Phase I study of pemetrexed with sorafenib in advanced solid tumors

Oncotarget. 2016 Jul 5;7(27):42625-42638. doi: 10.18632/oncotarget.9434.


Purpose: To determine if combination treatment with pemetrexed and sorafenib is safe and tolerable in patients with advanced solid tumors.

Results: Thirty-seven patients were enrolled and 36 patients were treated (24 in cohort A; 12 in cohort B). The cohort A dose schedule resulted in problematic cumulative toxicity, while the cohort B dose schedule was found to be more tolerable. The maximum tolerated dose (MTD) was pemetrexed 750 mg/m2 every 14 days with oral sorafenib 400 mg given twice daily on days 1-5. Because dosing delays and modifications were associated with the MTD, the recommended phase II dose was declared to be pemetrexed 500 mg/m2 every 14 days with oral sorafenib 400 mg given twice daily on days 1-5. Thirty-three patients were evaluated for antitumor activity. One complete response and 4 partial responses were observed (15% overall response rate). Stable disease was seen in 15 patients (45%). Four patients had a continued response at 6 months, including 2 of 5 patients with triple-negative breast cancer.

Experimental design: A phase I trial employing a standard 3 + 3 design was conducted in patients with advanced solid tumors. Cohort A involved a novel dose escalation schema exploring doses of pemetrexed every 14 days with continuous sorafenib. Cohort B involved a modified schedule of sorafenib dosing on days 1-5 of each 14-day pemetrexed cycle. Radiographic assessments were conducted every 8 weeks.

Conclusions: Pemetrexed and intermittent sorafenib therapy is a safe and tolerable combination for patients, with promising activity seen in patients with breast cancer.

Keywords: clinical trial; pemetrexed; solid tumors; sorafenib.

Publication types

  • Clinical Trial, Phase I

MeSH terms

  • Adult
  • Aged
  • Antineoplastic Agents / therapeutic use
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use
  • Biomarkers, Tumor
  • Cohort Studies
  • Female
  • Humans
  • Inflammation
  • Male
  • Maximum Tolerated Dose
  • Middle Aged
  • Neoplasms / drug therapy*
  • Niacinamide / administration & dosage
  • Niacinamide / analogs & derivatives*
  • PTEN Phosphohydrolase / metabolism
  • Pemetrexed / administration & dosage*
  • Phenylurea Compounds / administration & dosage*
  • Sorafenib
  • Treatment Outcome
  • Triple Negative Breast Neoplasms / drug therapy


  • Antineoplastic Agents
  • Biomarkers, Tumor
  • Phenylurea Compounds
  • Pemetrexed
  • Niacinamide
  • Sorafenib
  • PTEN Phosphohydrolase
  • PTEN protein, human