By Brady Huggett

ImClone Systems Inc. presented data at the American Society of Clinical Oncology meeting in San Francisco over the weekend from three Phase II trials evaluating the use of IMC-C225 and standard chemotherapies.

IMC-C225 is New York-based ImClone¿s investigational monoclonal antibody designed to target and block the epidermal growth factor receptor expressed on the surface of certain cancer cells.

A Phase II study of IMC-C225 and gemcitabine in patients with pancreatic cancer found that the combination therapy produced a one-year survival rate of 32.5 percent. Five patients in the study achieved a partial response and an additional 21 patients achieved stabilization of disease. The median time to disease progression was about 3.5 months.

The combination produced a median overall survival of 6.75 months.

A Phase II study of IMC-C225 and cisplatin showed the combination can produce major responses in patients with cisplatin-refractory head and neck cancer. Sixty-three patients received the combination following treatment with cisplatin before the study. Cohort 1 of the trial (41 patients with stable disease) had one patient with complete response and nine partial responses. The median duration of response was 24 weeks. Cohort 2 (22 patients with progressive disease) had five partial responses with a median duration of response of 12 weeks.

From the Phase II study of IMC-C225 and irinotecan in patients with irinotecan-refractory colorectal cancer, 22.5 percent of patients achieved a partial response. Of the 120 patients in the trial, 27 achieved a partial response, and an additional nine patients achieved a stabilization of disease. The median duration response was 186 days.

Side affects for the three trials included diarrhea, neutropenia, nausea, fatigue, vomiting and an acne-like rash. IMC-C225 did not appear to exacerbate the toxicities associated with the chemotherapies.

In other news from ASCO:

¿ AEterna Laboratories Inc., of Quebec City, Quebec, presented data showing Neovastat/AE-941 is able to increase the level of angiostatin in mice with implanted human glioblastoma, a form of brain cancer. Human glioblastoma cells were injected into the brain of nude mice and the mice were then given Neovastat in order to test its antitumoral activity. Results showed antitumoral activity and that it increased tissue type plasminogen activator, an enzyme involved in the production of angiostatin. Neovastat is an anti-angiogenic product with multiple mechanisms of action.

¿ Allos Therapeutics Inc., of Denver, presented positive response rate and survival results from its Phase II trial of RSR13 combined with radiation therapy in patients with non-small-cell lung cancer. Data from 44 evaluable patients demonstrated an overall response rate of 89 percent within the radiation therapy portal in the chest, with 80 percent partial responses and 9 percent complete responses. The estimated one-year survival rate was 65 percent and projected two-year survival rate was 51 percent. Median survival had not been reached. The one-year progression-free rate was 55 percent and the two-year rate was 21 percent.

¿ AltaRex Corp., of Waltham, Mass., presented interim results from its lead 345-patient OvaRex double-blind, placebo-controlled trial for ovarian cancer. Data showed that the proportion of high-risk patients in the 252-patient dataset with disease-free survival of six months was significantly higher (p=0.0397) in patients treated with OvaRex MAb (79 percent) than patients receiving placebo (39 percent). AltaRex has analyzed data from two Phase II trials and said the results demonstrate that treatment with OvaRex MAb can provide comparable efficacy to salvage chemotherapies in late-stage ovarian cancer patients with recurrent disease, but without toxicities. Also, the company highlighted preliminary findings from a completed Phase II trial involving 55 (27 active, 28 placebo) patients with subclinical disease recurrence therapy of surgery and chemotherapy. Initial findings include indications that measurements of ovarian tumor marker CA 125 at baseline are strongly predictive of patient time to disease relapse, a finding also observed in the 345-patient trial.

¿ Antigenics Inc., of New York, presented results of two Phase II trials evaluating Oncophage, its cancer vaccine, in patients with advanced melanoma and colon cancer. The Phase II melanoma study evaluated 28 patients with advanced cancer incurable with surgery. Five responded favorably, including two in whom all evidence of melanoma disappeared for nearly two years and who were still disease free. In the second Phase II trial presented, 29 patients with advanced colon cancer that had spread to the liver received Oncophage after liver surgery. Data indicate Oncophage therapy generated anticolon cancer immunity in close to half of the patients. Two other presentations described results of cancer vaccines that incorporated QS-21, Antigenics¿ immune adjuvant, in disease therapy.

