Overcoming tumor antigen anergy in human malignancies using the novel indeolamine 2,3-dioxygenase (IDO) enzyme inhibitor, 1-methyl-D-tryptophan (1MT)

3004 Background: The limited effect of cancer immunotherapy is due to the tumor's ability to induce host anergy towards its antigens. The enzyme indoleamine 2,3-dioxygenase (IDO) is thought to play a key role in anergy induction. IDO metabolizes tryptophan (trp) into immunosuppressive metabolites such as kynurenine (kyn). The oral IDO inhibitor, 1-methyl-D-tryptophan (1MT), was studied in preclinical models. The preclinical data support the activity of 1-MT in preventing T-cell anergy in TDLN, slowing growth of LLC mouse xenografts, and synergizing with chemotherapy in regression of autochthonous breast tumors in MMTV-Neu mice. This led to a phase I first-in-man trial using 1-MT in solid tumors. Methods: This is a phase I study treating adults with refractory solid malignancies. Patients are treated with up to 6 consecutive 28-day cycles starting at 200mg once daily. A 3+3 dose escalation to MTD is used. PK analysis, weekly labs, and CT scans every 2 cycles were done. Correlative studies include serum kyn/trp levels, T-reg cell quantification by flow, tumor IDO expression by IHC, and humoral immune response using a proprietary tumor antigen microarray. Results: Ten pts have recieved 1-MT at 200mg daily. Tumors treated included 1 esophageal, 1 peritoneal, 3 melanomas, 2 sarcomas, and 3 NSCLC. PK results show good bioavailability and a t1/2 of 2–4 hrs. Of the 7 evaluable pts, 4 had SD and 3 had PD. Attributable toxicities were 1 case of grade 1 fatigue and 2 cases of grade 2 hypophysitis. Both cases occurred in pts who received prior immunotherapies. Six new pts without prior immunotherapy were enrolled at the 200mg dose level. Five pts remain on treatment currently. Three pts had decreased T-reg cells after treatment with 1MT and 4 pts showed marked CRP increases. One pt had increased autoantibody titers against 3 tumor antigens compared to baseline. Conclusions: 1-MT appears to be an active, orally bioavailable, and reasonably well tolerated immunomodulator at 200mg daily. Development of hypophysitis in 2 patients indicates the drug can break tolerance resulting in autoimmunity. Enrollment to the trial continues. Future trials will combine 1-MT with other immunotherapies and chemotherapies for solid tumors. [Table: see text]

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Phase I study assessing the mass balance, pharmacokinetics, and excretion of [14C]-pevonedistat, a NEDD8-activating enzyme inhibitor in patients with advanced solid tumors

Investigational New Drugs ◽

10.1007/s10637-020-01017-x ◽

2020 ◽

Author(s):

Xiaofei Zhou ◽

Farhad Sedarati ◽

Douglas V. Faller ◽

Dan Zhao ◽

Hélène M. Faessel ◽

...

Keyword(s):

Phase I ◽

Mass Balance ◽

Solid Tumors ◽

Whole Blood ◽

Enzyme Inhibitor ◽

Systemic Exposure ◽

Clinical Activity ◽

Advanced Solid Tumors ◽

Related Material ◽

The Mean

Summary Pevonedistat (TAK-924/MLN4924) is an investigational small-molecule inhibitor of the NEDD8-activating enzyme that has demonstrated preclinical and clinical activity across solid tumors and hematological malignancies. Here we report the results of a phase I trial characterizing the mass balance, pharmacokinetics, and clearance pathways of [14C]-pevonedistat in patients with advanced solid tumors (NCT03057366). In part A (n = 8), patients received a single 1-h intravenous infusion of [14C]-pevonedistat 25 mg/m2. In part B (n = 7), patients received pevonedistat 25 or 20 mg/m2 on days 1, 3, and 5 in combination with, respectively, docetaxel 75 mg/m2 or carboplatin AUC5 plus paclitaxel 175 mg/m2 on day 1 every 3 weeks. Following the single dose of [14C]-pevonedistat 25 mg/m2 in part A, there was a parallel log-linear decline in plasma and whole blood pevonedistat concentration, with systemic exposure of unchanged pevonedistat representing 41% of drug-related material (i.e., unchanged pevonedistat and its metabolites). The mean terminal half-life of pevonedistat and drug-related material in plasma was 8.4 and 15.6 h, respectively. Pevonedistat distributed preferentially in whole blood with a mean whole-blood-to-plasma ratio for pevonedistat AUC∞ of 40.8. By 1 week post dose, the mean recovery of administered radioactivity was 94% (41% in urine and 53% in feces). The pevonedistat safety profile during both study parts was consistent with previous clinical experience, with no new safety signals observed. In part B, pevonedistat in combination with docetaxel or carboplatin plus paclitaxel was generally well tolerated. ClinicalTrials.gov identifier: NCT03057366.

