title: Veliparib Alone or in Combination with Mitomycin C in Patients with Solid Tumors With Functional Deficiency in Homologous Recombination Repair.
abstract: BACKGROUND
  BRCA germline mutations are being targeted for development of PARP inhibitors. BRCA genes collaborate with several others in the Fanconi Anemia (FA) pathway. We screened cancer patients' tumors for FA functional defects then aimed to establish the safety/feasibility of administering PARP inhibitors as monotherapy and combined with a DNA-breaking agent.
  
  
  METHODS
  Patients underwent FA functional screening for the presence (or lack) of tumor FancD2 nuclear foci formation on their archival tumor material, utilizing a newly developed method (Fanconi Anemia triple-stain immunofluorescence [FATSI]), performed in a Clinical Laboratory Improvement Amendments-certified laboratory. FATSI-negative patients were selected for enrollment in a two-arm dose escalation trial of veliparib, or veliparib/mitomycin-C (MMC).
  
  
  RESULTS
  One hundred eighty-five of 643 (28.7%) screened patients were FATSI-negative. Sixty-one received veliparib or veliparib/MMC through 14 dose levels. Moderate/severe toxicities included fatigue (DLT at veliparib 400mg BID), diarrhea, and thrombocytopenia. Recommended doses are 300mg BID veliparib and veliparib 200mg BID for 21 days following 10mg/m(2) MMC every 28 days. Six antitumor responses occurred, five in the combination arm (3 breast, 1 ovarian, 1 endometrial [uterine], and 1 non-small cell lung cancer). Two patients have received 36 and 60 cycles to date. BRCA germline analysis among 51 patients revealed five deleterious mutations while a targeted FA sequencing gene panel showed missense/nonsense mutations in 29 of 49 FATSI-negative tumor specimens.
  
