Breast Neoplasms
Conditions
Brief summary
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.
Interventions
DRUGErismodegib
DRUGPlacebo
Sponsors
Washington University School of Medicine
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of patients who are bone marrow DTC-negative after therapy | at 6 months | Comparing LDE225 to placebo using a stratified Cochran-Mantel-Haenszel test for difference of proportions |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) | 2 years from initiation of study treatment | 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 | At 6 months | 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 | For 30 days following the last day of study treatment; up to 25 months | Toxicities described and graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v4.0. |
| Disease-free survival (DFS) | 2 years from initiation of study treatment | Defined as duration after surgery that the patient survives without signs or symptoms of cancer; analyzed using a stratified Cox proportional hazards model. |
| Time to recurrence and death in ICC negative versus ICC positive patients | 2 years from initiation of treatment | 95% confidence intervals using Cox proportional hazard regression |
| Concordance of DTC determination by ICC or gene expression | Baseline | 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. |
| Time to recurrence and death in DTC-negative patients and DTC-positive patients | 2 years from initiation of study treatment | 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 |
Outcome results
None listed