Prospective multicenter phase II trial of systemic ADH-1 in combination with melphalan via isolated limb infusion in patients with advanced extremity melanoma

Georgia M. Beasley, Jonathan C. Riboh, Christina K. Augustine, Jonathan S. Zager, Steven N. Hochwald, Stephen R. Grobmyer, Bercedis Peterson, Richard Royal, Merrick I. Ross, Douglas Tyler

Research output: Contribution to journalArticle

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Abstract

Purpose: Isolated limb infusion (ILI) with melphalan (M-ILI) dosing corrected for ideal body weight (IBW) is a well-tolerated treatment for patients with in-transit melanoma with a 29% complete response rate. ADH-1 is a cyclic pentapeptide that disrupts N-cadherin adhesion complexes. In a preclinical animal model, systemic ADH-1 given with regional melphalan demonstrated synergistic antitumor activity, and in a phase I trial with M-ILI it had minimal toxicity. Patients and Methods: Patients with American Joint Committee on Cancer (AJCC) stage IIIB or IIIC extremity melanoma were treated with 4,000 mg of ADH-1, administered systemically on days 1 and 8, and with M-ILI corrected for IBW on day 1. Drug pharmacokinetics and N-cadherin immunohistochemical staining were performed on pretreatment tumor. The primary end point was response at 12 weeks determined by Response Evaluation Criteria in Solid Tumors (RECIST) criteria. Results: In all, 45 patients were enrolled over 15 months at four institutions. In-field responses included 17 patients with complete responses (CRs; 38%), 10 with partial responses (22%), six with stable disease (13%), eight with progressive disease (18%), and four (9%) who were not evaluable. Median duration of in-field response among the 17 CRs was 5 months, and median time to in-field progression among 41 evaluable patients was 4.6 months (95% CI, 4.0 to 7.1 months). N-cadherin was detected in 20 (69%) of 29 tumor samples. Grade 4 toxicities included creatinine phosphokinase increase (four patients), arterial injury (one), neutropenia (one), and pneumonitis (one). Conclusion: To the best of our knowledge, this phase II trial is the first prospective multicenter ILI trial and the first to incorporate a targeted agent in an attempt to augment antitumor responses to regional chemotherapy. Although targeting N-cadherin may improve melanoma sensitivity to chemotherapy, no difference in response to treatment was seen in this study.

Original languageEnglish (US)
Pages (from-to)1210-1215
Number of pages6
JournalJournal of Clinical Oncology
Volume29
Issue number9
DOIs
StatePublished - Mar 20 2011
Externally publishedYes

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Melphalan
Melanoma
Extremities
Cadherins
Ideal Body Weight
Drug Therapy
Neoplasms
Neutropenia
Creatinine
Pneumonia
Phosphotransferases
Animal Models
Pharmacokinetics
Staining and Labeling
Wounds and Injuries
Therapeutics
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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Prospective multicenter phase II trial of systemic ADH-1 in combination with melphalan via isolated limb infusion in patients with advanced extremity melanoma. / Beasley, Georgia M.; Riboh, Jonathan C.; Augustine, Christina K.; Zager, Jonathan S.; Hochwald, Steven N.; Grobmyer, Stephen R.; Peterson, Bercedis; Royal, Richard; Ross, Merrick I.; Tyler, Douglas.

In: Journal of Clinical Oncology, Vol. 29, No. 9, 20.03.2011, p. 1210-1215.

Research output: Contribution to journalArticle

Beasley, Georgia M. ; Riboh, Jonathan C. ; Augustine, Christina K. ; Zager, Jonathan S. ; Hochwald, Steven N. ; Grobmyer, Stephen R. ; Peterson, Bercedis ; Royal, Richard ; Ross, Merrick I. ; Tyler, Douglas. / Prospective multicenter phase II trial of systemic ADH-1 in combination with melphalan via isolated limb infusion in patients with advanced extremity melanoma. In: Journal of Clinical Oncology. 2011 ; Vol. 29, No. 9. pp. 1210-1215.
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abstract = "Purpose: Isolated limb infusion (ILI) with melphalan (M-ILI) dosing corrected for ideal body weight (IBW) is a well-tolerated treatment for patients with in-transit melanoma with a 29{\%} complete response rate. ADH-1 is a cyclic pentapeptide that disrupts N-cadherin adhesion complexes. In a preclinical animal model, systemic ADH-1 given with regional melphalan demonstrated synergistic antitumor activity, and in a phase I trial with M-ILI it had minimal toxicity. Patients and Methods: Patients with American Joint Committee on Cancer (AJCC) stage IIIB or IIIC extremity melanoma were treated with 4,000 mg of ADH-1, administered systemically on days 1 and 8, and with M-ILI corrected for IBW on day 1. Drug pharmacokinetics and N-cadherin immunohistochemical staining were performed on pretreatment tumor. The primary end point was response at 12 weeks determined by Response Evaluation Criteria in Solid Tumors (RECIST) criteria. Results: In all, 45 patients were enrolled over 15 months at four institutions. In-field responses included 17 patients with complete responses (CRs; 38{\%}), 10 with partial responses (22{\%}), six with stable disease (13{\%}), eight with progressive disease (18{\%}), and four (9{\%}) who were not evaluable. Median duration of in-field response among the 17 CRs was 5 months, and median time to in-field progression among 41 evaluable patients was 4.6 months (95{\%} CI, 4.0 to 7.1 months). N-cadherin was detected in 20 (69{\%}) of 29 tumor samples. Grade 4 toxicities included creatinine phosphokinase increase (four patients), arterial injury (one), neutropenia (one), and pneumonitis (one). Conclusion: To the best of our knowledge, this phase II trial is the first prospective multicenter ILI trial and the first to incorporate a targeted agent in an attempt to augment antitumor responses to regional chemotherapy. Although targeting N-cadherin may improve melanoma sensitivity to chemotherapy, no difference in response to treatment was seen in this study.",
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AU - Riboh, Jonathan C.

AU - Augustine, Christina K.

AU - Zager, Jonathan S.

AU - Hochwald, Steven N.

AU - Grobmyer, Stephen R.

AU - Peterson, Bercedis

AU - Royal, Richard

AU - Ross, Merrick I.

AU - Tyler, Douglas

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