There is a need for effective “broad spectrum” therapies for metastatic melanoma which would be suitable for all patients. The objectives of Phase Ia/Ib studies were to evaluate the safety, pharmacokinetics, dosimetry, and antitumor activity of 188Re-6D2, a 188-Rhenium-labeled antibody to melanin. Stage IIIC/IV metastatic melanoma (MM) patients who failed standard therapies were enrolled in both studies. In Phase Ia, 10？mCi 188Re-6D2 were given while unlabeled antibody preload was escalated. In Phase Ib, the dose of 188Re-6D2 was escalated to 54？mCi. SPECT/CT revealed 188Re-6D2 uptake in melanoma metastases. The mean effective half-life of 188Re-6D2 was 12.4？h. Transient HAMA was observed in 9 patients. Six patients met the RECIST criteria for stable disease at 6 weeks. Two patients had durable disease stabilization for 14 weeks and one for 22 weeks. Median overall survival was 13 months with no dose-limiting toxicities. The data demonstrate that 188Re-6D2 was well tolerated, localized in melanoma metastases, and had antitumor activity, thus warranting its further investigation in patients with metastatic melanoma. 1. Introduction The incidence of melanoma is increasing worldwide, with a concomitant rise in mortality from metastatic disease. Patients who progress to stage IV metastatic melanoma (MM) have a median survival of less than 1 year [1]. In the United States, about 9,180 people will die from melanoma in 2012 (American Cancer Society, 2012). Until recently, treatment options for patients with stage IV disease were limited and offered marginal, if any, improvement in overall survival. This situation changed with the newly approved by FDA ipilimumab (anti-CTLA4 monoclonal antibody), an immunomodulator which in a phase III trial was shown to improve overall survival [2]. In addition, vemurafenib that inhibits mutated B-RAF protein offers hope for 40–60% melanoma patients carrying this mutation [3, 4]. However, the responses to the latter have been relatively short lasting followed by recurrences. In our search for alternative therapeutic options for MM we turned to radioimmunotherapy (RIT). RIT takes advantage of the specificity of the antigen-antibody interaction to deliver cytotoxic radiation to tumors [5, 6]. The clinical success of FDA-approved drugs such as ibritumomab tiuxetan (anti-CD20 monoclonal antibody (mAb) labeled with 90Yttrium) for treatment of primary, relapsed or refractory B-cell non-Hodgkin lymphoma demonstrates RIT potential as antineoplastic strategy. Unlike other therapies, RIT does not rely on specific genotypes, biochemical
References
[1]
E. Linos, S. M. Swetter, M. G. Cockburn, G. A. Colditz, and C. A. Clarke, “Increasing burden of melanoma in the United States,” Journal of Investigative Dermatology, vol. 129, no. 7, pp. 1666–1674, 2009.
[2]
F. S. Hodi, S. J. O'Day, D. F. McDermott et al., “Improved survival with ipilimumab in patients with metastatic melanoma,” The New England Journal of Medicine, vol. 363, no. 8, pp. 711–723, 2010.
[3]
A. Ribas, K. B. Kim, L. M. Schuchter, et al., “BRIM-2: An open-label, multicenter phase II study of vemurafenib in previously treated patients with BRAF V600E mutation-positive metastatic melanoma,” Journal of Clinical Oncology, vol. 29, supplement 1, abstract 8509, 2011.
[4]
P. B. Chapman, A. Hauschild, C. Robert, et al., “Phase III randomized, open-label, multicenter trial (BRIM3) comparing BRAF inhibitor vemurafenib with dacarbazine (DTIC) in patients with V600EBRAF-mutated melanoma,” Journal of Clinical Oncology, vol. 29, supplement 1, abstract LBA4, 2011.
[5]
D. E. Milenic, E. D. Brady, and M. W. Brechbiel, “Antibody-targeted radiation cancer therapy,” Nature Reviews Drug Discovery, vol. 3, no. 6, pp. 488–498, 2004.
[6]
R. M. Sharkey and D. M. Goldenberg, “Perspectives on cancer therapy with radiolabeled monoclonal antibodies,” Journal of Nuclear Medicine, vol. 46, supplement 1, pp. 115S–121S, 2005.
[7]
K. A. Cohen-Solal, S. M. Crespo-Carbone, J. Namkoong et al., “Progressive appearance of pigmentation in amelanotic melanoma lesions,” Pigment Cell Research, vol. 15, no. 4, pp. 282–289, 2002.
[8]
K. J. Busam, K. Hester, C. Charles et al., “Detection of clinically amelanotic malignant melanoma and assessment of its margins by in vivo confocal scanning laser microscopy,” Archives of Dermatology, vol. 137, no. 7, pp. 923–929, 2001.
[9]
A. L. Rosas, J. D. Nosanchuk, M. Feldmesser, et al., “Synthesis of polymerized melanin by Cryptococcus neoformans in infected rodents,” Infection and Immunity, vol. 68, no. 5, pp. 2845–2853, 2000.
[10]
E. Dadachova, J. D. Nosanchuk, L. Shi et al., “Dead cells in melanoma tumors provide abundant antigen for targeted delivery of ionizing radiation by a mAb to melanin,” Proceedings of the National Academy of Sciences of the United States of America, vol. 101, no. 41, pp. 14865–14870, 2004.
[11]
E. Dadachova, E. Revskaya, M. A. Sesay et al., “Pre-clinical evaluation and efficacy studies of a melanin-binding IgM antibody labeled with 188Re against experimental human metastatic melanoma in nude mice,” Cancer Biology and Therapy, vol. 7, no. 7, pp. 1116–1127, 2008.
[12]
A. D. Schweitzer, V. Rakesh, E. Revskaya, A. Datta, A. Casadevall, and E. Dadachova, “Computational model predicts effective delivery of 188-Re-labeled melanin-binding antibody to metastatic melanoma tumors with wide range of melanin concentrations,” Melanoma Research, vol. 17, no. 5, pp. 291–303, 2007.
[13]
M. G. Stabin, R. B. Sparks, and E. Crowe, “OLINDA/EXM: the second-generation personal computer software for internal dose assessment in nuclear medicine,” Journal of Nuclear Medicine, vol. 46, no. 6, pp. 1023–1027, 2005.
[14]
B. W. Wessels, W. E. Bolch, L. G. Bouchet et al., “Bone marrow dosimetry using blood-based models for radiolabeled antibody therapy: a multiinstitutional comparison,” Journal of Nuclear Medicine, vol. 45, no. 10, pp. 1725–1733, 2004.
[15]
B. Emami, J. Lyman, A. Brown, et al., “Tolerance of normal tissue to therapeutic irradiation,” International Journal of Radiation Oncology *Biology* Physics, vol. 21, pp. 109–122, 1991.
[16]
S. J. DeNardo, K. L. Erickson, E. Benjamin, et al., “Radioimmunotherapy for melanoma,” Clinical Research, vol. 29, pp. 434–440, 1981.
[17]
S. M. Larson, J. A. Carrasquillo, and R. W. McGuffin, “Use of I-131 labeled, murine Fab against a high molecular weight antigen of human melanoma: preliminary experience,” Radiology, vol. 155, no. 2, pp. 487–492, 1985.
[18]
W. C. Taddei-Peters, M. V. Haspel, P. Vente et al., “Quantitation of human tumor-reactive monoclonal antibody 16.88 in the circulation and localization of 16.88 in colorectal metastatic tumor tissue using murine antiidiotypic antibodies,” Cancer Research, vol. 52, no. 9, pp. 2603–2609, 1992.
