263 Background: Preclinical studies suggested that bortezomib (B) enhanced the activity of gemcitabine and doxorubicin (GA) in UC; thus we sought to define possible combinations of bortezomib with this doublet. We employed a novel phase I trial design systematically exploring doses in 2 dimensions. The method estimates an isotoxic curve allowing not only a combination with approximately equal (with respect to single component MTD) contributions of the two components to be found, but also combinations emphasizing one component or the other. Methods: Since 11/06, 74 patients with previously treated metastatic cancer were enrolled (70 UC, 3 prostate, 1 renal). GA was treated as a single component and given in a fixed ratio to a maximum of 900 and 50 mg/m2, and B to a maximal dose of 1.6 mg/m2 IV, with dosing every 14 days. After determining the MTD along the diagonal, we then decreased the dose of B, increasing GA, and vice versa, exploring doses along an isotoxic curve aiming for ≤ 30% dose limiting toxicity (DLT) in cycle 1. The objective response rate (ORR) includes PR or CR, and excludes SD. Results: The MTD along the diagonal for GAB was 756, 42, and 1.4 mg/m2, respectively. Doses maximizing the GA (900, 50) required reduction of B to 1.2 mg/m2. Likewise, doses maximizing B (1.6) required reduction of GA to 559 and 33 mg/m2. The most common DLT were thrombocytopenia 14%, neutropenic fever 5%, and mucositis 1%. There was minimal activity at the on-diagonal MTD with an ORR 1/10. Of the tolerable doses along the isotoxic curve, the greatest activity was seen when maximizing B (1.5-1.6 mg/m2, ORR 7/12 (58%)). The ORR when maximizing GA was 4/10. The most frequent ≥ G3 toxicities include: thrombocytopenia (26%), neutropenia (26%), anemia (24%), fatigue (8%), and neutropenic fever or infection (12%). Treatment was tolerable in poor renal function; 36 patients (49%) had a GFR < 50 ml/min. Conclusions: The combination of GAB has promising activity at doses maximizing proteosome inhibition, despite relatively low doses of GA. Traditional phase I design dosing to the MTD "along the diagonal" would have lead to the incorrect conclusion that there was minimal activity. Clinical trial information: NCT00479128.
Pediatric Phase I Trial Design Using Maximum Target Inhibition as the Primary Endpoint
