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Medelis: Is it necessary to have animal data on each arm?
Dr. Von Hoff: I like to have some animal model data that establishes the combination effects, ensuring excessive weight loss and other effects do not occur, for instance. If the animals haven't lost weight, then I'm usually not worried about the combination in patients. As an extra safety measure, we also do abbreviated kinetic sampling.
Medelis: How important is entry criteria in the context of the complete phase Ib?
Dr. Von Hoff: Entry criteria are important and can change the value of an agent under study. If, for example, a monoclonal antibody appears to sensitize to a drug such as Doxil, you might establish an entry criterion specifying the patient can have prior exposure to Doxil. Adding the monoclonal antibody in this context puts enormous value on it, in a sense rescuing the patients.
Medelis: What you mean by “rescuing patients?”
Dr. Von Hoff: A good example involves one of the best trials ever done. It was by Merck AG for the approval of ERBITUX® (Cetuximab). The entry criterion was patients with colon cancer progressing on CPT-11 (irinotecan). Patients were either given Erbitux plus CPT-11, or Erbitux alone.
What was so clever about the trial was that the investigators exploited preclinical evidence that the Erbitux/CPT-11 combination would be rescuing some of these patients, and they established Erbitux as the control.
The trial was highly positive. It showed clinically what the preclinical findings demonstrated — that adding Erbitrux to the CPT-11 dose at which patients’ disease was progressing reverses resistance. There was the additional advantage of greater patient support for this type of phase I since they were getting standard therapy, something an Institutional Review Board is very positive about.
Medelis: How are accrual rates affected with your approach?
Dr. Von Hoff: Compared to the typical phase I approach, the complete phase Ib can produce rapid accrual rates because of patient acceptance. You’re adding an agent to standard therapy and not complicating patients’ involvement by doing things sequentially.
Medelis: Can you discuss the logistical aspects for the complete phase Ib — total number of sites and patients, for instance?
Dr. Von Hoff: With our group, U.S. Oncology Research, we would run a complete phase Ib in up to six sites, depending on the number of arms. Keep in mind, this is not a randomization and each arm could be, say, the monoclonal antibody in combination with any appropriate standard agent. Each arm includes about 9 to 12 patients. If you really know your investigational agent well, you can cut the investigational agent down to half the dose and then the full dose, so it is either one or two escalations. That would mean three patients per level so it could be six patients for evaluation plus an additional 3 to 6 patients to firm up the phase II dose.
Medelis: While the complete phase Ib looks to be more costly than a single phase I trial, are there cost savings compared to conducting sequential phase I trials?
Dr. Von Hoff: The real savings is time. You don’t have to deal with separate amendments. There is only one protocol, creating an operational economy of scale in a sense. In weekly calls, everybody is on the same page. If one arm has a problem — for instance, two out of three people have dose-limiting toxicity — then you substitute in your next arm with an amendment. Previously, if this happened, you would have to shut down that one trial, losing all your start-up costs. It’s a “plug-and-play” modular approach.
The other advantage is that sponsors are happy because the trial gets up and running quickly. The one problem we may have is there are more patients than slots to be filled.
Medelis: In other words, you might be over-accrued?
Dr. Von Hoff: Yes, and it can be a problem because it yields a lot of data, and the CMO has to tease apart the best potential directions to pursue. In this context, a randomized phase II becomes the obvious next step.
Here is a classic example. We have many patients with colon cancer who are on Avastin, an inhibitor of VEGF. Stopping Avastin is problematic because it leaves the VEGF unopposed, potentially leading to a cancer flare. In a case such as this one, clinicians are much more comfortable with a complete phase Ib that has an Avastin arm — if they see activity with the monoclonal antibody plus Avastin, it is extremely important. If the patient was on an Avastin-containing combination for five months before the cancer progressed, and then s/he goes on the monoclonal antibody plus Avastin for up to nine months, what you are in fact doing is changing the natural history of the patient’s tumor. You can see how there is a lot of information to be mined from this approach, giving the CMO many options for phase II.
Medelis: What effect does the complete phase Ib have on the randomized phase II?
Dr. Von Hoff: The complete phase Ib gets you ready for your randomized phase II faster by cutting down time for the whole development program. Instead of a sponsor funding, negotiating, and managing, say, five trial sites, five budgets, five contracts, five protocols, with the complete phase Ib, you test all the possible combinations suggested by the animal systems or cultures in one trial. The first scenario could take a few years; the latter, probably about six months … and that includes doing the trial.
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