A Pre-surgical Study of LDE225 in Men With High-risk Localized Prostate Cancer
Condition: Prostate Cancer
MeSH terms: Prostatic Neoplasms
Intervention: LDE225
Intervention description: Sonidegib was given as an oral drug at 800mg daily for 28 days prior to prostetoctomy
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 14.0
Sex: Male
Minimum age: 18 Years
Maximum age: 100 Years
Healthy volunteers: No
Keywords: LDE225; High risk localized prostate cancer; Pre-surgical

Summary:

      This trial is designed as a randomized two-arm (LDE225 vs. observation groups) open-label
      prospective clinical trial in men with localized high-risk prostate cancer undergoing radical
      prostatectomy.

      The investigators propose to determine the effects of LDE225 on neoplastic prostate tissue
      from men at high risk of systemic disease progression, by comparing pre-surgical core-biopsy
      specimens to tumor tissue harvested at the time of prostatectomy.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Provide written informed consent prior to any screening procedures.

          2. Age 18 years or older.

          3. Histologically-documented prostatic adenocarcinoma in ≥2 cores

          4. ECOG performance status ≤2

          5. Localized prostate cancer with at least one of the following NCCN high-risk features:

               -  Gleason sum ≥8

               -  PSA >20 ng/mL

               -  Clinical stage ≥T3

          6. Must be a candidate for radical prostatectomy

          7. No evidence of known metastatic disease (M0 or Mx allowed)

          8. Adequate bone marrow, liver and renal function as specified below:

               -  Absolute neutrophil count (ANC) ≥ 1500/µL

               -  Hemoglobin (Hgb) ≥ 9.0 g/dL

               -  Platelets ≥100,000/µL

               -  Serum total bilirubin ≤ 1.5 x ULN (upper limit of normal)

               -  AST and ALT ≤ 2.5 x ULN

               -  Plasma creatine phosphokinase (CK) < 1.5 x ULN, if known

               -  Serum creatinine ≤ 1.5 x ULN [or 24-hour creatinine clearance ≥ 50ml/min]

          9. Patient is able to swallow and retain oral medications

        Exclusion Criteria:

          1. Patients who have had major surgery within 4 weeks of enrollment.

          2. Patients with concurrent uncontrolled medical conditions that may interfere with their
             participation in the study.

          3. Patients unable to take oral drugs (e.g. lack of physical integrity of the upper GI
             tract or known malabsorption syndromes).

          4. Patients who have previously been treated with LDE225 or other Hh pathway inhibitors

          5. Patients who have neuromuscular or muscular disorders (e.g. inflammatory myopathies,
             muscular dystrophy, amyotrophic lateral sclerosis and spinal muscular atrophy) or are
             on concomitant treatment with drugs that are known to cause rhabdomyolysis (such as
             statins and fibrates), and that cannot be discontinued at least 2 weeks prior to
             starting LDE225. If it is essential that the patient stays on a statin for
             hyperlipidemia, only pravastatin may be used with extra caution. Patients should not
             plan to embark 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).

          6. Patients who have taken part in an experimental drug study within 4 weeks or 5
             half-lives (whichever is longer) of initiating treatment with LDE225.

          7. Patients who are receiving other anti-neoplastic therapy (e.g. chemotherapy, targeted
             therapy or radiotherapy) concurrently or within 2 weeks of starting LDE225.

          8. Patients taking moderate/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 for at least 7 days and strong CYP3A/5
             inducers for at least 2 weeks prior to starting treatment with LDE225.

          9. No concurrent use of statins (except for pravastatin, if absolutely necessary)

         10. No concurrent warfarin or Coumadin-derivatives

         11. Impaired cardiac function or significant heart disease, including any one of the
             following:

               -  Angina pectoris within 3 months

               -  Acute myocardial infarction within 3 months

               -  QTc >450 msec 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. heart failure,
                  uncontrolled/labile hypertension, or history of poor compliance with an
                  antihypertensive regimen)

         12. Patients who are not willing to apply highly effective contraception during the study
             and through the duration of LDE225 treatment.

               -  Male patients must use highly effective (double barrier) methods of contraception
                  (e.g., spermicidal gel plus condom) for the entire duration of the study, and
                  continuing using contraception and refrain from fathering a child for 6 months
                  following the last dose of the study drug. A condom is also required to be used
                  by vasectomized men as well as during intercourse with a male partner in order to
                  prevent delivery of the study treatment via seminal fluid. Sexually active males
                  must be willing to use a condom during intercourse while taking the study drug
                  and for 6 months after stopping investigational medications and agree not to
                  father a child during this period.

         13. Patients unwilling or unable to comply with the research protocol.