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Brain MetastasesPhase 3NIBIT-M2NCT02460068

A Study of Fotemustine(FTM) Vs FTM and Ipilimumab (IPI) or IPI and Nivolumab in Melanoma Brain Metastasis

A Phase 3 study testing Fotemustine, Fotemustine and Ipilimumab and Ipilimumab and nivolumab in people with Brain Metastases, run by Italian Network for Tumor Biotherapy Foundation at 11 sites in Italy.

Unknown status

Status not confirmed. The sponsor has not verified this record for over two years, so it may be out of date.

Official record
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Trial summary

This Phase 3, open-label, triple arm study aims to evaluate the overall survival (OS) of fotemustine versus the combination of ipilimumab and fotemustine or the combination of Ipilimumab and nivolumab in patients with metastatic melanoma with brain metastasis. Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Brain Metastases
What is being tested?
Fotemustine, Fotemustine and Ipilimumab and Ipilimumab and nivolumab
Type of treatment
Injection or infusion
Could I receive a placebo?
No, everyone receives an active treatment
How many people
168 participants
Where
11 sitesItaly
Study dates
Dec 2012to Jan 2020
Phase
Phase 3
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Willing and able to give written informed consent.
  • Histologic diagnosis of malignant melanoma;
  • Stage IV melanoma;
  • No prior therapy for advanced (unresectable Stage III or Stage IV) disease;
  • No previous systemic corticosteroid therapy within 7 days;
  • Prior adjuvant treatment with IFN or other immunotherapy allowed with exception of anti-CTLA-4;
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  • Presence of asymptomatic brain metastases: patients must have measurable metastases in the brain, defined as lesions that can be accurately measured in 2 dimensions as ≥ 0.5 cm (maximum 2 cm) in the brain MRI with contrast;
  • Pts who have been previously treated with brain stereotactic radiotherapy (SRT), whole-brain radiotherapy (WBRT) and/or surgery, must have developed new measurable brain lesions;
  • Life expectancy ≥ 12 weeks;
  • ECOG performance status of 0 or 1 (see Appendix 2);
  • Normal laboratory tests were required.
  • Subjects must have known BRAF V600E mutation status or consent to BRAF V600E mutation testing per local institutional standard.
  • Negative screening tests for HIV, Hepatitis B, and Hepatitis C.
  • Men and women, of and over 18 years old.Women of childbearing potential (WOCBP) must use appropriate method(s) of contraception. WOCBP should use an adequate method to avoid pregnancy for 23 weeks (30 days plus the time required for nivolumab to undergo five half-lives) after the last dose of investigational drug

Who cannot join

  • Any malignancy from which the patient has been disease-free for less than 5 years, with the exception of adequately treated and cured basal or squamous cell skin cancer, superficial bladder cancer, carcinoma in situ of the cervix;
  • Primary ocular or mucosal melanoma.
  • Medical History and Concurrent Diseases:
  • Symptomatic brain metastases requiring immediate local intervention (radiotherapy (RT) and/or surgery);
  • Autoimmune disease
  • Any underlying medical condition, which in the opinion of the investigator, will make the administration of study drug hazardous or obscure the interpretation of adverse events, such as a condition associated with frequent diarrhea.
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  • Prohibited Treatments and/or Therapies:
  • Concomitant therapy with any anti-cancer agent; immunosuppressive agents; any non-oncology vaccine therapy used for prevention of infectious diseases (for up to 1 month prior to or after any dose of study drug); surgery or radiotherapy ; other investigational anti-cancer therapies; or chronic use of systemic corticosteroids
  • Previous treatment with other investigational products, including cancer immunotherapy, within 30 days;
  • Prior treatment with anti-CTLA-4 and/or , anti-PD1/PD-L1 or fotemustine.
  • Sex and Reproductive Status:
  • WOCBP who are unwilling or unable to use an acceptable method to avoid pregnancy for the entire study period and for up to 8 weeks after the study;
  • Women who are pregnant or breastfeeding;
  • Women with a positive pregnancy test on enrollment or prior to investigational product administration;
  • Sexually active fertile men not using effective birth control if their partners are WOCBP.
  • Other Exclusion Criteria:
  • Prisoners or subjects who are involuntarily incarcerated;
  • Subjects who are compulsorily detained for treatment of either a psychiatric or physical illness.

Trial locations and contacts

11 sites in 1 country.

Anna Maria Di Giacomo, PhD,MD contact

0577-586305

a.m.digiacomo@ao-siena.toscana.it

Michele Maio, PhD,MD contact

0577-586335

mmaiocro@gmail.com

11 sites in 1 country

Italy11 sites, 8 recruiting

  • Medical Oncology, Cancer Institute "Giovanni Paolo II"

    Bari, 70124

    Michele Guida, PhD,MD, 080-5555238, micguida@libero.it

    Not yet recruiting

  • Medical Oncology, Pope Giovanni XXIII Hospital

    Bergamo, 24127

    Mario Mandalà, PhD, MD, mariomandala@tin.it

    Recruiting

  • National Institute for Cancer Research

    Genoa, 16132

    Paola Queirolo, PhD,MD, 010-5600667, paola.queirolo@istge.it

    Not yet recruiting

  • Immunotherapy and Somatic Cell Therapy Unit, Scientific Institute of Romagna

    Meldola, 47014

    Massimo Guidoboni, PhD, MD, 0543-739100, m.guidoboni@irst.emr.it

    Recruiting

  • Surgical Oncology, National Cancer Institute

    Milan, 20133

    Michele Del Vecchio, PhD, MD, 02 2390 2772, michele.delvecchio@istitutotumori.mi.it

    Recruiting

  • European Institute of Oncology

    Milan, 20141

    Active, not recruiting

  • Medical Oncology and Innovative Therapy, National Cancer Institute

    Naples, 80131

    Active, not recruiting

  • esophageal and melanoma oncology, Istituto Oncologico Veneto

    Padua, 35128

    Vanna Chiaron Sileni, 049 - 821 5931/5943, mgaliz@tiscali.it

    Not yet recruiting

  • Medical Oncology, National Cancer Institute "Regina Elena"

    Rome, 0014

    Active, not recruiting

  • Medical Oncology and Immunotherapy Unit, University Hospital of Siena

    Siena, 53100

    Anna Maria Di Giacomo, PhD,MD, 0577 586305, a.m.digiacomo@ao-siena.toscana.it

    Michele Maio, PhD,MD, 0577 586335, mmaiocro@gmail.com

    Recruiting

  • S C Dermatology, A.O.U. City of Health and Science of Turin

    Turin, 10126

    Pietro Quaglino, PhD, MD, pietro.quaglino@unito.it

    Not yet recruiting

Other trials in Italy

About this study

Official title: A Randomized, Phase III Study of Fotemustine Versus the Combination of Fotemustine and Ipilimumab or the Combination of Ipilimumab and Nivolumab in Patients With Metastatic Melanoma With Brain Metastasis

This Phase 3, open-label, triple arm study aims to evaluate the overall survival (OS) of fotemustine versus the combination of ipilimumab and fotemustine or the combination of Ipilimumab and nivolumab in patients with metastatic melanoma with brain metastasis.

