A phase 1 study of systemic ADH-1 in combination with melphalan via isolated limb infusion in patients with locally advanced in-transit malignant melanoma

Georgia M. Beasley, Nicole McMahon, Gretchen Sanders, Christina K. Augustine, Maria A. Selim, Bercedis Peterson, Robin Norris, William P. Peters, Merrick I. Ross, Douglas Tyler

Research output: Contribution to journalArticle

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Abstract

BACKGROUND: Isolated limb infusion with melphalan is a well-tolerated treatment for patients with in-transit extremity melanoma with an approximately 30% complete response (CR) rate. ADH-1 is a cyclic pentapeptide that disrupts N-cadherin adhesion complexes and when given systemically in a preclinical model of regional melphalan therapy demonstrated synergistic antitumor activity. A phase 1 dose escalation study to evaluate the safety, tolerability, pharmacokinetics, and antitumor activity of systemic ADH-1 in combination with melphalan via isolated limb infusion in patients with in-transit extremity melanoma was performed. METHODS: Dose escalation cohorts of 3 patients each received 1000, 2000, and 4000 mg (10 patients) of ADH-1 administered intravenously on Days 1 and 8 with standard dose melphalan via isolated limb infusion on Day 1. N-cadherin immunohistochemistry staining and quantitative polymerase chain reaction analysis were performed on pretreatment tumor. Response was defined at 3 months using modified Response Evaluation Criteria in Solid Tumors. RESULTS: Sixteen patients have been treated with no observed dose-limiting toxicities. Common treatment-related grade 1 or 2 toxicities included skin/dermatologic (n = 14) and pain (n = 12). Grade 3 toxicities included shortness of breath (n = 1), hypertension (n = 1), serologic toxicities (n = 4), and 1 grade 4 creatine phosphokinase elevation. In-field responses included 8 CRs, 2 partial responses, 1 stable disease, and 5 progressive diseases. Pharmacokinetic analysis demonstrated increasing ADH-1 concentrations at each dose and minimal variability in melphalan drug levels. CONCLUSIONS: Systemic ADH-1 at a dose of 4000 mg on Days 1 and 8 in combination with melphalan via isolated limb infusion is a well-tolerated, novel targeted therapy approach to regionally advanced melanoma. The number of CRs exceeded expectations, suggesting that targeting N-cadherin may be a new strategy for overcoming melanoma chemoresistance.

Original languageEnglish (US)
Pages (from-to)4766-4774
Number of pages9
JournalCancer
Volume115
Issue number20
DOIs
StatePublished - Oct 15 2009
Externally publishedYes

Fingerprint

Melphalan
Melanoma
Extremities
Cadherins
Pharmacokinetics
Therapeutics
Creatine Kinase
Dyspnea
Immunohistochemistry
Staining and Labeling
Hypertension
Safety
Pain
Polymerase Chain Reaction
Skin
Pharmaceutical Preparations
Neoplasms

Keywords

  • ADH-1
  • Limb infusion
  • Melanoma
  • Regional chemotherapy

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

A phase 1 study of systemic ADH-1 in combination with melphalan via isolated limb infusion in patients with locally advanced in-transit malignant melanoma. / Beasley, Georgia M.; McMahon, Nicole; Sanders, Gretchen; Augustine, Christina K.; Selim, Maria A.; Peterson, Bercedis; Norris, Robin; Peters, William P.; Ross, Merrick I.; Tyler, Douglas.

In: Cancer, Vol. 115, No. 20, 15.10.2009, p. 4766-4774.

Research output: Contribution to journalArticle

Beasley, GM, McMahon, N, Sanders, G, Augustine, CK, Selim, MA, Peterson, B, Norris, R, Peters, WP, Ross, MI & Tyler, D 2009, 'A phase 1 study of systemic ADH-1 in combination with melphalan via isolated limb infusion in patients with locally advanced in-transit malignant melanoma', Cancer, vol. 115, no. 20, pp. 4766-4774. https://doi.org/10.1002/cncr.24509
Beasley, Georgia M. ; McMahon, Nicole ; Sanders, Gretchen ; Augustine, Christina K. ; Selim, Maria A. ; Peterson, Bercedis ; Norris, Robin ; Peters, William P. ; Ross, Merrick I. ; Tyler, Douglas. / A phase 1 study of systemic ADH-1 in combination with melphalan via isolated limb infusion in patients with locally advanced in-transit malignant melanoma. In: Cancer. 2009 ; Vol. 115, No. 20. pp. 4766-4774.
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abstract = "BACKGROUND: Isolated limb infusion with melphalan is a well-tolerated treatment for patients with in-transit extremity melanoma with an approximately 30{\%} complete response (CR) rate. ADH-1 is a cyclic pentapeptide that disrupts N-cadherin adhesion complexes and when given systemically in a preclinical model of regional melphalan therapy demonstrated synergistic antitumor activity. A phase 1 dose escalation study to evaluate the safety, tolerability, pharmacokinetics, and antitumor activity of systemic ADH-1 in combination with melphalan via isolated limb infusion in patients with in-transit extremity melanoma was performed. METHODS: Dose escalation cohorts of 3 patients each received 1000, 2000, and 4000 mg (10 patients) of ADH-1 administered intravenously on Days 1 and 8 with standard dose melphalan via isolated limb infusion on Day 1. N-cadherin immunohistochemistry staining and quantitative polymerase chain reaction analysis were performed on pretreatment tumor. Response was defined at 3 months using modified Response Evaluation Criteria in Solid Tumors. RESULTS: Sixteen patients have been treated with no observed dose-limiting toxicities. Common treatment-related grade 1 or 2 toxicities included skin/dermatologic (n = 14) and pain (n = 12). Grade 3 toxicities included shortness of breath (n = 1), hypertension (n = 1), serologic toxicities (n = 4), and 1 grade 4 creatine phosphokinase elevation. In-field responses included 8 CRs, 2 partial responses, 1 stable disease, and 5 progressive diseases. Pharmacokinetic analysis demonstrated increasing ADH-1 concentrations at each dose and minimal variability in melphalan drug levels. CONCLUSIONS: Systemic ADH-1 at a dose of 4000 mg on Days 1 and 8 in combination with melphalan via isolated limb infusion is a well-tolerated, novel targeted therapy approach to regionally advanced melanoma. The number of CRs exceeded expectations, suggesting that targeting N-cadherin may be a new strategy for overcoming melanoma chemoresistance.",
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AU - McMahon, Nicole

