Phase I/II trial of carboplatin and paclitaxel chemotherapy in combination with intravenous oncolytic reovirus in patients with advanced malignancies

Eleni M. Karapanagiotou, Victoria Roulstone, Katie Twigger, Mercel Ball, MaryAnne Tanay, Chris Nutting, Kate Newbold, Martin E. Gore, James Larkin, Konstantinos N. Syrigos, Matt Coffey, Brad Thompson, Karl Mettinger, Richard Geoffrey Vile, Hardev S. Pandha, Geoff D. Hall, Alan A. Melcher, John Chester, Kevin J. Harrington

Research output: Contribution to journalArticle

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Abstract

Purpose: Reovirus type 3 Dearing (RT3D) replicates preferentially in Ras-activated cancers. RT3D shows synergistic in vitro cytotoxicity in combination with platins and taxanes. The purpose of this phase I/II study was to assess RT3D combined with carboplatin/paclitaxel in patients with advanced cancers. Experimental Design: Patients were initially treated in a dose-escalating, phase I trial with intravenous RT3D days 1 to 5, carboplatin [area under curve (AUC) 5, day 1] and paclitaxel (175 mg/m 2, day 1) 3-weekly. RT3D was escalated through three dose levels: 3 × 10 9, 1 × 10 10, and 3 × 10 10 TCID 50 in cohorts of three. Primary endpoints were to define the maximum tolerated dose and dose-limiting toxicity and to recommend a dose for phase II studies. Secondary endpoints included pharmacokinetics, immune response, and antitumor activity. A subsequent phase II study using the 3 × 10 10 TCID 50 dose characterized the response rate in patients with head and neck cancer. Results: Thirty-one heavily pretreated patients received study therapy. There were no dose-limiting toxicities during dose-escalation and most toxicities were grade I/II. Overall effectiveness rates were as follows: one patient had a complete response (3.8%), six patients (23.1%) had partial response, two patients (7.6%) had major clinical responses clinically evaluated in radiation pretreated lesions which are not evaluable by Response Evaluation Criteria in Solid Tumors (RECIST), nine patients (34.6%) had stable disease, and eight patients (30.8%) had disease progression. Viral shedding was minimal and antiviral immune responses were attenuated compared with previous single-agent data for RT3D. Conclusions: The combination of RT3D plus carboplatin/paclitaxel is well tolerated with evidence of activity in cancer of the head and neck. A randomized phase III study is currently open for recruitment.

Original languageEnglish (US)
Pages (from-to)2080-2089
Number of pages10
JournalClinical Cancer Research
Volume18
Issue number7
DOIs
StatePublished - Apr 1 2012
Externally publishedYes

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Mammalian orthoreovirus 3
Carboplatin
Paclitaxel
Combination Drug Therapy
Neoplasms
Head and Neck Neoplasms
Virus Shedding
Taxoids
Maximum Tolerated Dose
Area Under Curve
Antiviral Agents
Disease Progression
Research Design
Pharmacokinetics
Radiation

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Phase I/II trial of carboplatin and paclitaxel chemotherapy in combination with intravenous oncolytic reovirus in patients with advanced malignancies. / Karapanagiotou, Eleni M.; Roulstone, Victoria; Twigger, Katie; Ball, Mercel; Tanay, MaryAnne; Nutting, Chris; Newbold, Kate; Gore, Martin E.; Larkin, James; Syrigos, Konstantinos N.; Coffey, Matt; Thompson, Brad; Mettinger, Karl; Vile, Richard Geoffrey; Pandha, Hardev S.; Hall, Geoff D.; Melcher, Alan A.; Chester, John; Harrington, Kevin J.

In: Clinical Cancer Research, Vol. 18, No. 7, 01.04.2012, p. 2080-2089.

Research output: Contribution to journalArticle

Karapanagiotou, EM, Roulstone, V, Twigger, K, Ball, M, Tanay, M, Nutting, C, Newbold, K, Gore, ME, Larkin, J, Syrigos, KN, Coffey, M, Thompson, B, Mettinger, K, Vile, RG, Pandha, HS, Hall, GD, Melcher, AA, Chester, J & Harrington, KJ 2012, 'Phase I/II trial of carboplatin and paclitaxel chemotherapy in combination with intravenous oncolytic reovirus in patients with advanced malignancies', Clinical Cancer Research, vol. 18, no. 7, pp. 2080-2089. https://doi.org/10.1158/1078-0432.CCR-11-2181
Karapanagiotou, Eleni M. ; Roulstone, Victoria ; Twigger, Katie ; Ball, Mercel ; Tanay, MaryAnne ; Nutting, Chris ; Newbold, Kate ; Gore, Martin E. ; Larkin, James ; Syrigos, Konstantinos N. ; Coffey, Matt ; Thompson, Brad ; Mettinger, Karl ; Vile, Richard Geoffrey ; Pandha, Hardev S. ; Hall, Geoff D. ; Melcher, Alan A. ; Chester, John ; Harrington, Kevin J. / Phase I/II trial of carboplatin and paclitaxel chemotherapy in combination with intravenous oncolytic reovirus in patients with advanced malignancies. In: Clinical Cancer Research. 2012 ; Vol. 18, No. 7. pp. 2080-2089.
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abstract = "Purpose: Reovirus type 3 Dearing (RT3D) replicates preferentially in Ras-activated cancers. RT3D shows synergistic in vitro cytotoxicity in combination with platins and taxanes. The purpose of this phase I/II study was to assess RT3D combined with carboplatin/paclitaxel in patients with advanced cancers. Experimental Design: Patients were initially treated in a dose-escalating, phase I trial with intravenous RT3D days 1 to 5, carboplatin [area under curve (AUC) 5, day 1] and paclitaxel (175 mg/m 2, day 1) 3-weekly. RT3D was escalated through three dose levels: 3 × 10 9, 1 × 10 10, and 3 × 10 10 TCID 50 in cohorts of three. Primary endpoints were to define the maximum tolerated dose and dose-limiting toxicity and to recommend a dose for phase II studies. Secondary endpoints included pharmacokinetics, immune response, and antitumor activity. A subsequent phase II study using the 3 × 10 10 TCID 50 dose characterized the response rate in patients with head and neck cancer. Results: Thirty-one heavily pretreated patients received study therapy. There were no dose-limiting toxicities during dose-escalation and most toxicities were grade I/II. Overall effectiveness rates were as follows: one patient had a complete response (3.8{\%}), six patients (23.1{\%}) had partial response, two patients (7.6{\%}) had major clinical responses clinically evaluated in radiation pretreated lesions which are not evaluable by Response Evaluation Criteria in Solid Tumors (RECIST), nine patients (34.6{\%}) had stable disease, and eight patients (30.8{\%}) had disease progression. Viral shedding was minimal and antiviral immune responses were attenuated compared with previous single-agent data for RT3D. Conclusions: The combination of RT3D plus carboplatin/paclitaxel is well tolerated with evidence of activity in cancer of the head and neck. A randomized phase III study is currently open for recruitment.",
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T1 - Phase I/II trial of carboplatin and paclitaxel chemotherapy in combination with intravenous oncolytic reovirus in patients with advanced malignancies

AU - Karapanagiotou, Eleni M.

AU - Roulstone, Victoria

AU - Twigger, Katie

AU - Ball, Mercel

AU - Tanay, MaryAnne

AU - Nutting, Chris

AU - Newbold, Kate

AU - Gore, Martin E.

AU - Larkin, James

AU - Syrigos, Konstantinos N.

AU - Coffey, Matt

AU - Thompson, Brad

AU - Mettinger, Karl

AU - Vile, Richard Geoffrey

AU - Pandha, Hardev S.

AU - Hall, Geoff D.

AU - Melcher, Alan A.

AU - Chester, John

AU - Harrington, Kevin J.

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N2 - Purpose: Reovirus type 3 Dearing (RT3D) replicates preferentially in Ras-activated cancers. RT3D shows synergistic in vitro cytotoxicity in combination with platins and taxanes. The purpose of this phase I/II study was to assess RT3D combined with carboplatin/paclitaxel in patients with advanced cancers. Experimental Design: Patients were initially treated in a dose-escalating, phase I trial with intravenous RT3D days 1 to 5, carboplatin [area under curve (AUC) 5, day 1] and paclitaxel (175 mg/m 2, day 1) 3-weekly. RT3D was escalated through three dose levels: 3 × 10 9, 1 × 10 10, and 3 × 10 10 TCID 50 in cohorts of three. Primary endpoints were to define the maximum tolerated dose and dose-limiting toxicity and to recommend a dose for phase II studies. Secondary endpoints included pharmacokinetics, immune response, and antitumor activity. A subsequent phase II study using the 3 × 10 10 TCID 50 dose characterized the response rate in patients with head and neck cancer. Results: Thirty-one heavily pretreated patients received study therapy. There were no dose-limiting toxicities during dose-escalation and most toxicities were grade I/II. Overall effectiveness rates were as follows: one patient had a complete response (3.8%), six patients (23.1%) had partial response, two patients (7.6%) had major clinical responses clinically evaluated in radiation pretreated lesions which are not evaluable by Response Evaluation Criteria in Solid Tumors (RECIST), nine patients (34.6%) had stable disease, and eight patients (30.8%) had disease progression. Viral shedding was minimal and antiviral immune responses were attenuated compared with previous single-agent data for RT3D. Conclusions: The combination of RT3D plus carboplatin/paclitaxel is well tolerated with evidence of activity in cancer of the head and neck. A randomized phase III study is currently open for recruitment.

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