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RO5126766 has a manageable safety profile up to 2.25 mg/day once daily with a favorable PK/PD profile in Japanese patients with advanced solid tumors.

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RO4987655 is an oral and selective inhibitor of MEK, a key enzyme of the mitogen-activated protein kinase (MAPK) signaling pathway. This phase I dose-escalation study of RO4987655 in Japanese patients with advanced solid tumors aimed to determine maximum tolerated dose (MTD) and to evaluate safety, pharmacokinetics (PK), pharmacodynamics (PD), and anti-tumor activity. Patients received a single dose of RO4987655 (1, 2, 4, 5, or 6.5 mg) followed by continuous once-daily dosing (1, 2, or 4 mg QD) or twice-daily dosing (4, 5, or 6.5 mg BID) in 28-day cycles. A 3 + 3 dose-escalation design was used. PD was evaluated by pERK inhibition in peripheral blood mononuclear cells (PBMCs). In dose-escalation, 25 patients were enrolled. After the MTD was determined, a further six patients were administered the MTD for further confirmation of safety. MTD was determined as 8 mg/day (4 mg BID) due to a total of four dose-limiting toxicities (DLTs) of grade 3 creatine phosphokinase (CPK) elevation (2 DLTs each in 10 mg/day and 13 mg/day). Most commonly related adverse events included dermatitis acneiform, CPK elevation, and eye disorders. Plasma concentration of RO4987655 appeared to increase in a dose-proportional manner with a plasma half-life of 4.32 to 21.1 h. Following multiple dose administration, a steady-state condition was reached by Cycle 1 Day 8. The inhibitory effects of RO4987655 on pERK in PBMCs increased in a dose-dependent manner. One esophageal cancer patient had confirmed partial response and seven patients showed progression-free survival for longer than 16 weeks. The MTD of RO4987655 for Japanese patients was determined as 8 mg/day (4 mg BID). RO4987655 was tolerated up to the MTD with a favorable PK/PD profile in Japanese patients with advanced solid tumors.

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Background: ERY974, a bispecific T cell-redirecting antibody, redirects T cells to tumor cells by engaging the CD3 antigen on T cells and the glypican 3 (GPC3) antigen selectively expressed on tumors. ERY974 demonstrates T cell-dependent cellular cytotoxicity in vitro and transient cytokine elevations in preclinical toxicology studies (Ishiguro et al. 2017). The primary objective of this dose escalation (DE) study was to determine ERY974's maximum tolerated dose in patients with locally advanced or metastatic solid tumors expressing GPC3. Methods: The study included adult patients with advanced or metastatic solid tumors not amenable to standard therapy, histologically confirmed, with measurable disease and a life expectancy ≥ 3 months, including patients with ≤ 1cm and ≤ 1 brain metastasis. Patients with interstitial lung disease, or acute/active chronic infection were excluded. ERY974 was administered IV and dosed weekly. DE was initiated with an accelerated titration design of single patient cohorts followed by three patient cohorts. To mitigate for the toxicity of cytokine release syndrome (CRS), steroid prophylaxis and a flexible study design was implemented which included a two-step intra-patient escalation (regimen A), and a three-step intra-patient escalation (regimen B). Results: 29 patients were enrolled in dose levels ranging from 0.003 μg/kg to 0.81 μg/kg. Treatment-related adverse events that occurred in greater than 20% of patients included CRS and pyrexia. Dose level 0.81 μg/kg (regimen A) was confirmed not tolerable due to DLTs of Grade 3 CRS and Grade 2 CRS in two out of three patients (assessed according to Lee, et al. 2014). The Grade 3 CRS was associated with Grade 3 transaminitis and a Grade 3 elevation of bilirubin. Both CRS events led to dose delay and dose reduction. Increases in IL-6, IL-8 and IL-10 were observed in patients with the CRS. The severity and frequency of CRS in regimen B were similar to those observed in regimen A at the same dose level. One partial response (per modified RECIST criteria) was observed in a patient with esophageal cancer treated with 0.54 μg/kg (regimen B) and having 40% of the tumor tissue staining positive for GPC3 via immunohistochemistry. Stable disease lasting 3 months or longer was observed in four patients. Conclusions: The observed responses and CRS side effects are markers of ERY974 biologic activity. At doses below 0.81 μg/kg (regimen A), ERY974 was generally well tolerated with a manageable toxicity profile, including ERY-induced CRS which was manageable with steroid administration and anti-IL6R therapy. Further research is required to determine if combined prophylactic anti-IL6R and steroid therapy is a more effective strategy for managing CRS. References: 1. Ishiguro, Takahiro, et al. Science translational medicine, 2017, 9.410: eaal4291. 2. Lee, Daniel W., et al. Blood, 2014, 124.2: 188-195. Citation Format: Howard Safran, Mihaela Druta, Michael Morse, Filipa Lynce, Sofya Pintova, Khaldoun Almhanna, Daniel Weiss, Athos Gianella-Borradori, Yoshitaka Ogita, Roland Morley, Mikiko Nakamura, Junnosuke Matsushima, Takahiro Ishiguro. Results of a phase 1 dose escalation study of ERY974, an anti-glypican 3 (GPC3)/CD3 bispecific antibody, in patients with advanced solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT111.

TPS3112 Background: Bispecific antibodies to facilitate T-cell directed cytotoxicity (TDCC) is a proven therapy strategy in cancer. ERY974 is a humanized IgG4 bispecific antibody designed to simultaneously bind to cytotoxic T-cell CD3 receptors and GPC3 (a glycoprotein expressed on cell surface of several tumors) to elicit T-cell activation and TDCC. The objectives of this multi-country, phase 1 study of ERY974 is to determine the maximum tolerated dose (MTD) and to perform a preliminary assessment of anti-tumor activity in patients with solid tumors expressing GPC3. Methods: ERY974 is dosed IV weekly. All patients receive premedication with dexamethasone (DEX) prior to 1st and 2nd ERY974 dose. DE uses an accelerated titration design (ATD), then a modified continual reassessment method (mCRM) described by one-parameter logistic model, to determine MTD, where DLT occurrence rate is 0.25. Combining ATD and mCRM is to permit rapid dose escalation whilst minimizing patient numbers exposed to sub-therapeutic doses, and to accurately determine MTD. Once grade 2 (G2) cytokine release syndrome (CRS) is observed, DEX is increased. If ≥G2 CRS is again observed, then at all subsequent doses the 1st dose of ERY974 is fixed at the last dose level when < G2 CRS was not seen, DE proceeds with the 2nd dose. ATD commences with n = 1, increasing to n = 3 once drug-related ≥G2 toxicity is seen. mCRM starts after 1st dose limiting toxicity (DLT), with the modifications of at least 3 patients required to dose escalate and up to 1.5x increment to minimize risk of toxicity. CE has 3 arms: GPC3+ gastric/gastroesophageal junction adenocarcinoma; GPC3+ squamous esophageal cancer; and other GPC3+ tumors. A 2-stage design is used to allow CE to stop early for futility. Subjects are adults with histologically confirmed, measurable malignant solid tumors and/or metastatic disease not amenable to standard therapy, and life expectancy ≥3 months. Patients with > 1cm or > 1 brain metastasis, current/previous interstitial lung disease, and acute/chronic infection are excluded. 3 cohorts have been completed without DLT. Cohort 4 began in January 2017. Clinical trial information: NCT02748837.

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