Date: January 3, 2006
by Chaya Venkat
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In a recent article on Topics we reviewed the background and structure of the Phase-2 clinical trial of GenMab’s HuMax-CD20 Monoclonal Antibody. Like its more famous cousin Rituxan, this new monoclonal antibody targets the CD20 marker on CLL cells. However, this new drug is a fully human monoclonal antibody, unlike the mouse-based Rituxan. The company expected this new drug will have higher efficacy than Rituxan in CLL patients, with the same (or improved!) low toxicity profile that we have come to love in Rituxan. You can refresh your memory regarding the background of this clinical trial by clicking on this link: Sons of Rituxan and Campath. The high profile of this clinical trial was reflected in how fast the patient recruitment happened; the trial was sold out in record time.
ASH2005 had a paper on preliminary results of this important clinical trial. I thought I would share these results with you. All too often, we hear the initial hype when a new drug is lauded to the skies. But when / if it does not live up to expectations, that bit of disappointing news is buried out of sight. Patients and researchers have developed short attention spans — we simply move on to the next miracle-of-the-month drug getting hyped. I would like to break that pattern on Topics. As I am fond of saying, the devil is in the details!
This was a dose escalation study. The first and second cohorts were just 3 patients each. It looks like the third and highest-dose cohort was the largest and the one that the researchers focused on. These 27 patients got four weekly infusions of HuMax. The first week infusion was 500 mg, followed by 2,000 mg infusions for the remaining 3 weeks. For your reference, the standard dose of Rituxan is 375 mg/m2, usually administered for 4 weeks as well. Note the difference in units. Using a “typical” patient with body surface area (BSA) of 2.0 square meters, we can convert the mg/m2 of the Rituxan infusion to plain milligrams as in the HuMax trial: in other words, for this typical patient the corresponding doses of Rituxan would be 750 mg each week for 4 weeks. For what it is worth, comparing milligrams of each drug, it looks like HuMax was administered at a higher dose in the third cohort, compared to the typical dosage used for Rituxan.
I had hoped that the fully humanized nature of HuMax would mean that there would be less infusion day related adverse effects compared to Rituxan. This does not seem to be the case. The pattern of adverse effects on infusion of the drug seems to be quite similar to that in Rituxan infusions. Moreover, there were 5 serious adverse effects (see highlighted portion in the abstract below) associated with HuMax, usually not seen with Rituxan. This was a disappointing result, I truly expected the adverse effects profile would match or be better than that seen in Rituxan.
As for the response rates: 11 out of the 21 evaluable patients in the highest dose cohort had a response to the drug. There were 4 “complete responses” (CRs) and 7 partial responses (PRs), at eleven weeks out from start of therapy. These patients will be monitored for 12 months, so we will know how robust these responses are in the long haul. It is cold comfort for patients to get a CR, if the remission does not last any reasonable length of time! I suppose a response of some sort in 11 out of 21 patients is encouraging news, given that the patients were relapsed (i.e., not chemo naïve) patients. Typically, Rituxan gives good responses in chemo naïve patients but does not do such a good job as a single agent in relapsed CLL patients. Of particular note, there were 4 patients with complete responses, which is a lot better than one would expect in refractory CLL patients using Rituxan. This is a relatively small size study; we will have to wait until larger studies are done to compare Rituxan versus the HuMax-CD20 monoclonal antibody head on. It is otherwise very difficult to compare drugs in a true apples-to-apples fashion.
However, I would be less than candid if I did not admit some degree of disappointment with these results, hence the title of “half full glass” for this article. With the significantly higher dose and the much hyped fully humanized form of this new HuMax-CD20 monoclonal antibody, I expected and would have liked to see far fewer adverse effects and far higher response rates in this clinical trial. Oh well. I will be monitoring this trial and report on new information as it is published. As I said above, a critical piece of information is still to be reported, how long the hard won remissions last. Rituxan remissions in CLL patients do not last more than 10-12 months in most CLL patients. It would be interesting to see if HuMax-CD20 does better on that score.
