title: Phase I Trial of Consolidative Radiotherapy with Concurrent Bevacizumab, Erlotinib and Capecitabine for Unresectable Pancreatic Cancer.
abstract: OBJECTIVE
  To determine the safety, tolerability and maximum tolerated dose (MTD) of addition of erlotinib to bevacizumab and capecitabine-based definitive chemoradiation (CRT) in unresectable pancreatic cancer.
  
  
  METHODS
  Seventeen patients with CT-staged, biopsy-proven unresectable pancreatic cancer were enrolled between 3/2008 and 10/2010. Prior chemotherapy was permitted. Two patients each were enrolled at dose levels (DLs) 1-4 and 9 patients at DL 5. All patients received 50.4 Gy (GTV only) in 28 fractions with concurrent capecitabine, bevacizumab and erlotinib. Dose of each drug was escalated in 5 DLs using the continual reassessment method. Bevacizumab was escalated from 5mg/Kg q2weeks (DLs 1-4) to 10mg/Kg q2weeks (DL 5); daily erlotinib from 100mg/day (DLs 1-2) to 150 mg/Kg (DLs 3-5); and capecitabine from 400mg/m2 twice daily on days of radiation (DL 1) to 650mg/m2 (DLs 2-3) to 825 mg/m2 (DLs 4-5). Reassessment for potential resection was performed 6-8 weeks later.
  
  
  RESULTS
  Sixteen patients received gemcitabine-based chemotherapy prior to CRT. With a median clinical follow-up of 10 months, no grade 3 toxicities were observed in DLs 1-4. Three (33%) patients at DL 5 developed a grade 3 acute toxicity (2 diarrhea, 1 rash). No grade 4 or 5 toxicities were seen. DL 4 was selected as the MTD; therefore, the recommended doses in combination with radiation are: bevacizumab, 5mg/Kg q2weeks; erlotinib, 150 mg/Kg daily; and capecitabine, 825mg/m2 BID. Median survival was 17.4 months. Of the five patients who underwent resection, 4 were originally deemed locally advanced and 1 was borderline resectable. Three patients had excellent pathological response (2 complete response and 20% viable tumor) at surgery, and the 2 patients with complete response are still alive at 61 and 67 months of follow up with no local or distant failures.
  
  
  CONCLUSIONS
  This chemoradiation regimen at the recommended dose levels is safe and tolerable for patients with unresectable pancreatic cancer and merits further evaluation.
authors.affiliation: Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Awalpreet S
authors.initials: AS
authors.lastname: Chadha
authors.affiliation: Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Heath D
authors.initials: HD
authors.lastname: Skinner
authors.affiliation: Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Jillian R
authors.initials: JR
authors.lastname: Gunther
authors.affiliation: Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Mark F
authors.initials: MF
authors.lastname: Munsell
authors.affiliation: Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Prajnan
authors.initials: P
authors.lastname: Das
authors.affiliation: Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Minsky
authors.affiliation: Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Marc E
authors.initials: ME
authors.lastname: Delclos
authors.affiliation: Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Deyali
authors.initials: D
authors.lastname: Chatterjee
authors.affiliation: Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Huamin
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Marilyn
authors.initials: M
authors.lastname: Clemons
authors.affiliation: Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Geena
authors.initials: G
authors.lastname: George
authors.affiliation: Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Pankaj K
authors.initials: PK
authors.lastname: Singh
authors.affiliation: Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Matthew H
authors.initials: MH
authors.lastname: Katz
authors.affiliation: Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Jason B
authors.initials: JB
authors.lastname: Fleming
authors.affiliation: Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Milind M
authors.initials: MM
authors.lastname: Javle
authors.affiliation: Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Wolff
authors.affiliation: Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Gauri R
authors.initials: GR
authors.lastname: Varadhachary
authors.affiliation: Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Christopher H
authors.initials: CH
authors.lastname: Crane
authors.affiliation: Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Sunil
authors.initials: S
authors.lastname: Krishnan
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D000068258:Bevacizumab / Q000008:administration & dosage; D014408:Biomarkers, Tumor; D000069287:Capecitabine / Q000008:administration & dosage; D059248:Chemoradiotherapy; D003131:Combined Modality Therapy; D018450:Disease Progression; D000069347:Erlotinib Hydrochloride / Q000008:administration & dosage; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D020714:Maximum Tolerated Dose; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D010190:Pancreatic Neoplasms / Q000175:diagnosis* / Q000401:mortality / Q000628:therapy*; D011379:Prognosis; D011829:Radiation Dosage; D020266:Radiotherapy, Conformal / Q000009:adverse effects / Q000379:methods; D050397:Radiotherapy, Intensity-Modulated / Q000009:adverse effects / Q000379:methods; D012097:Repressor Proteins / Q000378:metabolism; D016896:Treatment Outcome
chemical_list: D014408:Biomarkers, Tumor; D012097:Repressor Proteins; C507993:SAMD4A protein, human; D000068258:Bevacizumab; D000069287:Capecitabine; D000069347:Erlotinib Hydrochloride