A Randomized, Phase II Trial of Cetuximab With or Without PX-866, an Irreversible Oral Phosphatidylinositol 3-Kinase Inhibitor, in Patients With Metastatic Colorectal Carcinoma.

BACKGROUND: The phosphotidylinositol-3 kinase (PI3K)/serine-threonine kinase/mammalian target of rapamycin signaling pathway is frequently altered in colorectal cancer (CRC). PX-866 is an oral, irreversible, pan-isoform inhibitor of PI3K. This randomized phase II study evaluated cetuximab with or without PX-866 in patients with metastatic, anti-epidermal growth factor receptor-naive, KRAS codon 12 and 13 wild-type CRC. PATIENTS AND METHODS: Patients with metastatic CRC who had received both oxaliplatin and irinotecan were randomized (1:1) to cetuximab (400 mg/m2 loading then 250 mg/m2 weekly) with or without PX-866 (8 mg orally daily; arms A and B, respectively). The primary endpoint was progression-free survival (PFS). Secondary endpoints included objective response rate, overall survival (OS), toxicity, and correlation of relevant biomarkers with efficacy outcomes. RESULTS: A total of 85 patients were enrolled. The median PFS was 59 days versus 104 days for arms A (cetuximab + PX-866) and B (cetuximab alone), respectively (P = .77). OS between the 2 arms (266 vs. 333 days for arm A vs. B) were similar (P = .83). Overall toxicity, including treatment-related toxicity, was higher in arm A compared with arm B, especially in terms of all-grade nausea (66% vs. 37%), vomiting (50% vs. 29%), diarrhea (64% vs. 18%), and rash (66% vs. 37%). Grade 3 diarrhea occurred in 19% of patients in Arm A and 0% in Arm B. PIK3CA mutations and PTEN loss by immunohistochemistry were infrequently seen. CONCLUSION: The addition of PX-866 to cetuximab did not improve PFS, objective response rate, or OS in patients with metastatic CRC. The combination arm had greater toxicity and may have been harmful in this study.

Weekly paclitaxel, gemcitabine, and external irradiation followed by randomized farnesyl transferase inhibitor R115777 for locally advanced pancreatic cancer.

PURPOSE: The Radiation Therapy Oncology Group (RTOG) multi-institutional Phase II study 98-12, evaluating paclitaxel and concurrent radiation (RT) for locally advanced pancreatic cancer, demonstrated a median survival of 11.3 months and a 1-year survival of 43%. The purpose of the randomized Phase II study by RTOG 0020 was to evaluate the addition of weekly low- dose gemcitabine with concurrent paclitaxel/RT and to evaluate the efficacy and safety of the farnesyl transferase inhibitor R115777 following chemoradiation. PATIENTS AND METHODS: Patients with unresectable, nonmetastatic adenocarcinoma of the pancreas were eligible. Patients in Arm 1 received gemcitabine, 75 mg/m(2)/week, and paclitaxel, 40 mg/m(2)/week, for 6 weeks, with 50.4 Gy radiation (CXRT). Patients in Arm 2 received an identical chemoradiation regimen but then received maintenance R115777, 300 mg twice a day for 21 days every 28 days (CXRT+R115777), until disease progression or unacceptable toxicity. RESULTS: One hundred ninety-five patients were entered into this study, and 184 were analyzable. Grade 4 nonhematologic toxicities occurred in less than 5% of CXRT patients. The most common grade 3/4 toxicity from R115777 was myelosuppression; however, grade 3/4 hepatic, metabolic, musculoskeletal, and neurologic toxicities were also reported. The median survival time was 11.5 months and 8.9 months for the CXRT and CXRT+R115777 arms, respectively. CONCLUSIONS: The CXRT arm achieved a median survival of almost 1-year, supporting chemoradiation as an important therapeutic modality for locally advanced pancreatic cancer. Maintenance R115777 is not effective and is associated with a broad range of toxicities. These findings provide clinical evidence that inhibition of farnesylation affects many metabolic pathways, underscoring the challenge of developing an effective K-ras inhibitor.