Meanwhile, Aptosyn fails yet again. Tarceva is fine, but OSI's taste in programs to purchase sucks, IMO:
>>MELVILLE, N.Y.--(BUSINESS WIRE)--June 11, 2004--OSI Pharmaceuticals, Inc. (Nasdaq: OSIP - News) today announced that a Phase III study of Aptosyn® (exisulind) in combination with Taxotere® (docetaxel), did not meet its primary endpoint of improving overall survival in patients with advanced non-small cell lung cancer (NSCLC). The trial also did not meet its secondary endpoints of improvement in one-year survival, progression-free survival and response rate. Aptosyn® is being developed by OSI and is part of the Selective Apoptotic Anti-Neoplastic Drug (SAANDs) platform acquired from Cell Pathways, Inc. in June 2003.
Survival in the Taxotere® plus Aptosyn® arm was essentially indistinguishable from that in the Taxotere® plus placebo arm. Median and one-year survival rates in the Aptosyn® plus Taxotere® arm were 6.9 months and 30.7 percent respectively, compared with 6.9 months and 29.5 percent in the Taxotere® plus placebo arm. Median progression-free survival was 13 weeks in the Taxotere® plus Aptosyn® arm and 12 weeks in the Taxotere® plus placebo arm and the respective response rates were 9.2 percent and 7.2 percent.
"Although we have previously communicated our view that this was a high-risk study we are nonetheless disappointed for lung cancer patients that the outcome was not more positive," stated Colin Goddard, Ph.D., Chief Executive Officer of OSI Pharmaceuticals. "We want to thank those patients and their families who volunteered for this study. We continue to believe that apoptosis is an important area of investigation in cancer research today and will continue with our efforts in developing pro-apoptotic anti-cancer drugs in appropriate disease settings."
About the Study
OSI assumed management of this fully enrolled randomized double-blind Phase III study upon completion of the acquisition of the apoptosis technology platform from Cell Pathways in June 2003. The multi-center, Phase III study evaluated Aptosyn® in combination with Taxotere® versus Taxotere® plus placebo in NSCLC patients after failure of prior platinum-based chemotherapy. Taxotere® is an approved chemotherapeutic agent used in the second-line treatment of locally advanced or metastatic non-small cell lung cancer. A total of 610 patients with locally advanced (Stage IIIb) or metastatic (Stage IV) NSCLC were enrolled in the trial. Approximately 90 percent of patients in the study were ECOG performance status 0-1 and approximately 10 percent were performance status 2. The Eastern Cooperative Oncology Group (ECOG) ranks performance status from 0 to 5 according to level of daily activity and symptoms of disease with 0 representing normal activity.
Safety Data
The addition of Aptosyn® to Taxotere® did not introduce any new toxicities beyond those typically associated with the use of Taxotere®. The frequency and severity of febrile neutropenia, diarrhea, nausea, and vomiting and other non-hematological toxicities were comparable in the two arms.
About Aptosyn® and the SAANDs Platform
Aptosyn® is a cGMP phosphodiesterases (cGMP-PDEs) inhibitor which leads to the activation of the intracellular signaling protein, Protein Kinase G (PKG), and subsequent stimulation of apoptosis through the c-Jun kinase pathway. Aptosyn® belongs to a new class of drugs termed Selective Apoptotic Anti-neoplastic Drugs (SAANDs) and is part of the technology platform which OSI acquired from Cell Pathways in June 2003. Cell Pathways had initiated the current Phase III trial based upon pre-clinical data in orthotopic rat models and the combined safety database of successive clinical programs that had originally focused on the pre-cancerous condition familial adenomatous polyposis (FAP). OSI had previously communicated that the lack of supporting Phase II data in advanced NSCLC made the prospects for success in the current study relatively low. However, the SAANDs platform, particularly in early stage and pre-cancerous conditions, remains an area of investigation at OSI.
About Non-Small Cell Lung Cancer
According to the World Health Organization, there are more than 1.2 million cases worldwide of lung and bronchial cancer each year, causing approximately 1.1 million deaths annually. It is estimated that more than 173,000 people will be diagnosed with lung cancer in the United States in 2004. According to the National Cancer Institute, lung cancer is the single largest cause of cancer deaths in the United States, and is responsible for nearly 30 percent of cancer deaths in the country. Non-small cell lung cancer is the most common form of the disease and accounts for almost 80 percent of all lung cancer.<<
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The other stuff being Gilead's also ran oncology program.
>>Ann Oncol. 2004 Apr;15(4):665-70.
A phase I study of OSI-211 and cisplatin as intravenous infusions given on days 1, 2 and 3 every 3 weeks in patients with solid cancers.
MacKenzie MJ, Hirte HW, Siu LL, Gelmon K, Ptaszynski M, Fisher B, Eisenhauer E.
Hamilton Regional Cancer Centre, Hamilton, Ontario, Canada.
BACKGROUND: OSI-211 (also known as NX211) is a liposomal preparation of the topoisomerase I inhibitor, lurtotecan, which has shown antitumor activity in phase I and II clinical trials. Cisplatin is a widely used antineoplastic agent with activity in a broad range of tumor types. This phase I trial was conducted to determine the recommended doses of these agents, and their pharmacokinetic properties and toxicities in patients with advanced solid malignancies. PATIENTS AND METHODS: Fourteen patients with advanced and/or metastatic solid malignancies were enrolled in this trial. The first planned dose level was OSI-211 0.9 mg/m(2) with cisplatin 25 mg/m(2) administered intravenously daily for the first three consecutive days of a 21-day cycle. Patients were evaluated for hematological and non-hematological toxicities, and pharmacokinetic studies were performed on both agents. RESULTS: The recommended phase II dose was determined to be 0.7 mg/m(2) OSI-211 given with 25 mg/m(2) cisplatin. Dose-limiting neutropenia was seen in two of three patients at the starting dose level. Three of 11 patients at the second (lower) dose level experienced dose-limiting thrombocytopenia; febrile neutropenia was also seen in one patient. Non-hematological toxicities were generally manageable and included fatigue, nausea and vomiting. Considerable variability was seen in both hematological toxicities and pharmacokinetics. One complete response and three partial responses were seen. CONCLUSIONS: The recommended phase II dose for this combination is 0.7 mg/m(2) OSI-211 with 25 mg/m(2) cisplatin given as an intravenous infusion on days 1, 2 and 3 of a 21-day cycle. The main toxicity was myelosuppression. Preliminary evidence of antitumor activity was seen.<<
Sounds pretty good: major objective responses in a P1? Hot stuff! However, the first monotherapy PII splutted:
>>Gynecol Oncol. 2004 Apr;93(1):229-32.
A phase II study of liposomal lurtotecan (OSI-211) in patients with topotecan resistant ovarian cancer.
Seiden MV, Muggia F, Astrow A, Matulonis U, Campos S, Roche M, Sivret J, Rusk J, Barrett E.
The Division of Medical Oncology, New York University, New York, NY 10016, USA. mseiden@partners.org
OBJECTIVES: To determine the safety and efficacy of a novel topoisomerase I inhibitor, liposomal lurtotecan, in patients with topotecan resistant ovarian cancer. METHODS: The trial was an open-label phase II study for patients stratified by resistance to either single agent topotecan or to a prior topotecan-containing regimen. Liposomal lurtotecan was delivered at a dose of 2.4 mg/m(2) on Days 1 and 8 of a 21-day cycle. Dose escalations and reductions were allowed based on hematologic toxicity. Patients were evaluated every two cycles for response to liposomal lurtotecan. RESULTS: Twenty-two women were accrued, with 16 women resistant to single agent topotecan and 6 women resistant to topotecan given in combination with a second chemotherapy agent. Hematologic toxicity consisted of mild to moderate thrombocytopenia, anemia, and neutropenia with mild to moderate gastrointestinal toxicity and fatigue. There were no responses, although eight patients had stable disease. CONCLUSIONS: Liposomal lurtotecan at this schedule demonstrates moderate hematologic toxicity and no evidence of clinical activity in a group of heavily pretreated women previously exposed to the topoisomerase I inhibitor topotecan. The study of this agent in alternative patient populations or with alternative schedules is ongoing.<<
Such as
>>Invest New Drugs. 2004 Aug;22(3):263-75.
A phase 1 study of OSI-211 given as an intravenous infusion days 1, 2, and 3 every three weeks in patients with solid cancers.
Gelmon K, Hirte H, Fisher B, Walsh W, Ptaszynski M, Hamilton M, Onetto N, Eisenhauer E.
British Columbia Cancer Agency, Vancouver Cancer Centre, Vancouver, BC, Canada.
Purpose: To define the maximum tolerated dose (MTD), recommended phase II dose (RD) and dose limiting toxicity (DLT) of liposomal lurtotecan, OSI-211 (formerly known as NX211), given as a short intravenous infusion on days 1, 2, and 3 every three weeks. Experimental design: Thirty-seven patients were enrolled and treated in a dose escalation study from a starting dose of 0.15 mg/m(2) daily x 3 to 2.1 mg/m(2) daily x 3. Detailed pharmacokinetic analyses of blood were done on both days 1 and 3 of the first cycle and toxicity was monitored. Results: Two MTDs were defined; one for patients defined as minimally pretreated and one for those heavily pretreated. Dose limiting toxicity was myelosuppression: primarily thrombocytopenia although neutropenia was also noted. The MTD was 2.1 mg/m(2)/d (total dose of 6.3 mg/m(2)) in minimally pretreated patients and 1.8 mg/m(2)/d (5.4 mg/m(2) total dose) in heavily pretreated patients. Pharmacokinetics revealed that AUC and C (max) increased with dose and were significantly higher than that of free lurtotecan (AUC approx. 100 fold higher). The half life and duration of the active lactone form were also significantly longer than historical data on free drug. Two partial responses were seen, one each in a patient with breast and ovarian cancer. Conclusions: Two Phase II recommended doses were established for OSI-211 given as a daily x 3 schedule every three weeks. The recommended phase II dose is 1.8 mg/m(2) daily x 3 for minimally pretreated patients and 1.5 mg/m(2) for those heavily pretreated. Phase II studies should be initiated in sensitive tumours.<<
Maybe they should stick with combos . . . But oncology stocks are generally up today despite a tough market, so whatever.
Cheers, Tuck |
