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

May 12, 2015 updated by: Italian Network for Tumor Biotherapy

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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

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.

Study Type

Interventional

Enrollment (Actual)

86

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Italy
      • Genoa, Italy
        • National Institute for Cancer Research
      • Meldola, Italy
        • Immunotherapy and Somatic Cell Therapy Unit, Scientific Institute of Romagna
      • Milan, Italy
        • European Institute of Oncology
      • Milan, Italy
        • Melanoma Unit, San Raffaele Hospital
      • Milan, Italy
        • Surgical Oncology, National Cancer Institute
      • Naples, Italy
        • Medical Oncology and Innovative Therapy, National Cancer Institute
      • Siena, Italy, 53100
        • Medical Oncology and Immunotherapy-University Hospital of Siena

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Single arm of ipilimumab and fotemustine
Ipilimumab in combination with Fotemustine
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)

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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.
Weeks 24

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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.
2 years
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).
up to 24 weeks
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.
Weeks 24
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).
Weeks 24
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).
2 years
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.
2 years
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.
2 years

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Italian Network for Tumor Biotherapy

Collaborators

Bristol-Myers Squibb

Investigators

  • Principal Investigator: Michele Maio, MD, PhD, Medical Oncology and Immunotherapy Unit, University Hospital of Siena

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

June 1, 2010

Primary Completion (Actual)

May 1, 2012

Study Completion (Actual)

September 1, 2014

Study Registration Dates

First Submitted

July 18, 2012

First Submitted That Met QC Criteria

July 28, 2012

First Posted (Estimate)

August 1, 2012

Study Record Updates

Last Update Posted (Estimate)

May 13, 2015

Last Update Submitted That Met QC Criteria

May 12, 2015

Last Verified

May 1, 2015

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • NIBIT-M1
  • 2010-019356-50 (EudraCT Number)

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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