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

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ClinicalTrials.gov Identifier: NCT03784326
Recruitment Status : Recruiting
First Posted : December 21, 2018
Last Update Posted : May 23, 2019
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
M.D. Anderson Cancer Center

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
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 Drug: Atezolizumab Procedure: Conventional Surgery Drug: Fluorouracil Drug: Oxaliplatin Early Phase 1

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.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 30 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Pilot Study of Perioperative Chemotherapy Plus Immunotherapy Followed by Surgery in Localized Esophageal and Gastroesophageal Adenocarcinoma
Actual Study Start Date : February 19, 2019
Estimated Primary Completion Date : December 31, 2021
Estimated Study Completion Date : December 31, 2021

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Treatment (oxaliplatin, fluorouracil, atezolizumab, surgery)
Patients 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.
Drug: Atezolizumab
Given IV
Other Names:
  • MPDL 3280A
  • MPDL 328OA
  • MPDL-3280A
  • MPDL3280A
  • MPDL328OA
  • RG7446
  • RO5541267
  • Tecentriq

Procedure: Conventional Surgery
Undergo surgical resection

Drug: Fluorouracil
Given IV
Other Names:
  • 5-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-2-9757

Drug: Oxaliplatin
Given IV
Other Names:
  • 1-OHP
  • Ai Heng
  • Aiheng
  • Dacotin
  • Dacplat
  • Diaminocyclohexane Oxalatoplatinum
  • Eloxatin
  • Eloxatine
  • JM-83
  • Oxalatoplatin
  • Oxalatoplatinum
  • RP 54780
  • RP-54780
  • SR-96669




Primary Outcome Measures :
  1. Pathological complete response (PathCR) [ Time Frame: Up to 3 years ]
    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 :
  1. Disease-free survival (DFS) [ Time Frame: Up to 3 years ]
    The Kaplan-Meier method will be used to estimate the probabilities of DFS.

  2. Overall survival (OS) [ Time Frame: Up to 3 years ]
    The Kaplan-Meier method will be used to estimate the probabilities of OS.

  3. Changes in tumor stroma profile after treatment [ Time Frame: Baseline up to 3 years ]
    The changes in tumor stroma profile after treatment assessed through paired t-tests or Wilcoxon signed rank tests if normality assumption is not satisfied.

  4. 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 ]
  5. Tumor regression determined by CT or MRI [ Time Frame: Baseline up to 3 years ]


Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

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): NCT03784326


Contacts
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Contact: Mariela Blum 713-792-2828 mblum1@mdanderson.org

Locations
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United States, Texas
M D Anderson Cancer Center Recruiting
Houston, Texas, United States, 77030
Contact: Mariela Blum    713-792-2828      
Principal Investigator: Mariela Blum         
Sponsors and Collaborators
M.D. Anderson Cancer Center
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Mariela Blum M.D. Anderson Cancer Center

Additional Information:
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Responsible Party: M.D. Anderson Cancer Center
ClinicalTrials.gov Identifier: NCT03784326     History of Changes
Other Study ID Numbers: 2018-0678
NCI-2018-02828 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
2018-0678 ( Other Identifier: M D Anderson Cancer Center )
P30CA016672 ( U.S. NIH Grant/Contract )
First Posted: December 21, 2018    Key Record Dates
Last Update Posted: May 23, 2019
Last Verified: May 2019

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Adenocarcinoma
Esophageal Neoplasms
Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Head and Neck Neoplasms
Digestive System Diseases
Esophageal Diseases
Gastrointestinal Diseases
Oxaliplatin
Fluorouracil
Atezolizumab
Antibodies, Monoclonal
Antineoplastic Agents
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antimetabolites, Antineoplastic
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs