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

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ClinicalTrials.gov Identifier: NCT04665739
Recruitment Status : Not yet recruiting
First Posted : December 14, 2020
Last Update Posted : September 5, 2021
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)

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. 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. 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.

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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
Estimated Study Start Date : September 10, 2021
Estimated Primary Completion Date : July 1, 2024
Estimated Study Completion Date : July 1, 2024


Arm Intervention/treatment
Experimental: Arm I (lutetium Lu 177 dotatate)
Patients receive lutetium Lu 177 dotatate IV over 30-40 minutes on day 1. 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. 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
  • RAD001
  • Votubia
  • Zortress




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.



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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 6 months prior to registration
  • REGISTRATION: Radiation therapy (conventional fractionated or stereotactic ablative) to the lung and/or mediastinum must be completed at least 28 days prior to registration
  • 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),
    • Has been on a stable dose of somatostatin analog therapy for at least three months, 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 adequately treated, stable, and off steroid support for at least 14 days prior to registration
  • 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 uncontrolled diabetes mellitus, defined as fasting glucose > 200 mg/dL, despite optimal medical therapy
  • REGISTRATION: No known uncontrolled hypercholesterolemia (defined as fasting cholesterol > 300 mg/dL OR > 7.75 mmol/L) or hypertriglyceridemia (defined as fasting triglycerides > 2.5 x ULN), despite optimal medical therapy
  • 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] [qualitative] is detected)
  • REGISTRATION: Patients with human immunodeficiency virus (HIV) positivity are allowed if CD4 count > 500 cells/uL
  • 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 been on a stable dose of somatostatin analog therapy for at least three months, and 3) has previously demonstrated radiographic disease progression while on somatostatin analog therapy. For subjects receiving lutetium Lu 177 dotatate, there should be a minimum of 14 days between long-acting somatostatin analogue and lutetium Lu 177 dotatate dosing. Short-acting somatostatin analogs should not be administered within 24 hours of lutetium Lu 177 dotatate dosing. Following lutetium Lu 177 dotatate dosing, long-acting somatostatin analogs may be administered between 4 and 24 hours after each dose
  • REGISTRATION: Chronic concomitant treatment with strong inhibitors or inducers of CYP3A4 is not allowed on this study. Patients on strong inhibitors or inducers of CYP3A4 must discontinue the drug(s) 7 days prior to registration
  • REGISTRATION: Chronic concomitant treatment with strong inhibitors or inducers of P-glycoprotein (PgP) is not allowed on this study. Patients on strong inhibitors or inducers of PgP 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04665739


Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Thomas A Hope Alliance for Clinical Trials in Oncology
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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    Key Record Dates
Last Update Posted: September 5, 2021
Last Verified: September 2021
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

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Neoplasms
Neuroendocrine Tumors
Carcinoid Tumor
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms, Nerve Tissue
Neoplasms, Glandular and Epithelial
Adenocarcinoma
Carcinoma
Everolimus
Lutetium Lu 177 dotatate
Antineoplastic Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Molecular Mechanisms of Pharmacological Action
Radiopharmaceuticals