Study of Radiotherapy Administered in Combination With Ipilimumab in Patients With Unresectable Stage III or Stage IV Advanced Malignant Melanoma (Mel-Ipi-Rx)
RATIONALE:Anti-melanoma activity of Ipilimumab both as a single therapy and in association with melanoma peptides has been shown as well as synergy between radiation therapy and anti-CTLA-A mAb in several tumor animal models for both local tumor control and distant effects.Radiotherapy increases tumor immunogenicity in several preclinical models by increasing MHC molecules expression and is able to induce significant tumor reduction in around 30% of cases. Thus, combining radiotherapy and administration of ipilimumab could elicit systemic antitumor response. Radiation therapy will expose tumor-associated antigens (TAA) and facilitate antigen presentation, and further blockade of CTLA-4 could amplify the immune antitumor response. In this therapeutical model, the use of the own patient tumor as a source of tumor antigens (in opposition with other vaccination protocols, where TAA are exogenic) is particularly adapted.
PURPOSE: This Phase I trial determines the side effects and best dose of radiation therapy administered in combination with ipilimumab.
|Study Design:||Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||A Dose Escalation Phase I Study of Radiotherapy Administered in Combination With Anti-CTLA4 Monoclonal Antibody (Ipilimumab) in Patients With Unresectable Stage III or Stage IV Advanced Malignant Melanoma|
- Maximum Tolerated Dose of radiation therapy administered in combination with ipilimumab [ Time Frame: between week 4 and week 10 ] [ Designated as safety issue: Yes ]To determine the Maximum Tolerated Dose (MTD), Dose Limiting Toxicity (DLT) andrecommended Phase 2 dose of radiation therapy administered in combination with ipilimumab.
- Adverse event profiles [ Time Frame: At an average of every four weeks during the treatment phase ] [ Designated as safety issue: Yes ]Adverse event profiles
- overall survival in patients treated with this combination [ Time Frame: At an average of every four weeks during the treatment phase and then every three months during the follow-up phase ] [ Designated as safety issue: Yes ]overall survival in patients treated with this combination
|Study Start Date:||March 2011|
|Estimated Study Completion Date:||March 2014|
|Estimated Primary Completion Date:||December 2012 (Final data collection date for primary outcome measure)|
|Experimental: radiation therapy with Ipilimumab||
Induction: Treatment with ipilimumab will be administered on weeks 1, 4, 7 and 10 at 10mg/kg.
Maintenance: Ipilimumab will be administered intravenously over 90-minutes at 10 mg/kg every 12 weeks starting at week 24, for as long as the treating physician believes that there is a clinical benefit or for as long as patient is tolerant of therapy
Radiation therapy 9 Grays in 3 Grays fractions Radiation therapy 15 Grays in 5 Grays fractions Radiation therapy 18 Grays in 6 Grays fractions Radiation therapy 24 Grays in 8 Grays fractions
Primary: To determine the Maximum Tolerated Dose (MTD), Dose Limiting Toxicity (DLT) and recommended Phase 2 dose of radiation therapy administered in combination with ipilimumab.
Adverse event profiles Preliminary anti-tumor activity following escalating doses of radiation combined to ipilimumab using the immune related response criteria irRC overall survival in patients treated with this combination systemic immunologic anti tumor response intratumoral immune response pharmacodynamic effects of ipilimumab and radiotherapy in combination on Absolute Lymphocyte Count (ALC) associations between ALC and anti-tumor activity of ipilimumab and radiotherapy in combination