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Phase I trial and pharmacokinetic (PK) study of ABT-751, an orally bioavailable tubulin binding agent, in pediatric patients with refractory solid tumors

Journal of Clinical Oncology ◽

10.1200/jco.2004.22.14_suppl.2080 ◽

2004 ◽

Vol 22 (14_suppl) ◽

pp. 2080-2080 ◽

Cited By ~ 4

Author(s):

S. Y. Cho ◽

P. C. Adamson ◽

A. E. Hagey ◽

B. C. Widemann ◽

J. M. Maris ◽

...

Keyword(s):

Phase I ◽

Solid Tumors ◽

Phase I Trial ◽

Pediatric Patients ◽

Binding Agent ◽

Tubulin Binding ◽

Orally Bioavailable

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Results of a phase I study of RX-5902: An orally bioavailable inhibitor of phosphorylated P68, targeting solid tumors.

Journal of Clinical Oncology ◽

10.1200/jco.2016.34.15_suppl.2554 ◽

2016 ◽

Vol 34 (15_suppl) ◽

pp. 2554-2554

Author(s):

S. Gail Eckhardt ◽

William Larry Gluck ◽

Martin Gutierrez ◽

Christine Peterson ◽

Reza Mazhari ◽

...

Keyword(s):

Phase I ◽

Solid Tumors ◽

Phase I Study ◽

Orally Bioavailable

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Phase I study of AG-120, an IDH1 mutant enzyme inhibitor: Results from the cholangiocarcinoma dose escalation and expansion cohorts.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.4015 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. 4015-4015 ◽

Cited By ~ 52

Author(s):

Maeve Aine Lowery ◽

Ghassan K. Abou-Alfa ◽

Howard A. Burris ◽

Filip Janku ◽

Rachna T. Shroff ◽

...

Keyword(s):

Phase I ◽

Solid Tumors ◽

Dose Escalation ◽

Stable Disease ◽

Phase I Study ◽

Enzyme Inhibitor ◽

Phase Iii ◽

Controlled Study ◽

Metabolic Enzyme ◽

Expansion Cohort

4015 Background: Mutations in the metabolic enzyme isocitrate dehydrogenase 1 (mIDH1) occur in patients (pts) with cholangiocarcinoma (CC) and are detected in up to 25% of intrahepatic CC. mIDH1 produce the oncometabolite, D-2-hydroxyglutarate (2-HG), resulting in epigenetic and genetic dysregulation and oncogenesis. AG-120 is a first-in-class, potent, oral inhibitor of mIDH1 tested in this phase I study in mIDH1 solid tumors, including CC. Methods: AG-120 was escalated in a 3+3 design from 100 mg twice daily to 1200 mg once daily (QD) in 28-day cycles (N = 60, mIDH1 advanced solid tumors). Key eligibility for CC: recurrence of progressive mIDH1 CC following standard therapy (dose escalation) or at least a prior gemcitabine-based regimen (expansion cohort). Response (RECIST 1.1) was assessed every 8 weeks. Plasma and tumor tissue were collected for exploratory analyses. Results: Based on the safety, pharmacokinetic, and pharmacodynamic data from dose escalation, the 500 mg QD dose was selected for expansion in mIDH1 CC and other mIDH1 solid tumors. As of Dec 16, 2016, 73 pts with mIDH1 CC had been dosed in the dose escalation (n = 24) and expansion (n = 49) cohorts. Demographics: M/F = 24/49, median number of prior therapies = 2 (range 1–5), ECOG 0–1 = 26/47. There were no dose-limiting toxicities. Treatment-related adverse events (AEs) in ≥5% pts: fatigue (21%), nausea (18%), vomiting (12%), diarrhea (10%), decreased appetite (8%), dysgeusia (5%), QT prolongation (5%). Two (3%) pts experienced related grade 3 AEs: fatigue and low phosphorus. There were no AG-120-related AEs leading to discontinuation. Among the 72 efficacy evaluable (≥1 post baseline response assessment or discontinued prematurely) mIDH1 CC pts (24 in escalation and 48 in expansion cohort), 6% (n = 4) had a confirmed partial response and 56% (n = 40) experienced stable disease. The progression-free survival rate at 6 months was 40%, and 8 pts have been treated with AG-120 for ≥1 year. Conclusions: In this pretreated mIDH1 CC population, AG-120 was associated with a favorable safety profile and prolonged stable disease. A global, phase III, randomized, placebo-controlled study of AG-120 in mIDH1 CC has been initiated (ClarIDHy). Clinical trial information: NCT02073994.

