Satraplatin (S, JM216), is the only platinum analog in clinical development that can be administered orally, and is currently undergoing a worldwide randomized Phase III trial as 2nd line treatment of patients with hormone refractory prostate cancer. S is better tolerated than cisplatin (C) and has shown no renal, neuro- or ototoxicity in patients. Several combination therapies have been recently introduced for the treatment of non-small cell lung cancer (NSCLC), with drugs such as vinorelbine, gemcitabine, taxanes and platinum agents. The combination of two agents resulted in prolonged survival and increased quality of life (QOL) over that managed with best supportive care. The current standard of treatment for NSCLC patients is paclitaxel (P) and carboplatin (Cb). In recent Phase III clinical trials, patients were treated with a combination of C and docetaxel (D), Cb and D, C and P, or Cb and P. The results showed that patients in the D arm had increased median survival time and increased % survival at 1 year in addition to improved QOL. Notably, patients treated with D and C had superior survival and response rates compared to P and C and vinorelbine and C. We have previously shown that the combination of 25 mg/kg S and 40 mg/kg P results in therapeutic synergy in the H460 human NSCLC xenotransplanted in nude mice, in a manner that is dose and schedule dependent (LCK 1.8 for the combination vs 0.5 for S and 0.97 for P as single agents). In the current study, we investigate the antitumor activity of S and D as single agents and in combination in the same model. 150 mg H460 tumors were established in athymic female nu/nu mice. S as a mono-agent administrated orally at 25 and 35 mg/kg/day, qdx5qwx2, caused a TGD (Tumor Growth Delay) equivalent to 0.3 and 0.6 Log Cell Kill (LCK), respectively. D administered iv q7dx2 at 15, 20 and 25 mg/kg/day caused a TGD equivalent to 0.3, 0.75 and 0.76 LCK. In all cases D treatment caused significant weight loss, though reversible and not lethal. In the combination arms, D was administered on day 1 followed by S qdx5; this cycle was repeated on day 8. D at 25 mg/kg plus S 25 mg/kg were very effective (LCK=3.4) but also toxic (20% deaths). When the dose of D was reduced to 20 mg/kg and this was combined with S 25 mg/kg, there were no toxic deaths and the LCK was 1.8. We conclude that the combination of S and D at tolerated doses results in therapeutic synergy in the H460 xenograft model, similarly to what previously reported for the combination of S and P in the same model, though the S and D treatment is accompanied by significant body weight loss. Additional studies are in progress to investigate different dosing schedules. The combination of S and D could therefore be an effective regimen for the treatment of cancer patients. A Phase I clinical trial for the combination of S and D is on-going.

[Proc Amer Assoc Cancer Res, Volume 47, 2006]