Phase I-II trial of ONYX-015 in combination with MAP chemotherapy in patients with advanced sarcomas

Evanthia Galanis, Scott Heitaka Okuno, A. G. Nascimento, B. D. Lewis, R. A. Lee, A. M. Oliveira, Jeff A Sloan, P. Atherton, J. H. Edmonson, C. Erlichman, B. Randlev, Q. Wang, S. Freeman, J. Rubin

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Abstract

ONYX-015 is a provisionally replication competent adenovirus with oncolytic activity in cells with malfunctioning p53. Sarcomas represent a rational target for this approach given the high frequency of p53 mutations (40-75%) and MDM-2 amplification (10-30%). We, therefore, undertook a phase I/II study of ONYX-015, days 1-5 every month administered intratumorally under radiographic guidance, in combination with MAP (mitomycin-C, doxorubicin, cisplatin) chemotherapy in patients with advanced sarcoma. Six patients were treated. Injected lesions included liver metastases in four patients and chest wall metastases in two patients. Sarcoma histologies were gastrointestinal stromal tumors (GIST, two patients), leiomyosarcoma (two patients), liposarcoma (one patient), and malignant peripheral nerve sheath tumor (1 patient). Dose escalation was performed from 109 plaque forming units (PFU)/dose (total dose of 5 × 109 PFU/cycle) to 1010 PFU/dose (total dose of 5 × 1010 PFU/cycle) without dose-limiting toxicity being encountered. Immunohistochemistry of the metastatic lesions prior to treatment showed that five out of six patients were positive for p53, while two patients also had mdm-2 overexpression. Adenoviral replication was detected in two out of six patient biopsies on day 5 of the first cycle, by in situ hybridization (ISH). Both patients were treated at the highest dose level. ONYX-015 viral DNA was detected by quantitative PCR in the plasma of 5/6 patients on day 5 of the first cycle, and up to day 12 (7 days after the last viral dose) in one patient who had extended sampling for viral kinetics performed, suggesting viral replication in sarcoma tissue. One patient with p53 mutation and MDM-2 amplification achieved a partial response to treatment that lasted 11 months. In conclusion, intratumoral administration of ONYX-015 in combination with MAP chemotherapy is well tolerated with no significant toxicity due to ONYX-015 being encountered. Detection of viral DNA in post treatment tumor specimens by ISH and detection of the ONYX-015 genome in the peripheral blood by quantitative PCR, up to 7 days after the last viral dose provide evidence for adenoviral replication. There was evidence of antitumor activity in one out of six patients. Further investigation of this approach in patients with recurrent sarcomas is warranted.

Original languageEnglish (US)
Pages (from-to)437-445
Number of pages9
JournalGene Therapy
Volume12
Issue number5
DOIs
StatePublished - Mar 2005

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Sarcoma
Drug Therapy
ONYX015
Viral DNA
In Situ Hybridization
Neoplasm Metastasis
Liposarcoma
Polymerase Chain Reaction
Gastrointestinal Stromal Tumors
Leiomyosarcoma
Neurilemmoma
Mitomycin
Thoracic Wall
Mutation Rate
Adenoviridae
Doxorubicin
Cisplatin
Histology

Keywords

  • MAP
  • ONYX-015
  • Sarcomas
  • Virotherapy

ASJC Scopus subject areas

  • Genetics

Cite this

Phase I-II trial of ONYX-015 in combination with MAP chemotherapy in patients with advanced sarcomas. / Galanis, Evanthia; Okuno, Scott Heitaka; Nascimento, A. G.; Lewis, B. D.; Lee, R. A.; Oliveira, A. M.; Sloan, Jeff A; Atherton, P.; Edmonson, J. H.; Erlichman, C.; Randlev, B.; Wang, Q.; Freeman, S.; Rubin, J.

In: Gene Therapy, Vol. 12, No. 5, 03.2005, p. 437-445.

Research output: Contribution to journalArticle

Galanis, E, Okuno, SH, Nascimento, AG, Lewis, BD, Lee, RA, Oliveira, AM, Sloan, JA, Atherton, P, Edmonson, JH, Erlichman, C, Randlev, B, Wang, Q, Freeman, S & Rubin, J 2005, 'Phase I-II trial of ONYX-015 in combination with MAP chemotherapy in patients with advanced sarcomas', Gene Therapy, vol. 12, no. 5, pp. 437-445. https://doi.org/10.1038/sj.gt.3302436
Galanis, Evanthia ; Okuno, Scott Heitaka ; Nascimento, A. G. ; Lewis, B. D. ; Lee, R. A. ; Oliveira, A. M. ; Sloan, Jeff A ; Atherton, P. ; Edmonson, J. H. ; Erlichman, C. ; Randlev, B. ; Wang, Q. ; Freeman, S. ; Rubin, J. / Phase I-II trial of ONYX-015 in combination with MAP chemotherapy in patients with advanced sarcomas. In: Gene Therapy. 2005 ; Vol. 12, No. 5. pp. 437-445.
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AU - Atherton, P.

AU - Edmonson, J. H.

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N2 - ONYX-015 is a provisionally replication competent adenovirus with oncolytic activity in cells with malfunctioning p53. Sarcomas represent a rational target for this approach given the high frequency of p53 mutations (40-75%) and MDM-2 amplification (10-30%). We, therefore, undertook a phase I/II study of ONYX-015, days 1-5 every month administered intratumorally under radiographic guidance, in combination with MAP (mitomycin-C, doxorubicin, cisplatin) chemotherapy in patients with advanced sarcoma. Six patients were treated. Injected lesions included liver metastases in four patients and chest wall metastases in two patients. Sarcoma histologies were gastrointestinal stromal tumors (GIST, two patients), leiomyosarcoma (two patients), liposarcoma (one patient), and malignant peripheral nerve sheath tumor (1 patient). Dose escalation was performed from 109 plaque forming units (PFU)/dose (total dose of 5 × 109 PFU/cycle) to 1010 PFU/dose (total dose of 5 × 1010 PFU/cycle) without dose-limiting toxicity being encountered. Immunohistochemistry of the metastatic lesions prior to treatment showed that five out of six patients were positive for p53, while two patients also had mdm-2 overexpression. Adenoviral replication was detected in two out of six patient biopsies on day 5 of the first cycle, by in situ hybridization (ISH). Both patients were treated at the highest dose level. ONYX-015 viral DNA was detected by quantitative PCR in the plasma of 5/6 patients on day 5 of the first cycle, and up to day 12 (7 days after the last viral dose) in one patient who had extended sampling for viral kinetics performed, suggesting viral replication in sarcoma tissue. One patient with p53 mutation and MDM-2 amplification achieved a partial response to treatment that lasted 11 months. In conclusion, intratumoral administration of ONYX-015 in combination with MAP chemotherapy is well tolerated with no significant toxicity due to ONYX-015 being encountered. Detection of viral DNA in post treatment tumor specimens by ISH and detection of the ONYX-015 genome in the peripheral blood by quantitative PCR, up to 7 days after the last viral dose provide evidence for adenoviral replication. There was evidence of antitumor activity in one out of six patients. Further investigation of this approach in patients with recurrent sarcomas is warranted.

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