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Everolimus and Combination Chemotherapy in Treating Patients With Metastatic Stomach or Esophageal Cancer

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT01231399
Recruitment Status : Completed
First Posted : November 1, 2010
Results First Posted : May 31, 2017
Last Update Posted : May 31, 2017
National Cancer Institute (NCI)
Information provided by (Responsible Party):
City of Hope Medical Center

Brief Summary:

RATIONALE: Everolimus may stop the growth of stomach or esophageal cancer by blocking blood flow to the tumor. Drugs used in chemotherapy, such as leucovorin calcium, fluorouracil, and oxaliplatin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing, or by stopping them from spreading. Giving everolimus together with combination chemotherapy may kill more tumor cells.

PURPOSE: This phase I trial is studying the side effects and best dose of everolimus when given together with combination chemotherapy in treating patients with metastatic stomach or esophageal cancer that has spread to other places in the body.

Condition or disease Intervention/treatment Phase
Adenocarcinoma of the Esophagus Adenocarcinoma of the Gastroesophageal Junction Diffuse Adenocarcinoma of the Stomach Intestinal Adenocarcinoma of the Stomach Mixed Adenocarcinoma of the Stomach Recurrent Esophageal Cancer Recurrent Gastric Cancer Stage IV Esophageal Cancer Stage IV Gastric Cancer Drug: fluorouracil Drug: leucovorin calcium Drug: oxaliplatin Drug: everolimus Other: laboratory biomarker analysis Other: immunohistochemistry staining method Genetic: microarray analysis Phase 1 Phase 2

Detailed Description:


I. To determine the maximum tolerated dose of everolimus to use in combination with mFOLFOX6 [oxaliplatin, leucovorin (leucovorin calcium), 5-FU (fluorouracil)].

II. To better describe the toxicities associated with the combination of everolimus with mFOLFOX6.

III. To assess response rate and progression-free survival in this patient population.

IV. To assess overall survival in patients with metastatic gastric, esophageal and gastroesophageal junction (GEJ) adenocarcinoma treated with the combination of mFOLFOX6 + everolimus.

OUTLINE: This is a dose-escalation study of everolimus. Patients receive fluorouracil intravenously (IV) continuously over 46 hours, leucovorin calcium IV over 2 hours, and oxaliplatin IV over 2 hours on day 1. Patients also receive oral everolimus once daily on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up periodically for 1 year.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 6 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase Ib Trial of mFOLFOX6 and Everolimus (NSC-733504) in Patients With Metastatic Gastroesophageal Adenocarcinoma
Study Start Date : February 2012
Actual Primary Completion Date : July 2016
Actual Study Completion Date : July 2016

Resource links provided by the National Library of Medicine

Drug Information available for: Everolimus

Arm Intervention/treatment
Experimental: Arm I
Patients receive fluorouracil IV continuously over 46 hours, leucovorin calcium IV over 2 hours, and oxaliplatin IV over 2 hours on day 1. Patients also receive oral everolimus once daily on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Drug: fluorouracil
Given IV
Other Names:
  • 5-fluorouracil
  • 5-Fluracil
  • 5-FU
  • Adrucil
  • Efudex
  • FU

Drug: leucovorin calcium
Given IV
Other Names:
  • calcium folinate
  • CF
  • CFR
  • citrovorum factor
  • LV
  • Wellcovorin

Drug: oxaliplatin
Given IV
Other Names:
  • 1-OHP
  • Dacotin
  • Dacplat
  • diaminocyclohexane oxalatoplatinum
  • Eloxatin
  • L-OHP

Drug: everolimus
Given orally
Other Names:
  • 42-O-(2-hydroxy)ethyl rapamycin
  • Afinitor
  • RAD001

Other: laboratory biomarker analysis
Correlative studies

Other: immunohistochemistry staining method
Correlative studies
Other Name: immunohistochemistry

Genetic: microarray analysis
Correlative studies
Other Name: gene expression profiling

Primary Outcome Measures :
  1. Maximum Tolerated Dose (MTD) of Everolimus [ Time Frame: Course 1 (first 28 days) ]
    The highest dose tested in which fewer than 33% of patients experience an attributable DLT to the study drug, when at least 6 patients are treated at that dose and are evaluable for toxicity. Toxicities will be assessed using Common Terminology Criteria for Adverse Events (CTCAE) v4.0.

  2. Number of Subject With Overall Response [ Time Frame: Up to 5 years ]
    Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR

  3. Progression-free Survival [ Time Frame: up to 5 years ]
    Estimated using the product-limit method of Kaplan and Meier. From the date treatment started until the date of first documented progression or date of death from any cause, whichever came first. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.

  4. Overall Survival [ Time Frame: Up to 5 years. ]
    Estimated using the product-limit method of Kaplan and Meier. From the date treatment started until the date of death from any cause.