¿ Aronex Pharmaceuticals Inc., of The Woodlands, Texas, reported Phase I data from a trial of Atragen combined with interferon-alpha for advanced renal cell cancer. Patients with advanced renal cell cancer were treated with Atragen intravenously at 15 mg/m2 every other day in combination with interferon-alpha given subcutaneously. Of the 16 evaluable patients, two had partial remission in bone and lung, including one patient whose remission has lasted more than 77 weeks ongoing. Five patients had stable disease; two progressed in bone only.

¿ Biomira Inc., of Edmonton, Alberta, presented data from a Phase II trial of Theratope vaccine being tested in 45 patients with metastatic colorectal cancer. The median survival from time of commencing Theratope vaccine was 14.2 months and 31 months from the time of diagnosis of metastasis. A subgroup of 27 patients who had previously received first-line chemotherapy treatment for metastasis had a median survival of 12.5 months.

¿ Cell Genesys Inc., of Foster City, Calif., reported interim clinical data from its multicenter Phase I/II GVAX lung cancer vaccine trial. The data included results on 30 evaluable patients with advanced or early stage lung cancer. Of 22 patients with advanced disease, three patients, two of whom had failed chemotherapy and one who failed radiation therapy, showed a complete disappearance of metastatic tumors following treatment with GVAX lung cancer vaccine. One patient who failed radiation and chemotherapy had greater than 50 percent tumor reduction. Four patients have nonprogressive disease and seven of eight patients with early stage lung cancer who received GVAX vaccine following surgery were disease free with a median follow-up time of seven months.

¿ Cell Pathways Inc., of Horsham, Pa., presented data on two of its selective apoptotic antineoplastic drugs in patients with advanced cancer. Investigators from the University of Pennsylvania and Cell Pathways detailed results of a Phase I safety and pharmacokinetic trial of CP461 and results of a Phase I/II trial with Aptosyn and Taxotere were presented by investigators from the University of Colorado Cancer Center and Cell Pathways. In the Phase I single-agent trial of CP461, 18 patients with a variety of tumors received the drug orally, twice daily, for 28 days at total doses ranging from 100 mg/day to 800 mg/day. CP461 was rapidly absorbed and at doses higher than 200 mg/day achieved plasma concentrations of drug that exceeded the concentrations required to induce apoptosis in laboratory cultured cancer cells.

¿ Chiron Corp., of Emeryville, Calif., presented preliminary results of a Phase III trial of high-dose Proleukin, a recombinant form of human interleukin-2, that demonstrated increased response rates with longer median duration compared to outpatient subcutaneous Proleukin in conjunction with interferon alfa-2b in patients with metastatic renal cell carcinoma. Tumor responses were assessed at weeks six and 12, and every 12 weeks thereafter. Twenty-five percent of patients had primary metastases and 19 percent and 32 percent had liver and bone metastases, respectively. The high-dose Proleukin group had a tumor response of 25 percent. The low-dose Proleukin group had a tumor response of 12 percent. Two patients received complete response and 10 achieved partial response.

¿ Corixa Corp., of Seattle, and GlaxoSmithKline plc, of London, reported trial results (three abstracts) that suggest the use of Patient-Optimized dosing with Bexxar therapy may provide low-grade non-Hodgkin¿s lymphoma patients with targeted treatment and a predictable side effect profile. In the multicenter studies, treatment with Bexxar was administered using a method of dosimetry to correct for individual patient variables that affect clearance, such as the amount of tumor in the body and the bone marrow to provide a consistent, targeted radiation dose.

¿ Dana-Farber Cancer Institute, an affiliate of the Harvard Medical School, was part of an international team of researchers that reported Gleevec (Novartis AG, of Basel, Switzerland) can benefit the majority of patients with a rare and otherwise incurable form of gastrointestinal cancer called gastrointestinal stromal tumor. The researchers ¿ from Dana-Farber, Oregon Health Sciences University, Fox Chase Cancer Center and Helsinki University Central Hospital ¿ found that more than 75 percent of patients had some shrinkage of their tumors, and that in more that 50 percent of patients, tumors shrank by at least 50 percent. Novartis announced last week that Gleevec was approved by the FDA as an oral therapy for the treatment of patients with chronic myeloid leukemia in the blast crisis, accelerated phase or in chronic phase after failure of interferon-alpha therapy.

