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

Primary Purpose

Neuroendocrine Tumors

Status

Not yet recruiting

Phase

Phase 3

Locations

Sweden

Study Type

Interventional

Intervention

177Lu-DOTATOC

Capecitabine

About this trial

This is an interventional treatment trial for Neuroendocrine Tumors focused on measuring Neuroendocrine tumors, Radionuclide therapy, Personalized radionuclide therapy, 177Lu-DOTATOC, Capecitabine, Dosimetry-based radionuclide therapy, Somatostatin receptor, Lutetium, Beta- and gamma-emitting radionuclide, Translational research

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.
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
Glomerular filtration rate (GFR) > 50 ml/min/1.73m2 as determined by iohexol- or 51-chromo Crethylendiaminetetraaceticacidtetraacetat) clearance (EDTA) clearance
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.

Sites / Locations

Sahlgrenska University Hospital, Dept. of Oncology
Skåne University Hospital, Dept. of Oncology
Karolinska University Hospital, Dept. of Oncology
Accademical Hospital, Uppsala, Dept. of Oncology

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Active Comparator

Arm Label

177Lu-DOTATOC + Capecitabine

177Lu-DOTATOC

Standard 177Lu-DOTATOC

Arm Description

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. .

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.

Standard treatment of 177Lu-DOTATOC with treatment for 4 cycles.

Outcomes

Primary Outcome Measures

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.

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.

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.

Secondary Outcome Measures

Rate of treatment-related adverse reactions

Treatment-related adverse reactions graded according to CTCAE v.5.0.

Median overall survival (OS).

Median OS defined as time from randomization to death of any cause.

Progression free survival.

Median progression free survival (PFS).

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.

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.

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.

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.

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).

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).

Full Information

NCT ID

NCT05387603

First Posted

April 21, 2022

Last Updated

May 19, 2022

Sponsor

Lund University Hospital

1. Study Identification

Unique Protocol Identification Number

NCT05387603

Brief Title

Systemic Targeted Adaptive RadioTherapy of NeuroEndocrine Tumors.

Acronym

START-NET

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

2. Study Status

Record Verification Date

May 2022

Overall Recruitment Status

Not yet recruiting

Study Start Date

June 2022 (Anticipated)

Primary Completion Date

October 2025 (Anticipated)

Study Completion Date

October 2025 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Lund University Hospital

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

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

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 3

Interventional Study Model

Parallel Assignment

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).

Masking

None (Open Label)

Allocation

Randomized

Enrollment

300 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

177Lu-DOTATOC + Capecitabine

Arm Type

Experimental

Arm Description

Arm Title

177Lu-DOTATOC

Arm Type

Experimental

Arm Description

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.

Arm Title

Standard 177Lu-DOTATOC

Arm Type

Active Comparator

Arm Description

Standard treatment of 177Lu-DOTATOC with treatment for 4 cycles.

Intervention Type

Drug

Intervention Name(s)

177Lu-DOTATOC

Intervention Description

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.

Intervention Type

Drug

Intervention Name(s)

Capecitabine

Intervention Description

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.

Primary Outcome Measure Information:

Title

Median progression free survival (PFS) defined as time from randomization to radiological progression.

Description

Time to progression is evaluated by CT (computed tomography) or MRI (magnetic resonance imaging) after every 16-22 weeks.

Time Frame

Before start of treatment (within 4 weeks), then every 10 +/- 2 weeks weeks, at follow up (every 3-6 month (investigators choice) until progression.

Title

Median progression free survival (PFS) defined as time from randomization to radiological progression.

Description

Time to progression is evaluated by CT (computed tomography) or MRI (magnetic resonance imaging) after every 10 +/- 2 weeks.

Time Frame

Before start of treatment (within 4 weeks), then every 10 +/- week at follow up (every 3-6 month (investigators choice) until death.

Title

Median progression free survival (PFS) defined as time from randomization to radiological progression,

Description

Time to progression is evaluated by CT (computed tomography) or MRI (magnetic resonance imaging) after every 16-22 weeks.

