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RecruitingInterventionalPhase 2

Randomized Phase II Trial of Lutetium Lu 177 Dotatate Versus Everolimus in Somatostatin Receptor Positive Bronchial Neuroendocrine Tumors

NCT ID: NCT04665739Sponsor: National Cancer Institute (NCI)Last updated: 2026-06-18

Summary

This phase II trial studies the effect of lutetium Lu 177 dotatate compared to the usual treatment (everolimus) in treating patients with somatostatin receptor positive bronchial neuroendocrine tumors that have spread to other places in the body (advanced). Lutetium Lu 177-dotate is a radioactive drug. It binds to a protein called somatostatin receptor, which is found on some neuroendocrine tumor cells. Lutetium Lu 177-dotatate builds up in these cells and gives off radiation that may kill them. It is a type of radioconjugate and a type of somatostatin analog. Lutetium Lu 177 dotatate may be more effective than everolimus in shrinking or stabilizing advanced bronchial neuroendocrine tumors.

Detailed description

PRIMARY OBJECTIVE: I. To compare progression-free survival (PFS) of receiving lutetium Lu 177 dotatate to that of receiving everolimus in patients with bronchial neuroendocrine tumor (NET). SECONDARY OBJECTIVES: I. To compare the overall survival (OS) of receiving lutetium Lu 177 dotatate versus everolimus in patients with bronchial NET. II. To compare the overall response rate (ORR) associated with lutetium Lu 177 dotatate versus everolimus in patients with bronchial NET. III. To evaluate and compare the toxicity profile of lutetium Lu 177 dotatate and everolimus. EXPLORATORY OBJECTIVES: I. To study late toxicities of lutetium Lu 177 dotatate therapy including renal dysfunction, myelodysplastic syndrome, and acute leukemia. II. To study the impact of pretreatment disease burden, somatostatin receptor status on lutetium Lu 177 dotatate (DOTATATE) positron emission tomography (PET) (or other somatostatin receptor \[SSTR\]-PET), and measured dosimetry of response. III. To evaluate the response rate (RR) and other efficacy parameters in typical and atypical carcinoid based on central retrospective pathology review. OUTLINE: Patients are randomized to 1 of 2 arms. ARM I: Patients receive lutetium Lu 177 dotatate intravenously (IV) over 30-40 minutes on day 1 of each cycle. Treatment repeats every 56 days for 4 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo PET during screening. Patients also undergo computed tomography (CT) or magnetic resonance imaging (MRI) during screening and on the trial as well as fludeoxyglucose F-18 (FDG) PET and single photon emission computed tomography (SPECT) on the trial. Additionally, patients undergo blood and tissue sample collection during screening and on the trial. ARM II: Patients receive everolimus orally (PO) once daily (QD) on days 1-28 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients with disease progression may be able to cross-over to Arm I. Patients undergo PET during screening. Patients also undergo CT or MRI during screening and on the trial as well as FDG PET and SPECT on the trial. Additionally, patients undergo blood and tissue sample collection during screening and on the trial. After completion of study treatment, patients are followed up every 3 months until disease progression and then every 6 months for up to 5 years following study registration.

Arms & interventions

  • ProcedureBiospecimen Collection

    Undergo blood and tissue sample collection

  • ProcedureComputed Tomography

    Undergo CT

  • DrugEverolimus

    Given PO

  • OtherFludeoxyglucose F-18

    Given FDG

  • DrugLutetium Lu 177 Dotatate

    Given IV

  • ProcedureMagnetic Resonance Imaging

    Undergo MRI

  • ProcedurePositron Emission Tomography

    Undergo PET

  • ProcedureSingle Photon Emission Computed Tomography

    Undergo SPECT

  • OtherSurvey Administration

    Ancillary studies

Outcome measures

Primary

  • Median progression-free survival (PFS)

    Will be compared between patients with a bronchial neuroendocrine tumor receiving lutetium Lu 177 dotatate to those receiving everolimus. The distribution of PFS will be estimated using the Kaplan Meier method. Will be tested using a one-sided stratified log rank test. The median PFS, along with 90% confidence intervals (CIs), will be estimated for the two treatment groups.

