A phase I study of 1-methyl-D-tryptophan in patients with advanced malignancies.

Abstract

2501 Background: The indoleamine 2, 3 dioxygenase pathway (IDO) can create immune suppression and unresponsiveness to tumor antigens in tumor-bearing hosts. 1-methyl-D-tryptophan (1-MT) is an oral inhibitor of the IDO pathway, currently in development as an immune adjuvant for anti-tumor vaccines and chemotherapy. The primary goal of this trial is to determine the MTD and toxicity for oral 1-MT. Secondary endpoints include response rates, PK, serum tryptophan catabolites, circulating T-reg cells, and C reactive protein (CRP) levels. Methods: This phase I study utilizes a 3+3 design comprised of ten dose levels (200, 300,400,600,800,mg QD, 600, 800,1200,1600,2000mg BID). Inclusion criteria: patients with measurable metastatic solid malignancy, age ≥18, life expectancy >4 months, and adequate organ/marrow function. Exclusion criteria: chemotherapy in the past 3 weeks, untreated brain metastases, active autoimmune disease, or malabsorptive GI disease. Continuous toxicity monitoring early stopping rules were used. Results: At submission, 48 out of the planned 50 patients were accrued. MTD was not reached at 2000mg BID. At 200mg QD dose, 3 patients previously treated with active immunotherapy (ipilimumab, n=2, CD40-mAb, n=1) developed an autoimmune hypophysitis. Since IDO is closely linked to both CTLA-4 and CD40/CD40L pathways this was considered on-target effect. Subsequently, patients with prior immunotherapy were excluded and no additional treatment related G3-5 adverse events were observed. Five patients showed SD>6 months (2 melanoma, 2 sarcoma 1 colon) as well as some mixed responses were seen in some patients including regression of a liver visceral metastases. 1-MT plasma PK AUC and Cmax were proportional with dose. Cmax (~40 μM at 2000mg BID) is at 2.9 hours and the t1/2 is at 10 hours. Elevations in CRP levels and declines in T-reg cell counts were seen across multiple dose levels. Additional correlative data analysis is ongoing. Conclusions: The treatment was well tolerated and orally bioavailable. Biologic activity in terms of prolonged disease stabilization, induction of hypophysitis, and changes in T-reg levels and CRP were observed. Trials combining 1-MT with docetaxel and a dendritic cell vaccine are ongoing.