Use of a targeted oncolytic poxvirus, JX-594, in patients with refractory primary or metastatic liver cancer: a phase I trial

Byeong Ho Park, Taeho Hwang, Ta Chiang Liu, Daniel Y. Sze, Jae Seok Kim, Hyuk Chan Kwon, Sung Yong Oh, Sang Young Han, Jin Han Yoon, Sook Hee Hong, Anne Moon, Kelly Speth, Chohee Park, Young Joo Ahn, Manijeh Daneshmand, Byung Geon Rhee, Herbert M. Pinedo, John C. Bell, David H. Kirn

Research output: Contribution to journalArticle

Abstract

Background: JX-594 is a targeted oncolytic poxvirus designed to selectively replicate in and destroy cancer cells with cell-cycle abnormalities and epidermal growth factor receptor (EGFR)-ras pathway activation. Direct oncolysis plus granulocyte-macrophage colony-stimulating factor (GM-CSF) expression also stimulates shutdown of tumour vasculature and antitumoral immunity. We aimed to assess intratumoral injection of JX-594 in patients with refractory primary or metastatic liver cancer. Methods: Between Jan 4, 2006, and July 4, 2007, 14 patients with histologically confirmed refractory primary or metastatic liver tumours (up to 10·9 cm total diameter) that were amenable to image-guided intratumoral injections were enrolled into this non-comparative, open-label, phase I dose-escalation trial (standard 3×3 design; two to six patients for each dose with 12-18 estimated total patients). Patients received one of four doses of intratumoral JX-594 (108 plaque-forming units [pfu], 3×108 pfu, 109 pfu, or 3×109 pfu) every 3 weeks at Dong-A University Hospital (Busan, South Korea). Patients were monitored after treatment for at least 48 h in hospital and for at least 4 weeks as out-patients. Adverse event-monitoring according to the National Cancer Institute Common Toxicity Criteria (version 3) and standard laboratory toxicity grading for haematology, liver and renal function, coagulation studies, serum chemistry, and urinalysis were done. The primary aims were to ascertain the maximum-tolerated dose (MTD) and safety of JX-594 treatment. Data were also collected on pharmacokinetics, pharmacodynamics, and efficacy. Analysis was per protocol. This study is registered with ClinicalTrials.gov, number NCT00629759. Findings: Of 22 patients with liver tumours who were assessed for eligibility, eight patients did not meet inclusion criteria. Therefore, 14 patients, including those with hepatocellular, colorectal, melanoma, and lung cancer, were enrolled. Patients were heavily pretreated (5·6 previous treatments, SD 2·8, range 2·0-12·0) and had large tumours (7·0 cm diameter, SD 2·7, range 1·8-10·9). Patients received a mean of 3·4 (SD 2·2, range 1·0-8·0) cycles of JX-594. All patients were evaluable for toxicity. All patients experienced grade I-III flu-like symptoms, and four had transient grade I-III dose-related thrombocytopenia. Grade III hyperbilirubinaemia was dose-limiting in both patients at the highest dose; the MTD was therefore 1×109 pfu. JX-594 replication-dependent dissemination in blood was shown, with resultant infection of non-injected tumour sites. GM-CSF expression resulted in grade I-III increases in neutrophil counts in four of six patients at the MTD. Tumour responses were shown in injected and non-injected tumours. Ten patients were radiographically evaluable for objective responses; non-evaluable patients had contraindications to contrast medium (n=2) or no post-treatment scans (n=2). According to Response Evaluation Criteria in Solid Tumors (RECIST), three patients had partial response, six had stable disease, and one had progressive disease. Interpretation: Intratumoral injection of JX-594 into primary or metastatic liver tumours was generally well-tolerated. Direct hyperbilirubinaemia was the dose-limiting toxicity. Safety was acceptable in the context of JX-594 replication, GM-CSF expression, systemic dissemination, and JX-594 had anti-tumoral effects against several refractory carcinomas. Phase II trials are now underway. Funding: Jennerex Biotherapeutics (San Francisco, CA, USA) and Green Cross Corporation (Giheung-Gu, Yongin, South Korea).

