A single-center, open-label, non-randomized phase I/II study to evaluate the efficacy, safety and tolerance of crizanlizumab monotherapy and in combination with nivolumab in patients with advanced glioblastoma (GB) who exhausted standard of care (SOC) therapy, patients with metastatic brain melanoma (MBM) and patients with newly diagnosed unmethylated GB.
Subjects will be screened for up to 28 days prior to treatment initiation. Eligible subjects will be allocated to one of 3 cohorts:
Cohort 1: Patients with metastatic melanoma with primarily diagnosed or newly progressing brain metastases who failed immunotherapy.
Cohort 2: Patients with recurrent or progressing GB following primary radiation therapy and temozolomide. Patients may have failed up to 2 prior systemic treatment lines (including temozolomide as adjuvant therapy) and are candidates for further treatment.
Cohort 3: Patients with newly diagnosed GB who were evaluated for methylguanine-DNA methyltransferase(MGMT) methylation status and have un-methylated MGMT promotor-therefore, they are not candidates for maintenance temozolomide therapy.
Estimated life expectancy at least 3 months
Have metastatic melanoma with primarily diagnosed or newly progressing brain metastases.
Was treated with 1 prior systemic line of immunotherapy - either PD-1 inhibitor monotherapy or combined CTLA4 and PD-1 antibodies or another investigational combination of immunotherapy. Patients with BRAF-mutant melanoma who have also received BRAF mutation targeted therapy are also eligible.
Have failed prior immunotherapy line, either due to primary resistance or acquired resistance.
Systemic steroid therapy for symptomatic brain disease. Note: a dose equivalent to 10 mg prednisone will be allowed
Have leptomeningeal spread.
Previous life-threatening toxicity to anti-PD-1 antibody monotherapy.
Auto-immune disease in the last 2 years requiring systemic immune-suppressive therapy.
Parallel
Crizanlizumab-Tmca 10 MG/1 ML Intravenous Solution [ADAKVEO]
Drug5 mg/kg solution for injection
Nivolumab 10 MG/1 ML Intravenous Solution [OPDIVO]
Drug3 mg/mL solution for injection
Incidence of treatment-related adverse, serious adverse events, immune-related AEs following treatment with crizanlizumab alone or in combination with nivolumab
Safety and tolerability assessed by CTCAE v 6.0
The proportion of treatment discontinuation events related to the treatment combination
Safety and tolerability assessed by CTCAE v 6.0
Response Rate (RR) to crizanlizumab monotherapy and in combination with nivolumab
evaluated by RECIST 1.1 and by RANO and RANO-BM criteria.
Progression-free survival (PFS) of patients with GB or MBM following treatment crizanlizumab monotherapy and in combination with nivolumab
by brain MRI and CT of chest/abdomen and pelvis using RECIST 1.1 and RANO/RANO-BM criteria
Overall survival (OS) in patients with GB or MBM following treatment crizanlizumab monotherapy and in combination with nivolumab.
Overall survival (OS) of the study population
Impact of the treatment protocol on health-related quality of life
using EORTC questionnaires ,All of the scales and single-item measures range in score from 0 to 100. A high scale score represents a higher response level. Thus a high score for a functional scale represents a high / healthy level of functioning, a high score for the global health status / QoL represents a high QoL, but a high score for a symptom scale / item represents a high level of symptomatology / problems.
The response to crizanlizumab monotherapy and in combination with nivolumab
by iRANO criteria
Plasma levels of Crizanlizumab measurements
Plasma levels of Crizanlizumab will be measured. The following parameters will be calculated: maximum (peak) plasma drug concentration (Cmax), area under the plasma concentration-time curve from time zero to time t (AUC0-t), area under the plasma concentration-time curve from time zero to infinity (AUC0-∞), mean residence time (MRT), elimination half-life (t½), elimination rate constant (Kel), apparent total body clearance of the drug from plasma (Cl), apparent volume of distribution (Vd). evaluated by blood for pharmacokinetics analyses that will be collected at the following time points: * Baseline (Day 1) prior to dosing and at 15 min, 30 min, 1 hour, 2 hours, 4 hours, and 8 ±1 hour post-dosing. * Day 2, at 20-24 hours post dosing. * Day 15±1 prior to dosing and at 15 min, 30 min, 1 hour, 2 hours, 4 hours, and 8 ±1 hour post-dosing.
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Sheba Medical Center
Lead sponsor
Prof. Ronit Satchi-Fainaro, Director, Cancer Biology Research Center, Tel Aviv University, Tel Aviv, Israel.
Collaborator
