Clinical trial NCT01088815: Hedgehog Inhibitors for Metastatic Adenocarcinoma of the Pancreas
Official title: A Phase II Study of Gemcitabine and Nab-Paclitaxel in Combination With GDC-0449 (Hedgehog Inhibitor) in Patients With Previously Untreated Metastatic Adenocarcinoma of the Pancreas
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Metastatic Pancreatic Cancer
Keywords: Adenocarcinoma
Hedgehog
Neoplasms
Digestive System Diseases
Neoplasms by Site
Digestive System Neoplasms
Neoplasms by Histologic Type
Pancreatic Neoplasms
Pancreatic Diseases
Carcinoma
Lead sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Sponsor class: OTHER
Collaborators: name: Stand Up To Cancer
name: Genentech, Inc.
name: Celgene Corporation
First posted: 2010-03-17
Enrollment: 98
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: This is an open-label, single arm, multi-center, Phase II trial to evaluate the progression free survival in patients with metastatic adenocarcinoma of the pancreas treated with a hedgehog inhibitor (GDC-0449) in combination with chemotherapy (gemcitabine and nab-Paclitaxel).

Detailed description: The emergence of new small molecules with capacity of blocking the Hedgehog signaling pathway provides a novel therapeutic approach in pancreatic adenocarcinoma treating the primary tumor, stroma, systemic metastases and pancreatic cancer stem cells by hedgehog pathway inhibition. This phase 2 clinical trial will evaluate the progression free survival (PFS) in patients with previously untreated metastatic pancreatic adenocarcinoma. We hypothesize that the combination of cytotoxic agents (gemcitabine and nab-paclitaxel) with the Hedgehog inhibitor GDC-0449 may increase PFS.

This study includes correlative studies to attempt to understand the stem cell biology and mechanism for any observed clinical benefits with the use of Hedgehog inhibitor GDC-0449. These include changes in the hedgehog pathway and changes in pancreatic cancer stem cell markers with pre and post treatment biopsies. The safety of GDC-0449 when combined with chemotherapy gemcitabine and nab-paclitaxel will also be assessed by evaluating adverse event rate.

Following the determination of eligibility patients will receive the following treatment:

1. One cycle of Gemcitabine 1000 mg/m2 and nab-Paclitaxel 125 mg/m2 on days 1, 8, and 15 (28 days cycle) then
2. Gemcitabine 1000 mg/m2 and nab-Paclitaxel 125 mg/m2 on days 1, 8, and 15 every 28 days cycle in combination with oral GDC-0449 150 mg daily

Patients may continue on treatment regimen until they experience progressive disease or unacceptable toxicity, require palliative radiotherapy, withdraw consent or the physician feels it is not longer in their best interest to continue on treatment.

Eligibility criteria: Inclusion Criteria:

1. Patient has histologically or cytologically confirmed metastatic adenocarcinoma of the pancreas. Patients with islet cells tumors are excluded. Biopsy within 14 days of starting treatment.
2. Patient has 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 CT scan.
3. Patient has NOT received previous radiotherapy, surgery or chemotherapy or investigational drug therapy for the treatment of metastatic disease. If the patient received radiotherapy, chemotherapy or investigational therapy in the adjuvant setting it should be completed 3 weeks prior to enrollment. If a patient received gemcitabine in the adjuvant setting, tumor recurrence must have occurred at least six months after completing the last dose of gemcitabine
4. Age \>18 years.
5. Life expectancy of greater than 1 month.
6. ECOG performance status 0 or 1 (Karnofsky \>70%).
7. Patients must have adequate organ and marrow function

Exclusion Criteria:

1. Patient had received chemotherapy or radiotherapy for metastatic disease
2. Patient is receiving other investigational agents.
3. Patient has known brain metastases, unless previously treated and well controlled for at least three months (defined as clinically stable, no edema, no steroids and stable in 2 scans at least 4 weeks apart)
4. History of allergic reactions attributed to compounds of similar chemical or biologic composition to GDC-0449 or other agents used in the study.
5. Patients taking medications with narrow therapeutic indices that are metabolized by cytochrome P450 (CYP450), including warfarin sodium (Coumadin®) are ineligible.
6. Uncontrolled illness including, but not limited to, ongoing or active infection requiring IV antibiotics, symptomatic congestive heart failure not controlled with medication, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
7. Pregnant women are excluded
8. Patient has undergone a major surgery, other than diagnostic surgery (i.e. surgery done to obtain a biopsy for diagnosis without removal of an organ) within four weeks prior to Day 1 of treatment on this study.
9. History of other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates use of an investigational drug or that might affect interpretation of the results of the study or render the patient at high risk from treatment complications

Primary outcomes:
measure: Progression Free Survival With the Combination of GDC-0449 With Gemcitabine and Nab-paclitaxel.
timeFrame: 6 years
measure: Safety of Combination Therapy in Patients With Metastatic Adenocarcinoma of the Pancreas as Assessed by Number of Grade 3 or 4 Adverse Events
timeFrame: 6 years
Secondary outcomes:
measure: Efficacy of Combination of GDC-0449 With Gemcitabine and Nab-Paclitaxel as Assessed by Overall Survival
timeFrame: 6 years
measure: Efficacy of Combination of GDC-0449 With Gemcitabine and Nab-Paclitaxel as Assessed by Tumor Response
timeFrame: 6 years
measure: Efficacy of Combination of GDC-0449 With Gemcitabine and Nab-Paclitaxel as Assessed by Changes in Pancreatic Cancer Stem Cell
timeFrame: 6 years
measure: Efficacy of Combination of GDC-0449 With Gemcitabine and Nab-Paclitaxel as Assessed by Hedgehog Signaling Pathway Downregulation
timeFrame: 6 years
Other outcomes:
Locations:
city: Scottsdale
country: United States
facility: Translational Genomics Research Institute (TGen)
state: Arizona
city: Baltimore
country: United States
facility: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
state: Maryland
city: Philadelphia
country: United States
facility: University of Pennsylvania
state: Pennsylvania
Study officials:
affiliation: Sidney Kimmel Comprehensive Cancer Center JHMI
name: Daniel Laheru, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
name: Ana De Jesus-Acosta, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: De Jesus-Acosta A, Sugar EA, O'Dwyer PJ, Ramanathan RK, Von Hoff DD, Rasheed Z, Zheng L, Begum A, Anders R, Maitra A, McAllister F, Rajeshkumar NV, Yabuuchi S, de Wilde RF, Batukbhai B, Sahin I, Laheru DA. Phase 2 study of vismodegib, a hedgehog inhibitor, combined with gemcitabine and nab-paclitaxel in patients with untreated metastatic pancreatic adenocarcinoma. Br J Cancer. 2020 Feb;122(4):498-505. doi: 10.1038/s41416-019-0683-3. Epub 2019 Dec 20.