A dose escalation/expansion study evaluating dose, safety, and efficacy of the novel tyrosine kinase inhibitor surufatinib, which inhibits VEGFR 1, 2, & 3, FGFR 1, and CSF1R, in US patients with neuroendocrine tumors.

Surufatinib, is a potent inhibitor of vascular endothelial growth factor receptors 1-3; fibroblast growth factor receptor-1; colony-stimulating factor 1 receptor. This Phase 1/1b escalation/expansion study in US patients with solid tumors evaluated 5 once daily (QD) surufatinib doses (3 + 3 design) to identify maximum tolerated dose (MTD), recommended Phase 2 dose (RP2D), and evaluate safety and efficacy at the RP2D in 4 disease-specific expansion cohorts including pancreatic neuroendocrine tumors [pNET] and extrapancreatic NETs [epNET]. MTD and RP2D were 300 mg QD (escalation [n = 35]); 5 patients (15.

Randomized, Double-Blind, Phase III Trial of Enzastaurin Versus Placebo in Patients Achieving Remission After First-Line Therapy for High-Risk Diffuse Large B-Cell Lymphoma.

Purpose: To compare disease-free survival (DFS) after maintenance therapy with the selective protein kinase C β (PKCβ) inhibitor, enzastaurin, versus placebo in patients with diffuse large B-cell lymphoma (DLBCL) in complete remission and with a high risk of relapse after first-line therapy.

Patients And Methods: This multicenter, phase III, randomized, double-blind, placebo-controlled trial enrolled patients who were at high risk of recurrence after rituximab-cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). Patients (N = 758) with stage II bulky or stage III to IV DLBCL, three or more International Prognostic Index risk factors at diagnosis, and a complete response or unconfirmed complete response after 6 to 8 cycles of R-CHOP were assigned 2:1 to receive oral enzastaurin 500 mg daily or placebo for 3 years or until disease progression or unacceptable toxicity.

A randomized, open-label clinical trial of tasisulam sodium versus paclitaxel as second-line treatment in patients with metastatic melanoma.

Background: Tasisulam sodium (hereafter referred to as tasisulam) is a novel, highly albumin-bound agent that demonstrated activity in a phase 2 melanoma study.

Methods: In this open-label phase 3 study, patients with AJCC stage IV melanoma received tasisulam (targeting an albumin-corrected exposure of 1200-6400 h (hour).μg/mL on day 1) or paclitaxel (80 mg/m(2) on days 1, 8, and 15) every 28 days as second-line treatment.

A placebo-controlled, randomized phase II study of maintenance enzastaurin following whole brain radiation therapy in the treatment of brain metastases from lung cancer.

Introduction: Enzastaurin is a protein kinase C inhibitor with anti-tumor activity. This study was designed to determine if maintenance enzastaurin improved the outcome of whole brain radiotherapy (WBRT) in lung cancer (LC) patients with brain metastases (BMs).

Methods: Patients with LC (any histology) who had received WBRT for BMs were randomized to receive oral maintenance enzastaurin (1125 mg on Day 1 followed by 500 mg daily) or placebo.

Serum angiogenin levels predict treatment response in patients with stage IV melanoma.

This work was conducted to find out new potential serum markers and study their role as predictive factors in patients with metastatic melanoma. Serum samples from 68 patients with stage IV malignant melanoma were collected just before current treatment and screened for 79 different cytokines by using a multi-cytokine array. Angiogenin, which is a protein capable of promoting angiogenesis, was found to be markedly elevated among a sub-group of patients with progressive disease (PD) and thus was subjected to further analysis.

Randomized trial of dacarbazine versus bleomycin, vincristine, lomustine and dacarbazine (BOLD) chemotherapy combined with natural or recombinant interferon-alpha in patients with advanced melanoma.

This randomized phase II study was designed to compare the efficacy and tolerability of dacarbazine (DTIC) and bleomycin, vincristine, lomustine and DTIC (BOLD) combined with natural interferon-alpha (nIFN-alpha) or recombinant interferon-alpha2b (rIFN-alpha2b) in patients with advanced melanoma. The treatment arms were: A, DTIC plus nIFN-alpha; B, BOLD plus nIFN-alpha; C, DTIC plus rIFN-alpha2b; D, BOLD plus rIFN-alpha2b. One hundred and eight patients were randomized, of whom 106 were eligible to be analysed for efficacy.

