Clinical Trials /

Atezolizumab, Oxaliplatin, and Fluorouracil in Treating Patients With Esophageal or Gastroesophageal Cancer

NCT03784326

Description:

This early phase I trial studies how well atezolizumab in combination with oxaliplatin and fluorouracil works in treating patients with esophageal or gastroesophageal cancer. Immunotherapy with monoclonal antibodies, such as atezolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Drugs used in chemotherapy, such as oxaliplatin and fluorouracil, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving atezolizumab, oxaliplatin, and fluorouracil may work better in treating patients with esophageal or gastroesophageal cancer.

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

Recruiting

Phase:

Early Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Atezolizumab, Oxaliplatin, and Fluorouracil in Treating Patients With Esophageal or Gastroesophageal Cancer
  • Official Title: Pilot Study of Perioperative Chemotherapy Plus Immunotherapy Followed by Surgery in Localized Esophageal and Gastroesophageal Adenocarcinoma

Clinical Trial IDs

  • ORG STUDY ID: 2018-0678
  • SECONDARY ID: NCI-2018-02828
  • SECONDARY ID: 2018-0678
  • SECONDARY ID: P30CA016672
  • NCT ID: NCT03784326

Conditions

  • Clinical Stage II Esophageal Adenocarcinoma AJCC v8
  • Clinical Stage II Gastroesophageal Junction Adenocarcinoma AJCC v8
  • Clinical Stage IIA Esophageal Adenocarcinoma AJCC v8
  • Clinical Stage IIA Gastroesophageal Junction Adenocarcinoma AJCC v8
  • Clinical Stage IIB Esophageal Adenocarcinoma AJCC v8
  • Clinical Stage IIB Gastroesophageal Junction Adenocarcinoma AJCC v8
  • Clinical Stage III Esophageal Adenocarcinoma AJCC v8
  • Clinical Stage III Gastroesophageal Junction Adenocarcinoma AJCC v8
  • Pathologic Stage IB Esophageal Adenocarcinoma AJCC v8
  • Pathologic Stage IB Gastroesophageal Junction Adenocarcinoma AJCC v8
  • Pathologic Stage IC Esophageal Adenocarcinoma AJCC v8
  • Pathologic Stage IC Gastroesophageal Junction Adenocarcinoma AJCC v8
  • Pathologic Stage II Esophageal Adenocarcinoma AJCC v8
  • Pathologic Stage II Gastroesophageal Junction Adenocarcinoma AJCC v8
  • Pathologic Stage IIA Esophageal Adenocarcinoma AJCC v8
  • Pathologic Stage IIA Gastroesophageal Junction Adenocarcinoma AJCC v8
  • Pathologic Stage IIB Esophageal Adenocarcinoma AJCC v8
  • Pathologic Stage IIB Gastroesophageal Junction Adenocarcinoma AJCC v8
  • Pathologic Stage III Esophageal Adenocarcinoma AJCC v8
  • Pathologic Stage III Gastroesophageal Junction Adenocarcinoma AJCC v8
  • Pathologic Stage IIIA Esophageal Adenocarcinoma AJCC v8
  • Pathologic Stage IIIA Gastroesophageal Junction Adenocarcinoma AJCC v8
  • Pathologic Stage IIIB Esophageal Adenocarcinoma AJCC v8
  • Pathologic Stage IIIB Gastroesophageal Junction Adenocarcinoma AJCC v8

Interventions

DrugSynonymsArms
AtezolizumabMPDL 3280A, MPDL 328OA, MPDL-3280A, MPDL3280A, MPDL328OA, RG7446, RO5541267, TecentriqTreatment (oxaliplatin, fluorouracil, atezolizumab, surgery)
Fluorouracil5-Fluoro-2,4(1H, 3H)-pyrimidinedione, 5-Fluorouracil, 5-Fluracil, 5-FU, AccuSite, Carac, Fluoro Uracil, Fluouracil, Flurablastin, Fluracedyl, Fluracil, Fluril, Fluroblastin, Ribofluor, Ro 2-9757, Ro-2-9757Treatment (oxaliplatin, fluorouracil, atezolizumab, surgery)
Oxaliplatin1-OHP, Ai Heng, Aiheng, Dacotin, Dacplat, Diaminocyclohexane Oxalatoplatinum, Eloxatin, Eloxatine, JM-83, Oxalatoplatin, Oxalatoplatinum, RP 54780, RP-54780, SR-96669Treatment (oxaliplatin, fluorouracil, atezolizumab, surgery)

Purpose

This early phase I trial studies how well atezolizumab in combination with oxaliplatin and fluorouracil works in treating patients with esophageal or gastroesophageal cancer. Immunotherapy with monoclonal antibodies, such as atezolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Drugs used in chemotherapy, such as oxaliplatin and fluorouracil, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving atezolizumab, oxaliplatin, and fluorouracil may work better in treating patients with esophageal or gastroesophageal cancer.

