Lenvatinib and Everolimus in Treating Patients With Advanced, Unresectable Carcinoid Tumors
Lenvatinib and Everolimus in Treating Patients With Advanced, Unresectable Carcinoid Tumors
This phase II trial studies how well lenvatinib and everolimus work in treating patients with
 carcinoid tumors that have spread to other places in the body and cannot be removed by
 surgery. Lenvatinib and everolimus may stop the growth of tumor cells by blocking some of the
 enzymes needed for cell growth.
PRIMARY OBJECTIVES:

 I. To estimate the Response Evaluation Criteria in Solid Tumors (RECIST) (per version 1.1)
 objective response rate of lenvatinib in combination with everolimus among patients with
 advanced carcinoid tumors.

 SECONDARY OBJECTIVES:

 I. To evaluate the progression free survival duration of lenvatinib in combination with
 everolimus among patients with advanced carcinoids.

 II. To evaluate the safety and tolerability of lenvatinib in combination with everolimus
 among patients with advanced carcinoid tumors.

 EXPLORATORY OBJECTIVES:

 I. To determine clinic benefit rate at 6 months (defined as complete response plus partial
 response plus stable disease) with lenvatinib + everolimus among patients with advanced
 carcinoid tumors.

 II. To determine early CgA and neuron-specific enolase (NSE) response rates.

 OUTLINE:

 Patients receive lenvatinib orally (PO) daily and everolimus PO daily on days 1-28.
 Treatments repeat every 28 days in the absence of disease progression or unacceptable
 toxicity.

 After completion of study treatment, patients are followed up at 30 days.
Inclusion Criteria:

 -  Histologically or cytologically confirmed low or intermediate grade, unresectable well
 differentiated carcinoid tumors. Patients with multiple neuroendocrine tumors
 associated with MEN1 syndrome will be eligible.

 -  Patients must have radiographically measurable disease. Lesions that have had
 locoregional therapies such as radiofrequency (RF) ablation, radiation or
 transarterial therapies must show evidence of progressive disease based on RECIST 1.1
 to be deemed a target lesion.

 -  Patients with other gastrointestinal neuroendocrine tumors must have had progressive
 disease over the last 12 months irrespective of number of prior therapies. Patients
 with both functional (who may continue somatostatin analogues as required for control
 of related symptoms) and non-functional tumors are eligible.

 -  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:

 -  Cytotoxic or targeted chemotherapy: >= 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)

 -  Biologic therapy (e.g., antibodies): >= 4 weeks.

 -  Absolute neutrophil count (ANC) >= 1.5 x 10^9/L.

 -  Hemoglobin (Hgb) >= 9 g/dL.

 -  Platelets >= 100 x 10^9/L.

 -  Serum total bilirubin =< 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]) =< 2.5 x
 ULN, except in patients with tumor involvement of the liver who must have AST and ALT
 =< 5 x ULN.

 -  Serum creatinine =< 1.5 x ULN or 24-hour clearance >= 50 mL/min.

 -  Serum potassium, sodium, magnesium, phosphorus and 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 repeated.).

 -  Spirometry and diffusion capacity of the lung for carbon monoxide (DLCO) 50% or
 greater of normal and oxygen (O2) saturation 88% or greater at rest on room air.
 Baseline testing is not required unless known severely impaired lung function.

 -  Negative pregnancy test (serum beta-human chorionic gonadotropin [HCG]) within 7 days
 of starting study treatment is required in women of childbearing potential. Beta-HCG
 may be secreted by a small percentage of neuroendocrine tumors (NETs) and be a tumor
 marker. Thus, NET patients with positive beta-HCG are eligible if pregnancy can be
 excluded by vaginal ultrasound or lack of expected doubling of beta-HCG.

 Exclusion Criteria:

 -  Patient has a known hypersensitivity to lenvatinib, everolimus or any of their
 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, vHL, 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), hepatitis B or hepatitis C
 (testing is not mandatory).

 -  Patient who has received radiotherapy within =< 4 weeks or limited field radiation for
 palliation within =< 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 >= 30% of the bone marrow was irradiated.

 -  Patient has had major surgery within 21 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:

 -  History of acute coronary syndromes (including myocardial infarction, unstable
 angina, coronary artery bypass grafting, coronary angioplasty, or stenting) or
 symptomatic pericarditis < 12 months prior to screening

 -  History of documented congestive heart failure (New York Heart Association
 functional classification III-IV)

 -  Documented cardiomyopathy

 -  Patient has a left ventricular ejection fraction (LVEF) < 50% as determined by
 multiple gated acquisition (MUGA) scan or echocardiogram (ECHO) at screening

 -  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

 -  Congenital long QT syndrome or a family history of QTc prolongation

 -  On screening, inability to determine the corrected QT interval using Fridericia's
 formula (QTcF) interval on the electrocardiogram (ECG) (i.e.: unreadable or not
 interpretable) or QTcF > 450 msec (using Fridericia's correction).

 -  Systolic blood pressure > 150 mmHg or diastolic blood pressure > 90 mmHg. Patients
 with systolic blood pressure < 150 mmHg or diastolic blood pressure < 90 mmHg on
 anti-hypertensives without any change in anti-hypertensives within 1 week prior to
 screening visit are eligible.

 -  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 > 1.5 ULN in spite of adequate medical treatment, clinically
 significant pulmonary disease, clinically significant neurological disorder, active or
 uncontrolled infection, fasting total cholesterol > 300 mg/dL (or > 7.75 mmol/L) or
 fasting triglycerides level > 2.5 x ULN.

 -  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 (> 5 mIU/mL).

 -  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 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 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

 -  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

 -  Placement of an intrauterine device (IUD) or intrauterine system (IUS)

 -  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 due to
 unknown effect of drug-drug interaction.

 -  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 28 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.

 -  Subjects having > 1 + proteinuria on urine dipstick testing will undergo 24 hour (h)
 urine collection for quantitative assessment of proteinuria. Subjects with urine
 protein >= 1 g/24 h will be ineligible.

 -  Active hemoptysis (bright red blood of at least 0.5 teaspoon) within 3 weeks prior to
 the first dose of study drug.

 -  Prior therapy with mTOR inhibitors (e.g. sirolimus, temsirolimus, deforolimus) and/or
 lenvatinib. Prior antiangiogenic therapies (including but not limited to bevacizumab,
 aflibercept, sunitinib and/or pazopanib) are allowed.

 -  Other active malignancy (except definitively treated melanoma in-situ, basal or
 squamous cell carcinoma of the skin, or carcinoma in-situ of the cervix or bladder)
 within past 24 months.