A Combination of Ipilimumab and Fotemustine for Treat Unresectable Locally Advanced or Metastatic Melanoma (NIBIT-M1)
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 Design:||Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: 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|
- 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 ] [ Designated as safety issue: No ]
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.
- safety and feasibility of the combination of ipilimumab and fotemustine [ Time Frame: 2 years ] [ Designated as safety issue: Yes ]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 ] [ Designated as safety issue: No ]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 ] [ Designated as safety issue: No ]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 ] [ Designated as safety issue: No ]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 ] [ Designated as safety issue: No ]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 ] [ Designated as safety issue: No ]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 ] [ Designated as safety issue: No ]
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.
|Study Start Date:||June 2010|
|Estimated Study Completion Date:||May 2013|
|Primary Completion Date:||May 2012 (Final data collection date for primary outcome measure)|
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
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.
|National Institute for Cancer Research|
|Immunotherapy and Somatic Cell Therapy Unit, Scientific Institute of Romagna|
|Melanoma Unit, San Raffaele Hospital|
|Surgical Oncology, National Cancer Institute|
|European Institute of Oncology|
|Medical Oncology and Innovative Therapy, National Cancer Institute|
|Medical Oncology and Immunotherapy-University Hospital of Siena|
|Siena, Italy, 53100|
|Principal Investigator:||Michele Maio, MD, PhD||Medical Oncology and Immunotherapy Unit, University Hospital of Siena|