Phase 1 study in Japan of siltuximab, an anti-IL-6 monoclonal antibody, in relapsed/refractory multiple myeloma

International Journal of Hematology

Volumn 101, Issue 3, 2015, Pages 286-294

  Suzuki, Kenshi ^a   Ogura, Michinori ^b   Abe, Yu ^a   Suzuki, Tatsuya ^b   Tobinai, Kensei ^c   Ando, Kiyoshi ^d   Taniwaki, Masafumi ^e   Maruyama, Dai ^c   Kojima, Minoru ^d   Kuroda, Junya ^e   Achira, Meguru ^f   Iizuka, Koho ^f  

^a JAPANESE RED CROSS MEDICAL CENTER   (Japan)

^b NAGOYA DAINI RED CROSS HOSPITAL   (Japan)

^c NATIONAL CANCER CENTER HOSPITAL   (Japan)

^d TOKAI UNIVERSITY SCHOOL OF MEDICINE   (Japan)

^e KYOTO PREFECTURAL UNIVERSITY OF MEDICINE   (Japan)

^f Janssen Pharmaceutical KK   (Japan)

Author keywords

Bortezomib; Dexamethasone; Interleukin 6; Multiple myeloma; Siltuximab

Indexed keywords

ANTIBIOTIC AGENT; BORTEZOMIB; DEXAMETHASONE; SILTUXIMAB; ANTINEOPLASTIC AGENT; BORONIC ACID DERIVATIVE; INTERLEUKIN 6; MONOCLONAL ANTIBODY; PYRAZINE DERIVATIVE;

ADULT; AGED; ALLERGIC PNEUMONITIS; AREA UNDER THE CURVE; ARTICLE; CANCER CHEMOTHERAPY; CANCER RECURRENCE; CHEMOTHERAPY INDUCED ANEMIA; CLINICAL ARTICLE; COLON CANCER; CONTROLLED CLINICAL TRIAL; CONTROLLED STUDY; DIARRHEA; DRUG CLEARANCE; DRUG DOSE ESCALATION; DRUG HALF LIFE; DRUG SAFETY; FEBRILE NEUTROPENIA; FEMALE; HUMAN; HYPERLIPIDEMIA; IMMUNOGENICITY; INTERSTITIAL LUNG DISEASE; JAPAN; JAPANESE (PEOPLE); LEUKOCYTOSIS; LEUKOPENIA; LIVER DISEASE; LYMPHOCYTOPENIA; MALE; MAXIMUM PLASMA CONCENTRATION; MAXIMUM TOLERATED DOSE; MEDICATION COMPLIANCE; MIDDLE AGED; MULTIPLE CYCLE TREATMENT; MULTIPLE MYELOMA; NEUTROPENIA; NEUTROPHILIA; OPEN STUDY; PHASE 1 CLINICAL TRIAL; PNEUMONIA; RASH; RECOMMENDED DRUG DOSE; THROMBOCYTOPENIA; VOLUME OF DISTRIBUTION; CLINICAL TRIAL; IMMUNOLOGY; NEOPLASM RECURRENCE, LOCAL;

AGED; ANTIBODIES, MONOCLONAL; ANTINEOPLASTIC AGENTS; BORONIC ACIDS; DEXAMETHASONE; FEMALE; HUMANS; INTERLEUKIN-6; JAPAN; MALE; MIDDLE AGED; MULTIPLE MYELOMA; NEOPLASM RECURRENCE, LOCAL; PYRAZINES;

EID: 84925494797     PISSN: 09255710     EISSN: 18653774     Source Type: Journal    
DOI: 10.1007/s12185-015-1743-y     Document Type: Article

References (24)