¿ EntreMed Inc., of Rockville, Md., reported data from a Phase I trial of rhAngiostatin that indicated the drug was safe, has linear and predictable pharmacokinetics, and does not alter blood clotting mechanisms, the company said. It also reported completion of the first clinical trial of Panzem as a single agent in patients with advanced stages of breast cancer. Panzem did not cause any serious drug-related adverse effects and caused no change in estrogen levels. According to a Reuters Ltd. story, a trial on EntreMed¿s rhEndostatin gave less than encouraging news. While rhEndostatin didn¿t show any signs of toxicity, the story said tumors shrank in two patients but later grew back. Tumors also got bigger in the remaining 23 patients in the trial, it said. EntreMed¿s stock (NASDAQ:ENMD) dropped $3.95 Monday, or about 20.5 percent, to close at $15.30.

¿ Genentech Inc., of South San Francisco, presented results from three retrospective studies demonstrating that fluorescence in situ hybridization (FISH) testing of tumor tissue for HER2 gene amplification appears to be an effective method for selecting women with HER2-positive metastatic breast cancer who are most likely to respond to Herceptin (trastuzumab) therapy. In the retrospective analysis of tumor tissue from women in the Phase III pivotal combination trial, those who were FISH positive for HER2 gene amplification survived 50 percent longer ¿ 27 months vs. 18 months ¿ when given Herceptin with chemotherapy as compared to those who received chemotherapy alone. This result contrasts the 24 percent increase in survival time seen when the same tumors tested positive for HER2 protein overexpression with immunohistochemistry testing.

¿ Genta Inc., of Berkeley Heights, N.J., presented data that showed antitumor activity when Genasense, its lead antisense compound, was used in combination for the treatment of prostate cancer. Patients were treated with a range of Genasense and Taxotere doses. Results showed 10 of 12 patients who had not previously received taxane-containing therapy had major reduction of serum prostate-specific antigen (PSA). Of these patients, seven had more than 50 percent reduction of PSA, accompanied by shrinkage of tumor metastases in liver and lymph nodes.

¿ Genvec Inc., of Gaithersburg, Md., presented data from studies with TNFerade, a candidate for use in combination with radiation therapy. The preclinical studies demonstrated that TNFerade was well tolerated in animal experiments. TNFerade is designed to deliver the tumor necrosis factor-alpha gene to tumors.

¿ ImmunoGen Inc., of Cambridge, Mass., presented safety and pharmacokinetic data from 37 patients enrolled in the Phase I trial of its Tumor Activated Prodrug, huC242-DM1/SB-408075, for the treatment of colorectal, pancreatic and certain non-small-cell lung cancers. Evidence of antitumor activity also was reported. Two patients demonstrated minor responses and four additional patients had persistent stable disease for more than three months. A total of nine patients showed decreases in carcinoembryonic antigen levels.

¿ IntraBiotics Pharmaceuticals Inc., of Mountain View, Calif., presented final results of a Phase III study of its product, Protegrin IB-367 Rinse, for the prevention of oral mucositis in patients undergoing high-dose chemotherapy. As previously announced, the study was negatively impacted by a third-party vendor error, causing 102 patients out of 323 to receive at least one incorrect bottle, either placebo or drug, during the trial. The company said it would conduct a repeat Phase III trial of the product in chemotherapy patients. (See BioWorld Today, April 27, 2001.)

¿ Introgen Therapeutics Inc., of Austin, Texas, reported biosafety information in INGN 201, its adenoviral p53 gene therapy candidate in Phase III testing. Data from 190 patients treated intratumorally demonstrated there were no infectious risks associated with the adenoviral vector to the patients treated, or to their families. The study suggested the vector used is genetically stable. Also, Introgen reported data from a Phase I study of the intravenous treatment of patients with advanced cancer and a Phase I study for the treatment of bladder cancer.