Detailed Description

      PRIMARY OBJECTIVES:

      I. Atezolizumab in combination with oxaliplatin and fluorouracil (5-FU) (modified
      fluorouracil/leucovorin calcium/oxaliplatin [FOLFOX]) therapy in the neoadjuvant setting will
      achieve a pathological complete response of approximately 20% in patients with localized
      esophageal and gastroesophageal (gastroesophageal junction [GEJ]) adenocarcinoma.

      SECONDARY OBJECTIVES:

      I. To evaluate safety and toxicity profile of intravenous atezolizumab in combination with
      oxaliplatin and 5-FU therapy.

      II. To assess the efficacy of the combination by tumor regression grade scoring in the
      surgical specimen.

      III. To assess the overall safety and tolerability of adjuvant atezolizumab in subjects with
      resected esophageal and GEJ cancer.

      IV. To evaluate disease free survival (DFS) and overall survival (OS). V. To explore changes
      in tumor stroma profile before and after immunotherapy in combination with chemotherapy.

      OUTLINE:

      Patients receive oxaliplatin intravenously (IV) over 2 hours, fluorouracil IV continuously
      over 48 hours, and atezolizumab IV over 30-60 minutes on days 1 and 15. Treatment repeats
      every 28 days for 3 courses in the absence of disease progression or unacceptable toxicity.
      Within 4-6 weeks of treatment completion, patients undergo surgical resection. Beginning 6
      weeks after surgery, patients continue to receive oxaliplatin IV over 2 hours, fluorouracil
      IV continuously over 48 hours, and atezolizumab IV over 30-60 minutes on days 1 and 15.
      Treatment repeats every 28 days for 3 courses in the absence of disease progression or
      unacceptable toxicity. Patients then receive atezolizumab monotherapy IV over 30-60 minutes
      on day 1. Treatment repeats every 21 days for up to 4 courses in the absence of disease
      progression or unacceptable toxicity.

      After completion of study treatment, patients are followed up for 90 days and then every 3
      months thereafter.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (oxaliplatin, fluorouracil, atezolizumab, surgery)ExperimentalPatients receive oxaliplatin IV over 2 hours, fluorouracil IV continuously over 48 hours, and atezolizumab IV over 30-60 minutes on days 1 and 15. Treatment repeats every 28 days for 3 courses in the absence of disease progression or unacceptable toxicity. Within 4-6 weeks of treatment completion, patients undergo surgical resection. Beginning 6 weeks after surgery, patients continue to receive oxaliplatin IV over 2 hours, fluorouracil IV continuously over 48 hours, and atezolizumab IV over 30-60 minutes on days 1 and 15. Treatment repeats every 28 days for 3 courses in the absence of disease progression or unacceptable toxicity. Patients then receive atezolizumab monotherapy IV over 30-60 minutes on day 1. Treatment repeats every 21 days for up to 4 courses in the absence of disease progression or unacceptable toxicity.
  • Atezolizumab
  • Fluorouracil
  • Oxaliplatin

Eligibility Criteria

        Inclusion Criteria:

          -  Signed informed consent form

          -  Ability to comply with the study protocol, in the investigator's judgment

          -  Histologically or cytologically confirmed esophageal or gastroesophageal type I or II
             adenocarcinoma

          -  No prior therapy including chemotherapy or radiation therapy

          -  Patients with T1N1, and T2-3 with any N will be eligible

          -  Eastern Cooperative Oncology Group (ECOG) performance status of 0-1

          -  Absolute neutrophil count (ANC) >= 1.5 x 10^9/L (1500/uL) without granulocyte
             colony-stimulating factor support (obtained within 14 days prior to initiation of
             study treatment)

          -  Lymphocyte count >= 0.5 x 10^9/L (500/uL) (obtained within 14 days prior to initiation
             of study treatment)

          -  Platelet count >= 100 x 10^9/L (100,000/uL) without transfusion (obtained within 14
             days prior to initiation of study treatment)

          -  Hemoglobin >= 90 g/L (9 g/dL); patients may be transfused to meet this criterion
             (obtained within 14 days prior to initiation of study treatment)

