Epacadostat with Standard Chemoradiation Therapy before Surgery in Treating Patients with Locally Advanced Rectal Cancer

Status: Active


This phase I trial studies the side effects and best dose of epacadostat when given together with standard cheotherapy and radiation therapy (chemoradiation) before surgery in treating patients with rectal cancer that has spread to nearby tissues and lymph nodes. Epacadostat may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving epacadostat in addition to standard chemoradiation before surgery may make the tumor smaller and reduce the amount of normal tissue that needs to be removed.

Eligibility Criteria

Inclusion Criteria

  • Newly diagnosed locally advanced rectal cancer with pathology confirmation as determined by any one of the below: * Clinical stage (c) T4a, i.e. overgrowth to an adjacent organ or structure like the prostate, urinary bladder, uterus, sacrum, pelvic floor, or side wall (according to TNM version 5). * cT4b, i.e. peritoneal involvement. * Extramural vascular invasion (EMVI+). * N2, i.e. four or more lymph nodes in the mesorectum showing morphological signs on magnetic resonance imaging (MRI) indicating metastatic disease. * Positive MRF, i.e. tumor 1 mm or less from the mesorectal fascia. * Metastatic lateral nodes, > 1 cm (lat LN+)
  • Eastern Cooperative Oncology Group (ECOG) performance status =< 1
  • Absolute neutrophil count >= 1,500/mcl
  • Platelets >= 100,000/mcl
  • Hemoglobin >= 9 g/dL
  • Total bilirubin =< institutional upper limit of normal (IULN)
  • Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x IULN
  • Serum creatinine < 1.5 x IULN OR measured or calculated creatinine clearance >= 50 mL/min/1.73 m^2
  • International normalized ratio (INR) or prothrombin time (PT) =< 1.5 x IULN unless patient is receiving anticoagulant therapy as long as INR or partial thromboplastin time (PTT) is within therapeutic range of intended use of anticoagulants
  • Activated partial thromboplastin time (aPTT) =< 1.5 x IULN unless patient is receiving anticoagulant therapy as long as INR or PTT is within therapeutic range of intended use of anticoagulants
  • Willing to undergo study-related biopsies subject to accessibility of tumor, appropriateness of biopsy (not contraindicated), and continued subject consent.
  • Women of childbearing potential and men must agree to contraceptive methods prior to study entry, for the duration of study participation, and for 120 days after the last dose of study treatment. Should a woman become pregnant or suspect she is pregnant while participating in this study, she must inform her treating physician immediately.
  • Able to understand and willing to sign an Institutional Review Board (IRB) approved written informed consent document (or that of legally authorized representative, if applicable).

