Systemic Targeted Adaptive RadioTherapy of NeuroEndocrine Tumors. An open-label, multi-center, randomized phase III trial comparing safety and efficacy of personalized vs non-personalized radionuclide therapy with 177Lu-DOTATOC

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Region Skane

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

21 Jun 2022 → ongoing

Decision date (initial)

2024-10-15

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

External identifiers

EU CT number

2023-508572-11-00

EudraCT number

2021-002218-15

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Safety

The primary objective of this study is to compare the efficacy of personalized vs nonpersonalized PRRT with 177Lu-DOTATOC in patients with SSTR-positive NET G1-G3.

Secondary objectives 9

1. To compare the safety of personalized vs non-personalized PRRT
2. To compare OS in personalized vs non-personalized PRRT
3. To compare PFS in personalized vs non-personalized PRRT in the following subgroups: a. FDG-PET negative patients b. FDG-PET-positive patients
4. To compare tumor shrinkage at time of best response between personalized vs nonpersonalized PRRT
5. To compare quality-of-life of personalized vs non-personalized PRRT
6. To compare cumulative AD to target tumors in patients with CR, PR, SD, and PD, respectively.
7. To study whether there is a correlation between cumulative median AD to target tumor lesions, and time to progression.
8. To compare AD and BED to kidneys, and rate of renal toxicity, between the two treatment arms
9. To compare health economic parameters between the two treatment arms

Conditions and MedDRA coding

neuroendocrine tumours

Study design 1 period

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 15

1. The subject has given written informed consent to participate in the study.
2. Age ≥18 years
3. ECOG performance status 0-1
4. Life expectancy > 3 months.
5. Presence of histologically confirmed, advanced, well-differentiated, inoperable NETof any primary tumor origin (except pheochromocytoma and paraganglioma) and any grade, with a maximum Ki67 of 50%
6. SSTR-expression (mean SUV) in tumor lesions ≥ 2x mean SUV in normal liver on 68Ga-DOTA-PET performed ≤ 6 months prior to randomization. Due to partial volume effects, tumor lesions smaller than 1 cm on CT or MRI should not be used to evaluate this eligibility criterium.
7. 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.
8. All previous anti-tumor treatment except SSA must be terminated at least 4 weeks before start of treatment within the trial
9. Measurable disease according to RECIST v 1.1
10. Given the available, approved anti-tumor treatments and the specific characteristics of the patient and the tumor, the investigator judges PRRT to be the treatment of choice
11. 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
12. Adequate hematological parameters as defined by: Hemoglobin > 90 g/L, platelets >100 x109/L, leukocytes > 3.0x109/L, neutrophils > 1.5 x109/L
13. Adequate hepatic function as defined by ASAT/ALAT < 3 x ULN, bilirubin < 2 x ULN, albumin > 25 g/L.
14. For women of child-bearing potential, highly effective contraception should be usedfrom the time of inclusion up to at least six months after the EOT visit. For details see appendix 5.
15. For male subjects living with a woman of child-bearing potential, adequate contraception should be used from the time of inclusion up to at least six months after the EOT visit. Adequate male contraception methods are vasectomy, surgical or pharmacological castration, or the use of condom during heterosexual intercourse.

Exclusion criteria 13

1. Pregnancy or lactation
2. Previous treatment with PRRT for NET
3. Concomitant systemic anti-tumor therapy other than SSA
4. Participation or recent participation in a clinical study with an investigational product within 30 days of randomization.
5. Known hypersensitivity to edotreotide, octreotide, capecitabine or any of the excipients included in the preparations.
6. Contraindications for treatment with capecitabine: a. Severe arterial thromboembolic events (myocardial infarction,unstable angina pectoris, stroke) less than 6 months before inclusion. b. New York Heart Association (NYHA) Class III or IV congestive heart failure, ventricular arrhythmias or uncontrolled blood pressure c. Previous serious or unexpected reactions to fluoropyrimidine treatment d. Known complete deficiency of dihydropyrimidine dehydrogenase (DPD) e. Recent or concomitant treatment with brivudine
7. Discordance between CT/MRI/18F-FDG-PET and 68Ga-DOTA-PET, with evidence of tumor lesions without uptake on 68Ga-DOTA-PET
8. Liver-directed therapy of metastases (i.e. radioembolization, chemoembolization, radiofrequency ablation, surgery, etc) < 4 weeks prior to randomization.
9. Major surgery < 12 weeks prior to randomization.
10. Previous radiotherapy of any kind which has resulted in irradiation of both kidneys and/or > 50% of the red bone marrow.
11. Any other serious, uncontrolled medical or psychiatric condition including other advanced or metastatic malignant disease that, in the opinion of the investigator, precludes the patient from participation in the trial
12. Mental inability, reluctance or language difficulties that result in difficulty understanding the meaning of study participation
13. Inability or reluctance to adhere to the radiation safety instructions

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Median PFS defined as time from randomization to radiological progression, or death from any cause

Secondary endpoints 9

1. Rate of treatment-related adverse reactions graded according to CTCAE v5.0
2. Median OS defined as time from randomization to death from any cause
3. Median PFS defined as time from randomization to radiological progression, or death from any cause
4. Percent change in SLD from baseline to time of best response
5. EORTC QoL-questionnaires GI-NET21
6. Cumulative median AD to target tumor lesions in subjects with CR, PR, SD and PD as best response, according to RECIST evaluations
7. Correlation between cumulative median AD to target tumor lesions and time to progression, defined as time from randomization to radiological progression.
8. Cumulative median AD and BED to kidneys vs rate of grade 3-4 renal toxicity (estimated and measured GFR)
9. Differences in resource utilization and treatment cost between the two treatment arms, in relation to the respective mPFS and mOS.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Region Skane

Sponsor organisation

Region Skane

Address

Dockplatsen 26, Malmo S:t Petri Malmo S:t Petri

City

Malmo

Postcode

211 74

Country

Sweden

Scientific contact point

Organisation

Region Skane

Contact name

Pernilla Asp

Public contact point

Organisation

Region Skane

Contact name

Pernilla Asp

Third parties 1

Locations

1 EU/EEA country · 4 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 13 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

5 submissions — initial application plus substantial / non-substantial modifications