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

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Brief Title

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

Official Title

Phase I/II Study of LDE225 in Combination With Gemcitabine and Nab-paclitaxel in Patients With Locally Advanced or Metastasized Pancreatic Cancer

Brief 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.
    

Detailed Description

      Growing body of evidence suggests that the stroma is not only a mechanical barrier that may
      prevent efficient delivery of various anticancer therapies to the tumor, but also constitutes
      a dynamic compartment of pancreatic tumors that is critically involved in tumor formation,
      progression and metastasis. Thus, targeting both tumor stroma and cancer cells could be a
      lucrative strategy to increase the efficacy of our therapeutic approach.

      In the present study we want to explore the safety and activity of the chemotherapy
      combination: Gemcitabine + nab-paclitaxel + LDE225. LDE225 is a hedgehog inhibitor with
      promising antitumor activity in several cancer models, including pancreatic cancer. One of
      the main activities is also the degradation of the tumor matrix.

      Patients with locally advanced or metastatic pancreatic cancer will be treated with fixed
      doses of gemcitabine + nab-paclitaxel, the same doses used in the recently presented phase
      III study (von Hoff American Society of Clinical Oncology ASCO 2013). In the phase I part of
      the study LDE225 will be added according to standard dose escalation strategy for phase I
      studies, and at the maximum tolerated dose (MTD) patients will be treated in the phase II
      part of the study.
    

Study Phase

Phase 1/Phase 2

Study Type

Interventional


Primary Outcome

Dose limiting Toxicity (DLT) and MTD of LDE225 co-administered with gemcitabine and nab-paclitaxel

Secondary Outcome

 Median survival

Condition

Pancreatic Cancer

Intervention

gemcitabine and nab paclitaxel

Study Arms / Comparison Groups

 LDE225
Description:  DLT adn MTD of LED225 co-administered with fixed doses of gemcitabine and nab-paclitaxel in patients with advanced or metastasized pancreatic cancer.

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

78

Start Date

September 2015

Completion Date

January 2019

Primary Completion Date

September 2018

Eligibility 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
      

Gender

All

Ages

18 Years - N/A

Accepts Healthy Volunteers

No

Contacts

J. W. Wilmink, MD, PhD, , 

Location Countries

Netherlands

Location Countries

Netherlands

Administrative Informations


NCT ID

NCT02358161

Organization ID

AMCMEDONC 2013-215

Secondary IDs

2013-002370-51

Responsible Party

Principal Investigator

Study Sponsor

Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)

Collaborators

 Novartis

Study Sponsor

J. W. Wilmink, MD, PhD, Principal Investigator, Academic Medical Center, Medical Oncology


Verification Date

January 2020