Vismodegib and Gemcitabine Hydrochloride in Treating Patients With Advanced Pancreatic Cancer

Phase 2

Completed

Conditions: Recurrent Pancreatic Carcinoma
Stage IV Pancreatic Cancer

Interventions: Drug: Gemcitabine Hydrochloride
Other: Laboratory Biomarker Analysis
Drug: Vismodegib

Registration Number: NCT01195415

Lead Sponsor: National Cancer Institute (NCI)

Brief 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.

Detailed Description: PRIMARY OBJECTIVES:

I. To obtain tumor biopsies before and after therapy with GDC-0449 (vismodegib) to evaluate the effect of inhibition of hedgehog signaling on pancreatic cancer stem cells by: evaluating the tumor for number and percentage of pancreatic cancer stem cells before and after treatment with GDC-0449.

SECONDARY OBJECTIVES:

I. To assess progression free survival (PFS) at 3 months following treatment with GDC-0449 and gemcitabine (gemcitabine hydrochloride).

II. To assess response rate to treatment and overall survival in patients with advanced pancreas cancer treated with GDC-0449 alone and in combination with gemcitabine.

III. To evaluate the toxicity of GDC-0449 alone and in combination with gemcitabine.

OUTLINE:

Patients receive vismodegib orally (PO) once daily (QD) on days 1-28 and gemcitabine hydrochloride intravenously (IV) over 30 minutes on days 1, 8, and 15 (beginning in course 2). Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 4 weeks.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 25

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Treatment (vismodegib, gemcitabine hydrochloride)	Laboratory Biomarker Analysis	Patients receive vismodegib PO QD on days 1-28 and gemcitabine hydrochloride IV over 30 minutes on days 1, 8, and 15 (beginning in course 2). Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Treatment (vismodegib, gemcitabine hydrochloride)	Vismodegib	Patients receive vismodegib PO QD on days 1-28 and gemcitabine hydrochloride IV over 30 minutes on days 1, 8, and 15 (beginning in course 2). Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Treatment (vismodegib, gemcitabine hydrochloride)	Gemcitabine Hydrochloride	Patients receive vismodegib PO QD on days 1-28 and gemcitabine hydrochloride IV over 30 minutes on days 1, 8, and 15 (beginning in course 2). Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Primary Outcome Measures

Name	Time	Method
Median Percent at Baseline and 3 Weeks in CD44+/ CD24+/ ESA+ Cells From Needle Biopsy Calculated Using FACS	3 weeks	The median percentage of CD44+CD24+ESA+ cells from needle biopsy were calculated at baseline and at 3 weeks using FACS. The difference between the two time points was calculated.

Secondary Outcome Measures

Name	Time	Method
The Number of Participants With an Objective Best Response (CR + PR)	Up to 4 weeks	The number of participants with either a complete response (CR) or a partial response (PR) will be calculated. A CR is defined as the disappearance of all target lesions. A PR is defined as at least a 30% decrease in the sum of the diameters of target lesions.
Median Progression Free Survival	Up to 24 months	Median progression free survival was calculated for all treated patients. Assessed using the Kaplan-Meier method. The 95% confidence interval for this estimate will be computed using the Greenwood's formula.
Percentage of Treated Patients Experiencing Grade 3+ Toxicity Per National Cancer Institute Common Toxicity Criteria (CTC) Version 3.0	Up to 4 weeks