ABSTRACT
PURPOSE: To evaluate the safety/tolerability and pharmacokinetics of simlukafusp alfa (FAP-IL2v), an immunocytokine containing an anti-fibroblast activation protein-α (FAP) antibody and an interleukin (IL)-2 variant, administered alone or with the programmed death-ligand 1 inhibitor atezolizumab, in Japanese patients with advanced solid tumors. PATIENTS AND METHODS: In this phase 1, open-label, dose-escalation study, patients received intravenous (IV) FAP-IL2v at 10 or 15/20 mg alone or 10 mg when combined with IV atezolizumab. Primary objectives were identification of dose-limiting toxicities (DLTs), recommended dose (RD), and maximum tolerated dose (MTD), and evaluation of the safety/tolerability and pharmacokinetics of FAP-IL2v alone and combined with atezolizumab. RESULTS: All 11 patients experienced adverse events (AEs) during FAP-IL2v treatment. Although most AEs were of mild severity, four treatment-related AEs led to study treatment discontinuation in two patients; one with infusion-related reaction, hypotension, and capillary leak syndrome, and the other with aspartate aminotransferase increased. No AE-related deaths occurred. One DLT (Grade 3 hypotension) occurred in a patient receiving FAP-IL2v 15/20 mg alone. The RD and MTD could not be determined. Pharmacokinetics of FAP-IL2v remained similar with or without atezolizumab. The study was terminated early as FAP-IL2v development was discontinued due to portfolio prioritization (not for efficacy/safety reasons). CONCLUSIONS: This study describes the safety/tolerability of FAP-IL2v 10 mg alone and in combination with atezolizumab in Japanese patients with advanced solid tumors; one DLT (hypotension) occurred with FAP-IL2v 15/20 mg. However, dose escalation of FAP-IL2v was not conducted due to early study termination.
ABSTRACT
INTRODUCTION: We aimed to assess the safety, pharmacokinetic profile, and antitumor activity of adavosertib monotherapy in Japanese patients with advanced solid tumors. MATERIALS AND METHODS: This was a single-center, open-label, phase I study with two consecutive cohorts (250 mg and 200 mg cohorts). Patients received adavosertib at 250 mg or 200 mg, orally once daily for 5 days on and 2 days off for Weeks 1 and 2 of a 21-day cycle. RESULTS: Dose-limiting toxicities (Grade 3 febrile neutropenia) occurred in 2/6 patients in the 250 mg cohort. None of the three patients in the 200 mg cohort developed dose-limiting toxicities. The most frequent treatment-emergent adverse event was nausea (250 mg: 83.3 %; 200 mg: 100.0 %). Median time to peak drug concentration was 4.03 and 2.08 h after the first dose and 2.82 and 1.90 h after multiple dosing in the 250 and 200 mg cohorts, respectively; respective mean terminal elimination half-lives were 7.36 and 7.30 h (first dose) and 10.55 and 8.88 h (multiple dosing). Systemic exposure increased in a slightly more than dose-proportional manner. No RECIST v1.1 response was observed. Disease control rate was 0 % and 33.3 % in the 250 and 200 mg cohorts, respectively. One patient (33.3 %) in the 200 mg cohort showed a best overall response of stable disease at ≥ 8 weeks; the rest showed progressive disease. CONCLUSIONS: Adavosertib 200 mg once daily was well tolerated in this patient population and no safety concerns were raised. Exposure increased in a slightly more than dose-proportional manner and limited antitumor activity was shown. TRIAL REGISTRATION: ClinicalTrials.gov, NCT04462952.
Subject(s)
Neoplasms , Humans , Neoplasms/drug therapy , Male , Female , Middle Aged , Aged , Adult , Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/adverse effects , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/therapeutic use , Dose-Response Relationship, Drug , Maximum Tolerated Dose , Japan , East Asian PeopleABSTRACT
BACKGROUND: Patients with cancer, particularly those undergoing chemotherapy, are at risk from the low immunogenicity of Coronavirus Disease 19 (COVID-19) vaccines. METHODS: This prospective study assessed the seroconversion rate of COVID-19 vaccines among patients with cancer and hospital staff. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein-specific IgG (S-IgG) concentrations were evaluated before the first vaccination, and 1-3 and 4-6 months after the second vaccination. The primary endpoint was the seroconversion rate measured 1-3 months after the second vaccine. RESULTS: In total, 590 patients and 183 healthy hospital staff were analyzed. At 1-3 months after the second vaccination, the S-IgG antibody concentration exceeded the cut-off value (20 BAU/mL) in 96.1% (567/590) of the patients with cancer and 100% (183/183) of the healthy controls (p = 0.0024). At 4-6 months after the second vaccination, the S-IgG antibody concentration exceeded the cut-off value (20 BAU/ml for S-IgG) in 93.1% (461/495) of the patients with cancer and 100% (170/170) of the healthy controls (p < 0.0001). Old age, being male, and low lymphocyte count were related to low SARS-CoV-2 S-IgG levels 1-3 months after the second vaccination among patients, while body mass index, smoking history, and serum albumin level were not. Patients undergoing platinum combination therapy and alkylating agent among cytotoxic drugs, and PARP inhibitor, mTOR inhibitor, and BCR-ABL inhibitor exhibited a low S-IgG antibody concentration compared to the no treatment group. CONCLUSIONS: COVID-19 vaccine immunogenicity was reduced among patients with cancer, especially under several treatment regimens.