title: The combination of axitinib followed by paclitaxel/carboplatin yields extended survival in advanced BRAF wild-type melanoma: results of a clinical/correlative prospective phase II clinical trial.
abstract: BACKGROUND
  Simultaneous chemotherapy with vascular endothelial growth factor (VEGF) inhibition has not shown additional benefit over chemotherapy alone in advanced melanoma. We tested administration of the potent VEGF inhibitor axitinib followed by paclitaxel/carboplatin to determine whether enhanced tumour proliferation during axitinib withdrawal leads to sustained chemosensitivity.
  
  
  METHODS
  We conducted a prospective phase II trial in metastatic melanoma patients with ECOG performance status 0-1 and normal organ function. Axitinib 5 mg PO b.i.d. was taken on days 1-14 of each 21-day treatment cycle, and carboplatin (AUC=5) with paclitaxel (175 mg m(-2)) was administered on day 1 starting with cycle 2. 3'-Deoxy-3'-(18)F-fluorothymidine ((18)F-FLT)-PET scans were performed in five patients to assess tumour proliferation on days 1, 14, 17, and 20 of cycle 1. Molecular profiling for BRAF was performed for all patients with cutaneous, acral, or mucosal melanoma.
  
  
  RESULTS
  The treatment was well tolerated. The most common grade 3 AEs were hypertension, neutropenia, and anaemia. Grade 4 non-haematologic AEs were not observed. Four of five patients completing (18)F-FLT-PET scans showed increases (23-92%) in SUV values during the axitinib holiday. Of 36 evaluable patients, there were 8 confirmed PRs by Response Evaluation Criteria in Solid Tumors. Overall, 20 patients had SD and 8 had PD as the best response. The median PFS was 8.7 months and the median overall survival was 14.0 months. Five BRAF(V600E/K) patients had significantly worse PFS than patients without these mutations.
  
  
  CONCLUSIONS
  Axitinib followed by carboplatin and paclitaxel was well tolerated and effective in BRAF wild-type metastatic melanoma. 3'-Deoxy-3'-(18)F-fluorothymidine-PET scans showed increased proliferation during axitinib withdrawal.
authors: Department of Medicine, Division of Hematology/Oncology, University of California, 1600 Divisadero St MTZ-A741, San Francisco, CA 94143-1770, USA.
authors: A P
authors: AP
authors: Algazi
authors: Department of Medicine, Division of Hematology/Oncology, University of California, 1600 Divisadero St MTZ-A741, San Francisco, CA 94143-1770, USA.
authors: E
authors: E
authors: Cha
authors: Department of Dermatology, University of California, 1600 Divisadero St MTZ-A741, San Francisco, CA 94143-1770, USA.
authors: S M
authors: SM
authors: Ortiz-Urda
authors: Department of Dermatology, University of California, 1600 Divisadero St MTZ-A741, San Francisco, CA 94143-1770, USA.
authors: T
authors: T
authors: McCalmont
authors: Department of Dermatology, University of California, 1600 Divisadero St MTZ-A741, San Francisco, CA 94143-1770, USA.
authors: B C
authors: BC
authors: Bastian
authors: Department of Medicine, Division of Hematology/Oncology, University of California, 1600 Divisadero St MTZ-A741, San Francisco, CA 94143-1770, USA.
authors: J
authors: J
authors: Hwang
authors: Department of Nuclear Medicine, University of California, 1600 Divisadero St MTZ-A741, San Francisco, CA 94143-1770, USA.
authors: M H
authors: MH
authors: Pampaloni
authors: Department of Nuclear Medicine, University of California, 1600 Divisadero St MTZ-A741, San Francisco, CA 94143-1770, USA.
authors: S
authors: S
authors: Behr
authors: Department of Dermatology, University of California, 1600 Divisadero St MTZ-A741, San Francisco, CA 94143-1770, USA.
authors: K
authors: K
authors: Chong
authors: Department of Medicine, Division of Hematology/Oncology, University of California, 1600 Divisadero St MTZ-A741, San Francisco, CA 94143-1770, USA.
authors: B
authors: B
authors: Cortez
authors: Department of Medicine, Division of Hematology/Oncology, University of California, 1600 Divisadero St MTZ-A741, San Francisco, CA 94143-1770, USA.
authors: A
authors: A
authors: Quiroz
authors: Department of Radiology, University of California, 1600 Divisadero St MTZ-A741, San Francisco, CA 94143-1770, USA.
authors: F
authors: F
authors: Coakley
authors: Department of Radiology, University of California, 1600 Divisadero St MTZ-A741, San Francisco, CA 94143-1770, USA.
authors: S
authors: S
authors: Liu
authors: Department of Medicine, Division of Hematology/Oncology, University of California, 1600 Divisadero St MTZ-A741, San Francisco, CA 94143-1770, USA.
authors: A I
authors: AI
authors: Daud
mesh_terms: D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects; D000077784:Axitinib; D016190:Carboplatin / Q000008:administration & dosage / Q000009:adverse effects; D015224:Dideoxynucleosides; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage* / Q000009:adverse effects; D007191:Indazoles / Q000008:administration & dosage* / Q000009:adverse effects; D008297:Male; D008545:Melanoma / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000235:genetics; D008875:Middle Aged; D017239:Paclitaxel / Q000008:administration & dosage / Q000009:adverse effects; D049268:Positron-Emission Tomography / Q000379:methods; D011446:Prospective Studies; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D011859:Radiography; D016896:Treatment Outcome
chemical_list: D015224:Dideoxynucleosides; D007093:Imidazoles; D007191:Indazoles; D047428:Protein Kinase Inhibitors; D016190:Carboplatin; D000077784:Axitinib; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D017239:Paclitaxel; C002854:alovudine