Brostallicin
"Phase I and Pharmacokinetic Study of Brostallicin (PNU-166196), a New DNA Minor-Groove Binder, Administered Intravenously Every 3 Weeks to Adult Patients with Metastatic Cancer"
Full text freebie:
clincancerres.aacrjournals.org
"Brostallicin, a Novel Anticancer Agent Whose Activity Is Enhanced upon Binding
to Glutathione"
Full text freebie:
cancerres.aacrjournals.org
"This randomized phase II trial is studying the side effects and how well brostallicin or doxorubicin works as first-line therapy in treating patients with relapsed, refractory, or metastatic soft tissue sarcoma."
clinicaltrials.gov
The one noted at the top of the page is no longer recruiting; the one immediately above is he only one that still is. Below is another trial that is done:
"Phase I/II trial to study the effectiveness of brostallicin in treating patients who have recurrent or refractory multiple myeloma."
clinicaltrials.gov
Can't find results; so I assume it whiffed, as it has in most solid tumors:
"A Phase I Dose-Escalation and Pharmacokinetic Study of Brostallicin (PNU-166196A), a Novel DNA Minor Groove Binder, in Adult Patients with Advanced Solid Tumors"
clincancerres.aacrjournals.org
Here's the abstract of the latest completed trial
Clin Cancer Res. 2004 Jan 15;10(2):468-75.
A phase I dose-escalation and pharmacokinetic study of brostallicin (PNU-166196A), a novel DNA minor groove binder, in adult patients with advanced solid tumors.
Lockhart AC, Howard M, Hande KR, Roth BJ, Berlin JD, Vreeland F, Campbell A, Fontana E, Fiorentini F, Fowst C, Paty VA, Lankford O, Rothenberg ML.
Vanderbilt-Ingram Cancer Center, Nashville, Tennessee, USA.
PURPOSE: This study was performed to determine the maximum tolerated dose, dose-limiting toxicities, and pharmacokinetics of brostallicin, a nonalkylating DNA minor groove binder and a synthetic derivative of distamycin A, given as a weekly i.v. infusion. EXPERIMENTAL DESIGN: Using an accelerated dose escalation design, patients with advanced solid tumor malignancies were treated with brostallicin administered as a 10-min i.v. infusion on days 1, 8, and 15 of a 28-day cycle. The starting dose of brostallicin was 0.3 mg/m(2)/week. To study the pharmacokinetic behavior of brostallicin, serial blood samples were obtained before and after the first and last infusions during cycle 1, and in cycles 2 and 4 in a limited number of patients. RESULTS: Fourteen patients received 32 complete cycles of brostallicin. Dose-limiting toxicity was febrile neutropenia and was observed in 3 of 5 patients treated at 4.8 mg/m(2)/week. The maximum tolerated dose and recommended Phase II dose was 2.4 mg/m(2)/week. The mean +/- SD terminal half-life at the maximum tolerated dose was 4.6 +/- 4.1 h. There was moderate distribution of brostallicin into tissues, and the clearance was approximately 20% of the hepatic blood flow. The area under the concentration time curve(0- infinity ) of brostallicin increased in a dose-linear fashion. No significant relationship was observed between any plasma pharmacokinetic parameter and clinical toxicities. There were no objective responses during the trial, but 5 patients had stable disease after two cycles of treatment. CONCLUSIONS: The dose-limiting toxicity of weekly brostallicin was neutropenia. Systemic exposure increases linearly with dose. The recommended dose for Phase II studies is 2.4 mg/m(2) on days 1, 8, and 15 of a 28-day cycle.<<
OK, not a complete whiff, but 30% or so with stable disease in P1 for advanced solid tumors . . . isn't great, either.
So sarcoma is the likely focus. A tough one, unmet need, but small market. They'll have an orphan drug designation from the EU:
emea.europa.eu
There is supposedly rationale for further combo studies based on the preclinical data, according to the PR. But if they are going to run those, burn is not going to so minimal unless they partner it. So here's the rationale:
"Enhancement of in vivo antitumor activity of classical anticancer agents by combination with the new, glutathione-interacting DNA minor groove-binder, brostallicin."
clincancerres.aacrjournals.org
Full text freebie.
Haven't read all this myself, just digging the links for myself and others, if anyone cares.
Cheers, Tuck |