1. Hideshima T, Mitsiades C, Tonon G, Richardson PG, Anderson KC. Understanding multiple myeloma pathogenesis in the bone marrow to identify new therapeutic targets. Nat Rev Cancer. 2007;7:585–98.
2. Kyle RA, Rajkumar SV. Multiple myeloma. N Engl J Med. 2004;351:1860–73.
3. Palumbo A, Rajkumar SV. Treatment of newly diagnosed myeloma. Leukemia. 2009;23:449–56.
4. Voorhees PM, Manges RF, Sonneveld P, Jagannath S, Somlo G, Krishnan A, et al. A phase 2 multicentre study of siltuximab, an anti-interleukin-6 monoclonal antibody, in patients with relapsed or refractory multiple myeloma. Br J Haematol. 2013;161:357–66.
5. Chauhan D, Pandey P, Hideshima T, Treon S, Raje N, Davies FE, et al. SHP2 mediates the protective effect of interleukin-6 against dexamethasone-induced apoptosis in multiple myeloma cells. J Biol Chem. 2000;275:27845–50.
6. Kawano M, Hirano T, Matsuda T, Taga T, Horii Y, Iwato K, et al. Autocrine generation and requirement of BSF-2/IL-6 for human multiple myelomas. Nature. 1988;332:83–5.
7. Klein B, Zhang XG, Lu ZY, Bataille R. Interleukin-6 in human multiple myeloma. Blood. 1995;85:863–72.
8. van Rhee F, Fayad L, Voorhees P, Furman R, Lonial S, Borghaei H, et al. Siltuximab, a novel anti-interleukin-6 monoclonal antibody, for Castleman’s disease. J Clin Oncol. 2010;28:3701–8.
9. Wong RS, Casper C, Munshi N, et al. A multicenter, randomized, double-blind, placebo-controlled study of the efficacy and safety of siltuximab, an anti-interleukin-6 monoclonal antibody, in patients with multicentric Castleman’s Disease. Blood. 2013;122: 505. https://ash.confex.com/ash/2013/webprogram/Paper58548.html.
10. Kurzrock R, Voorhees PM, Casper C, Furman RR, Fayad L, Lonial S, et al. A phase I, open-label study of siltuximab, an anti-IL-6 monoclonal antibody, in patients with B-cell non-Hodgkin lymphoma, multiple myeloma, or Castleman disease. Clin Cancer Res. 2013;19:3659–70.
11. Voorhees PM, Chen Q, Kuhn DJ, Small GW, Hunsucker SA, Strader JS, et al. Inhibition of interleukin-6 signaling with CNTO 328 enhances the activity of bortezomib in preclinical models of multiple myeloma. Clin Cancer Res. 2007;13:6469–78.
12. Voorhees PM, Chen Q, Small GW, Kuhn DJ, Hunsucker SA, Nemeth JA, et al. Targeted inhibition of interleukin-6 with CNTO 328 sensitizes pre-clinical models of multiple myeloma to dexamethasone-mediated cell death. Br J Haematol. 2009;145:481–90.
13. Rowley M, Liu P, Van Ness B. Heterogeneity in therapeutic response of genetically altered myeloma cell lines to interleukin 6, dexamethasone, doxorubicin, and melphalan. Blood. 2000;96:3175–80.
14. Hardin J, MacLeod S, Grigorieva I, Chang R, Barlogie B, Xiao H, et al. Interleukin-6 prevents dexamethasone-induced myeloma cell death. Blood. 1994;84:3063–70.
15. Lichtenstein A, Tu Y, Fady C, Vescio R, Berenson J. Interleukin-6 inhibits apoptosis of malignant plasma cells. Cell Immunol. 1995;162:248–55.
16. Balmanno K, Cook SJ. Tumour cell survival signalling by the ERK1/2 pathway. Cell Death Differ. 2009;16:368–77.
17. Angevin E, Tabernero J, Elez E, Cohen SJ, Bahleda R, van Laethem JL, et al. A phase I/II, multiple-dose, dose-escalation study of siltuximab, an anti-interleukin-6 monoclonal antibody, in patients with advanced solid tumors. Clin Cancer Res. 2014;20:2192–204.
18. Durie BG, Harousseau JL, Miguel JS, Bladé J, Barlogie B, Anderson K, et al. International uniform response criteria for multiple myeloma. Leukemia. 2006;20:1467–73.
19. Blade J, Samson D, Reece D, Apperley J, Björkstrand B, Gahrton G, et al. Criteria for evaluating disease response and progression in patients with multiple myeloma treated by high-dose therapy and haemopoietic stem cell transplantation. Myeloma Subcommittee of the EBMT. European Group for Blood and Marrow Transplant. Br J Haematol. 1998;102:1115–23.
20. Shah JJ, Orlowski RZ. Proteasome inhibitors in the treatment of multiple myeloma. Leukemia. 2009;23:1964–79.
21. Liu T, Fei Z, Gangavarapu KJ, Agbenowu S, Bhushan A, Lai JC, et al. Interleukin-6 and JAK2/STAT3 signaling mediate the reversion of dexamethasone resistance after dexamethasone withdrawal in 7TD1 multiple myeloma cells. Leuk Res. 2013;37:1322–8.
22. Fulciniti M, Hideshima T, Vermot-Desroches C, et al. A high-affinity fully human anti-IL-6 mAb, 1339, for the treatment of multiple myeloma. Clin Cancer Res. 2009;15:7144–52.
23. Orlowski RZ, Gercheva L, Williams C, Sutherland HJ, Robak T, Masszi T, et al. Phase II, randomized, double blind, placebo-controlled study comparing siltuximab plus bortezomib versus bortezomib alone in pts with relapsed/refractory multiple myeloma. ASCO Meeting Abstracts. 2012;30: 8018. http://meetinglibrary.asco.org/content/96732-114.
24. El-Osta HE, Kurzrock R. Castleman’s disease: from basic mechanisms to molecular therapeutics. Oncologist. 2011;16:497–511.