Phase I single-dose study of intracavitary-administered Nimotuzumab labeled with 188-Re in adult recurrent high-grade glioma

Abstract

This manuscript has been published online, prior to printing.Once the issue is complete and page numbers have been assigned, the citation will change accordingly.Radioimmunotherapy (RIT) may improve the management of malignant gliomas. A Phase I clinical trial was performed to evaluate, for the first time, the toxicity and clinical effect of an intracavitary administration of a single dose of Nimotuzumab (h-R3) labeled wit 188 Re. Nimotuzumab is a humanized monoclonal antibody directed against epidermal growth factor receptors. Three patients with anaplastic astrocytoma (AA) and 8 with glioblastoma multiforme (GBM) were intended to be treated with 3 mg of mAb labelled with 10 or 15 mCi of 188 Re. In patients treated with 10 mCi (n = 6) transitory worsening of pre-existing neurological symptoms were observed. Two patients treated with 15 mCi (n = 4) developed early severe neurological symptoms and one also developed late severe toxicity (radionecrosis). In the group treated with 10 mCi, 1 GBM patient died in progression 6 months after the treatment, 2 patients (1 GBM and 1 AA) developed stable disease during 3 months. One GBM patient had partial response for more than 1 year and 2 patients (1 GBM and 1 AA) were asymptomatic and in complete response after 3 years of treatment. Maximal tolerated dose of the radioimmunoconjugate 188 Re-Nimotuzumab was 3 mg of the h-R3 labelled with 10 mCi of 188 Re. The radioimmunoconjugate showed a high retention in the surgical created resection cavity and the brain adjacent tissues with a mean value of 85.5% of the injected dose one hour post-administration. This radioimmunoconjugate may be relatively safe and a promising therapeutic approach for treating high grade gliomas.

Tumor eradication in rat glioma and bypass of immunosuppressive barriers using internal radiation with 188Re-lipid nanocapsules

“…In this context, locoregional drug delivery modalities, such as stereotactic radiosurgery, which allow for blood-brain barrier (BBB) bypass and reduced systemic toxicity, are of major relevance. Clinical trials on GBM patients supported the usefulness of local radiolabeled peptide receptor therapy ( 90 Y-DOTATOC [4]) and radioimmunotherapy ( 131 Itenascin antibodies [5] and 188 Re-nimotuzumab [6]). Thus, nanoparticles issued from new technologies hold great promise for developing effective targeted therapies for gliomas.…”

“…Special attention was given to therapeutic efficiency and the potential involvement of the immune system. 6 …”

Trial watch: Tumor-targeting monoclonal antibodies for oncological indications

“…AFM11, a bispecific tandem mAb (TandAb Ò ) 147 that also targets CD3 and CD19, 148,149 is being tested as a standalone therapeutic intervention in patients with B-cell ALL and non-Hodgkin's lymphoma (NHL) (NCT02106091). Nimotuzumab, a humanized IgG1 targeting the EGFR, [150][151][152] is being assessed (most often in the context of standard, cisplatin-based chemotherapy) in patients with nasopharyngeal carcinoma (NCT02012062), esophageal carcinoma (NCT02011594; NCT02034968; NCT02041819) or cervical carcinoma (NCT02039791; NCT02083211; NCT02095119). Rilotumumab, a human IgG2 that neutralizes hepatocyte growth factor (HGF), [153][154][155] is being evaluated in combination with conventional chemotherapeutics or targeted anticancer agents (such as the EGFR inhibitor erlotinib) 156,157 in subjects with gastric carcinoma (NCT02137343; NCT02213289) or NSCLC (NCT02154490).…”

EGFR as a therapeutic target in glioblastoma

“…An average of 85.5% of the antibody remained in the tumor cavity 1 hour following injection, and it was reasonably well tolerated by patients. As 5 of 11 patients achieved at least SD, the authors suggest further investigation of the efficacy of intracavitary delivery [88]. …”