Dosimetry Based PRRT Versus Standard Dose PRRT With Lu-177-DOTATOC in NEN Patients (DOBATOC)

Dosimetry Based PRRT Versus Standard Dose PRRT With Lu-177-DOTATOC in NEN Patients- a Randomized Study; a Step Towards Tailored PRRT

In this study, we want to randomize patients with neuroendocrine neoplasms (NENs) who are eligible for peptide receptor radionuclide therapy (PRRT), to either standard PRRT consisting of 4 treatments with 7.4 GBq Lu-177-DOTATOC (standard arm) or 4 treatments with individualized doses of Lu-177-DOTATOC (dosimetry arm). In the dosimetry arm, the first dose depends on the patients' kidney function and thereafter the absorbed dose to the kidneys at the previous treatment. A max of 20GBq will be administered at the first treatment and 25GBq at treatment 2-4. We aim to reach an accumulated kidney dose of 24Gy.

After the first treatment all patients will go through three SPECT/CT scans 24 hours, 4 days, and 7 days, after treatment to calculate absorbed kidney dose. The patients in the standard dose treatment arm will have one SPECT/CT scan after each of the last three treatments; all performed 24 hours after treatment, used to approximate the kidney dose assuming the clearance of the Lu-177 DOTATOC is the same after all treatments. The patients in the dosimetry based treatment arm will go through three SPECT/CT scans after all four treatments for dosimetry calculation.

Bone marrow dosimetry is calculated after all treatments in the dosimetry based treatment arm and after the first treatment in the standard treatment arm. For bone marrow dosimetry, blood samples are drawn right before administration of Lu-177 DOTATOC (time 0) and 3 minutes, 45 minutes, 2 hours, 4 hours, 7-8 hours, 24 hours, 4 days, and 7 days after administration of Lu-177 DOTATOC.

Standard blood samples are routinely drawn every 2nd week after every treatment in all included patients and analysed regarding liver, kidney and bone marrow function. Kidney clearance is evaluated with Tc-DTPA clearance at baseline.

Blood and urinary samples will be collected at baseline and 3 months after the last treatment for kidney fibrosis analyses.

At baseline, blood and urine samples are collected for a biobank. All included patients fill in validated quality of life questionaires at all treatments.

To evaluate the effect of the treatment, all patients will be evaluated with standard CT scans prior to treatment and 3 and 9 months after the 4th treatment. Ga-68 DOTATOC PET will be performed at baseline and 6 and 12 months after the last treatment.

Study Overview

• Status: Recruiting
• Conditions: Neuroendocrine Neoplasm
• Intervention / Treatment: Drug: Lu-177-DOTA-Octreotide

• Study Type: Interventional
• Enrollment (Estimated): 100
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Tine N Gregersen, MD, PhD; Phone Number: +4522334161; Email: tigreg@rm.dk

Study Locations

• Denmark
  • Palle Juul-Jensens Boulevard
    • Aarhus, Palle Juul-Jensens Boulevard, Denmark, 8200
      • Recruiting
      • Aarhus University Hospital, department of Nuclear medicine and PET centre
      • Contact: Tine N Gregersen, MD, PhD; Phone Number: 004522334161; Email: tigreg@rm.dk
      • Sub-Investigator: Anne K Arveschoug, MD
      • Sub-Investigator: Peter F Staanum, Physicist, Ph.D
      • Sub-Investigator: Peter Iversen, MD, PhD
      • Sub-Investigator: Gitte A Dam, MD, PhD
      • Sub-Investigator: Henning Gronbaek, Prof MD, PhD
      • Sub-Investigator: Gerda E Villadsen, MD, PhD

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• 1. Male or female patients 18 years of age or more
• 2. NEN confirmed by histology
• 3. Clinical, PET/CT or CT proven progression despite standard treatment with somatostatin analogues, targeted therapy (Everolimus, sunitinib), chemotherapy (STZ/5-FU, temozolomide/capecitabine) OR intolerable side effects caused by these standard treatment OR unmanageable carcinoid symptoms
• 4. WHO/ ECOG Performance Status of 0-2
• 5. Life expectancy more than 6 months
• 6. Uptake higher than liver in primary tumor or metastases on Ga-DOTATOC PET/CT (Krenning 3 or 4), if the scan is more than 3 months old at inclusion time, a new scan should be done.
• 7. Adequate organ function as defined by:
• Adequate kidney function: Patient glomerular filtration rate >30 ml/min measured by Tc-DTPA clearance

• Adequate bone marrow function:

  • WBC ≥ 2.0 x 109/L
  • Platelets ≥ 100 x 109/L
  • Hb ≥ 6 mmol/l (≥9.67 g/dL)

• 8. Willingness and ability to comply with scheduled visits for SPECT/CT scans, treatment plans, laboratory tests and other study procedures.

