Clinical Trials /

Pembrolizumab in Treating Patients With Metastatic or Unresectable Gastroesophageal Adenocarcinoma

NCT03395847

Description:

This early phase I trial studies how well pembrolizumab works in treating patients with gastroesophageal adenocarcinoma that has spread to other places or cannot be removed by surgery. Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread.

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

Recruiting

Phase:

Early Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Pembrolizumab in Treating Patients With Metastatic or Unresectable Gastroesophageal Adenocarcinoma
  • Official Title: A Pilot Study of Pembrolizumab Monotherapy in Patients With Previously Treated Advanced Gastroesophageal Adenocarcinoma

Clinical Trial IDs

  • ORG STUDY ID: 2016-0905
  • SECONDARY ID: NCI-2018-00946
  • SECONDARY ID: 2016-0905
  • SECONDARY ID: P30CA016672
  • NCT ID: NCT03395847

Conditions

  • Advanced Gastroesophageal Junction Adenocarcinoma
  • Clinical Stage III Esophageal Adenocarcinoma AJCC v8
  • Clinical Stage III Gastric Cancer AJCC v8
  • Clinical Stage IV Esophageal Adenocarcinoma AJCC v8
  • Clinical Stage IV Gastric Cancer AJCC v8
  • Clinical Stage IVA Esophageal Adenocarcinoma AJCC v8
  • Clinical Stage IVA Gastric Cancer AJCC v8
  • Clinical Stage IVB Esophageal Adenocarcinoma AJCC v8
  • Clinical Stage IVB Gastric Cancer AJCC v8
  • Gastroesophageal Junction Adenocarcinoma
  • Metastatic Gastroesophageal Junction Adenocarcinoma
  • Pathologic Stage III Esophageal Adenocarcinoma AJCC v8
  • Pathologic Stage III Gastric Cancer AJCC v8
  • Pathologic Stage IIIA Esophageal Adenocarcinoma AJCC v8
  • Pathologic Stage IIIA Gastric Cancer AJCC v8
  • Pathologic Stage IIIB Esophageal Adenocarcinoma AJCC v8
  • Pathologic Stage IIIB Gastric Cancer AJCC v8
  • Pathologic Stage IIIC Gastric Cancer AJCC v8
  • Pathologic Stage IV Esophageal Adenocarcinoma AJCC v8
  • Pathologic Stage IV Gastric Cancer AJCC v8
  • Pathologic Stage IVA Esophageal Adenocarcinoma AJCC v8
  • Pathologic Stage IVB Esophageal Adenocarcinoma AJCC v8
  • Postneoadjuvant Therapy Stage III Gastric Cancer AJCC v8
  • Postneoadjuvant Therapy Stage IV Gastric Cancer AJCC v8
  • Unresectable Gastroesophageal Junction Adenocarcinoma

Interventions

DrugSynonymsArms
PembrolizumabKeytruda, Lambrolizumab, MK-3475, SCH 900475Treatment (pembrolizumab)

Purpose

This early phase I trial studies how well pembrolizumab works in treating patients with gastroesophageal adenocarcinoma that has spread to other places or cannot be removed by surgery. Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To estimate the overall response rate (ORR) of intravenous administration of pembrolizumab
      by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 in adult subjects with advanced
      (unresectable and/or metastatic) and previously treated gastroesophageal adenocarcinoma.

      SECONDARY OBJECTIVES:

      I. To evaluate the duration of response (DOR), disease control rate (DCR), time to
      progression (TTP), progression-free survival (PFS), and overall survival (OS) using RECIST
      1.1 and immune-related (ir)RECIST criteria.

      II. To perform exploratory biomarkers to study the correlation between immunological and
      molecular changes in tumor tissues and peripheral blood with clinical outcomes (DOR, DCR,
      TTP, PFS, and OS) using RECIST 1.1, and irRECIST rate of adverse events.

      III. To determine the safety and tolerability of intravenous administration of pembrolizumab
      or pembrolizumab plus ramucirumab in adult subjects with advanced (unresectable and/or
      metastatic) and previously treated gastroesophageal adenocarcinoma.

      EXPLORATORY OBJECTIVES:

      I. To explore the association between PD-L1 expression by immunohistochemistry, shed PD-L1
      levels, somatic gene expression profiling and antitumor efficacy of pembrolizumab based on
      RECIST 1.1 imaging criteria as well as overall survival.

