Phase i study of enzastaurin and bevacizumab in patients with advanced cancer: Safety, efficacy and pharmacokinetics

Nwabundo Nwankwo, Zhe Zhang, Ting Wang, Connie Collins, Lee Resta, Sabine Ermisch, Jeannette Day, Rodney Decker, Lori Kornberg, Steven Nicol, Donald Thornton, Deborah Kay Armstrong, Michael A Carducci

Research output: Contribution to journalArticle

Abstract

Purpose Given distinct mechanism of actions of enzastaurin and bevacizumab, preclinical studies suggest enhanced antitumor activity in combination. This phase I study assessed the combination's safety and efficacy. Patients and methods Six advanced cancer patients could be enrolled in each of 11 cohorts. Patients received an enzastaurin loading dose. Oral enzastaurin (500 mg once daily [QD], 250 mg twice daily [BID], 375 mg BID, 500 mg BID, and 750 mg BID) was escalated in each cohort in combination with bevacizumab dosed at 5 mg/kg every 2 weeks, 10 mg/kg every 2 weeks, or 15 mg/kg every 3 weeks until a dose-limiting toxicity (DLT) occurred in 2 of 6 patients in any cohort. Results Sixty-seven patients (31, ovarian cancer [ovcar]) were evaluable for safety and efficacy. Six treatment-related DLTs occurred: grade 3 fatigue (n = 4), grade 4 cerebral hemorrhage, and grade 3 elevated aspartate transaminase. Common drug-related toxicities included change in color of urine and stool, fatigue, pain, diarrhea, and nausea. The maximum tolerated dose of enzastaurin was 750 mg BID in combination with any tested bevacizumab dose/schedule. Overall response rate was 19.4 % (32.3 % ovcar). Median time to progression was 3.7 months (95 % confidence interval [CI], 2.7-5.5), with 8.3 months (95 % CI, 3.7-11.1) in ovcar. Overall, 35.9 % (50.4 % ovcar) of patients remained without disease progression after 6 months. Conclusion The recommended phase II doses of enzastaurin were 500 mg QD up to 500 mg BID with any tested dose/schedule of bevacizumab. This combination demonstrated encouraging clinical activity, particularly in ovcar.

Original languageEnglish (US)
Pages (from-to)653-660
Number of pages8
JournalInvestigational New Drugs
Volume31
Issue number3
DOIs
StatePublished - Jun 2013

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Ovarian Neoplasms
Pharmacokinetics
Safety
Neoplasms
Fatigue
Appointments and Schedules
Confidence Intervals
Maximum Tolerated Dose
Cerebral Hemorrhage
Aspartate Aminotransferases
Drug-Related Side Effects and Adverse Reactions
Nausea
Disease Progression
enzastaurin
Bevacizumab
Diarrhea
Color
Urine
Pain
Therapeutics

Keywords

  • Advanced cancer
  • Bevacizumab
  • Enzastaurin
  • Ovarian cancer
  • Phase I

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)
  • Oncology
  • Medicine(all)

Cite this

Phase i study of enzastaurin and bevacizumab in patients with advanced cancer : Safety, efficacy and pharmacokinetics. / Nwankwo, Nwabundo; Zhang, Zhe; Wang, Ting; Collins, Connie; Resta, Lee; Ermisch, Sabine; Day, Jeannette; Decker, Rodney; Kornberg, Lori; Nicol, Steven; Thornton, Donald; Armstrong, Deborah Kay; Carducci, Michael A.

In: Investigational New Drugs, Vol. 31, No. 3, 06.2013, p. 653-660.

Research output: Contribution to journalArticle

Nwankwo, N, Zhang, Z, Wang, T, Collins, C, Resta, L, Ermisch, S, Day, J, Decker, R, Kornberg, L, Nicol, S, Thornton, D, Armstrong, DK & Carducci, MA 2013, 'Phase i study of enzastaurin and bevacizumab in patients with advanced cancer: Safety, efficacy and pharmacokinetics', Investigational New Drugs, vol. 31, no. 3, pp. 653-660. https://doi.org/10.1007/s10637-012-9850-6
Nwankwo, Nwabundo ; Zhang, Zhe ; Wang, Ting ; Collins, Connie ; Resta, Lee ; Ermisch, Sabine ; Day, Jeannette ; Decker, Rodney ; Kornberg, Lori ; Nicol, Steven ; Thornton, Donald ; Armstrong, Deborah Kay ; Carducci, Michael A. / Phase i study of enzastaurin and bevacizumab in patients with advanced cancer : Safety, efficacy and pharmacokinetics. In: Investigational New Drugs. 2013 ; Vol. 31, No. 3. pp. 653-660.
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abstract = "Purpose Given distinct mechanism of actions of enzastaurin and bevacizumab, preclinical studies suggest enhanced antitumor activity in combination. This phase I study assessed the combination's safety and efficacy. Patients and methods Six advanced cancer patients could be enrolled in each of 11 cohorts. Patients received an enzastaurin loading dose. Oral enzastaurin (500 mg once daily [QD], 250 mg twice daily [BID], 375 mg BID, 500 mg BID, and 750 mg BID) was escalated in each cohort in combination with bevacizumab dosed at 5 mg/kg every 2 weeks, 10 mg/kg every 2 weeks, or 15 mg/kg every 3 weeks until a dose-limiting toxicity (DLT) occurred in 2 of 6 patients in any cohort. Results Sixty-seven patients (31, ovarian cancer [ovcar]) were evaluable for safety and efficacy. Six treatment-related DLTs occurred: grade 3 fatigue (n = 4), grade 4 cerebral hemorrhage, and grade 3 elevated aspartate transaminase. Common drug-related toxicities included change in color of urine and stool, fatigue, pain, diarrhea, and nausea. The maximum tolerated dose of enzastaurin was 750 mg BID in combination with any tested bevacizumab dose/schedule. Overall response rate was 19.4 {\%} (32.3 {\%} ovcar). Median time to progression was 3.7 months (95 {\%} confidence interval [CI], 2.7-5.5), with 8.3 months (95 {\%} CI, 3.7-11.1) in ovcar. Overall, 35.9 {\%} (50.4 {\%} ovcar) of patients remained without disease progression after 6 months. Conclusion The recommended phase II doses of enzastaurin were 500 mg QD up to 500 mg BID with any tested dose/schedule of bevacizumab. This combination demonstrated encouraging clinical activity, particularly in ovcar.",
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T1 - Phase i study of enzastaurin and bevacizumab in patients with advanced cancer