ASH 2005 abstract, #448
HuMax CD20 Fully Human Monoclonal Antibody in Chronic Lymphocytic Leuchemia. Early Results from an Ongoing Phase I/II Clinical Trial. Session Type: Oral Session
Bertrand Coiffier, H. Tilly, L. M. Pedersen, T. Plesner, H. Frederiksen, M.H.J. van Oers, J. Wooldridge, J. Kloczko, J. Holowiecki, A. Hellmann, J. J. Walewski, M.F. Flensburg, J. Petersen, T. Robak
Département d'Hématologie, Centre Hospitalier Lyon Sud, Pierre-Benite Cedex, France; Centre Henri Becquerel, Rouen, France; KAS Herlev, Herlev, Denmark; Vejle Hospital, Vejle, Denmark; Odense University Hospital, Odense, Denmark; University of Amsterdam, Amsterdam, Netherlands; The University of Iowa, Iowa City, IA, USA; Klinika Hematologii, Bialystok, Poland; Klinika Hematologii i Transplantacji Szpiku, Katowice, Poland; Klinika Hematologii Akademii Medycznej, Gdansk, Poland; MSCMCC, Warsaw, Poland; Genmab A/S, Copenhagen, Denmark; Medical University of Lodz, Lodz, Poland
The fully human monoclonal IgG1 antibody HuMax-CD20 targets a novel epitope of the CD20 molecule on B-cells. HuMax-CD20 stops growth of engrafted B-cell tumors in SCID mice more efficiently than Rituximab and i.v. infusion of HuMax-CD20 in cynomolgus monkeys leads to profound, long lasting, dose-dependent B-cell depletion. Data are presented from an open label, dose-escalation, multicenter phase I/II clinical trial. 3 cohorts of 3 (A), 3 (B) and an extended cohort of 27 (C) patients with relapsed or refractory chronic lymphocytic leukemia (B-CLL) received 4 weekly i.v. infusions of HuMax-CD20 and will be followed for 12 months. The first infusion administered was 100 mg, 300 mg and 500 mg in cohort A, B and C. The following 3 infusions were of 500, 1000 and 2000 mg, respectively. Patients were premedicated with oral acetaminophen and i.v antihistamine and received i.v. glucocorticoids before first and second infusions. The endpoints are B-cell depletion, adverse events, objective response according to the NCI working group guidelines for CLL, time to progression, duration of response, time to next anti-CLL treatment, and pharmacokinetics. Biopsies and CT images are evaluated centrally. Median age was 61 years; median time since diagnosis was 6.3 years. Maximum tolerated dose was not reached. Adverse events were predominantly observed on days of infusion and as expected most frequently symptoms of cytokine release e.g. rash, increased sweating, fatigue, rigors, pyrexia, and headache. 5 serious adverse events assessed as related to HuMax-CD20 treatment have been reported: hepatic cytolysis, herpes zoster, neutropenia (2 patients) and one death from pneumonia at week 4. In cohorts A and B, markedly reduced CD19+CD5+ cell counts were observed in 3 of 6 patients one week after final treatment and the depletion was sustained in one of these patients. In cohort C a pronounced CD19+CD5+ reduction was demonstrated by all patients; in fact the lymphocyte counts were ≤4.0 x 109/L in 21 patients. At week 11, ≥50% reduction in the product of diameters of lymph nodes was observed in 12 of 20 evaluable patients with enlarged lymph nodes. A response rate of 52% (11 of 21 evaluable patients in cohort C) was observed at week 11: 4 clinical CR (bone marrow and CT pending), 7 PR, 3 SD and 7 PD. In conclusion, this preliminary analysis of data from the first 33 CLL patients treated with HuMax-CD20 demonstrated significant depletion of CD19+CD5+ cells, a favorable safety profile and an indication of clinical efficacy. An updated report for all patients at week 19 will be presented.
Abstract #448 appears in Blood, Volume 106, issue 11, November 16, 2005
Keywords: B cell depletion|B-CLL|Monoclonal antibody
Monday, December 12, 2005 2:15 PM
Simultaneous Session: CLL: Therapy, excluding Transplantation I (1:30 PM-3:00 PM)
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Topic: Clinical Trials