Testing Lutetium Lu 177 Dotatate in Patients With Somatostatin Receptor Positive Advanced Bronchial Neuroendocrine Tumors

• ClinicalTrials.gov Identifier: NCT04665739
• Recruitment Status: Recruiting
• First Posted: December 14, 2020
• Last Update Posted: September 28, 2023
• Sponsor: National Cancer Institute (NCI)
• Information provided by (Responsible Party): National Cancer Institute (NCI)

Study Description

Brief 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). Radioactive drugs, such as lutetium Lu 177 dotatate, may carry radiation directly to tumor cells and may reduce harm to normal cells. Lutetium Lu 177 dotatate may be more effective than everolimus in shrinking or stabilizing advanced bronchial neuroendocrine tumors.

Condition or disease	Intervention/treatment	Phase
Advanced Lung Carcinoid Tumor; Functioning Lung Carcinoid Tumor; Locally Advanced Lung Neuroendocrine Neoplasm; Lung Atypical Carcinoid Tumor; Lung Neuroendocrine Neoplasm; Lung Typical Carcinoid Tumor; Metastatic Lung Carcinoid Tumor; Metastatic Lung Neuroendocrine Neoplasm; Non-Functioning Lung Carcinoid Tumor; Recurrent Lung Neuroendocrine Neoplasm; Unresectable Lung Carcinoid Tumor; Unresectable Lung Neuroendocrine Neoplasm	Drug: Everolimus; Drug: Lutetium Lu 177 Dotatate	Phase 2

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.

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.

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 108 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Randomized Phase II Trial of Lutetium Lu 177 Dotatate Versus Everolimus in Somatostatin Receptor Positive Bronchial Neuroendocrine Tumors
• Actual Study Start Date: February 3, 2023
• Estimated Primary Completion Date: July 1, 2024
• Estimated Study Completion Date: July 1, 2024

Arms and Interventions

Arm	Intervention/treatment
Experimental: Arm I (lutetium Lu 177 dotatate); Patients receive lutetium Lu 177 dotatate 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.	Drug: Lutetium Lu 177 Dotatate; Given IV; Other Names: 177 Lu-DOTA-TATE; 177 Lu-DOTA-Tyr3-Octreotate; 177Lu-DOTA0-Tyr3-Octreotate; Lutathera; Lutetium Lu 177 DOTA(0)-Tyr(3)-Octreotate; Lutetium Lu 177-DOTA-Tyr3-Octreotate; lutetium Lu 177-DOTATATE; Lutetium Oxodotreotide Lu-177
Active Comparator: Arm II (everolimus); Patients receive everolimus PO 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.	Drug: Everolimus; Given PO; Other Names: 42-O-(2-Hydroxy)ethyl Rapamycin; Afinitor; Certican; RAD 001; RAD-001; RAD001; Votubia; Zortress

Outcome Measures

Primary Outcome Measures :

1. Median progression-free survival (PFS) [ Time Frame: From randomization until either radiographic progression confirmed by central radiology review or death, assessed up to 5 years from study registration ]
   Will be compared between patients with a bronchial neuroendocrine tumor (NET) 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.

Secondary Outcome Measures :

1. 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 ]
   The distribution of OS will be estimated using the method of Kaplan-Meier. The median OS, along with 90% CIs, will be estimated by the two treatment groups. OS will be compared between the two between treatment arms using the stratified log-rank test at a one-sided 10% level of significance.
2. Overall response rate (ORR) [ Time Frame: Up to 5 years from study registration ]
   Defined as the proportion of patients in each arm whose best response is either complete response (CR) or partial response (PR). Will be estimated using point estimates and 95% CIs according to the methods in Duffy and Santner.
3. Incidence of adverse events [ Time Frame: Up to 5 years from study registration ]
   Will evaluate and compare the toxicity profile of lutetium Lu 177 dotatate and everolimus. As per National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version (v)5.0, the term toxicity is defined as adverse events that are classified as either possibly, probably, or definitely related to the study treatment.

Other Outcome Measures:

1. Incidence of late toxicities of lutetium Lu 177 dotatate therapy [ Time Frame: More than 30 days after treatment ]
   The incidence of grade 3+ late toxicities will be analyzed in a descriptive manner. Incidence will be described for each treatment arm. Frequency tables will be reviewed for patterns.
2. Pretreatment disease burden [ Time Frame: Baseline ]
3. Somatostatin receptor status on DOTATATE PET (or other SSTR-PET) [ Time Frame: Up to 5 years from study registration ]
4. Dosimetry of response [ Time Frame: Up to 5 years from study registration ]
5. Response rate [ Time Frame: Up to 5 years from study registration ]
   The proportion of patients in each carcinoid group with either CR or PR as their best response will be estimated using point estimates and 95% CIs according to the methods in Duffy and Santner. ORR will be compared between treatment arms using the 2-sample z-test to compare sample proportion at a one-sided 5% level of significance.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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 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 or other ablative treatment must be completed at least 28 days prior to registration
• REGISTRATION: Prior treatment with 90-Yttrium radioembolization must be completed at least 3 months 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, because this study involves:

