Systemic Targeted Adaptive RadioTherapy of NeuroEndocrine Tumors. (START-NET)

Systemic Targeted Adaptive RadioTherapy of NeuroEndocrine Tumors. An Open-label, Multicenter, Randomized Phase III Trial Comparing Safety and Efficacy of Personalized Versus Non-personalized Radionuclide Therapy With 177Lu (Lutetium)-DOTATOC.

There are several ways of personalizing PRRT (peptide receptor radionuclide treatment) in NEN (neuroendocrine neoplasia). Nevertheless, the current treatment regimen is not personalized. This trial aims to compare personalized PRRT to non-personalized PRRT in terms of safety, efficacy and resource demands in order to optimize treatment outcomes in an evidence-based manner in future.

Study Overview

• Status: Recruiting
• Conditions: Neuroendocrine Tumors
• Intervention / Treatment: Drug: 177Lu-DOTATOC; Drug: Capecitabine

• Study Type: Interventional
• Enrollment (Estimated): 300
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Pernilla Asp, MD, Senior Consultant; Phone Number: +46 46 17 75 20; Email: pernilla.p.asp@skane.se

Study Locations

• Sweden
  • Gothenburg, Sweden
    • Recruiting
    • Sahlgrenska University Hospital, Dept. of Oncology
    • Contact: Anders Hallqvist, MD; Senoor consultant; Phone Number: +46 31 -342 10 00; Email: anders.hallqvist@vgregion.se
    • Principal Investigator: Anders Hallqvist, MD, Senior Consultant
  • Lund, Sweden, SE-226 52
    • Recruiting
    • Skåne University Hospital, Dept. of Oncology
    • Contact: Pernilla Asp, MD, Senior Consultant; Phone Number: +46 46 17 75 20; Email: pernilla.p.asp@skane.se
    • Principal Investigator: Pernilla Asp, MD, Senior consultant
  • Stockholm, Sweden, SE-171 76
    • Recruiting
    • Karolinska University Hospital, Dept. of Oncology
    • Contact: Renske Altena, MD, Senior Consultant; Phone Number: +46 8 517 700 00
    • Principal Investigator: Renske ltena, MD, Senior Consultant
  • Uppsala, Sweden, SE-752 37
    • Recruiting
    • Accademical Hospital, Uppsala, Dept. of Oncology
    • Contact: Katarzyna Fröss-Baron, MD, Senior Consultant; Phone Number: +46 18 611 40 68; Email: katarzyna.fross_baron@medsci.uu.se
    • Principal Investigator: Katarzyna Fröss-Baron, MD, Senior Consultant

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Age ≥18 years
• Written informed consent
• Eastern Cooperative Oncology Group (ECOG) 0-1
• Presence of histologically confirmed, advanced, well-differentiated, inoperable neuroendocrine tumors (NET) of any primary tumor origin and any grade, except for pheochromocytoma and paraganglioma.
• Somatostatine receptor (SSTR)-expression in tumor lesions > basal liver uptake on 68Ga-DOTA-PET
• Radiologically progressive disease within the last 1-24 months according to common clinical criteria and confirmed by the institutional multidisciplinary conference for the treatment of NETs. The CT/MRI that shows tumor progression compared to screening/baseline must have been performed 1-24 months earlier.
• All previous anti-tumor treatment except SSA must be terminated at least 4 weeks before start of treatment within the trial.
• Measurable disease according to RECIST v 1.1
• Given the available, approved anti-tumor treatments and the specific characteristics of the patient and the tumor, the investigator judges peptide receptor radionuclide therapy (PRRT) to be the treatment of choice
• GFR > 50 ml/min/1.73 m2 as determined by iohexol- or 51Cr-EDTA clearance, calculated according to a combination of LMR18 and CAPA formulas, or equally accurate method
• Hemoglobin > 90 g/L, platelets >100 x109/L, leukocytes > 3.0x109/L, neutrophils > 1.5 x109/L, aspartate transaminase (ASAT)/alanine aminotransferase (ALAT) < 3 x ULN, bilirubin < 2 x upper limit of normal (ULN), albumin > 25 g/L
• For women of child-bearing potential, highly effective contraception should be used from the time of inclusion up to at least six months after the end of treatment (EOT) visit.

