The following is a summary of data presented at the American Association for Cancer Research, National Cancer Institute and European Organization for Research and Treatment of Cancer conference being held through Friday in San Francisco. (See also pages 5, 7 and 8.)
• Access Pharmaceuticals, of Dallas, presented initial data from an ongoing Phase II ovarian cancer study using ProLindac, a DACH platinum prodrug, at two- and three-week intervals showing there was a reduction of the Ca125 biomarker in five of the six patients in the cohort receiving the higher dose of ProLindac on a once-every-three-week dosing schedule. The Ca125 biomarker has been demonstrated to be a reliable indicator of the clinical progression of ovarian cancer, and it has been shown that a reduction in this biomarker provides an early sign that a treatment regimen is effective in combating ovarian cancer. Dose escalation in the trial is continuing.
• Active Biotech AB, of Lund, Sweden, presented the final results a Phase I study of the cancer project Anyara in combination with Taxotere in patients with non-small-cell lung cancer. The results showed that Anyara can be given safely in combination with Taxotere (Sanofi-Aventis), which is used for non-small-cell lung cancer. Thirteen patients with advanced NSCLC were included in the study. Observed side effects during Anyara treatment were expected and included transient fever, hypotension and nausea. Other toxicities recorded in the study were typical of Taxotere. Out of 10 evaluable patients, two received a partial response (a tumor reduction of at least 30 percent), including one patient who previously had failed with Taxotere treatment, and five patients had stable disease. Anyara presently is developed primarily for renal cancer, and a pivotal phase II/III is ongoing with an interim analysis planned for mid-2008.
• Ardea Biosciences Inc., of Carlsbad, Calif., said preclinical data suggested that its lead MEK inhibitor, RDEA119, can be dosed orally and has selectivity and low central nervous system penetration. When the drug was dosed in mouse xenografts once daily for 14 days, investigators observed significant inhibition and delay of tumor growth. Ardea plans to start a Phase I study this quarter in patients with advanced cancer and move the drug into inflammatory diseases next year.
• Biomira Inc., of Edmonton, Alberta, presented preclinical data for its targeted anticancer drug candidates PX-478 and PX-866. Results of studies showed that PX-478 is highly specific for HIF-1 alpha and does not inhibit the levels of any of the other proteins tested. Additionally, the inhibitory effect is independent of the tumor suppressor genes VHL and p53, genes that may significantly impact how cancer cells respond to a variety of therapeutic interventions. Studies of PX-866, a small-molecule inhibitor of phosphatidylinositol-3-kinase (PI-3 kinase), showed that in a range of different tumor types, response to PX-866 correlated with wild-type Ras, while mutations in Ras were associated with PX-866 resistance. Those results suggested that selecting for patient Ras status could improve the clinical benefit of PX-866.
• BiPar Sciences Inc., of Brisbane, Calif., reported data demonstrated that BSI-401 inhibited pancreatic cancer cell growth in vitro and in vivo, both alone and in combination with oxaliplatin. In animals with orthotopic human pancreatic tumors, the drug resulted in significantly reduced tumor burden and extended survival. It also showed a synergistic effect in combination with oxaliplatin. BSI-401 is a second-generation poly-ADP-ribose polymerase inhibitor.
• Cell Therapeutics Inc., of Seattle, reported its bis-platinate drug candidates, CT-47613 and CT-47609, killed tumors refractory to currently marketed platinum agents carboplatin, cisplatin and oxaliplatin. When tested in animal models of ovarian cancer and colon cancer, the bis-platinates were significantly more potent than the two most commonly used platinum-based chemotherapy drugs, carboplatin and cisplatin and oxaliplatin. The agents demonstrated potent antitumor activity in tumors with either acquired or intrinsic resistance to cisplatin or carboplatin, representing the first such class of binuclear platinum-based drugs to show activity in those tumor types. The compounds could enter human clinical trials in late 2008.
• Cytokinetics Inc., of South San Francisco, presented two posters of preclinical data relating to the mitotic kinesin centromere-associated protein E (CENP-E) and an inhibitor of CENP-E, GSK-923295. Data from one poster concluded that certain cell lines, namely SK-BR-3, HCC1954 and EFM19, are sensitive to apoptosis following mitotic arrest with the inhibitor of CENP-E and that heterogeneity of response was observed. In addition, the poster detailed that cell death following mitotic arrest is not increased when slippage is induced by decreasing checkpoint strength, and furthermore, accumulation of p53 is correlated with mitotic arrest but does not correlate with sensitivity or resistance. A second poster reported the findings of a preclinical study showing GSK923295A was tested for antiproliferative activity against 214 solid tumor cell lines and 85 hematological tumor cell lines. The authors concluded that this inhibitor of human CENP-E is active against a broad range of both solid and hematological tumor lines in cell culture.