    Time frame: From randomization until either radiographic progression confirmed by central radiology review or death, assessed up to 5 years from study registration

Secondary

  • Overall survival (OS)

    Time frame: From randomization until death due to any cause, with patients censored at the last date known to be alive or last contact date, assessed up to 5 years from study registration

  • Overall response rate (ORR)

    Time frame: Up to 5 years from study registration

  • Incidence of adverse events

    Time frame: Up to 5 years from study registration

Eligibility criteria

Sex: AllAge: 18 Years and olderHealthy volunteers: No
Inclusion Criteria: * PRE-REGISTRATION: Pathologic Documentation: Well- or moderately-differentiated neuroendocrine tumor(s) of bronchial origin (i.e. carcinoid) as assessed by local pathology * The pathology report must state ONE of the following: * Well- or moderately-differentiated neuroendocrine tumor, * Low- or intermediate-grade neuroendocrine tumor, or * Carcinoid tumor (including typical or atypical carcinoid tumors) * PRE-REGISTRATION: Documentation of histology from a primary or metastatic site is allowed * PRE-REGISTRATION: Functional (evidence of peptide hormones and/or bioactive substances associated with a clinical hormone syndrome such as carcinoid syndrome or Cushing's syndrome) or nonfunctional tumors are allowed * PRE-REGISTRATION: Patients with poorly-differentiated or high-grade neuroendocrine carcinoma (i.e. large cell neuroendocrine carcinoma of lung, small cell lung cancer) or mixed tumors (i.e. adenocarcinoid tumor) are not eligible * PRE-REGISTRATION: Recurrent or locally-advanced/unresectable or metastatic disease * PRE-REGISTRATION: Neuroendocrine tumor of bronchial (i.e. lung) primary site * PRE-REGISTRATION: Lesions must have shown radiological evidence of disease progression in the 12 months prior to pre-registration * Tumor must have shown somatostatin receptor (SSTR) positivity on 68Ga-DOTATATE PET or other SSTR-PET scan in the 12 months prior to pre-registration; however, documentation of SSTR positivity in the 6 months prior to pre-registration is preferred. SSTR positivity is defined as uptake greater than background liver in all measurable lesions * PRE-REGISTRATION: Patients must have measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1 by computer tomography (CT) scan or magnetic imaging (MRI). Any lesions which have undergone percutaneous therapies or radiotherapy should not be considered measurable unless the lesion has clearly progressed since the procedure * PRE-REGISTRATION: Lesions must be accurately measured in at least one dimension (longest diameter to be recorded) as \>= 1 cm with CT or MRI (or \>= 1.5 cm short axis for lymph nodes). Non-measurable disease includes disease smaller than these dimensions or lesions considered truly non-measurable including: leptomeningeal disease, bone metastases, ascites, pleural or pericardial effusion, lymphangitic involvement of skin or lung * REGISTRATION: Confirmation of SSTR positivity by Alliance Imaging Core Lab (ICL) at Imaging and Radiation Oncology Core (IROC) Ohio central radiographic review * REGISTRATION: Patients with treatment-naive or previously-treated disease are allowed. Patients with previously-treated disease must have demonstrated radiographic disease progression on the prior therapy * REGISTRATION: No prior treatment with peptide receptor radionuclide therapy (PRRT) (e.g. lutetium Lu 177 dotatate) * REGISTRATION: No prior treatment with mammalian target of rapamycin (mTOR) inhibitors (e.g. deforolimus, everolimus, sirolimus, temsirolimus, etc.) * REGISTRATION: Prior treatment with hepatic artery embolization (including bland embolization, chemoembolization, and selective radioembolization) or ablative therapies (i.e. cryoablation, radiofrequency ablation, etc.) is allowed if measurable disease remains outside of the treated area or if there is documented disease progression in a treated site. Prior liver-directed (including ablative) treatment must be completed at least 28 days prior to registration * REGISTRATION: Prior treatment with 90-Yttrium radioembolization must be completed at least 6-weeks prior to registration * REGISTRATION: Radiation therapy to the lung and/or mediastinum must be completed at least 14 days prior to registration for stereotactic ablative and at least 28 days prior to registration for conventional fractionation * REGISTRATION: Prior treatment with systemic anticancer therapy must be completed at least 28 days prior to registration (except for somatostatin analogs in patients with functional tumors). Continuation of treatment with somatostatin analogs while on protocol therapy is allowed provided that the patient: * Has functional tumors (evidence of peptide hormones and/or bioactive substances associated with a clinical hormone