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First-in-human, phase I/IIa clinical study of the peptidase potentiated alkylator melflufen administered every three weeks to patients with advanced solid tumor malignancies

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Summary

Purpose Melflufen (melphalan flufenamide, previously designated J1) is an optimized and targeted derivative of melphalan, hydrolyzed by aminopeptidases overexpressed in tumor cells resulting in selective release and trapping of melphalan, and enhanced activity in preclinical models. Methods This was a prospective, single-armed, open-label, first-in-human, dose-finding phase I/IIa study in 45 adult patients with advanced and progressive solid tumors without standard treatment options. Most common tumor types were ovarian carcinoma (n = 20) and non-small-cell lung cancer (NSCLC, n = 11). Results In the dose-escalating phase I part of the study, seven patients were treated with increasing fixed doses of melflufen (25–130 mg) Q3W. In the subsequent phase IIa part, 38 patients received in total 115 cycles of therapy at doses of 30–75 mg. No dose-limiting toxicities (DLTs) were observed at 25 and 50 mg; at higher doses DLTs were reversible neutropenias and thrombocytopenias, particularly evident in heavily pretreated patients, and the recommended phase II dose (RPTD) was set to 50 mg. Response Evaluation Criteria In Solid Tumors (RECIST) evaluation after 3 cycles of therapy (27 patients) showed partial response in one (ovarian cancer), and stable disease in 18 patients. One NSCLC patient received nine cycles of melflufen and progressed after 7 months of therapy. Conclusions In conclusion, melflufen can safely be given to cancer patients, and the toxicity profile was as expected for alkylating agents; RPTD is 50 mg Q3W. Reversible and manageable bone marrow suppression was identified as a DLT. Clinical activity is suggested in ovarian cancer, but modest activity in treatment of refractory NSCLC.

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References

  1. FDA (2011) Alkeran prescribing information NDA 14-691/S-029 and NDA 20-207/SLR-016

  2. Falco P, Bringhen S, Avonto I, Gay F, Morabito F, Boccadoro M et al (2007) Melphalan and its role in the management of patients with multiple myeloma. Expert Rev Anticancer Ther 7:945–957. doi:10.1586/14737140.7.7.945

    Article  CAS  PubMed  Google Scholar 

  3. Piver MS (2006) Treatment of ovarian cancer at the crossroads: 50 years after single-agent melphalan chemotherapy. Oncology (Williston Park) 20:1156–1158

    Google Scholar 

  4. Colvin M (1983) The alkylating agents. In: Chabner B (ed) The pharmacologic principles of cancer treatment. WB Saunders, Philadelphia, pp 276–308

    Google Scholar 

  5. Furner RL, Brown RK (1980) L-phenylalanine mustard (L-PAM): the first 25 years. Cancer Treat Rep 64:559–574

    CAS  PubMed  Google Scholar 

  6. Palumbo A, Rajkumar SV, San Miguel JF, Larocca A, Niesvizky R, Morgan G et al (2014) International Myeloma Working Group consensus statement for the management, treatment, and supportive care of patients with myeloma not eligible for standard autologous stem-cell transplantation. J Clin Oncol 32:587–600. doi:10.1200/JCO.2013.48.7934

    Article  PubMed Central  PubMed  Google Scholar 

  7. Wickstrom M, Larsson R, Nygren P, Gullbo J (2011) Aminopeptidase N (CD13) as a target for cancer chemotherapy. Cancer Sci 102:501–508. doi:10.1111/j.1349-7006.2010.01826.x

    Article  PubMed  Google Scholar 

  8. Wickström M et al (2010) The alkylating prodrug J1 can be activated by aminopeptidase N, leading to a possible target directed release of melphalan. Biochem Pharmacol 79:1281–1290

    Article  PubMed  Google Scholar 

  9. Chauhan D, Ray A, Viktorsson K, Spira J, Paba-Prada C, Munshi N et al (2013) In vitro and in vivo antitumor activity of a novel alkylating agent, melphalan-flufenamide, against multiple myeloma cells. Clin Cancer Res 19:3019–3031. doi:10.1158/1078-0432.CCR-12-3752

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  10. Gullbo J, Wickstrom M, Tullberg M, Ehrsson H, Lewensohn R, Nygren P et al (2003) Activity of hydrolytic enzymes in tumour cells is a determinant for anti-tumour efficacy of the melphalan containing prodrug J1. J Drug Target 11:355–363

    Article  CAS  PubMed  Google Scholar 

  11. Wickstrom M, Viktorsson K, Lundholm L, Aesoy R, Nygren H, Sooman L et al (2010) The alkylating prodrug J1 can be activated by aminopeptidase N, leading to a possible target directed release of melphalan. Biochem Pharmacol 79:1281–1290. doi:10.1016/j.bcp.2009.12.022

    Article  PubMed  Google Scholar 

  12. Wickstrom M, Haglund C, Lindman H, Nygren P, Larsson R, Gullbo J (2008) The novel alkylating prodrug J1: diagnosis directed activity profile ex vivo and combination analyses in vitro. Invest New Drugs 26:195–204

    Article  PubMed  Google Scholar 

  13. Gullbo J, Lindhagen E, Bashir-Hassan S, Tullberg M, Ehrsson H, Lewensohn R et al (2004) Antitumor efficacy and acute toxicity of the novel dipeptide melphalanyl- p -L-fluorophenylalanine ethyl ester (J1) in vivo. Invest New Drugs 22:411–420

    Article  CAS  PubMed  Google Scholar 

  14. Wickstrom M, Johnsen JI, Ponthan F, Segerstrom L, Sveinbjornsson B, Lindskog M et al (2007) The novel melphalan prodrug J1 inhibits neuroblastoma growth in vitro and in vivo. Mol Cancer Ther 6:2409–2417. doi:10.1158/1535-7163.MCT-07-0156

    Article  PubMed  Google Scholar 

  15. Oncopeptides (2014) Data on file

  16. Facon T, Mary JY, Pegourie B, Attal M, Renaud M, Sadoun A et al (2006) Dexamethasone-based regimens versus melphalan-prednisone for elderly multiple myeloma patients ineligible for high-dose therapy. Blood 107:1292–1298. doi:10.1182/blood-2005-04-1588

    Article  CAS  PubMed  Google Scholar 

  17. Kuhne A, Sezer O, Heider U, Meineke I, Muhlke S, Niere W et al (2008) Population pharmacokinetics of melphalan and glutathione S-transferase polymorphisms in relation to side effects. Clin Pharmacol Ther 83:749–757. doi:10.1038/sj.clpt.6100336

    Article  CAS  PubMed  Google Scholar 

  18. Nath CE, Shaw PJ, Trotman J, Zeng L, Duffull SB, Hegarty G et al (2010) Population pharmacokinetics of melphalan in patients with multiple myeloma undergoing high dose therapy. Br J Clin Pharmacol 69:484–497. doi:10.1111/j.1365-2125.2010.03638.x

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  19. Mina-Osorio P (2008) The moonlighting enzyme CD13: old and new functions to target. Trends Mol Med 14:361–371. doi:10.1016/j.molmed.2008.06.003

    Article  CAS  PubMed  Google Scholar 

  20. Bhagwat SV, Petrovic N, Okamoto Y, Shapiro LH (2003) The angiogenic regulator CD13/APN is a transcriptional target of Ras signaling pathways in endothelial morphogenesis. Blood 101:1818–1826

    Article  CAS  PubMed  Google Scholar 

  21. Pasqualini R, Koivunen E, Kain R, Lahdenranta J, Sakamoto M, Stryhn A et al (2000) Aminopeptidase N is a receptor for tumor-homing peptides and a target for inhibiting angiogenesis. Cancer Res 60:722–727

    PubMed Central  CAS  PubMed  Google Scholar 

  22. Chesi M, Matthews GM, Garbitt VM, Palmer SE, Shortt J, Lefebure M et al (2012) Drug response in a genetically engineered mouse model of multiple myeloma is predictive of clinical efficacy. Blood 120:376–385. doi:10.1182/blood-2012-02-412783

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  23. Strese S, Wickstrom M, Fuchs PF, Fryknas M, Gerwins P, Dale T et al (2013) The novel alkylating prodrug melflufen (J1) inhibits angiogenesis in vitro and in vivo. Biochem Pharmacol 86:888–895. doi:10.1016/j.bcp.2013.07.026

    Article  CAS  PubMed  Google Scholar 

  24. van Hensbergen Y, Broxterman HJ, Rana S, van Diest PJ, Duyndam MC, Hoekman K et al (2004) Reduced growth, increased vascular area, and reduced response to cisplatin in CD13-overexpressing human ovarian cancer xenografts. Clin Cancer Res 10:1180–1191

    Article  PubMed  Google Scholar 

  25. Surowiak P, Drag M, Materna V, Suchocki S, Grzywa R, Spaczynski M et al (2006) Expression of aminopeptidase N/CD13 in human ovarian cancers. Int J Gynecol Cancer 16:1783–1788

    Article  CAS  PubMed  Google Scholar 

  26. Tokuhara T, Hattori N, Ishida H, Hirai T, Higashiyama M, Kodama K et al (2006) Clinical significance of aminopeptidase N in non-small cell lung cancer. Clin Cancer Res 12:3971–3978

    Article  CAS  PubMed  Google Scholar 

  27. Sarosy G, Leyland-Jones B, Soochan P, Cheson BD (1988) The systemic administration of intravenous melphalan. J Clin Oncol 6:1768–1782

    CAS  PubMed  Google Scholar 

  28. Wadler S, Yeap B, Vogl S, Carbone P (1996) Randomized trial of initial therapy with melphalan versus cisplatin-based combination chemotherapy in patients with advanced ovarian carcinoma: initial and long term results--Eastern Cooperative Oncology Group Study E2878. Cancer 77:733–742

    Article  CAS  PubMed  Google Scholar 

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Correspondence to Joachim Gullbo.

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Rolf Lewensohn, Peter Nygren, and Joachim Gullbo are cofounders and minor shareholders of OncoPeptides AB. Jack Spira was, during the conduct of this study, employed by OncoPeptides AB. Johan Harmenberg and Markus Jerling are consultants to OncoPeptides AB. Eva Nordström and Karin Söderlind are employees of OncoPeptides AB. Carina Alvfors and Magnus Ringbom are employees of Uppsala Clinical Research, conducting the study as a CRO.

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Berglund, Å., Ullén, A., Lisyanskaya, A. et al. First-in-human, phase I/IIa clinical study of the peptidase potentiated alkylator melflufen administered every three weeks to patients with advanced solid tumor malignancies. Invest New Drugs 33, 1232–1241 (2015). https://doi.org/10.1007/s10637-015-0299-2

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  • DOI: https://doi.org/10.1007/s10637-015-0299-2

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