A first in man phase I trial of the oral immunomodulator, indoximod, combined with docetaxel in patients with metastatic solid tumors

Abstract

BackgroundIndoleamine 2,3-dioxygenase (IDO) is an enzyme that tumors use to create a state of immunosuppression. Indoximod is an IDO pathway inhibitor. Preclinical studies demonstrated that indoximod combined with chemotherapy was synergistic in a mouse model of breast cancer. A phase I 3+3 trial was designed to study the combination of docetaxel and indoximod.MethodsDocetaxel was administered at 60 mg/m2 intravenously every 3 weeks dose levels 1-4 and 75 mg/m2 for dose level 5. Indoximod was given at 300, 600, 1000, 2000, and 1200 mg PO twice daily continuously for levels 1-5, respectively. Serum drug levels were measured.ResultsTwenty-seven patients were treated, with 22 evaluable for response. DLTs included grade 3 dehydration (level 1), hypotension(level 4), mucositis (level 4) and grade 5 enterocolitis (level 2). Dose level 5 is the recommended phase II dose. The most frequent adverse events were fatigue (58.6%), anemia (51.7%), hyperglycemia (48.3%), infection (44.8%), and nausea (41.4%). There were 4 partial responses (2 breast, 1 NSCLC, 1 thymic tumor). No drug-drug interactions were noted.ConclusionsDocetaxel plus indoximod was well tolerated with no increase in expected toxicities or pharmacokinetic interactions. It was active in a pretreated population of patients with metastatic solid tumors.

Tumor indoleamine 2,3-dioxygenase (IDO) inhibits CD19-CAR T cells and is downregulated by lymphodepleting drugs

“…A few clinical trials are evaluating the effects of IDO inhibitors (indoximod, INCB024360, and NLG919) that competitively block the degradation of tryptophan to kynurenine by the enzyme. 39,40 Our study focused on the interaction between IDO in tumor cells and adoptively transferred CD19-CARTs. Nevertheless, IDO is produced not only by tumor cells but also by host immune cells, such as dendritic cells, tumor-associated macrophages, and myeloid-derived suppressor cells, which inhibit T-cell response and promote recruitment of regulatory T cells.…”

Coinhibitory Pathways in Immunotherapy for Cancer

“…IDO expression has been associated with poor prognosis and mediates resistance to CTLA-4 blockade (238). Therapeutic agents interfering with the IDO pathway have entered clinical testing in conjunction with chemotherapy (239), and in combination with ipilimumab, where preliminary data indicate clinical activity (240).…”

Advances in the Treatment of Breast Cancer-Emphasis on fertility preservation-A Case Report

“…Further in women who received endocrine therapy those having a median or greater antibody response (titre>1:320 towards ovine submaxillary mucinto the STn -KLH vaccine had significantly longer median OS than those below this titre [37].…”