syndrome such as carcinoid syndrome or Cushing's syndrome), and * Has previously demonstrated radiographic disease progression while on somatostatin analog therapy * REGISTRATION: Patients must have completed any major surgery at least 28 days prior to registration. Complete wound healing from major surgery should occur prior to registration * REGISTRATION: Patients should have improvement of any toxic effects of prior therapy (except alopecia, fatigue, and other non-reversible toxic effects such as neuropathy from cisplatin) to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 5.0, grade 1 or less * REGISTRATION: Not pregnant and not nursing * Therefore, for women of childbearing potential only, a negative pregnancy test done =\< 28 days prior to registration is required * REGISTRATION: Age \>= 18 years * REGISTRATION: Eastern Cooperative Oncology Group (ECOG) performance status 0-2 * REGISTRATION: Hemoglobin \>= 8.0 g/dL * REGISTRATION: Platelet count \>= 75,000/mm\^3 * REGISTRATION: Absolute neutrophil count (ANC) \>= 1,500/mm\^3 * REGISTRATION: Creatinine =\< 1.5 x upper limit of normal (ULN) OR calculated creatinine clearance \>= 40 mL/min * Calculated by the Cockcroft-Gault equation * REGISTRATION: Total bilirubin =\< 2.0 x ULN * In patients with Gilbert's syndrome, if total bilirubin is \> 2.0 x ULN, then direct bilirubin must be =\< 2.0 x ULN * REGISTRATION: Albumin \>= 2.8 g/dL * REGISTRATION: Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =\< 3.0 x ULN * REGISTRATION: No known central nervous system metastases unless treated and clinically stable for at least 14 days prior to registration. Patients on steroid support must be clinically stable on weaning doses of steroids * REGISTRATION: No other currently active malignancy that requires therapy or is expected to require therapy during the study (excluding non-melanoma skin cancers or in situ carcinomas, such as breast or cervical) * REGISTRATION: No known active hepatitis B (defined as hepatitis B surface antigen \[HbsAg\] reactive) or known active hepatitis C virus (defined as hepatitis C virus \[HCV\] ribonucleic acid \[RNA\] viral load detected). The exception is for patients with known active hepatitis B virus (defined as HbsAg reactive) infection, where the HBV viral load must be undetectable on suppressive therapy for patient to be eligible * REGISTRATION: Patients with known human immunodeficiency virus (HIV) infections on effective anti-retroviral therapy with undetectable viral load within 6 months of registration are eligible for this trial * REGISTRATION: No known active or uncontrolled infections requiring ongoing antifungals or antibiotics in the 3 days prior to registration * REGISTRATION: No receipt of live attenuated vaccines in the 7 days prior to registration * REGISTRATION: No known decompensated liver cirrhosis * REGISTRATION: No known prior drug-induced pneumonitis that was symptomatic or required treatment * REGISTRATION: No known medical condition causing an inability to swallow and no known impairment of gastrointestinal function that may significantly alter the absorption of an oral agent * REGISTRATION: No known hypersensitivity to everolimus or other rapamycin analogs (e.g. sirolimus, temsirolimus, etc.) * REGISTRATION: Concurrent somatostatin analog use while on protocol therapy is allowed provided that the patient: 1) has a functional tumor (evidence of peptide hormones and/or bioactive substances associated with a clinical hormone syndrome such as carcinoid syndrome or Cushing's syndrome), 2) has previously demonstrated radiographic disease progression while on somatostatin analog therapy * REGISTRATION: Chronic concomitant treatment with P-gp and strong CYP3A4 inhibitors and/or inducers is not allowed on the everolimus treatment arm of this study. Given that the study is randomized, all patients on P-gp and strong CYP3A4 inhibitors and/or inducers must discontinue the drug(s) 7 days prior to registration * RE-REGISTRATION: Confirmation of disease progression by RECIST v1.1 by real-time Alliance ICL at IROC Ohio central radiographic review * RE-REGISTRATION: Not pregnant and not nursing * Women of childbearing potential only, a negative pregnancy test done =\< 28 days prior to re-registration is required * RE-REGISTRATION: ECOG performance status 0-2 * RE-REGISTRATION: Hemoglobin \>= 8.0 g/dL * RE-REGISTRATION: Platelet count \>= 75,000/mm\^3 * RE-REGISTRATION: Absolute neutrophil count (ANC) \>= 1,500/mm\^3 * RE-REGISTRATION: Creatinine =\< 1.5 x upper limit of normal (ULN) OR calculated creatinine clearance \>= 40 mL/min * Calculated by the Cockcroft-Gault equation * RE-REGISTRATION: Total bilirubin =\< 2.0 x ULN * In patients with Gilbert's syndrome, if total bilirubin is \> 2.0 x ULN, then direct bilirubin must be =\< 2.0 x ULN * RE-REGISTRATION: Albumin \>= 2.8 g/dL * RE-REGISTRATION: AST/ALT =\< 3.0 x ULN