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Phase I Study of the Investigational NEDD8-Activating Enzyme Inhibitor Pevonedistat (TAK-924/MLN4924) in Patients with Advanced Solid Tumors

Clinical Cancer Research ◽

10.1158/1078-0432.ccr-15-1338 ◽

2015 ◽

Vol 22 (4) ◽

pp. 847-857 ◽

Cited By ~ 83

Author(s):

John Sarantopoulos ◽

Geoffrey I. Shapiro ◽

Roger B. Cohen ◽

Jeffrey W. Clark ◽

John S. Kauh ◽

...

Keyword(s):

Phase I ◽

Solid Tumors ◽

Phase I Study ◽

Enzyme Inhibitor ◽

Advanced Solid Tumors

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Epacadostat Plus Pembrolizumab in Patients With Advanced Solid Tumors: Phase I Results From a Multicenter, Open-Label Phase I/II Trial (ECHO-202/KEYNOTE-037)

Journal of Clinical Oncology ◽

10.1200/jco.2018.78.9602 ◽

2018 ◽

Vol 36 (32) ◽

pp. 3223-3230 ◽

Cited By ~ 82

Author(s):

Tara C. Mitchell ◽

Omid Hamid ◽

David C. Smith ◽

Todd M. Bauer ◽

Jeffrey S. Wasser ◽

...

Keyword(s):

Antitumor Activity ◽

Phase I ◽

Cell Carcinoma ◽

Solid Tumors ◽

Enzyme Inhibitor ◽

Endometrial Adenocarcinoma ◽

Maximum Tolerated Dose ◽

Advanced Solid Tumors ◽

Open Label ◽

Open Label Phase

Purpose Tumors may evade immunosurveillance through upregulation of the indoleamine 2,3-dioxygenase 1 (IDO1) enzyme. Epacadostat is a potent and highly selective IDO1 enzyme inhibitor. The open-label phase I/II ECHO-202/KEYNOTE-037 trial evaluated epacadostat plus pembrolizumab, a programmed death protein 1 inhibitor, in patients with advanced solid tumors. Phase I results on maximum tolerated dose, safety, tolerability, preliminary antitumor activity, and pharmacokinetics are reported. Patients and Methods Patients received escalating doses of oral epacadostat (25, 50, 100, or 300 mg) twice per day plus intravenous pembrolizumab 2 mg/kg or 200 mg every 3 weeks. During the safety expansion, patients received epacadostat (50, 100, or 300 mg) twice per day plus pembrolizumab 200 mg every 3 weeks. Results Sixty-two patients were enrolled and received one or more doses of study treatment. The maximum tolerated dose of epacadostat in combination with pembrolizumab was not reached. Fifty-two patients (84%) experienced treatment-related adverse events (TRAEs), with fatigue (36%), rash (36%), arthralgia (24%), pruritus (23%), and nausea (21%) occurring in ≥ 20%. Grade 3/4 TRAEs were reported in 24% of patients. Seven patients (11%) discontinued study treatment because of TRAEs. No TRAEs led to death. Epacadostat 100 mg twice per day plus pembrolizumab 200 mg every 3 weeks was recommended for phase II evaluation. Objective responses (per Response Evaluation Criteria in Solid Tumors [RECIST] version 1.1) occurred in 12 (55%) of 22 patients with melanoma and in patients with non–small-cell lung cancer, renal cell carcinoma, endometrial adenocarcinoma, urothelial carcinoma, and squamous cell carcinoma of the head and neck. The pharmacokinetics of epacadostat and pembrolizumab and antidrug antibody rate were comparable to historical controls for monotherapies. Conclusion Epacadostat in combination with pembrolizumab generally was well tolerated and had encouraging antitumor activity in multiple advanced solid tumors.

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Phase I Clinical Trial of Cancer Vaccine Combined with Chemotherapy Targeting both Tumor Antigen and Immune Tolerance Against Advanced Solid Tumors

Annals of Oncology ◽

10.1016/s0923-7534(20)34216-2 ◽

2012 ◽

Vol 23 ◽

pp. ix536

Author(s):

M. Murahashi ◽

Y. Hijikata ◽

Y. Tanaka ◽

H. Inoue ◽

T. Marumoto ◽

...

