Abstract
Abstract CT087: Phase II trial of theiIndoleamine 2, 3-dioxygenase pathway (IDO) inhibitor indoximod plus immune checkpoint inhibitors for the treatment of unresectable stage 3 or 4 melanoma
Cancer research (Chicago, Ill.), Vol.76(14_Supplement), pp.CT087-CT087
07/15/2016
DOI: 10.1158/1538-7445.AM2016-CT087
Abstract
Abstract
Background: IDO is an enzyme that catalyzes the initial and rate limiting step in the conversion of tryptophan to kynurenine. Tryptophan depletion enhances the number and function of the Treg (suppressive) arm of the immune system and inhibits the effector T cell (stimulatory) arm. In addition, it has been shown that kynurenine metabolites may augment the suppressive effects on inflammation and immune responses. The normal physiologic function of IDO is the regulation of acquired local and peripheral immune tolerance. In cancer, IDO can either be expressed directly by the tumor cells themselves, or induced indirectly in host antigen presenting cells by the presence of tumor. In these settings, the IDO pathway mediates an acquired immune tolerance towards tumors, allowing tumors to thwart an immune response by the host. Therefore, the IDO pathway is an attractive target. Anti- CTLA-4 (ipilimumab) and anti-PD-1 (pembrolizumab and nivolumab) are monoclonal antibodies that block the immunosuppressive receptor CTLA-4/ PD-1 on T cells, thus enhancing immune responses against tumors. Tumor models have shown synergistic effects with anti-CTLA-4 treatment and anti-PD-1 treatment in combination with indoximod providing a rationale for combination therapy for the treatment of melanoma. The phase 1b study has enrolled 9 patients combining a dose escalation indoximod (twice daily oral dose, continuously for each 21 day cycle) with ipilimumab (3mg/kg q3 weeks x 4 doses) in a standard 3+3 design. The phase II dose for indoximod has been established at 1200 mg twice daily (BID), which is the maximum biologically achievable dose of oral indoximod.
Methods: This is an ongoing multicenter phase II clinical trial combining indoximod 1200 mg BID with provider choice of a standard of care immune checkpoint inhibitor, consisting of 4 cycles of concomitant ipilimumab, repeat cycles of nivolumab or repeat cycles of pembrolizumab. In the event of progression, the provider can change therapy from one checkpoint inhibitor (anti-CTLA-4 or anti-PD-1) to another (ipilimumab to pembrolizumab or nivolumab as well as pembrolizumab or nivolumab to ipilimumab) while continuing indoximod. In the case of toxicity requiring stoppage of checkpoint blockade with either anti-CTLA-4 or anti-PD-1 treatment patients can continue on indoximod monotherapy until progression. Eligible patients have unresectable Stage 3 or 4 melanoma. Up to 96 subjects are planned to enroll in phase II. Treatment can be continued until disease progression on sequential checkpoint blockade or toxicity. Primary objective is overall response rate, secondary objectives median progression free and overall survival. Correlative studies include qualitative analysis of IDO expression by immunohistochemistry in tumor samples.
ClinicalTrials.gov Identifier: NCT02073123
Citation Format: Yousef Zakharia, Joseph Drabick, Samir Khleif, David Munn, Charles Link, Nicholas Vahanian, Eugene Kennedy, Montaser Shaheen, Olivier Rixe, Mohammed Milhem. Phase II trial of theiIndoleamine 2, 3-dioxygenase pathway (IDO) inhibitor indoximod plus immune checkpoint inhibitors for the treatment of unresectable stage 3 or 4 melanoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT087.
Details
- Title: Subtitle
- Abstract CT087: Phase II trial of theiIndoleamine 2, 3-dioxygenase pathway (IDO) inhibitor indoximod plus immune checkpoint inhibitors for the treatment of unresectable stage 3 or 4 melanoma
- Creators
- Yousef Zakharia - University of IowaJoseph Drabick - Penn State Milton S. Hershey Medical CenterSamir Khleif - Augusta UniversityDavid Munn - Georgia Regents Medical CenterCharles Link - NewLink GeneticsNicholas Vahanian - NewLink GeneticsEugene Kennedy - NewLink GeneticsMontaser Shaheen - New Mexico Cancer CenterOlivier Rixe - New Mexico Cancer CenterMohammed Milhem - University of Iowa
- Resource Type
- Abstract
- Publication Details
- Cancer research (Chicago, Ill.), Vol.76(14_Supplement), pp.CT087-CT087
- DOI
- 10.1158/1538-7445.AM2016-CT087
- ISSN
- 0008-5472
- eISSN
- 1538-7445
- Language
- English
- Date published
- 07/15/2016
- Academic Unit
- Hematology, Oncology, and Blood & Marrow Transplantation; Internal Medicine
- Record Identifier
- 9984548378602771
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