A Phase Ib pharmacokinetic study of the anti-angiogenic agent CKD-732 used in combination with capecitabine and oxaliplatin (XELOX) in metastatic colorectal cancer patients who progressed on irinotecan-based chemotherapy

Sang Joon Shin, Joong Bae Ahn, Kyung Soo Park, Yoon Jung Lee, Yong Sang Hong, Tae Won Kim, Hye Ryun Kim, SunYoung Rha, Jae Kyung Roh, Dal Hyun Kim, Chin Kim, Hyuncheol Chung

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

Background: We conducted a Phase I clinical trial to evaluate the safety, tolerability, and pharmacokinetics (PK) of CKD-732 [6-O-(4-dimethylaminoethoxy) cinnamoyl fumagillol hemioxalate] in combination with capecitabine and oxaliplatin (XELOX) in nine metastatic colorectal cancer patients who had progressed on irinotecan-based chemotherapy. Methods: Using a dose-escalation schedule, CKD-732 doses of 2, 5, or 10 mg/m 2 /d were administered twice weekly for 2 weeks, followed by a 1-week rest. Oxaliplatin (130 mg/m 2 ) was administered on day 1, and capecitabine (1,000 mg/m 2 twice a day) was orally administered for 14 days of a 3-week cycle. Results: In the group given the 10 mg/m 2 /d dose, two patients experienced dose limiting toxicities (one had grade 3 nausea, insomnia, and fatigue; the other had grade 3 insomnia). The maximum tolerated dose was 10 mg/m 2 /d, and the clinically recommended dose was 5 mg/m 2 /d for CKD-732 in combination with XELOX. Frequently encountered non-hematological grade 3/4 adverse events included insomnia (22.2%), fatigue (11.1%), sensory neuropathy (11.1%), hyperbilirubinemia (11.1%), and dyspnea (11.1%). The area under the concentration-time curve and maximum concentration of CKD-732 increased in a dose-dependent manner. There were no notable effects of CKD-732 on the PK of capecitabine and oxaliplatin-derived platinum. Conclusion: The Phase II recommended dose of CKD-732 was determined to be 5 mg/m 2 /d, and this dose was safely combined with a conventional dose of capecitabine and oxaliplatin in this patient population. Further studies on the effects of CKD-732 in combination with XELOX and other chemotherapies using a larger study population are warranted.

Original languageEnglish
Pages (from-to)672-680
Number of pages9
JournalInvestigational New Drugs
Volume30
Issue number2
DOIs
Publication statusPublished - 2012 Apr 1

Fingerprint

oxaliplatin
irinotecan
Colorectal Neoplasms
Pharmacokinetics
Drug Therapy
Sleep Initiation and Maintenance Disorders
Fatigue
Clinical Trials, Phase I
Hyperbilirubinemia
Maximum Tolerated Dose
CKD732
Capecitabine
XELOX
Platinum
Dyspnea
Nausea
Population

All Science Journal Classification (ASJC) codes

  • Oncology
  • Pharmacology
  • Pharmacology (medical)

