Isis Pharmaceuticals Inc. presented positive data from a planned interim analysis of a pancreatic cancer Phase II trial evaluating ISIS 2503 in combination with gemcitabine.
Clinical investigators found pancreatic cancer patients survived six months or longer when taking ISIS 2503 and gemcitabine, surpassing the primary endpoint of the study. The trial was designed to test improvement in patient survival and in patient response rates. The trial is being conducted by the North Central Cancer Trial Group.
The criteria for success at the interim analysis were the survival of nine or more patients for at least six months. The analysis was performed after the first 20 patients were enrolled, received treatment and completed six months of follow-up. The median length of survival for the patients at the interim analysis was 6.7 months, and 60 percent (12 of the 20 patients) survived six months or longer. In total, 48 patients have been enrolled.
Twenty percent of patients achieved a complete or partial response and the safety profile appeared to be the same as gemcitabine. Complete response is defined as no detectable evidence of cancer by standard medical techniques and partial response is a 50 percent or greater reduction in measurable tumor size on X-ray.
ISIS 2503 is an antisense anticancer compound that inhibits the expression of Harvey-ras, a molecule involved in the development and maintenance of human cancers. Isis also is evaluating the compound in combination with chemotherapy in two Phase II trials in patients with either metastatic breast or non-small-cell lung cancer.
In other news from the meeting:
Celgene Corp., of Warren, N.J., presented data from preclinical studies of JNK (c-Jun N-terminal kinase) inhibitors demonstrating they have antitumor effects in in vivo models of solid tumor cancers. Celgene’s JNK inhibitor was used to determine the effect of inhibition of the JNK pathway in cancer. Celgene’s compound inhibited tumor cell proliferation and endothelial cell migration in preclinical models of breast, prostate and lung cancers. The data support a correlation of tumor growth inhibition with reduced JNK activity. The data also suggest that Celgene’s JNK inhibitors specifically and selectively block the cellular activity of JNK, and therefore have therapeutic anticancer potential.
Cell Genesys Inc., of Foster City, Calif., reported data from preclinical studies evaluating CG8840, an oncolytic virus therapy for bladder cancer. Significant antitumor activity was demonstrated evaluating CG8840 alone and in combination with taxotere (docetaxel) in mouse models of bladder cancer. Also, the oncolytic virus therapy demonstrated selective killing of up to 10,000 cancer cells for every normal cell. The preclinical study evaluated four groups in an experimental mouse model of bladder cancer a group receiving CG8840 alone, a group receiving taxotere chemotherapy, a group receiving CG8840 in combination with taxotere, and a group receiving no treatment. Seven weeks after single administrations of the therapies, animals receiving CG8840 alone demonstrated significant regression of tumor size compared to the no-treatment control (p<0.01), and CG8840 plus taxotere resulted in complete elimination of experimental bladder cancers. Treatment with taxotere alone did not provide significant benefit, and untreated animals’ tumors progressed.
FeRx Inc., of San Diego, reported preclinical results showing its lead product, MTC-DOX (doxorubicin), might be useful in treating bladder cancer via an intravesical route of administration. Also, MTCs may be broadly applicable as carriers for a range of pharmaceutical agents, including peptides and proteins. Data showed MTC-DOX can be localized and retained within the epithelium layers of the bladder wall using magnetic targeting combined with intravesical delivery. In a second presentation, data suggest that MTCs may be useful in the prelocalization of peptides or antibodies to an organ or tissue, improving targeting efficiency and therapeutic outcome while decreasing side effects. The MTC technology uses a small, externally positioned magnet to create a localized magnetic field within the body.
Genta Inc., of Berkeley Heights, N.J., reported preclinical data showing high activity of its lead Androgenics compound in prostate cancer. By inhibiting several different enzymes, Androgenics drugs block the chemical synthesis of hormones. Also, the drugs were found to block AR activation, thereby increasing their potential anticancer activity. The presentation reported results from a comparison of the receptor-blocking effects of three drugs: bicalutamide, cyproterone and G20000, Genta’s lead compound. G20000 had virtually no receptor-activating activity and data indicated that G20000 blocked AR activation before the receptor could bind to DNA. Also, the investigators tested G20000 in a preclinical model wherein human prostate cancer was implanted into mice, and the drug’s hormone-blocking activity was then compared with castration. Results showed that G20000 was superior to castration in suppressing prostate cancer growth.
MGI Pharma Inc., of Minneapolis, presented five posters relating to the synergistic antitumor activity of irofolven in combination with a variety of cancer therapies as well as its mechanism of action. Data from the posters suggest, among other things, that the therapeutic activity might be enhanced when combined with classes of therapeutic agents, cellular levels of nucleotide excision repair-related enzymes might be a predictive factor for the cellular sensitivity of tumor cells to irofulven’s cytotoxic activity, and that further trials in glioma should be considered.
Human Genome Sciences Inc., of Rockville, Md., presented abstracts suggesting the TRAIL Receptor-1 human agonistic monoclonal antibody has potential to treat solid tumors and that repifermin has no effect on the proliferation of receptor-positive tumor cell lines studied or on tumor growth in culture or in mice. Also, the company said its studies show repifermin does not interfere with the antitumor activity of 5-fluorouracil and repifermin demonstrates protective effects against radiation- and chemotherapy-induced mucosal damage when administered prior to injury. The repifermin results, the company said, support clinical use of repifermin administered before and after chemotherapy for the treatment of cancer therapy-induced mucositis. Data presented on Albuleukin demonstrated that Albuleukin retains the immunostimulatory and antitumor activities of interleukin-2, but has a longer half-life, indicating that Albuleukin has the potential to be administered at a reduced dosing frequency while still maintaining antitumor efficacy.
