Crizanlizumab Alone or in Combination With Nivolumab for Glioblastoma and Melanoma With Brain Metastases
- Conditions
- Metastatic Melanoma in the Central Nervous SystemMGMT-Unmethylated GlioblastomaAdvanced Glioblastoma
- Interventions
- Registration Number
- NCT05909618
- Lead Sponsor
- Sheba Medical Center
- Brief Summary
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.
- Detailed Description
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 MGMT methylation status and have un-methylated MGMT promotor-therefore, they are not candidates for maintenance temozolomide therapy.
The first 3 subjects enrolled to Cohort 1 and Cohort 2 will receive crizanlizumab 5 mg/kg at Cycle 1 Day 1 (C1D1) and Cycle 1 Day 15 (C1D15) followed by crizanlizumab 5 mg/kg every 4 weeks until disease progression evaluated by RECIST 1.1 and RANO criteria or intolerable toxicity. The subsequent 8 patients will receive crizanlizumab 5 miligram/kilogram (mg/kg) at C1D1 and C1D15 followed by 5 mg/kg every 4 weeks plus nivolumab 3mg/kg every 2 weeks until disease progression. The subjects will continue the treatment until disease progression or until completion of 27 cycles (2 years). Subjects who complete 2 years of therapy will maintain follow-up.
Subjects in Cohort 3 will receive crizanlizumab starting from 4 weeks after completing radiation therapy. The first 2 subjects will receive crizanlizumab 2.5 mg/kg at C1D1 and C1D15 followed by crizanlizumab 5 mg/kg every 4 weeks. The subsequent 6 subjects will receive crizanlizumab 5 mg/kg at C1D1 and C1D15 followed by crizanlizumab every 4 weeks. Treatment will continue for up to 12 months or until disease progression or unacceptable toxicity.
Safety and tolerability will be assessed by CTCAE v 6.0 every week for the first 4 weeks followed by assessments every 2 weeks until Week 12, and then every 4 weeks.
Tumor response will be evaluated by brain Magnetic resonance imaging (MRI) every 8 weeks using RANO criteria. Patients with metastatic melanoma will also be evaluated with chest-abdomen and pelvis Computed tomography (CT) every 8 weeks for the evaluation of visceral disease using RECIST 1.1.
Patients with MBM (Cohort 1) whose primary tumor/non-brain tumor progresses on RECIST 1.1 but whose brain tumor/metastases show benefit (stable disease or better), may continue in the study at the investigator's discretion.
Quality of life will be assessed by the Quality of Life Questionnaire (EORTC QLQ-30) and Brain Neoplasm(QLQ BN-20) and by cognitive function tests.
Archived tissue samples (and optional fresh biopsy), CSF and blood samples will be drawn to assess pharmacokinetics and pharmacodynamics of the combined therapy and for collateral research aiming to define biomarkers for response.
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 33
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Cohort 1 metastatic melanoma with brain metastases who failed immunotherapy Crizanlizumab-Tmca 10 MG/1 ML Intravenous Solution [ADAKVEO] The first 3 subjects enrolled to Cohort 1 and Cohort 2 will receive crizanlizumab 5 mg/kg at Cycle 1 Day 1 (C1D1) and C1D15 followed by crizanlizumab 5 mg/kg every 4 weeks until disease progression The subsequent 8 patients will receive crizanlizumab 5 mg/kg at C1D1 and C1D15 followed by 5 mg/kg every 4 weeks plus nivolumab 3mg/kg every 2 weeks until disease progression Cohort 2 - Patients with recurrent or progressing GB following radiation and temozolamide. Crizanlizumab-Tmca 10 MG/1 ML Intravenous Solution [ADAKVEO] The first 3 subjects enrolled to Cohort 1 and Cohort 2 will receive crizanlizumab 5 mg/kg at Cycle 1 Day 1 (C1D1) and C1D15 followed by crizanlizumab 5 mg/kg every 4 weeks until disease progression The subsequent 8 patients will receive crizanlizumab 5 mg/kg at C1D1 and C1D15 followed by 5 mg/kg every 4 weeks plus nivolumab 3mg/kg every 2 weeks until disease progression Cohort 3: Patients with newly diagnosed GB Crizanlizumab-Tmca 10 MG/1 ML Intravenous Solution [ADAKVEO] crizanlizumab starting from 4 weeks after completing radiation therapy. The first 2 subjects will receive crizanlizumab 2.5 mg/kg at C1D1 and C1D15 followed by crizanlizumab 5 mg/kg every 4 weeks. The subsequent 6 subjects will receive crizanlizumab 5 mg/kg at C1D1 and C1D15 followed by crizanlizumab every 4 weeks. Treatment will continue for up to 12 months or until disease progression or unacceptable toxicity. Cohort 1 metastatic melanoma with brain metastases who failed immunotherapy Nivolumab 10 MG/1 ML Intravenous Solution [OPDIVO] The first 3 subjects enrolled to Cohort 1 and Cohort 2 will receive crizanlizumab 5 mg/kg at Cycle 1 Day 1 (C1D1) and C1D15 followed by crizanlizumab 5 mg/kg every 4 weeks until disease progression The subsequent 8 patients will receive crizanlizumab 5 mg/kg at C1D1 and C1D15 followed by 5 mg/kg every 4 weeks plus nivolumab 3mg/kg every 2 weeks until disease progression Cohort 2 - Patients with recurrent or progressing GB following radiation and temozolamide. Nivolumab 10 MG/1 ML Intravenous Solution [OPDIVO] The first 3 subjects enrolled to Cohort 1 and Cohort 2 will receive crizanlizumab 5 mg/kg at Cycle 1 Day 1 (C1D1) and C1D15 followed by crizanlizumab 5 mg/kg every 4 weeks until disease progression The subsequent 8 patients will receive crizanlizumab 5 mg/kg at C1D1 and C1D15 followed by 5 mg/kg every 4 weeks plus nivolumab 3mg/kg every 2 weeks until disease progression
- Primary Outcome Measures
Name Time Method The proportion of treatment discontinuation events related to the treatment combination 48 months Safety and tolerability assessed by CTCAE v 6.0
Incidence of treatment-related adverse, serious adverse events, immune-related AEs following treatment with crizanlizumab alone or in combination with nivolumab 48 months Safety and tolerability assessed by CTCAE v 6.0
- Secondary Outcome Measures
Name Time Method Response Rate (RR) to crizanlizumab monotherapy and in combination with nivolumab 48 months evaluated by RECIST 1.1 and by RANO and RANO-BM criteria.
Overall survival (OS) in patients with GB or MBM following treatment crizanlizumab monotherapy and in combination with nivolumab. 48 months Overall survival (OS) of the study population
Progression-free survival (PFS) of patients with GB or MBM following treatment crizanlizumab monotherapy and in combination with nivolumab evaluated every 8 weeks for 48 months by brain MRI and CT of chest/abdomen and pelvis using RECIST 1.1 and RANO/RANO-BM criteria
Incidence of treatment-related adverse, serious adverse events, immune-related AEs of crizanlizumab maintenance therapy following whole-brain irradiation in patients with unmethylated GB 48 months evaluated by adverse events monitoring using CTCAE Version 6.0 and by documenting study treatment discontinuation and delays.
Impact of the treatment protocol on health-related quality of life evaluated every 6 weeks for 48 months 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.
Disease control rate (DCR) 48 months valuated by rate of progression in patients with un-methylated GB treated with crizanlizumab maintenance therapy following whole-brain irradiation.
Trial Locations
- Locations (1)
Sheba medical center
🇮🇱Ramat Gan, Israel