LDE225 in Treating Patients With Stage II-III Estrogen Receptor- and HER2-Negative Breast Cancer

This study is not yet open for participant recruitment.
Verified July 2013 by Washington University School of Medicine
Information provided by (Responsible Party):
Washington University School of Medicine
ClinicalTrials.gov Identifier:
First received: December 20, 2012
Last updated: July 22, 2013
Last verified: July 2013

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.

Condition Intervention Phase
Breast Neoplasms
Drug: erismodegib
Drug: placebo
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Randomized Placebo-Controlled Phase II Trial Evaluating the Effect of Hedgehog Inhibitor LDE225 on Bone Marrow Disseminated Tumor Cells in Women With Early Stage Estrogen Receptor Negative and HER2 Negative Breast Cancer

Resource links provided by NLM:

Further study details as provided by Washington University School of Medicine:

Primary Outcome Measures:
  • Proportion of patients who are bone marrow DTC-negative after therapy [ Time Frame: at 6 months ] [ Designated as safety issue: No ]
    Comparing LDE225 to placebo using a stratified Cochran-Mantel-Haenszel test for difference of proportions

Secondary Outcome Measures:
  • Disease-free survival (DFS) [ Time Frame: 2 years from initiation of study treatment ] [ Designated as safety issue: No ]
    Defined as duration after surgery that the patient survives without signs or symptoms of cancer; analyzed using a stratified Cox proportional hazards model.

  • Overall Survival (OS) [ Time Frame: 2 years from initiation of study treatment ] [ Designated as safety issue: No ]
    Defined as time from date of diagnosis to death of any cause or to last follow-up; analyzed using a stratified Cox proportional hazards model.

  • Ptch1 expression after treatment with LDE225 or placebo [ Time Frame: At 6 months ] [ Designated as safety issue: No ]
    Stratified, repeated measures ANOVA will be used to compare Ptch1 expression in the two treatment arms

  • Incidence of toxicities associated with LDE225 or placebo treatment [ Time Frame: For 30 days following the last day of study treatment; up to 25 months ] [ Designated as safety issue: Yes ]
    Toxicities described and graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v4.0.

Estimated Enrollment: 68
Study Start Date: December 2013
Estimated Study Completion Date: December 2019
Estimated Primary Completion Date: December 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Arm I (erismodegib [LDE225])
Patients receive erismodegib PO daily
Drug: erismodegib
Given PO, treatment repeats every 28 days for up to 26 cycles in the absence of disease progression or unacceptable toxicity.
Other Name: Smoothened antagonist LDE225
Placebo Comparator: Arm II (placebo)
Patients receive placebo PO daily.
Drug: placebo
Given PO, treatment repeats every 28 days for up to 26 cycles in the absence of disease progression or unacceptable toxicity.
Other Name: PLCB


Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • Patient must have been diagnosed with pathologic stage II or III ER and HER2 negative primary invasive ductal or invasive lobular breast carcinoma, ER negative is defined as an Allred score of 0-2. HER2 negative is defined as an IHC score of 0-1 and/or not-amplified by FISH testing.
  • Patients must have completed all surgery for their breast cancer as defined by surgical excision of the cancer with a negative margin or mastectomy.
  • Patient must have had an axillary lymph node surgery (either sentinel lymph node biopsy or axillary lymph node dissection) per institutional standard.
  • Patient must have completed all (neo) adjuvant chemotherapy and radiation therapy as recommended by the treating physicians.
  • Patient must have completed the most recent cancer therapy (surgery, radiation, or chemotherapy) within 3 to 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 LDE225 trial will not compromise the endpoints (primary and secondary) of the primary clinical trial. . In addition, patients must have completed the experimental therapy within the 4 weeks or 5 half lives (whichever is longer), to 24 weeks period 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 LDE225 trial.

-Patient must have the 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.

  • Patient must be ≥ 18 years of age.
  • Patient must have an ECOG performance status ≤ 1.
  • Patient must have 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
  • Patient must be able to swallow capsules.

    11. 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 6 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.

  • Patient (or legally authorized representative if applicable) must be able to understand and willing to sign an IRB approved written informed consent document.
  • Women of all races and ethnic groups are eligible for this trial.

Exclusion Criteria:

  • Patient must not have evidence of distant metastasis present by CT scan, bone scan, or physical exam within one year prior to entry into the trial.
  • Patient must not have a concurrent treatment with any other standard therapy (e.g. chemotherapy, targeted therapy or radiotherapy) or within 3 weeks of starting LDE225.
  • Patients must not have taken part in an investigational anticancer agent within 4 weeks or 5 half-lives whichever is longer, of initializing treatments with LDE225.
  • Patient must not have a 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.
  • Patient must not have previously been treated with systemic LDE225 or with other Hh pathway inhibitors.
  • Patient must not have a neuromuscular disorder (e.g., inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis, spinal muscular atrophy) or be 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 hyperlipidemia, only pravastatin may be used with extra caution.
  • Patient must not have a history of allergic reactions attributed to compounds of similar chemical or biologic composition to LDE225 or other agents used in the study.
  • Patient must not be 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 LDE225 treatment.
  • Patients must be able to take oral drugs or without any medical condition that lead to lack of physical integrity of the upper gastrointestinal tract or known malabsorption syndromes.
  • Patient must not be talking warfarin and Coumadin derivatives because of potential interactions with LDE225.
  • Patient must not be 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 LDE225. 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 LDE225.
  • Patients must not have concurrent uncontrolled medical conditions that may interfere with their participation in the study or potentially affect the interpretation of the study data.
  • Patient must not have 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)
  • Patient must not be pregnant and/or breastfeeding. Pregnant women are excluded from this study because LDE225 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 LDE225, breastfeeding should be discontinued if the mother is treated with LDE225.
  • Patients must be willing to apply highly effective contraception during the study and through the duration as defined below after the final dose of study treatment
  • Patient must not be known to be HIV-positive on combination antiretroviral therapy because of the potential for pharmacokinetic interactions with LDE225. 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.
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT01757327

Contact: Cynthia Ma, M.D., Ph.D. 314-362-9383 cam@dom.wustl.edu
Contact: Rebecca Aft, M.D., Ph.D. 314-747-0063 aftr@wudosis.wustl.edu

United States, Missouri
Washington University School of Medicine Not yet recruiting
St. Louis, Missouri, United States, 63110
Contact: Cynthia Ma, M.D., Ph.D.         
Sub-Investigator: Ron Bose, M.D., Ph.D.         
Sub-Investigator: Matthew Ellis, M.B., Ph.D.         
Sub-Investigator: Michael Naughton, M.D.         
Sub-Investigator: Timothy Pluard, M.D.         
Sub-Investigator: Steven Sorscher, M.D.         
Sub-Investigator: Rama Suresh, M.D.         
Sub-Investigator: Katherine Weilbaecher, M.D.         
Sub-Investigator: Amy Cyr, M.D.         
Sub-Investigator: Timothy Eberlein, M.D.         
Sub-Investigator: William Gillanders, M.D.         
Sub-Investigator: Julie Margenthaler, M.D.         
Sub-Investigator: Erika Crouch, M.D.         
Sub-Investigator: Shashikant Kuulkarni, Ph.D.         
Sub-Investigator: Mark Watson, M.D., Ph.D.         
Sub-Investigator: Cory Bernadt, M.D., Ph.D.         
Sub-Investigator: Deborah Novack, M.D., Ph.D.         
Sub-Investigator: Katherine Schwetye, M.D., Ph.D.         
Sponsors and Collaborators
Washington University School of Medicine
Principal Investigator: Cynthia Ma, M.D., Ph.D. Washington University School of Medicine
Principal Investigator: Rebecca Aft, M.D., Ph.D. Washington University School of Medicine
  More Information

Additional Information:
No publications provided

Responsible Party: Washington University School of Medicine
ClinicalTrials.gov Identifier: NCT01757327     History of Changes
Other Study ID Numbers: 12-X238
Study First Received: December 20, 2012
Last Updated: July 22, 2013
Health Authority: United States: Institutional Review Board

Additional relevant MeSH terms:
Breast Neoplasms
Neoplasms by Site
Breast Diseases
Skin Diseases
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Pharmacologic Actions

ClinicalTrials.gov processed this record on April 16, 2014