Combination Chemotherapy With or Without Vismodegib in Treating Patients With Advanced Stomach Cancer or Gastroesophageal Junction Cancer

Phase 2

Completed

Conditions: Adenocarcinoma of the Gastroesophageal Junction
Adenocarcinoma of the Stomach
Recurrent Gastric Cancer
Stage IV Gastric Cancer
Stage IIIA Gastric Cancer
Stage IIIB Gastric Cancer
Stage IIIC Gastric Cancer

Interventions: Drug: oxaliplatin
Drug: leucovorin calcium
Drug: fluorouracil
Other: placebo
Drug: vismodegib
Other: laboratory biomarker analysis

Registration Number: NCT00982592

Lead Sponsor: National Cancer Institute (NCI)

Brief Summary: This randomized phase II trial studies combination chemotherapy when given together with vismodegib to see how well it works compared with combination chemotherapy without vismodegib in treating patients with advanced stomach cancer or gastroesophageal junction cancer. Drugs used in chemotherapy, such as oxaliplatin, leucovorin calcium, 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 more than one drug (combination chemotherapy) may kill more tumor cells. Vismodegib may stop the growth of stomach or gastroesophageal junction cancer by blocking the growth of new blood vessels necessary for tumor growth. It is not yet known whether combination chemotherapy is more effective when given with or without vismodegib in treating stomach cancer and gastroesophageal junction cancer.

Detailed Description: PRIMARY OBJECTIVES:

I. To determine if the addition of GDC-0449 (vismodegib) to FOLFOX (fluorouracil, leucovorin calcium, oxaliplatin) chemotherapy improves median progression free survival (PFS) in the first line treatment of patients with advanced gastric and gastroesophageal junction (GEJ) adenocarcinoma.

SECONDARY OBJECTIVES:

I. To determine if the addition of GDC-0449 to FOLFOX chemotherapy affects overall survival.

II. To determine if the addition of GDC-0449 to FOLFOX chemotherapy affects response rate.

III. To determine if the addition of GDC-0449 to FOLFOX chemotherapy affects toxicity rates in the first line treatment of patients with advanced gastric and GEJ adenocarcinoma.

TERTIARY OBJECTIVES:

I. To determine the level of baseline hedgehog pathway activation and correlate with clinical outcome and response to treatment with GDC-0449.

II. In those patients who consent to repeat biopsy at week 4-5, hedgehog pathway expression will again be assessed (every attempt will be made to obtain repeat biopsy from the same site as the initial biopsy) and compared to baseline values and clinical outcome.

III. To determine a primary gastric cancer gene expression profile that may predict response to GDC-0449.

IV. To determine if serum shed collagen epitopes correlate with clinical outcome and may be used to assess efficacy of GDC-0449 treatment.

V. To determine if circulating endothelial progenitor cells (EPC)'s correlate with treatment response and may be used to assess efficacy of GDC-0449 treatment.

VI. To determine if hedgehog pathway expression is downregulated in EPC's following treatment with GDC-0449.

VII. To determine if serum expression of vascular endothelial growth factor (VEGF), transforming growth factor (TGF)-beta, and insulin-like growth factor binding protein (IGFBP) 3 correlate with clinical outcome and may be used to assess efficacy of GDC-0449 treatment.

VIII. To determine if human epidermal growth factor receptor 2 (Her2) expression is predictive in assessing the efficacy of GDC-0449 treatment. Of note, Her2 status will be collected retrospectively for those patients who were tested as part of standard of care established in October 2010.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive FOLFOX chemotherapy comprising oxaliplatin intravenously (IV) over 2 hours, leucovorin calcium IV over 2 hours, and fluorouracil IV over 46-48 hours on day 1. Patients also receive placebo orally (PO) once daily (QD) on days 1-14.

ARM II: Patients receive FOLFOX chemotherapy as in Arm I. Patients also receive vismodegib PO on days 1-14. In both arms, treatment repeats every 2 weeks in the absence of unacceptable toxicity or disease progression.