AU - Sanders, Gretchen

AU - Augustine, Christina K.

AU - Selim, Maria A.

AU - Peterson, Bercedis

AU - Norris, Robin

AU - Peters, William P.

AU - Ross, Merrick I.

AU - Tyler, Douglas

PY - 2009/10/15

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N2 - BACKGROUND: Isolated limb infusion with melphalan is a well-tolerated treatment for patients with in-transit extremity melanoma with an approximately 30% complete response (CR) rate. ADH-1 is a cyclic pentapeptide that disrupts N-cadherin adhesion complexes and when given systemically in a preclinical model of regional melphalan therapy demonstrated synergistic antitumor activity. A phase 1 dose escalation study to evaluate the safety, tolerability, pharmacokinetics, and antitumor activity of systemic ADH-1 in combination with melphalan via isolated limb infusion in patients with in-transit extremity melanoma was performed. METHODS: Dose escalation cohorts of 3 patients each received 1000, 2000, and 4000 mg (10 patients) of ADH-1 administered intravenously on Days 1 and 8 with standard dose melphalan via isolated limb infusion on Day 1. N-cadherin immunohistochemistry staining and quantitative polymerase chain reaction analysis were performed on pretreatment tumor. Response was defined at 3 months using modified Response Evaluation Criteria in Solid Tumors. RESULTS: Sixteen patients have been treated with no observed dose-limiting toxicities. Common treatment-related grade 1 or 2 toxicities included skin/dermatologic (n = 14) and pain (n = 12). Grade 3 toxicities included shortness of breath (n = 1), hypertension (n = 1), serologic toxicities (n = 4), and 1 grade 4 creatine phosphokinase elevation. In-field responses included 8 CRs, 2 partial responses, 1 stable disease, and 5 progressive diseases. Pharmacokinetic analysis demonstrated increasing ADH-1 concentrations at each dose and minimal variability in melphalan drug levels. CONCLUSIONS: Systemic ADH-1 at a dose of 4000 mg on Days 1 and 8 in combination with melphalan via isolated limb infusion is a well-tolerated, novel targeted therapy approach to regionally advanced melanoma. The number of CRs exceeded expectations, suggesting that targeting N-cadherin may be a new strategy for overcoming melanoma chemoresistance.

AB - BACKGROUND: Isolated limb infusion with melphalan is a well-tolerated treatment for patients with in-transit extremity melanoma with an approximately 30% complete response (CR) rate. ADH-1 is a cyclic pentapeptide that disrupts N-cadherin adhesion complexes and when given systemically in a preclinical model of regional melphalan therapy demonstrated synergistic antitumor activity. A phase 1 dose escalation study to evaluate the safety, tolerability, pharmacokinetics, and antitumor activity of systemic ADH-1 in combination with melphalan via isolated limb infusion in patients with in-transit extremity melanoma was performed. METHODS: Dose escalation cohorts of 3 patients each received 1000, 2000, and 4000 mg (10 patients) of ADH-1 administered intravenously on Days 1 and 8 with standard dose melphalan via isolated limb infusion on Day 1. N-cadherin immunohistochemistry staining and quantitative polymerase chain reaction analysis were performed on pretreatment tumor. Response was defined at 3 months using modified Response Evaluation Criteria in Solid Tumors. RESULTS: Sixteen patients have been treated with no observed dose-limiting toxicities. Common treatment-related grade 1 or 2 toxicities included skin/dermatologic (n = 14) and pain (n = 12). Grade 3 toxicities included shortness of breath (n = 1), hypertension (n = 1), serologic toxicities (n = 4), and 1 grade 4 creatine phosphokinase elevation. In-field responses included 8 CRs, 2 partial responses, 1 stable disease, and 5 progressive diseases. Pharmacokinetic analysis demonstrated increasing ADH-1 concentrations at each dose and minimal variability in melphalan drug levels. CONCLUSIONS: Systemic ADH-1 at a dose of 4000 mg on Days 1 and 8 in combination with melphalan via isolated limb infusion is a well-tolerated, novel targeted therapy approach to regionally advanced melanoma. The number of CRs exceeded expectations, suggesting that targeting N-cadherin may be a new strategy for overcoming melanoma chemoresistance.

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