The prognostic role of CD4+ and CD8+ lymphocytes during chemoimmunotherapy in metastatic melanoma.

We have observed that an early increase in the CD4+/CD8+ ratio of metastatic melanoma patients during chemoimmunotherapy is the most favourable independent prognostic factor. In this study, 87 patients with metastatic melanoma were monitored for peripheral blood lymphocyte subsets (CD4+ and CD8+) before and during chemoimmunotherapy (dacarbazine, vinblastine, lomustine and bleomycin or dacarbazine alone plus interferon-alpha) to confirm our previous observation. Blood samples were systematically obtained from patients who received either of these chemoimmunotherapies.

Integrin chains beta1 and alphav as prognostic factors in human metastatic melanoma.

The expression pattern of integrin-type cell adhesion receptors is often changed during malignant transformation. In the present work, we studied the prognostic significance of beta1 and alphav integrin chains for survival of patients with metastatic melanoma. The expression levels of beta1 integrin were also compared with those of Bcl-2, an anti-apoptotic protein, the presence of which is associated with treatment response and survival in melanoma.

BRAF mutations in metastatic melanoma: a possible association with clinical outcome.

Purpose: The RAS-RAF-mitogen-activated protein kinase pathways mediate the cellular response to growth signals. In melanocytes, BRAF is involved in cAMP-dependent growth signals. Recently, activating mutations in the BRAF gene, were reported in a large proportion of melanomas.

A prognostic model and staging for metastatic uveal melanoma.

Background: To identify factors that independently contribute to overall survival in Stage IVB uveal melanoma and to subcategorize by prognosis.

Methods: Data of 91 consecutive patients who died of metastatic uveal melanoma in 1985-2000 were analyzed by Kaplan-Meier and Cox regression analysis. Main covariates were participation in annual review, symptoms, Karnofsky index, metastatic burden, liver function tests, and age.

Chemoimmunotherapy with bleomycin, vincristine, lomustine, dacarbazine (BOLD), and human leukocyte interferon for metastatic uveal melanoma.

Background: A Phase II trial comprising patients with metastatic uveal melanoma (Stage IVB) was undertaken to determine the activity of bleomycin, vincristine, lomustine, and dacarbazine (BOLD) chemotherapy with human leukocyte interferon, as well as the progression-free and overall survival of the patients according to the substage before treatment.

Methods: Twenty-two patients with histologically proven metastatic uveal melanoma received 15 mg of bleomycin (Days 2 and 5), 1 mg/m(2) vincristine (Days 1 and 4), 200 mg/m(2) dacarbazine (Days 1 to 5), and 80 mg lomustine (Day 1) every 4 weeks together with a leukocyte interferon preparation (3 x 10(6) IU daily for 6 weeks followed by 6 x 10(6) IU three times per week).

Results: Of 20 evaluable patients, 3 (15%; 95% confidence interval [CI] 0-38) obtained a partial objective response in hepatic and extrahepatic sites and 11 (55%; 95% CI 32-77) showed stable disease after receiving more than two cycles.

Immunohistochemically detectable bcl-2 expression in metastatic melanoma: association with survival and treatment response.

Objective: The antiapoptotic protein Bcl-2 is supposed to influence the treatment responsiveness of different malignancies. In the present study the prognostic and predictive significance of Bcl-2 expression for survival and response to an administered therapy was explored in patients with metastatic melanoma. Also, the correlation between Bcl-2 expression and proliferation activity of tumor cells was defined to examine the regulatory role of Bcl-2 in proliferation.

High expression levels of collagenase-1 and stromelysin-1 correlate with shorter disease-free survival in human metastatic melanoma.

Matrix metalloproteinases (MMPs) are proteolytic enzymes capable of degrading extracellular matrix. Their role has been emphasized in tumor invasion, metastasis and tumor-induced angiogenesis. We studied the expression of collagenase-1 (MMP-1), stromelysin-1 (MMP-3) and collagenase-3 (MMP-13) in 70 melanoma metastases obtained from 56 patients treated with combined chemoimmunotherapy.