• EntreMed Inc., of Rockville, Md., reported data from a Phase II study demonstrated that Panzem NCD, administered as a single agent in patients with platinum-refractory epithelial ovarian cancer, resulted in one patient with a confirmed partial response of their CA-125. Five patients, out of the 18 patients enrolled, achieved stable disease lasting greater than three months. Panzem NCD was well tolerated, and no significant neuropathy, myelosuppression or thromboembolic side effects were reported. Three patients remained on study for more than six months, and two of the patients are still on study. Data from in vitro studies demonstrated that it has activity against a variety of ovarian carcinoma cell lines including those resistant to other chemotherapeutic agents. In preclinical models of ovarian cancer, it demonstrated a significant survival advantage compared to animals that did not receive treatment. In a Phase I clinical study, an ovarian cancer patient with the clear-cell subtype experienced a durable partial response to the compound lasting over three years after failing three prior chemotherapy regimens.
• Exelixis Inc., of South San Francisco, reported encouraging data from an ongoing Phase I trial of XL184, an inhibitor of MET, RET and VEGFR kinases, in patients with advanced solid tumors or lymphoma. Antitumor activity was observed in a variety of cancers at doses not associated with significant toxicity. Consistent with the anti-VEGFR activity of XL184, preliminary pharmacodynamic analyses show reductions in several biomarkers of angiogenesis. Of seven patients with medullary thyroid cancer (MTC), three have had partial responses (two confirmed and one unconfirmed). Six of the seven patients had tumor shrinkage and one had nonmeasurable disease. All seven assessable patients with MTC experienced a rapid decrease in plasma levels of calcitonin, a marker frequently elevated in medullary thyroid cancer, and six of the seven patients had a decrease in the tumor marker carcinoembryonic antigen. A Phase II trial is planned to begin in late 2007.
• Genmab A/S, of Copenhagen, Denmark, announced results from a Phase I study of the monoclonal antibody R1507 in patients with solid tumors, conducted by its partner F. Hoffmann-La Roche Ltd., of Basel, Switzerland. In the trial, nine of 34 adult patients with solid tumors experienced disease stabilization and four of seven heavily pretreated patients with Ewing's sarcoma demonstrated clinical benefit. The most frequently observed side effects were fatigue, anorexia and weight loss.
• Human Genome Sciences Inc., of Rockville, Md., said results of its Phase Ib trial for HGS-ETR2 (lexatumumab) showed the drug was safe and well tolerated in combination with four different standard chemotherapy regimens for a wide range of cancer types. Objective responses were reported for two patients, and stable disease was observed in 22 patients. The company also presented preclinical data showing HGS-ETR1 (mapatumumab) and HGS-ETR2 in combination with chemotherapy enhanced antitumor activity in cancer of the bile ducts. In a xenograft model of cholangiocarcinoma, the results demonstrated that HGS-ETR1 and either co-treatment or pretreatment with cisplatin and gemcitabine were more effective than chemotherapy or HGS-ETR1 alone.
• Jennerex Biotherapeutics, of San Francisco, presented clinical data from a Phase I/II trial of JX-594, its targeted lytic and immunostimulatory armed virus therapy, demonstrating efficacy in 10 of the 13 evaluable patients with advanced treatment-refractory tumors in the liver (primary and metastatic). Responses were particularly encouraging in primary liver cancers, squamous cell cancers (including lung) and melanoma. All three patients with primary liver cancer had evidence of efficacy, including tumor marker decreases of 65 percent, 80 percent and 98 percent. Seven patients survived for at least eight months (double the life expectancy), and four still are alive up to 17 months post-treatment; two are alive more than one year. It also was shown to be generally well tolerated.
• Kosan Biosciences Inc., of Hayward, Calif., presented data from a Phase I trial showing that KOS-1584/R1645, an epothilone, demonstrated antitumor activity and tolerability in patients with solid tumors. KOS-1584/R1645 showed signs of activity in patients with non-small-cell lung, ovarian, breast, prostate, pancreatic, head and neck and colon cancer. The trial explored two different schedules of KOS-1584/R1645 using escalating doses. Data reported were from a trial investigating weekly dosing schedules. Common toxicities generally were low-grade and manageable.
