Bevacizumab and ICIs + hSRT in Symptomatic Melanoma Brain Metastases

NCT06163820 | Recruiting Phase 1 DMC

• 1 other identifier: 05.21 BETTER
• Study Type: interventional
• Target: 46
• Locations: 1 country
• Sites: 1

Brief Summary

Single arm phase I/II trial to evaluate the safety and efficacy of the combination of bevacizumab, with ipilimumab plus nivolumab, and hypofractionated stereotactic radiotherapy (hSRT) in patients with symptomatic melanoma brain metastases (MBM).

Conditions

Melanoma Brain Metastases

Outcome Measures

Primary Outcomes (1)

• To determine the safety of bevacizumab, in combination with ipilimumab, nivolumab and hSRT

  Number of participants with bevacizumab-related SAEs. A dose-limiting toxicity rate of \<33% with a minimum of 3 patients treated will be considered safe.

  5 years

Secondary Outcomes (7)

• Determining the magnitude in reduction in prednisolone equivalent dose (relative to baseline dose)

  2 years

• Intracranial clinical benefit

  5 years

• Response rate

  5 years

• Progression-free survival

  5 years

• Overall survival

  5 years

Other Outcomes (2)

• To correlate anti-tumour activity with the detection of putative biomarkers of response/resistance in paired blood samples.

  5 years

• Rate of cerebral radiation necrosis

  2 years

Study Arms (1)

Intervention

EXPERIMENTAL

Patients will receive the following: 1. Bevacizumab 7.5 mg/kg every 3 weeks for 4 cycles 2. Nivolumab 1 mg /kg + ipilimumab 3 mg/kg every 3 weeks for 4 cycles (induction phase) followed by nivolumab monotherapy at 480mg every 4 weeks (maintenance phase) 3. hSRT (24-27Gy/3# or 25-30Gy/5#)

Drug: Bevacizumab; Drug: Ipilimumab; Drug: Nivolumab; Radiation: Hypofractionated stereotactic radiotherapy

Interventions

Bevacizumab DRUG

Bevacizumab is a humanised monoclonal antibody with molecular weight 167kD that inhibits all isoforms of the vascular endothelial growth factor (VEGF) and is produced from a Chinese hamster ovary mammalian system. It has high specificity for isoform-A and has a half-life of \~21 days.

Also known as: Avastin

Intervention

Ipilimumab DRUG

Ipilimumab is an immune checkpoint inhibitor (ICI) that targets anti-tumour immunity. Ipilimumab is a recombinant human immunoglobulin monoclonal antibody that binds CTLA4 and blocks the interaction between CD80/86 and CTLA4.

Also known as: Yervoy

Intervention

Nivolumab DRUG

Nivolumab ia an immune checkpoint inhibitor (ICI) that targets anti-tumour immunity. Nivolumab is a fully human monoclonal IgG4 antibody targeting PD-1 which demonstrates activity across a range of tumours.

Also known as: Opdivo

Intervention

Hypofractionated stereotactic radiotherapy RADIATION

Hypofractionated stereotactic radiotherapy (hSRT) will be delivered to previously untreated brain metastases in eligible participants. hSRT will be delivered to all symptomatic brain metastases, all brain metastases \>1 cm and all brain metastases located in eloquent areas of the brain. hSRT will be commenced after the first cycle of nivolumab plus ipilimumab and completed before the second cycle of nivolumab plus ipilimumab. hSRT should be commenced within 1 week from the planning MRI.

Intervention

Eligibility Criteria

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

You may qualify if:

• \. Histologically (or cytologically) proven metastatic melanoma, with radiologically confirmed brain metastases.
• \. Symptomatic from brain metastases at the time of study enrolment, or brain metastases that requires corticosteroids for the management of neurological symptoms.
• \. Intracranial lesions amenable to hypofractionated stereotactic radiotherapy. These are defined as all intracranial melanoma lesions greater or equal to 5 mm in diameter, all intracranial lesions that are causing symptoms, and all intracranial lesions located in the eloquent areas of the brain.
• \. World Health Organisation (WHO) performance status of 0 - 2
• \. At least one brain metastasis has to be symptomatic.
• \. Laboratory tests required: Haemoglobin (Hb) ≥ 9.0 g/dL Absolute neutrophil count ≥ 1 x 109/L Platelet count ≥ 100 x 109/L Either: Serum bilirubin ≤ 1.5 x upper limit of normal (ULN) (Patients with isolated hyperbilirubinaemia due to Gilbert's syndrome are allowed.) Or: Alanine aminotransferase (ALT), aspartate aminotransferase (AST) ≤ 2.5 x (ULN) unless raised due to tumour in which case up to 5 x ULN is permissible Creatinine clearance ≥ 40 mL/min (Cockcroft-Gault or MDRD are acceptable)
• \. Age ≥ 18 years
• \. Able to provide informed written consent (signed and dated), attend trial site for study visits and be capable of co-operating with treatment and follow-up

