Gemcitabine Hydrochloride With or Without Vismodegib in Treating Patients With Recurrent or Metastatic Pancreatic Cancer

Phase 2

Completed

Conditions: Pancreatic Adenocarcinoma
Recurrent Pancreatic Carcinoma
Stage IV Pancreatic Cancer AJCC v6 and v7

Interventions: Drug: Gemcitabine Hydrochloride
Other: Hydrocortisone/Placebo
Drug: Vismodegib

Registration Number: NCT01064622

Lead Sponsor: National Cancer Institute (NCI)

Brief Summary: This randomized phase I/II trial studies gemcitabine hydrochloride and vismodegib to see how well they work compared with gemcitabine hydrochloride alone in treating patients with recurrent or metastatic pancreatic cancer. Drugs used in chemotherapy, such as gemcitabine hydrochloride, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Vismodegib may slow the growth of tumor cells. It is not yet known whether giving gemcitabine hydrochloride together with vismodegib is more effective than gemcitabine hydrochloride alone in treating patients with pancreatic cancer.

Detailed Description: PRIMARY OBJECTIVES:

l. To compare the progression-free survival of advanced pancreatic cancer patients treated with the combination of gemcitabine plus GDC-0449 (vismodegib) versus gemcitabine plus placebo.

SECONDARY OBJECTIVES:

I. To compare overall survival of advanced pancreatic cancer patients treated with the combination of gemcitabine plus GDC-0449 versus gemcitabine plus placebo.

II. To compare the objective response rate of advanced pancreatic cancer patients treated with the combination of gemcitabine plus GDC-0449 versus gemcitabine alone.

III. To determine the toxicity experienced by pancreatic cancer patients treated with the combination of gemcitabine plus GDC-0449.

IV. To determine the activity, in an exploratory analysis, of gemcitabine plus GDC-0449 in patients who progress on gemcitabine plus placebo.

TERTIARY OBJECTIVES:

I. To determine if tumor immunohistochemical expression patterns of proteins in the Hh pathway, including sonic hedgehog (Shh), indian hedgehog (Ihh), patched tumor suppressor gene (PTCH), smoothened protein (SMO), and GLI1 and 2, within pancreatic tissue obtained at the time of curative intent surgery predict response and prognosticate outcome of patients treated with or without GDC-0449 at the time of relapse.

II. To determine the prognostic ability (relapse free survival, \[RFS\]) of these biologic markers for resected patients in an archival cohort of patients undergoing resection.

III. To determine expression pattern of pancreatic CSC markers, including CD44, CD24, CD133, aldehyde dehydrogenase (ALDH) and epithelial specific antigen (ESA) by immunohistochemistry (IHC) on these archival tissues in relation to Hh pathway markers and correlate these with clinical outcomes.

IV. To determine whether high baseline serum Shh, as well as changes in serum Shh during treatment, predict treatment efficacy and/or prognosticate clinical outcome.

V. To determine the frequency of mutation of Hh pathway genes, PTCH, SMO, SuFU, and if the presence or absence of mutations are correlated with clinical outcome.

VI. To determine the frequency of amplification of Hh pathway genes, gene copy number by quantitative polymerase chain reaction (qPCR) of GLI1 and SMO in those tumors that have high protein expression as seen by IHC. Gene amplification will be correlated with clinical outcome.

VII. To determine if there is a correlation of K-ras mutation, and MET and RON expression, amplification, or mutation status with Hh pathway abnormalities, CSC markers, and clinical outcomes.

VIII. To determine if baseline contrast perfusion imaging volume transfer constant (Ktrans) within primary and liver metastatic lesions as measured on a 256-detector computed tomography (CT) scanner predicts objective response rates, and other clinical endpoints including progression-free survival (PFS), to treatment with gemcitabine and GDC-0449/placebo. (University of Chicago ONLY) IX. To determine if treatment with Gemcitabine and GDC-0449 improves tumor perfusion, as measured by Ktrans, over the course of treatment by serial CT scans every 2 cycles, compared to tumors treated with Gemcitabine and placebo. (University of Chicago ONLY) X. To determine if improved tumor perfusion with GDC-0449 treatment (if observed) improves objective response rates and other clinical endpoints including PFS. (University of Chicago ONLY)

OUTLINE: This is a multicenter, safety lead-in study (part I) followed by a randomized study (part II).

