Phase I trial of combination of FOLFIRI and pasireotide, a somatostatin analogue, in advanced gastrointestinal malignancies.
BACKGROUND
Pasireotide (SOM230) is a somatostatin analog with high binding affinity for somatostatin receptors including sst1, 2, 3 and 5 and inhibit insulin like growth factor-1. Blocking of IGF-1 receptor (IGF-1R) in combination with cytotoxic chemotherapy has demonstrated additive or synergistic activity in pre-clinical models. This study aimed to evaluate the maximum tolerated dose (MTD) of pasireotide in combination with standard FOLFIRI (5-fluorouracil, leucovorin and irinotecan) regimen in patients with gastrointestinal malignancies.


METHODS
This was a phase 1, 3 + 3 design, open-label dose escalation study conducted in sequential cohorts to determine the MTD of pasireotide in combination with FOLFIRI. All patients had gastrointestinal malignancies and were previously treated. Sixteen patients enrolled in five dose cohorts at pasireotide doses of 40, 60, 80, 100 and 120 mg were evaluated for safety and tolerability of the combination.


RESULTS
The tumor types of the enrolled subjects included esophageal (n = 5), biliary tract (n = 3), colon (n = 3), gastric (n = 2), pancreatic (n = 1), anal (n = 1) and small bowel (n = 1). No dose limiting toxicities were observed. The most common adverse events related to the study treatment included hyperglycemia (81 %), neutropenia (62 %), thrombocytopenia (44 %), anorexia (44 %), dehydration (25 %) and elevated alkaline phosphatase (25 %). Two patients had partial response and 7 patients had stable disease. Plasma levels of IGF-1 and IGFBP-3 were significantly reduced after treatment with pasireotide.


CONCLUSIONS
Combination of pasireotide and FOLFIRI has manageable safety profile and is feasible in patients with gastrointestinal malignancies. Preliminary signals of activity were observed. Larger phase II trials are warranted.
Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive FOB-2, Tampa, FL, 33612, USA.
Amit
A
Mahipal
Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive FOB-2, Tampa, FL, 33612, USA.
Dave
D
Shibata
Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive FOB-2, Tampa, FL, 33612, USA.
Erin
E
Siegel
Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive FOB-2, Tampa, FL, 33612, USA.
Gregory
G
Springett
Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive FOB-2, Tampa, FL, 33612, USA.
Khaldoun
K
Almhanna
Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
William
W
Fulp
Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive FOB-2, Tampa, FL, 33612, USA.
Irene
I
Williams-Elson
Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive FOB-2, Tampa, FL, 33612, USA. richard.kim@moffitt.org.
Richard
R
Kim
D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D002166:Camptothecin / Q000031:analogs & derivatives / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D005260:Female; D005472:Fluorouracil / Q000627:therapeutic use; D005770:Gastrointestinal Neoplasms / Q000188:drug therapy*; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000037:antagonists & inhibitors; D002955:Leucovorin / Q000627:therapeutic use; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D013004:Somatostatin / Q000031:analogs & derivatives / Q000627:therapeutic use; D016019:Survival Analysis
D013004:Somatostatin; D007334:Insulin-Like Growth Factor I; C517782:pasireotide; D002955:Leucovorin; D005472:Fluorouracil; D002166:Camptothecin
Chemotherapy; Gastrointestinal cancers; Irinotecan; SOM230