Clinical trial NCT00982592: Combination Chemotherapy With or Without Vismodegib in Treating Patients With Advanced Stomach Cancer or Gastroesophageal Junction Cancer
Official title: A Randomized, Double Blind Placebo Controlled Phase 2 Study of FOLFOX Plus or Minus GDC-0449 in Patients With Advanced Gastric and Gastroesophageal Junction (GEJ) Carcinoma
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Adenocarcinoma of the Gastroesophageal Junction
Adenocarcinoma of the Stomach
Recurrent Gastric Cancer
Stage IIIA Gastric Cancer
Stage IIIB Gastric Cancer
Stage IIIC Gastric Cancer
Stage IV Gastric Cancer
Lead sponsor: National Cancer Institute (NCI)
Sponsor class: NIH
First posted: 2009-09-23
Enrollment: 124
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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

Primary outcomes:
measure: Median Progression-free Survival (PFS)
timeFrame: up to 4 years
Secondary outcomes:
measure: Objective Response Rate
timeFrame: Up to 4 years
measure: Overall Survival
timeFrame: up to 4 years
measure: Incidence of Toxicities (Grade 3 and Higher)
timeFrame: Up to 4 years
measure: Incidence of Toxicities (grades1 and 2)
timeFrame: Up to 4 years
Other outcomes:
Locations:
city: Sacramento
country: United States
facility: University of California at Davis Cancer Center
state: California
city: Chicago
country: United States
facility: University of Chicago
state: Illinois
city: Decatur
country: United States
facility: Cancer Care Center of Decatur
state: Illinois
city: Decatur
country: United States
facility: Decatur Memorial Hospital
state: Illinois
city: Effingham
country: United States
facility: Crossroads Cancer Center
state: Illinois
city: Evanston
country: United States
facility: NorthShore University HealthSystem-Evanston Hospital
state: Illinois
city: Harvey
country: United States
facility: Ingalls Memorial Hospital
state: Illinois
city: Maywood
country: United States
facility: Loyola University Medical Center
state: Illinois
city: Peoria
country: United States
facility: Illinois CancerCare-Peoria
state: Illinois
city: Peoria
country: United States
facility: Illinois Oncology Research Association CCOP
state: Illinois
city: Springfield
country: United States
facility: Memorial Medical Center
state: Illinois
city: Fort Wayne
country: United States
facility: Fort Wayne Medical Oncology and Hematology Inc-Parkview
state: Indiana
city: Indianapolis
country: United States
facility: Indiana University Medical Center
state: Indiana
city: Ann Arbor
country: United States
facility: University of Michigan University Hospital
state: Michigan
city: Ann Arbor
country: United States
facility: University of Michigan
state: Michigan
city: Saint Louis
country: United States
facility: Saint John's Mercy Medical Center
state: Missouri
city: Bronx;
country: United States
facility: New York Cancer Consortium
state: New York
city: Bronx
country: United States
facility: Albert Einstein College of Medicine
state: New York
city: Bronx
country: United States
facility: Montefiore Medical Center - Moses Campus
state: New York
city: New York
country: United States
facility: Beth Israel Medical Center
state: New York
city: New York
country: United States
facility: New York University Langone Medical Center
state: New York
city: New York
country: United States
facility: Saint Luke's Roosevelt Hospital Center - Saint Luke's Division
state: New York
city: New York
country: United States
facility: Columbia University Medical Center
state: New York
city: New York
country: United States
facility: Memorial Sloan-Kettering Cancer Center
state: New York
city: New York
country: United States
facility: Weill Medical College of Cornell University
state: New York
city: Columbus
country: United States
facility: Arthur G. James Cancer Hospital and Solove Research Institute at Ohio State University Medical Center
state: Ohio
city: Columbus
country: United States
facility: Ohio State University Medical Center
state: Ohio
city: Pittsburgh
country: United States
facility: University of Pittsburgh
state: Pennsylvania
city: Nashville
country: United States
facility: Vanderbilt-Ingram Cancer Center
state: Tennessee
city: Richmond
country: United States
facility: Virginia Commonwealth University
state: Virginia
Study officials:
affiliation: NYU Langone Health
name: Deirdre Cohen
role: PRINCIPAL_INVESTIGATOR
References: