Phase i trial of combination of FOLFIRI and pasireotide, a somatostatin analogue, in advanced gastrointestinal malignancies

Amit Mahipal, David Shibata, Erin Siegel, Gregory Springett, Khaldoun Almhanna, William Fulp, Irene Williams-Elson, Richard Kim

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

Summary: Introduction 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. Discussion 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.

Original languageEnglish (US)
Pages (from-to)1093-1099
Number of pages7
JournalInvestigational New Drugs
Volume33
Issue number5
DOIs
StatePublished - Oct 22 2015

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Somatostatin
Neoplasms
irinotecan
Maximum Tolerated Dose
Safety
Somatostatin Receptors
IGF Type 1 Receptor
Insulin-Like Growth Factor Binding Protein 3
Leucovorin
Biliary Tract
Anorexia
Somatomedins
pasireotide
Neutropenia
Insulin-Like Growth Factor I
Dehydration
Fluorouracil
Hyperglycemia
Thrombocytopenia
Alkaline Phosphatase

All Science Journal Classification (ASJC) codes

  • Oncology
  • Pharmacology
  • Pharmacology (medical)

Cite this

Phase i trial of combination of FOLFIRI and pasireotide, a somatostatin analogue, in advanced gastrointestinal malignancies. / Mahipal, Amit; Shibata, David; Siegel, Erin; Springett, Gregory; Almhanna, Khaldoun; Fulp, William; Williams-Elson, Irene; Kim, Richard.

In: Investigational New Drugs, Vol. 33, No. 5, 22.10.2015, p. 1093-1099.

Research output: Contribution to journalArticle

Mahipal, Amit ; Shibata, David ; Siegel, Erin ; Springett, Gregory ; Almhanna, Khaldoun ; Fulp, William ; Williams-Elson, Irene ; Kim, Richard. / Phase i trial of combination of FOLFIRI and pasireotide, a somatostatin analogue, in advanced gastrointestinal malignancies. In: Investigational New Drugs. 2015 ; Vol. 33, No. 5. pp. 1093-1099.
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abstract = "Summary: Introduction 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. Discussion 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.",
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AU - Mahipal, Amit

AU - Shibata, David

AU - Siegel, Erin

AU - Springett, Gregory

AU - Almhanna, Khaldoun

AU - Fulp, William

AU - Williams-Elson, Irene

AU - Kim, Richard

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AB - Summary: Introduction 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. Discussion 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.

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