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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03516708
Recruitment Status : Active, not recruiting
First Posted : May 4, 2018
Last Update Posted : June 2, 2020
Sponsor:
Collaborator:
Incyte Corporation
Information provided by (Responsible Party):
Washington University School of Medicine

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.

Condition or disease Intervention/treatment Phase
Rectal Cancer Drug: Epacadostat Procedure: Tumor biopsy Procedure: Peripheral blood draw Phase 1

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 39 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase I Study of Epacadostat (INCB024360) Added to Preoperative Chemoradiation in Patients With Locally Advanced Rectal Cancer
Actual Study Start Date : October 10, 2019
Estimated Primary Completion Date : May 31, 2023
Estimated Study Completion Date : May 31, 2023

Arm Intervention/treatment
Experimental: Dose Escalation Cohort
  • Patients will receive 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 weeks' preoperative therapy followed by surgery. Breakdown of the 20 weeks of preoperative therapy are as follows:

    • Short-course pelvic radiation therapy, 5 fractions over 1 week
    • 2 to 3 weeks of break; 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 (so may be more than 21 days long depending on when exactly CAPOX starts).
Drug: Epacadostat
Self-administered orally BID without regard to food
Other Name: INCB024360

Procedure: Tumor biopsy
  • 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)
  • Between the end of RT and initiation of chemotherapy (target days 5-28)
  • 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

Experimental: Dose Expansion Cohort
  • Patients will receive 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 weeks' preoperative therapy followed by surgery. Breakdown of the 20 weeks of preoperative therapy are as follows:

    • Short-course pelvic radiation therapy, 5 fractions over 1 week
    • 2 to 3 weeks of break; 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 (so may be more than 21 days long depending on when exactly CAPOX starts).
Drug: Epacadostat
Self-administered orally BID without regard to food
Other Name: INCB024360

Procedure: Tumor biopsy
  • 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)
  • Between the end of RT and initiation of chemotherapy (target days 5-28)
  • 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




Primary Outcome Measures :
  1. 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 38 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.


Secondary Outcome Measures :
  1. 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.

  2. 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

  3. 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.

  4. 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.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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
  • 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 registration
  • 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03516708


Locations
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United States, Missouri
Washington University School of Medicine
Saint Louis, Missouri, United States, 63110
Sponsors and Collaborators
Washington University School of Medicine
Incyte Corporation
Investigators
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Principal Investigator: Haeseong Park, M.D., M.P.H. Washington University School of Medicine
Additional Information:
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Responsible Party: Washington University School of Medicine
ClinicalTrials.gov Identifier: NCT03516708    
Other Study ID Numbers: 201902040
First Posted: May 4, 2018    Key Record Dates
Last Update Posted: June 2, 2020
Last Verified: June 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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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
Additional relevant MeSH terms:
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Rectal Neoplasms
Colorectal Neoplasms
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Neoplasms
Digestive System Diseases
Gastrointestinal Diseases
Intestinal Diseases
Rectal Diseases