Study locations (29)

University of Alabama at Birmingham Cancer Center

Birmingham, Alabama, 35233

Withdrawn

Tower Cancer Research Foundation

Beverly Hills, California, 90211

Recruiting
Site Public Contact · Contact
Andrew E. Hendifar · Principal Investigator

Loma Linda University Medical Center

Loma Linda, California, 92354

Recruiting
Site Public Contact · Contact
Hamid R. Mirshahidi · Principal Investigator

Cedars-Sinai Medical Center

Los Angeles, California, 90048

Recruiting
Site Public Contact · Contact
Andrew E. Hendifar · Principal Investigator

UCSF Medical Center-Mission Bay

San Francisco, California, 94158

Recruiting
Site Public Contact · Contact
Claire Mulvey · Principal Investigator

Torrance Memorial Physician Network - Cancer Care

Torrance, California, 90505

Recruiting
Andrew E. Hendifar · Principal Investigator

MedStar Georgetown University Hospital

Washington D.C., District of Columbia, 20007

Recruiting
Site Public Contact · Contact
Chul Kim · Principal Investigator

UM Sylvester Comprehensive Cancer Center at Aventura

Aventura, Florida, 33180

Suspended

UM Sylvester Comprehensive Cancer Center at Coral Gables

Coral Gables, Florida, 33146

Recruiting
Site Public Contact · Contact
Lawrence M. Negret · Principal Investigator

UM Sylvester Comprehensive Cancer Center at Deerfield Beach

Deerfield Beach, Florida, 33442

Recruiting
Site Public Contact · Contact
Lawrence M. Negret · Principal Investigator

University of Miami Miller School of Medicine-Sylvester Cancer Center

Miami, Florida, 33136

Recruiting
Site Public Contact · Contact
Lawrence M. Negret · Principal Investigator

UM Sylvester Comprehensive Cancer Center at Plantation

Plantation, Florida, 33324

Recruiting
Site Public Contact · Contact
Lawrence M. Negret · Principal Investigator

University of Chicago Comprehensive Cancer Center

Chicago, Illinois, 60637

Recruiting
Christine M. Bestvina · Principal Investigator

UC Comprehensive Cancer Center at Silver Cross

New Lenox, Illinois, 60451

Recruiting
Christine M. Bestvina · Principal Investigator

University of Chicago Medicine-Orland Park

Orland Park, Illinois, 60462

Recruiting
Christine M. Bestvina · Principal Investigator

UI Health Care Mission Cancer and Blood - Ankeny Clinic

Ankeny, Iowa, 50023

Recruiting
Site Public Contact · Contact
Seema Harichand-Herdt · Principal Investigator

Iowa Methodist Medical Center

Des Moines, Iowa, 50309

Recruiting
Site Public Contact · Contact
Seema Harichand-Herdt · Principal Investigator

UI Health Care Mission Cancer and Blood - Des Moines Clinic

Des Moines, Iowa, 50309

Recruiting
Site Public Contact · Contact
Seema Harichand-Herdt · Principal Investigator

Dana-Farber Cancer Institute

Boston, Massachusetts, 02215

Recruiting
Site Public Contact · Contact
Jennifer A. Chan · Principal Investigator

Mayo Clinic in Rochester

Rochester, Minnesota, 55905

Recruiting
Site Public Contact · Contact
Thorvardur R. Halfdanarson · Principal Investigator

Missouri Baptist Medical Center

St Louis, Missouri, 63131

Recruiting
Site Public Contact · Contact
Bryan A. Faller · Principal Investigator

Duke University Medical Center

Durham, North Carolina, 27710

Recruiting
Site Public Contact · Contact
Michael A. Morse · Principal Investigator

Case Western Reserve University

Cleveland, Ohio, 44106

Recruiting
Site Public Contact · Contact
Amr Mohamed · Principal Investigator

Ohio State University Comprehensive Cancer Center

Columbus, Ohio, 43210

Suspended

Fox Chase Cancer Center

Philadelphia, Pennsylvania, 19111

Recruiting
Site Public Contact · Contact
Sukhmani K. Padda · Principal Investigator

Temple University Hospital

Philadelphia, Pennsylvania, 19140

Recruiting
Site Public Contact · Contact
Sukhmani K. Padda · Principal Investigator

University of Pittsburgh Cancer Institute (UPCI)

Pittsburgh, Pennsylvania, 15232

Recruiting
Site Public Contact · Contact
Liza C. Villaruz · Principal Investigator

Vanderbilt University/Ingram Cancer Center

Nashville, Tennessee, 37232

Recruiting
Site Public Contact · Contact
Robert A. Ramirez · Principal Investigator

Huntsman Cancer Institute/University of Utah

Salt Lake City, Utah, 84112

Recruiting
Site Public Contact · Contact
Heloisa P. Soares · Principal Investigator
Testing Lutetium Lu 177 Dotatate in Patients With Somatostatin Receptor Positive Advanced Bronchial Neuroendocrine Tumors | Cancerify