  • An investigational agent whose genotoxic, mutagenic, and teratogenic effects on the developing fetus and newborn are unknown, and
  • An agent that has known genotoxic, mutagenic, and teratogenic effects
  • Therefore, for women of childbearing potential only, a negative pregnancy test done =< 14 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 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 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

  • Therefore, for women of childbearing potential only, a negative pregnancy test done =< 14 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

Contacts and Locations

Locations

United States, California

Tower Cancer Research Foundation; Recruiting

Beverly Hills, California, United States, 90211

Contact: Site Public Contact towercancerresearch@toweroncology.com

Principal Investigator: Andrew E. Hendifar

Cedars Sinai Medical Center; Recruiting

Los Angeles, California, United States, 90048

Contact: Site Public Contact 310-423-8965

Principal Investigator: Andrew E. Hendifar

UCSF Medical Center-Mission Bay; Recruiting

San Francisco, California, United States, 94158

Contact: Site Public Contact 877-827-3222 cancertrials@ucsf.edu

Principal Investigator: Emily K. Bergsland

Torrance Memorial Physician Network - Cancer Care; Recruiting

Torrance, California, United States, 90505

Contact: Site Public Contact 310-750-3300 courtney.steeneken@tmphysicians.com

Principal Investigator: Andrew E. Hendifar

United States, Iowa

Iowa Methodist Medical Center; Recruiting

Des Moines, Iowa, United States, 50309

Contact: Site Public Contact 515-241-6727

Principal Investigator: Joshua Lukenbill

Medical Oncology and Hematology Associates-Des Moines; Recruiting

Des Moines, Iowa, United States, 50309

Contact: Site Public Contact 515-241-3305

Principal Investigator: Joshua Lukenbill

United States, Massachusetts

Alliance for Clinical Trials in Oncology; Recruiting

Boston, Massachusetts, United States, 02115

Contact: Thomas A. Hope thomas.hope@ucsf.edu

Principal Investigator: Thomas A. Hope

Dana-Farber Cancer Institute; Recruiting

Boston, Massachusetts, United States, 02215

Contact: Site Public Contact 877-442-3324

Principal Investigator: Jennifer A. Chan

United States, Minnesota

Mayo Clinic in Rochester; Recruiting

Rochester, Minnesota, United States, 55905

Contact: Site Public Contact 855-776-0015

Principal Investigator: Thorvardur R. Halfdanarson

United States, Ohio

Case Western Reserve University; Recruiting

Cleveland, Ohio, United States, 44106

Contact: Site Public Contact 800-641-2422 CTUReferral@UHhospitals.org

Principal Investigator: Amr Mohamed

Ohio State University Comprehensive Cancer Center; Recruiting

Columbus, Ohio, United States, 43210

Contact: Site Public Contact 800-293-5066 Jamesline@osumc.edu

Principal Investigator: Vineeth Sukrithan

United States, Pennsylvania

University of Pittsburgh Cancer Institute (UPCI); Recruiting

Pittsburgh, Pennsylvania, United States, 15232

Contact: Site Public Contact 412-647-8073

Principal Investigator: Liza C. Villaruz

United States, Tennessee

Vanderbilt University/Ingram Cancer Center; Suspended

Nashville, Tennessee, United States, 37232

United States, Utah

Huntsman Cancer Institute/University of Utah; Recruiting

Salt Lake City, Utah, United States, 84112

Contact: Site Public Contact 888-424-2100 cancerinfo@hci.utah.edu

Principal Investigator: Sonam Puri

Sponsors and Collaborators

National Cancer Institute (NCI)

Investigators

• Principal Investigator: Thomas A Hope; Alliance for Clinical Trials in Oncology

More Information

• Responsible Party: National Cancer Institute (NCI)
• ClinicalTrials.gov Identifier: NCT04665739
• Other Study ID Numbers: NCI-2020-12905; NCI-2020-12905 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ); A021901 ( Other Identifier: Alliance for Clinical Trials in Oncology ); A021901 ( Other Identifier: CTEP ); U10CA180821 ( U.S. NIH Grant/Contract )
• First Posted: December 14, 2020
• Last Update Posted: September 28, 2023
• Last Verified: September 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: NCI is committed to sharing data in accordance with NIH policy. For more details on how clinical trial data is shared, access the link to the NIH data sharing policy page.
• URL: https://grants.nih.gov/policy/sharing.htm

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Neuroendocrine Tumors; Neoplasms; Carcinoid Tumor; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms, Nerve Tissue; Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Everolimus; Lutetium Lu 177 dotatate; MTOR Inhibitors; Protein Kinase Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs; Antineoplastic Agents; Radiopharmaceuticals