IDH1-vac in Patients With Newly Diagnosed IDH1R132H-positive High-grade Astrocytomas

Astrocytomas with mutations in the IDH1 gene are incurable diffusely infiltrating primary brain tumors in young adults with a median overall survival (OS) of 4-7 years. A principle characteristic largely contributing to this aggressive biology is the highly invasive behavior, which allows the active evasion of glioma cells from the main tumor mass not only into the surrounding but also into distant normal brain tissue.

The standard of care (SOC) consists of resection and radiotherapy alone or with concomitant temozolomide (TMZ) chemotherapy followed by 6 to 12 cycles of adjuvant TMZ. Recurrence and malignant transformation following SOC, however, are inevitable. To date, there are no effective measures preventing recurrence and/or malignant transformation. Achieving an effective prevention by stimulating the immune system to control transformed tumor cells could result in long-term remission of the disease.

A recently approved small molecule inhibitor of IDH demonstrated efficacy in preventing tumor growth in IDH-mutant low-grade gliomas. The drug is not yet approved for patients with high grade (grade 3 and grade 4) astrocytomas.

From an immunological point of view IDH1R132H represents an attractive tumor antigen specifically expressed in tumor but not normal cells. Patients with IDH1R132H-mutated gliomas may harbor mutation-specific T cells and antibodies, indicating that IDH1R132H is specifically presented to and recognized by the immune system in a mutation-specific manner.

The patient population will be molecularly defined and include IDH1R132H mutant grade 3 and grade 4 gliomas without co-deletion of 1p/19q and with loss of alpha-thalassemia/mental retardation syndrome X-linked (ATRX) expression. Patients must have received radiotherapy alone or with concomitant temozolomide (TMZ) chemotherapy as standard of care (SOC) prior to enrollment.

In STAR-VACC, IDH1-vac treatment will be added to SOC starting with adjuvant TMZ chemotherapy. Primary endpoint of the study is OS. Secondary endpoints include PFS and patient-reported outcomes (PROs). Immunological biomarkers are assessed in exploratory endpoints. Detailed molecular analyses from tumor tissue will allow for defining subgroups with differential benefit.

IDH1-vac demonstrated safety and biological activity in a Phase 1 first-in human clinical trial (NOA-16, ClinicalTrias.gov Identifier NCT02454634) when added to SOC and patients who received IDH1-vac showed favorable clinical courses.

The trial will be performed within the National Center of Tumor Diseases (NCT) network and additional sites of the Neurooncology Working Group (NOA) of the German Cancer Society.

STAR-VACC is a controlled double-blind clinical trial, two of three patients recruited to the trial will receive IDH1-vac, one of three will receive an immune stimulator (IS-vac). IDH1-vac contains an IDH1R132H 20-mer peptide emulsified in Montanide™ and will be administered subcutaneously in combination with topical imiquimod (Aldara®). IS-vac contains Montanide™ in combination with topical imiquimod (Aldara®).

In total 204 evaluable patients will be enrolled in the clinical trial. A futility analysis, assessing if the primary objective (improving OS) can be reached, is performed after patients have experienced 20% of the primary endpoint-related event (expected when 135 evaluable patients have been enrolled).

In an initial therapy phase, patients will receive up to 8 vaccinations every two (vaccination 1-4) or four weeks (5-8) followed by a boosting regime every 24 weeks (6 months). After four boosts (approximately three years after treatment initiation), end of study (EOS) is reached. Patients with stable disease at EOS will undergo watchful waiting with magnetic resonance imaging every 3 months and clinical assessment as part of the routine follow up.