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A Pilot Study of a Hedgehog Pathway Inhibitor (LDE-225) in Surgically Resectable Pancreas Cancer

Phase 0
18 Years
Open (Enrolling)
Resectable Pancreatic Cancer

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Trial Information

A Pilot Study of a Hedgehog Pathway Inhibitor (LDE-225) in Surgically Resectable Pancreas Cancer

Primary Objective(s) The primary objective of this study is to determine if a key biological
relationship between autocrine and paracrine Hedgehog signaling exists in human pancreas
cancer as suggested by mouse models of pancreas cancer

Secondary Objective(s)

- To verify that tumor tissue levels are sufficient for pharmacologic activity using a
dose of 800 mg/day.

- To determine if inhibition of Hedgehog signaling by LDE-225 in the tumor stroma results
in modulation of the stroma to increase tumor angiogenesis and decrease stromal
collagen deposition.

- To determine the safety of LDE-225 administered preoperatively relative to
post-operative complications from pancreatic surgery

- Primary Hypothesis/hypotheses:

We hypothesize that administration of LDE-225 in humans with pancreatic cancer will result
in inhibition of paracrine HH signaling in the pancreatic tumor stroma while having no
effect on autocrine signaling in the tumor cell compartment. Furthermore we hypothesize
that treatment with LDE-225 will result in changes in the tumor stroma (decreased
desmoplasia, increased vascularity) that will result in improved tumor blood flow.

Primary Endpoint(s) The primary and secondary endpoints are surgery as this is time that the
patients blood and tumor will be removed for analysis following 14 days of treatment

The secondary endpoint for secondary objective will be any complications from surgery by
time of hospital discharge up to 30 days post-operatively.

Inclusion Criteria:

- Patients with biopsy probable, resectable pancreatic cancer. Patients will be
expected to undergo surgery a minimum of 14 days following signing consent.

- Patients must give informed consent.

- Patients must be over 18 and have an ECOG performance status ≤2 and life expectancy >
3 months.

- Patients must have normal organ and marrow function as defined below:

- ANC ≥1,500 /µL

- Platelets ≥100,000 /µL

- Hemoglobin>10gm/dl

- creatinine <1.5 X ULN

- Plasma creatine phosphokinase (CK) < 1.5 x ULN


- Patients may have abnormal bilirubin, which is concluded by the surgeon to be
related to biliary ductal obstruction, may be included if bilirubin < 3 X ULN.

- Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) < 2.5 x
upper limit of normal (ULN).

Exclusion Criteria

- Poor surgical risk due to comorbidities or poor performance status

- Patients who have received prior treatment with a smoothened antagonist, (GDC-0449
(Genentech), IPI-926 (Infinity).

- Patients who have received chemotherapy within a period of time that is < the cycle
length used for that treatment (e.g. <6 weeks for nitrosoureas, mitomycin-C) prior to
starting study drug or who have not recovered from the side effects of such therapy

- Patients who have received wide field radiotherapy (including therapeutic
radioisotopes such as strontium 89) ≤ 4 weeks or limited field radiation for
palliation ≤ 2 weeks prior to starting study drug or who have not recovered from side
effects of such therapy.

- Patients who have received biologic therapy (e.g. antibodies) ≤ 4 weeks prior to
starting study drug or who have not recovered from the side effects of such therapy

- Patients who have been treated with a targeted agent ≤ 5 t1/2 or ≤ 4 weeks (whichever
is shorter) prior to starting study drug or who have not recovered from the side
effects of such therapy

- Patients who have received any other investigational agents ≤ 5 t1/2 or ≤ 4 weeks
(whichever is shorter) prior to starting study drug or who have not recovered from
the side effects of such therapy

- Poor oral intake and/or inability to take capsules

- Impairment of gastrointestinal function or gastrointestinal disease such as Chron's
Disease or Ulcerative Cholitis, short-gut syndrome, celiac sprue disease that may
significantly alter the absorption of LDE225

- Urgent/emergent need for surgery (< 7 days)

- Documented cirrhotic liver disease, ongoing alcohol abuse, or known active or acute

