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Trial record 50 of 510 for:    melanoma phase III

A Study of Fotemustine(FTM) Vs FTM and Ipilimumab (IPI) or IPI and Nivolumab in Melanoma Brain Metastasis (NIBIT-M2)

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ClinicalTrials.gov Identifier: NCT02460068
Recruitment Status : Recruiting
First Posted : June 2, 2015
Last Update Posted : June 2, 2015
Sponsor:
Collaborator:
Bristol-Myers Squibb
Information provided by (Responsible Party):
Italian Network for Tumor Biotherapy Foundation

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.

Condition or disease Intervention/treatment Phase
Brain Metastases Drug: Fotemustine Drug: Fotemustine and Ipilimumab Drug: Ipilimumab and nivolumab Phase 3

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 168 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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 Start Date : December 2012
Estimated Primary Completion Date : January 2018
Estimated Study Completion Date : January 2020

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Melanoma

Arm Intervention/treatment
Active Comparator: fotemustine
fotemustine alone
Drug: 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.
Other Name: Fotemustine (Muphoran);

Experimental: fotemustine and ipilimumab
fotemustine in combination with ipilimumab
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.
Other Names:
  • Fotemustine (Muphoran);
  • Ipilimumab (YERVOY)

Experimental: ipilimumab and nivolumab
ipilimumab in combination with nivolumab
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.
Other Names:
  • Ipilimumab (YERVOY)
  • Nivolumab (OPDIVO)




Primary Outcome Measures :
  1. Overall Survival (OS) [ Time Frame: 2 years ]
    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.


Secondary Outcome Measures :
  1. safety (adverse events) [ Time Frame: 2 years ]
    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

  2. m-WHO and immune-related Disease Control Rate (DCR) in and outside the brain [ Time Frame: Weeks 24 ]
    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.

  3. Immune-related Progression-free Survival (irPFS) [ Time Frame: 2 years ]
    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.

  4. m-WHO Progression-free Survival (irPFS) [ Time Frame: 2 years ]
    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.

  5. Objective Response Rate (ORR) [ Time Frame: Weeks 24 ]
    is the proportion of treated subjects with a BOR of confirmed CR or confirmed PR.

  6. Immune-related Objective Response Rate (irORR) [ Time Frame: Weeks 24 ]
    is the proportion of treated subjects with a irBOR of confirmed irCR or confirmed irPR.

  7. Time to Response (TTR) [ Time Frame: Weeks 24 ]
    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).

  8. Immune-related Time to Response (irTTR) [ Time Frame: Weeks 24 ]
    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).

  9. Duration of Response (DoR) [ Time Frame: 2 years ]
    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.

  10. Immune-related Duration of Response (irDoR) [ Time Frame: 2 years ]
    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.

  11. Brain progression-free survival (Brain-PFS) [ Time Frame: 6 months ]
    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.



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

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): NCT02460068


Contacts
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Contact: Anna Maria Di Giacomo, PhD,MD 0577-586305 a.m.digiacomo@ao-siena.toscana.it
Contact: Michele Maio, PhD,MD 0577-586335 mmaiocro@gmail.com

Locations
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Italy
Medical Oncology, Cancer Institute "Giovanni Paolo II" Not yet recruiting
Bari, Italy, 70124
Contact: Michele Guida, PhD,MD    080-5555238    micguida@libero.it   
Medical Oncology, Pope Giovanni XXIII Hospital Recruiting
Bergamo, Italy, 24127
Contact: Mario Mandalà, PhD, MD       mariomandala@tin.it   
National Institute for Cancer Research Not yet recruiting
Genoa, Italy, 16132
Contact: Paola Queirolo, PhD,MD    010-5600667    paola.queirolo@istge.it   
Immunotherapy and Somatic Cell Therapy Unit, Scientific Institute of Romagna Recruiting
Meldola, Italy, 47014
Contact: Massimo Guidoboni, PhD, MD    0543-739100    m.guidoboni@irst.emr.it   
Surgical Oncology, National Cancer Institute Recruiting
Milan, Italy, 20133
Contact: Michele Del Vecchio, PhD, MD    02 2390 2772    michele.delvecchio@istitutotumori.mi.it   
European Institute of Oncology Active, not recruiting
Milan, Italy, 20141
Medical Oncology and Innovative Therapy, National Cancer Institute Active, not recruiting
Naples, Italy, 80131
esophageal and melanoma oncology, Istituto Oncologico Veneto Not yet recruiting
Padua, Italy, 35128
Contact: Vanna Chiaron Sileni    049 - 821 5931/5943    mgaliz@tiscali.it   
Medical Oncology, National Cancer Institute "Regina Elena" Active, not recruiting
Rome, Italy, 0014
Medical Oncology and Immunotherapy Unit, University Hospital of Siena Recruiting
Siena, Italy, 53100
Contact: Anna Maria Di Giacomo, PhD,MD    0577 586305    a.m.digiacomo@ao-siena.toscana.it   
Contact: Michele Maio, PhD,MD    0577 586335    mmaiocro@gmail.com   
S C Dermatology, A.O.U. City of Health and Science of Turin Not yet recruiting
Turin, Italy, 10126
Contact: Pietro Quaglino, PhD, MD       pietro.quaglino@unito.it   
Sponsors and Collaborators
Italian Network for Tumor Biotherapy Foundation
Bristol-Myers Squibb
Investigators
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Principal Investigator: Anna Maria Di Giacomo, PhD,MD Medical Oncology and Immunotherapy Unit, University Hospital of Siena

Additional Information:
Publications:

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Responsible Party: Italian Network for Tumor Biotherapy Foundation
ClinicalTrials.gov Identifier: NCT02460068     History of Changes
Other Study ID Numbers: NIBIT-M2
First Posted: June 2, 2015    Key Record Dates
Last Update Posted: June 2, 2015
Last Verified: May 2015

Keywords provided by Italian Network for Tumor Biotherapy Foundation:
melanoma brain metastases
nivolumab
ipilimumab

Additional relevant MeSH terms:
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Melanoma
Nevi and Melanomas
Neoplasm Metastasis
Neoplasms, Second Primary
Brain Neoplasms
Neuroendocrine Tumors
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Nerve Tissue
Neoplastic Processes
Pathologic Processes
Central Nervous System Neoplasms
Nervous System Neoplasms
Neoplasms by Site
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Nivolumab
Ipilimumab
Fotemustine
Antineoplastic Agents, Immunological
Antineoplastic Agents