A Trial of CDX-1401 in Combination With Poly-ICLC and Pembrolizumab, in Previously Treated Advanced Solid Tumor Patients

Non Small Cell Lung Cancer Clinical Trial

Official title: A Phase I/II Trial of CDX-1401 (a Vaccine Consisting of a Human Monoclonal Antibody Specific for DEC-205, Fused to Full-length Tumor Antigen NY-ESO-1) in Combination With Poly-ICLC and Pembrolizumab, in Previously Treated Advanced Solid Tumor Patients

Status Withdrawn

Clinical Trial Summary

This study will look at the safety of the combination of three drugs (CDX-1401, Poly-ICL, and Pembrolizumab) and its effect on decreasing tumors. Pembrolizumab is an experimental cancer drug. CDX-1401 is a tumor specific antigen and Poly-ICL is a Toll-like receptor agonist tumor specific antigens which when combined with Pembrolizumab may increase the tumor response to this drug.

Clinical Trial Description

Antigen presentation and cellular immunity are complex processes, and subject to modulation because of the tumor microenvironment. Antigen presenting cells in the tumor microenvironment acquire the antigens from tumor cells. Tumors express several tumor specific antigens that can be leveraged by the immune system to mount an effective anti-tumor response. NY-ESO-1, one of the cancer testis antigens, is expressed in several tumors including non-small cell lung cancer (NSCLC), triple negative breast cancer (TNBC), and melanoma. NY-ESO-1 is highly immunogenic and spontaneous tumor regressions in association with humoral and cellular responses to NY-ESO-1 have been reported. NY-ESO-1 is tumor specific and is not detected in non-malignant tissues with the exception of germ cells and trophoblasts, thus making it an attractive target for cancer vaccine development. Cancer vaccines can augment the process of cancer specific antigen presentation, however the efficacy of protein-based vaccines is limited due to weak immunogenicity and inefficient uptake by antigen presenting cells for presentation to T and B cells, and lack of targeting to appropriate antigen presenting cells. Dendritic cells (DCs) are highly specialized antigen-presenting cells that play a central role in initiating and regulating immunity. Deca-lectin, DEC-205 (CD205) is a surface receptor of DCs, which is highly expressed by human DCs and can mediate antigen uptake, processing, and presentation. CDX-1401 is a fully human anti-DEC-205 mAb (3G9) genetically fused to the full length NY-ESO-1. In preclinical studies, Dec-205 fused to NY-ESO-was more efficiently cross-presented to T-cells than NY-ESO-1 protein alone. In a recently concluded phase 1 study of CDX-1401 in combination with adjuvant Toll-like receptor agonists with Resiquimod (TLR7/8 agonist) and Hiltonol (poly-ICLC; TLR3 agonist), CDX-1401 was well tolerated with no dose-limiting toxicities and no treatment related grade 3/4 toxicities. Clinical activity was noted in solid tumors including NSCLC. Interestingly, few of the patients who progressed on CDX-1401 subsequently received immune checkpoint inhibitors and several of these patients with NY-ESO-1-specific cellular response had partial responses by RECISTimmune-related response criteria (IRRC). Previous studies reported enhanced T-cell responses in autologous dendritic cell/myeloma fusion vaccines with PD-1 blockade using CT-011 (Anti-PD1 antibody). In addition, increased tumor-infiltrating dendritic cells which are PD1 positive mediate immune suppression and PD-1 blockade in mice ovarian cancer models enhance effector T-cell responses and reduce tumor burden. Thus, we hypothesize that the ability of CDX-1401 to generate an effective anti-tumor immune response could be enhanced when co-administered with an anti-PD1 antibody.

In this study, investigators will examine the safety of the three drug combination of CDX-1401, Poly-ICL (TLR-3 agonist), and Pembrolizumab, and its impact in generating robust and effective anti-tumor immune responses. The preliminary clinical data from Pembrolizumab are promising, and strategies such as this to enhance tumor specific antigen presentation may augment the responses and clinical benefit from Pembrolizumab.

Primary Objective:

To assess the safety, and tolerability of CDX-1401 in combination with Pembrolizumab

Secondary Objectives:

1. To determine whether the anti-tumor response is substantially increased by vaccination with CDX-1401 (anti-DEC205-NY-ESO-1 fusion protein vaccine) in combination with an immune-checkpoint inhibitor, Pembrolizumab (anti-PD1 mAb) in previously treated patients with advanced solid tumors.

2. To determine immune response to NY-ESO-1 and other tumor specific antigens in patients treated with CDX-1401 and Pembrolizumab.

3. To evaluate changes in Tumor infiltrating lymphocytes and other immune evasive pathway biomarkers post treatment with CDX-1401 and Pembrolizumab.

4. To perform exploratory analysis to identify biomarkers to predict both antigen specific T-cell responses and clinical benefit to CDX-1401 and Pembrolizumab. ;

Study Design

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

Related Conditions & MeSH terms

• Advanced Triple Negative Breast Cancer
• Carcinoma, Non-Small-Cell Lung
• Lung Neoplasms
• Malignant Melanoma
• Melanoma
• Mesothelioma
• Non Small Cell Lung Cancer
• Small Cell Lung Cancer
• Small Cell Lung Carcinoma
• Triple Negative Breast Neoplasms
• Urothelial Cancer

• NCT number: NCT02661100
• Study type: Interventional
• Source: Case Comprehensive Cancer Center
• Status: Withdrawn
• Phase: Phase 1/Phase 2
• Start date: January 2017
• Completion date: July 2018