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

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ClinicalTrials.gov Identifier: NCT03516708
Recruitment Status : Recruiting
First Posted : May 4, 2018
Last Update Posted : October 25, 2021
Sponsor:
Collaborator:
Incyte Corporation
Information provided by (Responsible Party):
Washington University School of Medicine

Tracking Information
First Submitted Date  ICMJE April 24, 2018
First Posted Date  ICMJE May 4, 2018
Last Update Posted Date October 25, 2021
Actual Study Start Date  ICMJE October 10, 2019
Estimated Primary Completion Date July 31, 2024   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: October 22, 2021)
Recommended phase II dose (RP2D) of epacadostat with standard of care radiation and chemotherapy in preoperative treatment of locally advanced rectal cancer [ Time Frame: Completion of the first 2 cycles of treatment for all patients (estimated to be 50 months) ]
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.
Original Primary Outcome Measures  ICMJE
 (submitted: April 24, 2018)
  • (Phase 1b only) Recommended phase II dose (RP2D) for the combination of epacadostat, pembrolizumab, and radiation therapy [ Time Frame: Completion of Phase 1b portion of study (estimated to be 12 months) ]
    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. If the first 3 patients enrolled at the first dose level (100 mg BID) do not experience any DLTs, that dose will be the RP2D.
  • (Phase II only) Antitumor activity of the combination in preoperative treatment of locally advanced rectal cancer, as measured by pathological complete response rate [ Time Frame: At the time of surgery (approximately week 25) ]
    -Pathologic complete response is defined as no histology evidence of invasive tumor cells in the surgical specimen.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: February 22, 2021)
  • Safety and toxicity profile of the combination as measured by adverse events experienced [ Time Frame: Through 4 weeks after completion of treatment (approximately 25 weeks) ]
    • 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.
  • Antitumor activity of the combination as measured by Neoadjuvant Rectal (NAR) Score [ Time Frame: At the time of surgery (approximately week 25) ]
    • The NAR formula is = [5pN-3(cT-pT) + 12]^2 divided by 9.61
    • pN = pathologic nodal stage
    • cT = clinical tumor stage
    • pT=pathologic tumor stage
  • Antitumor activity of the combination as measured by pathological complete response rate [ Time Frame: At the time of surgery (approximately week 25) ]
    --Pathologic complete response is defined as no histology evidence of invasive tumor cells in the surgical specimen.
  • Antitumor activity of the combination as measured by progression-free survival (PFS) [ Time Frame: At the time of surgery (approximately week 25) ]
    -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, the investigators will censor them at the time of loss to follow-up.
  • Antitumor activity as measured by complete clinical response rate (cCR) [ Time Frame: At the time of surgery (approximately week 25) ]
    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.
Original Secondary Outcome Measures  ICMJE
 (submitted: April 24, 2018)
  • Safety and toxicity profile of the combination as measured by adverse events experienced [ Time Frame: 30 days after completion of treatment (approximately 25 weeks) ]
    -The descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for all toxicity reporting.
  • Antitumor activity of the combination as measured by Neoadjuvant Rectal (NAR) Score [ Time Frame: At the time of surgery (approximately week 25) ]
    • The NAR formula is = [5pN-3(cT-pT) + 12]^2 divided by 9.61
    • pN = pathologic nodal stage
    • cT = clinical tumor stage
    • pT=pathologic tumor stage
  • Antitumor activity of the combination as measured by overall response rate [ Time Frame: At the time of surgery (approximately week 25) ]
    • Overall response rate = pathologic complete response + pathologic partial response --Pathologic complete response is defined as no histology evidence of invasive tumor cells in the surgical specimen.
    • Pathologic partial response is defined as any pathologic response (downstaging) as determined by a pathologist, other than complete response
    • Pathologic partial response is defined as
  • Antitumor activity of the combination as measured by progression-free survival (PFS) [ Time Frame: At the time of surgery (approximately week 25) ]
    -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, the investigators will censor them at the time of loss to follow-up.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Epacadostat (INCB024360) Added to Preoperative Chemoradiation in Patients With Locally Advanced Rectal Cancer
Official Title  ICMJE Phase I Study of Epacadostat (INCB024360) Added to Preoperative Chemoradiation in Patients With Locally Advanced Rectal Cancer
Brief Summary 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.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Rectal Cancer
Intervention  ICMJE
  • Drug: Epacadostat
    Self-administered orally BID without regard to food
    Other Name: INCB024360
  • Procedure: Tumor biopsy
    • Washington University patients only
    • Baseline (no more than 28 days prior to Day 1 of RT) (this is standard of care from the diagnostic biopsy)
    • Between the end of RT and prior to initiation of chemotherapy via proctoscopy or sigmoidoscopy (target days 5-28)
    • Surgery (part of the resection specimen) or at the time of SOC pre-surgical proctoscopy
  • Procedure: Peripheral blood draw
    • Baseline (no more than 28 days prior to Day 1 of RT) (this is standard of care from the diagnostic biopsy)
    • Day 1 of each chemotherapy cycle (target days 5-28)
    • Surgery (part of the resection specimen) or at the time of SOC pre-surgical proctoscopy
Study Arms  ICMJE
  • Experimental: Dose Escalation Cohort
    • 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
    Interventions:
    • Drug: Epacadostat
    • Procedure: Tumor biopsy
    • Procedure: Peripheral blood draw
  • Experimental: Dose Expansion Cohort
    • 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
    Interventions:
    • Drug: Epacadostat
    • Procedure: Tumor biopsy
    • Procedure: Peripheral blood draw
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: February 13, 2019)
39
Original Estimated Enrollment  ICMJE
 (submitted: April 24, 2018)
57
Estimated Study Completion Date  ICMJE November 30, 2024
Estimated Primary Completion Date July 31, 2024   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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 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.).
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Haeseong Park, M.D., M.P.H. 314-747-7401 haeseongpark@wustl.edu
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03516708
Other Study ID Numbers  ICMJE 201902040
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Washington University School of Medicine
Study Sponsor  ICMJE Washington University School of Medicine
Collaborators  ICMJE Incyte Corporation
Investigators  ICMJE
Principal Investigator: Haeseong Park, M.D., M.P.H. Washington University School of Medicine
PRS Account Washington University School of Medicine
Verification Date October 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP