Strong vaccine responses during chemotherapy are associated with prolonged cancer survival.

Therapeutic cancer vaccines have effectively induced durable regressions of premalignant oncogenic human papilloma virus type 16 (HPV16)-induced anogenital lesions. However, the treatment of HPV16-induced cancers requires appropriate countermeasures to overcome cancer-induced immune suppression. We previously showed that standard-of-care carboplatin/paclitaxel chemotherapy can reduce abnormally high numbers of immunosuppressive myeloid cells in patients, allowing the development of much stronger therapeutic HPV16 vaccine (ISA101)-induced tumor immunity.

Mobilization of hematopoietic stem cells with the novel CXCR4 antagonist POL6326 (balixafortide) in healthy volunteers-results of a dose escalation trial.

Background: Certain disadvantages of the standard hematopoietic stem and progenitor cell (HSPC) mobilizing agent G-CSF fuel the quest for alternatives. We herein report results of a Phase I dose escalation trial comparing mobilization with a peptidic CXCR4 antagonist POL6326 (balixafortide) vs. G-CSF.

The combination of HDAC and aminopeptidase inhibitors is highly synergistic in myeloma and leads to disruption of the NFκB signalling pathway.

There is a growing body of evidence supporting the use of epigenetic therapies in the treatment of multiple myeloma. We show the novel HDAC inhibitor CHR-3996 induces apoptosis in myeloma cells at concentrations in the nanomolar range and with apoptosis mediated by p53 and caspase pathways. In addition, HDAC inhibitors are highly synergistic, both in vitro and in vivo, with the aminopeptidase inhibitor tosedostat (CHR-2797).

A phase I first-in-human study with tefinostat - a monocyte/macrophage targeted histone deacetylase inhibitor - in patients with advanced haematological malignancies.

Tefinostat (CHR-2845) is a monocyte/macrophage targeted histone deacetylase inhibitor (HDACi). This first-in-human, standard 3 + 3 dose escalating trial of oral, once daily tefinostat was conducted to determine the safety, tolerability, pharmacokinetic and pharmacodynamic profile of tefinostat in relapsed/refractory haematological diseases. Eighteen patients were enrolled at doses of 20-640 mg.

A phase I pharmacokinetic and pharmacodynamic study of CHR-3996, an oral class I selective histone deacetylase inhibitor in refractory solid tumors.

Purpose: This clinical trial investigated the safety, tolerability, pharmacokinetic (PK), and pharmacodynamic (PD) profile of CHR-3996, a selective class I histone deacetylase inhibitor.

Patients And Methods: CHR-3996 was administered orally once a day. This phase I trial used a 3+3 dose-escalation design.

Phase I/II clinical study of Tosedostat, an inhibitor of aminopeptidases, in patients with acute myeloid leukemia and myelodysplasia.

Purpose: To identify the maximum-tolerated dose (MTD) and to evaluate the antileukemic activity of tosedostat (formerly CHR-2797), an orally bioavailable aminopeptidase inhibitor.

Patients And Methods: In phase I, the MTD of once daily oral doses of tosedostat in hematologic malignancies was defined. In phase II, the therapeutic activity of the maximum-acceptable dose (MAD) of tosedostat was evaluated in elderly and/or relapsing patients with acute myeloid leukemia (AML) or myelodysplastic syndrome.

A first-in-man phase i and pharmacokinetic study on CHR-2797 (Tosedostat), an inhibitor of M1 aminopeptidases, in patients with advanced solid tumors.

Purpose: To determine the maximum tolerated dose, dose-limiting toxicity, pharmacokinetics, and preliminary therapeutic activity profile of CHR-2797 (tosedostat), a novel, orally bioavailable inhibitor of the M1 family of aminopeptidases with antiproliferative and antiangiogenic activity in vitro.

Experimental Design: A phase I study of accelerated titration design that escalated through nine doses (10-320 mg) in patients (Eastern Cooperative Oncology Group performance status, < or =2) with advanced solid tumors. CHR-2797 was administered once daily.

Aminopeptidase inhibition as a targeted treatment strategy in myeloma.

Myeloma cells are highly dependent on the unfolded protein response to assemble folded immunoglobulins correctly. Therefore, targeting protein handling within a myeloma cell by inhibiting the aminopeptidase enzyme system, which catalyses the hydrolysis of amino acids from the proteins NH2 terminus, represents a therapeutic approach. CHR-2797, a novel aminopeptidase inhibitor, is able to inhibit proliferation and induce growth arrest and apoptosis in myeloma cells, including cells resistant to conventional chemotherapeutics.

Phase I evaluation of a 40-kDa branched-chain long-acting pegylated IFN-alpha-2a with and without cytarabine in patients with chronic myelogenous leukemia.

Purpose: Pegasys (PEG-IFN) is a modified form of recombinant human IFN-alpha-2a in which IFN-alpha is attached to a branched methoxypolyethylene glycol (PEG) moiety of large molecular weight (40 kDa). Such molecular modification results in sustained absorption after s.c.

Protocol core needle biopsy and histologic Chronic Allograft Damage Index (CADI) as surrogate end point for long-term graft survival in multicenter studies.

This study is an investigation of whether a protocol biopsy may be used as surrogate to late graft survival in multicenter renal transplantation trials. During two mycophenolate mofetil trials, 621 representative protocol biopsies were obtained at baseline, 1 yr, and 3 yr. The samples were coded and evaluated blindly by two pathologists, and Chronic Allograft Damage Index (CADI) score was constructed.