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1.
J Clin Oncol ; 19(2): 289-98, 2001 Jan 15.
Article in English | MEDLINE | ID: mdl-11208818

ABSTRACT

PURPOSE: To determine the safety, humoral immune response replication, and activity of multiple intratumoral injections of ONYX-015 (replication selective adenovirus) in patients with recurrent squamous cell carcinoma of the head and neck (SCCHN). PATIENTS AND METHODS: This phase II trial enrolled patients with SCCHN who had recurrence/relapse after prior conventional treatment. Patients received ONYX-015 at a dose of 2 x 10(11) particles via intratumoral injection for either 5 consecutive days (standard) or twice daily for 2 consecutive weeks (hyperfractionated) during a 21-day cycle. Patients were monitored for tumor response, toxicity, and antibody formation. RESULTS: Forty patients (30 standard and 10 hyperfractionated) received 533 injections of ONYX-015. Standard treatment resulted in 14% partial to complete regression, 41% stable disease, and 45% progressive disease rates. Hyperfractionated treatment resulted in 10% complete response, 62% stable disease, and 29% progressive disease rates. Treatment-related toxicity included mild to moderate fever (67% overall) and injection site pain (47% on the standard regimen, 80% on the hyperfractionated regimen). Detectable circulating ONYX-015 genome suggestive of intratumoral replication was identified in 41% of tested patients on days 5 and 6 of cycle 1; 9% of patients had evidence of viral replication 10 days after injection during cycle 1, and no patients had evidence of replication > or = 22 days after injection. CONCLUSION: ONYX-015 can be safely administered via intratumoral injection to patients with recurrent/refractory SCCHN. ONYX-015 viremia is transient. Evidence of modest antitumoral activity is suggested.


Subject(s)
Adenoviruses, Human , Carcinoma, Squamous Cell/therapy , Genetic Therapy , Head and Neck Neoplasms/therapy , Neoplasm Recurrence, Local/therapy , Adenovirus E1B Proteins , Adenoviruses, Human/genetics , Adenoviruses, Human/physiology , Adult , Aged , Carcinoma, Squamous Cell/genetics , Female , Gene Expression Regulation, Neoplastic , Genes, p53 , Head and Neck Neoplasms/genetics , Humans , Injections, Intralesional , Male , Middle Aged , Neoplasm Recurrence, Local/genetics , Neutralization Tests , Remission Induction , Viremia , Virus Replication
2.
Gene Ther ; 8(21): 1618-26, 2001 Nov.
Article in English | MEDLINE | ID: mdl-11895000

ABSTRACT

Both replication-incompetent and replication-selective adenoviruses are being developed for the treatment of cancer and other diseases. Concerns have been raised about the safety of intra-vascular adenovirus administration following a patient death on a clinical trial with a replication-defective adenovirus. In addition, the feasibility of vascular delivery to distant tumors has been questioned. dl1520 (ONYX-015) is a replication-selective adenovirus that has previously shown safety and antitumoral activity following intratumoral injection. This is the first report of intra-vascular administration with a genetically engineered, replication-selective virus. A phase I dose-escalation trial was performed in patients with liver-predominant gastrointestinal carcinoma (n = 11 total; primarily colorectal). dl1520 was infused into the hepatic artery at doses of 2 x 10(8)-2 x 10(1)2 particles for two cycles (days 1 and 8). Subsequent cycles of dl1520 were administered in combination with intravenous 5-fluorouracil (5-FU) and leucovorin. No dose-limiting toxicity, maximally tolerated dose or treatment-emergent clinical hepatotoxicity were identified following dl1520 infusion. Mild to moderate fever, rigors and fatigue were the most common adverse events. Antibody titers increased significantly in all patients. Viral replication was detectable in patients receiving the highest two doses. An objective response was demonstrated in combination with chemotherapy in a patient who was refractory to both 5-FU and dl1520 as single agents. Therefore, hepatic artery infusion of the attenuated adenovirus dl1520 was well-tolerated at doses resulting in infection, replication and chemotherapy-associated antitumoral activity.


Subject(s)
Adenoviridae/genetics , Colorectal Neoplasms/therapy , Genetic Therapy/methods , Liver Neoplasms/secondary , Liver Neoplasms/therapy , Adenovirus E1B Proteins/genetics , Aged , Antibodies, Viral/blood , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Colorectal Neoplasms/immunology , Combined Modality Therapy , Female , Fluorouracil/administration & dosage , Gene Deletion , Genetic Therapy/adverse effects , Genome, Viral , Hepatic Artery , Humans , Infusions, Intra-Arterial , Leucovorin/administration & dosage , Liver Neoplasms/drug therapy , Male , Maximum Tolerated Dose , Middle Aged , Virus Replication/genetics
3.
Cancer Res ; 60(22): 6359-66, 2000 Nov 15.
Article in English | MEDLINE | ID: mdl-11103798

ABSTRACT

ONYX-015 is an E1B-55kDa gene-deleted adenovirus engineered to selectively replicate in and lyse p53-deficient cancer cells. To evaluate the selectivity of ONYX-015 replication and cytopathic effects for the first time in humans, we carried out a Phase II clinical testing of intratumoral and peritumoral ONYX-015 injection in 37 patients with recurrent head and neck carcinoma. Patients received ONYX-015 at a daily dose of 1 x 10(10) plaque-forming units (pfu) via intratumoral injection for 5 days during week 1 of each 3-week cycle (n = 30; cohort A), or 1 x 10(10) pfu twice a day for 10 days during weeks 1 and 2 of each 3-week cycle. Posttreatment biopsies documented selective ONYX-015 presence and/or replication in the tumor tissue of 7 of 11 patients biopsied on days 5-14, but not in immediately adjacent normal tissue (0 of 11 patients; P = 0.01). Tissue destruction was also highly selective; significant tumor regression (>50%) occurred in 21% of evaluable patients, whereas no toxicity to injected normal peritumoral tissues was demonstrated. p53 mutant tumors were significantly more likely to undergo ONYX-015-induced necrosis (7 of 12) than were p53 wild-type tumors (0 of 7; P = 0.017). High neutralizing antibody titers did not prevent infection and/or replication within tumors. ONYX-015 is the first genetically engineered replication-competent virus to demonstrate selective intratumoral replication and necrosis in patients. This agent demonstrates the promise of replication-selective viruses as a novel therapeutic platform against cancer.


Subject(s)
Adenoviruses, Human/physiology , Carcinoma, Squamous Cell/therapy , Genes, p53/genetics , Head and Neck Neoplasms/therapy , Neoplasm Recurrence, Local/therapy , Adenovirus E1B Proteins/genetics , Adenoviruses, Human/genetics , Aged , Antibodies, Neoplasm/biosynthesis , Antibodies, Neoplasm/blood , Biopsy , Carcinoma, Squamous Cell/genetics , Carcinoma, Squamous Cell/pathology , Carcinoma, Squamous Cell/virology , Female , Head and Neck Neoplasms/genetics , Head and Neck Neoplasms/pathology , Head and Neck Neoplasms/virology , Humans , Injections, Intralesional , Male , Middle Aged , Mutation , Neoplasm Recurrence, Local/genetics , Neoplasm Recurrence, Local/pathology , Neoplasm Recurrence, Local/virology , Virus Replication
4.
Nat Med ; 6(8): 879-85, 2000 Aug.
Article in English | MEDLINE | ID: mdl-10932224

ABSTRACT

ONYX-015 is an adenovirus with the E1B 55-kDa gene deleted, engineered to selectively replicate in and lyse p53-deficient cancer cells while sparing normal cells. Although ONYX-015 and chemotherapy have demonstrated anti-tumoral activity in patients with recurrent head and neck cancer, disease recurs rapidly with either therapy alone. We undertook a phase II trial of a combination of intratumoral ONYX-015 injection with cisplatin and 5-fluorouracil in patients with recurrent squamous cell cancer of the head and neck. There were substantial objective responses, including a high proportion of complete responses. By 6 months, none of the responding tumors had progressed, whereas all non-injected tumors treated with chemotherapy alone had progressed. The toxic effects that occurred were acceptable. Tumor biopsies obtained after treatment showed tumor-selective viral replication and necrosis induction.


Subject(s)
Adenoviruses, Human/genetics , Cisplatin/therapeutic use , Fluorouracil/therapeutic use , Genetic Therapy/methods , Head and Neck Neoplasms/drug therapy , Head and Neck Neoplasms/therapy , Neoplasm Recurrence, Local/drug therapy , Neoplasm Recurrence, Local/therapy , Adenoviruses, Human/physiology , Adult , Aged , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carcinoma, Squamous Cell/drug therapy , Carcinoma, Squamous Cell/pathology , Carcinoma, Squamous Cell/therapy , Combined Modality Therapy , Female , Genetic Therapy/adverse effects , Head and Neck Neoplasms/pathology , Humans , Male , Middle Aged , Neoplasm Recurrence, Local/pathology , Virus Replication
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