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Phase IA/IB Study of Single-Agent Tislelizumab, an Investigational Anti Open access Original research J Immunother Cancer: first published as 10.1136/jitc-2019-000453 on 14 June 2020. Downloaded from Phase IA/IB study of single-agent tislelizumab, an investigational anti- PD-1 antibody, in solid tumors Jayesh Desai,1 Sanjeev Deva,2 Jong Seok Lee,3 Chia- Chi Lin,4 Chia- Jui Yen,5 Yee Chao,6 Bhumsuk Keam,7 Michael Jameson,8 Ming- Mo Hou,9 Yoon- Koo Kang,10 Ben Markman,11 Chang- Hsien Lu,12 Kun- Ming Rau,13 Kyung- Hun Lee,7 Lisa Horvath,14,15 Michael Friedlander,16 Andrew Hill,17 Shahneen Sandhu,1 Paula Barlow,2 Chi- Yuan Wu,18 Yun Zhang,19 Liang Liang,19 John Wu,18 Virginia Paton,18 Michael Millward20 To cite: Desai J, Deva S, ABSTRACT were observed in heavily pretreated patients with Lee JS, et al. Phase IA/IB study Background The programmed cell death-1/programmed advanced solid tumors, supporting the evaluation of of single- agent tislelizumab, cell death ligand-1 (PD-1/PD-L1) axis plays a central role tislelizumab 200 mg every 3 weeks, as monotherapy and in an investigational anti- PD-1 in suppressing antitumor immunity; axis dysregulation combination therapy, for the treatment of solid tumors and antibody, in solid tumors. can be used by cancer cells to evade the immune system. hematological malignancies. Journal for ImmunoTherapy Trial registration number NCT02407990. of Cancer 2020;8:e000453. Tislelizumab, an investigational monoclonal antibody doi:10.1136/jitc-2019-000453 with high affinity and binding specificity for PD-1, was engineered to minimize binding to FcγR on macrophages to limit antibody- dependent phagocytosis, a potential ► Additional material is INTRODUCTION published online only. To view, mechanism of resistance to anti-PD-1 therapy. The aim The programmed cell death-1/programmed please visit the journal online of this phase IA/IB study was to investigate the safety/ cell death ligand-1 (PD-1/PD- L1) axis plays (http:// dx. doi. org/ 10. 1136/ jitc- tolerability, antitumor effects and optimal dose and a central role in suppressing antitumor 2019- 000453). schedule of tislelizumab in patients with advanced solid immunity; dysregulation of the PD-1/PD-L1 tumors. axis can be used by cancer cells to evade the Accepted 23 April 2020 Methods Patients (aged ≥18 years) enrolled in phase 1 2 IA received intravenous tislelizumab 0.5, 2, 5 or 10 mg/ immune system. PD- L1 is an immune check- kg every 2 weeks; 2 or 5 mg/kg administered every point protein that is often overexpressed on 2 weeks or every 3 weeks; or 200 mg every 3 weeks; the surface of tumor and immune cells in http://jitc.bmj.com/ 3 4 patients in phase IB received 5 mg/kg every 3 weeks. the tumor microenvironment. PD-1, the Primary objectives were to assess tislelizumab’s safety/ cell receptor for PD-L1, is mainly expressed tolerability profile by adverse event (AE) monitoring and in activated T cells.5 An increase in PD-1 antitumor activity using RECIST V.1.1. PD- L1 expression expression in the tumor microenvironment was assessed retrospectively with the VENTANA PD-L1 has been reported in many cancer types.6–8 (SP263) Assay. Increased expression of PD-1 and PD-L1 is on September 30, 2021 by guest. Protected copyright. Results Between May 2015 and October 2017, 451 often associated with poor survival but may patients (n=116, IA; n=335, IB) were enrolled. Fatigue be predictive of anti-PD-1/PD- L1 antitumor (28%), nausea (25%) and decreased appetite (20%) were 9–11 the most commonly reported AEs. Most AEs were grade activity. 1–2 severity; anemia (4.9%) was the most common grade Tislelizumab is an investigational human- 3–4 AE. Treatment-rela ted AEs led to discontinuation ized IgG4 monoclonal antibody with high 12 in 5.3% of patients. Grade 5 AEs were reported in 14 affinity and binding specificity for PD-1. patients; 2 were considered related to tislelizumab. Tislelizumab was engineered to minimize Pneumonitis (2%) and colitis (1%) were the most common binding to FcγR on macrophages in order © Author(s) (or their serious tislelizumab-rela ted AEs. As of May 2019, 18% to limit antibody-dependent phagocytosis, employer(s)) 2020. Re- use of patients achieved a confirmed objective response in a potential mechanism of resistance to anti- permitted under CC BY-NC. No phase IA and 12% in phase IB; median follow-up duration PD-1 therapy.1 Preclinical data suggest tisleli- commercial re- use. See rights was 13.6 and 7.6 months, respectively. Pharmacokinetics, and permissions. Published by zumab does not bind to FcγRI, whereas BMJ. safety and antitumor activity obtained from both phase IA and IB determined the tislelizumab recommended dose; other anti- PD-1 antibodies bind to FcγRI in a For numbered affiliations see ultimately, tislelizumab 200 mg intravenous every 3 weeks manner consistent with human IgG4 antibody end of article. 