After completion of study treatment, patients are followed up every 3 months.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 124

Inclusion Criteria

Patients must have histologically or cytologically confirmed gastric or gastroesophageal junction (GEJ) adenocarcinoma not amenable to surgical resection
Patients must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded) as >= 20 mm with conventional techniques or as >= 10 mm with spiral computed tomography (CT) scan
No prior chemotherapy for advanced disease; patients may have receive adjuvant chemotherapy or chemoradiation if > 6 months has elapsed since completion of treatment
Life expectancy of greater than 3 months
Eastern Cooperative Oncology Group (ECOG) performance status < 2 (Karnofsky > 70%)
Absolute neutrophil count >= 1,500/mcL
Platelets >= 100,000/mcL
Total bilirubin =< 1.5 times upper limit of normal (ULN)
Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 X institutional upper limit of normal (=< 5.0 X institutional upper limit of normal with presence of liver metastases)
Creatinine =< 1.5 X institutional upper limit of normal OR creatinine clearance >= 60 mL/min/1.73 m^2 for patients with creatinine levels above institutional normal
Baseline imaging studies performed =< 28 days of study registration; the treating investigator will determine the appropriate imaging studies, which may include CT scan, magnetic resonance imaging (MRI), and/or fludeoxyglucose F 18 (FDG)-positron emission tomography (PET)/CT
Must be willing to provide blood and tissue samples for research purposes; patient has the right to later withdraw consent for research studies and/or tissue specimens
Patients must agree to placement of a central venous catheter for chemotherapy administration
Patients must be able to swallow whole capsules
Patients taking medications with narrow therapeutic indices that are metabolized by cytochrome P450 (CYP450), including warfarin sodium (Coumadin), must be on a stable, therapeutic dose and have close monitoring of their levels
Women of child-bearing potential and men must use two forms of contraception (i.e., barrier contraception and one other method of contraception) at least 4 weeks prior to study entry, for the duration of study participation, and for at least 12 months post-treatment; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately
Pregnancy testing: women of childbearing potential are required to have a negative serum pregnancy test (with a sensitivity of at least 25 mIU/mL) within 10-14 days and within 24 hours prior to the first dose of GDC-0449/placebo (serum or urine); a pregnancy test (serum or urine) will be administered every 4 weeks if their menstrual cycles are regular or every 2 weeks if their cycles are irregular while on study within the 24-hour period prior to the administration of GDC-0449/placebo; a positive urine test must be confirmed by a serum pregnancy test; prior to dispensing GDC-0449/placebo, the investigator must confirm and document the patient's use of two contraceptive methods, dates of negative pregnancy test, and confirm the patient's understanding of the teratogenic potential of GDC-0449/placebo
Female subjects of childbearing potential are defined as follows:
- Patients with regular menses
- Patients, after menarche with amenorrhea, irregular cycles, or using a contraceptive method that precludes withdrawal bleeding
- Women who have had tubal ligation
Female subjects may be considered to NOT be of childbearing potential for the following reasons:
- The patient has undergone hysterectomy and/or bilateral oophorectomy.
- The patient is post-menopausal defined by amenorrhea for at least 1 year in a woman > 45 years old
Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria

Patients who have had chemotherapy or radiotherapy within 6 months prior to entering the study
Patients may not be receiving any other investigational agents
Patients with known brain metastases should be excluded from this clinical trial
History of allergic reactions attributed to compounds of similar chemical or biologic composition to GDC-0449, 5-fluorouracil or oxaliplatin
GDC-0449 inhibits cytochrome P450, family 2, subfamily C, polypeptide 8 (CYP2C8), cytochrome P450, family 2, subfamily C, polypeptide 9 (CYP2C9), and cytochrome P450, family 2, subfamily C, polypeptide 19 (CYP2C19) drug metabolism enzymes in vitro at concentrations that may be clinically relevant; therefore, caution should be exercised when dosing GDC-0449 concurrently with medications that are substrates of CYP2C8, CYP2C9, and CYP2C19 and have narrow therapeutic windows
Patients with malabsorption syndrome or other condition that would interfere with intestinal absorption
Patients unable to swallow whole capsules
Patients with clinically active liver disease, including viral or other hepatitis or cirrhosis are ineligible
Patients with uncontrolled hypocalcemia, hypomagnesemia, hyponatremia or hypokalemia defined as less than the lower limit of normal for the institution, despite adequate electrolyte supplementation are excluded from this study
Pre-existing > grade 1 peripheral sensory neuropathy
Previous or concurrent malignancy; exceptions: treated basal cell or squamous cell skin cancer, in situ cervical cancer, or lobular carcinoma in situ in one breast; or other cancer which the patient has been disease-free ≥5 years
Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
Pregnant women are excluded from this study; breastfeeding should be discontinued if the mother is treated with GDC-0449
Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Arm I (FOLFOX regimen and placebo)	leucovorin calcium	Patients receive FOLFOX chemotherapy comprising oxaliplatin IV over 2 hours, leucovorin calcium IV over 2 hours, and fluorouracil bolus and then IV over 46-48 hours on day 1. Patients also receive placebo PO QD on days 1-14. Courses repeat every 2 weeks in the absence of unacceptable toxicity or disease progression.
Arm I (FOLFOX regimen and placebo)	placebo	Patients receive FOLFOX chemotherapy comprising oxaliplatin IV over 2 hours, leucovorin calcium IV over 2 hours, and fluorouracil bolus and then IV over 46-48 hours on day 1. Patients also receive placebo PO QD on days 1-14. Courses repeat every 2 weeks in the absence of unacceptable toxicity or disease progression.
Arm I (FOLFOX regimen and placebo)	laboratory biomarker analysis	Patients receive FOLFOX chemotherapy comprising oxaliplatin IV over 2 hours, leucovorin calcium IV over 2 hours, and fluorouracil bolus and then IV over 46-48 hours on day 1. Patients also receive placebo PO QD on days 1-14. Courses repeat every 2 weeks in the absence of unacceptable toxicity or disease progression.
Arm II (FOLFOX regimen and vismodegib)	leucovorin calcium	Patients receive FOLFOX chemotherapy as in arm I. Patients also receive vismodegib PO on days 1-14. Courses repeat every 2 weeks in the absence of unacceptable toxicity or disease progression.
Arm II (FOLFOX regimen and vismodegib)	laboratory biomarker analysis	Patients receive FOLFOX chemotherapy as in arm I. Patients also receive vismodegib PO on days 1-14. Courses repeat every 2 weeks in the absence of unacceptable toxicity or disease progression.
Arm I (FOLFOX regimen and placebo)	oxaliplatin	Patients receive FOLFOX chemotherapy comprising oxaliplatin IV over 2 hours, leucovorin calcium IV over 2 hours, and fluorouracil bolus and then IV over 46-48 hours on day 1. Patients also receive placebo PO QD on days 1-14. Courses repeat every 2 weeks in the absence of unacceptable toxicity or disease progression.
Arm I (FOLFOX regimen and placebo)	fluorouracil	Patients receive FOLFOX chemotherapy comprising oxaliplatin IV over 2 hours, leucovorin calcium IV over 2 hours, and fluorouracil bolus and then IV over 46-48 hours on day 1. Patients also receive placebo PO QD on days 1-14. Courses repeat every 2 weeks in the absence of unacceptable toxicity or disease progression.
Arm II (FOLFOX regimen and vismodegib)	oxaliplatin	Patients receive FOLFOX chemotherapy as in arm I. Patients also receive vismodegib PO on days 1-14. Courses repeat every 2 weeks in the absence of unacceptable toxicity or disease progression.
Arm II (FOLFOX regimen and vismodegib)	fluorouracil	Patients receive FOLFOX chemotherapy as in arm I. Patients also receive vismodegib PO on days 1-14. Courses repeat every 2 weeks in the absence of unacceptable toxicity or disease progression.
Arm II (FOLFOX regimen and vismodegib)	vismodegib	Patients receive FOLFOX chemotherapy as in arm I. Patients also receive vismodegib PO on days 1-14. Courses repeat every 2 weeks in the absence of unacceptable toxicity or disease progression.