Hybridon Inc., of Cambridge, Mass., presented preclinical data showing the antitumor activity of various immunomodulatory oligonucleotides (IMOs) when used alone or in combination with a monoclonal antibody and selected chemotherapeutic agents. Administration of IMOs containing YpG or CpR motifs at various doses inhibited tumor growth in nude mice bearing xenografts of human colon, prostate and glioblastoma cancers. The IMOs increased the therapeutic effects of the monoclonal antibody Rituxan and chemotherapeutic agent paclitaxel, in all three models tested. Hybridon’s YpG or CpR motifs reflect substitutions where Y and R refer to specific pyrimidines and purines other than C and G. Separately, the company and its collaborators presented preclinical studies of GEM 231, its lead antisense drug, in combination with irinotecan. The two presentations indicated that the combination treatment of GEM 231 together with irinotecan delays tumor growth and increases survival time in human colon, melanoma, pancreas, prostate and lung tumor models, compared to either agent alone.
Onyx Pharmaceuticals Inc., of Richmond, Calif., presented seven abstracts, including biochemical evidence that BAY 43-9006, its product in development with Bayer Corp., of Pittsburgh, inhibits the Raf kinase pathway. The data demonstrated inhibition of ERK phosphorylation in a study of 66 patients treated with BAY 43-9006. The company also presented data on one of its cytosine deaminase (CD)-Armed Therapeutic Virus (ATV) product candidates, ONYX-411. Data presented describe the ONYX-411 virus with selectivity for cancer cells defective in the Retinoblastoma pathway, and demonstrate its use for selective expression of CD in tumor cells. Onyx said the results suggest therapeutic viruses armed with a prodrug-activating enzyme represent anticancer therapeutics with increased efficacy over virus alone.
OSI Pharmaceuticals Inc., of Melville, N.Y., presented studies on its lead anticancer drug, Tarceva, and two of its next-generation cytotoxics, OSI-7904L and OSI-7836. Data were presented outlining a series of studies on the dimerization of EGFRvIII. The studies indicated that EGFRvIII can form dimers and that this dimerization is induced for both EGFR and mutant EGFR by Tarceva. Furthermore, these studies show Tarceva is effective in inhibiting the tyrosine kinase activity of EGFRvIII, thus blocking cell signaling through EGFRvIII. The data also indicated that long-term exposure to Tarceva resulted in a decrease in the number of mutant receptors at the cell surface. Tarceva is being developed by OSI in collaboration with Genentech Inc., of South San Francisco, and F. Hoffmann-La Roche Ltd., of Basel, Switzerland. OSI also presented preclinical data on OSI-7904L and OSI-7836, both in Phase I trials for the treatment of certain cancers.
Rigel Pharmaceuticals Inc., of South San Francisco, presented data on its cancer therapy targets. Rigel identified several proteins that influence cell arrest and the proteins that regulate those cells. One regulator, called LETM-1, caused cell arrest at the earliest stages of reproduction. A second regulator, part of the Mi-2 histone deacetylase complex, allowed cells to reproduce following exposure to a protein known to induce cell arrest. Rigel researchers also presented findings on ubiquitin ligases. Researchers at Rigel have identified small-molecule inhibitors of that class of enzyme that exhibit antiproliferative activity against several tumor cell types.
SangStat Medical Corp., of Fremont, Calif., said its tumor necrosis factor alpha inhibitor, RDP58, improved survival and decreased diarrhea related to irinotecan in preclinical studies. Two studies were presented. In the first study, nontumor-bearing mice that received irinotecan alone demonstrated 27 percent survival. By adding RDP58 to the drinking water of mice, irinotecan improved survival by 93 percent. Diarrhea was reduced from 97 percent in mice receiving irinotecan alone to 33 percent in mice treated with the combination of irinotecan and RDP58. The second study showed survival of tumor-bearing mice treated with irinotecan and RDP58 was 100 percent. The company said the data suggest RDP58 might reduce the major dose-limiting toxicity of irinotecan-based chemotherapy regimens.
SciClone Pharmaceuticals Inc., of San Mateo, Calif., presented results of an animal model study demonstrating improved and expanded immunological effects for cancer treatment when Zadaxin is administered as a continuous infusion vs. a subcutaneous injection. The results include increased response rates and positive effects on granulocytes. The results indicate that Zadaxin provided by continuous infusion increased the percentage of animals showing restoration of activity of their natural killer cells.
Telik Inc., of South San Francisco, presented data supporting the apoptotic mechanism of action of TLK286, a small-molecule drug candidate for the treatment of cancer. TLK286 is in Phase II testing in colorectal, ovarian, non-small-cell lung and breast cancer. TLK286 is activated by glutathione S-transferase (GST) P1-1, an enzyme that is overexpressed in many human cancers.
Titan Pharmaceuticals Inc., of South San Francisco, said studies demonstrated its small-molecule drug, Pivanex, has antitumor activity in preclinical studies of lung cancer and bladder cancer, and may be combined with current chemotherapeutic agents to increase anticancer activity. Titan also reported in separate studies that RB94 gene therapy demonstrated antitumor effects and growth inhibition in a preclinical model of head and neck cancer, and can be combined with cisplatin, a current therapy for the disease, to enhance tumor destruction. Pivanex, which attacks cancer cells through changing the expression of cancer-related genes, is in Phase II testing in lung cancer.
U3 Pharma AG, of Martinsried, Germany, presented data demonstrating that fibroblast growth factor receptor 4 (FGFR4) may serve as a therapeutic target for cancer. FGFR4 is a transmembrane tyrosine kinase receptor that forms part of a signal transduction cascade implicated in several hyperproliferative disorders, including breast, lung, prostate and ovarian cancers.