Read the detailed description

Metastatic melanoma is an aggressive tumor associated with very poor prognosis. Brain metastases develop in nearly half of MM pts and in 30 to 40% of these subjects, the brain is the first site of relapse. The limited activity of available agents, along with relative resistance to radiotherapy and poor CNS penetration of most chemotherapeutic agents, make this one of the most daunting problems in oncology. There is no optimal systemic or local therapy for melanoma metastatic to the brain. Though MM pts with brain metastases have been excluded from most phase II-III trials with ipilimumab, initial evidences suggest that the anti-CTLA-4 monoclonal antibody ipilimumab might be active as single-agent also in this clinical setting. Preliminary results from the NIBIT-M1 phase II trial suggest for the safety and efficacy of the combination of fotemustine plus ipilimumab in MM pts with or w/o brain metastases.Recent data from a phase I study in MM pts w/o brain metastases have shown that concurrent administration of ipilimumab (3 mg/kg) plus the anti-PD1 mAb nivolumab (1 mg/kg) induced objective responses in 53% of pts, with a tumor reduction of ≥80% in 41% of pts, with an 82% 1-year OS, and with an acceptable safety profile.Based on the long-term follow-up of the NIBIT-M1 study, and on the activity of the concurrent administration of ipilimumab and nivolumabthe NIBIT-M2 study will explore the efficacy of the combination of ipilimumab and fotemustine or ipilimumab and nivolumab versus fotemustine alone in pts with melanoma metastatic to the brain.

Being tested
Fotemustine, Fotemustine and Ipilimumab, Ipilimumab and nivolumab
Keywords
melanoma brain metastases, nivolumab, ipilimumab
Medical subject headings
Brain Neoplasms

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • FotemustineDrug

    Also called Fotemustine (Muphoran);

    Fotemustine: fotemustine at 100 mg/mq intravenously (i.v.) over 60 minutes once every week for 3 doses, and once every 3 weeks from week 9 for 6 doses.

  • Fotemustine and IpilimumabDrug

    Also called Fotemustine (Muphoran);, Ipilimumab (YERVOY)

    Fotemustine and ipilimumab:fotemustine 100 mg/m2 i.v. over 60 minutes once every week for 3 weeks (Weeks 1, 2, 3) plus ipilimumab at 10 mg/kg i.v. over 90 minutes every 3 weeks for 4 cycles (Weeks 1, 4, 7, 10); fotemustine 100 mg/m2 i.v. over 60 minutes once every 3 weeks from week 9 for 6 doses plus ipilimumab at 10 mg/kg i.v. over 90 minutes every 12 weeks from week 24.

  • Ipilimumab and nivolumabDrug

    Also called Ipilimumab (YERVOY), Nivolumab (OPDIVO)

    ipilimumab and nivolumab: ipilimumab 3 mg/kg i.v over 90 minutes combined with nivolumab 1 mg/kg i.v over 60 minutes every three weeks for 4 doses, then nivolumab 3 mg/kg IV over 60 minutes every two weeks.

Study groups in NCT02460068
Study groupRoleWhat they receive
fotemustineActive comparatorfotemustine alone
Receives: Drug: Fotemustine
fotemustine and ipilimumabExperimentalfotemustine in combination with ipilimumab
Receives: Drug: Fotemustine and Ipilimumab
ipilimumab and nivolumabExperimentalipilimumab in combination with nivolumab
Receives: Drug: Ipilimumab and nivolumab

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Overall Survival (OS)

    To compare the efficacy of the combination of ipilimumab and fotemustine or the Combination of ipilimumab and nivolumab versus fotemustine in terms of overall survival (OS) in patients with metastatic melanoma with brain metastasis.Overall Survival (OS) is defined as the time from randomization until the date of death. For those subjects who have not died, OS will be censored at the recorded last date of subject contact, and for subjects with a missing recorded last date of contact, OS will be censored at the last date the subject was known to be alive.

    Measured: 2 years

Secondary outcomes (11)

  1. safety (adverse events)

    Reporting of safety, extent of exposure, concomitant medications and discontinuation of study therapy will be based on all treated subjects; for on-study laboratory test results, all treated subjects with at least one on-study laboratory measurement available will be included in the analysis. The reporting period for safety data will be from the date of first dose received on this study to 70 days (5 half-lives) after the last dose is received. Serious adverse events are reported from the time of consent forward for all subjects.All subjects who receive at least 1 dose of study treatment will be evaluated for safety parameters

    Measured: 2 years

  2. m-WHO and immune-related Disease Control Rate (DCR) in and outside the brain

    m-WHO and immune-related is the proportion of treated subjects with a ir-BOR of confirmed irCR, confirmed irPR or irSD in and outside the brain.

    Measured: Weeks 24

  3. Immune-related Progression-free Survival (irPFS)

    Immune-related progression free survival (irPFS) per irRC will be defined as the time between the date of randomization and the date of progression per irRC or death, whichever occurs first. A subject who dies without reported progression per irRC will be considered to have progressed on the date of death.

    Measured: 2 years

  4. m-WHO Progression-free Survival (irPFS)

    Progression-free survival (PFS) per mWHO criteria will be defined as the time between the date of randomization and the date of progression per mWHO criteria or death, whichever occurs first. A subject who dies without reported progression per mWHO criteria will be considered to have progressed on the date of death.

    Measured: 2 years

  5. Objective Response Rate (ORR)

    is the proportion of treated subjects with a BOR of confirmed CR or confirmed PR.

    Measured: Weeks 24

  6. Immune-related Objective Response Rate (irORR)

    is the proportion of treated subjects with a irBOR of confirmed irCR or confirmed irPR.

    Measured: Weeks 24

  7. Time to Response (TTR)

    Time to Response (TTR) is defined as the time from first dosing date until the measurement criteria are first met for overall response of PR or CR (whichever status comes first, and provided it is subsequently confirmed).

    Measured: Weeks 24

  8. Immune-related Time to Response (irTTR)

    Immune-related Time to Response (irTTR) is defined as the time from first dosing date until the measurement criteria are first met for overall response of irPR or irCR (whichever status comes first, and provided it is subsequently confirmed).

    Measured: Weeks 24

  9. Duration of Response (DoR)

    Duration of Response (DoR) is defined as the time between the date the measurement criteria are first met for an CR or PR (whichever status comes first and provided it is subsequently confirmed) and the date of PD or death (whichever comes first). For a subject who undergoes tumor resection following response but prior to disease progression, DOR will be censored at the date of the last evaluable TA on or prior to the date of resection. For subjects who remain alive and have no progressive disease as assessed by the investigator using RC, DOR will be censored on the date of last evaluable tumor assessment.

    Measured: 2 years

  10. Immune-related Duration of Response (irDoR)

    Immune-related Duration of Response (irDoR) for the subjects whose irBOR is irCR or irPR will be defined as the time between the date of response of confirmed irCR or confirmed irPR (whichever occurs first) and the date of irPD or death (whichever occurs first). The onset of a confirmed irCR or irPR is determined by the initial assessment of response, not by the confirmatory assessment. Note that if an assessment of irPR occurs before confirmation of irCR, the duration of immune-related response endpoint will not begin at the time that the irBOR of irCR is shown but rather at the earlier time-point showing irPR. For subjects who remain alive and have not progressed following response, irDoR will be censored on the date of last evaluable TA.

    Measured: 2 years

  11. Brain progression-free survival (Brain-PFS)

    Brain progression-free survival (Brain-PFS) (3 and 6 months rates) is defined as the time from randomization date to the date of progression as per MRI of existing brain lesions, or of occurrence as per MRI of a new lesion located in the brain, or of death, whichever occurs first. For subjects who remain alive and have not progressed as per definition above, Brain-PFS will be censored at the day of last evaluable brain imaging assessment.

    Measured: 6 months

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted2 Jun 2015 (estimated)
  2. Study startDec 2012
  3. Primary completionJan 2018 (estimated)
  4. Study completionJan 2020 (estimated)

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 3
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
None (open label)
Enrolment
168 participants (estimated)
IDs, dates and publications
ClinicalTrials.gov ID
NCT02460068
Sponsor's protocol ID
NIBIT-M2
Acronym
NIBIT-M2
Status last verified
May 2015
First submitted
22 May 2015
Last updated
2 Jun 2015
Results posted
No
Data monitoring committee
Yes

Publications

  • Avril MF, Aamdal S, Grob JJ, Hauschild A, Mohr P, Bonerandi JJ, Weichenthal M, Neuber K, Bieber T, Gilde K, Guillem Porta V, Fra J, Bonneterre J, Saiag P, Kamanabrou D, Pehamberger H, Sufliarsky J, Gonzalez Larriba JL, Scherrer A, Menu Y. Fotemustine compared with dacarbazine in patients with disseminated malignant melanoma: a phase III study. J Clin Oncol. 2004 Mar 15;22(6):1118-25. doi: 10.1200/JCO.2004.04.165.

    PubMed 15020614

  • Margolin K, Ernstoff MS, Hamid O, Lawrence D, McDermott D, Puzanov I, Wolchok JD, Clark JI, Sznol M, Logan TF, Richards J, Michener T, Balogh A, Heller KN, Hodi FS. Ipilimumab in patients with melanoma and brain metastases: an open-label, phase 2 trial. Lancet Oncol. 2012 May;13(5):459-65. doi: 10.1016/S1470-2045(12)70090-6. Epub 2012 Mar 27.

    PubMed 22456429

  • Di Giacomo AM, Ascierto PA, Pilla L, Santinami M, Ferrucci PF, Giannarelli D, Marasco A, Rivoltini L, Simeone E, Nicoletti SV, Fonsatti E, Annesi D, Queirolo P, Testori A, Ridolfi R, Parmiani G, Maio M. Ipilimumab and fotemustine in patients with advanced melanoma (NIBIT-M1): an open-label, single-arm phase 2 trial. Lancet Oncol. 2012 Sep;13(9):879-86. doi: 10.1016/S1470-2045(12)70324-8. Epub 2012 Aug 13.

    PubMed 22894884

  • Di Giacomo AM, Ascierto PA, Queirolo P, Pilla L, Ridolfi R, Santinami M, Testori A, Simeone E, Guidoboni M, Maurichi A, Orgiano L, Spadola G, Del Vecchio M, Danielli R, Calabro L, Annesi D, Giannarelli D, Maccalli C, Fonsatti E, Parmiani G, Maio M. Three-year follow-up of advanced melanoma patients who received ipilimumab plus fotemustine in the Italian Network for Tumor Biotherapy (NIBIT)-M1 phase II study. Ann Oncol. 2015 Apr;26(4):798-803. doi: 10.1093/annonc/mdu577. Epub 2014 Dec 23.

    PubMed 25538176

  • Wolchok JD, Kluger H, Callahan MK, Postow MA, Rizvi NA, Lesokhin AM, Segal NH, Ariyan CE, Gordon RA, Reed K, Burke MM, Caldwell A, Kronenberg SA, Agunwamba BU, Zhang X, Lowy I, Inzunza HD, Feely W, Horak CE, Hong Q, Korman AJ, Wigginton JM, Gupta A, Sznol M. Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med. 2013 Jul 11;369(2):122-33. doi: 10.1056/NEJMoa1302369. Epub 2013 Jun 2.

    PubMed 23724867

Questions about this trial

What is this clinical trial studying?

A Phase 3 study testing Fotemustine, Fotemustine and Ipilimumab and Ipilimumab and nivolumab in people with Brain Metastases, run by Italian Network for Tumor Biotherapy Foundation at 11 sites in Italy.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 14 inclusion and 18 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: status not confirmed, as of the sponsor's last update on 2 Jun 2015. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 11 sites in Italy. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Results are not available in the source record.

How can a doctor refer a patient or contact the research team?

Contact Anna Maria Di Giacomo, PhD,MD (0577-586305, a.m.digiacomo@ao-siena.toscana.it), or a site near the patient. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Overall Survival (OS) (time frame: 2 years). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT02460068, which also lists 5 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 2 Jun 2015.

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