Epacadostat (INCB024360) Added to Preoperative Chemoradiation in Patients With Locally Advanced Rectal Cancer

Epacadostat (INCB024360) Added to Preoperative Chemoradiation in Patients With Locally Advanced Rectal Cancer

Phase I/II Study of Epacadostat (INCB024360) Added to Preoperative Chemoradiation in Patients With Locally Advanced Rectal Cancer

The purpose of this research study is to evaluate epacadostat when given with routine radiation therapy and chemotherapy (capecitabine and oxaliplatin) to treat rectal cancer before routine surgery is performed to remove the tumor. The Phase II portion of the trial has not started recruiting.

Based on preclinical data from Ciorba Lab (WUSM) the investigators hypothesize that "SCRT is a foundational regimen to examine adjunctive immunotherapy in LARC and that inhibition of IDO1 mediated tryptophan metabolism will safely improve anti-tumor immunity and therapeutic response to SCRT based therapy." In this multi-center phase II clinical trial, first 20 patients will be randomized to either Treatment Cohort or Biomarker Cohort. Patients on Biomarker Cohort will undergo standard SCRT and CAPOX chemotherapy, and provide research biopsies before and after SCRT, and at the time of surgery. Patients on Treatment Cohort will receive epacadostat 400mg twice daily, along with standard SCRT and CAPOX chemotherapy. After the first 20 patients, additional patients will be enrolled to Treatment Cohort until 27 patients who are evaluable for the primary endpoint are enrolled. Patients will be assessed for clinical outcomes including response to therapy as measured by neoadjuvant rectal score (NAR score), local and distant control of their disease, toxicities and survival. Up to 37 evaluable patients (27 patients in treatment cohort and 10 patients in biomarker cohort) of any gender, race, or ethnicity with locally advanced rectal cancer will be included in this clinical trial. Tumor and blood samples will be collected for analyses to determine factors that underlie treatment response or resistance.

Participants enrolled in the Phase I portion were enrolled sequentially. Participants enrolled in the Phase II portion will be enrolled parallel.

Epacadostat at the designated dose level starting the day of radiation therapy, throughout chemotherapy, and until the day of surgery Epacadostat is taken by mouth twice per day every day of each 21 day cycle Standard of care preoperative therapy will consist of a total of approximately 20-24 weeks' preoperative therapy followed by surgery. Breakdown of the 20-24 weeks of preoperative therapy are as follows: Week 1: Short-course pelvic radiation therapy, 5 fractions over 1 week Weeks 2-4: Treatment break for 2 to 4 weeks; for patients enrolled at Washington University only, tumor biopsy will be obtained on or after the last radiation day (D5-8) and before the start of chemotherapy (D21-28) 6 cycles of CAPOX for a total of 18 weeks surgery will follow approximately 4 to 6 weeks after completion of chemotherapy CAPOX is typically capecitabine at 1000 mg/m2 PO BID and oxaliplatin 130 mg/m2 IV Q3W. The second cycle of epacadostat will begin when CAPOX starts

Epacadostat 400 mg BID starting the day of radiation therapy, throughout chemotherapy, and until the day of surgery Epacadostat is taken by mouth twice per day every day of each 21 day cycle Standard of care preoperative therapy will consist of a total of approximately 20-24 weeks' chemoradiation followed by surgery. Breakdown of the preoperative therapy are as follows: Cycle 1 Days 1-7 (Week 1): Short-course pelvic radiation therapy, typically 5 fractions over 1 week Cycle 0 Days 8-21 or 28 (Weeks2-4): Treatment break for 2-3 weeks; tumor biopsy will be obtained between the end of RT and prior to chemotherapy (for patients enrolled at Washington University and Dana Farber Cancer Institute only) Cycles 1-6: 6 21 day cycles of CAPOX for a total of 18 weeks: CAPOX is typically capecitabine at 1000 mg/m^2 PO BID (days 1-14 of each 3-week cycle) and oxaliplatin 130 mg/m^2 IV Q3W. Surgery will follow approximately 4 to 6 weeks after completion of chemotherapy

-Patients enrolled to the biomarker cohort will not receive epacadostat but will only receive standard of care preoperative therapy consisting of a total of approximately 20 to 24 weeks of chemoradiation as follows: Cycle 0 Days 1-7 (Week 1): Short-course pelvic radiation therapy, typically 5 Gy x 5 fractions over 1 week Cycle 0 Days 8-21 or 28 (Weeks 2-4): treatment break for 2 to 3 weeks; for patients enrolled at Washington University and Dana Farber Cancer Institute ONLY, tumor biopsy will be obtained between the end of RT and prior to initiation of chemotherapy via proctoscopy or sigmoidoscopy (if safe, feasible, and evidence of necessary) (target Days 5-28) Cycles 1-6: 6 21-day cycles of CAPOX for a total of 18 weeks; CAPOX is typically capecitabine at 1000 mg/m*2 PO BID (Days 1-14 of each 3-week cycle) and oxaliplatin 130 mg/m^2 IV Q3W. Surgery will follow approximately 4 to 6 weeks after completion of CAPOX, although surgery may occur outside this timeframe.