You may not qualify if:

• \. Prior radiotherapy to the brain
• \. Active concurrent malignancy requiring systemic anti-cancer therapy within the last 2 years. Patients with any malignancy treated with curative intent and no evidence of disease will be eligible for this trial.
• \. Prior systemic therapy for melanoma, unless given in the neoadjuvant or adjuvant setting for extracranial disease only, completed more than \>6 months prior to enrolment in this trial and if administered with radiological proof of the absence of brain metastases
• \. Inability to undergo MRI of the brain
• \. Definitive leptomeningeal disease. Patients with equivocal leptomeningeal disease may be included on the trial after discussion with CPI.
• \. Female patients who are pregnant or lactating. Patients who are able to become pregnant, must return a negative serum or urine pregnancy test before enrolment and agree to use two forms of contraception (one effective form plus a barrier method) \[oral, injected or implanted hormonal contraception and condom; intra-uterine device and condom; diaphragm with spermicidal gel and condom\] or agree to sexual abstinence, effective from signing the consent form, throughout the trial and for six months after any treatment for melanoma, radiotherapy or immunotherapy, are considered eligible.
• \. Male patients with partners of child-bearing potential (unless they agree to take measures not to father children by using a barrier method of contraception or to sexual abstinence effective from the first administration of bevacizumab, throughout the trial and for six months afterwards after treatment the end-of-trial visit. Men with partners of child-bearing potential must also be willing to ensure that their partner uses an effective method of contraception for the same duration for example, hormonal contraception, intrauterine device, diaphragm with spermicidal gel or sexual abstinence). Men with pregnant or lactating partners must be advised to use barrier method contraception to prevent exposure of the foetus or neonate. Abstinence is only considered to be an acceptable method of contraception when this is in line with the preferred and usual lifestyle of the participant. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception.
• \. Haemorrhage encompassing \>50% of any lesion that is \>10 mm in diameter (excluding surrounding oedema). A modern susceptibility-sensitive MRI sequence such as SWI is mandatory.
• \. Brain metastases greater than 5 cm in maximal diameter
• \. Increasing corticosteroid dose for 48 hours prior to initiation of study therapy OR current dexamethasone-equivalent dose of \>8 mg per day
• \. Major thoracic or abdominal surgery within 28 days prior to initiation of trial treatment
• \. Neurosurgery within 14 days prior to initiation of trial treatment
• \. Active or history of severe auto-immune disease requiring systemic anti-inflammatory therapy. Patients with well-controlled auto-immune diseases not requiring systemic anti-inflammatory therapy may be included after consultation with the CPI. Severe auto-immune respiratory disease will be excluded from the trial.
• \. History of inflammatory bowel disease
• \. Requirement for ongoing concurrent systemic immunosuppressive therapy (other than corticosteroids).

Sponsors & Collaborators

• Melanoma and Skin Cancer Trials Limited: lead

Study Sites (1)

Alfred Health

Melbourne, Victoria, 3004, Australia

RECRUITING

MeSH Terms

Interventions

Bevacizumab; Ipilimumab; 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

• Malaka Ameratunga

  Monash University

  STUDY CHAIR

Central Study Contacts

Katja Loewe

CONTACT

+61399039022; better@masc.org.au

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: The trial is a phase I/II, single arm, unblinded, multi-centre dose de-escalation trial to evaluate the safety and efficacy of the combination of bevacizumab, with ipilimumab plus nivolumab, and hypofractionated stereotactic radiotherapy (hSRT).

Study Record Dates

• First Submitted: October 17, 2023
• First Posted: December 11, 2023
• Study Start: May 31, 2025
• Primary Completion: January 30, 2026
• Study Completion: January 30, 2026
• Last Updated: May 13, 2025

Record last verified: 2025-05

Data Sharing

• IPD Sharing: Will not share

Locations

AU (1)