title: A phase I study of weekly topotecan in combination with pemetrexed in patients with advanced malignancies.
abstract: BACKGROUND
  This phase I study evaluated the safety, tolerability, preliminary antitumor activity, and pharmacokinetic interaction of weekly topotecan (days 1 and 8) in combination with pemetrexed (day 1 only) in patients with advanced solid tumors.
  
  
  METHODS
  Patients received topotecan (3.0-4.0 mg/m(2) i.v. days 1 and 8) and pemetrexed (375-500 mg/m(2) i.v. day 1) over 21-day cycles. Patients were accrued across five different dose levels and were observed for safety, tolerability, and preliminary activity.
  
  
  RESULTS
  Twenty-six patients received 120 cycles of pemetrexed and topotecan, including five patients who received 8, 8, 10, 12, and 17 cycles without dose reductions, confirming a lack of cumulative myelosuppression. Four patients received topotecan (4.0 mg/m(2) i.v.) and pemetrexed (500 mg/m(2) i.v.), but experienced two dose-limiting toxicities (febrile neutropenia, grade 4 thrombocytopenia). As a result, the topotecan (3.5 mg/m(2) i.v.) and pemetrexed (500 mg/m(2) i.v.) group was expanded to 12 patients. The only grade 3 or 4 nonhematologic toxicity was one episode of grade 3 fatigue; no grade 3 or 4 nausea/vomiting/diarrhea, mucositis, or rash was reported. One non-small cell lung cancer (NSCLC) patient (12 months) and one soft tissue sarcoma patient (6 months) achieved a partial response.
  
  
  CONCLUSIONS
  Weekly topotecan plus every-3-week pemetrexed was well tolerated and active. Full doses of topotecan plus pemetrexed caused brief reversible myelosuppression with minimal dose delays/reductions; no grade 3 or 4 nausea/vomiting/diarrhea, mucositis, or rash was reported. All six NSCLC patients at the recommended phase II dose had at least stable disease as a best response, including one partial response lasting 12 months. There was no evidence of an effect of pemetrexed on topotecan pharmacokinetics. Collectively, these data suggest that further phase II exploration of weekly topotecan plus every-3-week pemetrexed for advanced malignancies is indicated.
authors.affiliation: Sarah Cannon Research Institute, Nashville, Tennessee 37203, USA.
authors.forename: Howard A
authors.initials: HA
authors.lastname: Burris
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Infante
authors.forename: Roxanne C
authors.initials: RC
authors.lastname: Jewell
authors.forename: David R
authors.initials: DR
authors.lastname: Spigel
authors.forename: F Anthony
authors.initials: FA
authors.lastname: Greco
authors.forename: Dana S
authors.initials: DS
authors.lastname: Thompson
authors.forename: Suzanne F
authors.initials: SF
authors.lastname: Jones
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D005260:Female; D005971:Glutamates / Q000008:administration & dosage / Q000009:adverse effects; D006147:Guanine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D000068437:Pemetrexed; D019772:Topotecan / Q000008:administration & dosage / Q000009:adverse effects
chemical_list: D005971:Glutamates; D000068437:Pemetrexed; D006147:Guanine; D019772:Topotecan
references.citation: Am J Clin Oncol. 1998 Oct;21(5):438-41
references.pmid: 9781595
references.citation: J Clin Oncol. 1996 Feb;14(2):503-13
references.pmid: 8636764
references.citation: Oncologist. 2002;7(6):509-15
references.pmid: 12490738
references.citation: Ann Oncol. 1997 Oct;8(10):1003-8
references.pmid: 9402174
references.citation: Cancer Invest. 2003;21(4):517-25
references.pmid: 14533441
references.citation: Cancer. 2002 Sep 15;95(6):1274-8
references.pmid: 12216095
references.citation: Oncology. 2001;61 Suppl 1:47-54
references.pmid: 11598415
references.citation: Br J Cancer. 1997;76(12):1636-9
references.pmid: 9413954
references.citation: Lung Cancer. 2003 Feb;39(2):215-9
references.pmid: 12581576
references.citation: Ann Oncol. 2002 May;13(5):737-41
references.pmid: 12075742
references.citation: Lung Cancer. 2000 May;28(2):157-62
references.pmid: 10717333
references.citation: J Clin Oncol. 2004 May 1;22(9):1589-97
references.pmid: 15117980
references.citation: J Clin Oncol. 1999 Apr;17(4):1194
references.pmid: 10561178
references.citation: Cancer Invest. 2001;19(5):467-74
references.pmid: 11458814
references.citation: Oncology. 2001;61 Suppl 1:30-4
references.pmid: 11598412
references.citation: Cancer Chemother Pharmacol. 2001;47(2):141-8
references.pmid: 11269740
references.citation: Ann Oncol. 2003 Mar;14(3):455-60
references.pmid: 12598353
references.citation: Oncology. 2001;61 Suppl 1:35-41
references.pmid: 11598413
references.citation: Clin Cancer Res. 2000 Mar;6(3):868-73
references.pmid: 10741709
references.citation: J Clin Oncol. 1994 Feb;12(2):347-52
references.pmid: 8113842