- Impaired cardiac function or clinically significant heart disease, including any one
of the following:

- Angina pectoris within 3 months

- Acute myocardial infarction within 3 months

- QTcF > 450 msec for males and > 470 msec for females on the screening ECG

- A past medical history of clinically significant ECG abnormalities or a family
history of prolonged QT-interval syndrome

- Other clinically significant heart disease (e.g. congestive heart failure,
uncontrolled hypertension, history of labile hypertension, or history of poor
compliance with an antihypertensive regimen)

- Patients who have had a venous thromboembolic event (e.g., pulmonary embolism or deep
vein thrombosis) requiring anticoagulation

- Presence of active infection or systemic use of antibiotics within 72 hours of

- Significant co-morbid condition or disease which in the judgment of the Investigator
would place the patient at undue risk or interfere with the study. Examples include,
but are not limited to sepsis, recent significant cardiac or pulmonary disease, or
other conditions.

- Known human immunodeficiency virus (HIV) positivity

- Known hypersensitivity to LDE-225, or any of the excipients in LDE-225

- Pregnant or lactating women.

- Patients who are receiving treatment with medications known to be moderate and strong
inhibitors or inducers of CYP3A4/5 or drugs metabolized by CYP2B6 or CYP2C9 that have
narrow therapeutic index, and that cannot be discontinued before starting treatment
with LDE225. Medications that are strong CYP3A4/5 inhibitors should be discontinued
at least 7 days and strong CYP3A/5 inducers for at least 2 weeks prior to starting
treatment with LDE225.

- Patients who have neuromuscular disorders (e.g. inflammatory myopathies, muscular
dystrophy, amyotrophic lateral sclerosis and spinal muscular atrophy) or are on
concomitant treatment with drugs that are recognized to cause rhabdomyolysis, such as
HMG CoA inhibitors (statins), clofibrate and gemfibrozil, and that cannot be
discontinued at least 2 weeks prior to starting LDE225 treatment. If it is essential
that the patient stays on a statin to control hyperlididemia, only pravastatin may be
used with extra caution.

b) Patients who are planning on embarking on a new strenuous exercise regimen after
initiation of study treatment. NB: Muscular activities, such as strenuous exercise,
that can result in significant increases in plasma CK levels should be avoided whilst
on LDE225 treatment.

- Women of child-bearing potential, defined as all women physiologically capable of
becoming pregnant, unless they are using highly effective methods of contraception
during dosing and for 4 months after stopping study treatment. Highly effective
contraception methods include:

- Total abstinence or

- Male or female sterilization or

- Combination of any two of the following (a+b or a+c, or b+c):

1. Use of oral, injected or implanted hormonal methods of contraception

2. Placement of an intrauterine device (IUD) or intrauterine system (IUS)

3. Barrier methods of contraception: condom or occlusive cap (diaphragm or
cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal

- Women are considered post-menopausal and not of child bearing potential if they have
had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical
profile (e.g. age appropriate, history of vasomotor symptoms) or have had surgical
bilateral oophorectomy (with or without hysterectomy) or tubal ligation at least six
weeks ago. In the case of oophorectomy alone, only when the reproductive status of
the woman has been confirmed by follow up hormone level assessment is she considered
not of child bearing potential.

- Sexually active males must use a condom during intercourse while taking the drug and
for 6 months after stopping treatment and should not father a child in this period. A
condom is required to be used also by vasectomized men in order to prevent delivery
of the drug via seminal fluid.

- Patients unwilling or unable to comply with the protocol.

Step Two Adequate Fine Needle Biopsy

Type of Study:


Study Design:

Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Principal Investigator

Darren Carpizo, MD, PhD

Investigator Role:

Principal Investigator

Investigator Affiliation:

University of Medicine and Dentistry New Jersey


United States: Food and Drug Administration

Study ID:




Start Date:

September 2012

Completion Date:

October 2014

Related Keywords:

  • Resectable Pancreatic Cancer
  • pancreas canacer
  • pancreatic cancer
  • Pancreatic Neoplasms



Cancer Institute of New Jersey New Brunswick, New Jersey  08901