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

NCT ID: NCT05909618

Last Updated: 2025-07-22

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: PHASE2
• Total Enrollment: 33 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2023-07-11
• Study Completion Date: 2030-07-30

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.

Conditions

Advanced Glioblastoma; Metastatic Melanoma in the Central Nervous System; MGMT-Unmethylated Glioblastoma

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Cohort 1 metastatic melanoma with brain metastases who failed immunotherapy

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

Group Type: EXPERIMENTAL

No interventions assigned to this group

Cohort 2 - Patients with recurrent or progressing GB following radiation and temozolamide.

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

Group Type: EXPERIMENTAL

Crizanlizumab-Tmca 10 MG/1 ML Intravenous Solution [ADAKVEO]

Intervention Type: DRUG

5 mg/kg solution for injection

Nivolumab 10 MG/1 ML Intravenous Solution [OPDIVO]

Intervention Type: DRUG

3 mg/mL solution for injection

Cohort 3: Patients with newly diagnosed GB

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.

Group Type: EXPERIMENTAL

Crizanlizumab-Tmca 10 MG/1 ML Intravenous Solution [ADAKVEO]

Intervention Type: DRUG

5 mg/kg solution for injection

Interventions

Crizanlizumab-Tmca 10 MG/1 ML Intravenous Solution [ADAKVEO]

5 mg/kg solution for injection

Intervention Type: DRUG

Nivolumab 10 MG/1 ML Intravenous Solution [OPDIVO]

3 mg/mL solution for injection

Intervention Type: DRUG

Other Intervention Names

crizanlizumab; nivolumab

Eligibility Criteria

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.

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.

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

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.

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.

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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Prof. Ronit Satchi-Fainaro, Director, Cancer Biology Research Center, Tel Aviv University, Tel Aviv, Israel.

UNKNOWN

Sponsor Role: collaborator

Sheba Medical Center

OTHER_GOV

Sponsor Role: lead

Responsible Party

Dr. Ronnie Shapira

M.D, Head onco-gynecological service, Principal Investigator

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Ronnie Shapira Frommer, Dr

Role: PRINCIPAL_INVESTIGATOR

Ronnie Shapira, MD Study Principal Investigator Ronnie.Shapira@sheba.health.gov.il

Locations

Sheba medical center

Ramat Gan, Israel, Israel

Site Status: RECRUITING

Countries

Israel

Central Contacts

Ronnie Shapira Frommer, Dr

Role: CONTACT

ronnie.shapira@sheba.health.gov.il

972-3-5302243

Meital Bar

Role: CONTACT

meital.bar@sheba.health.gov.il

972-3-5305201

Facility Contacts

Ronnie Shapira, MD

Role: primary

Ronnie.Shapira@sheba.health.gov

Meital Bar

Role: backup

meital.bar@sheba.health.gov.il

972-3-5305201

Study Documents

Document Type: Nature Communications manuscript

View Document

Other Identifiers

Sheba-9411-22-RS-crizanlizumab

Identifier Type: -

Identifier Source: org_study_id