Patients will receive epacadostat at the designated dose level starting the day of radiation therapy, throughout the chemotherapy, and until the day of surgery. If the patient dose not proceed with the surgery, epacadostat will be discontinued after the last biopsy is performed, and after the investigator confirms non-operative management plans.

CAPOX is typically capecitabine at 1000 mg/m2 PO BID (Days 1-14 of each 3-week cycle) and oxaliplatin 130 mg/m2 IV Q3W. The second cycle of epacadostat will begin when CAPOX starts. Patient will receive a total of 6 cycles of CAPOX chemotherapy.

Phase I only: Recommended phase II dose (RP2D) of epacadostat with standard of care radiation and chemotherapy in preoperative treatment of locally advanced rectal cancer

The recommended phase 2 dose (RP2D) is defined as the dose level immediately below the maximally administered dose at which 0 or 1 of a cohort of 3 to 6 patients experienced a dose-limiting toxicity (DLT) during first 2 cycles.

Neoadjuvant Rectal Score (NAR Score) is calculated by following formula: NAR = ([5pN - 3(cT - pT) + 12]2)/9.61 (with higher scores representing poorer prognosis), where cT=clinical tumor stage, pT=pathologic tumor stage, and pN=pathologic nodal stage.

Phase I and Phase II Treatment Cohort only: Safety and toxicity profile of the combination as measured by adverse events experienced

The descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 will be utilized for all toxicity reporting. Adverse events will be tracked from first dose of epacadostat through 4 weeks after the last day of epacadostat. Surgical complications will not be tracked if not thought to be at least possibly related to epacadostat.

Neoadjuvant Rectal Score (NAR Score) is calculated by following formula: NAR = ([5pN - 3(cT - pT) + 12]2)/9.61 (with higher scores representing poorer prognosis), where cT=clinical tumor stage, pT=pathologic tumor stage, and pN=pathologic nodal stage.

Pathologic complete response (pCR) is defined as no histology evidence of invasive tumor cells in the surgical specimen.

Progression-free survival (PFS) is defined as the duration of time from start of treatment to time of progression or death, whichever occurs first. For those who are alive and do not experience progression, they are censored at the time of loss to follow-up.

Clinical complete response (cCR) is defined as no clinical evidence of tumor as assessed by radiographic, endoscopic, and physical examinations after completion of planned protocol therapy.

Inclusion Criteria: Newly diagnosed locally advanced rectal cancer with pathology confirmation with plans to proceed with neoadjuvant short course radiation and chemotherapy as confirmed by treating physician At least 18 years of age. ECOG performance status ≤ 1 Normal bone marrow and organ function as defined below: Absolute neutrophil count ≥ 1,500/mcl Platelets ≥ 100,000/mcl Hemoglobin > 9 g/dL Total bilirubin ≤ IULN AST(SGOT)/ALT(SGPT) ≤ 2.5 x IULN Serum creatinine < 1.5 x IULN OR measured or calculated creatinine clearance ≥ 50 mL/min/1.73 m2 INR or PT ≤ 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 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 Applicable to subjects enrolled at Washington University and Dana Farber Cancer Institute only: 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 as described in protocol 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 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-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or 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 IDO pathway (including indoximod) Previous radiotherapy in the pelvic region or previous rectal surgery (e.g. 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, pembrolizumab, 5-FU, 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 the use of MAOIs, meriperidine, 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 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. An abnormal screening 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-Guérin (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 cycle 1 day 1. Evidence of interstitial lung disease or active, non-infectious pneumonitis including symptomatic and/or pneumonitis requiring treatment Known presence of active TB. Known active hepatitis B (e.g. HBsAg reactive or HBV DNA detected) or hepatitis C (e.g. HCV RNA [qualitative] is detected) infection. Testing at screening is required (Serology testing with HBsAg, HBsAb, and HCV Ab are required; HBV DNA or HCV RNA are only required in the setting of serology tests compatible with possible active infection.). Known microsatellite instability- high (MSI-H) or mismatch repair deficient rectal cancer.

Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine