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

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

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Abstract

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.

Original languageEnglish
Pages (from-to)561-568
Number of pages8
JournalInvestigational New Drugs
Volume32
Issue number3
DOIs
Publication statusPublished - 2014 Jan 1

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oxaliplatin
Multicenter Studies
Colorectal Neoplasms
S 1 (combination)
5-((1,2-dihydro-2-oxo-3H-indol-3-ylidene)methyl)-2,4-dimethyl-1H-pyrrole-3-propanoic acid

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)
  • Oncology

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

In: Investigational New Drugs, Vol. 32, No. 3, 01.01.2014, p. 561-568.

Research output: Contribution to journalArticle

Lee, Jeeyun ; Shin, Sang Joon ; Chung, Ik Joo ; Kim, Tae Won ; Chun, Hoo Geun ; Shin, Dong Bok ; Kim, Yeul Hong ; Song, Hong Suk ; Han, Sae Won ; Kim, Jong Gwang ; Kim, Sun Young ; Choi, Young Jin ; Chung, Hyun Cheol. / 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. In: Investigational New Drugs. 2014 ; Vol. 32, No. 3. pp. 561-568.
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abstract = "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.",
keywords = "Chemotherapy, Colorectal cancer, TSU-68",
author = "Jeeyun Lee and Shin, {Sang Joon} and Chung, {Ik Joo} and Kim, {Tae Won} and Chun, {Hoo Geun} and Shin, {Dong Bok} and Kim, {Yeul Hong} and Song, {Hong Suk} and Han, {Sae Won} and Kim, {Jong Gwang} and Kim, {Sun Young} and Choi, {Young Jin} and Chung, {Hyun Cheol}",
year = "2014",
month = "1",
day = "1",
doi = "10.1007/s10637-014-0075-8",
language = "English",
volume = "32",
pages = "561--568",
journal = "Investigational New Drugs",
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TY - JOUR

T1 - 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

AU - Lee, Jeeyun

AU - Shin, Sang Joon

AU - Chung, Ik Joo

AU - Kim, Tae Won

AU - Chun, Hoo Geun

AU - Shin, Dong Bok

AU - Kim, Yeul Hong

AU - Song, Hong Suk

AU - Han, Sae Won

AU - Kim, Jong Gwang

AU - Kim, Sun Young

AU - Choi, Young Jin

AU - Chung, Hyun Cheol

PY - 2014/1/1

Y1 - 2014/1/1

N2 - 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.

AB - 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.

KW - Chemotherapy

KW - Colorectal cancer

KW - TSU-68

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