Original languageEnglish (US)
Pages (from-to)533-542
Number of pages10
JournalThe Lancet Oncology
Volume9
Issue number6
DOIs
StatePublished - Jun 2008
Externally publishedYes

Fingerprint

Poxviridae
Liver Neoplasms
Neoplasms
Maximum Tolerated Dose
Granulocyte-Macrophage Colony-Stimulating Factor
Republic of Korea
Hyperbilirubinemia
Liver
Injections
Safety

ASJC Scopus subject areas

  • Oncology

Cite this

Use of a targeted oncolytic poxvirus, JX-594, in patients with refractory primary or metastatic liver cancer : a phase I trial. / Park, Byeong Ho; Hwang, Taeho; Liu, Ta Chiang; Sze, Daniel Y.; Kim, Jae Seok; Kwon, Hyuk Chan; Oh, Sung Yong; Han, Sang Young; Yoon, Jin Han; Hong, Sook Hee; Moon, Anne; Speth, Kelly; Park, Chohee; Ahn, Young Joo; Daneshmand, Manijeh; Rhee, Byung Geon; Pinedo, Herbert M.; Bell, John C.; Kirn, David H.

In: The Lancet Oncology, Vol. 9, No. 6, 06.2008, p. 533-542.

Research output: Contribution to journalArticle

Park, BH, Hwang, T, Liu, TC, Sze, DY, Kim, JS, Kwon, HC, Oh, SY, Han, SY, Yoon, JH, Hong, SH, Moon, A, Speth, K, Park, C, Ahn, YJ, Daneshmand, M, Rhee, BG, Pinedo, HM, Bell, JC & Kirn, DH 2008, 'Use of a targeted oncolytic poxvirus, JX-594, in patients with refractory primary or metastatic liver cancer: a phase I trial', The Lancet Oncology, vol. 9, no. 6, pp. 533-542. https://doi.org/10.1016/S1470-2045(08)70107-4
Park, Byeong Ho ; Hwang, Taeho ; Liu, Ta Chiang ; Sze, Daniel Y. ; Kim, Jae Seok ; Kwon, Hyuk Chan ; Oh, Sung Yong ; Han, Sang Young ; Yoon, Jin Han ; Hong, Sook Hee ; Moon, Anne ; Speth, Kelly ; Park, Chohee ; Ahn, Young Joo ; Daneshmand, Manijeh ; Rhee, Byung Geon ; Pinedo, Herbert M. ; Bell, John C. ; Kirn, David H. / Use of a targeted oncolytic poxvirus, JX-594, in patients with refractory primary or metastatic liver cancer : a phase I trial. In: The Lancet Oncology. 2008 ; Vol. 9, No. 6. pp. 533-542.
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abstract = "Background: JX-594 is a targeted oncolytic poxvirus designed to selectively replicate in and destroy cancer cells with cell-cycle abnormalities and epidermal growth factor receptor (EGFR)-ras pathway activation. Direct oncolysis plus granulocyte-macrophage colony-stimulating factor (GM-CSF) expression also stimulates shutdown of tumour vasculature and antitumoral immunity. We aimed to assess intratumoral injection of JX-594 in patients with refractory primary or metastatic liver cancer. Methods: Between Jan 4, 2006, and July 4, 2007, 14 patients with histologically confirmed refractory primary or metastatic liver tumours (up to 10·9 cm total diameter) that were amenable to image-guided intratumoral injections were enrolled into this non-comparative, open-label, phase I dose-escalation trial (standard 3×3 design; two to six patients for each dose with 12-18 estimated total patients). Patients received one of four doses of intratumoral JX-594 (108 plaque-forming units [pfu], 3×108 pfu, 109 pfu, or 3×109 pfu) every 3 weeks at Dong-A University Hospital (Busan, South Korea). Patients were monitored after treatment for at least 48 h in hospital and for at least 4 weeks as out-patients. Adverse event-monitoring according to the National Cancer Institute Common Toxicity Criteria (version 3) and standard laboratory toxicity grading for haematology, liver and renal function, coagulation studies, serum chemistry, and urinalysis were done. The primary aims were to ascertain the maximum-tolerated dose (MTD) and safety of JX-594 treatment. Data were also collected on pharmacokinetics, pharmacodynamics, and efficacy. Analysis was per protocol. This study is registered with ClinicalTrials.gov, number NCT00629759. Findings: Of 22 patients with liver tumours who were assessed for eligibility, eight patients did not meet inclusion criteria. Therefore, 14 patients, including those with hepatocellular, colorectal, melanoma, and lung cancer, were enrolled. Patients were heavily pretreated (5·6 previous treatments, SD 2·8, range 2·0-12·0) and had large tumours (7·0 cm diameter, SD 2·7, range 1·8-10·9). Patients received a mean of 3·4 (SD 2·2, range 1·0-8·0) cycles of JX-594. All patients were evaluable for toxicity. All patients experienced grade I-III flu-like symptoms, and four had transient grade I-III dose-related thrombocytopenia. Grade III hyperbilirubinaemia was dose-limiting in both patients at the highest dose; the MTD was therefore 1×109 pfu. JX-594 replication-dependent dissemination in blood was shown, with resultant infection of non-injected tumour sites. GM-CSF expression resulted in grade I-III increases in neutrophil counts in four of six patients at the MTD. Tumour responses were shown in injected and non-injected tumours. Ten patients were radiographically evaluable for objective responses; non-evaluable patients had contraindications to contrast medium (n=2) or no post-treatment scans (n=2). According to Response Evaluation Criteria in Solid Tumors (RECIST), three patients had partial response, six had stable disease, and one had progressive disease. Interpretation: Intratumoral injection of JX-594 into primary or metastatic liver tumours was generally well-tolerated. Direct hyperbilirubinaemia was the dose-limiting toxicity. Safety was acceptable in the context of JX-594 replication, GM-CSF expression, systemic dissemination, and JX-594 had anti-tumoral effects against several refractory carcinomas. Phase II trials are now underway. Funding: Jennerex Biotherapeutics (San Francisco, CA, USA) and Green Cross Corporation (Giheung-Gu, Yongin, South Korea).",
author = "Park, {Byeong Ho} and Taeho Hwang and Liu, {Ta Chiang} and Sze, {Daniel Y.} and Kim, {Jae Seok} and Kwon, {Hyuk Chan} and Oh, {Sung Yong} and Han, {Sang Young} and Yoon, {Jin Han} and Hong, {Sook Hee} and Anne Moon and Kelly Speth and Chohee Park and Ahn, {Young Joo} and Manijeh Daneshmand and Rhee, {Byung Geon} and Pinedo, {Herbert M.} and Bell, {John C.} and Kirn, {David H.}",
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TY - JOUR