12 was the dose and schedule recommended to be taken into affinity. Furthermore, in cell- based assays, Correspondence to subsequent clinical trials. tislelizumab enhanced the functional activity Dr Jayesh Desai; Conclusions Tislelizumab monotherapy demonstrated an of human T cells and pre- activated primary Jayesh. Desai@ petermac. org acceptable safety/tolerability profile. Durable responses peripheral blood mononuclear cells.12 Desai J, et al. J Immunother Cancer 2020;8:e000453. doi:10.1136/jitc-2019-000453 1 Open access J Immunother Cancer: first published as 10.1136/jitc-2019-000453 on 14 June 2020. Downloaded from KEY PHASE IA, PART 1 PHASE IA, PART 2 PHASE IA, PART 3 OBJECTIVES Dose Escalations Schedule Expansion* Fixed Dose Expansion†‡ PHASE IA 0.5 mg/kg Q2W, n=3 2 mg/kg Q2W, n=20 Safety, 2 mg/kg Q2W, n=6 2 mg/kg Q3W, n=21 200 mg Q3W RP2D, and n=13 preliminary 5 mg/kg Q2W, n=6 5 mg/kg Q2W, n=20 efficacy 10 mg/kg Q2W, n=7 5 mg/kg Q3W, n=20 5 mg/kg Q3W PHASE IB: Indication Expansion Expansion in ~330 patients with multiple tumor types ARM 1: n=50 ARM 2: n=20 ARM 3: n=50 ARM 4: n=50 Non-small cell Hepatocellular PHASE IB Ovarian cancer Gastric cancer lung cancer carcinoma Efficacy and safety in ARM 5: n=20 ARM 6: n=50 ARM 7: n=20 ARM 8: n=20 Head and neck Triple-negative Esophageal carcinoma Cholangiocarcinoma multiple squamous cell carcinoma breast cancer tumor types ARM 9: n=50 Renal cell carcinoma, urothelial cancer, melanoma, Merkel cell carcinoma, sarcoma, gastrointestinal stromal tumor, or cutaneous squamous cell carcinoma. Or any other metastatic microsatellite instability-high or mismatch repair deficient solid tumors, such as CRC or pancreatic cancer Figure 1 Study design. CRC, colorectal cancer; Q3W, every 3 weeks. This first- in- human (FIH), dose- escalation/dose- diarrhea, nausea and vomiting; asymptomatic biochem- expansion study assessed the safety/tolerability, pharma- ical abnormalities that improve to grade ≤2 within 3 days cology and clinical activity of tislelizumab in patients with of institution of supportive care and grade 2 ophthalmo- advanced solid tumors. The primary objective was to eval- logical toxicities. Hematological toxicities meeting DLT uate the safety and tolerability of tislelizumab (phase IA), criteria include febrile neutropenia (defined as absolute as well as the antitumor response (phase IB). Secondary neutrophil count <1000/mm3 with a single temperature end points included determining the maximum toler- of 38.3°C or a sustained temperature of 38°C for >1 hour); http://jitc.bmj.com/ ated dose (MTD) and the optimal dose and treatment grade 4 thrombocytopenia, grade 4 anemia or grade 4 regimen. Confirmed objective response rate (ORR) to neutropenia lasting >7 days; grade 3 thrombocytopenia tislelizumab by PD- L1 status was an exploratory end point. with bleeding and grade 3 neutropenic infection. No additional patients were required if a DLT was observed METHODS in one of six patients. Dose escalation continued until on September 30, 2021 by guest. Protected copyright. Study design and treatment administration two out of six patients in each dose cohort experienced a The design of this phase IA/IB study is detailed in DLT. If an MTD could not be established after evaluation figure 1. Phase IA comprised three parts. Part 1 was a of all planned doses, then the dose for subsequent studies dose- escalation/dose- finding phase that followed a modi- would be determined based on safety and pharmacoki- fied 3+3 design. Four weight-based dose levels (0.5, 2, netic (PK) profile from aggregated data across the study. 5 and 10 mg/kg every 2 weeks) were assessed for dose- Part 2 of phase IA was a schedule expansion that evaluated limiting toxicity (DLT). If a DLT was observed in the first tislelizumab at 2 and 5 mg/kg every 2 weeks and every 3 three patients completing one cycle of treatment at a weeks. Part 3 of phase IA (fixed-dose expansion) evalu- given dose level, three additional patients were enrolled. ated tislelizumab 200 mg administered every 3 weeks. The A DLT was defined as an adverse event (AE) occurring phase IB component of this study was an expansion phase in the first 28- day cycle that met the predefined criteria of tislelizumab at 5 mg/kg every 3 weeks in nine disease- based on grading per NCI-CTCAE V.4.03. DLT criteria included any grade ≥4 non-hematological toxicity or specific cohorts. The initial administration of tislelizumab grade 4 laboratory anomaly irrespective of duration; was administered via a 60 min infusion, if tolerated, the any grade ≥3 immune- related AE (irAE), grade 3 tumor infusion was shortened to 30 min for all subsequent flare (ie, local pain, irritation or rash localized at sites of administrations.
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