Dual Src and EGFR inhibition in combination with gemcitabine in advanced pancreatic cancer

phase I results: A phase I clinical trial

Dana B. Cardin, Laura W. Goff, Emily Chan, Jennifer G. Whisenant, G. Dan Ayers, Naoko Takebe, Lori R. Arlinghaus, Thomas E. Yankeelov, Jordan Berlin, Nipun Merchant

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Summary: 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/m2) of a 28-day cycle (L0). Nineteen patients were enrolled, yet 18 evaluable for dose-limiting toxicities (DLTs). One DLT observed at L0, however dasatinib was reduced to 50 mg (L−1) given side effects observed in the first two patients. At L−1, a DLT occurred in 1/6 patients and dose was re-escalated to L0, where zero DLTs reported in next four patients. Dasatinib was escalated to 100 mg (L1) where 1/6 patients experienced a DLT. Although L1 was tolerable, dose escalation was stopped as investigators felt L1 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.

Original languageEnglish (US)
Pages (from-to)1-9
Number of pages9
JournalInvestigational New Drugs
DOIs
StateAccepted/In press - Oct 9 2017

Fingerprint

gemcitabine
Clinical Trials, Phase I
Pancreatic Neoplasms
Lymphopenia
Maximum Tolerated Dose
Leukopenia
Aspartate Aminotransferases
Neutropenia
Alanine Transaminase
Thrombocytopenia
Nausea
Disease-Free Survival
Fatigue
Anemia
Adenocarcinoma
Survival Rate
Research Personnel
Dasatinib
Therapeutics
Growth

Keywords

  • Dasatinib
  • Dual Src and EGFR inhibition
  • Erlotinib
  • Pancreatic cancer

ASJC Scopus subject areas

  • Oncology
  • Pharmacology
  • Pharmacology (medical)

Cite this

Dual Src and EGFR inhibition in combination with gemcitabine in advanced pancreatic cancer : phase I results: A phase I clinical trial. / Cardin, Dana B.; Goff, Laura W.; Chan, Emily; Whisenant, Jennifer G.; Dan Ayers, G.; Takebe, Naoko; Arlinghaus, Lori R.; Yankeelov, Thomas E.; Berlin, Jordan; Merchant, Nipun.

In: Investigational New Drugs, 09.10.2017, p. 1-9.

Research output: Contribution to journalArticle

Cardin, Dana B. ; Goff, Laura W. ; Chan, Emily ; Whisenant, Jennifer G. ; Dan Ayers, G. ; Takebe, Naoko ; Arlinghaus, Lori R. ; Yankeelov, Thomas E. ; Berlin, Jordan ; Merchant, Nipun. / Dual Src and EGFR inhibition in combination with gemcitabine in advanced pancreatic cancer : phase I results: A phase I clinical trial. In: Investigational New Drugs. 2017 ; pp. 1-9.
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