Comparing Retreatment of 177Lu-DOTATATE PRRT Versus Everolimus in Patients With Metastatic Unresectable Midgut Neuroendocrine Tumors, NET RETREAT Trial

Sponsor
National Cancer Institute (NCI) (NIH)
Overall Status
Not yet recruiting
CT.gov ID
NCT05773274
Collaborator
(none)
100
2
36.4

Study Details

Study Description

Brief Summary

This phase II trial compares the effect of retreatment with 177Lu-DOTATATE peptide receptor radionuclide therapy (PRRT) to treatment with everolimus in patients with midget neuroendocrine tumors that have spread from where it first started (primary site) to other places in the body (metastatic) and that cannot be removed by surgery (unresectable). PRRT involves treatment with a radioactive substance that is linked to a peptide receptor so that it will attach to a specific cell type when injected into the body. 177Lu-DOTATATE, a PRRT drug, may increase the length of time until worsening of disease by 8 months compared to the usual approach. Everolimus treats cancer by stopping cancer cells from reproducing and by decreasing blood supply to the cancer cells. Everolimus prevents transplant rejection by decreasing the activity of the immune system. Giving 177Lu-DOTATATE may work better in shrinking and stabilizing tumors in patients with neuroendocrine tumors.

Condition or Disease Intervention/Treatment Phase
  • Procedure: Biospecimen Collection
  • Procedure: Computed Tomography
  • Drug: Everolimus
  • Drug: Lutetium Lu 177 Dotatate
  • Other: Quality-of-Life Assessment
  • Other: Questionnaire Administration
Phase 2

Detailed Description

PRIMARY OBJECTIVE:
  1. To evaluate the effect of lutetium Lu 177 dotatate (177Lu-DOTATATE) versus (vs.) everolimus on progression-free survival (PFS) in patients with metastatic/unresectable midgut neuroendocrine tumour (NET) who have progressed following previous peptide receptor radionuclide therapy (PRRT).
SECONDARY OBJECTIVES:
  1. To evaluate the toxicity and safety of 177Lu-DOTATATE and everolimus. II. To determine the effect of 177Lu-DOTATATE vs. everolimus on overall response rate (ORR).

  2. To evaluate the effect of 177Lu-DOTATATE vs. everolimus on overall survival (OS).

  3. To evaluate post progression survival (PPS) and time to second objective disease progression (PFS2) for patients randomized to Arm 2 of the study and crossed over to Arm 1 at time of objective progression per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.

  4. To evaluate the effect of 177Lu-DOTATATE vs. everolimus on patient quality of life (QoL).

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM I: Patients receive 177Lu-DOTATATE intravenously (IV) on study. Patients also undergo computed tomography (CT) scan and collection of blood samples on study.

ARM II: Patients receive everolimus orally (PO) on study. Patients whose cancer worsens may receive re-treatment with 177Lu-DOTATATE IV on study. Patients also undergo CT scan and collection of blood samples on study.

Study Design

Study Type:
Interventional
Anticipated Enrollment :
100 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
NET RETREAT: A Phase II Study of 177 Lutetium-DOTATATE Retreatment vs. Everolimus in Metastatic/Unresectable Midgut NET
Anticipated Study Start Date :
Apr 19, 2023
Anticipated Primary Completion Date :
Apr 30, 2026
Anticipated Study Completion Date :
Apr 30, 2026

Arms and Interventions

Arm Intervention/Treatment
Experimental: Arm I (177Lu-DOTATATE)

Patients receive 177Lu-DOTATATE IV on study. Patients also undergo CT scan and collection of blood samples on study.

Procedure: Biospecimen Collection
Undergo collection of blood samples
Other Names:
  • Biological Sample Collection
  • Biospecimen Collected
  • Specimen Collection
  • Procedure: Computed Tomography
    Undergo CT scan
    Other Names:
  • CAT
  • CAT Scan
  • Computed Axial Tomography
  • Computerized Axial Tomography
  • Computerized Tomography
  • CT
  • CT Scan
  • tomography
  • 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
  • Other: Quality-of-Life Assessment
    Ancillary studies
    Other Names:
  • Quality of Life Assessment
  • Other: Questionnaire Administration
    Ancillary studies

    Active Comparator: Arm II (everolimus)

    Patients receive everolimus PO on study. Patients whose cancer worsens may receive re-treatment with 177Lu-DOTATATE IV on study. Patients also undergo CT scan and collection of blood samples on study.