¿ Isis Pharmaceuticals Inc., of Carlsbad, Calif., presented updated Phase I/II study data on its product, ISIS 3521, its investigational antisense, anticancer drug, demonstrating prolonged survival and time to progression of disease, and robust overall response rates in people with stage IIIb and stage IV non-small-cell lung cancer. ISIS 3521 was given in combination with standard chemotherapy agents. The median survival time for patients in the trial was 15.9 months. Typical median survival of patients receiving standard chemotherapy alone is about eight months. Of the 48 patients evaluable for response in the Phase I/II trial, 81 percent improved through tumor responses or stable disease. One patient has experienced a complete response, and 21 patients have experienced a partial response, producing an objective response rate of 46 percent. Five patients have experienced a minor response and 12 patients have had stabilization of their disease.

¿ Matrix Pharmaceutical Inc., of Fremont, Calif., said a combination of tezacitabine, an experimental agent, and the chemotherapy agent fluorouracil demonstrated antitumor activity at tolerable doses in an ongoing Phase I study in patients with a variety of solid tumors. Patients in the study had a range of cancers, including esophageal, non-small-cell lung, small-cell lung, ovarian and renal.

¿ Maxim Pharmaceuticals Inc., of San Diego, reported results from a completed Phase II trial of its lead drug candidate, Ceplene, in combination with interferon-alpha and interleukin-2 for the treatment of metastatic renal cell carcinoma. Forty-six patients in the single-arm study were treated with Ceplene triple-drug combination and achieved a median survival on an intent-to-treat basis of 16.3 months. Maxim said published reports suggest that patients with metastatic renal cell carcinoma have a median survival of about eight to 10 months.

¿ MGI Pharma Inc., of Minneapolis, presented data from a Phase II trial of irofulven sponsored by the Bethesda, Md.-based National Cancer Institute. Interim results for the 38 patients showed seven patients demonstrated objective responses (one had complete clinical response, six patients has partial responses) and 13 had stable disease. Patients with partial responses remained progression free for more than five months and up to 20 months. Patients with stable disease remained progression free for two to nine months. Five abstracts were published that included interim results of several ongoing Phase I irofulven trials using weekly dosing schedules, as well as a summary of irofulven¿s antitumor activity in Phase I and Phase II trials. Also, MGI presented data on two Phase II trials of Palonesetron.

¿ Onyx Pharmaceuticals Inc., of Richmond, Calif., presented results of a Phase I/II trial with its lead product, CI-1042 (ONYX-015), administered via hepatic artery infusion for the treatment of colorectal cancer liver metastases. CI-1042 was well tolerated and data demonstrated that patients treated at the highest dose had prolonged survival compared to the patients treated with the lower dose. The median survival in the low-dose arm was 155 days compared to 342 days in the high-dose arm. CI-1042 is a tumor-selective, modified adenovirus that has been genetically engineered to replicate in and kill cancer cells that have dysfunctional p53.

¿ OSI Pharmaceuticals Inc., of Uniondale, N.Y.; Genentech Inc., of South San Francisco; and F. Hoffmann-La Roche Ltd., of Basel, Switzerland, reported updated findings on two ongoing Phase II studies of Tarceva (OSI-774), an inhibitor of the epidermal growth factor receptor tyrosine kinase. Data from a Phase II study of 57 evaluable patients with advanced, refractory non-small-cell lung cancer showed one complete response and eight partial responses. A total of 15 patients demonstrated evidence of disease stabilization for periods of three or more months. Twenty-eight patients in the study were still alive at the date of data assessment, with 10 patients having survived for more than 300 days. Median survival of patients in the study was 257 days and statistical analysis indicated a one-year survival rate of 48 percent. Of the 124 patients in the Phase II head and neck cancer trial, seven had partial responses and 49 patients showed documented evidence of disease stabilization for periods of three or more months. Forty-five percent of patients had either a response or disease stabilization. Median survival of the patients in the study was 174 days, with 42 patients alive at the date of data assessment and 14 patients having survived for more than 300 days.

¿ Oxigene Inc., of Watertown, Mass., reported Phase I data from its UK trial of Combretastatin A4 Prodrug (CA4P). The trial showed that CA4P can be given safely at doses that reduce malignant tumor blood flow. The results also indicated blood flow reduction in malignant tumors within the toleration range. CA4P is a vascular targeting agent that attacks blood vessels that support a tumor.

