A Phase I Trial of TNFerade Biologic in Patients with Soft Tissue Sarcoma in the Extremities

• Published in: Clinical cancer research Vol. 10; no. 17; pp. 5747 - 5753
• Main Authors: MUNDT, Arno J, VIJAYAKUMAR, Srinivasan, KESSLER, Paul D, RASMUSSEN, Henrik S, WARSO, Michael, KUFE, Donald W, TAPAS DAS GUPTA, WEICHSELBAUM, Ralph R, NEMUNAITIS, John, SANDLER, Alan, SCHWARTZ, Herbert, HANNA, Nader, PEABODY, Terrence, SENZER, Neil, CHU, Karen, RASMUSSEN, Camilla S
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01.09.2004
• Subjects: Adenoviridae - genetics; Adult; Aged; Aged, 80 and over; Antineoplastic agents; Antineoplastic Agents - therapeutic use; Biological and medical sciences; Combined Modality Therapy; Dose-Response Relationship, Drug; Dose-Response Relationship, Radiation; Extremities; Female; Humans; Male; Maximum Tolerated Dose; Medical sciences; Middle Aged; Pharmacology. Drug treatments; Sarcoma - drug therapy; Sarcoma - genetics; Sarcoma - radiotherapy; Treatment Outcome; Tumor Necrosis Factor-alpha - therapeutic use; Tumors; Human; Phase I trial; Soft tissue; Malignant tumor; Sarcoma
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-04-0296

Purpose: TNFerade is a second-generation replication-deficient adenovector carrying a transgene encoding human tumor necrosis factor α under control of a radiation- induced promoter. The objective of this study was to assess the tolerance of combining TNFerade and radiation therapy in patients with soft tissue sarcomas of the extremity. Experimental Design: TNFerade was administered in combination with single-daily fractionated radiation therapy in 14 patients with soft tissue sarcoma of the extremities. Three escalating dose levels of TNFerade (4 × 10 9 −4 × 10 11 particle units) were planned, given in 1 log increments by intratumoral injections, twice weekly during week 1 and once weekly during weeks 2–5 of radiation therapy. Results: TNFerade was well tolerated with no dose-limiting toxicities noted. Grade 1–2 chills (50.0%), fever (43.0%), fatigue (36.0%), and flu-like symptoms (21.0%) were the most common side effects. Serum-tumor necrosis factor α levels were low in all of the patients (<15 pg/mL). No patients had virus-detected blood, sputum, or urine cultures. Of the 13 evaluable patients, 11 received TNFerade preoperatively, and 2 received the treatment for palliation. Eleven patients (85%) showed objective or pathological tumor responses (2 complete and 9 partial), and 1 had stable disease. Partial responses were achieved despite some of these tumors being very large (up to 675 cm 2 ). Of the 11 patients who underwent surgery, 10 (91%) showed a pathological complete response/partial response. Conclusion: TNFerade + radiation therapy was well tolerated in the treatment of patients with soft-tissue sarcoma of the extremity. The high number of objective responses observed warrants additional studies of this approach in a larger controlled prospective trial.