An initial 6 patients are enrolled in the part I portion of the study. If no dose-limiting toxicities occur in these patients, subsequent patients are enrolled in the part II portion of the study.

PART I (safety lead-in study): Patients receive gemcitabine hydrochloride intravenously (IV) over 30 minutes on days 1, 8, and 15 and hedgehog antagonist GDC-0449 orally (PO) once daily (QD) on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

PART II (randomized study): Patients are stratified according to disease status (recurrent after surgery vs metastatic) and Eastern Cooperative Oncology Group (ECOG) performance status (0 vs 1). Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive gemcitabine hydrochloride 1000 mg/m\^2 IV over 30 minutes on days 1, 8, and 15 and placebo PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. At the time of disease progression, patients are unblinded and may crossover to arm II.

ARM II: Patients receive gemcitabine hydrochloride 1000 mg/m\^2 IV over 30 minutes on days 1, 8, and 15 and hedgehog antagonist GDC-0449 PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Tumor tissue, blood, serum, and plasma samples are collected periodically for biomarker and other analyses.

After completion of study treatment, patients are followed periodically.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 118

Inclusion Criteria

Patients must have histologically or cytologically confirmed adenocarcinoma of the pancreas
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
Patients must have either:
- Newly diagnosed chemo-naïve metastatic pancreatic cancer; only patients who have not received any chemotherapy for their metastatic disease are eligible
- Recurrent disease after curative-intent surgery which has now recurred and is metastatic; patients who have recurrent disease may have received adjuvant chemotherapy or adjuvant chemoradiation, but may not have received any chemotherapy for metastatic disease; adjuvant therapy must have been completed >= 6 months prior to the diagnosis of recurrent disease, or if not adjuvant therapy received, surgery must have been performed >= 6 months prior to the diagnosis of recurrent disease
Age >= 21 years
Life expectancy > 3 months
Karnofsky performance status >= 80%
Granulocytes >= 1,500/mcL
Platelet count >= 100,000/mcL
Total bilirubin =< 1.5 times upper limit of normal (ULN)
Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 2.5 times upper limit of normal (ULN) (=< 5 times ULN in the presence of liver metastases)
Creatinine within normal institutional limit (< 1.5) OR creatinine clearance >= 65 mL/min/1.73 m^2 for patients with creatinine levels above institutional normal
International normalized ratio (INR) =< 1.5 (=< 3 for patients on warfarin)
Patients who are on warfarin anticoagulation are allowed to participate as long as they fit the following 4 criteria:
- They are therapeutic on a stable warfarin dose
- Their INR target range is no greater than 3
- They are monitored with weekly INR testing
- They have no active bleeding or pathological condition that carries high risk of bleeding Other anticoagulants, including enoxaparin (Lovenox) and fondaparinux (Arixtra) are also permitted
Women of child-bearing potential and men must use at least one form of contraception (i.e., barrier contraception) at least 4 weeks prior to study entry and then two forms of contraception (i.e barrier contraception and one other method of contraception), 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: 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 (at initial screening/consideration for the trial - 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
Ability to understand and the willingness to sign a written informed consent document
Patients with recurrent disease after curative-intent surgical resection must have sufficient archival material for correlative studies (20 unstained 5 micron slides and 20 unstained 10 micron slides, or an archival tissue block

Exclusion Criteria

No prior chemotherapy for metastatic pancreatic cancer; patients who have received any chemotherapy and/or radiation therapy in the adjuvant setting must have completed this therapy ≥6 months prior to enrollment on the trial at the time of recurrence
Patients may not be receiving (or received prior to enrollment) any other investigational agents for metastatic disease
Patients with known brain metastases should be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events
History of allergic reactions attributed to compounds of similar chemical or biologic composition to hedgehog antagonist GDC-0449 or any other agents used in this study
History of allergic reactions attributed to compounds of similar chemical or biologic composition to GDC-0449 or other agents used in the study
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
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 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
No currently active second malignancy other than non-melanoma skin cancer or carcinoma in-situ of the cervix; patients are not considered to have a "currently active" malignancy if they have completed therapy and have no evidence of recurrence for at least 5 years
Uncontrolled intercurrent illness including, but not limited to,
- Ongoing or active infection,
- Symptomatic congestive heart failure
- Unstable angina pectoris
- Cardiac arrhythmia
- Psychiatric illness or social situation 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; 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: PARALLEL