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

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Ages Eligible for Study:   19 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • Patients must have histologically confirmed diagnosis of gastric, esophageal, and GEJ adenocarcinoma
  • Patients must have metastatic disease
  • Patients must not have received any chemotherapy for metastatic disease
  • Patients may have received prior adjuvant chemotherapy; completion of chemotherapy must be greater than 6 months from date of recurrent disease
  • Patients must have computed tomography (CT) or magnetic resonance imaging (MRI) scan; patients must have at least one measurable site of disease according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria that has not been previously irradiated; if the patient has had previous radiation to the marker lesion(s), there must be evidence of progression since the radiation
  • Patients must have a ECOG Performance Status of 0-1
  • Absolute neutrophil count (ANC) > 1,500/mcl
  • Platelet count > 100,000/mcl
  • Hemoglobin (Hg) > 9 g/dL
  • Serum creatinine < 1.5 mg/dl and/or Creatinine clearance > 60 cc/min
  • Bilirubin < 1.5 mg/dl
  • Serum glutamic oxaloacetic transaminase (SGOT) and/or serum glutamic pyruvic transaminase (SGPT) =< 2.5 x institutional upper limit of normal (IULN) (=< 5 x upper limit of normal [ULN] in patients with liver metastases)
  • Fasting serum cholesterol =< 300 mg/dL or =< 7.75 mmol/L
  • Fasting triglycerides =< 2.5 x ULN; NOTE: in case one or both of these thresholds are exceeded, the patient can only be included after initiation of appropriate lipid lowering medication
  • Patients should have controlled diabetes as evidenced by hemoglobin (Hb)A1C =< 8%
  • International normalized ratio (INR) and partial thromboplastin time (PTT) =< 1.5; (anticoagulation is allowed if target INR =< 1.5 on a stable dose of warfarin or on a stable dose of low molecular weight [LMW] heparin for > 2 weeks at time of randomization)
  • Due to the possibility of harm to a fetus or nursing infant from this treatment regimen, patients must not be pregnant or nursing (or plan to become pregnant); women and men of reproductive potential must have agreed to use a highly effective contraceptive method for at least 8 weeks after treatment
  • Patients with risk factors for contraction hepatitis B or C should undergo screening prior to treatment on protocol. Patients with detectable viral titers are required to receive treatment for 4 weeks prior to starting protocol therapy.
  • Patients must be able to swallow pills
  • No other prior malignancy within the past 3 years is allowed except for the following: adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, adequately treated Stage I or II cancer from which the patient is currently in complete remission, or any other cancer from which the patient has been disease free for five years
  • All patients must be informed of the investigational nature of this study and must sign and give written informed consent in accordance with institutional and federal guidelines
  • Patients must have pathology specimen available for submission

Exclusion Criteria:

  • Patients currently receiving anticancer therapies or who have received anticancer therapies within 4 weeks of the start of study drug (including chemotherapy, radiation therapy, antibody based therapy, etc)
  • Patients who have received prior treatment with an mammalian target of rapamycin (mTOR) inhibitor (sirolimus, temsirolimus, everolimus)
  • Patients with a known hypersensitivity to everolimus or other rapamycins (sirolimus, temsirolimus) or to its excipients
  • Patients, who have had a major surgery or significant traumatic injury within 4 weeks of start of study drug, patients who have not recovered from the side effects of any major surgery (defined as requiring general anesthesia) or patients that may require major surgery during the course of the study
  • Prior treatment with any investigational drug within the preceding 4 weeks
  • Patients receiving chronic, systemic treatment with corticosteroids (prednisone > 10 mg per day) or another immunosuppressive agent; topical or inhaled corticosteroids are allowed
  • Patients should not receive immunization with attenuated live vaccines within one week of study entry or during study period
  • Uncontrolled brain or leptomeningeal metastases, including patients who continue to require glucocorticoids for brain or leptomeningeal metastases
  • Patients who have any severe and/or uncontrolled medical conditions or other conditions that could affect their participation in the study such as:

    • Symptomatic congestive heart failure of New York heart Association Class III or IV
    • Unstable angina pectoris, symptomatic congestive heart failure, myocardial infarction within 6 months of start of study drug, serious uncontrolled cardiac arrhythmia or any other clinically significant cardiac disease
    • Severely impaired lung function as defined as spirometry and diffusion lung capacity of carbon monoxide (DLCO) that is 50% of the normal predicted value and/or 02 saturation that is 88% or less at rest on room air
    • Uncontrolled diabetes as defined by fasting serum glucose > 1.5 x ULN
    • Active (acute or chronic) or uncontrolled severe infections
    • Liver disease such as cirrhosis, chronic active hepatitis or chronic persistent hepatitis
  • A known history of human immunodeficiency virus (HIV) seropositivity
  • Impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of everolimus (e.g., ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome or small bowel resection)
  • Patients with an active, bleeding diathesis; history of noncompliance to medical regimens
  • Patients unwilling to or unable to comply with the protocol

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 identifier (NCT number): NCT01231399

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United States, California
City of Hope Medical Center
Duarte, California, United States, 91010
South Pasadena Cancer Center
South Pasadena, California, United States, 91030
United States, Florida
H. Lee Moffitt Cancer Center and Research Institute
Tampa, Florida, United States, 33612
Sponsors and Collaborators
City of Hope Medical Center
National Cancer Institute (NCI)
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Principal Investigator: Vincent Chung City of Hope Medical Center

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Responsible Party: City of Hope Medical Center Identifier: NCT01231399     History of Changes
Other Study ID Numbers: 10064
First Posted: November 1, 2010    Key Record Dates
Results First Posted: May 31, 2017
Last Update Posted: May 31, 2017
Last Verified: April 2017
Additional relevant MeSH terms:
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Stomach Neoplasms
Esophageal Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Digestive System Diseases
Gastrointestinal Diseases
Stomach Diseases
Head and Neck Neoplasms
Esophageal Diseases
Calcium, Dietary
Calcium-Regulating Hormones and Agents
Physiological Effects of Drugs
Bone Density Conservation Agents
Antineoplastic Agents
Molecular Mechanisms of Pharmacological Action
Antimetabolites, Antineoplastic
Immunosuppressive Agents