Vismodegib and Gemcitabine Hydrochloride in Treating Patients With Advanced Pancreatic Cancer
Condition: Recurrent Pancreatic Carcinoma; Stage IV Pancreatic Cancer
MeSH terms: Pancreatic Neoplasms
Intervention: Gemcitabine Hydrochloride; Laboratory Biomarker Analysis; Vismodegib
Intervention description: Given IV; Correlative studies; Given PO
Intervention MeSH terms: Gemcitabine
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 25.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      This pilot clinical trial studies vismodegib and gemcitabine hydrochloride in treating
      patients with advanced pancreatic cancer. Vismodegib may stop the growth of pancreatic cancer
      by blocking blow flow to the tumor. Gemcitabine hydrochloride may stop the growth of tumor
      cells by blocking some of the enzymes needed for cell growth. Giving vismodegib and
      gemcitabine hydrochloride may kill more tumor cells.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Patients must have histologically or cytologically confirmed pancreas cancer

          -  Patients must have metastatic disease or recurrent disease following surgical therapy

          -  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) >= 20
             mm with conventional techniques or as >= 10 mm with spiral computed tomography (CT)
             scan

          -  Patients must have disease accessible for core needle biopsy both prior to initiation
             of therapy and on day 21 (+ or - 1 day) of GDC-0449 treatment

          -  No previous systemic therapy for metastatic pancreas cancer is permitted; prior
             neoadjuvant or adjuvant therapy with chemotherapy and/or radiation is allowed provided
             that the last day of therapy was at least 6 months prior to registration

          -  Life expectancy of greater than 12 weeks

          -  Eastern Cooperative Oncology Group (ECOG) performance status =< 1 (Karnofsky >= 70%)

          -  Leukocytes >= 3,000/mcL

          -  Absolute neutrophil count >= 1,500/mcL

          -  Platelets >= 100,000/mcL

          -  Total bilirubin =< 2.0 mg/dl

          -  Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
             [SGOT])/alanine aminotransferase (ALT) (serum glutamic pyruvate transaminase [SGPT])
             =< 2.5 x institutional upper limit of normal; < 5 x if liver involved in tumor

          -  Creatinine < 2.0 mg/dl

          -  The effects of GDC-0449 on the developing human fetus at the recommended therapeutic
             dose are unknown; for this reason and because hedgehog (Hh) signal pathway inhibitors
             as well as gemcitabine are known to be teratogenic, 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; for appropriate
             methods of contraception considered acceptable; should a woman become pregnant or
             suspect she is pregnant while participating in this study, she should inform her
             treating physician immediately;

               -  Pregnancy testing: omen of childbearing potential are required to have a negative
                  serum pregnancy test (with a sensitivity of at least 25 mIU/mL beta-human
                  chorionic gonadotropin [bHCG]) within 10-14 days and within 24 hours prior to the
                  first dose of GDC-0449 (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; a positive urine test must be confirmed
                  by a serum pregnancy test; prior to dispensing GDC-0449, 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

          -  Patients taking medications with narrow therapeutic indices that are metabolized by
             cytochrome P450 (CYP450) may be enrolled with caution; GDC-0449 is a substrate of
             CYP3A4; however, the in vitro metabolic conversion of GDC-0449 is low; effects of
             cytochrome (CYP) inducers (e.g., carbamazepine, phenobarbital, phenytoin, rifabutin,
             rifampin, St. John's wart, and troglitazone) on clinical concentrations of GDC-0449
             are unknown; likewise, the effects of strong inhibitors of CYP3A4 (e.g.,
             clarithromycin, erythromycin, itraconazole, ketoconazole, nefazodone, and
             telithromycin) on GDC-0449 clinical concentrations are unknown, and caution should be
             exercised when dosing GDC-0449 concurrently with inhibitors of CYP3A4; in addition,
             GDC-0449 inhibits CYP2C8, CYP2C9, and 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

          -  Ability to understand and willingness to provide written informed consent

        Exclusion Criteria:

          -  Patients who have had chemotherapy or radiotherapy within 6 months prior to entering
             the study or those who have not recovered from adverse events due to agents
             administered more than 6 months earlier

          -  Patients may not be receiving any other investigational agents

          -  Patients with known brain metastases

          -  History of allergic reactions attributed to compounds of similar chemical or biologic
             composition to GDC-0449 or other agents used in the study

          -  Patients on anticoagulation with Coumadin are ineligible; however anticoagulation with
             enoxaparin is acceptable for study entry

          -  Patients with malabsorption syndrome or other condition that would interfere with
             intestinal absorption; patients must be able to swallow capsules

          -  Patients with clinically active liver disease, including active viral or other
             hepatitis or cirrhosis, are ineligible

          -  Patients with uncontrolled hypomagnesemia or hypokalemia defined as less than the
             lower limit of normal for the institution, despite adequate electrolyte
             supplementation are excluded from this study

          -  Patients with > grade 1 hyponatremia or hypocalcemia are excluded from this study

          -  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 because GDC-0449 is a Hh pathway
             inhibiting agent with the potential for teratogenic or abortifacient effects; because
             there is an unknown but potential risk for adverse events in nursing infants secondary
             to treatment of the mother with GDC-0449, breastfeeding should be discontinued if the
             mother is treated with GDC-0449; these potential risks may also apply to other agents
             used in this study

          -  Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral
             therapy are ineligible because of the potential for pharmacokinetic interactions with
             GDC-0449; in addition, these patients are at increased risk of lethal infections when
             treated with marrow-suppressive therapy; appropriate studies will be undertaken in
             patients receiving combination antiretroviral therapy when indicated