ClinicalTrials.gov
ClinicalTrials.gov Menu

Epacadostat (INCB024360) and Pembrolizumab 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. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT03516708
Recruitment Status : Not yet recruiting
First Posted : May 4, 2018
Last Update Posted : August 24, 2018
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 the combination of two drugs, epacadostat and pembrolizumab, when given with routine radiation therapy and chemotherapy (capecitabine and oxaliplatin) to treat rectal cancer before routine surgery is performed to remove the tumor. In the first part of the study, the investigators are looking at how the body processes epacadostat when given with radiation and chemotherapy (without pembrolizumab) and what types of side effects occur. In the second part of the study, the investigators are determining the best dose of epacadostat to given when it's given with pembrolizumab and radiation and chemotherapy. In the final part of the study, the investigators are studying how the cancer responds to the treatment regimen.

Condition or disease Intervention/treatment Phase
Rectal Cancer Drug: Epacadostat Drug: Pembrolizumab Drug: Capecitabine Drug: Oxaliplatin Radiation: Radiation Procedure: Tumor biopsy Procedure: Peripheral blood draw Procedure: Surgery Phase 1 Phase 2

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 57 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase Ib/II Study of Epacadostat (INCB024360) and Pembrolizumab Added to Preoperative Chemoradiation in Patients With Locally Advanced Rectal Cancer
Estimated Study Start Date : October 31, 2018
Estimated Primary Completion Date : May 31, 2022
Estimated Study Completion Date : May 31, 2022

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Arm A: Pharmacodynamic Cohort
  • Patients will receive epacadostat at 100mg PO BID during the 21 weeks of standard of care preoperative therapy.
  • 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

Drug: Capecitabine
Standard of care
Other Name: Xeloda

Drug: Oxaliplatin
Standard of care
Other Name: Eloxatin

Radiation: Radiation
Standard of care

Procedure: Tumor biopsy
  • Baseline (no more than 14 days prior to Day 1 of RT) (this is standard of care from the diagnostic biopsy)
  • After the end of RT (target days 5-8)
  • Prior to the start of chemotherapy (target days 14-21)
  • Surgery (part of the resection specimen)

Procedure: Peripheral blood draw
  • Baseline (no more than 14 days prior to Day 1 of RT)
  • After the end of radiation therapy (target days 5-8)
  • Prior to the start of chemotherapy (target days 14-21)
  • Surgery (part of the resection specimen)

Procedure: Surgery
Standard of care

Experimental: Arm B: Phase 1b Safety Lead-In

-Receive epacadostat at 100mg PO BID. Pembrolizumab administered as a 200 mg IV infusion over 30 minutes on Day 1 of each 21-day cycle during the 21 weeks of standard of care preoperative therapy. Pembrolizumab will be administered after epacadostat and before IV chemotherapy if given on the same day.

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 -The second cycle of epacadostat and pembrolizumab 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

Drug: Pembrolizumab
Arm B participants only
Other Name: Keytruda

Drug: Capecitabine
Standard of care
Other Name: Xeloda

Drug: Oxaliplatin
Standard of care
Other Name: Eloxatin

Radiation: Radiation
Standard of care

Procedure: Tumor biopsy
  • Baseline (no more than 14 days prior to Day 1 of RT) (this is standard of care from the diagnostic biopsy)
  • After the end of RT (target days 5-8)
  • Prior to the start of chemotherapy (target days 14-21)
  • Surgery (part of the resection specimen)

Procedure: Peripheral blood draw
  • Baseline (no more than 14 days prior to Day 1 of RT)
  • After the end of radiation therapy (target days 5-8)
  • Prior to the start of chemotherapy (target days 14-21)
  • Surgery (part of the resection specimen)

Procedure: Surgery
Standard of care

Experimental: Arm B: Phase II

-Receive epacadostat at 100mg PO BID. Pembrolizumab administered as a 200 mg IV infusion over 30 minutes on Day 1 of each 21-day cycle during the 21 weeks of standard of care preoperative therapy. Pembrolizumab will be administered after epacadostat and before IV chemotherapy if given on the same day.

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 -The second cycle of epacadostat and pembrolizumab 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

Drug: Pembrolizumab
Arm B participants only
Other Name: Keytruda

Drug: Capecitabine
Standard of care
Other Name: Xeloda

Drug: Oxaliplatin
Standard of care
Other Name: Eloxatin

Radiation: Radiation
Standard of care

Procedure: Tumor biopsy
  • Baseline (no more than 14 days prior to Day 1 of RT) (this is standard of care from the diagnostic biopsy)
  • After the end of RT (target days 5-8)
  • Prior to the start of chemotherapy (target days 14-21)
  • Surgery (part of the resection specimen)

Procedure: Peripheral blood draw
  • Baseline (no more than 14 days prior to Day 1 of RT)
  • After the end of radiation therapy (target days 5-8)
  • Prior to the start of chemotherapy (target days 14-21)
  • Surgery (part of the resection specimen)

Procedure: Surgery
Standard of care




Primary Outcome Measures :
  1. (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.

  2. (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.


Secondary Outcome Measures :
  1. 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.

  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 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

  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.


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 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 MRI indicating metastatic disease
    • Positive MRF, i.e. tumor 1 mm or less from the mesorectal fascia.
    • Metastatic lateral nodes, > 1 cm (lat LN+)
  • 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 pembrolizumab. 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).
  • 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.
  • Receiving monoamine oxidase inhibitors (MAOIs) or drug which has significant MAOI activity (meperidine, linezolid, methylene blue) within the 21 days before screening.
  • Use of any UGT1A9 inhibitor from screening through follow-up period, including the following: diclofenac, imipramine, ketoconazole, mefenamic acid, and probenecid.
  • Any history of serotonin syndrome (SS) after receiving serotonergic drugs.
  • Uncontrolled intercurrent illness including, but not limited to symptomatic congestive heart failure, unstable angina pectoris, or cardiac arrhythmia.
  • Active infection requiring systemic therapy.
  • Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone or equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of pembrolizumab (other than replacement-dose steroids in the setting of adrenal insufficiency). Topical, inhaled, nasal, and ophthalmic steroids are allowed.
  • Has an active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids, or immunosuppressive drugs). Replacement therapy (e.g. thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
  • History or presence of an abnormal ECG that, in the investigator's opinion, is clinically meaningful. Screening QTc interval > 480 msec is excluded (corrected by Fridericia or Bazett formula). In the event that a single QTc is > 480 msec, the participant may enroll if the average QTc for 3 ECGs is < 480 msec.
  • 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 study entry.
  • Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis.
  • Known history of active TB.
  • Known HIV-positivity (HIV 1/2 antibodies).
  • 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


Contacts
Contact: Haeseong Park, M.D., M.P.H. 314-747-7401 guebertk@wustl.edu

Locations
United States, Missouri
Washington University School of Medicine Not yet recruiting
Saint Louis, Missouri, United States, 63110
Contact: Haeseong Park, M.D., M.P.H.    314-747-7401    guebertk@wustl.edu   
Principal Investigator: Haeseong Park, M.D., M.P.H.         
Sub-Investigator: Manik Amin, M.D.         
Sub-Investigator: Olivia Aranha, M.D., Ph.D.         
Sub-Investigator: Salman Chaudhry, M.D.         
Sub-Investigator: Matthew Ciorba, M.D.         
Sub-Investigator: Eric Knoche, M.D.         
Sub-Investigator: Kian-Huat Lim, M.D.         
Sub-Investigator: Peter Oppelt, M.D.         
Sub-Investigator: Parag Parikh, M.D.         
Sub-Investigator: Katrina Pedersen, M.D.         
Sub-Investigator: Joel Picus, M.D.         
Sub-Investigator: Timothy Rearden, M.D.         
Sub-Investigator: Caron Rigden, M.D.         
Sub-Investigator: Anna Roshal, M.D.         
Sub-Investigator: Rama Suresh, M.D.         
Sub-Investigator: Benjamin Tan, M.D.         
Sub-Investigator: Nikolaos Trikalinos, M.D.         
Sub-Investigator: Andrea Wang-Gillam, M.D., Ph.D.         
Sponsors and Collaborators
Washington University School of Medicine
Incyte Corporation
Investigators
Principal Investigator: Haeseong Park, M.D., M.P.H. Washington University School of Medicine

Additional Information:
Responsible Party: Washington University School of Medicine
ClinicalTrials.gov Identifier: NCT03516708     History of Changes
Other Study ID Numbers: 18-x083
First Posted: May 4, 2018    Key Record Dates
Last Update Posted: August 24, 2018
Last Verified: August 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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:
Rectal Neoplasms
Colorectal Neoplasms
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Neoplasms
Digestive System Diseases
Gastrointestinal Diseases
Intestinal Diseases
Rectal Diseases
Capecitabine
Oxaliplatin
Pembrolizumab
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents