Evofosfamide for the treatment of human papillomavirus-negative head and neck squamous cell carcinoma.

Evofosfamide (TH-302) is a clinical-stage hypoxia-activated prodrug of a DNA-crosslinking nitrogen mustard that has potential utility for human papillomavirus (HPV) negative head and neck squamous cell carcinoma (HNSCC), in which tumor hypoxia limits treatment outcome. We report the preclinical efficacy, target engagement, preliminary predictive biomarkers and initial clinical activity of evofosfamide for HPV-negative HNSCC. Evofosfamide was assessed in 22 genomically characterized cell lines and 7 cell line-derived xenograft (CDX), patient-derived xenograft (PDX), orthotopic, and syngeneic tumor models.

Systemic versus local responses in melanoma patients treated with talimogene laherparepvec from a multi-institutional phase II study.

Background: We previously reported that talimogene laherparepvec, an oncolytic herpes virus encoding granulocyte-macrophage colony-stimulating factor (GM-CSF), resulted in an objective response rate of 26 % in patients with advanced melanoma in a phase II clinical trial. The response of individual lesions, however, was not reported. Since talimogene laherparepvec is thought to mediate anti-tumor activity through both direct tumor cytolysis and induction of systemic tumor-specific immunity, we sought to determine the independent response rate in virus-injected and non-injected lesions.

Phase I study of intravenously administered ATI-1123, a liposomal docetaxel formulation in patients with advanced solid tumors.

Purpose: ATI-1123 is a liposomal formulation of docetaxel and may be administered without the premedications and hypersensitivity reactions. This Phase I study examines the safety, tolerability, pharmacokinetics (PKs), and antitumor activity of ATI-1123.

Methods: Patients with advanced solid malignancies received escalating doses of ATI-1123 intravenously over 1-h every 3 weeks.

Phase 1 study of N(1),N(11)‑diethylnorspermine (DENSPM) in patients with advanced hepatocellular carcinoma.

Purpose: N(1),N(11)-diethylnorspermine (DENSPM), a synthetic analog of the naturally occurring polyamine spermine, can induce polyamine depletion and inhibit tumor cell growth. The objectives of this phase I study were to assess the safety, maximum-tolerated dose (MTD), pharmacokinetics, and preliminary antitumor activity of DENSPM in advanced HCC.

Methods: Patients with measurable advanced HCC, Child-Pugh A or B cirrhosis, CLIP score ≤3, and Karnofsky score ≥60 % were eligible.

Phase I clinical study of Seneca Valley Virus (SVV-001), a replication-competent picornavirus, in advanced solid tumors with neuroendocrine features.

Purpose: Seneca Valley Virus (SVV-001) is a novel naturally occurring replication-competent picornavirus with potent and selective tropism for neuroendocrine cancer cell types, including small cell lung cancer. We conducted a first-in-human, first-in-class phase I clinical trial of this agent in patients with cancers with neuroendocrine features, including small cell lung cancer.

Experimental Design: Clinical evaluation of single intravenous doses in patients with cancers with neuroendocrine features was performed across five log-increments from 10(7) to 10(11) vp/kg.

Activity of IPI-504, a novel heat-shock protein 90 inhibitor, in patients with molecularly defined non-small-cell lung cancer.

Purpose: IPI-504 is a novel, water-soluble, potent inhibitor of heat-shock protein 90 (Hsp90). Its potential anticancer activity has been validated in preclinical in vitro and in vivo models. We studied the activity of IPI-504 after epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) therapy in patients with advanced, molecularly defined non-small-cell lung cancer (NSCLC).

Phase III multicenter trial of doxorubicin plus cyclophosphamide followed by paclitaxel compared with doxorubicin plus paclitaxel followed by weekly paclitaxel as adjuvant therapy for women with high-risk breast cancer.

Purpose: This study compared disease-free survival (DFS) obtained with two different regimens of adjuvant therapy in high-risk breast cancer.

Methods: Women (who had performance status [PS] of 0 to 1) with operable, histologically confirmed, stage I to III adenocarcinoma of the breast were eligible. Patients had undergone primary surgery with no residual tumor.

Phase II clinical trial of a granulocyte-macrophage colony-stimulating factor-encoding, second-generation oncolytic herpesvirus in patients with unresectable metastatic melanoma.

Purpose: Treatment options for metastatic melanoma are limited. We conducted this phase II trial to assess the efficacy of JS1/34.5-/47-/granulocyte-macrophage colony-stimulating factor (GM-CSF) in stages IIIc and IV disease.

Phase II assessment of talabostat and cisplatin in second-line stage IV melanoma.

Background: Metastatic melanoma is an incurable disease with an average survival of less than one year. Talabostat is a novel dipeptidyl peptidase inhibitor with immunostimulatory properties.

Methods: This phase II, open label, single arm study was conducted to evaluate the safety and efficacy of 75-100 mg/m2 cisplatin combined with 300-400 mcg talabostat bid for 6, 21-day cycles.

Emerging technologies for the genomic analysis of cancer.

Cancer-cell survival, growth and metastatic potential are directed by dominant molecular signalling patterns, the components of which have been shown to be qualitatively different from their normal tissue counterparts. These signalling patterns can now be further distinguished by quantitative assessment, either at a single point in time or at intervals. This commentary will focus on the emergence of proteomic analysis which, in conjunction with the genomic expression data, is an evolving technology that one day will enable personalized therapeutic strategies that are differentially targeted against cancer.

Chemo-inducible gene therapy.

Chemo-inducible cancer gene therapy is a potential new treatment for solid tumors that may in part enhance the anti-tumor effects of chemotherapy while minimizing toxicity. This approach combines viral vectors expressing cytotoxic transgenes that can be transcriptionally activated by DNA-damaging agents. The development of chemo-inducible gene therapy has numerous implications for the treatment of both localized and metastatic disease in patients with solid tumors.

Phase I trial of irinotecan, infusional 5-fluorouracil, and leucovorin (FOLFIRI) with erlotinib (OSI-774): early termination due to increased toxicities.

Purpose: This phase I study was conducted to establish the dose-limiting toxicities and maximum-tolerated dose of erlotinib, an oral epidermal growth factor receptor tyrosine kinase inhibitor, in combination with FOLFIRI, a standard regimen of irinotecan, leucovorin, and infusional 5-fluorouracil (5-FU) in patients with advanced colorectal cancer.

Experimental Design: The trial used a dose-escalation design beginning with 100 mg/day erlotinib continuously and dose-reduced FOLFIRI (150 mg/m2 i.v.

Multicenter phase II study of erlotinib, an oral epidermal growth factor receptor tyrosine kinase inhibitor, in patients with recurrent or metastatic squamous cell cancer of the head and neck.

Purpose: To determine the efficacy and safety profiles of erlotinib in patients with advanced recurrent and/or metastatic squamous cell cancer of the head and neck (HNSCC).

Patients And Methods: Patients with locally recurrent and/or metastatic HNSCC, regardless of their HER1/EGFR status, were treated with erlotinib at an initial dose of 150 mg daily. Dose reductions or escalations were allowed based on tolerability of erlotinib.