• Mersana, of Cambridge, Mass., presented interim results of a Phase I study of its lead product candidate, XMT-1001, in patients with advanced solid tumors. Results were presented from 12 patients enrolled in an ongoing Phase I open-label, dose-escalation trial designed to determine the safety, tolerability and pharmacokinetic profile of XMT-1001. To date, XMT-1001 has been well tolerated in patients and no serious drug related adverse events have been reported. Preliminary results demonstrated a favorable pharmacokinetic profile with low levels of CPT, both total and free, recovered in urine. The maximum tolerated dose has not been reached and the study continues to accrue patients.
• Novogen Ltd., of Sydney, Australia, presented data demonstrating that drug candidate NV-128 induces autophagy, a novel mode of cell death in multidrug-resistant ovarian cancer cells. While phenoxodiol induces caspase-mediated apoptosis, which is often nonfunctional in highly chemoresistant cancer cells due to highly over-expressed anti-apoptotic proteins, NV-128 has been shown to induce caspase-independent DNA degradation and cancer cell death. NV-128 is a derivative of phenoxodiol, an investigational drug licensed by Novogen to Marshall Edwards Inc., also of Sydney, that is now in Phase III clinical development for patients with late-stage ovarian cancer.
• Oncolytics Biotech Inc., of Calgary, Alberta, presented interim results from a UK Phase Ia/Ib combination Reolysin/radiation clinical trial for patients with advanced or metastatic cancers. The interim results demonstrated that intratumoural treatment with Reolysin and radiation was well tolerated and results in both local and remote anti-tumor activity in patients with a variety of advanced cancers. Oncolytics continues to enroll patients in the Ib portion of the trial, and also is enrolling patients in a Phase II trial for the same treatment combination.
• OSI Pharmaceuticals Inc., of Melville, N.Y., presented preclinical data on OSI-906 showing it blocks IGF-1R activation of the key cancer cell signaling pathways called AKT and MAP kinase that are known to drive tumor cell growth. OSI-906 not only slowed tumor growth, but also decreased the size of pre-existing tumors known to be dependent on the human IGF-1R. Additionally, when OSI-906 was combined with Tarceva (erlotinib) in mice with human colorectal tumors, the two drugs together decreased the size of pre-existing tumors more effectively than either drug alone. OSI is enrolling patients with advanced solid tumors in two Phase I dose escalation studies of OSI-906.
• Spectrum Pharmaceuticals Inc., of Irvine, Calif., presented preclinical data on SPI-1620 showing it significantly increased tumor blood perfusion, and enhanced the uptake and delivery of paclitaxel to the tumor tissues without affecting other organs. Mice administered with SPI-1620 increased tumor perfusion by up to approximately 200 percent from baseline, and the effect lasted more than two hours, compared to no significant change in saline treated mice. SPI-1620-treated mice also had more than fivefold increased concentration of paclitaxel in tumors, and no significant change in normal tissues compared to saline treated animals.
• Tapestry Pharmaceuticals Inc., of Boulder, Colo., presented a poster on lead candidate TPI 287, a taxane for the treatment of multiple cancer indications. The poster outlined a number of different assays confirming that TPI 287 is less sensitive in a variety of cancer cell lines to MDR1 mediated efflux than other approved taxanes. Additionally, TPI 287 was retained at higher levels in MDR1 expressing cell lines than either paclitaxel or IDN 5109, another taxane in development purported to be active in MDR1 expressing tumors. TPI 287 also has demonstrated tumor growth inhibition when delivered orally in subcutaneous mouse xenograft models of both pancreatic cancer and glioblastoma multiforme (GBM). Tapestry has Phase II studies under way for TPI 287 in pancreatic and prostate cancer and plans to evaluate TPI 287 in a Phase II study in GBM.
• Tranzyme Pharma, of Research Park Triangle, N.C., presented data indicating that product candidate TZP-201 can dose-dependently prevent or substantially mitigate otherwise lethal irinotecan-induced diarrhea under conditions mimicking the clinical situation. In the study, TZP-201 achieved its desired therapeutic results by reducing symptom severity and restoring normal motility more effectively, more rapidly and for a longer duration than the most common current drug treatment options, loperamide and octreotide. The study also provided excellent pharmacokinetic and safety data to support continued development of the compound.