A Phase I Study of Ad.P53 Dc Vaccine in Combination with Indoximod in Metastatic Solid Tumors.

3069 Background: Indeolamine 2,3 dioxygenase (IDO) is an inducible tryptophan-catabolizing enzyme that downregulates the immune system. Many tumor cell types overexpress IDO to avoid elimination by infiltrating cytotoxic T cells. 1-methyl-D-tryptophan (1-MT, indoximod) is an IDO pathway modulator. Published preclinical data suggested that blockade of IDO with indoximod enhances the immunologic response to dendritic cell (DC) vaccines. Ad.p53 is an adenovirus used for generating DC vaccines directed against p53 epitopes. Ad.p53 when given to previously treated SCLC patients significantly increased their response rate to subsequent chemotherapy. The primary goal in phase I is the MTD of indoximod +Ad.p53. Methods: This phase 1 study used a 3+3 design with 7 indoximod dose levels (DL) (100 mg, 200 mg, 400 mg, 800 mg QD then 800 mg, 1,200 mg, and 1,600 mg PO BID)+up to 6 fixed dose Ad.p53 DC vaccinations q2wks. Standard eligibility/exclusion criteria applied along with exclusion of patients previously treated with ipilimumab. Treatment will continue until disease progression or unacceptable toxicity. DLT rules are 1st cycle ≥G3 AE related to treatment. Results: Total patients accrued to phase I=32. Types treated were 22 breast, 3 colon, 2 gastric, 1 ovarian, 1 NSCLC, 1 oropharynx, 1 sarcoma. No. of patients treated at DL 1-7 were 3, 3, 4, 6, 6, 3, 6, respectively. Toxicities possibly related to therapy were G1-2 fatigue, nausea, constipation, diarrhea, photosensitivity, hyponatremia, hyperglycemia, AST elevation. The MAD was 1,600 mg BID of indoximod with no DLTs noted. All discontinuations were due to progression of disease. No objective responses to study therapy were noted, but 6/10 breast patients treated with carboplatin/gemcitabine or gemcitabine alone responded to salvage therapy. Conclusions: The combination of indoximod+Ad.p53DC vaccine was well tolerated.The RP2D of indoximod is 1,600 mg BID + Ad.p53DC vaccine. There may be a chemosensitizing effect of Ad.p53DC+indoximod with chemo. The phase II trial in metastatic breast is looking at the response rate of indoximod+Ad.p53DC vaccine followed by salvage carboplatin/gemcitabine in previously treated patients. NCT01042535 Clinical trial information: NCT01042535.