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

Sponsor

Italian Network for Tumor Biotherapy (Other)

Overall Status

Completed

CT.gov ID

NCT01654692

Collaborator

Bristol-Myers Squibb (Industry)

Enrollment

Locations

Arm

Duration (Months)

12.3

Patients Per Site

0.2

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Metastatic Malignant Melanoma	Drug: Ipilimumab and Fotemustine	Phase 2

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 Design

Study Type:

Interventional

Actual Enrollment :

86 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Study Start Date :

Jun 1, 2010

Actual Primary Completion Date :

May 1, 2012

Actual Study Completion Date :

Sep 1, 2014

Arms and Interventions

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)

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)

Outcome Measures

Primary Outcome Measures

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. [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.

Secondary Outcome Measures

safety and feasibility of the combination of ipilimumab and fotemustine [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) [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) [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) [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) [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) [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) [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.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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.

Contacts and Locations

Locations

	Site	City	Country	Postal Code
1	National Institute for Cancer Research	Genoa	Italy
2	Immunotherapy and Somatic Cell Therapy Unit, Scientific Institute of Romagna	Meldola	Italy
3	European Institute of Oncology	Milan	Italy
4	Melanoma Unit, San Raffaele Hospital	Milan	Italy
5	Surgical Oncology, National Cancer Institute	Milan	Italy
6	Medical Oncology and Innovative Therapy, National Cancer Institute	Naples	Italy
7	Medical Oncology and Immunotherapy-University Hospital of Siena	Siena	Italy	53100