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Biotech / Medical : VD's Model Portfolio & Discussion Thread -- Ignore unavailable to you. Want to Upgrade?

To: scaram(o)uche who wrote (7251)	12/4/1999 8:08:00 PM
From: Vector1	Read Replies (2) \| Respond to of 9719

Rick, as always great questions. This is the ealier abstract. Patients were 6-8 weeks into the program before Bex. Iodine I 131 tositumomab, a radiolabeled IgG2a monoclonal antibody directed against the CD20 antigen, is effective in the treatment of previously untreated as well as relapsed and refractory low-grade and transformed low-grade NHL. Fludarabine is also active as a single agent or in combination in NHL. In vitro data has shown that Iodine I 131 tositumomab and fludarabine have a markedly supra-additive effect on tumor cell killing. We are evaluating the safety and efficacy of a sequential regimen of 3 cycles of fludarabine (25 mg/m2 x 5 d every 5 wks) followed 6-8 wks later by BexxarTM (tositumomab and iodine I 131 tositumomab) for patients with previously untreated low-grade, transformed low-grade or follicular NHL. Thirty-eight patients were enrolled, 14 of which are evaluable for response at least 3 months post treatment with Iodine I 131 tositumomab. Baseline patient characteristics (n = 14) were: median age 52.5 yrs, >60 yrs (2), male (7), median time from diagnosis (62 mo) and stage at time of treatment (Stage II = 1, Stage IV = 13). Patients received a single dosimetric dose (450 mg of tositumomab IV followed by 35 mg (5 mCi) of Iodine I 131 tositumomab) and then had 3 whole body counts obtained over the next 7 days. The whole body counts were used to calculate the required activity (mCi) to deliver the desired therapeutic dose (65 cGy for platelets 100,000-149,000/mm3 and 75 cGy for platelets 150,000/mm3). The single therapeutic dose (450 mg of tositumomab IV followed by 35 mg of tositumomab containing an appropriate amount of activity (mCi) of Iodine-131 to deliver the specified total body dose (cGy) ) was administered 7-14 days after the dosimetric dose. The toxicity following fludarabine was mainly hematologic. The principal toxicity following Iodine I 131 tositumomab was also hematologic: ANC < 500 = 5 pts (36%), platelets < 10,000 = 1 pt (7%). Non-hematologic toxicity was typically mild to moderate and the most frequent events were nausea, asthenia, headache and rhinitis. No patient developed anti-murine antibodies (HAMA). An investigator-assessed response was seen in 13 of 14 pts (93%) (2 CR, 11 PR) after fludarabine. Following treatment with Iodine I 131 tositumomab, 13 of 14 (93%) pts had a response (6 CR, 7 PR). Of the 11 PRs after fludarabine, 4 converted to CR. One SD after fludarabine converted to PR. Experience with Iodine I 131 tositumomab suggests that further improvement in the degree of response may occur with longer follow-up. These preliminary data show that Iodine I 131 tositumomab can be administered safely after fludarabine as part of a sequential regimen while adding to the efficacy. The immunosuppressive effect of fludarabine appears to suppress HAMA response to Iodine I 131 tositumomab. Interesting that in the earlier abstract had no HAMA responses. On the issue of why the complete response rate improved as time went on is one possible reason is that it is the MAB not the I 131 that is doing the cleanup. Remember in preclinical Bex and Fludarabine were superadditive. Interestingly IDPH had to halt the Rit plus Fludara trial because of toxicity. V1