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Biotech / Medical : CLTR COULTER PHARMACEUTICAL -- Ignore unavailable to you. Want to Upgrade?

To: Vector1 who wrote (242)	8/20/1999 4:18:00 AM
From: Gordon James	Read Replies (4) \| Respond to of 666

V1, Thanks so much for mentioning a fludarabine+Bexxar study and putting two and two together for me - I think it's a piece of the puzzle I've been missing. I've known that fludarabine looks very promising for NHL, but I wasn't aware of a study using this combo, and the Coulter website doesn't mention this study. Do you know where this study is being done? (my guess would be the Fred Hutchinson center in Seattle, the other Bexxar studies there involving Bexxar and high dose chemo/BMT haven't appeared on the Coulter website either). So I've assumed that the relatively high HAMA experienced in the early first-line Bexxar trials might limit first-line use somewhat, or limit subsequent Bexxar treatment after first-line use. But add to first-line Bexxar an already very promising chemo (fludarabine), which also happens to be immunosuppressive, and perhaps you get the best of both worlds for your first shot at the disease, a combination of two of the most powerful agents known, plus minimized HAMA (making room for more Bexxar re-treatment). The duration of response could be best yet, perhaps allowing more and longer subsequent remissions, and if we're ever going to cure some people of indolent NHL, surely it will require the strongest first shot we can muster. Give people either of those hopes, and I agree, they'll be lining up. Ran across some interesting tidbits related to this while looking through some abstracts. Don't know if you've seen this first one, but over at Fred Hutchinson, a pre-clinical study revealed that fludarabine or cytarabine provided the maximum anti-neoplastic synergy with Bexxar out of all the chemos they tried. From a 1998 ASCO abstract: "Iodine-131-labeled anti-CD20 monoclonal antibodies are effective single agents for the treatment of relapsed non-Hodgkin's B cell lymphomas, with observed response rates between 50% and 95%. Despite these encouraging results, many patients treated in this manner eventually relapse. We hypothesize that combination regimens employing I-131-anti-CD20 antibodies in conjunction with standard chemotherapy drugs may provide synergistic anti-neoplastic effects, and may improve the durability of responses in patients with B cell lymphomas. <snip> "ID50 isobolographic data analysis was employed to classify cytotoxic interactions between the I-131-anti-B1 and the chemotherapeutic agents as supra-additive, additive, and subadditive. Cytarabine and fludarabine were found to be markedly supra-additive when used in combination with I-131-labeled anti-B1. Etoposide, doxorubicin, and SN-38 were moderately supra-additive. Cisplatin and 4-hydroxycyclophosphamide (4-HC) were additive. 5-Fluorouracil had no cytotoxic effect either alone or in combination with the radioimmunoconjugate." <snip> "Markedly supra-additive"! So at least the pre-clinical data supports your gut... ;-) Another reference that suggests we should be excited about fludarabine here: "RESULTS: Purine analogues have revolutionized the treatment of indolent lymphomas. Fludarabine induces responses in almost 50% of patients with relapsed or refractory indolent NHL and produces complete remissions (CRs) in 10% to 15% of patients. In patients receiving fludarabine as initial treatment, CRs are achieved in almost 40%, with an overall response rate of 70% and a median time to progression > 1 year. <snip> "CONCLUSION: The purine analogues should provide the basis for new treatment strategies with the goal of curing patients with indolent NHL." <snip> Cancer J Sci Am 1998 Jul;4 Suppl 2:S27-36 ncbi.nlm.nih.gov One study that really caught my eye was a first-line fludarabine combination regimen, from 1998 ASCO: "PROLONGED TIME TO PROGRESSION (TTP) IN PATIENTS WITH LOW GRADE LYMPHOMA (LGL) TREATED WITH CYCLOPHOSPHAMIDE (C) AND FLUDARABINE (F) [ECOG 1491] <snip> "Response rate was 100%: 24/27 (89%) CR and 3/27 (11%) PR. LONG-TERM FOLLOW-UP: Median follow-up is 53+ mos. with 14 patients in continuous CR, 8 relapses, 4 dead NED, and 1 off study with PR. Median TTP and median overall survival (OS) have not yet been reached. Actuarial 3 and 5-year freedom from progression was 80% (95% CI 63--96%) and 60% (38--83%) with OS 85% (72--99%) and 76% (52--93%). Median time to failure [progression, relapse or death] was 56 (95% CI 50--76+) mos. CONCLUSION: Based on these promising results we are conducting phase III study of CF vs. CVP ñ anti-CD20 maintenance with PCP & H-Z prophylaxis (E1496)." These promising results make me think that perhaps our best hope in the near future for longest remission or actually curing some folks of indolent NHL may be something like first-line Bexxar+fludarabine+cyclophosphamide, assuming such a combination can be tolerated. I also saw a 1999 ASCO abstract which described excellent results from fludarabine+mitoxantrone for first-line patients, with 2-year progression-free survival comparable to prior experience with CHOP chemo regimens. One caveat here, I saw in an ASCO abstract from a Rituxan + fludarabine study that they found the myelosuppression to be more than what they expected from the agents alone, and had to reduce the fludarabine dose from what they initially thought would be safe. Presumably we might see the same effect with Bexxar, although it looked like they got good results with the lower dose anyway. So in answer to Bob's question about "why Bexxar+fludarabine instead of Rituxan+CHOP for first-line treatment" I'll throw out the following. If you believe as I do that Bexxar has superior efficacy to Rituxan (especially remission duration as V1 has noted), and fludarabine or fludarabine combinations are equal to or better than CHOP for lgNHL, then the most powerful combination is obvious, especially when the pre-clinical data shows that Bexxar and fludarabine are optimally synergistic, with an effect that is "markedly" better than simply adding together the effects of the two agents. By the way, thanks for the link to the shorties discussion, I will enjoy following that one. And hey, my very first post on SI and there's already a link to it on another thread, nice feeling for a newbie! Regards, Gordon