  9. Written informed consent obtained prior to any screening procedures

Exclusion Criteria:

• 1. Tumor amenable to surgery and/or radiofrequency ablation
• 2. Patients who are unable to stay isolated for 24 hours
• 3. Previous PRRT
• 4. Female patients who are pregnant or lactating. Women who are of childbearing potential (defined as all women physiologically capable of becoming pregnant) have to practice an effective method of contraception/birth control. Fertile female patients have to take a urinary pregnancy test, to ensure that they are not pregnant, before they can enter the study. After entering the study, they have to use effective contraception during the study period and 6 months after. Effective contraception methods include:
• Use of oral, injected or implanted hormonal methods of contraception or
• Placement of an intrauterine device (IUD) or intrauterine system (IUS)
• Total abstinence or patient sterilization (male or female)
• 5. Male patients are not allowed to conceive pregnancy for 6 months after last treatment cycle
• 6. Known to be hypersensitive to any component of the Lu-177-DOTATOC
• 7. Patients with meningioma

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Standard; Patients in this arm receive our standard treatment. Four treatment with standard dose of 7.4 GBq Lu-177-DOTATOC	Drug: Lu-177-DOTA-Octreotide; Lu-177-DOTATOC in standard doses or individualized doses.
Experimental: Dosimetry; Patients in this treatment arm receive individualized calcuted treatment depending on kidney function and kidney dose. The treatment activity can differ from one treatment to the next.	Drug: Lu-177-DOTA-Octreotide; Lu-177-DOTATOC in standard doses or individualized doses.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression free survival	Defined as time from randomization to documented disease progression or death by any cause, evaluated by CT, RECIST 1.1.	12 months after LPLV

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Tumor dose	Difference in tumor dose between dosimetry based and standard PRRT treatment groups and between patients in the dosimetry based treatment group over time.	Through out the study efter each patient has completed treatment, up to 48 weeks

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Kidney toxicity	Measured by Tc-DTPA clearance	At baseline and after 3, 6 and 12 months
Kidney toxicity	Measured by kidney fibrosis markers PRO-C6, PRO-C3, and C3M two groups	At baseline and 3 months after the last treatment
Bone marrow function, hemoglobin	Measured by hemoglobin in the two groups	Every second week in up to 64 weeks
Bone marrow function, white blood cells	Measured by white blood cells in the two groups	Every second week in up to 64 weeks
Bone marrow function, platelets	Measured by platelets in the two groups	Every second week in up to 64 weeks
Subjective side effects	Evaluated by use of dedicated questionaire with score from 0-3	After every treatment, up to 48 weeks
Quality of life score 1	Evaluated by questionnaire EORTC QLQ-30 filled out at every treatment	After every treatment, up to 48 weeks
Quality of life score 2	Evaluated by questionnaire QLQ-GI.NET21. filled out at every treatment	After every treatment, up to 48 weeks
Overall survival	Registration of time for baseline to death	3 years after LPLV

Collaborators and Investigators

• Sponsor: Tine Gregersen, MD

Study record dates

Study Major Dates

• Study Start (Actual): February 1, 2020
• Primary Completion (Estimated): December 1, 2025
• Study Completion (Estimated): December 1, 2026

Study Registration Dates

• First Submitted: September 1, 2020
• First Submitted That Met QC Criteria: June 7, 2021
• First Posted (Actual): June 8, 2021

Study Record Updates

• Last Update Posted (Actual): December 9, 2024
• Last Update Submitted That Met QC Criteria: December 6, 2024
• Last Verified: December 1, 2024

More Information

Terms related to this study

• Keywords: Dosimetry; Peptide receptor radionuclide therapy
• Additional Relevant MeSH Terms: Neoplasms; Neoplasms by Histologic Type; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Neuroendocrine Tumors; Antineoplastic Agents; Molecular Mechanisms of Pharmacological Action; Gastrointestinal Agents; Antineoplastic Agents, Hormonal; Radiopharmaceuticals; Lutetium Lu 177 dotatate; Octreotide
• Other Study ID Numbers: EudraCT 2019-002450-23

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No