Cite this

Shin, Sang Joon ; Ahn, Joong Bae ; Park, Kyung Soo ; Lee, Yoon Jung ; Hong, Yong Sang ; Kim, Tae Won ; Kim, Hye Ryun ; Rha, SunYoung ; Roh, Jae Kyung ; Kim, Dal Hyun ; Kim, Chin ; Chung, Hyuncheol. / A Phase Ib pharmacokinetic study of the anti-angiogenic agent CKD-732 used in combination with capecitabine and oxaliplatin (XELOX) in metastatic colorectal cancer patients who progressed on irinotecan-based chemotherapy. In: Investigational New Drugs. 2012 ; Vol. 30, No. 2. pp. 672-680.
@article{4632f932e2484b70ab4d69133991f525,
title = "A Phase Ib pharmacokinetic study of the anti-angiogenic agent CKD-732 used in combination with capecitabine and oxaliplatin (XELOX) in metastatic colorectal cancer patients who progressed on irinotecan-based chemotherapy",
abstract = "Background: We conducted a Phase I clinical trial to evaluate the safety, tolerability, and pharmacokinetics (PK) of CKD-732 [6-O-(4-dimethylaminoethoxy) cinnamoyl fumagillol hemioxalate] in combination with capecitabine and oxaliplatin (XELOX) in nine metastatic colorectal cancer patients who had progressed on irinotecan-based chemotherapy. Methods: Using a dose-escalation schedule, CKD-732 doses of 2, 5, or 10 mg/m 2 /d were administered twice weekly for 2 weeks, followed by a 1-week rest. Oxaliplatin (130 mg/m 2 ) was administered on day 1, and capecitabine (1,000 mg/m 2 twice a day) was orally administered for 14 days of a 3-week cycle. Results: In the group given the 10 mg/m 2 /d dose, two patients experienced dose limiting toxicities (one had grade 3 nausea, insomnia, and fatigue; the other had grade 3 insomnia). The maximum tolerated dose was 10 mg/m 2 /d, and the clinically recommended dose was 5 mg/m 2 /d for CKD-732 in combination with XELOX. Frequently encountered non-hematological grade 3/4 adverse events included insomnia (22.2{\%}), fatigue (11.1{\%}), sensory neuropathy (11.1{\%}), hyperbilirubinemia (11.1{\%}), and dyspnea (11.1{\%}). The area under the concentration-time curve and maximum concentration of CKD-732 increased in a dose-dependent manner. There were no notable effects of CKD-732 on the PK of capecitabine and oxaliplatin-derived platinum. Conclusion: The Phase II recommended dose of CKD-732 was determined to be 5 mg/m 2 /d, and this dose was safely combined with a conventional dose of capecitabine and oxaliplatin in this patient population. Further studies on the effects of CKD-732 in combination with XELOX and other chemotherapies using a larger study population are warranted.",
author = "Shin, {Sang Joon} and Ahn, {Joong Bae} and Park, {Kyung Soo} and Lee, {Yoon Jung} and Hong, {Yong Sang} and Kim, {Tae Won} and Kim, {Hye Ryun} and SunYoung Rha and Roh, {Jae Kyung} and Kim, {Dal Hyun} and Chin Kim and Hyuncheol Chung",
year = "2012",
month = "4",
day = "1",
doi = "10.1007/s10637-010-9625-x",
language = "English",
volume = "30",
pages = "672--680",
journal = "Investigational New Drugs",
issn = "0167-6997",
publisher = "Kluwer Academic Publishers",
number = "2",

}

A Phase Ib pharmacokinetic study of the anti-angiogenic agent CKD-732 used in combination with capecitabine and oxaliplatin (XELOX) in metastatic colorectal cancer patients who progressed on irinotecan-based chemotherapy. / Shin, Sang Joon; Ahn, Joong Bae; Park, Kyung Soo; Lee, Yoon Jung; Hong, Yong Sang; Kim, Tae Won; Kim, Hye Ryun; Rha, SunYoung; Roh, Jae Kyung; Kim, Dal Hyun; Kim, Chin; Chung, Hyuncheol.

In: Investigational New Drugs, Vol. 30, No. 2, 01.04.2012, p. 672-680.

Research output: Contribution to journalArticle

TY - JOUR

T1 - A Phase Ib pharmacokinetic study of the anti-angiogenic agent CKD-732 used in combination with capecitabine and oxaliplatin (XELOX) in metastatic colorectal cancer patients who progressed on irinotecan-based chemotherapy