Keyword(s):

Clinical Trial ◽

Phase I ◽

Solid Tumors ◽

Cancer Vaccine ◽

Immune Tolerance ◽

Tumor Antigen ◽

Phase I Clinical Trial ◽

Advanced Solid Tumors

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Phase I trial and pharmacokinetic (PK) study of ABT-751, an orally bioavailable tubulin binding agent, in pediatric patients with refractory solid tumors

Journal of Clinical Oncology ◽

10.1200/jco.2004.22.90140.2080 ◽

2004 ◽

Vol 22 (14_suppl) ◽

pp. 2080-2080 ◽

Cited By ~ 1

Author(s):

S. Y. Cho ◽

P. C. Adamson ◽

A. E. Hagey ◽

B. C. Widemann ◽

J. M. Maris ◽

...

Keyword(s):

Phase I ◽

Solid Tumors ◽

Phase I Trial ◽

Pediatric Patients ◽

Binding Agent ◽

Tubulin Binding ◽

Orally Bioavailable

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First-in-man phase I clinical trial evaluating TTI-101, an orally bioavailable, small molecule inhibitor of STAT3, in patients with advanced solid tumors.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.tps3158 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. TPS3158-TPS3158

Author(s):

Apostolia Maria Tsimberidou ◽

Sofia de Achaval ◽

Imran Alibhai ◽

Ahmed Omar Kaseb

Keyword(s):

Clinical Trial ◽

Phase I ◽

Solid Tumors ◽

Small Molecule ◽

Dose Escalation ◽

Advanced Solid Tumors ◽

Dose Escalation Study ◽

Alcoholic Fatty Liver ◽

Wide Range ◽

Orally Bioavailable

TPS3158 Background: Signal transducer and activator of transcription 3 (STAT3) is a transcription factor that is a key signaling node and a master regulator of the key hallmarks of cancer, including tumor angiogenesis, resistance to apoptosis, metastasis, and immune evasion. STAT3 activation is observed in ̃70% of all cancers and up to 95% of hepatocellular carcinomas (HCC). Thus, inhibition of STAT3 signaling is expected to have a therapeutic effect against a wide range of cancers. TTI-101 is a first-in-class, orally bioavailable, selective small molecule that binds STAT3 and prevents phosphorylation, homodimerization, nuclear translocation, and ultimately, STAT3-mediated transcriptional activity. TTI-101 has demonstrated anti-tumor activity across a broad range of preclinical cancer models, including a Hep Pten- (hepatocyte-specific deletion of Pten) murine model of liver cancer, which recapitulates the pathogenesis of HCC in non-alcoholic fatty liver disease (NAFLD) with chronic inflammation and liver fibrosis leading to cancer at 11 months. TTI-101 treatment starting at 11 months arrested tumor growth as well as reversed liver injury and fibrosis (1). Given these findings, a clinical trial is being conducted examining the effect of this novel, targeted therapeutic agent in patients with advanced solid malignancies. Methods: This single-site Phase I trial (NCT03195699) is evaluating TTI-101 as monotherapy in patients with advanced solid tumors who are refractory to prior therapies. The primary objectives of this dose-escalation study include establishing tolerability and safety at each dose level, pharmacokinetics (PK), and establishing the recommended phase 2 dose (RP2D). The secondary and exploratory objectives include assessing clinical outcomes of patients and pharmacodynamics (PD) of TTI-101 via timed, paired tumor biopsies. The initial dose-escalation study is stratified by disease type (HCC and non-HCC) with independent dose-escalation schemas and will be followed by dose expansion cohorts where safety, PK and PD will be evaluated. TTI-101 is administered orally, twice daily for a 28-day cycle. Key eligibility criteria include: 18 years of age or older, having metastatic or unresectable solid tumor refractory to standard therapies, and measurable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, an Eastern Cooperative Oncology Group (ECOG) score of 0-2, and normal organ function. Additional criteria are specified for patients with HCC including Child-Pugh class A. HCC cohorts 1-4 and non-HCC cohorts 1-3 have been completed without dose limiting toxicities (DLTs). Enrollment to the HCC dose expansion began in February 2021. 1. Jung KH, et al. Multifunctional Effects of a Small-Molecule STAT3 Inhibitor on NASH and Hepatocellular Carcinoma in Mice. Clin Cancer Res. 2017;23(18):5537-46. Clinical trial information: NCT03195699.

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