Abstract
REOLYSIN® (pelareorep) is an investigational new drug, consisting of a live, replication-competent, Reovirus Type 3 Dearing strain in a proprietary formulation. Several preclinical and clinical trials with REOLYSIN® on a wide range of cancer indications have demonstrated antineoplastic activity on cells with activated RAS-signaling pathway. Furthermore, long-term survival benefits were evident in post-treatment patients indicating a potential antitumor immune response triggered by REOLYSIN®. Numerous mono and/or combination therapy studies with the agent showed a consistent safety profile. The current study is a phase II, single-arm, open label trial of REOLYSIN® in combination with carboplatin and paclitaxel for patients with advanced melanoma. Results from the 14 patients enrolled in the study exhibited no grade 4 adverse events or deaths but manageable grade-3 toxicities commonly attributed to REOLYSIN®, including pyrexia, chills, myalgia, pain, fatigue, and nausea. The number of treatment cycles ranged from 2 to 20 with a median of 6 cycles. The study met its treatment and efficacy goal for the first stage with three partial responses (ORR was 21%). No complete responses were noted. The median PFS and OS were 5.2 and 10.9 months, respectively. The 1-year OS was 43% with a disease control rate of 85%. In conclusion, REOLYSIN® combined with carboplatin and paclitaxel is a safe and potentially efficacious therapy for patients with advanced malignant melanoma. Additional combination studies using REOLYSIN® with chemo/immunotherapy drugs may support more favorable outcomes for patients in this indication.
Similar content being viewed by others
References
Siegel RL, Miller KD, Jemal A (2016) Cancer statistics, 2016. CA Cancer J Clin 66(1):7–30. doi:10.3322/caac.21332
Eigentler TK, Caroli UM, Radny P, Garbe C (2003) Palliative therapy of disseminated malignant melanoma: a systematic review of 41 randomised clinical trials. Lancet Oncol 4(12):748–759
Ugurel S, Röhmel J, Ascierto PA, Flaherty KT, Grob JJ, Hauschild A, Larkin J, Long GV, Lorigan P, McArthur GA, Ribas A, Robert C, Schadendorf D, Garbe C (2016) Survival of patients with advanced metastatic melanoma: the impact of novel therapies. Eur J Cancer 53:125–134. doi:10.1016/j.ejca.2015.09.013
Coffey MC, Strong JE, Forsyth PA, Lee PW (1998) Reovirus therapy of tumors with activated Ras pathway. Science 282(5392):1332–1334
Strong JE, Coffey MC, Tang D, Sabinin P, Lee PW (1998) The molecular basis of viral oncolysis: usurpation of the Ras signaling pathway by reovirus. Embo J 17 (12):3351–3362
Errington F, White CL, Twigger KR, Rose A, Scott K, Steele L, Ilett LJ, Prestwich R, Pandha HS, Coffey M, Selby P, Vile R, Harrington KJ, Melcher AA (2008) Inflammatory tumour cell killing by oncolytic reovirus for the treatment of melanoma. Gene Ther 15(18):1257–1270
Morris DG, Feng X, DiFrancesco LM, Fonseca K, Forsyth PA, Paterson AH, Coffey MC, Thompson B (2013) REO-001: a phase I trial of percutaneous intralesional administration of reovirus type 3 dearing (Reolysin®) in patients with advanced solid tumors. Invest New Drugs 31(3):696–706. doi:10.1007/s10637-012-9865-z
Galanis E, Markovic SN, Suman VJ, Nuovo GJ, Vile RG, Kottke TJ, Nevala WK, Thompson MA, Lewis JE, Rumilla KM, Roulstone V, Harrington K, Linette GP, Maples WJ, Coffey M, Zwiebel J, Kendra K (2012) Phase II trial of intravenous administration of reolysin[reg] (reovirus serotype-3-dearing strain) in patients with metastatic melanoma. Mol Ther 20(10):1998–2003
Prestwich RJ, Errington F, Ilett EJ, Morgan RSM, Scott KJ, Kottke T, Thompson J, Morrison EE, Harrington KJ, Pandha HS, Selby PJ, Vile RG, Melcher AA (2008) Tumor infection by oncolytic reovirus primes adaptive antitumor immunity. Am Assoc Cancer Res 14(22):7358–7366. doi:10.1158/1078-0432.ccr-08-0831
Prestwich RJ, Ilett EJ, Errington F, Diaz RM, Steele LP, Kottke T, Thompson J, Galivo F, Harrington KJ, Pandha HS, Selby PJ, Vile RG, Melcher AA (2009) Immune-mediated antitumor activity of reovirus is required for therapy and is independent of direct viral oncolysis and replication. Am Assoc Cancer Res 15(13):4374–4381. doi:10.1158/1078-0432.ccr-09-0334
White CL, Twigger KR, Vidal L, De Bono JS, Coffey M, Heinemann L, Morgan R, Merrick A, Errington F, Vile RG, Melcher AA, Pandha HS, Harrington KJ (2008) Characterization of the adaptive and innate immune response to intravenous oncolytic reovirus (Dearing type 3) during a phase I clinical trial. Gene Ther 15(12):911–920. http://www.nature.com/gt/journal/v15/n12/suppinfo/gt200821s1.html
Qiao J, Wang H, Kottke T, White C, Twigger K, Diaz RM, Thompson J, Selby P, de Bono J, Melcher A, Pandha H, Coffey M, Vile R, Harrington K (2008) Cyclophosphamide facilitates antitumor efficacy against subcutaneous tumors following intravenous delivery of reovirus. Am Assoc Cancer Res 14(1):259–269. doi:10.1158/1078-0432.ccr-07-1510
Hirasawa K, Nishikawa SG, Norman KL, Coffey MC, Thompson BG, Yoon C-S, Waisman DM, Lee PWK (2003) Systemic reovirus therapy of metastatic cancer in immune-competent mice. Cancer Res 63(2):348–353
Rao RD, Holtan SG, Ingle JN, Croghan GA, Kottschade LA, Creagan ET, Kaur JS, Pitot HC, Markovic SN (2006) Combination of paclitaxel and carboplatin as second-line therapy for patients with metastatic melanoma. Cancer 106(2):375–382. doi:10.1002/cncr.21611
Zimpfer-Rechner C, Hofmann U, Figl R, Becker JC, Trefzer U, Keller I, Hauschild A, Schadendorf D (2003) Randomized phase II study of weekly paclitaxel versus paclitaxel and carboplatin as second-line therapy in disseminated melanoma: a multicentre trial of the Dermatologic Co-operative Oncology Group (DeCOG). Melanoma Res 13(5):531–536. doi:10.1097/01.cmr.0000056274.56735.c6
Hodi FS, Soiffer RJ, Clark J, Finkelstein DM, Haluska FG (2002) Phase II study of paclitaxel and carboplatin for malignant melanoma. Am J Clin Oncol 25(3):283–286
Karapanagiotou EM, Roulstone V, Twigger K, Ball M, Tanay M, Nutting C, Newbold K, Gore ME, Larkin J, Syrigos KN, Coffey M, Thompson B, Mettinger K, Vile RG, Pandha HS, Hall GD, Melcher AA, Chester J, Harrington KJ (2012) Phase I/II trial of carboplatin and paclitaxel chemotherapy in combination with intravenous oncolytic reovirus in patients with advanced malignancies. Am Assoc Cancer Res 18(7):2080–2089. doi:10.1158/1078-0432.ccr-11-2181
Pandha HS, Heinemann L, Simpson GR, Melcher A, Prestwich R, Errington F, Coffey M, Harrington KJ, Morgan R (2009) Synergistic effects of oncolytic reovirus and cisplatin chemotherapy in murine malignant melanoma. Am Assoc Cancer Res 15(19):6158–6166. doi:10.1158/1078-0432.ccr-09-0796
Sei S, Mussio JK, Yang Q-e, Nagashima K, Parchment RE, Coffey MC, Shoemaker RH, Tomaszewski JE (2009) Synergistic antitumor activity of oncolytic reovirus and chemotherapeutic agents in non-small cell lung cancer cells. Mol Cancer 8:47–47. doi:10.1186/1476-4598-8-47
Mita AC, Argiris A, Coffey M, Gill G, Mita M (2013) Abstract C70: A phase 2 study of intravenous administration of REOLYSIN® (reovirus type 3 dearing) in combination with paclitaxel (P) and carboplatin (C) in patients with squamous cell carcinoma of the lung. Am Assoc Cancer Res 12(11 Supplement):C70-C70. doi:10.1158/1535-7163.targ-13-c70
Villalona-Calero MA, Lam E, Otterson GA, Zhao WQ, Timmons M, Subramaniam D, Hade EM, Gill GM, Coffey M, Selvaggi G, Bertino E, Chao B, Knopp MV (2016) Oncolytic reovirus in combination with chemotherapy in metastatic or recurrent non-small cell lung cancer patients with KRAS-activated tumors. Cancer 122(6):875–883. doi:10.1002/cncr.29856
Andtbacka RHI, Kaufman HL, Collichio F, Amatruda T, Senzer N, Chesney J, Delman KA, Spitler LE, Puzanov I, Agarwala SS, Milhem M, Cranmer L, Curti B, Lewis K, Ross M, Guthrie T, Linette GP, Daniels GA, Harrington K, Middleton MR, Miller WH, Zager JS, Ye YN, Yao B, Li A, Doleman S, VanderWalde A, Gansert J, Coffin RS (2015) Talimogene laherparepvec improves durable response rate in patients with advanced melanoma. J Clin Oncol 33(25):2780–2798. doi:10.1200/jco.2014.58.3377
Puzanov I, Milhem MM, Andtbacka RHI, Minor DR, Hamid O, Li A, Chastain M, Gorski K, Anderson A, Vanderwalde AM, Chou J, Kaufman H (2014) Primary analysis of a phase 1b multicenter trial to evaluate safety and efficacy of talimogene laherparepvec (T-VEC) and ipilimumab (ipi) in previously untreated, unresected stage IIIB-IV melanoma. ASCO Meeting Abstr 32(15_suppl):9029
Puzanov I, Milhem MM, Andtbacka RHI, Minor DR, Hamid O, Li A, Chou J, Kaufman H (2015) Survival, safety, and response patterns in a phase 1b multicenter trial of talimogene laherparepvec (T-VEC) and ipilimumab (ipi) in previously untreated, unresected stage IIIB-IV melanoma. ASCO Meeting Abstr 33(15_suppl):9063
Long GV, Dummer R, Ribas A, Puzanov I, VanderWalde A, Andtbacka RHI, Michielin O, Olszanski AJ, Malvehy J, Cebon JS, Fernandez E, Kirkwood JM, Gajewski T, Gause CK, Chen L, Gorski K, Anderson A, Kaufman DR, Chou J, Hodi FS (2016) Efficacy analysis of MASTERKEY-265 phase 1b study of talimogene laherparepvec (T-VEC) and pembrolizumab (pembro) for unresectable stage IIIB-IV melanoma. ASCO Meeting Abstr 34 (15_suppl):9568
Roulstone V, Pedersen M, Kyula J, Mansfield D, Khan AA, McEntee G, Wilkinson M, Karapanagiotou E, Coffey M, Marais R, Jebar A, Errington-Mais F, Melcher A, Vile R, Pandha H, McLaughlin M, Harrington KJ (2015) BRAF- and MEK-targeted small molecule inhibitors exert enhanced antimelanoma effects in combination with oncolytic reovirus through ER stress. Mol Ther 23(5):931–942. doi:10.1038/mt.2015.15
Rajani K, Parrish C, Kottke T, Thompson J, Zaidi S, Ilett L, Shim KG, Diaz R-M, Pandha H, Harrington K, Coffey M, Melcher A, Vile R (2016) combination therapy with reovirus and anti-PD-1 blockade controls tumor growth through innate and adaptive immune responses. Mol Ther 24(1):166–174. doi:10.1038/mt.2015.156
Acknowledgements
Devalingam Mahalingam (first author) and the sponsor (Oncolytics Biotech Inc.) designed the study. The sponsor also covered all study-related expenses and provided REOLYSIN® free of charge. Christos Fountzilas is a recipient of a Cancer Research Training Award from the Cancer Prevention and Research Institute of Texas (RP140105).
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Funding
This study was funded by Oncolytics Inc (study sponsor).
Conflict of interest
Devalingam Mahalingam declares that he has no conflict of interest. Christos Fountzilas declares that he has no conflict of interest. Jennifer Moseley declares that she has no conflict of interest. John Sarantopoulos declares that he has no conflict of interest. Nicole Noronha, Hue Tran, Romit Chakrabarty, Matt Coffey, and Brad Thompson are employed by Oncolytics Biotech Inc., with stock options and/or stock. Giovanni Selvaggi was employed with Oncolytics Biotech Inc. during a portion of this study and manuscript preparation.
Ethical approval
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Informed consent
Informed consent was obtained from all individual participants included in the study.
Electronic supplementary material
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Mahalingam, D., Fountzilas, C., Moseley, J. et al. A phase II study of REOLYSIN® (pelareorep) in combination with carboplatin and paclitaxel for patients with advanced malignant melanoma. Cancer Chemother Pharmacol 79, 697–703 (2017). https://doi.org/10.1007/s00280-017-3260-6
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00280-017-3260-6