Phase I study of pemetrexed with sorafenib in advanced solid tumors.

Abstract

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.

• Authors: Andrew Poklepovic, Sarah Gordon, Danielle A Shafer, John D Roberts, Prithviraj Bose, Charles E Geyer Jr, William P McGuire, Mary Beth Tombes, Ellen Shrader, Katie Strickler, Maria Quigley, Wen Wan, Maciej Kmieciak, H Davis Massey, Laurence Booth, Richard G Moran, Paul Dent
• Journal: Oncotarget (Oncotarget) Vol. 7 Issue 27 Pg. 42625-42638 (07 05 2016) ISSN: 1949-2553 [Electronic] United States
• PMID: 27213589 (Publication Type: Clinical Trial, Phase I, Journal Article)

Chemical References

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

Topics

• 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, analogs & derivatives)
• PTEN Phosphohydrolase (metabolism)
• Pemetrexed (administration & dosage)
• Phenylurea Compounds (administration & dosage)
• Sorafenib
• Treatment Outcome
• Triple Negative Breast Neoplasms (drug therapy)