T2 - Safety, efficacy and pharmacokinetics

AU - Nwankwo, Nwabundo

AU - Zhang, Zhe

AU - Wang, Ting

AU - Collins, Connie

AU - Resta, Lee

AU - Ermisch, Sabine

AU - Day, Jeannette

AU - Decker, Rodney

AU - Kornberg, Lori

AU - Nicol, Steven

AU - Thornton, Donald

AU - Armstrong, Deborah Kay

AU - Carducci, Michael A

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N2 - Purpose Given distinct mechanism of actions of enzastaurin and bevacizumab, preclinical studies suggest enhanced antitumor activity in combination. This phase I study assessed the combination's safety and efficacy. Patients and methods Six advanced cancer patients could be enrolled in each of 11 cohorts. Patients received an enzastaurin loading dose. Oral enzastaurin (500 mg once daily [QD], 250 mg twice daily [BID], 375 mg BID, 500 mg BID, and 750 mg BID) was escalated in each cohort in combination with bevacizumab dosed at 5 mg/kg every 2 weeks, 10 mg/kg every 2 weeks, or 15 mg/kg every 3 weeks until a dose-limiting toxicity (DLT) occurred in 2 of 6 patients in any cohort. Results Sixty-seven patients (31, ovarian cancer [ovcar]) were evaluable for safety and efficacy. Six treatment-related DLTs occurred: grade 3 fatigue (n = 4), grade 4 cerebral hemorrhage, and grade 3 elevated aspartate transaminase. Common drug-related toxicities included change in color of urine and stool, fatigue, pain, diarrhea, and nausea. The maximum tolerated dose of enzastaurin was 750 mg BID in combination with any tested bevacizumab dose/schedule. Overall response rate was 19.4 % (32.3 % ovcar). Median time to progression was 3.7 months (95 % confidence interval [CI], 2.7-5.5), with 8.3 months (95 % CI, 3.7-11.1) in ovcar. Overall, 35.9 % (50.4 % ovcar) of patients remained without disease progression after 6 months. Conclusion The recommended phase II doses of enzastaurin were 500 mg QD up to 500 mg BID with any tested dose/schedule of bevacizumab. This combination demonstrated encouraging clinical activity, particularly in ovcar.

AB - Purpose Given distinct mechanism of actions of enzastaurin and bevacizumab, preclinical studies suggest enhanced antitumor activity in combination. This phase I study assessed the combination's safety and efficacy. Patients and methods Six advanced cancer patients could be enrolled in each of 11 cohorts. Patients received an enzastaurin loading dose. Oral enzastaurin (500 mg once daily [QD], 250 mg twice daily [BID], 375 mg BID, 500 mg BID, and 750 mg BID) was escalated in each cohort in combination with bevacizumab dosed at 5 mg/kg every 2 weeks, 10 mg/kg every 2 weeks, or 15 mg/kg every 3 weeks until a dose-limiting toxicity (DLT) occurred in 2 of 6 patients in any cohort. Results Sixty-seven patients (31, ovarian cancer [ovcar]) were evaluable for safety and efficacy. Six treatment-related DLTs occurred: grade 3 fatigue (n = 4), grade 4 cerebral hemorrhage, and grade 3 elevated aspartate transaminase. Common drug-related toxicities included change in color of urine and stool, fatigue, pain, diarrhea, and nausea. The maximum tolerated dose of enzastaurin was 750 mg BID in combination with any tested bevacizumab dose/schedule. Overall response rate was 19.4 % (32.3 % ovcar). Median time to progression was 3.7 months (95 % confidence interval [CI], 2.7-5.5), with 8.3 months (95 % CI, 3.7-11.1) in ovcar. Overall, 35.9 % (50.4 % ovcar) of patients remained without disease progression after 6 months. Conclusion The recommended phase II doses of enzastaurin were 500 mg QD up to 500 mg BID with any tested dose/schedule of bevacizumab. This combination demonstrated encouraging clinical activity, particularly in ovcar.

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KW - Bevacizumab

KW - Enzastaurin

KW - Ovarian cancer

KW - Phase I

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