oral aurora a kinase inhibitor, administered both as monotherapy and in combination with docetaxel, in patients with advanced or refractory solid tumors.

Background: MK-5108 is a potent/highly selective Aurora A kinase inhibitor.

Methods: A randomized Phase I study of MK-5108, administered p.o.

Pharmacokinetic drug-drug interaction assessment of peptibody trebananib in combination with chemotherapies.

Purpose: To provide the first evaluation of pharmacokinetic (PK) drug-drug interactions (DDIs) between trebananib and chemotherapies across tumor types.

Methods: PK data of trebananib and chemotherapies (paclitaxel, carboplatin, pegylated liposomal doxorubicin, topotecan, capecitabine, lapatinib, 5-FU, irinotecan, or docetaxel) were collected from trials of ovarian cancer, metastatic breast cancer, colorectal carcinoma, and mixed solid tumor. A dedicated PK DDI study of trebananib and paclitaxel in patients with mixed solid tumors was also conducted.

Trebananib (AMG 386) plus weekly paclitaxel with or without bevacizumab as first-line therapy for HER2-negative locally recurrent or metastatic breast cancer: A phase 2 randomized study.

Introduction: This phase 2 randomized study evaluated trebananib (AMG 386), a peptide-Fc fusion protein that inhibits angiogenesis by neutralizing the interaction of angiopoietin-1 and -2 with Tie2, in combination with paclitaxel with or without bevacizumab in previously untreated patients with HER2-negative locally recurrent/metastatic breast cancer.

Methods: Patients received paclitaxel 90 mg/m(2) once weekly (3-weeks-on/1-week-off) and were randomly assigned 1:1:1:1 to also receive blinded bevacizumab 10 mg/kg once every 2 weeks plus either trebananib 10 mg/kg once weekly (Arm A) or 3 mg/kg once weekly (Arm B), or placebo (Arm C); or open-label trebananib 10 mg/kg once a week (Arm D). Progression-free survival was the primary endpoint.

Capecitabine therapy for refractory metastatic thyroid carcinoma: a case series.

Objective: There are few effective therapies for metastatic medullary (MTC) or radioiodine-resistant follicular thyroid carcinomas (FTC). We report a single institution's experience with capecitabine, a thymidylate synthase (TS) inhibitor, in the treatment of MTC and FTC.

Design: We retrospectively analyzed five cases of metastatic thyroid carcinoma, three MTCs and two radioiodine-resistant FTCs, treated with capecitabine alone or in combination with other chemotherapeutics.

[11C]metahydroxyephedrine and [18F]fluorodeoxyglucose positron emission tomography improve clinical decision making in suspected pheochromocytoma.

Background: Pheochromocytomas are rare tumors of chromaffin cells for which the optimal management is surgical resection. Precise diagnosis and localization may be elusive. We evaluated whether positron emission tomography (PET) scanning with the combination of [18F]fluorodeoxyglucose (FDG) and the norepinephrine analogue [11C]metahydroxyephedrine (mHED) would allow more exact diagnosis and localization.

Altered expression of cyclins and cell cycle inhibitors in papillary thyroid cancer: prognostic implications.

Currently we lack biochemical or molecular markers that predict recurrence and metastases in thyroid cancer. Recent studies in a number of other human malignancies indicate that expression and/or subcellular localization of certain cell cycle regulators has prognostic utility. We have investigated the expression of cyclins D1 and E and of cyclin-dependent kinase inhibitor's p21 and p27 in papillary thyroid cancer (PTC) and correlated this with clinical/histological stage at diagnosis and with clinical outcome.

Update on the medical management of pituitary adenomas.

The medical treatment of pituitary adenomas has changed significantly over the past decade. Pharmacologic therapy for prolactinomas in the form of dopamine agonists has been available since the 1970s, and somatostatin analogues for treatment of growth hormone (GH)-secreting adenomas were introduced in the 1980s. However, the recent introduction of long-acting forms of these agents has markedly improved efficacy.

Diagnosis and management of pituitary tumors: recent advances.

In recent years, the medical therapy for prolactinomas and GH-secreting adenomas has greatly improved due to the availability of new, highly effective, long-acting dopamine and somatostatin analogues. Although medical therapy has for some time been the first-line approach to prolactinoma management, the incidence of patients requiring surgery for resistance or intolerance/noncompliance is likely to decrease substantially with these new agents. Increasing efficacy and greater ease of administration of somatostatin analogues for GH, and for rare TSH, adenomas are also anticipated to lead to less reliance on surgery and radiation therapy as the primary therapy in these disorders.

Role of specific protein kinase C isozymes in mediating epidermal growth factor, thyrotropin-releasing hormone, and phorbol ester regulation of the rat prolactin promoter in GH4/GH4C1 pituitary cells.

Epidermal growth factor (EGF) and TRH both produce enhanced prolactin (PRL) gene transcription and PRL secretion in GH4 rat pituitary tumor cell lines. These agents also activate protein kinase C (PKC) in these cells. Previous studies have implicated the PKCepsilon isozyme in mediating TRH-induced PRL secretion.