Avid Bioservices Inc (CDMO)

[freethemice]

As a follow-up to this data I looked at one notable failure from these phase III trials. That is the Avastin
phase III trial from which these plots of the effect of PS and disease extent originate. I looked at the
phase II trial that prompted the phase III trial. So what went wrong?
From the Kindler et al, 2010 paper on the phase III trial.

Purpose
The combination of gemcitabine plus bevacizumab produced a 21% response rate and a median
survival of 8.8 months in a multicenter phase II trial in patients with metastatic pancreatic cancer.
These encouraging data led Cancer and Leukemia Group B (CALGB) to conduct a double-blind,
placebo-controlled, randomized phase III trial of gemcitabine/bevacizumab versus gemcitabine
placebo in advanced pancreatic cancer patients.

The single-arm phase II trial produced a MOS of 8.8 months for Avastin + gemcitabine, yet the phase III trial yielded a MOS
of 5.8 months. The phase II and phase III trials used the same dosage and schedule of administration of gemcitabine and Avastin.
The phase II trial enrolled 52 patients, the phase III trial enrolled 602 patients. Obviously the small number of patients in the
phase II trial could be a contributing factor. The phase II trial enrolled only metastatic patients (100% stage IV), but the
phase III trial enrolled locally advanced (16%) and metastatic (84%) patients. The biggest difference is the distribution of PS
scores between the two trials. In the phase II trial the PS scores of 0, 1, 2 were 60%, 38%, 2%, whereas in the phase III trial these
were 37%, 51%, 12% in the treatment arm and very similar in the control arm. So the percentage of PS = 0 and PS = 1 were
reversed and more patients had PS = 2 in the phase III trial compared with the phase II trial.
Just a cautionary note on how patient characteristics can affect the trial outcome. It may be that in some cancers this is more
important than in others.