Exclusion Criteria

  • Received prior anti-cancer therapy for rectal cancer.
  • Prior treatment with an anti-programmed death ligand 1 (anti-PD-1), anti-PD-L1, anti-PD-L2, anti-CD137, anti-cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) antibody (including ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways), or other agents targeting indoleamine 2,3-dioxygenase (IDO) pathway (including indoximod).
  • Previous radiotherapy in the pelvic region or previous rectal surgery (e.g. transanal endoscopic microsurgery [TEM]) or any investigational treatment for rectal cancer within the past month.
  • A history of prior malignancy active within the previous 3 years except for locally curable cancers that have been apparently cured, including, but not limited to, basal or squamous cell skin cancer, superficial bladder cancer, or carcinoma in situ of the prostate, cervix, or breast.
  • Currently receiving any other investigational agents.
  • Extensive growth into cranial part of the sacrum (above S3) or the lumbosacral nerve roots indicating that surgery will never be possible even if substantial tumor downsizing is seen.
  • Presence of metastatic disease or recurrent rectal tumor.
  • Diagnosis of familial adenomatosis polyposis coli (FAP), hereditary non-polyposis colorectal cancer (HNPCC), active Crohn’s disease, or active ulcerative colitis.
  • A history of allergic reactions attributed to compounds of similar chemical or biologic composition to epacadostat, capecitabine, oxaliplatin, or other agents used in the study.
  • Has an active infection requiring systemic therapy.
  • Warfarin (Coumadin): patients currently on warfarin are excluded. Patients who go off warfarin and have INR within normal limits have no washout period
  • Any history of serotonin syndrome (SS) after receiving serotonergic drugs. This syndrome has been most closely associated with use of monoamine oxidase inhibitors (MAOIs), meperidine, linezolid, or methylene blue; all of these agents are prohibited during the study
  • Uncontrolled intercurrent illness including, but not limited to symptomatic congestive heart failure, unstable angina pectoris, or cardiac arrhythmia.
  • Has an active or inactive autoimmune disease or syndrome (i.e. rheumatoid arthritis, moderate or severe psoriasis, multiple sclerosis, inflammatory bowel disease) that has required systemic treatment in the past 2 years or is receiving systemic therapy for an autoimmune or inflammatory disease (i.e. with use of disease modifying agents, corticosteroids, or immunosuppressive drugs). Exceptions include subjects with vitiligo or resolved childhood asthma/atopy, hypothyroidism stable on hormone replacement, controlled asthma, Type I diabetes, Graves’ disease, or Hashimoto’s disease.
  • Presence of an abnormal electrocardiogram (ECG) that, in the investigator’s opinion, is clinically meaningful.
  • Presence of a gastrointestinal condition that may affect drug absorption.
  • Receipt of live attenuated vaccine within 30 days before the first dose of study treatment. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, chicken pox, yellow fever, rabies, Bacillus Calmette-Guerin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (e.g. FluMist) are live attenuated vaccines and are not allowed.
  • Pregnant and/or breastfeeding. Women of childbearing potential must have a negative pregnancy test within 72 hours of study entry.
  • Evidence of interstitial lung disease or active, non-infectious pneumonitis including symptomatic and/or pneumonitis requiring treatment.
  • Known presence of active tuberculosis (TB).
  • Known active hepatitis B (e.g. hepatitis B surface antigen [HBsAg] reactive or hepatitis B virus [HBV] deoxyribonucleic acid [DNA] detected) or hepatitis C (e.g. hepatitis C virus [HCV] ribonucleic acid [RNA] [qualitative] is detected) infection. Testing at screening is required.

Locations & Contacts


Saint Louis
Siteman Cancer Center at Washington University
Status: Active
Contact: Haeseong Park
Phone: 314-362-5740
Email: haeseongpark@wustl.edu

Trial Objectives and Outline


I. To determine the recommended phase II dose (RP2D) of epacadostat for combination with standard chemoradiation (SCRT) and chemotherapy in preoperative treatment of locally advanced rectal cancer.


I. To characterize the safety and toxicity profile of the combination (as measured by Common Terminology Criteria for Adverse Events [CTCAE] version [v]5).

II. To determine the antitumor activity of the combination as measured by neoadjuvant rectal (NAR) score, pathological complete response (pCR) rate, and progression free survival.


I. To evaluate the pharmacodynamic effect of the combination, as measured by the levels of plasma and tissue biomarkers.

II. To determine the effect of treatment on patients’ quality of life (as measured by European Organization for Research and Treatment of Cancer [EORTC] Quality of Life Questionnaires and Bristol Stool Scale measurements).

OUTLINE: This is a dose-escalation study.

Patients receive standard of care preoperative therapy including short course of pelvic radiation over 1 week, capecitabine orally (PO) twice daily (BID) on days 1-14 of each 3-week cycle for 6 cycles, and oxaliplatin intravenously (IV) every 3 weeks for 18 weeks. Patients also receive epacadostat PO BID on days 1-21 starting the day of radiation therapy. Cycles of epacadostat repeat every 21 days for up to 28 weeks in the absence of disease progression or unacceptable toxicity. Patients then undergo surgery approximately 4-6 weeks after completion of chemotherapy.

After completion of study treatment, patients are followed up for 4 weeks.

Trial Phase & Type

Trial Phase

Phase I

Trial Type


Lead Organization

Lead Organization
Siteman Cancer Center at Washington University

Principal Investigator
Haeseong Park

Trial IDs

Primary ID 201902040
Secondary IDs NCI-2019-01785
Clinicaltrials.gov ID NCT03516708