Primary Outcome Measures

Name	Time	Method
Median Progression-free Survival (PFS)	up to 4 years	PFS is defined as the time from randomization until objective tumor progression or death from any cause and is evaluated per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.

Secondary Outcome Measures

Name	Time	Method
Objective Response Rate	Up to 4 years	Defined as the percentage of the patients who had complete response (CR) or partial response (PR) per RECIST 1.1.
Overall Survival	up to 4 years	Defined as time from randomization day until death from any cause.
Incidence of Toxicities (Grade 3 and Higher)	Up to 4 years	Defined as percentage of patients who experienced a toxicity with grade 3 or higher related to the protocol therapy. Assessed by National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0
Incidence of Toxicities (grades1 and 2)	Up to 4 years	Defined as percentage of patients who experienced a toxicity with grade 1 or 2 (worst grade) related to the protocol therapy. Assessed by National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0.

Trial Locations

Locations (30): University of Pittsburgh
🇺🇸
Pittsburgh, Pennsylvania, United States
Decatur Memorial Hospital
🇺🇸
Decatur, Illinois, United States
New York Cancer Consortium
🇺🇸
Bronx;, New York, United States
Illinois CancerCare-Peoria
🇺🇸
Peoria, Illinois, United States
NorthShore University HealthSystem-Evanston Hospital
🇺🇸
Evanston, Illinois, United States
Fort Wayne Medical Oncology and Hematology Inc-Parkview
🇺🇸
Fort Wayne, Indiana, United States
Beth Israel Medical Center
🇺🇸
New York, New York, United States
Montefiore Medical Center - Moses Campus
🇺🇸
Bronx, New York, United States
Ingalls Memorial Hospital
🇺🇸
Harvey, Illinois, United States
Memorial Sloan-Kettering Cancer Center
🇺🇸
New York, New York, United States
Columbia University Medical Center
🇺🇸
New York, New York, United States
Loyola University Medical Center
🇺🇸
Maywood, Illinois, United States
Saint John's Mercy Medical Center
🇺🇸
Saint Louis, Missouri, United States
Saint Luke's Roosevelt Hospital Center - Saint Luke's Division
🇺🇸
New York, New York, United States
Cancer Care Center of Decatur
🇺🇸
Decatur, Illinois, United States
Crossroads Cancer Center
🇺🇸
Effingham, Illinois, United States
Arthur G. James Cancer Hospital and Solove Research Institute at Ohio State University Medical Center
🇺🇸
Columbus, Ohio, United States
New York University Langone Medical Center
🇺🇸
New York, New York, United States
Weill Medical College of Cornell University
🇺🇸
New York, New York, United States
University of Chicago
🇺🇸
Chicago, Illinois, United States
Indiana University Medical Center
🇺🇸
Indianapolis, Indiana, United States
Vanderbilt-Ingram Cancer Center
🇺🇸
Nashville, Tennessee, United States
Illinois Oncology Research Association CCOP
🇺🇸
Peoria, Illinois, United States
Memorial Medical Center
🇺🇸
Springfield, Illinois, United States
Ohio State University Medical Center
🇺🇸
Columbus, Ohio, United States
Albert Einstein College of Medicine
🇺🇸
Bronx, New York, United States
University of California at Davis Cancer Center
🇺🇸
Sacramento, California, United States
University of Michigan University Hospital
🇺🇸
Ann Arbor, Michigan, United States
University of Michigan
🇺🇸
Ann Arbor, Michigan, United States
Virginia Commonwealth University
🇺🇸
Richmond, Virginia, United States