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

NCT ID: NCT02460068

Last Updated: 2015-06-02

Basic Information

• Recruitment Status: UNKNOWN
• Clinical Phase: PHASE3
• Total Enrollment: 168 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2012-12-31
• Study Completion Date: 2020-01-31

Brief 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.

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.

Conditions

Brain Metastases

Study Design

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

Study Groups

fotemustine

fotemustine alone

Group Type: ACTIVE_COMPARATOR

Fotemustine

Intervention Type: DRUG

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 ipilimumab

fotemustine in combination with ipilimumab

Group Type: EXPERIMENTAL

Fotemustine and Ipilimumab

Intervention Type: DRUG

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 nivolumab

ipilimumab in combination with nivolumab

Group Type: EXPERIMENTAL

Ipilimumab and nivolumab

Intervention Type: DRUG

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.

Interventions

Fotemustine

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.

Intervention Type: DRUG

Fotemustine and Ipilimumab

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.

Intervention Type: DRUG

Ipilimumab and nivolumab

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.

Intervention Type: DRUG

Other Intervention Names

Fotemustine (Muphoran); Fotemustine (Muphoran); Ipilimumab (YERVOY); Ipilimumab (YERVOY); Nivolumab (OPDIVO)

Eligibility Criteria

Inclusion Criteria

• 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;
• 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

Exclusion Criteria

• 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.

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.

• Prisoners or subjects who are involuntarily incarcerated;
• Subjects who are compulsorily detained for treatment of either a psychiatric or physical illness.

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

Sponsors

Bristol-Myers Squibb

INDUSTRY

Sponsor Role: collaborator

Italian Network for Tumor Biotherapy Foundation

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Anna Maria Di Giacomo, PhD,MD

Role: PRINCIPAL_INVESTIGATOR

Medical Oncology and Immunotherapy Unit, University Hospital of Siena

Locations

Medical Oncology, Cancer Institute "Giovanni Paolo II"

Bari, , Italy

Site Status: NOT_YET_RECRUITING

Medical Oncology, Pope Giovanni XXIII Hospital

Bergamo, , Italy

Site Status: RECRUITING

National Institute for Cancer Research

Genoa, , Italy

Site Status: NOT_YET_RECRUITING

Immunotherapy and Somatic Cell Therapy Unit, Scientific Institute of Romagna

Meldola, , Italy

Site Status: RECRUITING

Surgical Oncology, National Cancer Institute

Milan, , Italy

Site Status: RECRUITING

European Institute of Oncology

Milan, , Italy

Site Status: ACTIVE_NOT_RECRUITING

Medical Oncology and Innovative Therapy, National Cancer Institute

Naples, , Italy

Site Status: ACTIVE_NOT_RECRUITING

esophageal and melanoma oncology, Istituto Oncologico Veneto

Padua, , Italy

Site Status: NOT_YET_RECRUITING

Medical Oncology, National Cancer Institute "Regina Elena"

Rome, , Italy

Site Status: ACTIVE_NOT_RECRUITING

Medical Oncology and Immunotherapy Unit, University Hospital of Siena

Siena, , Italy

Site Status: RECRUITING

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

Turin, , Italy

Site Status: NOT_YET_RECRUITING

Countries

Italy

Central Contacts

Anna Maria Di Giacomo, PhD,MD

Role: CONTACT

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

0577-586305

Michele Maio, PhD,MD

Role: CONTACT

mmaiocro@gmail.com

0577-586335

Facility Contacts

Michele Guida, PhD,MD

Role: primary

micguida@libero.it

080-5555238

Mario Mandalà, PhD, MD

Role: primary

mariomandala@tin.it

Paola Queirolo, PhD,MD

Role: primary

paola.queirolo@istge.it

010-5600667

Massimo Guidoboni, PhD, MD

Role: primary

m.guidoboni@irst.emr.it

0543-739100

Michele Del Vecchio, PhD, MD

Role: primary

michele.delvecchio@istitutotumori.mi.it

02 2390 2772

Vanna Chiaron Sileni

Role: primary

mgaliz@tiscali.it

049 - 821 5931/5943

Anna Maria Di Giacomo, PhD,MD

Role: primary

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

0577 586305

Michele Maio, PhD,MD

Role: backup

mmaiocro@gmail.com

0577 586335

Pietro Quaglino, PhD, MD

Role: primary

pietro.quaglino@unito.it

References

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.

Reference Type: BACKGROUND

PMID: 15020614 (View on PubMed)

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.

Reference Type: BACKGROUND

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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.

Reference Type: BACKGROUND

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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.

Reference Type: BACKGROUND

PMID: 25538176 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 23724867 (View on PubMed)

Related Links

http://www.fondazionenibit.org/

Fondazione NIBIT

Other Identifiers

NIBIT-M2

Identifier Type: -

Identifier Source: org_study_id