A phase I/II trial of RAD 001 with gefitinib in patients with castrate metastatic prostate cancer and glioblastoma multiforme

Abstract

14520 Background: Inactivation of the Pten tumor suppressor gene, leading to constitutive activation of the PI3K/AKT/mTOR pathway, is correlated with resistance to EGFR-targeted therapies. This trial tested the concept that inhibition of mTOR by RAD 001 (NOVARTIS) will restore sensitivity to EGFR inhibition by gefitinib (ASTRA ZENECA), in patients with progressive PC and GBM. Methods: Phase I was designed to determine a safe and tolerable dose and the pharmacokinetics (PK) of RAD (30/ 50/ 70 mg po weekly) with a fixed dose of gefitinib (250 mg po qd) in patients with PC and GBM. Phase II evaluated the proportion of PC patients with no change or a decline in PSA at 12 weeks, without clinical or radiographic progression. FDG PET imaging and immunohistochemistry were included as correlative studies. Results: 12 patients (2 GBM, 10 PC) were treated in Phase I, and 22 of 27 PC patients have been treated in Phase II. (The GBM Phase II results are reported separately). 20/32 (63%) of PC patients had received prior chemotherapy. No dose limiting toxicities were observed in Phase I, and 70 mg of RAD 001 weekly with gefitinib 250 mg qd was studied as the Phase II dose. PK parameters estimated during a 3 week single agent lead-in phase and during subsequent combined therapy suggested no clinically relevant PK interactions between RAD and gefitinib. The most common drug-related grade 3/4 toxicities were lymphopenia (28%) and elevated ALT (7%). Serial FDG PET scans showed > 25% decline in SUV uptake in 9/23 evaluable patients during the first week of treatment; of these, 3 patients showed no progression at 12 weeks. Overall, 5/29 PC patients showed no progression at 12 weeks, 3 (60%) of whom had received prior chemotherapy. Conclusions: Combination therapy with RAD 70 mg weekly and gefitinib 250 mg daily appears to be safe and is associated with modest activity in metastatic prostate cancer. Support: Novartis Pharmaceuticals, Astra Zeneca Pharmaceuticals. [Table: see text]