title: Phase I Study of Amrubicin and Cyclophosphamide in Patients With Advanced Solid Organ Malignancies: HOG LUN 07-130.
abstract: OBJECTIVE
  Relapsed small cell lung cancer (SCLC) has limited treatment options. Anthracyclines and cyclophosphamide have shown synergy in many tumors. Amrubicin (AMR) and cyclophosphamide both have single-agent activity in SCLC. This phase I trial evaluated the combination of AMR and cyclophosphamide in refractory solid organ malignancies and in relapsed SCLC.
  
  
  METHODS
  The primary endpoint was to determine maximum-tolerated dose and dose-limiting toxicities of the combination. Eligible patients were enrolled in sequential dose escalation cohorts in a standard 3+3 design. Treatment consisted of cyclophosphamide IV at 500 mg/m on day 1 with escalating doses of AMR IV on days 1 to 3 (25 to 40 mg/m with increments of 5 mg/m per cohort). Cycles were repeated every 21 days. Exploratory objectives analyzed the presence of NQO1 polymorphisms and topoisomerase IIA amplification and correlation with response.
  
  
  RESULTS
  Thirty-six patients were enrolled, of whom 18 patients had SCLC (50%). Maximum-tolerated dose was determined to be dose level 2 (cyclophosphamide 500 mg/m, AMR 30 mg/m) due to grade 4 thrombocytopenia. The main grade 3 to 4 toxicities were hematologic. Efficacy results are available for 34 patients. Partial responses, stable disease, and progressive disease rates in the overall study population were 20.6% (n=7), 38.2% (n=13), and 41.2% (n=14), respectively. Partial response, stable disease, and progressive disease rates in the SCLC patients and 1 patient with extrathoracic small cell were 36.8% (n=7), 26.3% (n=5), and 36.8% (n=7), respectively. There was no correlation between topoisomerase IIA amplification or NQO1 polymorphisms and response.
  
  
  CONCLUSIONS
  AMR and cyclophosphamide can be safely combined with little activity observed in heavily pretreated SCLC patients.
authors.affiliation: Departments of *Medicine, Division of Hematology/Oncology #Pathology and Laboratory Medicine ††Biostatistics, Indiana University School of Medicine †Indiana University Melvin and Bren Simon Cancer Center, Indianapolis ¶Cancer Care Center of Southern Indiana, Bloomington ‡Northern Indiana Cancer Research Consortium, South Bend, IN §Christiana Care Health Services, Newark, DE ∥Fox Chase Cancer Center, Philadelphia, PA **The University of Texas MD Anderson Cancer Center, Houston, TX.
authors.forename: Shadia I
authors.initials: SI
authors.lastname: Jalal
authors.forename: Nasser
authors.initials: N
authors.lastname: Hanna
authors.forename: Robin
authors.initials: R
authors.lastname: Zon
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Masters
authors.forename: Hossein
authors.initials: H
authors.lastname: Borghaei
authors.forename: Karuna
authors.initials: K
authors.lastname: Koneru
authors.forename: Sunil
authors.initials: S
authors.lastname: Badve
authors.forename: Nagendra
authors.initials: N
authors.lastname: Prasad
authors.forename: Neeta
authors.initials: N
authors.lastname: Somaiah
authors.forename: Jingwei
authors.initials: J
authors.lastname: Wu
authors.forename: Zhangsheng
authors.initials: Z
authors.lastname: Yu
authors.forename: Lawrence
authors.initials: L
authors.lastname: Einhorn
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018943:Anthracyclines / Q000008:administration & dosage / Q000009:adverse effects; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects* / Q000627:therapeutic use*; D003520:Cyclophosphamide / Q000008:administration & dosage / Q000009:adverse effects; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000473:pathology; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000235:genetics; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D055752:Small Cell Lung Carcinoma / Q000188:drug therapy / Q000473:pathology; D013921:Thrombocytopenia / Q000139:chemically induced; D016896:Treatment Outcome
chemical_list: D018943:Anthracyclines; D003520:Cyclophosphamide; C055866:amrubicin; D016660:NAD(P)H Dehydrogenase (Quinone); C447479:NQO1 protein, human