Abstract P2-11-09: A phase 2 randomized trial of the IDO pathway inhibitor indoximod in combination with taxane based chemotherapy for metastatic breast cancer: Preliminary data

Abstract

Background: Indoleamine 2,3 dioxygenase (IDO) is a tryptophan-catabolizing enzyme that plays a key role in the normal regulation of peripheral immune tolerance. Tumors also employ this mechanism to induce a state of immunosuppression, evading immune mediated destruction. Indoximod (D-1-methyltryptophan) is a broad IDO pathway inhibitor as it has been shown to potentially interfere with multiple targets within the IDO pathway. Preclinical studies in MMTV-neu mouse models have demonstrated that combining indoximod with cytotoxic chemotherapy had a greater in-vivo anti-tumor effect than either agent alone. A phase 1 trial combining docetaxel and indoximod demonstrated safety and responses in metastatic breast cancer (mBC) patients. Based on these data a phase 2 trial evaluating indoximod in combination with taxane chemotherapy as first line therapy in patients with metastatic breast cancer was initiated. Methods: The study is a 1:1 randomized, placebo controlled, four arm phase 2 trial. The study treatment is docetaxel 75mg/m2 IV D8 plus indoximod 1200mg PO BID D1-14 every 21 days or matching placebo in study arms 1A and 2A or paclitaxel 80 mg/m2 IV weekly 3 out of 4 weeks with indoximod or matching placebo given BID Days 1-14 in arms 1B and 2B. The primary endpoint is progression free survival. Secondary endpoints include overall survival, response rate, safety, and immune response correlative assays. Patients with measurable, histologically confirmed mBC, no prior chemotherapies (hormonal therapies allowed) in the metastatic setting, ER+ or ER –, HER2 -, ECOG PS 0-1, no active CNS disease, no active autoimmune disease are eligible. Target enrollment is 154 patients. Results: At submission, 65 patients have evaluable safety data on trial. The pooled, blinded data was evaluated for any safety signals. Patient demographics include median age 58 years, 95% female, 17% African American, 25% triple-negative disease, and 82% with multiple sites of metastatic disease. 28% of patients had at least one Grade 3 or 4 adverse event. Those occurring in multiple patients include dyspnea 5%, pleural effusion 3%, non-cardiac chest pain 3%, and febrile neutropenia 3%. Most patients had at least one adverse event (86%). The most common were anemia 14%, tearing 11%, constipation 19%, diarrhea34%, nausea 44%, vomiting 22%, fatigue 48%, peripheral edema 17%, increased liver function tests 10%, lymphopenia 17%, hyperglycemia 15%, myalgia 14%, dizziness 14%, dysguesia 16%, headache 20%, peripheral neuropathy 12%, dyspnea 19%, alopecia 34%, and rash 14%, all compatible with the side effect profile of single agent taxanes. No immune specific serious advents were reported. No treatment related deaths have been reported. Conclusion: The aggregate safety data for these 65 patient are similar to what is typically observed with docetaxel and paclitaxel. No unexpected serious immune linked adverse events were reported. The trial is currently open at multiple clinical sites in the US and Europe and actively enrolling patients. Updated data will be presented. NCT01191216. Citation Format: Tang S-C, Montero A, Munn D, Link C, Vahanian N, Kennedy E, Soliman H. A phase 2 randomized trial of the IDO pathway inhibitor indoximod in combination with taxane based chemotherapy for metastatic breast cancer: Preliminary data. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P2-11-09.

The Combined Use of Melatonin and an Indoleamine 2,3-Dioxygenase-1 Inhibitor Enhances Vaccine-Induced Protective Cellular Immunity to HPV16-Associated Tumors

“…In the present study, we observed that treatment with one metabolic adjuvant provided enhanced gDE7-mediated antitumor protection but only the combination of melatonin and one IDO inhibitor conferred complete tumor protection. Regarding IDO1 inhibitors, we observed a superior preclinical antitumor activity relative to DL-1MT in side-by-side comparisons to D-1MT, which is the isoform actually under clinical trials ( 23 ). Previous evidences indicated that D-1MT was more effective than DL-1MT as an anti-cancer agent and reversed the T cell suppression effect mediated by IDO1-expressing DCs ( 33 ).…”

“…Since IDO1 is an endogenous mechanism of immune tolerance in vivo , IDO1 inhibitors are emerging as experimental molecules in oncology ( 22 ). Indeed, small-molecules inhibitors of IDO1, like epacadostat, navoximod and indoximod (D-1MT enantiomer), are under phase II or II/III clinical trials ( 23 , 24 ). However, based on recent negative results of ECHO-301/KEYNOTE-252 phase 3 trial in metastatic melanoma (clinical trial information: NCT02752074) ( 25 ), many trials, particularly those that use the IDO inhibitor epacadostat, needed to be halted.…”

“…In the present study, we evaluated the therapeutic potential of a novel immunotherapy focusing on three components: melatonin, 1MT and an HPV-16 therapeutic vaccine (gDE7) based on a recombinant protein generated after the genetic fusion of the HPV-16 E7-oncoprotein with the envelope glycoprotein (gD) of herpes virus simplex virus (HSV). The IDO inhibitors 1MT (enantiomers and racemic mixture) were chosen to compose our therapeutic approach based on their preclinical and clinical data as adjuvants of antitumor therapies ( 20 , 22 , 23 , 27 ). The gDE7 vaccine ( 28 , 29 ), as well as its DNA version (pgDE7h) ( 30 ), has shown excellent therapeutic effects in experimental conditions based in mice transplanted with TC-1 cells, a murine tumor cell line encoding the HPV-16 oncoproteins.…”

First Report of Parkinsonism Associated With Indoximod, an Immune-Modulating Agent

“…We reported the preliminary safety data of 128 patients who were treated with indoximod or placebo in combination with taxane for metastatic breast cancer (NLG2101 trial)—none developed autoimmune toxicity. 4 Indoleamine 2,3-dioxygenase is responsible for the degradation of tryptophan to kynurenine in effector T cells and regulatory cells, which leads to downregulation of effector T cells and immune escape. 2 Indoximod blocks this action, thereby stimulating the immune system.…”

1-Methyl-tryptophan enantiomers differently affect the cross-talking between mononuclear and tumor cells and interferon-γ production

“…In spite of the Ki values, D-1-MT show higher antitumor activity in vivo in different tumors and combined therapy regimens. D-1-MT was more effective in reducing tumor mass in experimental models (Hou DY, et al, 2007; Liu K T, et al, 2016), and for that reason it is used in Phase 1 and 2 clinical trials with the commercial name of Indoximod ® (Tang SC, et al, 2016). Indoximod has been trial in mono and combined therapy to treat sarcoma, NSCLC, melanoma and colorectal cancer (Yentz S and Smith D, 2018).…”