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A Combination of Ipilimumab and Fotemustine for Treat Unresectable Locally Advanced or Metastatic Melanoma (NIBIT-M1)

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ClinicalTrials.gov Identifier: NCT01654692
Recruitment Status : Completed
First Posted : August 1, 2012
Last Update Posted : May 13, 2015
Bristol-Myers Squibb
Information provided by (Responsible Party):
Italian Network for Tumor Biotherapy

July 18, 2012
August 1, 2012
May 13, 2015
June 2010
May 2012   (Final data collection date for primary outcome measure)
The immune response disease control rate (irDCR) using the immune-related (ir) tumor response criteria of the combination of ipilimumab and fotemustine in patients with unresectable locally advanced or metastatic melanoma. [ Time Frame: Weeks 24 ]

Immune-related Disease Control Rate (irDCR) is the proportion of treated subjects with a BOR of confirmed irCR, confirmed irPR or irSD.

Tumor assessment (including determination of overall response at each tumor assessment and best overall response (BOR) taken over all tumor assessments prior to subsequent therapy is performed using the immune-related (ir) tumor response criteria.

Same as current
Complete list of historical versions of study NCT01654692 on ClinicalTrials.gov Archive Site
  • safety and feasibility of the combination of ipilimumab and fotemustine [ Time Frame: 2 years ]
    A first clinical safety assessment will be performed to identify any early safety signals from ipilimumab given in combination with fotemustine at the first 18 treated patients. All subjects who receive at least 1 dose of study drug will be evaluable for safety parameters. Additionally, any occurrence of a SAE from time of consent forward will be reported.
  • Immune-related Major Durable Disease Control Rate (irMDDCR) [ Time Frame: up to 24 weeks ]
    Immune-related Major Durable Disease Control Rate (irMDDCR) is the proportion of treated subjects with a duration of disease control of >= 24 weeks measured from Week 12, or (for those subjects with a confirmed irCR or confirmed irPR prior to Week 12) from the date of first overall response of irCR or irPR, until the date of irPD or death (whichever occurs first).
  • Immune-related Objective Response Rate (irORR) [ Time Frame: Weeks 24 ]
    Immune-related Objective Response Rate (irORR) is the proportion of treated subjects with a BOR of confirmed irCR or confirmed irPR.
  • Immune-related Time to Response (irTTR) [ Time Frame: Weeks 24 ]
    irTTR is defined as the time from first dosing date until the measurement criteria (using irRC) are first met for overall response of irPR or irCR (whichever status comes first, and provided it is subsequently confirmed).
  • Immune-related Progression-Free Survival (irPFS) [ Time Frame: 2 years ]
    Immune-related Progression-Free Survival (irPFS) is defined as the time between the first dosing date and the date of irPD, or date of death, whichever occurs first. (ie, subjects who die without reported irPD will be considered to have progressed on the date of death).
  • Brain Progression-free Survival (Brain-PFS) [ Time Frame: 2 years ]
    Brain Progression-free Survival (Brain-PFS) is defined as the time from first dosing 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.
  • Overall Survival (OS) [ Time Frame: 2 years ]

    Overall Survival (OS) is defined as the time from first dosing date 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.

    OS will be further described using the survival rate at one year, defined as the probability that a subject is alive at 1 and 2 years following first dose of study therapy and estimated via the Kaplan-Meier method.

Same as current
Not Provided
Not Provided
A Combination of Ipilimumab and Fotemustine for Treat Unresectable Locally Advanced or Metastatic Melanoma
A Phase II Study of the Combination of Ipilimumab and Fotemustine in Patients With Unresectable Locally Advanced or Metastatic Malignant Melanoma
This study is designed to assess the safety and efficacy of a combination of ipilimumab and fotemustine in Patients with Unresectable Locally Advanced or Metastatic Malignant Melanoma.

Immunotherapy, chemotherapy and chemotherapy combinations are currently the most effective accepted systemic treatments for metastatic melanoma. However, significant and prolonged responses are rare.

The trial will determine the additional benefit achieved from adding fotemustine to the anti-CTLA-4 monoclonal antibody,ipilimumab .

It is assumed that the mechanism by which ipilimumab augments the effects of chemotherapy in animal models relies on the ability of the cytotoxic agent to induce apoptosis of tumor cells. These apoptotic cells then can function as potent inducers of an immune response against any non-tolerized antigen that they contain. Thus, the chemotherapy may be creating an in vivo autologous tumor vaccine. Ipilimumab prevents the down regulation of this immune response, allowing for tumor rejection. Animal models evaluating the combination of anti-CTLA4 antibody and chemotherapy have given only a brief acute treatment with chemotherapy - presumably adequate to induce some tumor apoptosis, but inadequate to induce significant prolonged tumor rejection.

Since patients with metastatic melanoma generally require therapy within a relatively short period of time, this protocol will allow for the use of fotemustine. Standard dosing of fotemustine will be used to optimize the chance for tumor control.

Phase 2
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Metastatic Malignant Melanoma
Drug: Ipilimumab and Fotemustine
Ipilimumab: 10 mg/kg q3 weeks for 4 doses, q12 weeks starting at Week 24 Fotemustine: 100 mg/m2 q1 week for 3 doses, q3 weeks starting at Week 9
Other Names:
  • Ipilimumab (Yervoy)
  • Fotemustine (Muphoran)
Experimental: Single arm of ipilimumab and fotemustine
Ipilimumab in combination with Fotemustine
Intervention: Drug: Ipilimumab and Fotemustine

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
September 2014
May 2012   (Final data collection date for primary outcome measure)

Inclusion Criteria:

  • Histologic diagnosis of malignant melanoma
  • Stage III (unresectable) or Stage IV melanoma
  • Maximum 1 line of chemotherapy for advanced disease allowed
  • No prior chemotherapy within 4 weeks from treatment start (6 weeks in case of nitrosourea)
  • No previous systemic corticosteroid therapy within 10 days
  • Prior adjuvant treatment with IFN or other immunotherapy allowed
  • Asymptomatic brain metastases allowed
  • Measurable disease
  • Prior treatment of brain metastases. In case stereotactic radiotherapy (or surgery) was not applicable, whole brain radiotherapy should have been performed
  • Life expectancy >= 16 weeks
  • ECOG performance status of 0 or 1
  • Normal laboratory tests were required
  • 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 be using an adequate method of contraception to avoid pregnancy throughout the study and for up to 8 weeks after the study in such a manner that the risk of pregnancy is minimized.

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;
  • Previous enrollment in another clinical trial or prior treatment with a CD137 agonist or anti-CTLA-4 and/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.
Sexes Eligible for Study: All
18 Years and older   (Adult, Senior)
Contact information is only displayed when the study is recruiting subjects
2010-019356-50 ( EudraCT Number )
Not Provided
Not Provided
Italian Network for Tumor Biotherapy
Italian Network for Tumor Biotherapy
Bristol-Myers Squibb
Principal Investigator: Michele Maio, MD, PhD Medical Oncology and Immunotherapy Unit, University Hospital of Siena
Italian Network for Tumor Biotherapy
May 2015

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP