Clinical Trials /

Epacadostat and Pembrolizumab in Treating Patients With Metastatic or Unresectable Gastroesophageal Junction or Gastric Cancer

NCT03196232

Description:

This phase 2 trial evaluatesteh benefit of epacadostat plus pembrolizumab in combination to treat patients with gastroesophageal junction or gastric cancer that has spread to other parts of the body and cannot be removed by surgery. Epacadostat may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Monoclonal antibodies, such as pembrolizumab, may block tumor growth in different ways by targeting certain cells. Giving epacadostat and pembrolizumab may work better in treating patients with gastroesophageal junction or gastric cancer.

Related Conditions:
  • Adenocarcinoma of the Gastroesophageal Junction
  • Esophageal Adenocarcinoma
  • Gastric Adenocarcinoma
Recruiting Status:

Completed

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Epacadostat and Pembrolizumab in Treating Patients With Metastatic or Unresectable Gastroesophageal Junction or Gastric Cancer
  • Official Title: Phase II Study of Epacadostat (INCB024360) With Pembrolizumab (MK3475) in Metastatic or Unresectable Gastroesophageal Junction and Gastric Adenocarcinoma Requiring Paired Biopsies

Clinical Trial IDs

  • ORG STUDY ID: GI0015
  • SECONDARY ID: NCI-2017-00895
  • SECONDARY ID: 40823
  • NCT ID: NCT03196232

Conditions

  • Gastric Adenocarcinoma
  • Gastroesophageal Junction Adenocarcinoma
  • Recurrent Esophageal Carcinoma
  • Recurrent Gastric Carcinoma
  • Stage IV Esophageal Cancer AJCC v7
  • Stage IV Gastric Cancer AJCC v7
  • Unresectable Esophageal Carcinoma

Interventions

DrugSynonymsArms
EpacadostatINCB 024360, INCB024360Treatment (epacadostat, pembrolizumab)
PembrolizumabKeytruda, Lambrolizumab, MK-3475, SCH 900475Treatment (epacadostat, pembrolizumab)

Purpose

This phase II trial studies how well epacadostat and pembrolizumab work in treating patients with gastroesophageal junction or gastric cancer that has spread to other parts of the body and cannot be removed by surgery. Epacadostat may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Monoclonal antibodies, such as pembrolizumab, may block tumor growth in different ways by targeting certain cells. Giving epacadostat and pembrolizumab may work better in treating patients with gastroesophageal junction or gastric cancer.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To assess 6-month progression free survival (PFS).

      SECONDARY OBJECTIVES:

      I. To evaluate objective response rate (RR) by Response Evaluation Criteria in Solid Tumors
      (RECIST) version (v) 1.1 and immune-related response criteria (irRC).

      II. To evaluate overall survival (OS). III. To assess the safety and tolerability of
      epacadostat in combination with pembrolizumab by National Cancer Institute (NCI) Common
      Terminology Criteria for Adverse Events (CTCAE) v4.03.

      TERTIARY OBJECTIVES:

      I. To determine the responder rate defined as the proportion of subjects with an increased
      ratio of CD8+ to Treg cells in on-treatment compared with pre-treatment biopsies.

      II. To identify putative immunologic biomarkers of tumor response.

      OUTLINE:

      Patients receive epacadostat orally (PO) twice daily (BID) on days 1-21 and pembrolizumab
      intravenously (IV) over 30 minutes on day 1. Courses repeat every 21 days for up to 24 months
      in the absence of disease progression or unacceptable toxicity.

      After completion of study treatment, patients are followed up at 30 days, every 9 weeks for
      18 months, and then every 12 weeks thereafter.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (epacadostat, pembrolizumab)ExperimentalPatients receive epacadostat PO BID on days 1-21 and pembrolizumab IV over 30 minutes on day 1. Courses repeat every 21 days for up to 24 months in the absence of disease progression or unacceptable toxicity.
  • Epacadostat
  • Pembrolizumab

Eligibility Criteria

        Inclusion Criteria:

          -  Be willing and able to provide written informed consent/assent for the study

          -  Histologically or cytologically confirmed adenocarcinoma of the distal esophagus,
             gastroesophageal junction or stomach, including patients with HER2+ disease; distal
             esophagus is defined as within 5 centimeters of the gastroesophageal junction (GEJ)

          -  Patients must have metastatic or unresectable disease, including those with HER2+
             disease

          -  Must have progressed on at least one line of prior therapy for metastatic disease, and
             for HER2+ disease should have received prior trastuzumab

          -  Life expectancy >= 12 weeks

          -  Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG)
             performance scale

          -  Have measurable disease per RECIST v1.1, assessed within 4 weeks prior to study entry

          -  Tumor deemed amenable to biopsy by core for metastatic site or endoscopic biopsy for
             primary tumor (for both before and on-treatment biopsies)

          -  Patient must be willing to undergo two biopsies- before and on-treatment, provided the
             procedure is not deemed high-risk and is clinically feasible; the before-treatment
             biopsy may either be newly obtained or archival, should a biopsy be deemed
             inaccessible or unsafe; newly-obtained is defined as a specimen obtained up to 6 weeks
             (42 days) prior to initiation of treatment on day 1

          -  Absolute neutrophil count (ANC) >= 1,500/mcL

          -  Platelets >= 100,000/mcL

          -  Hemoglobin >= 9 g/dL or >= 5.6 mmol/L without transfusion or erythropoietin (EPO)
             dependency (within 7 days of assessment)

          -  Serum creatinine OR measured or calculated creatinine clearance (glomerular filtration
             rate [GFR] can also be used in place of creatinine or CrCl) =< 1.5 x upper limit of
             normal (ULN) OR >= 60 mL/min for subject with creatinine levels > 1.5 x institutional
             ULN

          -  Total bilirubin =< 1.5 x ULN OR direct bilirubin =< ULN for subjects with total
             bilirubin levels > 1.5 ULN

          -  Aspartate aminotransferase (AST) serum glutamic-oxaloacetic transaminase (SGOT) and
             alanine aminotransferase (ALT) serum glutamate pyruvate transaminase (SGPT) =< 2.5 x
             ULN OR =< 5 x ULN for subjects with liver metastases

          -  Albumin >= 2.5 mg/dL

          -  International normalized ratio (INR) or prothrombin time (PT) =< 1.5 x ULN unless
             subject is receiving anticoagulant therapy as long as PT or partial thromboplastin
             time (PTT) is within therapeutic range of intended use of anticoagulants

          -  Activated partial thromboplastin time (aPTT) =< 1.5 x ULN unless subject is receiving
             anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use
             of anticoagulants

          -  Female subject of childbearing potential should have a negative urine or serum
             pregnancy within 3 days prior to receiving the first dose of study medication; if the
             urine test is positive or cannot be confirmed as negative, a serum pregnancy test will
             be required

          -  Female subjects of childbearing potential must be willing to use an adequate method of
             contraception starting with the date of consent through 120 days after the last dose
             of study medication; NOTE: abstinence is acceptable if this is the usual lifestyle and
             preferred contraception for the subject

          -  Male subjects of childbearing potential must agree to use an adequate method of
             contraception starting with the date of consent through 120 days after the last dose
             of study therapy; NOTE: abstinence is acceptable if this is the usual lifestyle and
             preferred contraception for the subject

        Exclusion Criteria:

          -  Is currently participating and receiving study therapy or has participated in a study
             of an investigational agent and received study therapy or used an investigational
             device within 4 weeks of the first planned dose of treatment

          -  Has known hypersensitivity to pembrolizumab and/or epacadostat or any of their
             excipients

          -  Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study
             day 1 or who has not recovered (i.e., =< grade 1 or to baseline) from adverse events
             due to agents administered more than 4 weeks earlier; note that denosumab for
             treatment for bone metastases is allowed

          -  Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy
             within 2 weeks prior to study day 1 or who has not recovered (i.e., =< grade 1 or to
             baseline) from adverse events due to a previously administered agent

               -  NOTE: subjects with =< grade 2 neuropathy are an exception to this criterion and
                  may qualify for the study

               -  NOTE: if subject received major surgery, they must have recovered adequately from
                  surgery prior to starting therapy

          -  Have been treated on any Merck-sponsored pembrolizumab-containing gastric cancer
             pivotal trial will require prior authorization by Merck in order to enroll in this
             study

          -  Has had prior therapy with indoleamine-pyrrole 2,3-dioxygenase (IDO)-inhibitors

          -  Has 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

          -  Has known history of, or any evidence of active, non-infectious pneumonitis

          -  Has received a live vaccine within 30 days of planned start of study therapy; NOTE:
             seasonal influenza vaccines for injection are generally inactivated flu vaccines and
             are allowed; however intranasal influenza vaccines (e.g., Flu-Mist) are live
             attenuated vaccines, and are not allowed