          -  Aspartate aminotransferase (AST) =< 2.5 x upper limit of normal (ULN) (obtained within
             14 days prior to initiation of study treatment)

          -  Alanine aminotransferase (ALT) =< 2.5 x ULN (obtained within 14 days prior to
             initiation of study treatment)

          -  Alkaline phosphatase (ALP) =< 2.5 x ULN (obtained within 14 days prior to initiation
             of study treatment)

          -  Serum bilirubin =< 1.5 x ULN with the following exception:

               -  Patients with known Gilbert disease: serum bilirubin level =< 3 x ULN (obtained
                  within 14 days prior to initiation of study treatment)

          -  Serum creatinine =< 1.5 x ULN [or] creatinine clearance >= 70 mL/min (calculated using
             the Cockcroft-Gault formula) (obtained within 14 days prior to initiation of study
             treatment)

          -  Serum albumin >= 25 g/L (2.5 g/dL) (obtained within 14 days prior to initiation of
             study treatment)

          -  For patients not receiving therapeutic anticoagulation: international normalized ratio
             (INR) or activated partial thromboplastin time (aPTT) =< 1.5 x ULN (obtained within 14
             days prior to initiation of study treatment)

          -  For patients receiving therapeutic anticoagulation: stable anticoagulant regimen

          -  Medically fit for surgery

          -  No supraclavicular, or para-aortic nodal enlargement unless biopsy negative

          -  Male or female but both sexes must practice adequate contraception while on therapy

          -  Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy
             test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin
             [HCG]) within 14 days prior to the start of study drug. Women must not be
             breastfeeding

          -  Availability of a representative tumor specimen that is suitable for determination of
             PDL-1 via central testing. A formalin-fixed paraffin-embedded (FFPE) tumor specimen in
             a paraffin block (preferred) or at least 10 slides containing unstained, freshly cut,
             serial sections should be submitted along with an associated pathology report prior to
             study enrollment. If < 10 slides are available, the patient may still be eligible for
             the study, after principal investigator approval has been obtained. If archival tumor
             tissue is unavailable or is determined to be unsuitable for required testing, tumor
             tissue must be obtained from a biopsy performed at screening

        Exclusion Criteria:

          -  Patients with T1aN0, T4b, or M1 cancer will be excluded

          -  Squamous cell carcinoma histology

          -  Invasion into nearby organs (T4b) with or increased risk for fistula

          -  Significant comorbid conditions (defined as uncontrolled diabetes, active angina or
             heart failure, uncontrolled hypertension, or active psychiatric condition that
             prevents consistent participation and compliance)

          -  More than grade 1 neuropathy

          -  Unable to comprehend the requirements of the study or comply with it

          -  Active bleeding from primary tumor requiring radiation therapy

          -  Uncontrolled or symptomatic hypercalcemia (> 1.5 mmol/L ionized calcium or calcium >
             12 mg/dL or corrected serum calcium > ULN)

          -  Active or history of autoimmune disease or immune deficiency, including, but not
             limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus
             erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid
             antibody syndrome, Wegener granulomatosis, Sjogren's syndrome, Guillain-Barre
             syndrome, or multiple sclerosis with the following exceptions: Patients with a history
             of autoimmune-related hypothyroidism who are on thyroid replacement hormone are
             eligible for the study. Patients with controlled type 1 diabetes mellitus who are on
             an insulin regimen are eligible for the study

          -  Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with
             dermatologic manifestations only (e.g., patients with psoriatic arthritis are
             excluded) are eligible for the study provided all of following conditions are met:

               -  Rash must cover < 10% of body surface area

               -  Disease is well controlled at baseline and requires only low-potency topical
                  corticosteroids

               -  No occurrence of acute exacerbations of the underlying condition requiring
                  psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologic agents,
                  oral calcineurin inhibitors, or high potency or oral corticosteroids within the
                  previous 12 months

          -  History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis
             obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of
             active pneumonitis on screening chest computed tomography (CT) scan

          -  Positive human immunodeficiency virus (HIV) test at screening

          -  Active hepatitis B virus (HBV) infection (chronic or acute), defined as having a
             positive hepatitis B surface antigen (HBsAg) test at screening

          -  Patients with a negative HBsAg test and a positive total hepatitis B core antibody
             (HBcAb) test at screening, are eligible for the study

          -  Active hepatitis C virus (HCV) infection, defined as having a positive HCV antibody
             test followed by a positive HCV ribonucleic acid (RNA) test at screening. The HCV RNA
             test will be performed only for patients who have a positive HCV antibody test

          -  Active tuberculosis

          -  Significant cardiovascular disease, such as New York Heart Association class II or
             greater cardiac disease, myocardial infarction, or cerebrovascular accident within 3
             months prior to initiation of study treatment, unstable arrhythmia, or unstable angina

          -  Major surgical procedure other than for diagnosis within 4 weeks prior to initiation
             of study treatment, or anticipation of need for a major surgical procedure during the
             course of the study

          -  History of other malignancy within 5 years prior to screening, with the exception of
             those with a negligible risk of metastasis or death (e.g., 5-year OS of > 90%), such
             as adequately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma,
             localized prostate cancer, ductal carcinoma in situ, or stage I uterine cancer

          -  Severe infection within 4 weeks prior to initiation of study treatment, including, but
             not limited to, hospitalization for complications of infection, bacteremia, or severe
             pneumonia

          -  Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to initiation
             of study treatment. Patients receiving prophylactic antibiotics (e.g., to prevent a
             urinary tract infection or chronic obstructive pulmonary disease exacerbation) are
             eligible for the study

          -  Any other disease, metabolic dysfunction, physical examination finding, or clinical
             laboratory finding that contraindicates the use of an investigational drug, may affect
             the interpretation of the results, or may render the patient at high risk from
             treatment complications

          -  Prior allogeneic stem cell or solid organ transplantation

          -  Treatment with a live, attenuated vaccine within 4 weeks prior to initiation of study
             treatment, or anticipation of need for such a vaccine during the course of the study
             or within 5 months after the last dose of atezolizumab

          -  Treatment with investigational therapy within 28 days prior to initiation of study
             treatment

          -  Prior treatment with CD137 agonists or immune checkpoint blockade therapies, including
             anti-CTLA-4, anti-PD-1, and anti-PD-L1 therapeutic antibodies

          -  Treatment with systemic immunostimulatory agents (including, but not limited to,
             interferon and interleukin 2 [IL-2]) within 4 weeks or five half-lives of the drug
             (whichever is longer) prior to initiation of study treatment

          -  Treatment with systemic immunosuppressive medication (including, but not limited to,
             corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and
             anti-TNF-agents) within 2 weeks prior to initiation of study treatment, or
             anticipation of need for systemic immunosuppressive medication during the course of
             the study, with the following exceptions: Patients who received acute, low-dose
             systemic immunosuppressant medication or a one-time pulse dose of systemic
             immunosuppressant medication (e.g., 48 hours of corticosteroids for a contrast
             allergy) are eligible for the study after principal investigator approval. Patients
             who received mineralocorticoids (e.g., fludrocortisone), corticosteroids for chronic
             obstructive pulmonary disease (COPD) or asthma, or low-dose corticosteroids for
             orthostatic hypotension or adrenal insufficiency are eligible for the study

          -  History of severe allergic anaphylactic reactions to chimeric or humanized antibodies
             or fusion proteins

          -  Known hypersensitivity to Chinese hamster ovary cell products or to any component of
             the atezolizumab formulation

          -  Known allergy or hypersensitivity to any component of the oxaliplatin or 5-FU
             formulation

          -  Pregnant or breastfeeding, or intending to become pregnant during the study or within
             5 months for atezolizumab
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Pathological complete response (PathCR)
Time Frame:Up to 3 years
Safety Issue:
Description:The optimum two-stage design proposed by Simon will be implemented. The PathCR rate will be estimated along with the exact 95% confidence interval.

Secondary Outcome Measures

Measure:Disease-free survival (DFS)
Time Frame:Up to 3 years
Safety Issue:
Description:The Kaplan-Meier method will be used to estimate the probabilities of DFS.
Measure:Overall survival (OS)
Time Frame:Up to 3 years
Safety Issue:
Description:The Kaplan-Meier method will be used to estimate the probabilities of OS.
Measure:Changes in tumor stroma profile after treatment
Time Frame:Baseline up to 3 years
Safety Issue:
Description:The changes in tumor stroma profile after treatment assessed through paired t-tests or Wilcoxon signed rank tests if normality assumption is not satisfied.
Measure:Incidence of toxicities defined as any treatment-related grade 3 or greater non-hematologic adverse events (AEs) determined by CTCAE version v 4.03.
Time Frame:From the start of study treatment up to 3 months
Safety Issue:
Description:
Measure:Tumor regression determined by CT or MRI
Time Frame:Baseline up to 3 years
Safety Issue:
Description:

Details

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

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