  
  CONCLUSIONS
  FATSI screening showed that a substantial number of patients' tumors have FA functional deficiency, which led to germline alterations in several patients' tumors. Veliparib alone or with MMC was safely administered to these patients and produced clinical benefit in some. However, a better understanding of resistance mechanisms in this setting is needed.
authors: Divisions of Medical Oncology (MAVC, WD, JR, ML, TBS) and Clinical Cancer Genetics (JAW), Department of Pathology (WZ, KS), Comprehensive Cancer Center (MAVC, WD, LJS, JT, TBS, CT), and Center for Biostatistics (LX), The Ohio State University , Columbus, OH ; Lombardi Cancer Center, Georgetown University , Washington, DC (JM); National Cancer Institute , Bethesda, MD (JJ, AC).
authors: Miguel A
authors: MA
authors: Villalona-Calero
authors: Divisions of Medical Oncology (MAVC, WD, JR, ML, TBS) and Clinical Cancer Genetics (JAW), Department of Pathology (WZ, KS), Comprehensive Cancer Center (MAVC, WD, LJS, JT, TBS, CT), and Center for Biostatistics (LX), The Ohio State University , Columbus, OH ; Lombardi Cancer Center, Georgetown University , Washington, DC (JM); National Cancer Institute , Bethesda, MD (JJ, AC).
authors: Wenrui
authors: W
authors: Duan
authors: Divisions of Medical Oncology (MAVC, WD, JR, ML, TBS) and Clinical Cancer Genetics (JAW), Department of Pathology (WZ, KS), Comprehensive Cancer Center (MAVC, WD, LJS, JT, TBS, CT), and Center for Biostatistics (LX), The Ohio State University , Columbus, OH ; Lombardi Cancer Center, Georgetown University , Washington, DC (JM); National Cancer Institute , Bethesda, MD (JJ, AC).
authors: Weiqiang
authors: W
authors: Zhao
authors: Divisions of Medical Oncology (MAVC, WD, JR, ML, TBS) and Clinical Cancer Genetics (JAW), Department of Pathology (WZ, KS), Comprehensive Cancer Center (MAVC, WD, LJS, JT, TBS, CT), and Center for Biostatistics (LX), The Ohio State University , Columbus, OH ; Lombardi Cancer Center, Georgetown University , Washington, DC (JM); National Cancer Institute , Bethesda, MD (JJ, AC).
authors: Konstantin
authors: K
authors: Shilo
authors: Divisions of Medical Oncology (MAVC, WD, JR, ML, TBS) and Clinical Cancer Genetics (JAW), Department of Pathology (WZ, KS), Comprehensive Cancer Center (MAVC, WD, LJS, JT, TBS, CT), and Center for Biostatistics (LX), The Ohio State University , Columbus, OH ; Lombardi Cancer Center, Georgetown University , Washington, DC (JM); National Cancer Institute , Bethesda, MD (JJ, AC).
authors: Larry J
authors: LJ
authors: Schaaf
authors: Divisions of Medical Oncology (MAVC, WD, JR, ML, TBS) and Clinical Cancer Genetics (JAW), Department of Pathology (WZ, KS), Comprehensive Cancer Center (MAVC, WD, LJS, JT, TBS, CT), and Center for Biostatistics (LX), The Ohio State University , Columbus, OH ; Lombardi Cancer Center, Georgetown University , Washington, DC (JM); National Cancer Institute , Bethesda, MD (JJ, AC).
authors: Jennifer
authors: J
authors: Thurmond
authors: Divisions of Medical Oncology (MAVC, WD, JR, ML, TBS) and Clinical Cancer Genetics (JAW), Department of Pathology (WZ, KS), Comprehensive Cancer Center (MAVC, WD, LJS, JT, TBS, CT), and Center for Biostatistics (LX), The Ohio State University , Columbus, OH ; Lombardi Cancer Center, Georgetown University , Washington, DC (JM); National Cancer Institute , Bethesda, MD (JJ, AC).
authors: Judith A
authors: JA
authors: Westman
authors: Divisions of Medical Oncology (MAVC, WD, JR, ML, TBS) and Clinical Cancer Genetics (JAW), Department of Pathology (WZ, KS), Comprehensive Cancer Center (MAVC, WD, LJS, JT, TBS, CT), and Center for Biostatistics (LX), The Ohio State University , Columbus, OH ; Lombardi Cancer Center, Georgetown University , Washington, DC (JM); National Cancer Institute , Bethesda, MD (JJ, AC).
authors: John
authors: J
authors: Marshall
authors: Divisions of Medical Oncology (MAVC, WD, JR, ML, TBS) and Clinical Cancer Genetics (JAW), Department of Pathology (WZ, KS), Comprehensive Cancer Center (MAVC, WD, LJS, JT, TBS, CT), and Center for Biostatistics (LX), The Ohio State University , Columbus, OH ; Lombardi Cancer Center, Georgetown University , Washington, DC (JM); National Cancer Institute , Bethesda, MD (JJ, AC).
authors: Li
authors: L
authors: Xiaobai
authors: Divisions of Medical Oncology (MAVC, WD, JR, ML, TBS) and Clinical Cancer Genetics (JAW), Department of Pathology (WZ, KS), Comprehensive Cancer Center (MAVC, WD, LJS, JT, TBS, CT), and Center for Biostatistics (LX), The Ohio State University , Columbus, OH ; Lombardi Cancer Center, Georgetown University , Washington, DC (JM); National Cancer Institute , Bethesda, MD (JJ, AC).
authors: Jiuping
authors: J
authors: Ji
authors: Divisions of Medical Oncology (MAVC, WD, JR, ML, TBS) and Clinical Cancer Genetics (JAW), Department of Pathology (WZ, KS), Comprehensive Cancer Center (MAVC, WD, LJS, JT, TBS, CT), and Center for Biostatistics (LX), The Ohio State University , Columbus, OH ; Lombardi Cancer Center, Georgetown University , Washington, DC (JM); National Cancer Institute , Bethesda, MD (JJ, AC).
authors: Jeffrey
authors: J
authors: Rose
authors: Divisions of Medical Oncology (MAVC, WD, JR, ML, TBS) and Clinical Cancer Genetics (JAW), Department of Pathology (WZ, KS), Comprehensive Cancer Center (MAVC, WD, LJS, JT, TBS, CT), and Center for Biostatistics (LX), The Ohio State University , Columbus, OH ; Lombardi Cancer Center, Georgetown University , Washington, DC (JM); National Cancer Institute , Bethesda, MD (JJ, AC).
authors: Maryam
authors: M
authors: Lustberg
authors: Divisions of Medical Oncology (MAVC, WD, JR, ML, TBS) and Clinical Cancer Genetics (JAW), Department of Pathology (WZ, KS), Comprehensive Cancer Center (MAVC, WD, LJS, JT, TBS, CT), and Center for Biostatistics (LX), The Ohio State University , Columbus, OH ; Lombardi Cancer Center, Georgetown University , Washington, DC (JM); National Cancer Institute , Bethesda, MD (JJ, AC).
authors: Tanios
authors: T
authors: Bekaii-Saab
authors: Divisions of Medical Oncology (MAVC, WD, JR, ML, TBS) and Clinical Cancer Genetics (JAW), Department of Pathology (WZ, KS), Comprehensive Cancer Center (MAVC, WD, LJS, JT, TBS, CT), and Center for Biostatistics (LX), The Ohio State University , Columbus, OH ; Lombardi Cancer Center, Georgetown University , Washington, DC (JM); National Cancer Institute , Bethesda, MD (JJ, AC).
authors: Alice
authors: A
authors: Chen
authors: Divisions of Medical Oncology (MAVC, WD, JR, ML, TBS) and Clinical Cancer Genetics (JAW), Department of Pathology (WZ, KS), Comprehensive Cancer Center (MAVC, WD, LJS, JT, TBS, CT), and Center for Biostatistics (LX), The Ohio State University , Columbus, OH ; Lombardi Cancer Center, Georgetown University , Washington, DC (JM); National Cancer Institute , Bethesda, MD (JJ, AC).
authors: Cynthia
authors: C
authors: Timmers
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D001562:Benzimidazoles / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D003967:Diarrhea / Q000139:chemically induced; D004334:Drug Administration Schedule; D005199:Fanconi Anemia / Q000235:genetics*; D005221:Fatigue / Q000139:chemically induced; D005240:Feasibility Studies; D005260:Female; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D018095:Germ-Line Mutation; D006801:Humans; D008297:Male; D008875:Middle Aged; D016685:Mitomycin / Q000008:administration & dosage*; D009369:Neoplasms / Q000188:drug therapy*; D010375:Pedigree; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D059767:Recombinational DNA Repair / Q000187:drug effects / Q000235:genetics; D013921:Thrombocytopenia / Q000139:chemically induced
chemical_list: D000970:Antineoplastic Agents; D001562:Benzimidazoles; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C521013:veliparib; D016685:Mitomycin