¿ Pharmacyclics Inc., of Sunnyvale, Calif., reported results from several trials with its lead product, Xcytrin Injection, in a variety of cancers. In a Phase I trial, 28 adults with newly diagnosed glioblastoma multiforme (GBM) received up to 22 doses of Xcytrin combined with standard whole-brain radiation over 6.5 weeks. Median survival to date was 17.3 months. The company presented data on three other trails at the conference.

¿ Pro-Virus Inc., of Gaithersburg, Md., had results of a Phase I trial of its product, PV701, presented by a member of the Hackensack University Medical Center. The patients in the trial had a range of late-stage tumors, including melanoma, mesothelioma, and cancers of the head and neck, colon and pancreas, and had failed other therapies. Using PV701 as a single agent, one patient with head and neck cancer had complete tumor regression, two patients ¿ one with colon cancer and one with mesothelioma ¿ had tumor regression of more than 50 percent. Six patients with diverse malignancies had measurable tumor reduction. Overall, 14 of 62 evaluable patients had freedom from tumor progression of between four and 29-plus months (ongoing).

¿ Radiation Therapy Oncology Group, of Philadelphia, reported thalidomide is showing promise in treating malignant brain tumors in combination with radiation therapy. Separately, it said higher doses of radiation delivered through 3-D conformal radiation therapy have resulted in less late toxicity among prostate cancer patients compared to lower doses delivered using conventional radiation techniques.

¿ Telik Inc., of South San Francisco, presented Phase I results of TLK286 in refractory cancers. Fifty patients have been enrolled, 35 in the completed Schedule A and 15 patients in the ongoing Schedule B. Schedule A patients received two doses of TLK286 administrated once every three weeks, with tumor assessment on day 43. Those who showed evidence of clinical benefit continued to received TLK286 until disease progression. Patients in Schedule B receive weekly doses of TLK286 for six weeks, with continued treatment for patients showing evidence of clinical benefit. Overall results indicate TLK286 is well tolerated over a range of doses in two dosing schedules. Evidence of clinical benefit was observed in 11 of the 32 patients treated in Schedule A and in three of the seven patients currently evaluable in Schedule B. Telik initiated a Phase II trial in patients with refractory colorectal cancer in March and anticipates Phase II trials in ovarian and non-small-cell lung cancers shortly.

¿ Titan Pharmaceuticals Inc., of South San Francisco, reported positive results from a multicenter Phase II study of its monoclonal antibody immunotherapy, TriGem, for the treatment of stage III melanoma. The study enrolled 64 patients and was designed to assess overall survival, relapse-free survival, safety and immune responses in patients. Data suggest TriGem provides a therapeutic benefit both as a single agent and in combination with alpha-interferon. Forty patients received TriGem alone, and after two years, overall survival and relapse-free survival for these patients was 90 percent and 67 percent, respectively. Also, 24 patients treated with both TriGem and alpha-interferon had overall survival and relapse-free survival rates after two years of 96 percent and 80 percent, respectively.

¿ Vical Inc., of San Diego, presented interim safety and efficacy data from its Phase II Allovectin-7 registration trial for patients with late-stage metastatic melanoma. In the trial, treatment with Allovectin-7 resulted in a reduction in total tumor burden of 50 percent or more in 14.8 percent of the evaluable patients with a current median duration of response of about five months. Two patients experienced complete responses and an additional 26 percent of evaluable patients achieved stable disease, some with reductions in total tumor burden that are significant but did not reach 50 percent. On an intent-to-treat basis, 11 percent experienced systemic clinical responses, and an additional 19 percent achieved stable disease.

¿ Vion Pharmaceuticals Inc., of New Haven, Conn., reported preliminary results from the Phase I trial of its first-generation Tapet vector (VNP20009) administered by intratumoral injection, demonstrating it was well tolerated. The trial is designed to determine the maximum tolerated dose and biologic effects of the base Salmonella vector. In seven of 10 patients, and in all patients at the second and third dose levels, VNP20009 bacteria remained in the tumors for at least two weeks following injection.

¿ Zeltia-PharmaMar, of Madrid, Spain, presented final Phase II trial results of its marine compound, Ecteinascidin 743, demonstrating the product may control disease and increase survival rates of patients with soft-tissue sarcoma. ET-743 was shown to shrink some tumors and control disease for prolonged periods with acceptable tolerability in patients. The compound is obtained from the tunicate Ecteinascidia turbinata, or the sea squirt.

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