Exclusion Criteria:

• Pregnancy or lactation
• Previous treatment with PRRT
• Concomitant systemic anti-tumor therapy other than somatostatin analogue (SSA)
• Contraindications for treatment with capecitabine according to the approved label.
• Discordance between CT/MRI/18F-FDG-PET and 68Ga-DOTA-PET, with evidence of tumor lesions without uptake on 68Ga-DOTATOC.
• Any other serious, uncontrolled medical or psychiatric condition that, in the opinion of the investigator, precludes the patient from participation in the trial
• Unwillingness, or inability, to participate in any part of the trial procedures or treatments.

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

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 177Lu-DOTATOC + Capecitabine; Patients with 68Ga-DOTA- and 18F-FDG-PET-positive NET will receive a combination of intravenous 7.5 GBG (gigabequerel) 177Lu-DOTATOC for about 7 cycles in combination with capecitabine (4 cycles, cycle length 3 weeks, with one week without capecitabine, dosing 825 mg twice daily) and PRRT to a cumulative renal AD (absorbed dose) limit of 30 Gy and dosimetry-based PRRT. .	Drug: 177Lu-DOTATOC; The investigational medicinal product (IMP) is 177Lu-DOTATOC which is registered as an orphan drug by the EMA ( European Medicines Agency) for the treatment of GEP-NEN (gastro-entero-pancreatic neuroendocrine tumor). The IMP will be administered to participants both in the control arm and the experimental arms, but with different intervals, but the same activity; 7.5 Gbq per dosing.; Drug: Capecitabine; Will be given orally with a dose of 825/m2 twice daily, starting on day 1 of each of the 4 first treatment cycles, cycle length 3 weeks.
Experimental: 177Lu-DOTATOC; Intravenous infusion for about 7 treatment cycles with 7.5 GBq 177Lu-DOTATOC with an interval of 10 ± 2 weeks and PRRT to a cumulative renal AD limit of 30 Gy and dosimetry-based PRRT.	Drug: 177Lu-DOTATOC; The investigational medicinal product (IMP) is 177Lu-DOTATOC which is registered as an orphan drug by the EMA ( European Medicines Agency) for the treatment of GEP-NEN (gastro-entero-pancreatic neuroendocrine tumor). The IMP will be administered to participants both in the control arm and the experimental arms, but with different intervals, but the same activity; 7.5 Gbq per dosing.
Active Comparator: Standard 177Lu-DOTATOC; Standard treatment of 177Lu-DOTATOC with treatment for 4 cycles.	Drug: 177Lu-DOTATOC; The investigational medicinal product (IMP) is 177Lu-DOTATOC which is registered as an orphan drug by the EMA ( European Medicines Agency) for the treatment of GEP-NEN (gastro-entero-pancreatic neuroendocrine tumor). The IMP will be administered to participants both in the control arm and the experimental arms, but with different intervals, but the same activity; 7.5 Gbq per dosing.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Median progression free survival (PFS) defined as time from randomization to radiological progression.	Time to progression is evaluated by CT (computed tomography) or MRI (magnetic resonance imaging) after every 16-22 weeks.	Before start of treatment (within 4 weeks), then every 10 +/- 2 weeks weeks, at follow up (every 3-6 month (investigators choice) until progression.
Median progression free survival (PFS) defined as time from randomization to radiological progression.	Time to progression is evaluated by CT (computed tomography) or MRI (magnetic resonance imaging) after every 10 +/- 2 weeks.	Before start of treatment (within 4 weeks), then every 10 +/- week at follow up (every 3-6 month (investigators choice) until death.
Median progression free survival (PFS) defined as time from randomization to radiological progression,	Time to progression is evaluated by CT (computed tomography) or MRI (magnetic resonance imaging) after every 16-22 weeks.	Before start of treatment (within 4 weeks), then every 10 +/- 2 weeks, at follow up (every 3-6 month (investigators choice) or patients withdrawal of concent.. No end can be given.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Rate of treatment-related adverse reactions	Treatment-related adverse reactions graded according to CTCAE v.5.0.	At every treatment cycle, cycle length is 10 +/-2 weeks, at treatment follow up every 3-6 month (investigators choice) until progression. No time point can be given.
Median overall survival (OS).	Median OS defined as time from randomization to death of any cause.	From date of randomization until the date of death. Timepoint unknown, as date of death can´t be predicted.
Progression free survival.	Median progression free survival (PFS).	From time of randomization until the date of first documented progression. Is evaluated within 4 weeks before randomization, after each treatment, every 10 +/2 weeks. Timepoint unknown, as date of progression can´t be predicted.
Percent change in sum of longest diameters (SLD) of tumor lesions.	Percent change in SLD from baseline (within 4 weeks before treatment) to time of best response.	At each radiological investigation with CT or MRI of thorax and abdomen. Is done every 10 +/- 2 weeks. In the follow up period, evaluations are done every 3-6 months until death.
Quality of Life as judged by the patient.	All patients complete the Eastern Cooperative Oncology Group (EORTC) QoL (quality of life)-questionnaires GI- neuroendocrine tumors (NET)21.	Patients complete the QoL forms before start of treatment, at cycle 2 (cycle length 10+/-2 weeks), at each treatment cycle (4-approximately 7), until progression.
Cumulative median absorbed dose (AD)	AD to target tumor lesions in subjects with complete remission (CR), partial remission (PR), stable disease (SD) and progressive disease (PD) as best response, according to RECIST evaluations.	After each dosimetry measurements after each treatment cycle (cycle length 10 +/2 weeks), up to 18 +/-2 months.
Correlation between cumulative median absorbed dose and time to progression.	Correlation between cumulative median absorbed dose to target tumor lesions and time to progression, defined as time from randomization to radiological progression.	Every 10 +/- 2 weeks up to 18 +/- 2 months.
Cumulative median absorbed dose (AD) and biological effective dose to kidneys.	Cumulative median AD and biological effective dose (BED) to kidneys vs rate of grade 3-4 renal toxicity (estimated and measured GFR ( glomerular filtration rate).	Is evaluated with dosimetry after each treatment, 10 +/- 2 weeks, up to 18 +/- 2 months.
Differences in resource utilization and treatment cost.	Differences in resource utilization and treatment cost between the two treatment arms, in relation to the progressive free survival (PFS) and overall survival (OS).	Through study completion, an average of 18 months, assessed every 10 +/- 2 weeks by questionnaires.

