Ribociclib in Treating Patients With Advanced Neuroendocrine Tumors of Foregut Origin
Condition: Advanced Digestive System Neuroendocrine Neoplasm; Duodenal Neuroendocrine Tumor G1; Functional Pancreatic Neuroendocrine Tumor; Gastric Neuroendocrine Tumor; Intermediate Grade Lung Neuroendocrine Neoplasm; Low Grade Lung Neuroendocrine Neoplasm; Nonfunctional Pancreatic Neuroendocrine Tumor; Thymus Neoplasm
MeSH terms: Neoplasms; Neuroendocrine Tumors; Adenoma, Islet Cell; Thymus Neoplasms; Thymoma
Intervention: Laboratory Biomarker Analysis; Pharmacological Study; Ribociclib
Intervention description: Correlative studies; Correlative studies; Given PO
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 21.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      This phase II trial studies how well ribociclib works in treating patients with
      neuroendocrine tumors of the foregut, which includes the thymus, lung, stomach, and pancreas,
      that have spread to other places in the body and usually cannot be cured or controlled with
      treatment (advanced tumors). Ribociclib may stop the growth of tumor cells by blocking some
      of the enzymes needed for cell growth.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Histologically or cytologically confirmed low or intermediate grade, unresectable well
             differentiated foregut neuroendocrine tumors (thymic, bronchopulmonary, gastric,
             duodenal and pancreatic); patients with multiple neuroendocrine tumors associated with
             MEN1 syndrome will be eligible

          -  Patients must have radiographically measurable disease

          -  Pancreatic neuroendocrine patients must have had progression after prior therapy;
             patients with other foregut neuroendocrine tumors must have had progressive disease
             over the last 12 months, irrespective of prior therapy; patients with both functional
             (who may continue somatostatin analogues as required for control of related symptoms)
             and non-functional tumors are eligible; in patients who have previously received
             therapy, the number of prior lines of therapy should not be more than 2 lines of
             systemic therapy not including somatostatin analogues

          -  Written informed consent must be obtained prior to any screening procedures

          -  Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status of
             0 - 1

          -  A sufficient interval must have elapsed between the last dose of prior anti-cancer
             therapy (including cytotoxic and biological therapies and major surgery) and
             enrollment, to allow the effects of prior therapy to have abated: a) cytotoxic or
             targeted chemotherapy: greater than or equal to the duration of the cycle of the most
             recent treatment regimen (a minimum of 3 weeks for all regimens, except 6 weeks for
             nitrosoureas and mitomycin-C); b) biologic therapy (e.g., antibodies): greater than or
             equal to 4 weeks

          -  Absolute neutrophil count (ANC) greater than or equal to 1.5 x 10^9/L

          -  Hemoglobin (Hgb) greater than or equal to 9 g/dL

          -  Platelets greater than or equal to 100 x 10^9/L

          -  Serum total bilirubin less than or equal to 1.5 x upper limit of normal (ULN)

          -  Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and
             alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) less
             than or equal to 2.5 x ULN, except in patients with tumor involvement of the liver who
             must have AST and ALT less than or equal to 5 x ULN

          -  Serum creatinine less than or equal to 1.5 x ULN or 24-hour clearance greater than or
             equal to 50 mL/min

          -  Serum potassium (corrected for serum albumin) must be within clinically relevant
             limits (e.g., a patient can be enrolled if a lab value may be outside the normal
             laboratory range but the abnormality is not clinically relevant or can be repleted)

          -  Sodium (corrected for serum albumin) must be within clinically relevant limits (e.g.,
             a patient can be enrolled if a lab value may be outside the normal laboratory range
             but the abnormality is not clinically relevant or can be repleted)

          -  Magnesium (corrected for serum albumin) must be within clinically relevant limits
             (e.g., a patient can be enrolled if a lab value may be outside the normal laboratory
             range but the abnormality is not clinically relevant or can be repleted)

          -  Phosphorus (corrected for serum albumin) must be within clinically relevant limits
             (e.g., a patient can be enrolled if a lab value may be outside the normal laboratory
             range but the abnormality is not clinically relevant or can be repleted)

          -  Total calcium (corrected for serum albumin) must be within clinically relevant limits
             (e.g., a patient can be enrolled if a lab value may be outside the normal laboratory
             range but the abnormality is not clinically relevant or can be repleted)

          -  Negative pregnancy test (serum beta-human chorionic gonadotropin [B-HCG]) within 7
             days of starting study treatment is required in women of childbearing potential; NET
             patients with positive B-HCG are eligible if pregnancy can be excluded by vaginal
             ultrasound or lack of expected doubling of B-HCG

        Exclusion Criteria:

          -  Patient has a known hypersensitivity to LEE011 or any of its excipients

          -  Patients with known or suspected brain metastases; however, if radiation therapy
             and/or surgery has been completed and serial evaluation by computed tomography (CT)
             (with contrast enhancement) or magnetic resonance imaging (MRI) over a minimum of 3
             months demonstrates the disease to be stable and if the patient remains asymptomatic,
             then the patient may be enrolled; such patients must have no need for treatment with
             steroids or anti-epileptic medications

          -  Patients with concurrent malignancies or malignancies within 3 years prior to starting
             study drug (with the exception of tumors common to a single genetic cancer syndrome,
             i.e. MEN1, MEN2, von Hippel-Lindau [vHL], tuberous sclerosis complex [TSC] etc., or
             adequately treated, basal cell skin cancer, squamous cell carcinoma, non-melanoma skin
             cancer or curatively resected cervical cancer)

          -  Patient is not able to swallow oral medication and/or has 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 diagnosis of human immunodeficiency virus (HIV) or hepatitis C (testing is not
             mandatory)

          -  Patient has any other concurrent severe and/or uncontrolled medical condition that
             would, in the investigator's judgment, contraindicate patient participation in the
             clinical study (e.g. chronic pancreatitis, chronic active hepatitis, etc.)

          -  Patient who has received radiotherapy within less than or equal to 4 weeks or limited
             field radiation for palliation within less than or equal to 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 greater than or equal to
             30% of the bone marrow was irradiated

          -  Patient 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)

          -  Impaired cardiac function or clinically significant cardiac diseases, including any of
             the following: a) history of acute coronary syndromes (including myocardial
             infarction, unstable angina, coronary artery bypass grafting, coronary angioplasty, or
             stenting) or symptomatic pericarditis less than 12 months prior to screening b)
             history of documented congestive heart failure (New York Heart Association functional
             classification III-IV) c) documented cardiomyopathy d) patient has a left ventricular
             ejection fraction (LVEF) less than 50% as determined by multiple gated acquisition
             (MUGA) scan or echocardiogram (ECHO) at screening e) history of ventricular,
             supraventricular, nodal arrhythmias, or any other cardiac arrhythmias, long QT
             syndrome or conduction abnormality within 12 months prior to starting study drug f)
             congenital long QT syndrome or a family history of corrected QT interval (QTc)
             prolongation g) on screening, inability to determine the corrected QT for Fridericia
             (QTcF) interval on the electrocardiogram (ECG) (i.e.: unreadable or not interpretable)
             or QTcF > 450 msec (using Fridericia's correction); all as determined by screening ECG
             (mean of triplicate ECGs)

          -  Systolic blood pressure greater than 160 mmHg or less than 90 mmHg at screening

          -  Patients who are currently receiving treatment with agents that are known to cause QTc
             prolongation or inducing Torsade de Pointes in humans and are unable to discontinue or
             switch to an alternate medication

          -  Patients who are currently receiving treatment (within 5 days prior to starting study
             drug) with agents that are known strong inducers or inhibitors of cytochrome P450,
             family 3, subfamily A polypeptide 4 (CYP3A4)/cytochrome P450, family 3, subfamily A
             polypeptide 5 (5), or that have a narrow therapeutic window and are predominantly
             metabolized through CYP3A4/5

          -  Patients with concurrent severe and/or uncontrolled concurrent medical conditions that
             could compromise participation in the study (e.g., uncontrolled diabetes mellitus
             defined by a glucose greater than 1.5 ULN in spite of adequate medical treatment,
             clinically significant pulmonary disease, clinically significant neurological
             disorder, active or uncontrolled infection)

          -  Patient has a history of non-compliance to medical regimen or inability to grant
             consent

          -  Pregnant or lactating women, where pregnancy is defined as the state of a female after
             conception and until the termination of gestation, confirmed by a positive hCG
             laboratory test (greater than 5 mIU/mL)

          -  Women of child-bearing potential, defined as all women physiologically capable of
             becoming pregnant, unless they are using effective methods of contraception throughout
             the study and for 8 weeks after study drug discontinuation; highly effective
             contraception methods include: total abstinence when this is in line with the
             preferred and usual lifestyle of the patient; periodic abstinence (e.g., calendar,
             ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable
             methods of contraception; female sterilization (have had surgical bilateral
             oophorectomy with or without hysterectomy) or tubal ligation at least six weeks before
             taking study treatment; in case of oophorectomy alone, only when the reproductive
             status of the woman has been confirmed by follow up hormone level assessment; male
             sterilization (at least 6 months prior to screening); for female patients on the
             study, the vasectomized male partner should be the sole partner for that patient;
             combination of any of the two following (a+b or a+c or b+c) a. use of oral, injected
             or implanted hormonal methods of contraception or other forms of hormonal
             contraception that have comparable efficacy (failure rate < 1%), for example hormone
             vaginal ring or transdermal hormone contraception b. placement of an intrauterine
             device (IUD) or intrauterine system (IUS) c. barrier methods of contraception: condom
             or occlusive cap (diaphragm or cervical/vault caps) with spermicidal
             foam/gel/film/cream/vaginal suppository; in case of use of oral contraception, women
             should have been stable on the same pill before taking study treatment; note: oral
             contraceptives are allowed but should be used in conjunction with a barrier method of
             contraception; women are considered post-menopausal and not of child bearing potential
             if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate
             clinical profile (e.g. age appropriate, history of vasomotor symptoms) or have had
             surgical bilateral oophorectomy (with or without hysterectomy) or tubal ligation at
             least six weeks ago; in the case of oophorectomy alone, only when the reproductive
             status of the woman has been confirmed by follow up hormone level assessment is she
             considered not of child bearing potential

          -  Sexually active males unless they use a condom during intercourse while taking the
             drug and for 21 days after stopping treatment and should not father a child in this
             period; a condom is required to be used also by vasectomized men in order to prevent
             delivery of the drug via seminal fluid

          -  Patients unwilling or unable to comply with the protocol

          -  Patient is 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