T1 - Use of a targeted oncolytic poxvirus, JX-594, in patients with refractory primary or metastatic liver cancer

T2 - a phase I trial

AU - Park, Byeong Ho

AU - Hwang, Taeho

AU - Liu, Ta Chiang

AU - Sze, Daniel Y.

AU - Kim, Jae Seok

AU - Kwon, Hyuk Chan

AU - Oh, Sung Yong

AU - Han, Sang Young

AU - Yoon, Jin Han

AU - Hong, Sook Hee

AU - Moon, Anne

AU - Speth, Kelly

AU - Park, Chohee

AU - Ahn, Young Joo

AU - Daneshmand, Manijeh

AU - Rhee, Byung Geon

AU - Pinedo, Herbert M.

AU - Bell, John C.

AU - Kirn, David H.

PY - 2008/6

Y1 - 2008/6

N2 - Background: JX-594 is a targeted oncolytic poxvirus designed to selectively replicate in and destroy cancer cells with cell-cycle abnormalities and epidermal growth factor receptor (EGFR)-ras pathway activation. Direct oncolysis plus granulocyte-macrophage colony-stimulating factor (GM-CSF) expression also stimulates shutdown of tumour vasculature and antitumoral immunity. We aimed to assess intratumoral injection of JX-594 in patients with refractory primary or metastatic liver cancer. Methods: Between Jan 4, 2006, and July 4, 2007, 14 patients with histologically confirmed refractory primary or metastatic liver tumours (up to 10·9 cm total diameter) that were amenable to image-guided intratumoral injections were enrolled into this non-comparative, open-label, phase I dose-escalation trial (standard 3×3 design; two to six patients for each dose with 12-18 estimated total patients). Patients received one of four doses of intratumoral JX-594 (108 plaque-forming units [pfu], 3×108 pfu, 109 pfu, or 3×109 pfu) every 3 weeks at Dong-A University Hospital (Busan, South Korea). Patients were monitored after treatment for at least 48 h in hospital and for at least 4 weeks as out-patients. Adverse event-monitoring according to the National Cancer Institute Common Toxicity Criteria (version 3) and standard laboratory toxicity grading for haematology, liver and renal function, coagulation studies, serum chemistry, and urinalysis were done. The primary aims were to ascertain the maximum-tolerated dose (MTD) and safety of JX-594 treatment. Data were also collected on pharmacokinetics, pharmacodynamics, and efficacy. Analysis was per protocol. This study is registered with ClinicalTrials.gov, number NCT00629759. Findings: Of 22 patients with liver tumours who were assessed for eligibility, eight patients did not meet inclusion criteria. Therefore, 14 patients, including those with hepatocellular, colorectal, melanoma, and lung cancer, were enrolled. Patients were heavily pretreated (5·6 previous treatments, SD 2·8, range 2·0-12·0) and had large tumours (7·0 cm diameter, SD 2·7, range 1·8-10·9). Patients received a mean of 3·4 (SD 2·2, range 1·0-8·0) cycles of JX-594. All patients were evaluable for toxicity. All patients experienced grade I-III flu-like symptoms, and four had transient grade I-III dose-related thrombocytopenia. Grade III hyperbilirubinaemia was dose-limiting in both patients at the highest dose; the MTD was therefore 1×109 pfu. JX-594 replication-dependent dissemination in blood was shown, with resultant infection of non-injected tumour sites. GM-CSF expression resulted in grade I-III increases in neutrophil counts in four of six patients at the MTD. Tumour responses were shown in injected and non-injected tumours. Ten patients were radiographically evaluable for objective responses; non-evaluable patients had contraindications to contrast medium (n=2) or no post-treatment scans (n=2). According to Response Evaluation Criteria in Solid Tumors (RECIST), three patients had partial response, six had stable disease, and one had progressive disease. Interpretation: Intratumoral injection of JX-594 into primary or metastatic liver tumours was generally well-tolerated. Direct hyperbilirubinaemia was the dose-limiting toxicity. Safety was acceptable in the context of JX-594 replication, GM-CSF expression, systemic dissemination, and JX-594 had anti-tumoral effects against several refractory carcinomas. Phase II trials are now underway. Funding: Jennerex Biotherapeutics (San Francisco, CA, USA) and Green Cross Corporation (Giheung-Gu, Yongin, South Korea).

