ABSTRACT
Background: Patients with cancer have an increased risk of complications from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections. Vaccination is recommended, but the impact of chemotherapy and immunotherapy on immunogenicity and safety is still unclear. Methods: This prospective multicenter non-inferiority trial comprises four cohorts: individuals without cancer (A) and patients with solid tumors who were treated with immunotherapy (B), chemotherapy (C) or chemo-immunotherapy (D). Participants received two mRNA-1273 vaccinations 28 days apart. The primary endpoint was SARS-CoV-2 Spike S1-specific IgG serum antibody response, defined as >10 binding antibody units (BAU)/ml 28 days after the second vaccination. We also assessed the virus neutralizing capacity of these antibodies, SARS-CoV-2 Spike-specific interferon-gamma T cell response, and adverse events. Results: Of the 791 participants enrolled, 743 were evaluable for the primary endpoint in cohort A (n=240), B (n=131), C (n=229) and D (n=143). A SARS-CoV-2-binding antibody response was found in 100%, 99.3%, 97.4%, and 100% of the participants in cohorts A, B, C, and D, respectively. To discriminate between suboptimal and adequate responders, we defined a cut-off level at 300 BAU/ml, based on neutralizing capacity. The antibody response was considered adequate after the first vaccination in 66.0%, 37.1%, 32.5%, and 33.3% of the participants in cohorts A, B, C, and D, respectively. This raised 28 days after the second vaccination to respectively 99.6%, 93.1%, 83.8%, and 88.8% in cohorts A, B, C, and D. Spike-specific T cell responses were detected in 46.7% of suboptimal and non-responders. No new safety signals were observed. Conclusions: mRNA-1273 vaccination is safe in the patient populations studied. For each cohort, the proportion of patients with a SARS-CoV-2-binding antibody response after two vaccinations is non-inferior compared to individuals without cancer. However, a significant minority lacks an adequate response. Most patients have an antibody concentration increase after the second vaccination. Therefore, an additional booster may turn inadequate into adequate responders. Clinical trial identification: NCT04715438. Legal entity responsible for the study: University Medical Center Groningen, the Netherlands. Funding: ZonMw, The Netherlands Organisation for Health Research and Development. Disclosure: All authors have declared no conflicts of interest.
ABSTRACT
Background: The Wee1 tyrosine kinase is activated upon DNA damage and regulates the G2-M cell cycle checkpoint. Inhibition of Wee1, in conjunction with additional genetic alterations and/or addition of a DNA damaging agent, results in mitotic catastrophe and apoptosis of cancer cells, being an attractive approach for treating cancer. Debio 0123 is a potent and highly specific WEE1 inhibitor with an IC50 in the low nanomolar range. Debio 0123 was demonstrated to inhibit phospho-CDC2 which translated into an increase in DNA damage and premature entry into mitosis (AACR 2019, abstract 4423). Debio 0123 combination with carboplatin (CbPt) was synergic in vitro. In vivo, Debio 0123 was demonstrated to increase antitumoral activity of cbPt in models where neither agent was active alone. Trial design: Methods This is a phase I, multi-center, open-label, dose escalation study of Debio 0123 as monotherapy (first cycle only) and in combination with CbPt, from cycle 2 in subjects with advanced solid tumors that recurred or progressed following prior platinum therapy. Primary objective: determination of the recommended phase II dose (RP2D) of Debio 0123 when administered in combination with CbPt using a modified Continual Reassessment Method (mCRM). Patients receive Debio 0123 orally once daily for the first 3 days of a 21 day-cycle as monotherapy during first cycle and in combination with CbPt in following cycles. Secondary objectives: includes determination of occurrence of dose-limiting toxicities (DLT) and characterization of the pharmacokinetics of Debio 0123 and its active metabolite, which are evaluated after single and repeated administration when administered alone or in combination with CbPt. Potential risk of QTc prolongation is evaluated by exposure-response modeling. Pharmacodynamics biomarkers including phospho-CDC2 are explored in pre- and post-treatment tumors and skin biopsies. Recruitment started in July 2019. Cohort 2 has been completed. Start of enrollment into cohort 3 is currently unknow due to COVID-19 but will begin as soon as possible. Clinical trial identification: NCT03968653. Legal entity responsible for the study: Debiopharm Interbational S.A. Funding: Debiopharm International S.A. Disclosure: V. Nicolas: Full/Part-time employment: Debiopharm AS. A. Vaslin: Full/Part-time employment: Debiopharm AS. K. Tobal: Full/Part-time employment: Debiopharm AS. D. Purcea: Full/Part-time employment: Debiopharm AS. S.F. van Haren: Full/Part-time employment: Debiopharm AS. L. Damstrup: Full/Part-time employment: Debiopharm International S.A. All other authors have declared no conflicts of interest.