Clinical trial NCT05387603: Systemic Targeted Adaptive RadioTherapy of NeuroEndocrine Tumors.
Official title: 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.
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Neuroendocrine Tumors
Keywords: Neuroendocrine tumors
Radionuclide therapy
Personalized radionuclide therapy
177Lu-DOTATOC
Capecitabine
Dosimetry-based radionuclide therapy
Somatostatin receptor
Lutetium
Beta- and gamma-emitting radionuclide
Translational research
Lead sponsor: Lund University Hospital
Sponsor class: OTHER
First posted: 2022-05-24
Enrollment: 300
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: This is a randomized, open-label, controlled trial in which patients are assigned to either non-personalized treatment with 4 cycles of 7.5 gigabequerel (GBq) 177Lu-DOTATOC (TOC), or personalized treatment based on dual imaging. In the personalized arm patients are treated according to the results of the dual imaging at screening:

A. Patients with 68Ga-1,4,7,10-tetra-azacyclododecane-N.n,N,N-tetraacetic acid (DOTA)-positron emission tomography (PET)-positive but 18F-2-fluoro-2-deoxy-D-glucosefluorodeoxyglucose (FDG)-PET-negative NET will receive dosimetry-based PRRT only (dTOC) B. Patients with 68Ga-DOTA- and 18F-FDG-PET-positive NET will receive a combination of capecitabine and dosimetry-based PRRT (CAP-dTOC).
Primary purpose: TREATMENT

Brief summary: 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.


Eligibility criteria: 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.

Primary outcomes:
measure: Median progression free survival (PFS) defined as time from randomization to radiological progression.
timeFrame: Before start of treatment (within 4 weeks), then every 10 +/- 2 weeks weeks, at follow up (every 3-6 month (investigators choice) until progression.
measure: Median progression free survival (PFS) defined as time from randomization to radiological progression.
timeFrame: Before start of treatment (within 4 weeks), then every 10 +/- week at follow up (every 3-6 month (investigators choice) until death.
measure: Median progression free survival (PFS) defined as time from randomization to radiological progression,
timeFrame: 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 outcomes:
measure: Rate of treatment-related adverse reactions
timeFrame: 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.
measure: Median overall survival (OS).
timeFrame: From date of randomization until the date of death. Timepoint unknown, as date of death can´t be predicted.
measure: Progression free survival.
timeFrame: 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.
measure: Percent change in sum of longest diameters (SLD) of tumor lesions.
timeFrame: 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.
measure: Quality of Life as judged by the patient.
timeFrame: 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.
measure: Cumulative median absorbed dose (AD)
timeFrame: After each dosimetry measurements after each treatment cycle (cycle length 10 +/2 weeks), up to 18 +/-2 months.
measure: Correlation between cumulative median absorbed dose and time to progression.
timeFrame: Every 10 +/- 2 weeks up to 18 +/- 2 months.
measure: Cumulative median absorbed dose (AD) and biological effective dose to kidneys.
timeFrame: Is evaluated with dosimetry after each treatment, 10 +/- 2 weeks, up to 18 +/- 2 months.
measure: Differences in resource utilization and treatment cost.
timeFrame: Through study completion, an average of 18 months, assessed every 10 +/- 2 weeks by questionnaires.
Other outcomes:
Locations:
city: Göteborg
country: Sweden
facility: Sahlgrenska University Hospital, Dept. of Oncology
city: Lund
country: Sweden
facility: Skåne University Hospital, Dept. of Oncology
city: Stockholm
country: Sweden
facility: Karolinska University Hospital, Dept. of Oncology
city: Uppsala
country: Sweden
facility: Accademical Hospital, Uppsala, Dept. of Oncology
Study officials:
References: