Clinical Trials /

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

NCT03516708

Description:

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.

Related Conditions:
  • Rectal Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Epacadostat (INCB024360) Added to Preoperative Chemoradiation in Patients With Locally Advanced Rectal Cancer
  • Official Title: Phase I Study of Epacadostat (INCB024360) Added to Preoperative Chemoradiation in Patients With Locally Advanced Rectal Cancer

Clinical Trial IDs

  • ORG STUDY ID: 201902040
  • NCT ID: NCT03516708

Conditions

  • Rectal Cancer

Interventions

DrugSynonymsArms
EpacadostatINCB024360Dose Escalation Cohort

Purpose

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.

Trial Arms

NameTypeDescriptionInterventions
Dose Escalation CohortExperimentalPatients 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).
  • Epacadostat
Dose Expansion CohortExperimentalPatients 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).
  • Epacadostat

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 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 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.

          -  Presence of an abnormal 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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure: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)
Safety Issue:
Description: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

Measure: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)
Safety Issue:
Description: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.
Measure:Antitumor activity of the combination as measured by Neoadjuvant Rectal (NAR) Score
Time Frame:At the time of surgery (approximately week 25)
Safety Issue:
Description: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
Measure:Antitumor activity of the combination as measured by pathological complete response rate
Time Frame:At the time of surgery (approximately week 25)
Safety Issue:
Description:--Pathologic complete response is defined as no histology evidence of invasive tumor cells in the surgical specimen.
Measure:Antitumor activity of the combination as measured by progression-free survival (PFS)
Time Frame:At the time of surgery (approximately week 25)
Safety Issue:
Description:-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.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Washington University School of Medicine

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