Clinical Trials /

Lenvatinib and Everolimus in Treating Patients With Advanced, Unresectable Carcinoid Tumors

NCT03950609

Description:

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.

Related Conditions:
  • Carcinoid Tumor
  • Gastrointestinal Neuroendocrine Tumors
  • Multiple Endocrine Neoplasia Type 1
  • Neuroendocrine Tumor
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Lenvatinib and Everolimus in Treating Patients With Advanced, Unresectable Carcinoid Tumors
  • Official Title: A Phase II Study of Lenvatinib in Combination With Everolimus in Patients With Advanced Carcinoid Tumors

Clinical Trial IDs

  • ORG STUDY ID: 2018-0253
  • SECONDARY ID: NCI-2019-02051
  • SECONDARY ID: 2018-0253
  • SECONDARY ID: P30CA016672
  • NCT ID: NCT03950609

Conditions

  • Advanced Carcinoid Tumor
  • Digestive System Neuroendocrine Neoplasm
  • Multiple Endocrine Neoplasia Type 1
  • Neuroendocrine Neoplasm
  • Unresectable Carcinoid Tumor

Interventions

DrugSynonymsArms
Everolimus42-O-(2-Hydroxy)ethyl Rapamycin, Afinitor, Certican, RAD 001, RAD001, Votubia, ZortressTreatment (lenvatinib, everolimus)
LenvatinibE7080, ER-203492-00, Multi-Kinase Inhibitor E7080Treatment (lenvatinib, everolimus)

Purpose

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.

Detailed Description

      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.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (lenvatinib, everolimus)ExperimentalPatients receive lenvatinib PO daily and everolimus PO daily on days 1-28. Treatments repeat every 28 days in the absence of disease progression or unacceptable toxicity.
  • Everolimus
  • Lenvatinib

Eligibility Criteria

        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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Radiographic response rate
Time Frame:Up to 30 days after completion of study treatment
Safety Issue:
Description:Graded with Response Evaluation Criteria in Solid Tumors version 1.1

Secondary Outcome Measures

Measure:Progression-free survival
Time Frame:Up to 30 days after completion of study treatment
Safety Issue:
Description:
Measure:Incidence of adverse events
Time Frame:Up to 30 days after completion of study treatment
Safety Issue:
Description:Toxicity evaluations will be conducted every 2 weeks for the first 2 cycles and every cycle thereafter. Toxicity will be monitored using the Bayesian approach.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:M.D. Anderson Cancer Center

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