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

Cohort 1 (MBM) Inclusion Criteria 1. Age ≥ 18 years. 2. Estimated life expectancy at least 3 months 3. Have metastatic melanoma with primarily diagnosed or newly progressing brain metastases. 4. 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. 5. Have failed prior immunotherapy line, either due to primary resistance or acquired resistance. 6. 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. 7. Is clinically stable with no neurological deficits. Patients may receive steroid supportive therapy up to 10 mg of prednisone or the equivalent. 8. Have Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1. 9. Adequate organ function defined by blood tests for blood count and chemistry. 10. Women of childbearing potential practicing an acceptable method of birth control. 11. Understand study procedures and willingness to comply for the entire duration of the study and to give written informed consent. Exclusion Criteria 12. Systemic steroid therapy for symptomatic brain disease. Note: a dose equivalent to 10 mg prednisone will be allowed 13. Have leptomeningeal spread. 14. Previous life-threatening toxicity to anti-PD-1 antibody monotherapy. 15. Auto-immune disease in the last 2 years requiring systemic immune-suppressive therapy. 16. Previous exposure to Crizanlizumab or any other P-selectin inhibitor. 17. Previous or current brain hemorrhage. 18. The patient had, or is expected to undergo, allogeneic hematopoietic stem cell transplantation (HSCT). 19. The patient had a contraindication for undergoing brain MRI. 20. Any other severe concurrent disease which, in the judgment of the investigator, would make the subject inappropriate for entry into this study. 21. Pregnant or lactating 22. Treatment with other investigational drugs within \<21 days of start of day 1 of the study treatment. 23. Any contraindication for treatment with nivolumab according to the product's labels. Cohort 2 (Recurrent or Progressive GB) Inclusion Criteria 1. Age ≥ 18 years. 2. Estimated life expectancy at least 3 months 3. Have with recurrent or persistent GB 4. Received first line therapy with brain irradiation and maintenance temozolamide. 5. Measurable disease per RANO criteria on brain MRI. 6. Have Eastern Cooperative Oncology Group (ECOG) performance status \<2. 7. Adequate organ function defined by blood tests for blood count and chemistry. 8. Women of childbearing potential practicing an acceptable method of birth control. 9. Understand study procedures and willingness to comply for the entire duration of the study and to give written informed consent. Exclusion Criteria 1. Systemic steroid therapy for symptomatic brain disease. Note: a dose equivalent to 20 mg prednisone will be allowed 2. Have leptomeningeal spread. 3. Previous life-threatening toxicity to anti-PD-1 antibody monotherapy. 4. Auto-immune disease in the last 2 years requiring systemic immune-suppressive therapy. 5. Previous exposure to Crizanlizumab or any other P-selectin inhibitor. 6. Previous or current brain hemorrhage. 7. The patient had, or is expected to undergo, allogeneic HSCT. 8. The patient had a contraindication for undergoing brain MRI. 9. Any other severe concurrent disease which, in the judgment of the investigator, would make the subject inappropriate for entry into this study. 10. Pregnant or lactating 11. Treatment with other investigational drugs within \<21 days of start of day 1 of the study treatment. 12. Any contraindication for treatment with nivolumab according to the product's labels. Cohort 3 (Newly Diagnosed Unmethylated GB) Inclusion Criteria 1. Age ≥ 18 years. 2. Estimated life expectancy at least 3 months. 3. Histologically confirmed newly diagnosed GB. 4. Tumor test result shows MGMT unmethylated type. 5. Received definitive brain irradiation. 6. Patients may be treated with novo TTF (optune) per local standard. 7. Have Eastern Cooperative Oncology Group (ECOG) performance status ≤2. 8. Adequate organ function defined by blood tests for blood count and chemistry. 9. Women of childbearing potential practicing an acceptable method of birth control. 10. Understand study procedures and willingness to comply for the entire duration of the study and to give written informed consent. Exclusion Criteria 1. Systemic steroid therapy for symptomatic brain disease. Note: a dose equivalent to 20 mg prednisone will be allowed 2. Have leptomeningeal spread. 3. Previous life-threatening toxicity to anti-PD-1 antibody monotherapy. 4. Auto-immune disease in the last 2 years requiring systemic immune-suppressive therapy. 5. Previous exposure to Crizanlizumab or any other P-selectin inhibitor. 6. Previous or current brain hemorrhage. 7. The patient had, or is expected to undergo, allogeneic HSCT. 8. The patient had a contraindication for undergoing brain MRI. 9. Any other severe concurrent disease which, in the judgment of the investigator, would make the subject inappropriate for entry into this study. 10. Be pregnant or lactating 11. 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