Time Frame

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 Measure Information:

Title

Rate of treatment-related adverse reactions

Description

Treatment-related adverse reactions graded according to CTCAE v.5.0.

Time Frame

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.

Title

Median overall survival (OS).

Description

Median OS defined as time from randomization to death of any cause.

Time Frame

From date of randomization until the date of death. Timepoint unknown, as date of death can´t be predicted.

Title

Progression free survival.

Description

Median progression free survival (PFS).

Time Frame

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.

Title

Percent change in sum of longest diameters (SLD) of tumor lesions.

Description

Percent change in SLD from baseline (within 4 weeks before treatment) to time of best response.

Time Frame

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.

Title

Quality of Life as judged by the patient.

Description

All patients complete the Eastern Cooperative Oncology Group (EORTC) QoL (quality of life)-questionnaires GI- neuroendocrine tumors (NET)21.

Time Frame

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.

Title

Cumulative median absorbed dose (AD)

Description

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.

Time Frame

After each dosimetry measurements after each treatment cycle (cycle length 10 +/2 weeks), up to 18 +/-2 months.

Title

Correlation between cumulative median absorbed dose and time to progression.

Description

Correlation between cumulative median absorbed dose to target tumor lesions and time to progression, defined as time from randomization to radiological progression.

Time Frame

Every 10 +/- 2 weeks up to 18 +/- 2 months.

Title

Cumulative median absorbed dose (AD) and biological effective dose to kidneys.

Description

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).

Time Frame

Is evaluated with dosimetry after each treatment, 10 +/- 2 weeks, up to 18 +/- 2 months.

Title

Differences in resource utilization and treatment cost.

Description

Differences in resource utilization and treatment cost between the two treatment arms, in relation to the progressive free survival (PFS) and overall survival (OS).

Time Frame

Through study completion, an average of 18 months, assessed every 10 +/- 2 weeks by questionnaires.

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

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. 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 Glomerular filtration rate (GFR) > 50 ml/min/1.73m2 as determined by iohexol- or 51-chromo Crethylendiaminetetraaceticacidtetraacetat) clearance (EDTA) clearance 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.

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

Pernilla Asp, MD, Senior consultant

Phone

+46 46 17 75 20

pernilla.p.asp@skane.se

Facility Information:

Facility Name

Sahlgrenska University Hospital, Dept. of Oncology

City

Göteborg

Country

Sweden

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Anders Hallqvist, MD; Senoor consultant

Phone

+46 31 -342 10 00

anders.hallqvist@vgregion.se

First Name & Middle Initial & Last Name & Degree

Anders Hallqvist, MD, Senior Consultant

Facility Name

Skåne University Hospital, Dept. of Oncology

City

Lund

ZIP/Postal Code

SE-226 52

Country

Sweden

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Pernilla Asp, MD, Senior Consultant

Phone

+46 46 17 75 20

pernilla.p.asp@skane.se

First Name & Middle Initial & Last Name & Degree

Pernilla Asp, MD, Senior consultant

Facility Name

Karolinska University Hospital, Dept. of Oncology

City

Stockholm

ZIP/Postal Code

SE-171 76

Country

Sweden

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Renske Altena, MD, Senior Consultant

Phone

+46 8 517 700 00

First Name & Middle Initial & Last Name & Degree

Renske ltena, MD, Senior Consultant

Facility Name

Accademical Hospital, Uppsala, Dept. of Oncology

City

Uppsala

ZIP/Postal Code

SE-752 37

Country

Sweden

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Katarzyna Fröss-Baron, MD, Senior Consultant

Phone

+46 18 611 40 68

katarzyna.fross_baron@medsci.uu.se

First Name & Middle Initial & Last Name & Degree

Katarzyna Fröss-Baron, MD, Senior Consultant

12. IPD Sharing Statement

Plan to Share IPD

Learn more about this trial

Systemic Targeted Adaptive RadioTherapy of NeuroEndocrine Tumors.

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