Collaborators and Investigators

• Sponsor: Lund University Hospital

Study record dates

Study Major Dates

• Study Start (Actual): November 1, 2022
• Primary Completion (Estimated): October 1, 2026
• Study Completion (Estimated): October 1, 2026

Study Registration Dates

• First Submitted: April 21, 2022
• First Submitted That Met QC Criteria: May 19, 2022
• First Posted (Actual): May 24, 2022

Study Record Updates

• Last Update Posted (Estimated): September 10, 2025
• Last Update Submitted That Met QC Criteria: September 3, 2025
• Last Verified: September 1, 2025

More Information

Terms related to this study

• Keywords: Capecitabine; Neuroendocrine tumors; Radionuclide therapy; Somatostatin receptor; Translational research; Lutetium; Personalized radionuclide therapy; 177Lu-DOTATOC; Dosimetry-based radionuclide therapy; Beta- and gamma-emitting radionuclide
• Additional Relevant MeSH Terms: Neoplasms; Neoplasms by Histologic Type; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Neuroendocrine Tumors; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Nucleic Acids, Nucleotides, and Nucleosides; Deoxycytidine; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Nucleosides; Uracil; Pyrimidinones; Deoxyribonucleosides; Fluorouracil; Capecitabine; 177Lu-octreotide, DOTA(0)-Tyr(3)-
• Other Study ID Numbers: START-01; 2021-002218-15 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No