Phase i clinical and pharmacokinetic study of ombrabulin (AVE8062) combined with cisplatin/docetaxel or carboplatin/paclitaxel in patients with advanced solid tumors

Rastislav Bahleda, Cristiana Sessa, Gianluca Del Conte, Luca Gianni, Giuseppe Capri, Andrea Varga, Corina Oprea, Byzance Daglish, Marie Hospitel, Jean Charles Soria

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Abstract

Purpose Preclinical evidence supports synergy between the vascular disrupting agent ombrabulin and various chemotherapy agents. Ombrabulin was combined with two standard taxane/platinum doublets in a phase I study to determine the recommended combination doses. Methods Ombrabulin (30-min infusion, day 1 every 3 weeks) was escalated from 15.5 to 35 mg/m2 with two chemotherapy doublets; OCD, 75 mg/m2 cisplatin (C), day 1 (cohort 1) or day 2 (cohort 2) with 60/75 mg/m2 docetaxel (D), day 2; and OCP, AUC5/6 carboplatin (C) and paclitaxel (P) 175 mg/m2 (cohort 3) or 200 mg/m2 (cohort 4), day 2. Safety, pharmacokinetics, and tumor response were evaluated. Results Sixty-nine patients were treated (32 OCD, 37 OCP). Four had DLTs in cycle 1, two in cohort 1 (grade 4 febrile neutropenia, grade 4 pulmonary embolism) and one each in cohorts 2 (grade 3 ALT elevation) and 4 (grade 3 peripheral ischemia). Ombrabulin escalation in cohorts 2, 3 and 4 was halted at the highest planned dose (35 mg/m2). Asthenia, nausea, paresthesia, alopecia, vomiting, and stomatitis were common, as was grade 3-4 neutropenia. Ombrabulin clearance was high with a short terminal half-life and a medium volume of distribution. Pharmacokinetic analysis showed no clinically relevant drug interactions between the taxane-platinum doublet and ombrabulin or its active metabolite RPR258063, however docetaxel and carboplatin pharmacokinetics were slightly altered. One complete and 15 partial responses (10 OCD, 5 OCP; median duration 5.5 and 4.4 months, respectively) were reported. Conclusions The addition of ombrabulin to standard doses of cisplatin/docetaxel or carboplatin/paclitaxel proved feasible with manageable overlapping toxicities but appears to have limited impact on the efficacy of these doublets. Recommended combination doses are 35 mg/m2 ombrabulin with 75 mg/m2 cisplatin/75 mg/m2 docetaxel or 200 mg/m2 paclitaxel/AUC6 carboplatin, every 3 weeks.

Original languageEnglish
Pages (from-to)1188-1196
Number of pages9
JournalInvestigational New Drugs
Volume32
Issue number6
DOIs
Publication statusPublished - Dec 1 2014

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docetaxel
Carboplatin
Paclitaxel
Cisplatin
Pharmacokinetics
Neoplasms
Platinum
Asthenia
Drug Therapy
Febrile Neutropenia
Stomatitis
Clinical Studies
AC 7700
Paresthesia
Alopecia
Neutropenia
Pulmonary Embolism
Drug Interactions
Nausea
Vomiting

Keywords

  • Chemotherapy
  • Ombrabulin
  • Platinum
  • Taxane
  • Vascular disrupting agent

ASJC Scopus subject areas

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

Cite this

Phase i clinical and pharmacokinetic study of ombrabulin (AVE8062) combined with cisplatin/docetaxel or carboplatin/paclitaxel in patients with advanced solid tumors. / Bahleda, Rastislav; Sessa, Cristiana; Del Conte, Gianluca; Gianni, Luca; Capri, Giuseppe; Varga, Andrea; Oprea, Corina; Daglish, Byzance; Hospitel, Marie; Soria, Jean Charles.

In: Investigational New Drugs, Vol. 32, No. 6, 01.12.2014, p. 1188-1196.

