Clinical trial NCT02460068: A Study of Fotemustine(FTM) Vs FTM and Ipilimumab (IPI) or IPI and Nivolumab in Melanoma Brain Metastasis
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
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE3
Conditions: Brain Metastases
Keywords: melanoma brain metastases
nivolumab
ipilimumab
Lead sponsor: Italian Network for Tumor Biotherapy Foundation
Sponsor class: OTHER
Collaborators: name: Bristol-Myers Squibb
First posted: 2015-06-02
Enrollment: 168
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

Other Exclusion Criteria:

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

Primary outcomes:
measure: Overall Survival (OS)
timeFrame: 2 years
Secondary outcomes:
measure: safety (adverse events)
timeFrame: 2 years
measure: m-WHO and immune-related Disease Control Rate (DCR) in and outside the brain
timeFrame: Weeks 24
measure: Immune-related Progression-free Survival (irPFS)
timeFrame: 2 years
measure: m-WHO Progression-free Survival (irPFS)
timeFrame: 2 years
measure: Objective Response Rate (ORR)
timeFrame: Weeks 24
measure: Immune-related Objective Response Rate (irORR)
timeFrame: Weeks 24
measure: Time to Response (TTR)
timeFrame: Weeks 24
measure: Immune-related Time to Response (irTTR)
timeFrame: Weeks 24
measure: Duration of Response (DoR)
timeFrame: 2 years
measure: Immune-related Duration of Response (irDoR)
timeFrame: 2 years
measure: Brain progression-free survival (Brain-PFS)
timeFrame: 6 months
Other outcomes:
Locations:
city: Bari
country: Italy
facility: Medical Oncology, Cancer Institute "Giovanni Paolo II"
city: Bergamo
country: Italy
facility: Medical Oncology, Pope Giovanni XXIII Hospital
city: Genoa
country: Italy
facility: National Institute for Cancer Research
city: Meldola
country: Italy
facility: Immunotherapy and Somatic Cell Therapy Unit, Scientific Institute of Romagna
city: Milan
country: Italy
facility: Surgical Oncology, National Cancer Institute
city: Milan
country: Italy
facility: European Institute of Oncology
city: Naples
country: Italy
facility: Medical Oncology and Innovative Therapy, National Cancer Institute
city: Padua
country: Italy
facility: esophageal and melanoma oncology, Istituto Oncologico Veneto
city: Rome
country: Italy
facility: Medical Oncology, National Cancer Institute "Regina Elena"
city: Siena
country: Italy
facility: Medical Oncology and Immunotherapy Unit, University Hospital of Siena
city: Turin
country: Italy
facility: S C Dermatology, A.O.U. City of Health and Science of Turin
Study officials:
affiliation: Medical Oncology and Immunotherapy Unit, University Hospital of Siena
name: Anna Maria Di Giacomo, PhD,MD
role: PRINCIPAL_INVESTIGATOR
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citation: 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.