Crizanlizumab Alone or in Combination With Nivolumab for Glioblastoma and Melanoma With Brain Metastases

Inclusion criteria

• Age ≥ 18 years.
• 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.
• Have measurable disease defined by RECIST criteria and have at least one, non-previously irradiated brain metastasis of at least 1-cm short diameter. Otherwise, previously irradiated lesions should present with enlargement following radiation therapy.
• Is clinically stable with no neurological deficits. Patients may receive steroid supportive therapy up to 10 mg of prednisone or the equivalent.
• Have Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1.
• Adequate organ function defined by blood tests for blood count and chemistry.
• Women of childbearing potential practicing an acceptable method of birth control.
• Understand study procedures and willingness to comply for the entire duration of the study and to give written informed consent.

Exclusion criteria

• 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.
• Previous exposure to Crizanlizumab or any other P-selectin inhibitor.
• Previous or current brain hemorrhage.
• The patient had, or is expected to undergo, allogeneic hematopoietic stem cell transplantation (HSCT).
• The patient had a contraindication for undergoing brain MRI.
• Any other severe concurrent disease which, in the judgment of the investigator, would make the subject inappropriate for entry into this study.
• Pregnant or lactating
• Treatment with other investigational drugs within \<21 days of start of day 1 of the study treatment.
• Any contraindication for treatment with nivolumab according to the product's labels.
• Cohort 2 (Recurrent or Progressive GB) Inclusion Criteria
• Age ≥ 18 years.
• Estimated life expectancy at least 3 months
• Have with recurrent or persistent GB
• Received first line therapy with brain irradiation and maintenance temozolamide.
• Measurable disease per RANO criteria on brain MRI.
• Have Eastern Cooperative Oncology Group (ECOG) performance status \<2.
• Adequate organ function defined by blood tests for blood count and chemistry.
• Women of childbearing potential practicing an acceptable method of birth control.
• Understand study procedures and willingness to comply for the entire duration of the study and to give written informed consent.
• Exclusion Criteria
• Systemic steroid therapy for symptomatic brain disease. Note: a dose equivalent to 20 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.
• Previous exposure to Crizanlizumab or any other P-selectin inhibitor.
• Previous or current brain hemorrhage.
• The patient had, or is expected to undergo, allogeneic HSCT.
• The patient had a contraindication for undergoing brain MRI.
• Any other severe concurrent disease which, in the judgment of the investigator, would make the subject inappropriate for entry into this study.
• Pregnant or lactating
• Treatment with other investigational drugs within \<21 days of start of day 1 of the study treatment.
• Any contraindication for treatment with nivolumab according to the product's labels.
• Cohort 3 (Newly Diagnosed Unmethylated GB) Inclusion Criteria
• Age ≥ 18 years.
• Estimated life expectancy at least 3 months.
• Histologically confirmed newly diagnosed GB.
• Tumor test result shows MGMT unmethylated type.
• Received definitive brain irradiation.
• Patients may be treated with novo TTF (optune) per local standard.
• Have Eastern Cooperative Oncology Group (ECOG) performance status ≤2.
• Adequate organ function defined by blood tests for blood count and chemistry.
• Women of childbearing potential practicing an acceptable method of birth control.
• Understand study procedures and willingness to comply for the entire duration of the study and to give written informed consent.
• Exclusion Criteria
• Systemic steroid therapy for symptomatic brain disease. Note: a dose equivalent to 20 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.
• Previous exposure to Crizanlizumab or any other P-selectin inhibitor.
• Previous or current brain hemorrhage.
• The patient had, or is expected to undergo, allogeneic HSCT.
• The patient had a contraindication for undergoing brain MRI.
• Any other severe concurrent disease which, in the judgment of the investigator, would make the subject inappropriate for entry into this study.
• Be pregnant or lactating
• Treatment with other investigational drugs within \<21 days of start of day 1 of the study treatment.
• Any contraindication for treatment with nivolumab according to the product's labels