Research output: Contribution to journalArticle

Bahleda, Rastislav ; Sessa, Cristiana ; Del Conte, Gianluca ; Gianni, Luca ; Capri, Giuseppe ; Varga, Andrea ; Oprea, Corina ; Daglish, Byzance ; Hospitel, Marie ; Soria, Jean Charles. / Phase i clinical and pharmacokinetic study of ombrabulin (AVE8062) combined with cisplatin/docetaxel or carboplatin/paclitaxel in patients with advanced solid tumors. In: Investigational New Drugs. 2014 ; Vol. 32, No. 6. pp. 1188-1196.
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abstract = "Purpose Preclinical evidence supports synergy between the vascular disrupting agent ombrabulin and various chemotherapy agents. Ombrabulin was combined with two standard taxane/platinum doublets in a phase I study to determine the recommended combination doses. Methods Ombrabulin (30-min infusion, day 1 every 3 weeks) was escalated from 15.5 to 35 mg/m2 with two chemotherapy doublets; OCD, 75 mg/m2 cisplatin (C), day 1 (cohort 1) or day 2 (cohort 2) with 60/75 mg/m2 docetaxel (D), day 2; and OCP, AUC5/6 carboplatin (C) and paclitaxel (P) 175 mg/m2 (cohort 3) or 200 mg/m2 (cohort 4), day 2. Safety, pharmacokinetics, and tumor response were evaluated. Results Sixty-nine patients were treated (32 OCD, 37 OCP). Four had DLTs in cycle 1, two in cohort 1 (grade 4 febrile neutropenia, grade 4 pulmonary embolism) and one each in cohorts 2 (grade 3 ALT elevation) and 4 (grade 3 peripheral ischemia). Ombrabulin escalation in cohorts 2, 3 and 4 was halted at the highest planned dose (35 mg/m2). Asthenia, nausea, paresthesia, alopecia, vomiting, and stomatitis were common, as was grade 3-4 neutropenia. Ombrabulin clearance was high with a short terminal half-life and a medium volume of distribution. Pharmacokinetic analysis showed no clinically relevant drug interactions between the taxane-platinum doublet and ombrabulin or its active metabolite RPR258063, however docetaxel and carboplatin pharmacokinetics were slightly altered. One complete and 15 partial responses (10 OCD, 5 OCP; median duration 5.5 and 4.4 months, respectively) were reported. Conclusions The addition of ombrabulin to standard doses of cisplatin/docetaxel or carboplatin/paclitaxel proved feasible with manageable overlapping toxicities but appears to have limited impact on the efficacy of these doublets. Recommended combination doses are 35 mg/m2 ombrabulin with 75 mg/m2 cisplatin/75 mg/m2 docetaxel or 200 mg/m2 paclitaxel/AUC6 carboplatin, every 3 weeks.",
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T1 - Phase i clinical and pharmacokinetic study of ombrabulin (AVE8062) combined with cisplatin/docetaxel or carboplatin/paclitaxel in patients with advanced solid tumors

