The purpose of this clinical trial is to evaluate the safety and tolerability of amivantamab and to determine the preliminary antitumour activity of amivantamab administered at the recommended Phase 2 dose (RP2D). In the Phase 1b of this study a biomarker defined arm will be opened, initially in the relapsed GMB setting, enrolling 12 patients. These patients will be treated with amivantamab monotherapy. Amivantamab will be administered intravenously (IV) weekly for the first 4 weeks, then every 2 weeks thereafter until disease progression or unacceptable toxicity. The first dose will be given as a split infusion, 350 mg IV over 4 hours on cycle 1 day 1 and 1400 mg IV over 6 hours on cycle 1 day 2. Subsequent infusions are given at a dose of 1750 mg IV over 2-5 hours in cycle 1 and between 2-3 hours from cycle 2 onwards if the first dose was well-tolerated with no significant toxicity.
Progression to Phase 2 is dependent on emergent data and funding.
Glioblastoma, IDH-wildtype Grade 4
Astrocytoma, IDH-mutant, Grade 4 (lower Grade 2/3 are not included)
Diffuse hemispheric glioma, H3 G34 mutant Grade 4
Patients for Phase 1 will need to have consented to the Minderoo Precision Brain Tumour Programme and have available whole genome, and transcriptome data available.
16 years or over.
Life expectancy of at least 12 weeks.
World Health Organisation (WHO) performance status of 0-1.
Neurologically stable (e.g., without a progression of neurological symptoms or requiring escalating doses of systemic steroid therapy within the last week).
Single group
Amivantamab
DrugAmivantamab will be supplied in single-use 350 mg injectable solution, provided as a 7 ml per glass vial (50mg/ml), intended for IV infusion.
Phase 1b - To evaluate the safety and tolerability of investigational agent in patients with malignant brain tumours
To identify the incidence, nature and severity of adverse events and laboratory abnormalities, with severity determined according to NCI CTCAE v5.0
Phase 1b - To determine the preliminary antitumour activity of the investigational agent administered at the RP2D in patients with molecularly defined malignant brain tumours
Antitumour activity will be defined on the basis of the following outcomes. If any of the following occur, patients will be considered to have clinically benefitted: For relapsed GBM: Achievement of overall response of CR or PR per Response Assessment in Neuro-Oncology (RANO) within 6 months or Free of disease progression or death at 6 months For front line unmethylated GBM (MRD): • Progression-free survival (PFS)
Phase 1b - To identify molecular determinants of response and antitumour activity of the investigational agent in patients with molecularly selected brain tumours
Determination of biomarkers of response, including but not limited to changes in genomic, transcriptomic or immunological signatures from responders and non-responders using tumour sequencing analysis.
Exploratory objective - To determine mechanisms of resistance to the investigational agent in patients with malignant brain tumours
Correlate antitumour activity of the investigational agent with the detection of putative predictive biomarkers of response and resistance in archival tumours, patient derived cells lines and plasma samples banked as part of the Minderoo Precision Brain Tumour Programme.
Exploratory objective - To assess putative predictive biomarkers of the investigational agent in patients with malignant brain tumours
Correlate treatment response with co-segregating mutational landscapes and identify mechanism of precision drug resistance e.g., on target vs off target, on pathway.
Exploratory objective - To identify putative precision therapy combinations with the potential for additive benefit
Plan rational combination therapies based on these results.
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Institute of Cancer Research, United Kingdom
Lead sponsor
Royal Marsden NHS Foundation Trust
Collaborator
Cambridge University Hospitals NHS Foundation Trust
Collaborator
Janssen Pharmaceutica N.V., Belgium
Collaborator
Cancer Research UK
Collaborator
Minderoo Foundation
Collaborator
University of Cambridge
Collaborator
