Journal Article

A phase II open-label randomized multicenter trial of TSU-68 in combination with S-1 and oxaliplatin versus S-1 in combination with oxaliplatin in patients with metastatic colorectal cancer

Song, Hong Suk, Kim, Jong Gwang, Shin, Sang Joon, Chung, Hyun Cheol, Han, Sae-Won, Choi, Young Jin, Shin, Dong Bok, Kim, Sun Young, Lee, Jeeyun, Chun, Hoo-Geun, Kim, Yeul Hong, Chung, Ik Joo, Kim, Tae Won

2014

Overview

Summary Background Colorectal cancer (CRC) is the fourth leading cause of cancer-related deaths worldwide. The combination of oxaliplatin-based treatments (oxaliplatin plus infusional 5-fluorouracil and leucovorin [FOLFOX] or oxaliplatin plus capecitabine [CapeOX]) and bevacizumab is a standard chemotherapy regimen for metastatic CRC (mCRC). However, several clinical studies that tested S-1 plus oxaliplatin (SOX) indicate that SOX is also a treatment option for mCRC. TSU-68 is an oral compound that inhibits vascular endothelial growth factor receptor and platelet-derived growth factor receptor. The recommended dose of TSU-68 + SOX was previously determined in a phase I study of mCRC patients. The goal of this trial was to evaluate the efficacy of TSU-68 in combination with SOX. Methods This open-label multicenter randomized phase II trial was performed in Korea. Treatment-naive mCRC patients with a performance status of 0 or 1 were randomized in a 1:1 ratio to receive either TSU-68 + SOX or SOX alone. The primary endpoint was progression-free survival (PFS). Results A total of 105 patients (TSU-68 + SOX, 52 patients; SOX alone, 53 patients) were randomized. The median PFS was 7.0 months in the TSU-68 + SOX group (hazard ratio [HR], 1.057) and 7.2 months in the SOX group ( p  = 0.8401). The most frequent grade 3 and 4 adverse events were thrombocytopenia (9.6 % [TSU-68 + SOX] vs. 26.4 % [SOX]), neutropenia (13.5 % [TSU-68 + SOX] vs. 15.1 % [SOX]), and anemia (3.8 % [TSU-68 + SOX] vs. 13.2 % [SOX]). We observed a difference between the 2 groups for all grades of anemia (15.4 % [TSU-68 + SOX] vs. 32.1 % [SOX]), diarrhea (30.8 % [TSU-68 + SOX] vs. 47.2 % [SOX]), vomiting (50.0 % [TSU-68 + SOX] vs. 26.4 % [SOX]), and chromaturia (23.1 % [TSU-68 + SOX] vs. 0.0 % [SOX]). Analysis using a Cox proportional hazard model showed that baseline interleukin 6 (IL-6) levels were associated with a survival benefit of TSU-68 ( p  = 0.012). Conclusion TSU-68 + SOX had a favorable safety profile. However, TSU-68 did not have a synergistic effect on the efficacy of SOX. The baseline serum IL-6 level could be a prognostic factor for TSU-68 efficacy.

• Publisher: Springer US,Springer,Springer Nature B.V
• Subject: Adjuvants / Adult / Aged / Anemia / Antineoplastic agents / Antineoplastic Combined Chemotherapy Protocols - adverse effects / Antineoplastic Combined Chemotherapy Protocols - pharmacology / Antineoplastic Combined Chemotherapy Protocols - therapeutic use / Becaplermin / Biological and medical sciences / C-Reactive Protein - metabolism / Cancer therapies / Chemotherapy / Clinical trials / Colorectal cancer / Colorectal Neoplasms - blood / Colorectal Neoplasms - drug therapy / Consent / Disease-Free Survival / Drug Combinations / Drug dosages / Female / Gastroenterology. Liver. Pancreas. Abdomen / Hematology / Hospitals / Humans / Indoles - administration & dosage / Indoles - adverse effects / Interleukin-6 - blood / Interleukin-8 - blood / L-Lactate Dehydrogenase - blood / Liver cancer / Male / Medical sciences / Medicine / Medicine & Public Health / Metastasis / Middle Aged / Multiple tumors. Solid tumors. Tumors in childhood (general aspects) / Oncology / Organoplatinum Compounds - administration & dosage / Organoplatinum Compounds - adverse effects / Oxaliplatin / Oxonic Acid - administration & dosage / Oxonic Acid - adverse effects / Patients / Pharmaceuticals / Pharmacology. Drug treatments / Pharmacology/Toxicology / Phase II Studies / Platelet-Derived Growth Factor - metabolism / Propionates - administration & dosage / Propionates - adverse effects / Proto-Oncogene Proteins c-sis - blood / R&D / Research & development / Review boards / Statistical analysis / Stomach. Duodenum. Small intestine. Colon. Rectum. Anus / Tegafur - administration & dosage / Tegafur - adverse effects / Tumors / Vascular Cell Adhesion Molecule-1 - blood / Vascular endothelial growth factor / Vascular Endothelial Growth Factor A - blood