Trial design, patients and treatment
tumor, prostate cancer, cancer, human immunodeficiency virus/hepatitis C, non-melanoma skin cancer, non-metastatic carcinoma, primary cancer, autoimmune disease, Cancer
TUMOR, VIRUS, PROSTATE CANCER, SPINAL METASTASES, CANCER, DISEASE, RECRUITMENT, PROSTATE, SOLID TUMOR, REMISSION, CERVICAL CARCINOMA IN SITU, SUPERFICIAL BLADDER CANCER, PRIMARY CANCER, AUTOIMMUNE DISEASE, CANCER
This first-in-human, open label phase 1/2 trial is being conducted at six sites in Germany (University Medical Center Hamburg-Eppendorf, University Hospital of Cologne, University Hospital Regensburg, Hannover Medical School, University Hospital Erlangen and the University Medical Center Mainz) and one site in the Netherlands (Netherlands Cancer Institute, Amsterdam) to assess dose levels of CLDN6 CAR-T cells with or without CARVac using a 3 + 3 dose escalation approach. We recruited adults with a diagnosis of metastatic or unresectable solid tumor of any indication with no further treatment options, intermediate or high CLDN6 membrane staining intensity in at least 50% of tumor cells as assessed by semiquantitative immunohistochemistry, and measurable disease per RECIST 1.1. Patients were screened for adequate coagulation, hepatic, renal and hematologic function. GCT patients without initial measurable disease per RECIST 1.1 were eligible for this trial if they had disease evaluable by cancer antigen-125, Alpha-fetoprotein (AFP) or human chorionic gonadotropin (hCG, as applicable), which was introduced by protocol amendment (note that all patients recruited to this trial had measurable disease). Men were not allowed to father a child or donate sperm, and women of child-bearing potential had to agree not to become pregnant. Patients previously treated with another CAR-T cell therapy, who had received vaccination with live virus vaccines within six weeks before the start of LD, who had an active autoimmune disease or human immunodeficiency virus/hepatitis C positivity, or who were receiving concurrent systemic steroid therapy >10 mg were not eligible. Evidence of new or growing brain or spinal metastases during screening was a further exclusion criteria. A history of another primary cancer within the two years before enrollment also precluded entry into the trial, except for the following: non-melanoma skin cancer, cervical carcinoma in situ, superficial bladder cancer, prostate cancer with currently undetectable prostate specific antigen, or other non-metastatic carcinoma that has been in complete remission without treatment for more than two years. The full list of inclusion/exclusion criteria can be found in the trial protocol, available online at 10.1038/s41591-023-02612-0.As the decision was taken to repeat dose escalation using CAR-T cells manufactured using an automated process, a protocol amendment was introduced to cease recruitment to a planned third dose level using the manually produced CAR-T cells. This analysis of the 22 patients dosed between December 2020 and February 2022 with two DLs of CLDN6 CAR-T cells manufactured from autologous leukapheresis material by a manual process was therefore introduced by protocol amendment. All but two patients underwent LD (500 mg mThe dose for CARVac was selected based on prior clinical trial experience with the RNA-LPX vaccine platform in several hundred patients (for example, For further details, please refer to the trial protocol and statistical analysis plan in the 