From Terry's Techniclone Terrace Nov. 17 1998 by golfdad97

The following posts are offered only as a basis for informative discussion and do not reflect any clinical judgement on my behalf regarding endorsement of any product. The information is collated as a simplistic summary of how I view the history of drug development and probable outcome of these clinical products. Note: If the paragraphs run on to each other, its because this computer sometimes does not successfully insert my paragraphs into Yahoo messages, my apologies in advance!

Idec-C2B8 (Rituxan): This is a chimeric antibody directed against a B-cell specific antigen expressed on NHL cells. The target binding site of this antibody appears to allow several favorable biological effects, including mediation of complement-dependent lysis of malignant cells (a natural killing method mediated by serum proteins found in the course of many infectious states), the ability to provoke antibody-dependent cell killing (another natural consequence of binding antibodies to foreign cells) and the Rituxan antibody can directly inhibit the proliferation of NHL cells. Hence, these properties may be sufficient to not seek any radiolabel (which adds direct killing power to the vicinity of cells that bind the radiolabeled antibody), and allows its use as a "naked" antibody, although high concentrations (perhaps on the order of gram amounts) need to be infused.

Initial Phase I trials (and subsequent studies) were conducted in patients who eventually failed further chemotherapy and had few alternative therapies. The use of this antibody is attractive because of its structure (chimerized, therefore little impact on patients developing antibodies to Rituxan), the fact that it is not coupled to any toxic material (such as a radioactive isotope or drug) and can be administered repeatedly with few toxic side effects, other than eventual depletion of normal B-cells (which are needed for proper immune protection of the patient). The effects on immune cell depletion and function can be closely monitored. To summarize the early results in brief fashion (how can golfdad ever do that?)...a total reponse rate of about 45-50% was observed in patients with refractory, low-grade lymphoma. It must be emphasized that complete and partial responses are not entirely the same quantities between different clinical groups, but in general, in the lymphoma studies, a complete response requires no evidence for any disease for at least 1 month, whereas a partial reponse in normally considered to be a reduction of anywhere between 50-70% of tumor volumes measured by various parameters (dimensions off of radiograph films, CT scans, etc). However, many descriptions by academic physicians hedge different terms using phraseology like a "marked reduction", "although not significant, about 25% less disease", and remarks like that...but us simple folk know what we want to see: (1) percent of complete response, (2) percent of partial responses, (3) duration of the remission (time to treatment failure or time to relapse), and (4) overall survival. These early studies, like most Phase I set the dose, schedule and probable patient effects to monitor and watch for as the trials progress. They settled on about 750 mg/patient (depending on body size) once a week for 4 weeks, observed a fairly rapid depletion of B-cells and malignant cells (normal B-cell numbers would return in about 3-6 months) and the clinical responses lasted about 8-12 months, depending on the study reported. Low doses of the antibody resulted in some clinical responses that were encouraging but not impressive. Only a few patients with intermediate or high-grade lymphoma were attempted in the early trials. Responses tend to favor patients with follicular disease (a kind of localized network of webbed malignant cells, strung together in lymph node structures). The half life of the antibody is rather long...and increases to nearly 20-30 days as the number of infusions of the antibody increase. They also conducted a small Japanese study in Phase I at the Japan NCI and observed about a 40% response rate in relapsed patients.

The company quickly moved to Phase II trials in a multi-center study (31 centers, about 170 patients) and used the 750 mg/dose (approx) and 4 weekly doses as the gold standard. They observed a 48% total response rate (note that this was 6% complete response and 42% partial response, where a complete response was defined as complete clearing of the bone marrow and nodal sites and partial was a reduction of 50% or more) with a duration of response of about 13 months. Toxicity was mild and the effects on B-cell depletion were expected and monitored.

The company also performed studies in Europe and Austrailia and tested the product in more aggressive forms of lymphoma, including intermediate and high-grade lymphomas (diffuse large B-cell lymphoma, mantle cell lymphoma). They performed a prospective randomized Phase II study including patients if they were in first or second relapse, refractory to initial therapy, or elderly (>60 yo) and not previously treated. The patients recieved 8 weekly infusions of Rituxan at 750 mg/dose in one arm of the study and the patients in the other arm got one dose of 750 mg/dose followed by 7 weekly infusions of 1000 mg/dose (approx). 54 patients were evaluated, with 5 complete responses (10%) and a partial response of 22%, with an average duration of response of about 8 months, suggesting that this modest clinical activity (in my opinion) needed to be combined with chemotherapy...or this form of therapy limited mainly to low-grade lymphoma. I did not find any parameters that may "predict" for patients with high-grade lymphoma who would respond to this form of therapy (that is, how do you determine those 17 patients out of the 54 before starting therapy; is there any biological parameter you could measure, like extent of antibody binding to lymphoma cells, or??).

The company has recently reported pilot studies where Rituxan was combined with CHOP chemotherapy in patients with previously untreated intermediate and high-grade lymphoma (I will refrain from marketing remarks like..."in an attempt to break into that cohort of patient numbers"...). Rituxan was given on day 1 (750 mg/dose) followed a couple of days later by the usual CHOP chemo cycle and these cycles were repeated 6 times. Of the 30 evaluable patients, they reported a 63% complete response rate and 33% partial response. The authors do not clearly state whether this is better than what they would have observed using CHOP alone (with no Rituxan) on patients receiving their first chemotherapy, but I believe CHOP therapy alone in this grade of lymphoma would have resulted in about a 65% response rate...suggesting that this combination therapy may be of benefit as front-line therapy. But since they don't say it...I won't say it. Clearly these studies are continuing.

A multicenter study has also been performed with Rituxan combined with alpha-interferon (a protein produced by lymphocytes that modulate a variety of immune functions, including upregulation of cell antigens, direct antiproliferative effects on tumor cells, inhibition of cellular products that assist tumor growth and on and on). This study included 26 low-grade lymphoma patients that were refractory to therapy and treatment consisted of modest amounts of interferon given several times a week followed by 4 weeks of the gold standard Rituxan therapy. 8% complete response and 50% partial response was noted...and I suspect these studies will fade away...