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Dual Src and EGFR inhibition in combination with gemcitabine in advanced pancreatic cancer: phase I results : A phase I clinical trial.
- Source :
-
Investigational new drugs [Invest New Drugs] 2018 Jun; Vol. 36 (3), pp. 442-450. Date of Electronic Publication: 2017 Oct 09. - Publication Year :
- 2018
-
Abstract
- Pancreatic adenocarcinoma remains a major therapeutic challenge, as the poor (<8%) 5-year survival rate has not improved over the last three decades. Our previous preclinical data showed cooperative attenuation of pancreatic tumor growth when dasatinib (Src inhibitor) was added to erlotinib (EGFR inhibitor) and gemcitabine. Thus, this study was designed to determine the maximum-tolerated dose of the triplet combination. Standard 3 + 3 dose escalation was used, starting with daily oral doses of 70 mg dasatinib and 100 mg erlotinib with gemcitabine on days 1, 8, and 15 (800 mg/m <superscript>2</superscript> ) of a 28-day cycle (L <subscript>0</subscript> ). Nineteen patients were enrolled, yet 18 evaluable for dose-limiting toxicities (DLTs). One DLT observed at L <subscript>0</subscript> , however dasatinib was reduced to 50 mg (L <subscript>-1</subscript> ) given side effects observed in the first two patients. At L <subscript>-1</subscript> , a DLT occurred in 1/6 patients and dose was re-escalated to L <subscript>0</subscript> , where zero DLTs reported in next four patients. Dasatinib was escalated to 100 mg (L <subscript>1</subscript> ) where 1/6 patients experienced a DLT. Although L <subscript>1</subscript> was tolerable, dose escalation was stopped as investigators felt L <subscript>1</subscript> was within the optimal therapeutic window. Most frequent toxicities were anemia (89%), elevated aspartate aminotransferase (79%), fatigue (79%), nausea (79%), elevated alanine aminotransferase (74%), lymphopenia (74%), leukopenia (74%), neutropenia (63%), and thrombocytopenia (63%), most Grade 1/2. Stable disease as best response was observed in 69% (9/13). Median progression-free and overall survival was 3.6 and 8 months, respectively. Dasatinib, erlotinib, and gemcitabine was safe with manageable side effects, and with encouraging preliminary clinical activity in advanced pancreatic cancer.
- Subjects :
- Aged
Antineoplastic Agents adverse effects
Antineoplastic Agents therapeutic use
Antineoplastic Combined Chemotherapy Protocols adverse effects
CA-19-9 Antigen metabolism
Deoxycytidine adverse effects
Deoxycytidine therapeutic use
Diffusion Magnetic Resonance Imaging
ErbB Receptors antagonists & inhibitors
Female
Humans
Male
Middle Aged
Pancreatic Neoplasms diagnostic imaging
Protein Kinase Inhibitors adverse effects
Gemcitabine
Antineoplastic Combined Chemotherapy Protocols therapeutic use
Deoxycytidine analogs & derivatives
Pancreatic Neoplasms drug therapy
Protein Kinase Inhibitors therapeutic use
src-Family Kinases antagonists & inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 1573-0646
- Volume :
- 36
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Investigational new drugs
- Publication Type :
- Academic Journal
- Accession number :
- 28990119
- Full Text :
- https://doi.org/10.1007/s10637-017-0519-z