Background: P is an effective anti-angiogenic agent currently investigated in a wide variety of tumors outside its authorized indication. In a dose-escalation phase I study, we investigated the safety and tolerability of combining P with CDDP. Methods: Patients (pts) with metastatic refractory solid tumors eligible for CDDP chemotherapy were treated with oral P given once daily, in fasted condition, starting 8 days (d) before the first CDDP infusion. CDDP was given every 3 weeks (q3w) in a 1-hour iv infusion. Five dose levels (DL) were planned to investigate the occurrence of dose limiting toxicities (DLT) over cycle 1 and 2, and to determine the maximum tolerated dose (MTD). Results: 35 pts were enrolled with median age of 59 y., PS≤1. Tumor types were: ovary (8), H&N (5), sarcoma (5), breast (4), colorectal (4), choroidal melanoma (3), other (6). DLs explored are shown in the Table. MTD was confirmed at DL1. An inverted schedule (IS) was added at the MTD starting with CDDP followed by P to explore PK interaction. DLT were 2 Grade (G) 3 ALAT elevation, one associated with G4 hyponatremia (DL1 and DL2 respectively), 2 G3 thrombopenia + neutropenia (DL2), 1 G2 neutropenia (DL2), 2 G3 pulmonary embolism (DL1 and IS). Mean number of 21d-cycles was 3 for CDDP and 4.7 for P. 15 pts discontinued treatment for unacceptable toxicity, 5 pts are still under treatment. 2 complete (DL2) and 2 partial responses (DL1 and DL2) were achieved. Mean (CV% for interindividual variability) CDDP clearance was 13.6 L/h (27%) and not influenced by P. However, mean of P clearance was 0.78 L/h (69%) at d-1 (before CDDP), 24.5% lower at d1 (CDDP + aprepitant), and 30% lower at d2 (aprepitant), likely due to competitive inhibition of P metabolism and efflux by aprepitant. The plasma P exposures observed at 400 mg (at d-1) were similar to those observed at 800 mg of P during the first-in-man phase 1 [Hurwitz et al]: 676.2 µg.h/mL (47%) vs. 743.3 µg.h/mL (76%), respectively. A nonsignificant trend of higher P AUC was observed in patients with DLT. Conclusions: Despite activity observed in some patients, the potential to combine P and CDDP appears limited due to the safety profile and the PK interactions within the combination. Clinical trial information: NCT01165385.