A phase I study of intravenous bryostatin 1 in patients with advanced cancer

Our plain-English summary of A phase I study of intravenous bryostatin 1 in patients with advanced cancer, by J. Prendiville, D. Crowther, N. Thatcher, et al (British Journal of Cancer, 1993).

The study

• Authors: J. Prendiville, D. Crowther, N. Thatcher, P.J. Woll, B.W. Fox, A. McGown, N. Testa, P. Stern, R. McDermott, M. Potter
• Journal: British Journal of Cancer
• Published: 1993;68(2):418-24
• Cited by: 148 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Bryostatin 1 is a novel antitumour agent derived from Bugula neritina of the marine phylum Ectoprocta. Nineteen patients with advanced solid tumours were entered into a phase I study to evaluate the toxicity and biological effects of bryostatin 1. Bryostatin 1 was given as a one hour intravenous infusion at the beginning of each 2 week treatment cycle. A maximum of three treatment cycles were given. Doses were escalated in steps from 5 to 65 micrograms m-2 in successive patient groups. The maximum tolerated dose was 50 micrograms m-2. Myalgia was the dose limiting toxicity and was of WHO grade 3 in all three patients treated at 65 micrograms m-2. Flu-like symptoms were common but were of maximum WHO grade 2. Hypotension, of maximum WHO grade 1, occurred in six patients treated at doses up to and including 20 micrograms m-2 and may not have been attributable to treatment with bryostatin 1. Cellulitis and thrombophlebitis occurred at the bryostatin 1 infusion site of patients treated at all dose levels up to 50 micrograms m-2, attributable to the 60% ethanol diluent in the bryostatin 1 infusion. Subsequent patients treated at 50 and 65 micrograms m-2 received treatment with an intravenous normal saline flush and they did not develop these complications. Significant decreases of the platelet count and total leucocyte, neutrophil and lymphocyte counts were seen in the first 24 h after treatment at the dose of 65 micrograms m-2. Immediate decreases in haemoglobin of up to 1.9g dl-1 were also noted in patients treated with 65 micrograms m-2, in the absence of clinical evidence of bleeding or haemodynamic compromise. No effect was observed on the incidence of haemopoietic progenitor cells in the marrow. Some patients' neutrophils demonstrated enhanced superoxide radical formation in response to in vitro stimulation with opsonised zymosan (a bacterial polysaccharide) but in the absence of this additional stimulus, no bryostatin 1 effect was observed. Lymphocyte natural killing activity was decreased 2 h after treatment with bryostatin 1, but the effect was not consistently seen 24 h or 7 days later. With the dose schedule examined no antitumour effects were observed. We recommend that bryostatin 1 is used at a dose of 35 to 50 micrograms m-2 two weekly in phase II studies in patients with malignancies including lymphoma, leukaemia, melanoma or hypernephroma, for which pre-clinical investigations suggest antitumour activity.

In plain English

This article reports a phase I trial of an experimental cancer drug, bryostatin 1. It is not a study of asbestos. Six of its 19 patients had mesothelioma. The article does not say whether this was pleural or peritoneal and gives no asbestos exposure information. All had advanced solid tumours for which conventional therapy was unavailable or had failed. Each received a one-hour intravenous infusion every two weeks, at most three times, at 5 to 65 micrograms per square metre. Muscle pain (myalgia) limited the dose: all three patients given 65 had severe (WHO grade 3) myalgia. The maximum tolerated dose was 50. Flu-like symptoms were common but at most moderate. Infusion-site inflammation complicated 19 of 36 cycles given to patients at doses up to 35 and to two patients at 50. The authors attributed this mainly to the ethanol solvent but could not exclude bryostatin 1 itself. At 65, platelet, neutrophil and lymphocyte counts and haemoglobin fell. No antitumour effects were seen. The authors recommended 35 to 50 every two weeks for phase II studies in lymphoma, leukaemia, melanoma or hypernephroma.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Phase I dose-escalation drug trial (three patients planned per dose level, no dose escalation within the same patient)
• Who was studied: 19 patients with advanced solid tumours for which conventional therapy was not available or had failed, treated at Christie Hospital / Paterson Institute, Manchester, UK. By Table I: 10 ovarian carcinoma, 6 mesothelioma, 2 sarcoma and 1 colon carcinoma. Twelve had received prior intensive chemotherapy. The six mesothelioma patients and the colon cancer patient had received no prior chemotherapy or radiotherapy. Study dates are not given.
• Exposure: Bryostatin 1, a drug derived from the marine animal Bugula neritina. It was given as a one-hour intravenous infusion in 60% ethanol on day one of each two-week cycle, for a maximum of three cycles, at 5, 10, 20, 35, 50 or 65 micrograms per square metre. No asbestos exposure is reported.
• Main results:
  • Myalgia was the dose-limiting toxicity. All three patients treated at 65 micrograms per square metre developed WHO grade 3 myalgia. The maximum tolerated dose was 50 micrograms per square metre.
  • Flu-like symptoms (lethargy, fever, sweats, rigors, rhinitis, headache) made up most of the clinical toxicity and were at most WHO grade 2. Hypotension of at most WHO grade 1 occurred in six patients.
  • Cellulitis and thrombophlebitis at the infusion site complicated 19 of the total 36 cycles given to the patients treated at up to 35 micrograms per square metre and to two of the patients treated at 50. These were the cycles given without a normal saline flush, and the authors put the rate at 53%. Among later patients who received a saline flush, there was one case of mild phlebitis in 13 cycles.
  • There were no significant blood count changes at doses of 5 to 50. In the three patients treated at 65 micrograms per square metre, platelet counts fell by 34-44% and neutrophil counts by 44-64%.
  • At 65 micrograms per square metre, lymphocyte counts fell by 55-88%. Haemoglobin fell by up to 1.9 g/dl and did not recover over the next 2 weeks, with no clinical evidence of bleeding.
  • No effect on haemopoietic (blood-forming) progenitor cells in the bone marrow was demonstrated.
  • Natural killer activity decreased 2 h after treatment in patients 14 to 18.
  • No antitumour effects were observed with the dose schedule examined.
• The authors' conclusion: The authors recommended phase II testing of bryostatin 1 at 35 to 50 micrograms per square metre every two weeks in patients with malignancies including lymphoma, leukaemia, melanoma or hypernephroma, for which preclinical studies suggest antitumour activity. Mesothelioma is not among the cancers they named.
• Limitations the authors state:
  • The natural killer cytotoxicity values were low, so the authors said the observed decreases should be interpreted with caution.
  • The authors attributed infusion-site inflammation mainly to the ethanol diluent but could not exclude bryostatin 1 itself as a contributing factor.
  • The hypotension may not have been caused by bryostatin 1, and the cause of the myalgia is unknown.

Topics

Medical terms in this study, explained in our Lexicon: Superoxide.

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