      II. To explore the relationship between genomic variation and response to the treatment
      administered.

      III. Tissue and blood immune monitoring will be conducted through our immune platform group
      as detailed per the biomarker section based on 3 biopsies done at the following time points:
      1) pre-treatment, 2) 6 weeks after therapy, and 3) and an optional biopsy upon progression.

      OUTLINE:

      Patients receive pembrolizumab intravenously (IV) over 30 minutes on day 1. Treatment repeats
      every 21 days for up to 35 cycles in the absence of disease progression or unacceptable
      toxicity.

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

Trial Arms

NameTypeDescriptionInterventions
Treatment (pembrolizumab)ExperimentalPatients receive pembrolizumab IV over 30 minutes on day 1. Treatment repeats every 21 days for up to 35 cycles in the absence of disease progression or unacceptable toxicity.
  • Pembrolizumab

Eligibility Criteria

        Inclusion Criteria:

          -  The subject (or legally acceptable representative if applicable) provides written
             informed consent for the trial. The subject may also provide consent for future
             biomedical research. However the subject may participate in the main trial without
             participating in future biomedical research.

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

          -  Histologically and cytologically documented diagnosis as gastroesophageal
             adenocarcinoma.

          -  Have a documented advanced (metastatic and/or unresectable) gastroesophageal
             adenocarcinoma that is incurable and for which prior first-line or later-line standard
             of care (SOC) treatments have failed. There is no limit to the number of prior
             treatment regimens. Prior neoadjuvant or adjuvant therapy included in initial
             treatment may not be considered first- or later-line SOC treatment unless such
             treatments were completed less than 12 months prior to the current tumor recurrence.

          -  Have submitted an evaluable tissue sample for biomarker analysis from a newly obtained
             endoscopic, core, incisional, or excisional biopsy of a tumor lesion not previously
             irradiated. The tumor tissue submitted for analysis must be from a single tumor tissue
             specimen and of sufficient quantity and quality to allow biomarker study. A newly
             obtained tumor specimen, defined as a specimen obtained up to 6 weeks (42 days) prior
             to initiation of treatment on day 1, for biomarker characterization will be required
             for enrollment of all subjects. Tissue from tumor progressing at a site of prior
             radiation may be allowed for biomarker characterization upon agreement from Merck.
             Subjects for whom newly-obtained samples cannot be provided (e.g. inaccessible or
             subject safety concern) may submit an archived specimen only upon agreement from the
             Merck.

          -  Have measurable disease based on RECIST 1.1 as assessed by the investigator. Lesions
             situated in a previously irradiated area are considered measurable if progression has
             been demonstrated in such lesions.

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

          -  Life expectancy of greater than 3 months per the judgment of the investigators.

          -  Absolute neutrophil count (ANC) >= 1,500 /mcL (within 5 days prior to the start of
             study treatment).

          -  Platelets >= 100,000/mcL (within 5 days prior to the start of study treatment).

          -  Hemoglobin >= 9 g/dL or >= 5.6 mmol/L without transfusion or erythropoietin (EPO)
             dependency (within 7 days of assessment) (within 5 days prior to the start of study
             treatment).

          -  Serum creatinine OR measured or calculated creatinine clearance (glomerular filtration
             rate [GFR] can also be used in place of creatinine or creatinine clearance [CrCl]) =<
             1.5 X upper limit of normal (ULN) OR >= 60 mL/min for subject with creatinine levels >
             1.5 X institutional upper limit of normal (ULN) (within 5 days prior to the start of
             study treatment). Creatinine clearance should be calculated per institutional
             standard.

          -  Serum total bilirubin =< 1.5 X ULN OR direct bilirubin =< ULN for subjects with total
             bilirubin levels > 1.5 ULN (within 5 days prior to the start of study treatment).

          -  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 (within 5 days prior to the start
             of study treatment).

          -  Albumin: >= 2.5 mg/dL (within 5 days prior to the start of study treatment).

          -  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 (within 5
             days prior to the start of study treatment).

          -  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 (within 5 days prior to the start of study treatment).

          -  Female subject of childbearing potential should have a negative urine or serum
             pregnancy within 72 hours 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.

          -  Male and female subjects of childbearing potential must be willing to use an adequate
             method of contraception, for the course of the study 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.

        Exclusion Criteria:

          -  Is currently participating in or has participated in a study of an investigational
             agent or used an investigational device within 4 weeks prior to the first dose of
             study treatment. Note: Subjects who have entered the follow-up phase of an
             investigational trial may participate as long as it has been 4 weeks after the last
             dose of the previous investigational agent.

          -  Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy (in
             dosing exceeding 10 mg daily of prednisone equivalent) or any other form of
             immunosuppressive therapy within 7 days prior to the first dose of trial treatment.

          -  Has severe hypersensitivity (>= grade 3) to pembrolizumab or any of its 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 at baseline) from adverse events
             due to agents administered more than 4 weeks earlier.

          -  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 at
             baseline) from adverse events due to a previously administered agent.

               -  Note: Subjects with =< grade 2 neuropathy or alopecia are an exception to this
                  criterion.

               -  Note: If subject received major surgery, they must have recovered adequately from
                  the toxicity and/or complications from the intervention as determined by the
                  investigators prior to starting therapy.

          -  Has a known additional malignancy that is progressing or requires active treatment.
             Note: Subjects with basal cell carcinoma of the skin, squamous cell carcinoma of the
             skin, or carcinoma in situ (e.g., breast carcinoma, cervical cancer in situ) that have
             undergone potentially curative therapy are not excluded.

          -  Has known active central nervous system (CNS) metastases and/or carcinomatous
             meningitis. Subjects with previously treated brain metastases may participate provided
             they are radiological stable (i.e., without evidence of progression for at least 4
             weeks by repeat imaging (note that the repeat imaging should be performed during study
             screening), clinically stable and without requirement of steroid treatment for at
             least 14 days prior to the first dose of trial treatment. This exception does not
             include carcinomatous meningitis which is excluded regardless of clinical stability.

          -  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 and is allowed.

          -  Has a history of (non-infectious) pneumonitis that required treatment with steroids or
             has current pneumonitis.

          -  Has an active infection requiring systemic therapy.

          -  Has a history or current evidence of any condition, therapy, or laboratory abnormality
             that might confound the results of the trial, interfere with the subject's
             participation for the full duration of the trial, 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 trial.

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

          -  Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with
             an agent directed to another stimulatory or co-inhibitory T-cell receptor (TCR) (e.g.,
             CTLA-4, OX 40, CD137).

          -  Has a known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies). No HIV
             testing is required unless mandated by local health authority.

          -  Had a solid organ or hematologic transplant.

          -  Has a known history of hepatitis B virus (HBV; hepatitis B surface antigen [HBsAg]
             reactive) or known active hepatitis C virus (HCV; HCV ribonucleic acid [RNA]
             [qualitative] is detected) infection. No testing for hepatitis B and hepatitis C is
             required unless mandated by local health authority.

          -  Has received a live vaccine within 30 days prior to the first dose of the trial drug.
             Examples of live vaccines include, but are not limited to, the following: measles,
             mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus
             Calmette - Guerin (BCG), and typhoid vaccine.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Objective response rate (ORR)
Time Frame:Up to 4 years
Safety Issue:
Description:Defined as the proportion of the subjects in the analysis population who have a complete response (CR) or partial response (PR). Responses are based on assessments by the blinded MD Anderson radiology per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Exact method based on binomial distribution (Clopper-Pearson method).

Secondary Outcome Measures

Measure:Duration of response
Time Frame:From first documented evidence of CR or PR up to 4 years
Safety Issue:
Description:Based on assessments by MD Anderson radiology per RECIST 1.1. Summary statistics using Kaplan-Meier method, if sample size permits.
Measure:Disease control rate
Time Frame:Up to 4 years
Safety Issue:
Description:Defined as the percentage of subjects who have achieved CR, PR, or stable disease (SD) for at least 24 weeks based on assessments by MD Anderson radiology per RECIST 1.1. Exact method based on binomial distribution (Clopper-Pearson method).
Measure:Time to progression
Time Frame:From the first day of study treatment up to 4 years
Safety Issue:
Description:Assessed per RECIST 1.1 based on assessments by MD Anderson radiology. Summary statistics using Kaplan-Meier method.
Measure:Progression-free survival per RECIST 1.1 based on assessments by MD Anderson radiology
Time Frame:From the first day of study treatment to the first documented disease progression up to 4 years
Safety Issue:
Description:Summary statistics using Kaplan-Meier method.
Measure:Overall survival
Time Frame:From first dose of study medication up to 4 years
Safety Issue:
Description:Summary statistics using Kaplan-Meier method.
Measure:Incidence of adverse events
Time Frame:Up to 30 days post treatment
Safety Issue:
Description:Defined by National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 4.0. Adverse events will be assessed. Specific events will be collected and designated as events of clinical interest (ECIs).

Details

Phase:Early Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:M.D. Anderson Cancer Center

Last Updated

June 18, 2020