Dose escalation study of targeted alpha therapy with [225Ac]Ac-DOTA-substance P in recurrence glioblastoma – safety and efficacy

Abstract

Glioblastoma is the most common and malignant primary brain tumour, with a poor prognosis. Introduction of new treatment options is critically important. The study aimed to assess the appropriateness of escalation doses and toxicity of [225Ac]Ac-DOTA-SP therapy. Material and methods A total of 21 patients (age of 43.0 ± 9.5 years), with histologically confirmed recurrent or conversion glioblastoma grade 4 following a standard therapy, have been included in the study. One to 2 intracavitary port-a-cath systems were stereotactically inserted. Patients were treated with escalation dose protocol with 10, 20 and 30 MBq per cycle totally 1–6 doses of [225Ac]Ac-DOTA-SP in 2-month intervals. Therapeutic response was monitored by clinical performance status and MRI imaging. Results Treatment was well tolerated with mostly mild temporary adverse effects (oedema, epileptic seizures, aphasia, hemiparesis) mainly in the group of patients treated with 30 MBq of [225Ac]Ac-DOTA-SP. Only one patient treated with 30 MBq revealed thrombopenia grade 3. There was no other grade 3 and 4 toxicity related to [225Ac]Ac-DOTA-treatment in all groups. The median overall survival time from the primary diagnosis (OS-d) was 35.0 months and from the diagnosis of the recurrence/conversion (OS-r/c) was 13.2 months. From the start of treatment with [225Ac]Ac-DOTA-SP, the median PFS was 2.4 months, and the OS-t was 9.0 months. There were no statistically significant differences between the investigated dose escalation groups. Conclusions Treatment of recurrent glioblastoma with [225Ac]Ac-DOTA-SP is safe and well tolerated up to 30 MBq per cycle. The escalation dose protocol showed good tolerability. Only mild temporary adverse effects were observed. No remarkable haematological, kidney and liver toxicity was seen.

Novel NK1R-Targeted 68Ga-/177Lu-Radioconjugates with Potential Application against Glioblastoma Multiforme: Preliminary Exploration of Structure–Activity Relationships

“…These peptides, conjugated with the macrocyclic chelators (DOTA or DOTAGA), were labelled with 90 Y, 177 Lu or 213 Bi. SP-based radioconjugates labelled with 225 Ac have also been subject to in vitro [11] and in vivo [8,12] investigations.…”

Perspective on the Use of DNA Repair Inhibitors as a Tool for Imaging and Radionuclide Therapy of Glioblastoma

“…Complex DNA damage significantly contributes to exceeding the cellular capabilities of DNA repair, thereby forcing cells towards cell death [ 20 ]. The first positive clinical trials on TAT have emerged, and TAT was suggested as a facilitator to overcome tumoral resistance to chemotherapy [ 47 , 48 ]. A nice example is the astatine-211 radiolabeled PARPi, which induced cellular lethality by targeting alpha-emitters directly to the nucleus, with high sensitivity in neuroblastoma in vitro and in vivo.…”

The Evolving Coordination Chemistry of Radiometals for Targeted Alpha Therapy

“…[14] [ 225 Ac][Ac(DOTA)]administered intravenously to adult C57BL/6 mice cleared rapidly via the urine, demonstrating that the complex is stable in vivo for at least 5 h. [14,40] Several constructs using [ 225 Ac] [Ac(DOTA)]have subsequently been produced featuring targeting groups, including small molecules, peptides, and antibodies. [21,[24][25][26][27][28][29][30][31]39,[41][42][43][44][45][46][47] Initial studies to prepare [ 225 Ac][AcDOTA] --antibody constructs utilised a two-step procedure that involved radiolabelling the bifunctional p-SCN-Bn-H 4 DOTA (Bn ¼ benzyl) chelator with 225 Ac 3þ at 55-608C before attachment to temperaturesensitive antibodies. [48] This process was utilised successfully to prepare the anti-prostate specific membrane antigen (PSMA) construct [ 225 Ac][Ac(DOTA-J591)] -, which was readily internalised by cancer cells and led to tumour regression and prolonged survival of mice bearing prostate carcinoma.…”