    Procedure: Biospecimen Collection
    Undergo collection of blood samples
    Other Names:
  • Biological Sample Collection
  • Biospecimen Collected
  • Specimen Collection
  • Procedure: Computed Tomography
    Undergo CT scan
    Other Names:
  • CAT
  • CAT Scan
  • Computed Axial Tomography
  • Computerized Axial Tomography
  • Computerized Tomography
  • CT
  • CT Scan
  • tomography
  • Drug: Everolimus
    Given PO
    Other Names:
  • 42-O-(2-Hydroxy)ethyl Rapamycin
  • Afinitor
  • Certican
  • RAD 001
  • RAD001
  • Votubia
  • Zortress
  • Other: Quality-of-Life Assessment
    Ancillary studies
    Other Names:
  • Quality of Life Assessment
  • Other: Questionnaire Administration
    Ancillary studies

    Outcome Measures

    Primary Outcome Measures

    1. Progression-free survival (PFS) [From randomization to any documented evidence of tumour progression or death from any cause, assessed up to 3 years]

      The PFS of patients of both treatment groups will be described by Kaplan-Meier method and the median PFS will be estimated using the same method. A one-sided stratified log-rank test adjusting for the stratification factor at randomization will be the primary method to compare the difference in PFS between the experimental and control treatments, at the 5% level. A stratified Cox model adjusting for the stratification factor at randomization and with one single treatment covariate will be used to estimate the hazard ratio and associated one-sided 95% confidence interval.

    Secondary Outcome Measures

    1. Overall survival (OS) [From randomization to the death from any cause, assessed up to 3 years]

      The OS of patients of both treatment groups will be described by Kaplan-Meier method and the median OS will be estimated using the same method. A one-sided stratified log-rank test adjusting for the stratification factor at randomization will be the primary method to compare the difference in OS between the experimental and control treatments, at the 5% level. A stratified Cox model adjusting for the stratification factor at randomization and with one single treatment covariate will be used to estimate the hazard ratio and associated one-sided 95% confidence interval.

    2. Objective response rate (ORR) [Up to 3 years]

      Defined as the proportion of patients with a documented complete response and partial response based on Response Evaluation Criteria in Solid Tumors 1.1. The primary estimate of ORR will be based on all patients randomized. A Cochran-Mantel-Haenszel test adjusting for the stratification factor at the time of randomization will be used to compare the objective response rates between two arms.

    3. Post progression survival (PPS) [From objective progression on everolimus to objective progression or death from any cause after cross-over to receive 177Lu-DOTATATE, assessed up to 3 years]

      Median PPS and associated two-sided 90% confidence interval will be estimated using the Kaplan-Meier method.

    4. Time to second objective disease progression (PFS2) [From randomization to objective tumor progression or death from any cause after the cross-over, assessed up to 3 years]

      Median PFS2 and associated two-sided 90% confidence interval will be estimated using the Kaplan-Meier method.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:
    • Patients must be at least >= 18 years of age

    • Metastatic, histologically confirmed grade 1 or 2 well-differentiated midgut neuroendocrine tumours, including NETs of unknown primary thought to be of midgut origin, with positive Gallium-68 DOTATATE scan or Copper-64 DOTATATE scan within the last 12 months is recommended but within the last 36 months is allowed. Lesions on Gallium-68 or Copper-64 DOTATATE scan will be considered positive if the maximum standardized uptake value (SUVmax) of target lesion is > SUV mean of normal liver parenchyma

    • Have received 3 or 4 cycles of PRRT or a cumulative exposure of 22,200 MBq (600mCi) or 29,600 MBq (800 mCi) within a 52-week period. Previous therapy with everolimus for a maximum period of 1 month is permitted. No previous targeted alpha therapy is permitted. No previous alkylator therapy (i.e. Temodar) is permitted

    • Have had radiological progression per RECIST 1.1 after prior PRRT treatment and no sooner than 12 months from last scan performed post completion of initial PRRT where either stable disease, partial response, or complete response has been maintained throughout

    • Have not received any intervening therapy after initial PRRT

    • No ongoing toxicity from prior PRRT that is grade 3 or higher according to Common Terminology Criteria for Adverse Events (CTCAE) 5.0

    • Eastern Cooperative Oncology Group (ECOG) performance status =< 2

    • Hemoglobin >= 80 g/L (>= 8.0 g/dL) (measured within 28 days prior to enrollment)

    • Absolute neutrophil count >= 1.0 x 109/L (>= 1000/mm3) (measured within 28 days prior to enrollment)

    • Platelets >= 80 x 109/L (>= 80 x 103/mm^3) (measured within 28 days prior to enrollment)

    • Total bilirubin < 1.5 x upper limit of normal (ULN) (upper limit of normal) (measured within 28 days prior to enrollment)

