This phase I trial studies the side effects and best dose of Actimab-A when given together with cemiplimab (REGN2810) in treating patients with glioblastomas that have come back after a period of improvement (recurrent). Actimab-A consists of the monoclonal antibody lintuzumab combined with the radioactive drug actinium Ac 225. Lintuzumab specifically binds to the cell surface antigen CD33 which is found on the glioblastoma cells and delivers the actinium Ac 225. This may allow the glioblastoma to be found and treated by Actimab-A. Immunotherapy with monoclonal antibodies, such as cemiplimab (REGN2810), may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving Actimab-A with cemiplimab (REGN2810) may be safe, tolerable and/or effective in treating recurrent glioblastoma.
Patients must have histologically or cytologically confirmed glioblastoma isocitrate dehydrogenase wild type (IDH-WT) World Health Organization (WHO) grade 4 inclusive of gliosarcoma (Louis et al., 2021)
Note: Isocitrate dehydrogenase (IDH) status confirmed by immunohistochemistry (IHC) for IDH1 R132H + next-generation sequencing (NGS) for IDH1 and IDH2 hotspots
Evidence of recurrent disease (RD) that is measurable (1 x 1cm) at first or second relapse demonstrated by disease progression using Response Assessment in Neuro-Oncology 2.0 (RANO 2.0) criteria, unless the recurrence is outside the radiation field or has been histologically documented
Tumor O-6-methylguanine-deoxyribonucleic acid (DNA) methyltransferase (MGMT) methylation status must be available from any prior GBM tumor specimen; results of routinely used methods for MGMT methylation testing (e.g., mutagenically separated polymerase chain reaction [MSPCR] or quantitative polymerase chain reaction [PCR] are acceptable)
Patients who have not recovered to grade 0 or 1 or pre-treatment baseline from adverse events due to prior anti-cancer therapy (i.e., have residual toxicities > grade 1) with the exception of alopecia
Patients who are receiving any other investigational agents
Presence of extracranial metastatic or leptomeningeal disease
History of allergic reactions attributed to compounds of similar chemical or biologic composition to Actimab-A and cemiplimab (REGN2810)
Single group
Actinium Ac 225 Lintuzumab
RadiationGiven IV
Biospecimen Collection
Procedure/SurgeryUndergo blood sample collection
Cemiplimab
Biological/VaccineGiven IV
Computed Tomography
Procedure/SurgeryUndergo PET/CT and/or SPECT/CT
Positron Emission Tomography
Procedure/SurgeryUndergo PET/CT
Radiologic Imaging Procedure
Procedure/SurgeryUndergo radiologic imaging
Single Photon Emission Computed Tomography
Procedure/SurgeryUndergo SPECT/CT
Dose limiting toxicities (DLTs)
DLT is defined as any grade ≥ 3 non-hematologic toxicity regardless of supportive care or grade ≥ 4 hematologic toxicity per Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 that occurs during the first six (6) weeks after initiating treatment. DLTs per CTCAE version 5.0 will be tabulated for each dose level.
Maximum tolerated dose (MTD)
Will use a Bayesian optimal interval design to find the MTD. Recommended phase 2 dose determination will include both the DLT period for the MTD, as well as consideration of later cycle adverse events (AEs) and the overall safety profile, and available correlatives and will be determined by the study team and Cancer Therapy Evaluation Program collaborators.
Frequency of AEs
AEs per CTCAE version 5.0 will be tabulated for each dose level.
Objective response rate (ORR)
Treatment response will be assessed for all patients based on Response Assessment in Neuro-Oncology 2.0 (RANO 2.0) criteria: complete response (CR), partial response (PR), stable disease (SD), and progression of disease (PD). ORR is defined as the addition of CR and PR. ORR rate will be calculated by the proportion of evaluable patients with objective response (CR/PR), along with its exact 95% confidence interval (CI).
Progression free survival
Treatment response will be assessed for all patients based on RANO 2.0 criteria: CR, PR, SD, and PD. Kaplan-Meier estimates will be provided. The corresponding median survival time (with 95% CI) will be determined.
Overall survival
Treatment response will be assessed for all patients based on RANO 2.0 criteria: CR, PR, SD, and PD. Kaplan-Meier estimates will be provided. The corresponding median survival time (with 95% CI) will be determined.
Tumor mutational burden (TMB) (whole exome sequencing [somatic])
Will evaluate the impact of baseline TMB on response. TMB will be evaluated in each patient and correlation assessment will be performed with clinical activity by Spearman's correlation coefficient. Will also use a logistic regression model to test the association between TMB and ORR.
Change in variant allele frequencies (VAF) of tumor mutations in circulating tumor deoxyribonucleic acid (ctDNA)
Will evaluate ctDNA as a predictor for treatment response. The detectable VAFs will be assessed and trended during the course of treatment. VAF change will be assessed categorically for each patient (increased or decreased at start of C3 as compared to baseline). The association of VAF change with objective response will be tested using the Fisher's exact test, where p \< 0.05 will be considered statistically significant.
Expression of immune checkpoint receptors and myeloid derived suppressor cells markers by ribonucleic acid sequencing (RNAseq) on archival tissue
Will evaluate the impact of baseline tumor expression signatures on response. Expression levels will be evaluated in each patient and correlation assessment will be performed between T-cell density, gene response set values and other endpoints such as clinical response by Spearman's correlation coefficient.
Protein expression of CD33 and PD-L1 by immunohistochemistry on archival tissue
Will evaluate the impact of baseline tumor expression signatures on response. Expression levels will be evaluated in each patient and correlation assessment will be performed with clinical response by Spearman's correlation coefficient.
Interferon gamma in serum by enzyme-linked immunosorbent assay (ELISA)
Will evaluate the correlation of changes in cytokine production and arginase activity with response. ELISA will quantify interferon gamma evaluated in each patient over time (paired), and between patients (non paired), from baseline to each blood draw at a significance level (alpha) of 0.05, and correlated with objective response will be tested using the Fisher's exact test, where p \< 0.05 will be considered statistically significant.
Click on the lead sponsor to view all of their trials.
This trial is not recruiting at the moment. You can still explore other options:
