Study of LDE225 (Sonidegib) in Combination With Docetaxel in Triple Negative (TN) Advanced Breast Cancer (ABC) Patients
Condition: Advanced Breast Cancer
MeSH terms: Breast Neoplasms
Intervention: LDE225; Docetaxel
Intervention MeSH terms: Docetaxel
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 12.0
Sex: Female
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Advanced Breast Cancer; LDE225; Triple Negative; Hormonal Receptor negative; Her2 negative

Summary:

      This is a single-arm, open-label, phase Ib study. In this trial, patients with Triple
      Negative (TN) Advanced Breast Cancer (ABC) will be treated with increasing doses of LDE225
      (sonidegib) and docetaxel to determine the Maximum Tolerated Dose (MTD), Dose Limiting
      Toxicity (DLT) and Recommended Phase II Dose (RP2D) of the combination.

      Eligible patients with hormonal receptors negative and Human Epidermal Growth Factor Receptor
      2 (HER2) negative ABC will be included and treated with docetaxel intravenously in every
      three weeks cycles. LDE225 will be administered orally at three dose levels 400, 600 and
      800mg one a day (QD) (a -1 dose level is included just in case dose de-escalation is needed).
      Treatment will be repeated on day 1 of a 21-day cycle until radiographic or symptomatic
      progression, unacceptable toxicity or withdraws informed consent.

      The investigators propose to develop a phase Ib trial with the combination of docetaxel with
      LDE225 in TN ABC patients to define the safety, tolerability and RP2D, as well as to have
      some information about the efficacy of the combination.
    

Eligibility criteria:

        Inclusion Criteria:

          1. The patient is capable to understand and comply with the protocol and has signed the
             informed consent document.

          2. Females with histologically confirmed advanced breast cancer.

          3. TN breast cancer by local laboratory determination. Hormonal Receptor (HR) negative
             defined as < 1% positive cells by Immunohistochemistry (IHC) for both Estrogen
             Receptor (ER) and Progesterone Receptor (PgR), and HER2 negative defined as in situ
             hybridization (ISH) negative or IHC 0 or 1+ in the absence of ISH (Note: patients with
             IHC 2+ must have an ISH determination in order to confirm the HER2 negativity.

          4. Measurable or non-measurable disease according to RECIST 1.1 criteria.

          5. Patient is at least 18 years of age.

          6. World Health Organization (WHO) Performance Status ≤ 1.

          7. Life expectancy ≥ 12 weeks.

          8. Common laboratory values within normal range (…)

          9. A negative serum pregnancy test ≤ 72 hours before starting study treatment for
             pre-menopausal women and for women < 1 year from the last menstruation date.

        Exclusion Criteria:

          1. Have received more than 3 prior chemotherapy regimens for ABC.

          2. Patients with untreated brain metastases. However, a patient with Central Nervous
             System (CNS) metastases may participate in this trial if > 4 weeks from therapy
             completion (incl. radiation and/or surgery), is clinically stable with respect to the
             tumor at the time of study entry and is not receiving corticosteroid therapy.

          3. Patients with acute or chronic liver or renal disease or pancreatitis.

          4. Patients with a second primary malignancy that is clinically detectable at the time of
             consideration for study enrollment.

          5. Patients unable to swallow tablets.

          6. History of a positive HIV test (HIV testing is not mandatory).

          7. History of a positive Hepatitis B surface antigen (HBsAg) or Hepatitis C test result
             (Hepatitis B or C testing is not mandatory).

          8. Impairment of gastrointestinal (GI) function or GI disease (e.g. ulcerative disease,
             uncontrolled nausea, vomiting, grade ≥ 2 diarrhea, malabsorption syndrome or small
             bowel resection).

          9. Peripheral vascular disease requiring active therapy or having had surgery < 12 months
             prior to starting study drug.

         10. Impaired cardiac function or clinically significant heart disease (…)

               -  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. congestive heart failure,
                  uncontrolled hypertension, history of labile hypertension, or history of poor
                  compliance with an antihypertensive regimen)

         11. Patients who are receiving treatment with medications that are known to be strong
             inhibitors or inducers of CYP3A4/5 (listed in Protocol Attachment 3) or drugs
             metabolized by CYP2B6 or CYP2C9 (listed in Protocol Attachment 3) that cannot be
             discontinued prior to study entry and for the duration of the study. Medications that
             are strong CYP3A4/5 inhibitors should be discontinued for at least 2 days, and strong
             CYP3A4/5 inducers for at least 1 week prior to initiating LDE225 dosing.

         12. Patients who have received chemotherapy within a period of time that is < the cycle
             length used for that treatment (e.g. < 3 weeks for fluorouracil, doxorubicine,
             epirubicin) prior to starting study drug or who have not recovered from the side
             effects of such therapy.

         13. Patients who have received biologic therapy (e.g. antibodies) ≤ 4 weeks prior to
             starting study drug or who have not recovered from the side effects of such therapy.

         14. Patients who have been treated with a small molecule therapeutic ≤ 5 t1/2 or ≤ 4 weeks
             (whichever is shorter) prior to starting study drug or who have not recovered from the
             side effects of such therapy.

         15. Patients who have received any other investigational agents ≤ 5 t1/2 or ≤ 4 weeks
             (whichever is shorter) prior to starting study drug or who have not recovered from the
             side effects of such therapy.

         16. Patients who have received wide field radiotherapy (including therapeutic
             radioisotopes such as strontium 89) ≤ 4 weeks or limited field radiation for
             palliation ≤ 2 weeks prior to starting study drug or who have not recovered from side
             effects of such therapy.

         17. Patients who are currently receiving treatment with therapeutic doses of warfarin
             sodium (Coumadin) who cannot discontinue this treatment at least 5 days prior to
             starting study drug.

         18. Patients who are currently receiving immunosuppressive treatment and in whom the
             treatment cannot be discontinued prior to starting study drug, except in the case of
             patients with basal cell carcinoma (BCC). Immunosuppressive treatment should be
             discontinued for at least 1 week prior to initiating LDE225 dosing.

             …