AU - Bahleda, Rastislav

AU - Sessa, Cristiana

AU - Del Conte, Gianluca

AU - Gianni, Luca

AU - Capri, Giuseppe

AU - Varga, Andrea

AU - Oprea, Corina

AU - Daglish, Byzance

AU - Hospitel, Marie

AU - Soria, Jean Charles

PY - 2014/12/1

Y1 - 2014/12/1

N2 - Purpose Preclinical evidence supports synergy between the vascular disrupting agent ombrabulin and various chemotherapy agents. Ombrabulin was combined with two standard taxane/platinum doublets in a phase I study to determine the recommended combination doses. Methods Ombrabulin (30-min infusion, day 1 every 3 weeks) was escalated from 15.5 to 35 mg/m2 with two chemotherapy doublets; OCD, 75 mg/m2 cisplatin (C), day 1 (cohort 1) or day 2 (cohort 2) with 60/75 mg/m2 docetaxel (D), day 2; and OCP, AUC5/6 carboplatin (C) and paclitaxel (P) 175 mg/m2 (cohort 3) or 200 mg/m2 (cohort 4), day 2. Safety, pharmacokinetics, and tumor response were evaluated. Results Sixty-nine patients were treated (32 OCD, 37 OCP). Four had DLTs in cycle 1, two in cohort 1 (grade 4 febrile neutropenia, grade 4 pulmonary embolism) and one each in cohorts 2 (grade 3 ALT elevation) and 4 (grade 3 peripheral ischemia). Ombrabulin escalation in cohorts 2, 3 and 4 was halted at the highest planned dose (35 mg/m2). Asthenia, nausea, paresthesia, alopecia, vomiting, and stomatitis were common, as was grade 3-4 neutropenia. Ombrabulin clearance was high with a short terminal half-life and a medium volume of distribution. Pharmacokinetic analysis showed no clinically relevant drug interactions between the taxane-platinum doublet and ombrabulin or its active metabolite RPR258063, however docetaxel and carboplatin pharmacokinetics were slightly altered. One complete and 15 partial responses (10 OCD, 5 OCP; median duration 5.5 and 4.4 months, respectively) were reported. Conclusions The addition of ombrabulin to standard doses of cisplatin/docetaxel or carboplatin/paclitaxel proved feasible with manageable overlapping toxicities but appears to have limited impact on the efficacy of these doublets. Recommended combination doses are 35 mg/m2 ombrabulin with 75 mg/m2 cisplatin/75 mg/m2 docetaxel or 200 mg/m2 paclitaxel/AUC6 carboplatin, every 3 weeks.

AB - Purpose Preclinical evidence supports synergy between the vascular disrupting agent ombrabulin and various chemotherapy agents. Ombrabulin was combined with two standard taxane/platinum doublets in a phase I study to determine the recommended combination doses. Methods Ombrabulin (30-min infusion, day 1 every 3 weeks) was escalated from 15.5 to 35 mg/m2 with two chemotherapy doublets; OCD, 75 mg/m2 cisplatin (C), day 1 (cohort 1) or day 2 (cohort 2) with 60/75 mg/m2 docetaxel (D), day 2; and OCP, AUC5/6 carboplatin (C) and paclitaxel (P) 175 mg/m2 (cohort 3) or 200 mg/m2 (cohort 4), day 2. Safety, pharmacokinetics, and tumor response were evaluated. Results Sixty-nine patients were treated (32 OCD, 37 OCP). Four had DLTs in cycle 1, two in cohort 1 (grade 4 febrile neutropenia, grade 4 pulmonary embolism) and one each in cohorts 2 (grade 3 ALT elevation) and 4 (grade 3 peripheral ischemia). Ombrabulin escalation in cohorts 2, 3 and 4 was halted at the highest planned dose (35 mg/m2). Asthenia, nausea, paresthesia, alopecia, vomiting, and stomatitis were common, as was grade 3-4 neutropenia. Ombrabulin clearance was high with a short terminal half-life and a medium volume of distribution. Pharmacokinetic analysis showed no clinically relevant drug interactions between the taxane-platinum doublet and ombrabulin or its active metabolite RPR258063, however docetaxel and carboplatin pharmacokinetics were slightly altered. One complete and 15 partial responses (10 OCD, 5 OCP; median duration 5.5 and 4.4 months, respectively) were reported. Conclusions The addition of ombrabulin to standard doses of cisplatin/docetaxel or carboplatin/paclitaxel proved feasible with manageable overlapping toxicities but appears to have limited impact on the efficacy of these doublets. Recommended combination doses are 35 mg/m2 ombrabulin with 75 mg/m2 cisplatin/75 mg/m2 docetaxel or 200 mg/m2 paclitaxel/AUC6 carboplatin, every 3 weeks.

KW - Chemotherapy

KW - Ombrabulin

KW - Platinum

KW - Taxane

KW - Vascular disrupting agent

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