Neuroendocrine Tumors
Conditions
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
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.
Interventions
DRUG177Lu-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.
DRUGCapecitabine
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.
Sponsors
Lund University Hospital
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
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).
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Median progression free survival (PFS) defined as time from randomization to radiological progression. | Before start of treatment (within 4 weeks), then every 10 +/- 2 weeks weeks, at follow up (every 3-6 month (investigators choice) until progression. | Time to progression is evaluated by CT (computed tomography) or MRI (magnetic resonance imaging) after every 16-22 weeks. |
| Median progression free survival (PFS) defined as time from randomization to radiological progression, | 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. | Time to progression is evaluated by CT (computed tomography) or MRI (magnetic resonance imaging) after every 16-22 weeks. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression free survival. | 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. | Median progression free survival (PFS). |
| Percent change in sum of longest diameters (SLD) of tumor lesions. | 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. | Percent change in SLD from baseline (within 4 weeks before treatment) to time of best response. |
| Quality of Life as judged by the patient. | 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. | All patients complete the Eastern Cooperative Oncology Group (EORTC) QoL (quality of life)-questionnaires GI- neuroendocrine tumors (NET)21. |
| Rate of treatment-related adverse reactions | 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. | Treatment-related adverse reactions graded according to CTCAE v.5.0. |
| Correlation between cumulative median absorbed dose and time to progression. | Every 10 +/- 2 weeks up to 18 +/- 2 months. | Correlation between cumulative median absorbed dose to target tumor lesions and time to progression, defined as time from randomization to radiological progression. |
| Cumulative median absorbed dose (AD) and biological effective dose to kidneys. | Is evaluated with dosimetry after each treatment, 10 +/- 2 weeks, up to 18 +/- 2 months. | 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). |
| Differences in resource utilization and treatment cost. | Through study completion, an average of 18 months, assessed every 10 +/- 2 weeks by questionnaires. | Differences in resource utilization and treatment cost between the two treatment arms, in relation to the progressive free survival (PFS) and overall survival (OS). |
| Cumulative median absorbed dose (AD) | After each dosimetry measurements after each treatment cycle (cycle length 10 +/2 weeks), up to 18 +/-2 months. | 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. |
| Median overall survival (OS). | From date of randomization until the date of death. Timepoint unknown, as date of death can´t be predicted. | Median OS defined as time from randomization to death of any cause. |
Countries
Sweden
Contacts
Primary ContactPernilla Asp, MD, Senior consultant
Outcome results
None listed