Arm && Interventions

Group	Intervention	Description
Arm I (gemcitabine hydrochloride and placebo)	Gemcitabine Hydrochloride	Patients receive gemcitabine hydrochloride IV over 30 minutes on days 1, 8, and 15 and placebo PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. At the time of disease progression, patients are unblinded and may crossover to arm II.
Arm I (gemcitabine hydrochloride and placebo)	Hydrocortisone/Placebo	Patients receive gemcitabine hydrochloride IV over 30 minutes on days 1, 8, and 15 and placebo PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. At the time of disease progression, patients are unblinded and may crossover to arm II.
Arm II (gemcitabine hydrochloride and vismodegib)	Gemcitabine Hydrochloride	Patients receive gemcitabine hydrochloride IV over 30 minutes on days 1, 8, and 15 and vismodegib PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Arm II (gemcitabine hydrochloride and vismodegib)	Vismodegib	Patients receive gemcitabine hydrochloride IV over 30 minutes on days 1, 8, and 15 and vismodegib PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Primary Outcome Measures

Name	Time	Method
Progression-free Survival	Up to 3 years	Time from randomization to disease progression or death from any cause. Estimated in the two treatment groups by the Kaplan-Meier method and compared using a stratified logrank test.

Secondary Outcome Measures

Name	Time	Method
Overall Survival	Up to 3 years	Time from randomization to death from any cause. Estimated in the two treatment groups by the Kaplan-Meier method and compared using a stratified logrank test.
Objective Response Rate	Up to 6 months	Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by CT or 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.
Incidence of Adverse Events	Up to 3 years	Details are provided in Adverse Events section below. Reported here are percentage of patients in each arm with any grade 1 or higher adverse event, regardless of attribution.
Activity (Overall Response Rate) in Crossover Patients	Up to 6 months	RECIST response rate in patients after crossover from placebo to vismodegib arm. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by CT or 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.

Trial Locations

Locations (25): City of Hope Comprehensive Cancer Center
🇺🇸
Duarte, California, United States
USC / Norris Comprehensive Cancer Center
🇺🇸
Los Angeles, California, United States
University of California Davis Comprehensive Cancer Center
🇺🇸
Sacramento, California, United States
City of Hope South Pasadena
🇺🇸
South Pasadena, California, United States
University of Chicago Comprehensive Cancer Center
🇺🇸
Chicago, Illinois, United States
Southern Illinois University School of Medicine
🇺🇸
Springfield, Illinois, United States
UM Saint Joseph Medical Center
🇺🇸
Towson, Maryland, United States
University of Michigan Comprehensive Cancer Center
🇺🇸
Ann Arbor, Michigan, United States
Mercy Hospital Saint Louis
🇺🇸
Saint Louis, Missouri, United States
Montefiore Medical Center-Einstein Campus
🇺🇸
Bronx, New York, United States
Montefiore Medical Center - Moses Campus
🇺🇸
Bronx, New York, United States
Laura and Isaac Perlmutter Cancer Center at NYU Langone
🇺🇸
New York, New York, United States
NYP/Weill Cornell Medical Center
🇺🇸
New York, New York, United States
University of Pittsburgh Cancer Institute (UPCI)
🇺🇸
Pittsburgh, Pennsylvania, United States
Tower Cancer Research Foundation
🇺🇸
Beverly Hills, California, United States
Decatur Memorial Hospital
🇺🇸
Decatur, Illinois, United States
NorthShore University HealthSystem-Evanston Hospital
🇺🇸
Evanston, Illinois, United States
Ingalls Memorial Hospital
🇺🇸
Harvey, Illinois, United States
Loyola University Medical Center
🇺🇸
Maywood, Illinois, United States
Illinois CancerCare-Peoria
🇺🇸
Peoria, Illinois, United States
Central Illinois Hematology Oncology Center
🇺🇸
Springfield, Illinois, United States
Fort Wayne Medical Oncology and Hematology Inc-Parkview
🇺🇸
Fort Wayne, Indiana, United States
University of Maryland/Greenebaum Cancer Center
🇺🇸
Baltimore, Maryland, United States
Penn State Milton S Hershey Medical Center
🇺🇸
Hershey, Pennsylvania, United States
Medical College of Wisconsin
🇺🇸
Milwaukee, Wisconsin, United States