Canerpaturev (C-REV, formerly HF10) is an oncolytic, spontaneous mutant of HSV-1, and is one of immunotherapies that combine direct tumor cell killing with immune modulation. We report the safety and antitumor activity data of Phase II multicenter trial of C-REV in combination with ipilimumab (ipi) in melanoma.
The Phase II was to determine the efficacy and safety of i.t. C-REV and i.v. ipi. Key entry criteria: age ≥ 20 yrs, ECOG PS ≤ 2, Stage IIIB, IIIC or IV unresectable melanoma, who received prior therapies and had measurable non-visceral lesion(s) suitable for injection. C-REV was injected into each tumor (1 x 107 TCID50/mL/dose, up to 5mL); 4 injections q1wk; then up to 15 injections q3wk. Four ipi infusions (3 mg/kg) were administered at q3wk. AEs were graded per CTCAE 4.0. Tumor responses were assessed per irRC and mWHO at 6, 12, 18 and 24 wks. Primary endpoint was Best Overall Response Rate (BORR) by irRC at 24 wks.
Of 28 pts enrolled and treated as of the data cut-off 04 May 2018: 43% men, 31 to 81 yrs, disease stage 7% IIIB, 29% IIIC and 64% IV, and disease type 39% acral lentiginous and 21% mucosal melanoma. All pts were received prior cancer therapies: 89% PD-1 monotherapy, 7% DAVFeron and 11% DTIC. 12% had ≥G3 drug-related AEs; Hepatic function disorder, Malaise, Hyponatraemia, Constipation, Nausea, Toxicoderma, Adrenal insufficiency, and Muscle weakness lower limb. Of 27 efficacy evaluable pts, BORR by irRC at 24 wks was 7% and disease stability rate was 56%. One patient had PR in injected lesions and systemic lesions also showed the response after 6 wks of the combo therapy.
The combination of C-REV with ipi did not show the exacerbate ipi toxicity, and had a favorable benefit/risk profile. The encouraging antitumor activity was observed in Japanese pts who had received prior therapies such as PD-1. It is recently well-known that the response to ipi after anti-PD-1 therapy was unsatisfactory and associated with a high frequency of severe irAEs, in particular Asian populations. From this study, C-REV+ipi therapy has potential to become a new 2nd line treatment for melanoma.
Clinical trial identification
Legal entity responsible for the study
Takara Bio Inc.
Takara Bio Inc.
T. Isei: Honoraria: Novartis, Toray Industries, GlaxoSmithKline, Daiichi Sankyo, Maruho, Pola Pharma, BMS UK, Ono Pharmaceuticals, MSD China; Consulting or advisory role: Novartis, BMS UK, Ono Pharmaceuticals, Merck Serono Ltd, MSD China; Research funding: Nocartis, Takara Bio, Array BioPharma, Amgenm, BMS UK, Ono Pharmaceuticals, MSD China. K. Yokota, H. Uchi, H. Ihn, T. Inozume, S. Fukushima: Research funding: Takara Bio. H. Uhara: Honoraria: MSD, Chugai Pharma, Novartis, Pola Pharma, Maruho, BMS UK, Ono Pharmaceuticals; Consulting or advisory role: Chugai Pharma, Novartis, MSD, Kyowa Hakko Kirin, BMS UK, Ono Pharmaceuticals; Speakers' bureau: Chugai Pharma, Novartis, MSD, Kyowa Hakko Kirin, Mitsubisi Tanabe Pharma, Pola Pharma, BMS UK, Ono Pharmaceuticals, Janssen Inc. Pharmaceuticals; Research funding: Kyowa Hakko Kirin, Mitsubishi Tanabe Pharma, Eisai, Abbvie, Maruho, Daiichi Sankyo, Tsumura&Co., Pola Pharma, Mochida Pharmaceutical Co. Ltd., Nihonlayaku, Torii Pharmaceutical, Kaken Pharmaceutical, Takara Bio, Ono Pharmaceuticals, Taiho Pharmaceutical. Y. Fujisawa: Consulting or advisory role: Novartis; Research funding: Maruho, Eisai, Chugai Pharma, Novartis, Toray Industries, Takara Bio, BMS UK, Ono Pharmaceuticals; Patients, Royalities, Other intellectural property: Novartis. T. Takenouchi: Speakers' bureau: MSD, Chugai Pharma, Novartis, BMS UK, Ono Pharmaceuticals; Research Funding: Takara Bio. Y. Kiyohara: Honoraria: MSD, Novartis, Chugai Pharma, Toray Industries, Takara Bio, Amgen, BMS UK, Ono Pharmaceuticals, Boehringer Ingelheim International GmbH, Merck Serono Ltd; Research funding: MSD, Takara Bio, BMS UK, ONO Pharmaceuticals, Merck Serono Ltd; Travel, accommodations, expenses: Ono Pharmaceuticals. H. Saruta: Speakers' bureau: Kyowa Hakko Kirin, Ono Pharmaceuticals; Research funding: Takara Bio, MSD; Travel, accommodations, expenses: Novartis, Minophargen Pharmaceuticals. D. Watanabe: Consulting or advisory role: Maruho, Japan Vaccine; Speakers' Bureau: Maruho; Research funding: Maruho, Sanofi, Nihon Zouki, Daiichi Sankyo, Takara Bio. A. Takahashi: Honoraria: Novartis, BMS UK, Ono Pharmaceuticals; Research funding: Novartis, Takara Bio, BMS UK, Ono Pharmaceuticals. M. Tanaka: Employee: Takara Bio. N. Yamazaki: Honoraria: Novartis, MSD, BMS UK, Ono Pharmaceuticals; Consulting or advisory role: Novartis, MSD, BMS UK, Ono Pharmaceuticals; Research funding: Novartis, MSD, Takara Bio, BMS UK, Ono Pharmaceuticals.