LDE225 in Treating Patients With Stage II-III Estrogen Receptor- and HER2-Negative Breast Cancer
LDE225 in Treating Patients With Stage II-III Estrogen Receptor- and HER2-Negative Breast Cancer
This randomized phase II trial studies the effects of erismodegib (LDE225) on disseminated
 tumor cells (DTCs) in patients with stage III-III estrogen receptor (ER)-negative and human
 epidermal growth factor receptor 2 (HER2)-negative breast cancer. The presence of DTCs after
 completing treatment for breast cancer may be linked to recurrence of the disease. LDE225 may
 eliminate DTCs in bone marrow and reduce the risk of recurrence.
Pre-Registration Inclusion Criteria

 -  Diagnosis of pathologic stage II or III ER, PR, and HER2 negative primary invasive
 ductal or invasive lobular breast carcinoma. ER negative is defined as an Allred score
 of 0-2. PR negative is defined as an Allred score of 0-4. HER2 negative is defined as
 an IHC score of 0-1 and/or not-amplified by FISH testing.

 -  All surgery for breast cancer (as defined by surgical excision of the cancer with a
 negative margin or mastectomy) must be complete.

 -  Undergone axillary lymph node surgery (either sentinel lymph node biopsy or axillary
 lymph node dissection) per institutional standard.

 -  Completed all (neo) adjuvant chemotherapy and radiation therapy as recommended by the
 treating physicians.

 -  Completed the most recent cancer therapy (surgery, radiation, or chemotherapy) no less
 than 3 and no more than 24 weeks prior to registration. Note: patients who received
 experimental neoadjuvant or adjuvant therapy or surgical therapy (with the exception
 of Hh inhibitors) through participation in clinical trial are NOT excluded from this
 study as long as the other trial does not exclude patients from enrolling into an
 additional adjuvant clinical trial and enrolling into this trial will not compromise
 the endpoints (primary and secondary) of the primary clinical trial. In addition,
 patients must have completed the experimental therapy no less than 4 weeks or 5 half
 lives (whichever is longer) and no more than 24 weeks prior to registration. For those
 patients who have enrolled into a neoadjuvant / adjuvant / surgical trial, all
 endpoints of these trials will be reviewed prior to consenting the patient for the
 sonidegib trial.

 -  At least 18 years of age.

 -  ECOG performance status ≤ 1

 -  Patient (or legally authorized representative if applicable) must be able to
 understand and willing to sign an IRB approved written informed consent document.

 Pre-Registration Exclusion Criteria

 -  Concurrent treatment with any other standard therapy (e.g. chemotherapy, targeted
 therapy or radiotherapy) or within 3 weeks of starting sonidegib.

 -  Treatment with investigational anti-cancer agent within 4 weeks or 5 half-lives
 whichever is longer, of initializing treatments with sonidegib.

 -  Previous treatment with systemic sonidegib or with other Hh pathway inhibitors.

 -  Diagnosis of a neuromuscular disorder (e.g., inflammatory myopathies, muscular
 dystrophy, amyotrophic lateral sclerosis, spinal muscular atrophy) or 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 sonidegib treatment. If it is essential that the
 patient stays on a statin to control hyperlipidemia, only pravastatin may be used with
 extra caution.

 -  Known to be HIV-positive on combination antiretroviral therapy because of the
 potential for pharmacokinetic interactions with sonidegib. In addition, these patients
 are at increased risk of lethal infections when treated with marrow-suppressive
 therapy. Appropriate studies will be undertaken in patients receiving combination
 antiretroviral therapy when indicated.

 Registration Inclusion Criteria

 -  Presence of bone marrow DTCs after the completion of all intended breast cancer
 therapy including surgery, (neo) adjuvant chemotherapy therapy, and radiation as
 indicated. Note: Bone marrow aspiration will be performed in consented patients to
 evaluate DTCs provided patients meet all eligibility criteria as described in this
 section.

 -  ECOG performance status ≤ 1

 -  Normal bone marrow and organ function as defined below:

 -  Leukocytes ≥ 3,000/mcL

 -  Absolute neutrophil count ≥ 1,500/mcL

 -  Hemoglobin ≥ 9.0 g/dL

 -  Platelets ≥ 80,000/mcL

 -  Total bilirubin ≤ 1.5 x IULN

 -  AST(SGOT)/ALT(SGPT) ≤ 2.5 x IULN

 -  Plasma creatine phosphokinase (CK) < 1.5 x ULN

 -  Creatinine ≤ 1.5 x ULN OR Creatinine clearance ≥ 50 mL/min/1.73 m2 for patients
 with creatinine levels above institutional normal

 -  Able to swallow capsules.

 -  Women of childbearing potential must have a negative serum pregnancy test ≤ 7 days
 from date of registration. Women of childbearing potential must agree to use dual
 forms of adequate contraception (barrier method of birth control, non-hormonal IUD or
 IUS, abstinence) prior to study entry duration of study participation and 20 months
 after final dose of study treatment. Should a woman become pregnant or suspect she is
 pregnant while participating in this study, she must inform her treating physician
 immediately.

 Registration Exclusion Criteria

 -  Evidence of distant metastasis present by CT scan, bone scan, or physical exam within
 one year prior to entry into the trial.

 -  History of other malignancy ≤ 5 years previous with the exception of basal cell or
 squamous cell carcinoma of the skin which were treated with local resection only or
 carcinoma in situ of the cervix.

 -  History of allergic reactions attributed to compounds of similar chemical or biologic
 composition to sonidegib or other agents used in the study.

 -  Planning to embark on a new strenuous exercise regimen after initiation of study
 treatment. Muscular activities, such as strenuous exercise, that can result in
 significant increases in plasma CK levels should be avoided while on sonidegib
 treatment.

 -  Diagnosis of a medical condition that would lead to lack of physical integrity of the
 upper gastrointestinal tract or known malabsorption syndrome.

 -  Taking warfarin and Coumadin derivatives because of potential interactions with
 sonidegib.

 -  Receiving treatment with medications known to be moderate or strong inhibitors or
 inducers of CYP3A4/5 or drugs metabolized by CYP2B6 or CYP2C9 that have narrow
 therapeutic indices and that cannot be discontinued before starting treatment with
 sonidegib. Medications that are strong CYP3A4/5 inhibitors should be discontinued at
 least 7 days and strong CYP3A4/5 inducers at least 2 weeks prior to starting treatment
 with sonidegib.

 -  Concurrent uncontrolled medical conditions that may interfere with participation in
 the study or potentially affect the interpretation of the study data.

 -  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 medication 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)

 -  Pregnant and/or breastfeeding. Pregnant women are excluded from this study because
 sonidegib is an Hh inhibitor with the potential for teratogenic or abortifacient
 effects. Because there is an unknown but potential risk for adverse events in nursing
 infants secondary to treatment of the mother with sonidegib, breastfeeding should be
 discontinued if the mother is treated with sonidegib.