AU - Shin, Sang Joon

AU - Ahn, Joong Bae

AU - Park, Kyung Soo

AU - Lee, Yoon Jung

AU - Hong, Yong Sang

AU - Kim, Tae Won

AU - Kim, Hye Ryun

AU - Rha, SunYoung

AU - Roh, Jae Kyung

AU - Kim, Dal Hyun

AU - Kim, Chin

AU - Chung, Hyuncheol

PY - 2012/4/1

Y1 - 2012/4/1

N2 - Background: We conducted a Phase I clinical trial to evaluate the safety, tolerability, and pharmacokinetics (PK) of CKD-732 [6-O-(4-dimethylaminoethoxy) cinnamoyl fumagillol hemioxalate] in combination with capecitabine and oxaliplatin (XELOX) in nine metastatic colorectal cancer patients who had progressed on irinotecan-based chemotherapy. Methods: Using a dose-escalation schedule, CKD-732 doses of 2, 5, or 10 mg/m 2 /d were administered twice weekly for 2 weeks, followed by a 1-week rest. Oxaliplatin (130 mg/m 2 ) was administered on day 1, and capecitabine (1,000 mg/m 2 twice a day) was orally administered for 14 days of a 3-week cycle. Results: In the group given the 10 mg/m 2 /d dose, two patients experienced dose limiting toxicities (one had grade 3 nausea, insomnia, and fatigue; the other had grade 3 insomnia). The maximum tolerated dose was 10 mg/m 2 /d, and the clinically recommended dose was 5 mg/m 2 /d for CKD-732 in combination with XELOX. Frequently encountered non-hematological grade 3/4 adverse events included insomnia (22.2%), fatigue (11.1%), sensory neuropathy (11.1%), hyperbilirubinemia (11.1%), and dyspnea (11.1%). The area under the concentration-time curve and maximum concentration of CKD-732 increased in a dose-dependent manner. There were no notable effects of CKD-732 on the PK of capecitabine and oxaliplatin-derived platinum. Conclusion: The Phase II recommended dose of CKD-732 was determined to be 5 mg/m 2 /d, and this dose was safely combined with a conventional dose of capecitabine and oxaliplatin in this patient population. Further studies on the effects of CKD-732 in combination with XELOX and other chemotherapies using a larger study population are warranted.

AB - Background: We conducted a Phase I clinical trial to evaluate the safety, tolerability, and pharmacokinetics (PK) of CKD-732 [6-O-(4-dimethylaminoethoxy) cinnamoyl fumagillol hemioxalate] in combination with capecitabine and oxaliplatin (XELOX) in nine metastatic colorectal cancer patients who had progressed on irinotecan-based chemotherapy. Methods: Using a dose-escalation schedule, CKD-732 doses of 2, 5, or 10 mg/m 2 /d were administered twice weekly for 2 weeks, followed by a 1-week rest. Oxaliplatin (130 mg/m 2 ) was administered on day 1, and capecitabine (1,000 mg/m 2 twice a day) was orally administered for 14 days of a 3-week cycle. Results: In the group given the 10 mg/m 2 /d dose, two patients experienced dose limiting toxicities (one had grade 3 nausea, insomnia, and fatigue; the other had grade 3 insomnia). The maximum tolerated dose was 10 mg/m 2 /d, and the clinically recommended dose was 5 mg/m 2 /d for CKD-732 in combination with XELOX. Frequently encountered non-hematological grade 3/4 adverse events included insomnia (22.2%), fatigue (11.1%), sensory neuropathy (11.1%), hyperbilirubinemia (11.1%), and dyspnea (11.1%). The area under the concentration-time curve and maximum concentration of CKD-732 increased in a dose-dependent manner. There were no notable effects of CKD-732 on the PK of capecitabine and oxaliplatin-derived platinum. Conclusion: The Phase II recommended dose of CKD-732 was determined to be 5 mg/m 2 /d, and this dose was safely combined with a conventional dose of capecitabine and oxaliplatin in this patient population. Further studies on the effects of CKD-732 in combination with XELOX and other chemotherapies using a larger study population are warranted.

UR - http://www.scopus.com/inward/record.url?scp=84862256989&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84862256989&partnerID=8YFLogxK

U2 - 10.1007/s10637-010-9625-x

DO - 10.1007/s10637-010-9625-x

M3 - Article

C2 - 21188464

AN - SCOPUS:84862256989

VL - 30

SP - 672

EP - 680

JO - Investigational New Drugs

JF - Investigational New Drugs

SN - 0167-6997

IS - 2

ER -