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Anti-PD 1 Brain Collaboration + Radiotherapy Extension (ABC-X Study) (ABC-X)

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ClinicalTrials.gov Identifier: NCT03340129
Recruitment Status : Recruiting
First Posted : November 13, 2017
Last Update Posted : June 9, 2021
Sponsor:
Collaborator:
Bristol-Myers Squibb
Information provided by (Responsible Party):
Melanoma Institute Australia

Brief Summary:
This is a phase II, open label, randomised trial of ipilimumab and nivolumab with concurrent intracranial stereotactic radiotherapy versus ipilimumab and nivolumab alone in patients with asymptomatic, untreated melanoma brain metastases.

Condition or disease Intervention/treatment Phase
Melanoma Stage Iv Drug: Ipilimumab Drug: Nivolumab Radiation: Stereotactic Radiotherapy Other: Salvage therapy Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 218 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Open label, randomised trial.
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase II, Open Label, Randomised, Controlled Trial of Ipilimumab and Nivolumab With Concurrent Intracranial Stereotactic Radiotherapy Versus Ipilimumab and Nivolumab Alone in Patients With Melanoma Brain Metastases.
Actual Study Start Date : August 14, 2019
Estimated Primary Completion Date : August 2022
Estimated Study Completion Date : August 2025

Resource links provided by the National Library of Medicine

MedlinePlus Genetics related topics: Melanoma
MedlinePlus related topics: Melanoma

Arm Intervention/treatment
Active Comparator: Nivolumab + ipilimumab

Nivolumab 1mg/kg and ipilimumab 3mg/kg Q3W x 4 doses, then nivolumab 480 mg every 4 weeks.

Any form of salvage therapy (surgery or radiotherapy) may be administered to either cohort for the treatment of intracranial disease progression.

Drug: Ipilimumab
Ipilimumab 3mg per kg every 3 weeks for 4 doses
Other Name: Yervoy

Drug: Nivolumab
Nivolumab 1mg/kg every 3 weeks for 4 doses, then 480mg every 4 weeks.
Other Name: Opdivo

Other: Salvage therapy
Any form of salvage therapy (surgery or radiotherapy) for intracranial disease progression, further disease control at any site, symptom control or treatment of cerebral haemorrhage or cerebral radionecrosis.

Active Comparator: Nivolumab + ipilimumab,concurrent SRS

Nivolumab 1mg/kg and ipilimumab 3mg/kg Q3W x 4 doses, then nivolumab 480 mg every 4 weeks.

Stereotactic radiotherapy 16 to 22 Gy in 1 fraction or 24 to 30 Gy, hypofractionated for larger lesions. Stereotactic radiotherapy to commence within 7 days of of the baseline / planning MRI brain. Hypofractionated stereotactic radiotherapy should be completed within 14 day of the first fraction.

Any form of salvage therapy (surgery or radiotherapy) may be administered to either cohort for the treatment of intracranial disease progression.

Drug: Ipilimumab
Ipilimumab 3mg per kg every 3 weeks for 4 doses
Other Name: Yervoy

Drug: Nivolumab
Nivolumab 1mg/kg every 3 weeks for 4 doses, then 480mg every 4 weeks.
Other Name: Opdivo

Radiation: Stereotactic Radiotherapy
The first dose of immunotherapy Must be given prior to the start of radiotherapy. One fraction at between 16 to 22 Gy or 24 to 30 Gy hypofractionated for larger lesions.

Other: Salvage therapy
Any form of salvage therapy (surgery or radiotherapy) for intracranial disease progression, further disease control at any site, symptom control or treatment of cerebral haemorrhage or cerebral radionecrosis.




Primary Outcome Measures :
  1. Neurological specific cause of death [ Time Frame: One year ]
    Proportion of patients dead at one year from randomisation and whose immediate cause of death is neurological.


Secondary Outcome Measures :
  1. Intracranial response rate [ Time Frame: Approximately 3 years ]
    The best response in intracranial metastases as measured using brain modified (bm) RECIST, following at least ONE dose of nivolumab and ipilimumab and based on imaging from week 6 onwards and confirmed a minimum of 4 weeks later.

  2. Extracranial response rate [ Time Frame: Approximately 5 years ]
    The best response in extracranial disease for each patient measured using bm RECIST, following at least ONE dose of nivolumab and ipilimumab and based on imaging from week 12 onwards.

  3. Overall response rate [ Time Frame: Approximately 5 years ]
    Proportion of patients with an overall complete or partial response as measured using bm RECIST following at least ONE dose of nivolumab and ipilimumab and based on imaging from week 12 onwards .

  4. Overall progression free survival [ Time Frame: 1, 2 and 5 years ]
    Time from the start of study treatment to the date of any progression of disease as measured using bm RECIST and based on imaging from week 12 onwards.

  5. Non-Neurological specific cause of death [ Time Frame: 1 years ]
    Proportion of patients dead at one year from randomisation and whose immediate cause of death was due to melanoma but from causes other than brain metastases.

  6. Overall survival [ Time Frame: 1, 2 and 5 years. ]
    Time from commencing study treatment to the date of death from any cause. Patients still alive at the end of the study will be censored at the date of their last assessment.

  7. Incidence of radionecrosis [ Time Frame: 5 years ]
    Proportion of patients with a diagnosis of radionecrosis occuring within 5 years of the start of the first course of radiotherapy.

  8. Requirement for salvage radiotherapy [ Time Frame: 1 year ]
    Proportion of patients requiring salvage radiotherapy in each cohort

  9. Requirement for salvage intracranial surgery [ Time Frame: 1 year ]
    Proportion of patients requiring salvage craniotomy in each cohort

  10. Change in neurocognitive function scores [ Time Frame: Approximately 5 years ]
    The mean change from baseline assessment of neurocognitive function to the time of clinical response, stable disease and progression of disease.

  11. Description of impaired neurological function and neurological adverse events [ Time Frame: Approximately 5 years ]
    Description of the nature of impaired function and types of neurological adverse events.

  12. Time to neurological deterioration [ Time Frame: Approximately 5 years ]
    The time from starting immunotherapy to the time of deterioration of MoCA, CTCAE and FACT-Br.

  13. Duration of neurological deterioration [ Time Frame: Approximately 5 years ]
    The time to resolution (if any) of each functional neurocognitive deficit.

  14. Patient rated quality of life [ Time Frame: Approximately 5 years ]
    Time from starting study treatment to the time of deterioration in quality life scores and the duration of deterioration.

  15. Functional performance status [ Time Frame: Approximately 5 years ]
    Incidence of reduced functional performance by 1, 2 or 3 grades of the Eastern Cooperative Oncology Group (ECOG) performance status scale compared to baseline.

  16. Adverse events [ Time Frame: Approximately 5 years ]
    Description of all adverse events per National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 5.0

  17. Tissue, blood and gut biomarkers of response, progression and toxicity [ Time Frame: Approximately 5 years ]
    Correlation of the baseline PD-L1 status, immune markers, genomics and other biomarkers in tumour tissue and blood and the composition and diversity of the gut microbiome with RECIST response and toxicity. Correlation of gastrointestinal mucosal integrity with bacterial composition in stool samples, RECIST response and immune related adverse events.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 120 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Female or male patients, ≥18 years of age.
  2. Signed, written, informed consent.
  3. AJCC Stage IV [any T, any N, M1d (0) or M1D(1)] histologically confirmed cutaneous, acral or mucosal unresectable melanoma or unknown primary melanoma and at least 1 radiological definitive brain metastasis that is ≥ 5mm and ≤40mm, measurable per RECIST version 1.1 guidelines (modified for brain metastases, enabling up to 5 target lesions in the brain as well as up to 5 extracranial target lesions). There is no upper limit restriction in the number of brain metastases, provided the remaining eligibility criteria are met.
  4. The BRAF mutation status must be available prior to randomisation.
  5. The treating clinician(s) should consider the intracranial disease amenable to stereotactic radiotherapy over whole brain radiotherapy. Patients for whom there is a definite and immediate indication for radiotherapy (e.g. rapidly progressing disease with associated clinical signs and /or symptoms) should not be considered for enrolment.
  6. Brain metastases must be untreated with any modality of radiotherapy or systemic treatment. Previous surgery for melanoma brain metastases is permitted if it resulted in gross total resection and no radiotherapeutic cavity boost was required.
  7. No prior systemic treatment for brain metastases is permitted unless given in the neoadjuvant or adjuvant settings for systemic drug the treatment for extracranial disease only. At the time of neoadjuvant or adjuvant systemic therapy for extracranial disease, there should be radiological evidence of the absence of brain metastases. The presenting diagnosis of brain metastases at the time of enrolment in this study must have occurred a minimum of 6 months after stopping neoadjuvant or adjuvant systemic therapy (prior anti PD1, anti PD-L1, anti CTLA-4, BRAF / MEK inhibitors or clinical trial agents) are acceptable in the setting of neoadjuvant or adjuvant treatment
  8. Asymptomatic from brain metastases at the time of study enrolment without corticosteroids, analgesia or any other treatment for the management of neurological symptoms (with the exception of antiepileptics prescribed for any reason, provided patient is asymptomatic). Resolved neurological symptoms are permitted if complete resolution, without any intervention, has been sustained for a minimum of 7 days prior to randomisation.
  9. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-2.
  10. A life expectancy > 30 days.
  11. Able to undergo MRI with Gadolinium contrast agent. CT of the brain is not an acceptable alternative should patients be unable to safely undergo a contrast MRI.
  12. Adequate haematological, hepatic and renal organ function as defined by:

    1. White cell count ≥ 2.0 × 10x9/L
    2. Neutrophil count ≥ 1.5 × 10x9/L
    3. Haemoglobin ≥ 90 g/L
    4. Platelet count ≥ 100 x 10x9/L
    5. Total bilirubin ≤ 1.5 x ULN
    6. Alanine transaminase ≤ 3.0 x ULN
    7. Aspartate aminotransferase ≤ 3.0 x ULN
    8. Serum creatinine ≤ 1.5 x the upper limit of normal (ULN). If serum creatinine is > 1.5 x ULN, calculate creatinine clearance using standard Cockcroft-Gault formula. Creatinine clearance must be 40ml/min to be eligible.
  13. Women of childbearing potential (WOCBP) must have a negative serum pregnancy test within 7 days of the first dose of study treatment and agree to use effective contraception from 14 days prior to commencing study treatment, throughout the treatment period and for 23 weeks * after the last dose of study treatment. Effective contraception includes:

    1. Intrauterine device with a documented failure rate of less than 1% per year.
    2. Vasectomised partner who is sterile prior to the female partner patient's commencement of study treatment and is the sole sexual partner for that female.
    3. Combined (oestrogen and progestogen) hormonal contraception associated with inhibition of ovulation or progestogen only hormonal contraception associated with inhibition of ovulation.

    Women who are not of childbearing potential are defined as any female who has had a documented hysterectomy, bilateral oophorectomy or bilateral tubal ligation or any female who is post-menopausal (≥ one year without menses and >50 years of age in the absence of hormone replacement therapy).

  14. Men with any female partner of childbearing potential must agree to use effective contraception from 14 days prior to commencing study treatment, throughout the treatment period and for 31 weeks* after the last dose of study treatment. Effective contraception includes:

    1. Documented vasectomy and sterility
    2. In the partner - intrauterine device with a documented failure rate of less than 1% per year
    3. In the female partner - Combined (oestrogen and progestogen) hormonal contraception associated with inhibition of ovulation or progestogen only hormonal contraception associated with inhibition of ovulation.

      • These durations have been calculated using the upper limit of the half-life for nivolumab (25 days) and are based on the protocol requirement that WOCBP use contraception for 5 half-lives plus 30 days and men who are sexually active with WOCBP use contraception for 5 half-lives plus 90 days.

Exclusion Criteria

  1. Patients whose intracranial disease changes between the diagnostic MRI scan and the baseline / SRS planning MRI scan and who are no longer suitable for SRS and / or require a specific alternative treatment outside of this protocol.
  2. Melanoma brain metastasis greater than 40mm.
  3. Evidence of leptomeningeal disease, with the exception of pathological findings seen at a previous resection of brain disease, but with no evidence of leptomeningeal disease elsewhere at the time of resection or at study entry.
  4. History of, or current ocular melanoma (patients with mucosal and acral melanoma are eligible).
  5. Neurological symptoms from brain metastases present at baseline (resolved neurological symptoms, prior to enrolment, are permitted).
  6. Prior radiotherapy to the brain (surgery permitted).
  7. Prior systemic drug therapy for melanoma, unless given in the neoadjuvant or adjuvant setting and completed 6 months before enrolment in this study.
  8. Patients with active, known or suspected autoimmune disease. Patients with the following are permitted to enrol:

    1. Vitiligo
    2. Type I diabetes mellitus
    3. Residual hypothyroidism due to an autoimmune condition only requiring hormone replacement
    4. Psoriasis not requiring systemic treatment
    5. Autoimmune conditions not expected to recur in the absence of an external trigger.
  9. Current systemic treatment with corticosteroids, or within 7 days of randomisation, with the exception of prednisone at non-immunosuppressive doses of ≤ 10 mg/day (or equivalent, e.g. e.g. prednisone 10mg = dexamethasone 1.6mg = hydrocortisone 40mg). Patients with the following circumstances are permitted to enrol:

    1. Past treatment for non-neurological symptoms allowed, if this was ceased 7 days prior to randomisation
    2. Inhaled or intranasal corticosteroids (with minimal systemic absorption) may be continued if the patient is on a stable dose
    3. Non-absorbed intra-articular steroid injections.

    During the study, treatment with systemic corticosteroids is permitted during radiotherapy if the patient experiences radiation related symptoms but this should be tapered per standard clinical practice as soon as possible and before the next infusion of study drug is due. This also refers to steroids for drug related signs or symptoms.

  10. Any active infection requiring treatment.
  11. A history of interstitial lung disease.
  12. Any concurrent malignancy requiring any treatment or a history of another malignancy, unless the patient has been disease-free for 3 years.
  13. Serious or unstable pre-existing medical conditions or other conditions that could interfere with the patient's safety, consent, or compliance.
  14. Pregnant or breastfeeding females.
  15. Administration of any form of live vaccine within 30 days of starting the trial and during the trial. Administration of any other vaccine is cautionary within 30 days of starting the trial and for the duration of the treatment phase of the trial.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03340129


Contacts
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Contact: Georgina V Long, MBBS PhD +61 2 9911 7200 info@melanoma.org.au
Contact: Maria Gonzalez, RN MHSc +61 2 9911 7200 maria.gonzalez@melanoma.org.au

Locations
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Australia, New South Wales
Westmead Hospital Recruiting
Sydney, New South Wales, Australia, 2145
Contact: Matteo Carlino         
Principal Investigator: Matteo Carlino         
Calvary Mater NewcastleHospital Recruiting
Waratah, New South Wales, Australia, 2298
Contact: Andre van der Westhuizen         
Melanoma Institute Australia Recruiting
Wollstonecraft, New South Wales, Australia, 2065
Contact: Maria Gonzalez    +612 9911 7200    maria.gonzalez@melanoma.org.au   
Principal Investigator: Alexander Menzies         
Australia, Queensland
Princess Alexandra Hospital Recruiting
Woolloongabba, Queensland, Australia, 4102
Principal Investigator: Victoria Atkinson         
Australia, South Australia
Royal Adelaide Hospital Not yet recruiting
Adelaide, South Australia, Australia, 5000
Contact: Michael Brown         
Australia, Victoria
Peter MacCallum Cancer Centre Recruiting
East Melbourne, Victoria, Australia, 3002
Principal Investigator: Grant McArthur         
Alfred Hospital Not yet recruiting
Melbourne, Victoria, Australia, 3004
Contact: Andrew Haydon, MBBS         
Norway
Oslo Univesity Hospital Radiumhospitalet Not yet recruiting
Oslo, Norway, 0379
Contact: Kari Dolven-Jacobsen         
Sponsors and Collaborators
Melanoma Institute Australia
Bristol-Myers Squibb
Investigators
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Study Chair: Georgina V Long, MBBS PhD Melanoma Institute Australia
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Melanoma Institute Australia
ClinicalTrials.gov Identifier: NCT03340129    
Other Study ID Numbers: MIA2019/CT/258
First Posted: November 13, 2017    Key Record Dates
Last Update Posted: June 9, 2021
Last Verified: June 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Keywords provided by Melanoma Institute Australia:
Immunotherapy
Radiotherapy
Brain metastases
Stereotactic radiotherapy
Stereotactic radiosurgery
Cognitive function
Neurological-specific cause of death
Additional relevant MeSH terms:
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Melanoma
Neuroendocrine Tumors
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Nerve Tissue
Nevi and Melanomas
Nivolumab
Ipilimumab
Antineoplastic Agents, Immunological
Antineoplastic Agents
Immune Checkpoint Inhibitors
Molecular Mechanisms of Pharmacological Action