Development and clinical trials of Z100
Keiichi Fujiwara - Saitama Medical University, Saitama, Japan
I have presented the efficacy of Z100 which is the immune modulator developed in Japan since 1966. It’s a long time development period. Z100 is the hot water extract of bacillus tuberculosis and the difference between Z100 and BCG is Z100 has a polysaccharide so that makes the toxicity very, very less, virtually no side effects. Z100 has been shown to have an immunopotentiation effect in combination with radiation in the experimental work in vivo and in vitro. So we have done two clinical trials since 1995 and the first one that was done is a randomised phase II trial which is comparing the dose of 2µg, 20µg and 40µg in combination with radiation therapy for cervical cancer. We found that the tumour shrinkage is the best using 40µg. So we decided to test if 40µg of Z100 is beneficial in terms of overall survival compared to a placebo. However, when the trial was designed in Japan it was not possible to use the placebo for the circumstances. So we decided to use 0.2, a very, very low dose of Z100. The result was extremely overwhelming because the low dose was better than the high dose. So we thought that the high dose Z100 was really bad for the patients but when we looked at the historical survival data in the Japanese cervical cancer registry and it was almost the same in terms of the five year overall survival for the patients with advanced cervical cancer without having anything.
So we hypothesised that probably low dose Z100 may be beneficial for the patients and the higher dose will lose the potentiation effect. So we finally decided to conduct the randomised phase III trial, double blind, placebo controlled.
What were the results?
The result was the five year overall survival was compared. Unfortunately the problem was that the advanced death events did not occur as we anticipated before the trial started. So the power was really less than we planned. Actually the independent data monitoring safety committee decided to stop the follow-up after the five year follow-up period had passed and compare the five year overall survival rate and found that about 65% for the placebo arm and 75% for the Z100 low dose arm. So it was not statistically significant but we believe a clinically meaningful result.
Will there be any clinical implications?
Yes, of course. Because comparing to the placebo, the patient has a 10% more overall survival benefit by using the low dose of Z100 so that should be developed for clinical use, I hope.