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

This study is currently recruiting participants. (see Contacts and Locations)
Verified June 2014 by Washington University School of Medicine
Sponsor:
Information provided by (Responsible Party):
Washington University School of Medicine
ClinicalTrials.gov Identifier:
NCT01757327
First received: December 20, 2012
Last updated: June 25, 2014
Last verified: June 2014
  Purpose

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.

  • Time to recurrence and death in DTC-negative patients and DTC-positive patients [ Time Frame: 2 years from initiation of study treatment ] [ Designated as safety issue: No ]
    Cox regression will be used to compare time to recurrence or death in DTC-negative patients ineligible for randomization with those randomized to receive treatment

  • Time to recurrence and death in ICC negative versus ICC positive patients [ Time Frame: 2 years from initiation of treatment ] [ Designated as safety issue: No ]
    95% confidence intervals using Cox proportional hazard regression

  • Concordance of DTC determination by ICC or gene expression [ Time Frame: Baseline ] [ Designated as safety issue: No ]
    Expressed using kappa statistics with 95% confidence intervals. McNemar's test will be used to test for a statistically significant difference between the proportion positive by ICC and gene expression.


Estimated Enrollment: 68
Study Start Date: April 2014
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])
400 mg daily and treatment repeats every 28 days for up to 26 cycles in the absence of disease progression or unacceptable toxicity.
Drug: Erismodegib
Other Names:
  • Smoothened antagonist LDE225
  • Sonidegib
Placebo Comparator: Arm II (placebo)
Patients receive placebo PO daily and treatment repeats every 28 days for up to 26 cycles in the absence of disease progression or unacceptable toxicity.
Drug: Placebo
Other Name: PLCB

  Eligibility

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

Inclusion Criteria:

  • Diagnosis of with 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. 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 LDE225 trial.
  • 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.
  • At least 18 years of age.
  • 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.
  • Patient (or legally authorized representative if applicable) must be able to understand and willing to sign an IRB approved written informed consent document.

Exclusion Criteria:

  • Evidence of distant metastasis present by CT scan, bone scan, or physical exam within one year prior to entry into the trial.
  • Concurrent treatment with any other standard therapy (e.g. chemotherapy, targeted therapy or radiotherapy) or within 3 weeks of starting LDE225.
  • Treatment with investigational anticancer agent within 4 weeks or 5 half-lives whichever is longer, of initializing treatments with LDE225.
  • 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.
  • Previous treatment with systemic LDE225 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 LDE225 treatment. If it is essential that the patient stays on a statin to control hyperlipidemia, only pravastatin may be used with extra caution.
  • History of allergic reactions attributed to compounds of similar chemical or biologic composition to LDE225 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 LDE225 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 LDE225.
  • 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.
  • 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 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.
  • 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
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01757327

Contacts
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

Locations
United States, Missouri
Washington University School of Medicine Recruiting
St. Louis, Missouri, United States, 63110
Contact: Rebecca Aft, M.D., Ph.D.    314-747-0063    aftr@wudosis.wustl.edu   
Contact: Cynthia Ma, M.D., Ph.D.    314-362-8903    cma@dom.wustl.edu   
Sub-Investigator: Ron Bose, M.D., Ph.D.         
Sub-Investigator: Matthew Ellis, M.B., Ph.D.         
Sub-Investigator: Michael Naughton, 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.         
Sub-Investigator: Foluso Ademuyiwa, MD         
Sub-Investigator: Adel Tabchy, M.D.         
Sponsors and Collaborators
Washington University School of Medicine
Investigators
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: 201310007
Study First Received: December 20, 2012
Last Updated: June 25, 2014
Health Authority: United States: Institutional Review Board
United States: Food and Drug Administration

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

ClinicalTrials.gov processed this record on August 01, 2014