Overview

Phase I/II Study of LDE225 With Gemcitabine and Nab-paclitaxel in Patients With Pancreatic Cancer

Status:
Completed
Trial end date:
2019-01-01
Target enrollment:
0
Participant gender:
All
Summary
The 5 year survival of patients with locally advanced or metastatic pancreatic cancer is less than 5 %. Since the introduction of gemcitabine, further advances in therapy in the advanced/metastatic setting have been extremely slow. Numerous phase III studies have evaluated different gemcitabine-based regimens as first-line therapy, but in most cases, any observed benefits have been small and restricted to patients with a good performance status (PS). Recently two new chemotherapy combination schedules, FOLFIRINOX and Gemcitabine + nab-paclitaxel demonstrated a significant survival improvement compared to gemcitabine alone. Nab-paclitaxel is especially interesting because it is able to break-down the tumor matrix and increases the concentration of cytotoxic drugs in the tumor. Our study will explore the modification of the desmoplastic reaction seen in pancreatic cancer using two approaches, targeting tumor stroma by nab-paclitaxel and the hedgehog inhibitor LDE225 and targeting the tumor cells with gemcitabine and nab-paclitaxel.
Phase:
Phase 1/Phase 2
Accepts Healthy Volunteers?
No
Details
Lead Sponsor:
Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
Collaborators:
Celgene Corporation
Novartis
Treatments:
Albumin-Bound Paclitaxel
Gemcitabine
Paclitaxel
Criteria
Inclusion Criteria:

1. Patients must provide written informed consent according to International Conference
on Harmonisation of technical requirements for registration og pharmaceuticals for
human use (ICH)/Good cClinical Practice (GCP), and national/local regulations prior to
any screening procedures.

2. Male or female adult patients (> 18 years)

3. Patients with histologically/cytologically confirmed diagnosis of pancreatic ductal
adenocarcinoma.

4. a. Phase I: patients with non resectable or metastasized pancreatic ductal
adenocarcinoma.

b. Phase II: patients with non resectable or metastasized pancreatic ductal
adenocarcinoma not pre-treated with chemotherapy or radiotherapy, unless adjuvant
treatment with gemcitabine > 6 months prior to inclusion.

5. Measurable disease as assessed by RECIST 1.1 (Response Evaluation Criteria In Solid
Tumors) .

6. ECOG (Eastern Cooperative Oncology Group) (WHO) performance status 0-2

7. Patient has adequate bone marrow and organ function . Patient is able to swallow and
retain oral medication

9. Absence of any psychological, familial, sociological or geographical condition
potentially hampering compliance with the study protocol and follow-up schedule;

Exclusion Criteria:

1. History of hypersensitivity to LDE225, or to drugs of similar chemical classes.

2. Patient has received previous treatment with smoothened inhibitors.

3. Patients with known CNS (Central Nervous System) metastases or a primary CNS
malignancy.

4. Patients who have neuromuscular disorders or are on concomitant treatment with drugs
that are recognized to cause rhabdomyolysis, such as HMG CoA
(3-hydroxy-3-methyl-glutaryl Coenzyme A) inhibitors (statins), clofibrate and
gemfibrozil.

5. Patients who are planning on embarking on new physical activities, such as strenuous
exercise, that can result in significant increases in plasma CK (Creatine Kinase)
levels while on study treatment.

6. Patients who require the use of coumarin derivates cannot be enrolled as LDE225 is a
competitive inhibitors of CYP2C9 based on in-vitro data.

7. Patients with chronic use of corticosteroids

8. Patients who are not willing to avoid consumption of Seville oranges, grapefruit or
grapefruit juice grapefruit hybrids, pomelos and exotic citrus fruits during the
entire study and preferably 7 days before the first dose of study medications, due to
potential CYP3A4 interaction with the study medications.

9. Patients who are not willing to stop taking herbal medications at least 7 days prior
to the first dose of study treatment.

10. Patient is currently being treated with drugs known to be strong inhibitors or
inducers of CYP3A4/5, which cannot be discontinued or switched to a different
medication 7 days prior to starting study treatment and for the duration of the
study..

11. Current medical history of the following:

- History of or presence of clinically significant uncontrolled ventricular or
atrial tachyarrhythmia

- Clinically significant resting bradycardia (< 45 beats per minute) or any primary
of secondary heart block

- History of unstable angina pectoris

- Clinically significant cardio-vascular disease (e.g. congestive heart failure
NYHA Class III-IV (New York Heart Association), atherosclerosis, labile
hypertension or uncontrolled hypertension

12. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a
female after conception and until the termination of gestation, confirmed by a
positive HCG (Human Chorionic Gonadotropin) laboratory test

13. Patients who are not willing to apply highly effective contraception during the study
and through the duration as defined below after the final dose of study treatment.

14. Sexually active males who are unwilling to use a condom during intercourse while
taking drug and for 6 months after stopping investigational medications and agree not
to father a child in this period. Patients who in the investigators' opinion may be
unwilling, unable or unlikely to comply with requirements of the study protocol

15. Patient is currently receiving increasing or chronic treatment with corticosteroids
((≥ the anti-inflammatory potency of 4mg dexamethasone) or another immunosuppressive
agent.

16. Patient has been treated with any hematopoietic colony-stimulating growth factors
(e.g., G-CSF, GM-CSF) ≤ 2 weeks prior to starting study drug. Erythropoietin or
darbepoetin therapy, if initiated before enrollment, may be continued

17. Patient who has received targeted therapy or immunotherapy ≤ 3 weeks (6 weeks for
monoclonal antibodies) prior to starting study drug or who have not recovered to grade
1 or better from related side effects of such therapy

18. Patient has impairment of gastrointestinal (GI) function or GI disease that may
significantly alter the absorption of LDE225 (e.g., ulcerative colitis, uncontrolled
nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection)

19. Patient has any other concurrent severe and/or uncontrolled medical condition that
would, in the investigator's judgment contraindicate patient participation in the
clinical study.

20. HIV-positive patients on combination antiretroviral therapy.

21. Patients who in the investigators' opinion may be unwilling, unable or unlikely to
comply with requirements of the study protocol