Phase II study of BBR 3464 as treatment in patients with sensitive or refractory small cell lung cancer

Abstract

BBR 3464 is a novel triplatinum compound that has exhibited anti-tumor activity in both cisplatin-sensitive and cisplatin-resistant, as well as in p53 mutant tumor models. In phase I testing, the dose-limiting toxicities have included myelosuppression and diarrhea. Both an intermittent (day 1 every 21-28 days) and a continuous (dailyx5 days) schedule have been studied, and the intermittent schedule has been chosen for further development. The primary objective of this study was to assess the efficacy of BBR 3464 administered at a dose of 0.9 mg/m i.v. over 1 h every 21 days in patients with small cell lung cancer who have progressed after first-line therapy. Pharmacokinetic analysis was also performed and will be reported. Patients were stratified based on prior response into resistant and sensitive (response duration 3 months or longer) subgroups. Thirty-seven patients were enrolled onto this multicenter study. The median number of cycles delivered was 2 in the resistant subgroup (range 1-12) and 3 in the sensitive subgroup (range 1-8). Most common grade 3/4 hematological toxicities included neutropenia (62%), febrile neutropenia (16%), anemia (10%), fatigue (5%) and hypokalemia (5%). Although no objective responses were seen in 34 evaluable patients, 11 patients (32%) had disease stabilization (four resistant/seven sensitive) with 23 patients (68%) experiencing continued disease progression (12 resistant/11 sensitive). Median time to progression was 53 days in the resistant subgroup [95% confidence interval (CI) 37-63] and 66 days in the sensitive subgroup (95% CI 51-136). The median and 1-year survival rate based on subgroup was 78 (resistant) (95% CI 56-165) versus 209 days (sensitive) (95% CI 83-296) and 6 (resistant) (95% CI 0-17) versus 20% (95% CI 2-38%), respectively. We conclude that the toxicity profile of BBR 3464 in this phase II trial is consistent with the phase I experience. The lack of activity in either patient subgroup, however, does not support further evaluation of this drug as a single agent in this disease.

Synthesis of DNA‐Sequence‐Selective Hairpin Polyamide Platinum Complexes

“…Multinuclear platinum complexes have shown utility in overcoming resistance, [2,3] but while encapsulation within protective molecules can reduce their reactivity and degradation, [4,5] these complexes have not shown significant efficacy in recent phase II clinical trials. [6,7] The design of mononuclear or multinuclear platinum drugs that are capable of specifically targeting cancerous cells, by binding to mutant genes or extended telomere regions, could simultaneously reduce the side effects and increase efficacy. [8] Over the last ten years, polyamides have been synthesised that are capable of targeting specific DNA sequences.…”

The status of platinum anticancer drugs in the clinic and in clinical trials

“…The lack of activity observed in the gastric and SCLC did not warrant further evaluation for these cancer types, 189,190 and although positive results were observed for some patients in the NSCLC (two objective responses and 11 PR from 33 patients) and ovarian (five PR from 46 patients) the drug has not moved into Phase III trials. The results of another Phase II study of BBR3464 in locally advanced or metastatic pancreatic cancer which started in 2001 under contract to Theradex R and the National Cancer Institute (USA) has yet to be reported.…”

Anticancer activity of osmium metalla-rectangles

“…6 The trinuclear compound [(NH 3 ) 2 ClPtNH 2 -(CH 2 ) 6 NH 2 Pt(NH 3 ) 2 NH 2 (CH 2 ) 6 NH 2 PtCl(NH 3 ) 2 ] 4+ (BBR3464) was found to be 2 to 3 orders of magnitude more active than cisplatin and even entered phase II clinical trials before being abandoned. 7 Arene ruthenium complexes have also been evaluated as putative anticancer agents, and appear to exert 13 and a series of tetranuclear arene ruthenium complexes containing a porphyrin core demonstrated excellent photodynamic properties. 14 Tetra-and octanuclear arene ruthenium complexes attached to first and second generation polypyridyl dendritic cores were found to be cytotoxic with a good correlation between size and cytotoxicity.…”