TEEL Study- Phase 1 Tamoxifen and Ribociclib (LEE011) in Advanced ER+ (HER2 Negative) Breast Cancer
Condition: Breast Cancer; Breast Cancer - Female; Breast Cancer - Male
MeSH terms: Breast Neoplasms
Intervention: Tamoxifen; Ribociclib; Goserelin
Intervention description: Tamoxifen will be taken orally once daily on a continuous daily schedule (e.g., days 1-28 of each 28 day cycle).; Ribociclib (LEE011) will be taken orally once daily on days 1-21 of each 28 day cycle. Days 22-28 will be a "rest" period from dosing with Ribociclib. In the continuous cohort, 400 mg ribociclib will be given daily (QD).; Goserelin will be given as an injectable subcutaneous implant on day 1 of every 28 day cycle. This will be given in pre-menopausal and peri-menopausal women.
Intervention MeSH terms: Tamoxifen; Goserelin
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 7.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: ER+ breast cancer; PR+ breast cancer; hormone receptor positive; HER2- breast cancer; HER2 negative; locally advanced; metastatic

Summary:

      The purpose of this study is to find out if the investigational drug Ribociclib (LEE011),
      when taken with standard treatment (Tamoxifen +/- Goserelin) is safe and has beneficial
      effects in pre-menopausal and post-menopausal women and men who have a type of breast cancer
      known as hormone receptor positive/HER2- breast cancer.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Histologically and/or cytologically confirmed diagnosis of Estrogen Receptor-Positive
             (ER+) and/or Progesterone Receptor-Positive (PR+) breast cancer by local laboratory.

          -  Human Epidermal growth factor Receptor 2 Negative (HER2-) breast cancer defined as a
             negative in situ hybridization test or an Immunohistochemistry (IHC) status of 0, 1+
             or 2+. If IHC is 2+, a negative In Situ Hybridization (Fluorescence [FISH],
             Chromogenic [CISH], or Silver [SISH]) test is required by local laboratory testing.

          -  Participants are allowed (but not required) to have up to two lines of prior
             chemotherapy regimens in the metastatic setting for the dose expansion phase. For the
             dose escalation cohort, up to three previous lines of chemotherapy in the metastatic
             setting is acceptable.

          -  Measurable disease, i.e., at least one measurable lesion as per Response Evaluation
             Criteria in Solid Tumors (RECIST)1.1 criteria only *for expansion cohorts.

          -  For *escalation cohorts, bone only disease is allowed. For expansion cohorts, there
             must be measurable disease as stated above.

          -  Eastern Cooperative Oncology Group Performance Status (ECOG PS) 0 or 1.

          -  Written informed consent must be obtained prior to any screening procedures and
             according to local guidelines.

          -  Adequate bone marrow and organ function.

          -  Must be able to swallow ribociclib and Tamoxifen capsules/tablets.

          -  Pre-Menopausal Women Eligibility: 1) Pre-menopausal women who received adjuvant
             Aromatase Inhibitor and Ovarian Suppression (AI + OS) in the adjuvant setting and
             completed at least 12 months of hormonal therapy. 2) Pre-menopausal women with de novo
             metastatic disease are eligible if they have had no prior endocrine therapy. 3)
             Pre-menopausal women who have not received Tamoxifen in the metastatic setting, but
             have received up to two lines of chemotherapy.

          -  Post-Menopausal Women and Men Eligibility: 1) Post-menopausal women or men who have
             progressed on first-line or second line therapy with an aromatase inhibitor in the
             metastatic setting. 2) Post-menopausal women or men who have recurred while on or
             after completion of adjuvant treatment with aromatase inhibitors (they have completed
             at least one year of AI in the adjuvant setting before progression on AI). 3)
             Post-menopausal women or men who are not considered candidates for treatment with an
             aromatase inhibitory by their oncologist, patients not willing to go on AI, or
             patients who were intolerant to AI.

          -  Post-menopausal women or men are allowed (but not required) to have up to two lines of
             prior chemotherapy regimens in the metastatic setting for the dose expansion phase .
             For the dose escalation cohort, up to three previous lines of chemotherapy in the
             metastatic setting is acceptable.

        Exclusion Criteria:

          -  Potential participants with inflammatory breast cancer.

          -  Prior CDK 4/6 inhibitor exposure.

          -  Have received Tamoxifen in the metastatic setting (for more than 30 days) or has
             progressed while on Tamoxifen in the adjuvant setting.

          -  Known hypersensitivity to ribociclib or excipients of tamoxifen.

          -  A concurrent malignancy or malignancy within 3 years of starting study drug, with the
             exception of adequately treated, basal or squamous cell carcinoma, non-melanomatous
             skin cancer or curatively resected cervical cancer.

          -  Central nervous system (CNS) involvement unless specific criteria are met.

          -  Impairment of Gastrointestinal (GI) function or GI disease that may significantly
             alter the absorption of the study drugs (e.g., ulcerative diseases, uncontrolled
             nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection).

          -  Known history of HIV infection (testing not mandatory).

          -  Any other concurrent severe and/or uncontrolled medical condition that would, in the
             investigator's judgment, cause unacceptable safety risks, contraindicate patient
             participation in the clinical study or compromise compliance with the protocol (e.g.
             chronic pancreatitis, chronic active hepatitis, active untreated or uncontrolled
             fungal, bacterial or viral infections, etc.).

          -  Clinically significant, uncontrolled heart disease and/or a recent events as specified
             in the study protocol

          -  Currently receiving any of the following medications and cannot be discontinued 7 days
             prior to starting study drug: a. Known strong inducers or inhibitors of CYP3A4/5,
             including grapefruit, grapefruit hybrids, pummelos, star-fruit, and Seville oranges.
             b. That have a narrow therapeutic window and are predominantly metabolized through
             CYP3A4/5. c. That have a known risk to prolong the QT interval or induce Torsades de
             Pointes. d. Herbal preparations/medications, dietary supplements not prescribed by an
             M.D..

          -  Currently receiving or has received systemic corticosteroids ≤2 weeks prior to
             starting study drug, or who have not fully recovered from side effects of such
             treatment.

          -  The following uses of corticosteroids are permitted: single doses, topical
             applications (e.g., for rash), inhaled sprays (e.g., for obstructive airways
             diseases), eye drops or local injections (e.g., intra-articular).

          -  Currently receiving warfarin or other coumarin-derived anticoagulant for treatment,
             prophylaxis or otherwise. Therapy with heparin, low molecular weight heparin (LMWH) or
             fondaparinux is allowed.

          -  Participation in a prior investigational study within 30 days prior to enrollment..

          -  Has received radiotherapy ≤ 4 weeks or limited field radiation for palliation ≤ 2
             weeks prior to starting study drug, and who has not recovered to grade 1 or better
             from related side effects of such therapy (exceptions include alopecia) and/or in whom
             ≥ 25% of the bone marrow was irradiated.

          -  Has had major surgery within 14 days prior to starting study drug or has not recovered
             from major side effects (tumor biopsy is not considered as major surgery).

          -  Has not recovered from all toxicities related to prior anticancer therapies to NCI
             Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 Grade equal to or
             less than 1 (Exception to this criterion: patients with any grade of alopecia are
             allowed to enter the study).

          -  A Child-Pugh score B or C.

          -  History of non-compliance to medical regimen or inability to grant consent.

          -  Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a
             female after conception and until the termination of gestation, confirmed by a
             positive human Chorionic Gonadotropin (hCG) laboratory test.]

          -  Women of child-bearing potential, defined as all women physiologically capable of
             becoming pregnant, unless they are using highly effective methods of contraception
             throughout the study and for 12 weeks after study drug discontinuation. There are
             specific guidelines regarding the various acceptable highly effective contraception
             methods. Note: The use of oral contraception is not allowed.