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A Phase II Study of the Combination of Ipilimumab and Fotemustine in Patients With Unresectable Locally Advanced or Metastatic Malignant Melanoma

Phase 2
18 Years
Open (Enrolling)
Metastatic Malignant Melanoma

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Trial Information

A Phase II Study of the 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.

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

- 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

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

Other Exclusion Criteria

- Prisoners or subjects who are involuntarily incarcerated;

- Subjects who are compulsorily detained for treatment of either a psychiatric or
physical illness.

Type of Study:


Study Design:

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

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.

Outcome Description:

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.

Outcome Time Frame:

Weeks 24

Safety Issue:


Principal Investigator

Michele Maio, MD, PhD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Medical Oncology and Immunotherapy Unit, University Hospital of Siena


Italy: The Italian Medicines Agency

Study ID:




Start Date:

June 2010

Completion Date:

May 2013

Related Keywords:

  • Metastatic Malignant Melanoma
  • metastatic melanoma
  • Ipilimumab
  • Melanoma