A phase I dose-escalation and pharmacokinetic study of sunitinib in combination with pemetrexed in patients with advanced solid malignancies, with an expanded cohort in non-small cell lung cancer

• Published in: Cancer chemotherapy and pharmacology 2012-03, Vol.69 (3), p.709-722
• Main Authors: Chow, L. Q. M., Blais, N., Jonker, D. J., Laurie, S. A., Diab, S. G., Canil, C., McWilliam, M., Thall, A., Ruiz-Garcia, A., Zhang, K., Tye, L., Chao, R. C., Camidge, D. R.
• Format: Article
• Language: English
• Subjects: Administration, Oral; Adult; Aged; Aged, 80 and over; Antineoplastic agents; Antineoplastic Combined Chemotherapy Protocols - administration & dosage; Antineoplastic Combined Chemotherapy Protocols - adverse effects; Antineoplastic Combined Chemotherapy Protocols - pharmacokinetics; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Biological and medical sciences; Cancer Research; Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - metabolism; Cohort Studies; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Glutamates - administration & dosage; Glutamates - adverse effects; Glutamates - pharmacokinetics; Glutamates - therapeutic use; Guanine - administration & dosage; Guanine - adverse effects; Guanine - analogs & derivatives; Guanine - pharmacokinetics; Guanine - therapeutic use; Humans; Indoles - administration & dosage; Indoles - adverse effects; Indoles - pharmacokinetics; Indoles - therapeutic use; Lung Neoplasms - drug therapy; Lung Neoplasms - metabolism; Male; Maximum Tolerated Dose; Medical sciences; Medicine; Medicine & Public Health; Middle Aged; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Oncology; Original; Original Article; Pemetrexed; Pharmacology. Drug treatments; Pharmacology/Toxicology; Pneumology; Pyrroles - administration & dosage; Pyrroles - adverse effects; Pyrroles - pharmacokinetics; Pyrroles - therapeutic use; Treatment Outcome; Tumors; Tumors of the respiratory system and mediastinum
• ISSN: 0344-5704; 1432-0843
• DOI: 10.1007/s00280-011-1755-0

Purpose The primary objective of this phase I dose-escalation study was to identify the maximum tolerated dose (MTD) of sunitinib plus pemetrexed in patients with advanced cancer. Methods Using a 3 + 3 dose-escalation design, patients received oral sunitinib qd by continuous daily dosing (CDD schedule; 37.5 or 50 mg) or 2 weeks on/1 week off treatment schedule (Schedule 2/1; 50 mg). Pemetrexed (300–500 mg/m 2 IV) was administered q3w. At the proposed recommended phase 2 dose (RP2D), additional patients with non-small cell lung cancer (NSCLC) were enrolled. Results Thirty-five patients were enrolled on the CDD schedule and seven on Schedule 2/1. MTDs were sunitinib 37.5 mg/day (CDD/RP2D) or 50 mg/day (Schedule 2/1) with pemetrexed 500 mg/m 2 . Dose-limiting toxicities included grade (G) 5 cerebral hemorrhage, G3 febrile neutropenia, and G3 anorexia. Common G3/4 drug-related non-hematologic adverse events (AEs) at the CDD MTD included fatigue, anorexia, and hand–foot syndrome. G3/4 hematologic AEs included lymphopenia, neutropenia, and thrombocytopenia. No significant drug–drug interactions were identified. Five (24%) NSCLC patients had partial responses. Conclusions In patients with advanced solid malignancies, the MTD of sunitinib plus 500 mg/m 2 pemetrexed was 37.5 mg/day (CDD schedule) or 50 mg/day (Schedule 2/1). The CDD schedule MTD was tolerable and demonstrated promising clinical benefit in NSCLC.