          -  Has known active central nervous system (CNS) metastases and/or carcinomatous
             meningitis; subjects with previously treated brain metastases may participate provided
             they are stable (without evidence of progression by imaging for at least four weeks
             prior to the first dose of study treatment and any neurologic symptoms have returned
             to baseline), have no evidence of new or enlarging brain metastases, and are not using
             steroids for at least 7 days prior to study treatment; this exception does not include
             carcinomatous meningitis which is excluded regardless of clinical stability; patients
             with prior CNS metastases treated w/ prior radiation therapy (RT) will also need all
             of the following:

               -  2 months off RT before starting study or 4 weeks following radiation therapy
                  (XRT) if magnetic resonance imaging (MRI) is stable and the patient is off
                  steroids

               -  Baseline MRI with no edema and

               -  Stable for at least 8 weeks

          -  Has known additional malignancy that has progressed or requires active treatment;
             exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the
             skin, or in situ cervical cancer that has undergone potentially curative therapy

          -  Has active infection requiring systemic therapy

          -  Has a known history of active TB (Bacillus tuberculosis)

          -  Has known active hepatitis B (e.g., hepatitis B surface antigen [HBsAg] reactive) or
             hepatitis C (e.g., hepatitis C virus [HCV] ribonucleic acid [RNA] [qualitative]
             detected)

          -  Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any
             other form of immunosuppressive therapy within 7 days prior to the first dose of study
             medication

          -  Has a known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies)

          -  Is pregnant or breastfeeding, or expecting to conceive or father children within the
             projected duration of the study, starting with pre-screening or screening visit
             through 120 days after the last dose of study treatment

          -  Has had monoamine oxidase inhibitors within 21 days before screening

          -  Has any history of serotonin syndrome after receiving 1 or more serotonergic drugs

          -  Has presence of a gastrointestinal condition that may affect drug absorption

          -  Use of systemic corticosteroids

          -  Has history or presence of an abnormal electrocardiogram (ECG) which, in the
             investigator's opinion, is clinically significant

               -  Corrected QT Fredericia's formula (QTcF) >= 480 ms or presence of a left bundle
                  branch block (LBBB); if the QRS duration > 120ms, the JTc can be used in place of
                  the QTcF; the JTc must be < 340 ms

          -  Has history or current evidence of any condition, therapy, or laboratory abnormality
             that might confound the results of the study, interfere with the subject's
             participation for the full duration of the study, or is not in the best interest of
             the subject to participate, in the opinion of the treating investigator

          -  Has known psychiatric or substance abuse disorders that would interfere with
             cooperation with the requirements of the study

          -  Has known allergy or reaction to any component of either study drug or formulation
             components
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Progression-free survival assessed by Response Evaluation Criteria in Solid Tumors version 1.1
Time Frame:At 6 months
Safety Issue:
Description:Will be estimated using the Kaplan Meier method.

Secondary Outcome Measures

Measure:Clinical laboratory testing
Time Frame:Up to 2 years
Safety Issue:
Description:The clinical laboratory data will be analyzed using summary statistics (e.g., means and frequencies), and no formal statistical comparisons among the treatments are planned. In addition, distributions of key laboratory parameters (including hemoglobin, neutrophils, and platelets) will be plotted over time; these values will also be classified into Common Terminology Criteria for Adverse Events toxicity grades and tabulated. Descriptive statistics and mean change from baseline will be determined for vital signs at each assessment time. Vital sign results will be reviewed for clinically notable
Measure:Incidence of adverse events
Time Frame:Up to 2 years
Safety Issue:
Description:Adverse events will be coded by the Medical Dictionary for Regulatory Activities tabulated by preferred term and system organ class for all events, related events, and events >= grade 3. Severity of adverse events will be based on the Common Terminology Criteria for Adverse Events 4.03 scale as indicated. Quantitative safety variables and their changes from baseline (laboratory, vital signs) will be summarized with descriptive statistics. Clinically significant abnormal values will be flagged and tabulated based on predefined criteria. Exposure will be analyzed by describing dose intensity, wh
Measure:Overall survival
Time Frame:Up to 2 years
Safety Issue:
Description:Time-to-event data will be analyzed by the Kaplan-Meier method, treating subjects with no observed death or progression as censored at their last date known to be alive. For the overall survival analysis, the non-parametric Kaplan-Meier method will be used to estimate the survival time distribution and the median survival.
Measure:Response rate as determined by Response Evaluation Criteria in Solid Tumors
Time Frame:Up to 2 years
Safety Issue:
Description:The 95% exact confidence interval for the response rate will be estimated using the Clopper-Pearson method. For objective responders, the duration of response is the time from the first objective response contributing to an objective response, to the first objective response of progressive disease (by Response Evaluation Criteria in Solid Tumors) occurring after the first objective response contributing to the objective response.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Pamela L. Kunz

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