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

NCT05909618 | Recruiting Phase 2

• 1 other identifier: Sheba-9411-22-RS-crizanlizumab
• Study Type: interventional
• Target: 33
• Locations: 1 country
• Sites: 1

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.

Conditions

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

Outcome Measures

Primary Outcomes (2)

• 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

  48 months

• The proportion of treatment discontinuation events related to the treatment combination

  Safety and tolerability assessed by CTCAE v 6.0

  48 months

Secondary Outcomes (6)

• Response Rate (RR) to crizanlizumab monotherapy and in combination with nivolumab

  48 months

• 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

• Overall survival (OS) in patients with GB or MBM following treatment crizanlizumab monotherapy and in combination with nivolumab.

  48 months

• Impact of the treatment protocol on health-related quality of life

  evaluated every 6 weeks for 48 months

• 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

Other Outcomes (2)

• The response to crizanlizumab monotherapy and in combination with nivolumab

  48 months

• Plasma levels of Crizanlizumab measurements

  during the first treatment cycle at the following time points: Baseline (Day 1),Day 2 and Day 15.

Study Arms (3)

Cohort 1 metastatic melanoma with brain metastases who failed immunotherapy

EXPERIMENTAL

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.

EXPERIMENTAL

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

Drug: Crizanlizumab-Tmca 10 MG/1 ML Intravenous Solution [ADAKVEO]; Drug: Nivolumab 10 MG/1 ML Intravenous Solution [OPDIVO]

Cohort 3: Patients with newly diagnosed GB

EXPERIMENTAL

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.

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

Interventions

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

5 mg/kg solution for injection

Also known as: crizanlizumab

Cohort 2 - Patients with recurrent or progressing GB following radiation and temozolamide.; Cohort 3: Patients with newly diagnosed GB

Nivolumab 10 MG/1 ML Intravenous Solution [OPDIVO] DRUG

3 mg/mL solution for injection

Also known as: nivolumab

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

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.
• Age ≥ 18 years.
• Estimated life expectancy at least 3 months
• Have with recurrent or persistent GB

Sponsors & Collaborators

• Sheba Medical Center: lead
• Prof. Ronit Satchi-Fainaro, Director, Cancer Biology Research Center, Tel Aviv University, Tel Aviv, Israel.: collaborator

Study Sites (1)

Sheba medical center

Ramat Gan, Israel, Israel

RECRUITING

MeSH Terms

Interventions

crizanlizumab; Nivolumab

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Study Officials

• Ronnie Shapira Frommer, Dr

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

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Ronnie Shapira Frommer, Dr

CONTACT

972-3-5302243; ronnie.shapira@sheba.health.gov.il

Meital Bar

CONTACT

972-3-5305201; meital.bar@sheba.health.gov.il

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER GOV
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: M.D, Head onco-gynecological service, Principal Investigator

Study Record Dates

• First Submitted: May 1, 2023
• First Posted: June 18, 2023
• Study Start: July 11, 2023
• Primary Completion (Estimated): July 30, 2028
• Study Completion (Estimated): July 30, 2030
• Last Updated: July 22, 2025

Record last verified: 2025-07

Data Sharing

• IPD Sharing: Will not share

Locations

IL (1)