CTLA-4 Blockade and Low Dose Cyclophosphamide in Patients With Advanced Malignant Melanoma
The purpose of this study is to see whether the combination of low-dose Cyclophosphamide and Anti-CTLA4 (Ipilimumab) will stop tumor growth in patients with advanced skin cancer. The investigators expect to see an increase in response rate of the combination over Anti-CTLA-4 alone and estimate a response rate of approximately 20 % in the proposed population.
|Study Design:||Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||Phase II Study of CTLA-4 Blockade and Low Dose Cyclophosphamide in Patients With Advanced Malignant Melanoma|
- The primary objective of this study is: Evaluate the anti-tumor activity of the combination of low dose Cyclophosphamide and CTLA-4 blockade using Objective Response Rate (ORR) by 12 weeks following mWHO RC. [ Time Frame: 12 weeks ] [ Designated as safety issue: Yes ]Objective response rate (ORR) using mWHO RC Safety (CTEP v4.0; NCI CTCAE criteria) 2-stage design - 10 patients will be enrolled in Stage 1. The primary endpoint will be assessed when 10 patients have been followed for 12 weeks. In order to continue the study uninterrupted, additional patients will be enrolled in Stage 2 of the study, provided that safety does not become an issue. However, it is estimated that no more than 6 patients will be enrolled before the primary endpoint can be assessed in the initial 10 patients of the study.
- The secondary objectives are: 1. Progression-free survival 2. T regulatory cell profile in peripheral blood [ Time Frame: Progression-free survival is measured from date of entry to date of 1st documented evidence of recurrence, confirmation of PD, or death (whichever is 1st). T regulatory cells are measured on D1 (pre CTX) & D3 of each cycle. ] [ Designated as safety issue: No ]Peripheral blood taken at baseline/various therapeutic time points/possibly maintenance cycles to evaluate T regulatory cells identified, serially monitored by polychromatic flow cytometry using FoxP3+/CD4+/CD127low/CD25hi markers.
- Tumor-specific T cell responses will be measured in a subset of patients who have biopsy accessible tumor and have tumor biopsies taken. [ Time Frame: Two tumor punch biopsies (4mm in diameter) will be obtained before and after therapy (baseline and week 12, and optional during weeks 24, 36, and 48) if patients have accessible tumors. ] [ Designated as safety issue: No ]One of the tumor punch biopsy will be put in formalin for paraffin-embedding. The other tumor punch biopsy will be processed to obtain lysates to be used as antigens for the T cell assays.
|Study Start Date:||October 2012|
|Estimated Study Completion Date:||July 2014|
|Estimated Primary Completion Date:||December 2013 (Final data collection date for primary outcome measure)|
Experimental: Cyclophosphamide, Ipilimumab
Cyclophosphamide 300 mg/m2 po - Day 1 of Weeks 1, 4, 7, and 10, for a total of 4 doses; (premedication prior to each dose of Cyclophosphamide 8mg Zofran po, then prn)
Ipilimumab 10 mg/kg iv - Day 3 of Weeks 1, 4, 7, and 10 for a total of 4 doses Maintenance treatment will be given on Weeks 24, 36, and 48 Ipilimumab 10 mg/kg iv
Drug: Cyclophosphamide, Ipilimumab
This study consists of a Treatment Period, D1 Zofran 8mg pre-Cyclophosphamide 300mg/mg2 po and D3 Ipilimubab 10mg/kg iv wks 1,4,7 and 10; Tumor assessment at week 12; Follow-Up period weeks 13,16,and 20 with no treatment; Maintenance Period, D1 10mg/kg iv wks 24,36,48 and 60. Week 40=end of treatment; week 60=end of study
The transient removal of CTLA-4-mediated inhibition (CTLA-4 blockade) can induce effective anti-tumor immunity. Efficacy of CTLA-4 blockade as a single agent has been shown in melanoma 53. It has been hypothesized that anti-CTLA-4 antibody might deplete Treg cells 54, inducing autoimmunity. However, patients receiving Ipilimumab have not shown a decrease in Treg number or function in peripheral blood 55.
This trial will answer the question if the combination of Anti-CTLA 4 (following a well established regimen of Ipilimumab) and Cyclophosphamide (given at immunomodulatory doses) will result in antitumor activity in patients with metastatic melanoma due to synergistic immunomodulating effects by overcoming tolerance.
Please refer to this study by its ClinicalTrials.gov identifier: NCT01740401
|United States, New York|
|New York University Langone Clinical Cancer Center|
|New York, New York, United States, 10016|
|Principal Investigator:||Nina Bhardwaj, MD,PhD||New York University Langone Medical Center|