px-866 and Colorectal-Neoplasms

This phase I, dose-finding study determined the safety, maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D), and antitumor activity of PX-866, a phosphatidylinositol 3-kinase inhibitor, combined with cetuximab in patients with incurable colorectal cancer or squamous cell carcinoma of the head and neck.. PX-866 was administered at escalating doses (6-8 mg daily) combined with cetuximab given at a 400 mg/m(2) loading dose followed by 250 mg/m(2) weekly. A "3 + 3" study design was used. Prior therapy with anti-EGFR therapies, including cetuximab, was allowed.. Eleven patients were enrolled. The most frequent treatment-emergent adverse event was diarrhea (90.1%), followed by hypomagnesemia (72.2%), vomiting (72.2%), fatigue (54.5%), nausea (54.5%), rash (45.5%) and peripheral edema (40%). No dose limiting toxicities were observed. The RP2D was 8 mg, the same as the single-agent PX-866 MTD. Best responses in 9 evaluable patients were: 4 partial responses (44.4%), 4 stable disease (44.4%), and 1 disease progression (11.1%). The median progression free survival was 106 days (range: 1-271).. Treatment with PX-866 and cetuximab was tolerated with signs of anti-tumor activity. Further development of this combination is warranted.

Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Cetuximab; Class I Phosphatidylinositol 3-Kinases; Colorectal Neoplasms; Disease-Free Survival; Dose-Response Relationship, Drug; Female; Gonanes; Head and Neck Neoplasms; Humans; Male; Maximum Tolerated Dose; Middle Aged; Mutation; Neoplasm Recurrence, Local; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Proto-Oncogene Proteins; Proto-Oncogene Proteins p21(ras); ras Proteins; Response Evaluation Criteria in Solid Tumors; Squamous Cell Carcinoma of Head and Neck

Colorectal cancer (CRC) is the second leading cause of cancer deaths in the United States; the predominant cause for mortality is metastasis to distant organs (e.g., lung). A major problem limiting the success of chemotherapy in metastatic CRC is the inability to target tumor tissues selectively and avoid severe side effects to normal tissues and organs. Here, we demonstrate polymeric nanoparticles (PNPs) entrapping chemotherapeutic agents provide a new therapeutic option for treating CRC that has metastasized to the lung. PNPs assembled from FDA approved biocompatible block copolymer accumulated predominantly in lung tissue. PNPs showed negligible accumulation in liver, spleen and kidneys, which was confirmed by fluorescent nanoparticle imaging and analysis of PI3K inhibition in the organs. PNPs entrapping PI3K inhibitors (i.e., wortmannin and PX866) suppressed CRC lung metastasis growth, and SN-38-loaded PNPs completely eliminated CRC lung metastasis. Our results demonstrate that polymer-drug nanoparticles offer a new approach to reduce toxicity of cancer therapy and has the potential to improve outcomes for patients with lung metastasis.

Topics: Animals; Colorectal Neoplasms; Drug Carriers; Gonanes; HT29 Cells; Humans; Irinotecan; Lung Neoplasms; Male; Mice, Inbred BALB C; Mice, Nude; Mice, SCID; Nanoparticles; Phosphoinositide-3 Kinase Inhibitors; Polymers; Topoisomerase I Inhibitors; Wortmannin