Abstract P2-15-04: A phase 1/2 study of Ad.p53 DC vaccine with indoximod immunotherapy in metastatic breast cancer
Authors: Soliman Hatem H , Minton Susan E , Ismail-Khan Roohi , Han Hyo S , Vahanian Nicholas N , Link Charles J , Kennedy Gene , Streicher Howard , Sullivan Daniel , Antonia Scott J 
Published: May 2015

Abstract
Background: Indoleamine 2,3 dioxygenase (IDO) is a tryptophan-catabolizing enzyme that causes immunosuppression in the tumor microenvironment. Indoximod is an IDO pathway inhibitor. Preclinical data suggests indoximod enhancs the activity of dendritic cell (DC) vaccines. Ad.p53 is an adenovirus used to generate autologous dendritic cell (DC) vaccines against p53 epitopes. We initiated a phase 1/2a trial of indoximod + Ad.p53DC to explore the safety and efficacy of the combination along with response to subsequent chemo. The phase 1 safety data were previously presented and the treatment was well tolerated with no DLTs. (Soliman, ASCO 2013) This abstract includes new phase 2a safety/efficacy data and updated outcomes on all phase 1/2 metastatic breast cancer patients who received Adp53DC+indoximod and any subsequent response to salvage chemo.
Methods: The phase 2a study combined indoximod 1600mg PO BID with up to 6 Ad.p53 DC vaccinations q2wks. The trial used a single arm, Simon two stage design (n=12 in 1st stage, 25 in 2nd stage) with objective response as the primary endpoint. One response out of 12 was required for progression into second stage. The study had 90% power to detect 20% response rate with a p=.09. Patients with measurable, metastatic breast cancer, &lt;3 lines of chemo in metastatic setting, p53 IHC &gt;5%, ECOG 0-2, no autoimmune disease were eligible. Study treatment continued until disease progression or unacceptably toxicity.
Results: Twelve phase 2 patients were accrued, 9 (7 TNBC, 2 ER+/HER2-) received ≥ 1 dose of Ad.p53DC+indoximod (3 did not due to rapid disease progression during vaccine preparation). Six patients had ≥ 1 prior line of chemo. Seven (58%) subjects experienced any grade AE, there were no treatment related AEs ≥G3. All treatment attributable AEs were G1-2, &lt;10% frequency, and included anemia, nausea, lymphopenia, photophobia, and headache. All discontinuations were due to disease progression. Best response to immunotherapy in phase 2=1 SD, 8 PD. Phase 2 median TTP = 6.85 wks (3.8-18.1), OS = 18.1 wks (3.8-52) with 3 patients alive as of June 2014. Five patients who received ≥ 2 cycles of chemotherapy after immunotherapy demonstrated 1 PR, 3 PD, 1 pending scan. For the entire phase 1/2 breast cohort (21 in phase 1, 9 in phase 2) the median TTP = 9.85 weeks (3.8-22.1), OS=38.7 (3.8-122.1) weeks, with 1 patient from the phase 1 cohort alive as of June 2014. Ten out of 21 evaluable patients (1 CR, 7 PR, 2 SD, 11 PD) had clinical benefit from chemotherapy after immunotherapy (9 patients had rapid decline and did not get one full cycle of therapy). All but one of the responders had seen prior chemotherapy in the metastatic setting (including a CR after 4 prior lines of chemo). Median OS in the chemo responders was 69.4 wks (30.1-122.1).
Conclusions: Indoximod+Ad.p53DC was well tolerated. Across phase 1/2 the best response to immunotherapy alone was SD in 4 pts while 10 of 21 (47%) (including 1 CR) responded to subsequent chemotherapy in this largely pretreated cohort. There may be a chemosensitization effect of indoximod+Ad.p53DC. Future trials should combine this treatment with chemotherapy in appropriately selected patients.
Citation Format: Hatem H Soliman, Susan E Minton, Roohi Ismail-Khan, Hyo S Han, Nicholas N Vahanian, Charles J Link, Gene Kennedy, Howard Streicher, Daniel Sullivan, Scott J Antonia. A phase 1/2 study of Ad.p53 DC vaccine with indoximod immunotherapy in metastatic breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P2-15-04.