AB - Background: JX-594 is a targeted oncolytic poxvirus designed to selectively replicate in and destroy cancer cells with cell-cycle abnormalities and epidermal growth factor receptor (EGFR)-ras pathway activation. Direct oncolysis plus granulocyte-macrophage colony-stimulating factor (GM-CSF) expression also stimulates shutdown of tumour vasculature and antitumoral immunity. We aimed to assess intratumoral injection of JX-594 in patients with refractory primary or metastatic liver cancer. Methods: Between Jan 4, 2006, and July 4, 2007, 14 patients with histologically confirmed refractory primary or metastatic liver tumours (up to 10·9 cm total diameter) that were amenable to image-guided intratumoral injections were enrolled into this non-comparative, open-label, phase I dose-escalation trial (standard 3×3 design; two to six patients for each dose with 12-18 estimated total patients). Patients received one of four doses of intratumoral JX-594 (108 plaque-forming units [pfu], 3×108 pfu, 109 pfu, or 3×109 pfu) every 3 weeks at Dong-A University Hospital (Busan, South Korea). Patients were monitored after treatment for at least 48 h in hospital and for at least 4 weeks as out-patients. Adverse event-monitoring according to the National Cancer Institute Common Toxicity Criteria (version 3) and standard laboratory toxicity grading for haematology, liver and renal function, coagulation studies, serum chemistry, and urinalysis were done. The primary aims were to ascertain the maximum-tolerated dose (MTD) and safety of JX-594 treatment. Data were also collected on pharmacokinetics, pharmacodynamics, and efficacy. Analysis was per protocol. This study is registered with ClinicalTrials.gov, number NCT00629759. Findings: Of 22 patients with liver tumours who were assessed for eligibility, eight patients did not meet inclusion criteria. Therefore, 14 patients, including those with hepatocellular, colorectal, melanoma, and lung cancer, were enrolled. Patients were heavily pretreated (5·6 previous treatments, SD 2·8, range 2·0-12·0) and had large tumours (7·0 cm diameter, SD 2·7, range 1·8-10·9). Patients received a mean of 3·4 (SD 2·2, range 1·0-8·0) cycles of JX-594. All patients were evaluable for toxicity. All patients experienced grade I-III flu-like symptoms, and four had transient grade I-III dose-related thrombocytopenia. Grade III hyperbilirubinaemia was dose-limiting in both patients at the highest dose; the MTD was therefore 1×109 pfu. JX-594 replication-dependent dissemination in blood was shown, with resultant infection of non-injected tumour sites. GM-CSF expression resulted in grade I-III increases in neutrophil counts in four of six patients at the MTD. Tumour responses were shown in injected and non-injected tumours. Ten patients were radiographically evaluable for objective responses; non-evaluable patients had contraindications to contrast medium (n=2) or no post-treatment scans (n=2). According to Response Evaluation Criteria in Solid Tumors (RECIST), three patients had partial response, six had stable disease, and one had progressive disease. Interpretation: Intratumoral injection of JX-594 into primary or metastatic liver tumours was generally well-tolerated. Direct hyperbilirubinaemia was the dose-limiting toxicity. Safety was acceptable in the context of JX-594 replication, GM-CSF expression, systemic dissemination, and JX-594 had anti-tumoral effects against several refractory carcinomas. Phase II trials are now underway. Funding: Jennerex Biotherapeutics (San Francisco, CA, USA) and Green Cross Corporation (Giheung-Gu, Yongin, South Korea).

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