    • If confirmed Gilbert's, eligible providing =< criteria x ULN

    • Creatinine clearance > 50 mL/min (measured within 28 days prior to enrollment)

    • Creatinine clearance to be measured directly by 24 hour urine sampling or as calculated by Cockcroft and Gault equation

    • Patient is able (i.e. sufficiently fluent) and willing to complete the quality of life questionnaires in either English, French or Spanish. The baseline assessment must be completed within required timelines, prior to enrollment. Inability (lack of comprehension in English, French or Spanish, or other equivalent reason such as cognitive issues or lack of competency) to complete the questionnaires will not make the patient ineligible for the study. However, ability but unwillingness to complete the questionnaires will make the patient ineligible

    • Prior or current use of somatostatin analogues is allowed for carcinoid syndrome control or in PRRT re-treatment patient population (Arm 1). Patients randomized to everolimus (Arm 2) will not be allowed to continue somatostatin analogues unless they have functional carcinoid syndrome

    • Patient consent must be appropriately obtained in accordance with applicable local and regulatory requirements. Each patient must sign a consent form prior to enrollment in the trial to document their willingness to participate

    • Patients of childbearing potential must have agreed to use a highly effective contraceptive method during protocol treatment and for 7 months after the last dose of protocol treatment. A woman is considered to be of "childbearing potential" if she has had menses at any time in the preceding 12 consecutive months. In addition to routine contraceptive methods, "effective contraception" also includes heterosexual celibacy and surgery intended to prevent pregnancy (or with a side-effect of pregnancy prevention) defined as a hysterectomy, bilateral oophorectomy or bilateral tubal ligation, or vasectomy/vasectomized partner. However, if at any point a previously celibate patient chooses to become heterosexually active during the time period for use of contraceptive measures outlined in the protocol, he/she is responsible for beginning contraceptive measures

    • Women of childbearing potential will have a pregnancy test to determine eligibility as part of the Pre-Study Evaluation; this may include an ultrasound to rule-out pregnancy if a false-positive is suspected. For example, when beta-human chorionic gonadotropin is high and partner is vasectomized, it may be associated with tumour production of human chorionic gonadotropin (hCG), as seen with some cancers. Patient will be considered eligible if an ultrasound is negative for pregnancy

    • Patients must be accessible for treatment, response assessment, and follow up. Patients enrolled on this trial must be treated and followed at the participating center. Investigators must assure themselves the patients enrolled on this trial will be available for complete documentation of the treatment, adverse events, and follow-up

    • Patients must agree to return to their primary care facility for any adverse events which may occur through the course of the trial

    • Patient must have access to everolimus. In the event that site/investigator is unable to provide access to the drug, patient will not be eligible for this trial

    • Human immunodeficiency virus (HIV) infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial

    • Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial

    Exclusion Criteria:
    • Major surgical procedures within 6 weeks from randomization date

    • Known brain metastases, unless these metastases have been treated, stabilized and off steroids for at least 4 weeks prior to enrollment in the study. Patients with a history of brain metastases must have a head CT and/or MRI with contrast to document stable disease prior to enrollment in the study

    • Uncontrolled congestive heart failure no worse than New York Heart Association Class (NYHA) IIB

    • Inability to swallow oral medications or gastrointestinal disease limiting absorption of oral agents

    • Patients with any other significant medical or surgical condition, currently uncontrolled by treatment, which may interfere with completion of the study

    • Pregnant women are excluded from this study because 177Lu-DOTATATE is a peptide receptor radionuclide therapy with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with 177Lu-DOTATATE, breastfeeding should be discontinued if the mother is treated with everolimus or 177Lu-DOTATATE and for 2.5 months following the last treatment

    Contacts and Locations

    Locations

    No locations specified.

    Sponsors and Collaborators

    • National Cancer Institute (NCI)

    Investigators

    • Principal Investigator: Simron Singh, Canadian Cancer Trials Group

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    None provided.
    Responsible Party:
    National Cancer Institute (NCI)
    ClinicalTrials.gov Identifier:
    NCT05773274
    Other Study ID Numbers:
    • NCI-2023-00118
    • NCI-2023-00118
    • CCTG-NE1
    • CCTG-NE1
    • U10CA180863
    First Posted:
    Mar 17, 2023
    Last Update Posted:
    Mar 17, 2023
    Last Verified:
    Jan 1, 2023
    Individual Participant Data (IPD) Sharing Statement:
    Yes
    Plan to Share IPD:
    Yes
    Studies a U.S. FDA-regulated Drug Product:
    Yes
    Studies a U.S. FDA-regulated Device Product:
    No
    Additional relevant MeSH terms:

    Study Results

    No Results Posted as of Mar 17, 2023