Background to the Trial
Eligible Lymphoma Cell Types
Rituxan Dosing
Severity of the Lymphomas Being Studied
Related Trials
Closing Remarks

GREG BERK, MD:  Welcome. My name is Dr. Gregory Berk of Cornell University Medical College and I am pleased to have Dr. Myron Czuczman who is Head of the Lymphoma Section at the Roswell Park Cancer Institute with us today. We will discuss his insights on the use of Rituxan, specifically as an agent in intermediate grade lymphoma. Dr. Czuczman is going to talk about the new phase III trial comparing the standard of care CHOP to a combination of CHOP-Rituxan program. I would like to welcome you Dr. Czuczman.

MYRON CZUCZMAN, MD:  Thank you, Greg.

GREG BERK, MD:  Dr. Czuczman, can you give us a little background to what really led up to this phase III trial?

MYRON CZUCZMAN, MD:  A pilot study, phase II study, of combination of CHOP plus Rituxan was performed as a multi-institutional study, approximately four or five years ago. In particular, it was at that time in a low-grade lymphoma setting.  It demonstrated what appeared to be significant responses—a high CR rate which also included good duration. The median duration has not been reached yet after a period of 4+ years. Also we saw activity demonstrating clearing of even molecular disease in a small subset of patients which were tested for BCL-2 or chromosome 14:18 translocation within marrow and blood.

Based on those results there was also a phase II study in newly diagnosed or untreated patients with intermediate grade lymphomas, which demonstrated promising results. They will soon be submitted for publication by Julie Vose from University of Nebraska. We collaborated on that.

Based on those promising results, a phase III study, an upfront study now, will be performed to more fully evaluate the potential benefit that the addition of Rituxan has in the CHOP combination with respect to the treatment of patients with intermediate grade lymphomas.

GREG BERK, MD:  Myron, can you comment on what subtypes of intermediate grade lymphomas are eligible.

MYRON CZUCZMAN, MD:  Sure. In particular it's diffuse large cell lymphoma, diffuse mixed, as well immunoblastic large cell lymphomas.

GREG BERK, MD:  Mantle cells will not be included in this trial.

MYRON CZUCZMAN, MD:  With this particular trial, mantle cell lymphomas will not be included.

GREG BERK, MD:  I see. The design of the combination arm. How will the Rituxan be given in comparison to the CHOP? Is this combination given at the same time as you did in your studies?

MYRON CZUCZMAN, MD:  Yes.  Basically—

GREG BERK, MD:  Rather than the sequential approach.

MYRON CZUCZMAN, MD:  Basically the way it is planned to be given is that, 48 hours before each CHOP chemotherapy is to be given, an infusion of rituximab or Rituxan will be given at the 375 mg/m2 dose. That is planned to be given, depending on the patient's response, for a total of six to eight cycles.

GREG BERK, MD:  Will they continue the Rituxan after the trial is completed?

MYRON CZUCZMAN, MD:  At the current time there will not be a maintenance arm with respect to the rituximab.

GREG BERK, MD:  I see. Dr. Czuczman, you were also looking at some of the molecular markers in the disease prior to therapy.

MYRON CZUCZMAN, MD:  With this particular study, I do not believe the molecular markers will be particularly evaluated. However, we know that with respect to the intermediate grade lymphomas we are going to be following patients that have International Prognostic Index of greater than or equal to two. This means that we will be stratifying and looking very carefully to evaluate patients who have worse prognostic factors or higher numbers of poor prognostic indicators. In particular patients who have advanced tumor stage, high serum LDH levels, greater than one extranodal disease sites, advanced stage and poor performance status. Depending on the number of factors, we know that those patients don't do as well with standard therapy.

Based on that there will be an analysis to try to evaluate whether or not the addition Rituxan to CHOP really has a definite advantage in those patients receiving it than those patients receiving the gold standard at the current time, which would be considered CHOP chemo.

GREG BERK, MD:  Dr. Czuczman, can you comment on whether or not there are any similar types of trials in the arena of upfront therapy for intermediate grade lymphoma which are combining chemotherapy with biological therapies, perhaps other antibodies or other types of biologic therapies to try to improve on our present results with CHOP?

MYRON CZUCZMAN, MD:  There is basically a certain approach currently. The one that comes to mind in particular is a CALGB and ECOG study. It is a phase III trial of CHOP vs. CHOP plus Rituxan in older patients only with diffuse mixed and diffuse large cell and immunoblastic large cell NHL, which is accruing patients. But in particular they are studying patients that are greater than or equal to 60 years of age. In addition to that they also are looking at patients, following the completion of it, whether it is CHOP vs. CHOP plus Rituxan, they then get a second randomization getting Rituxan for four weekly doses repeated every six months for two years vs. observation alone. So it’s a little bit different set up with respect to the trial. In particular, it is just looking at the older patient population.

Another approach that is being looked is to look at the stratification. Basically this is looking at patients who have a high IPI or International Prognostic Index.  This means a higher number of bad prognostic factors. A number of smaller pilot studies in particular are trying to evaluate whether or not using more intensive therapy, such as bone marrow transplantation as part of the initial therapy of the patient may potentially benefit those patients that have a worse prognosis. What we need to keep in mind though, in that group of patients we are doing more aggressive therapy so it is associated with a higher toxicity and more morbidity.

For example, if we can show that in addition to the standard at the current time (which I believe is CHOP) by adding Rituxan, which we already know from the phase II study does not add a significant amount of toxicity, but what appears to be additional activity, and if we can show that we don't have to take patients to the more aggressive route, which is transplant, and be able to achieve a similar type of activity or say improved overall responses, then I think we've accomplished a significant amount by this trial which has just started recently.

GREG BERK, MD:  Dr. Czuczman, I want to thank you very much for joining us today and giving us your insights into this important trial. Do you have any final comments regarding this particular study?

MYRON CZUCZMAN, MD:  My final comment would be that it's a very exciting time with respect to the treatment of lymphoma, with respect to the approval recently and in recent years of the rituximab antibody, but in particular also exciting other agents looking at other antibodies both unlabeled, which are without any radiation or toxins associated with them, as well as radiolabeled antibodies which will directly attach radioactive particles and then when they reach their destination, which is the tumor sites, will give directed internal radiation therapy to the tumors. I think that we will be seeing an increased number of durable remissions, higher response rates, more durable remissions. Potentially I feel that we will increase the cure rates in patients with non-Hodgkin's lymphoma in the near future.

GREG BERK, MD:  Dr. Czuczman, thanks so much for joining us today.

MYRON CZUCZMAN, MD:  Thank you very much.
 

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