Clinical Trials Register

Summary
EudraCT Number:	2021-002218-15
Sponsor's Protocol Code Number:	START-01
National Competent Authority:	Sweden - MPA
Clinical Trial Type:	EEA CTA
Trial Status:	Trial now transitioned
Date on which this record was first entered in the EudraCT database:	2021-10-26
Trial results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Sweden - MPA

A.2

EudraCT number

2021-002218-15

A.3

Full title of the trial

Systemic Targeted Adaptive RadioTherapy of NeuroEndocrine Tumors - An open-label, multicenter, randomized controlled trial comparing safety and efficacy of personalized vs non-personalized radionuclide therapy with 177Lu-DOTATOC

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

START-NET: A randomized clinical trial to compare personalized vs non-personalized radionuclide therapy with 177Lu-DOTATOC

START-NET: En randomiserad klinisk prövning som jämför individualiserad och icke-individualiserad lutetium-behandling för neuroendokrina tumörer

A.3.2

Name or abbreviated title of the trial where available

START-NET

A.4.1

Sponsor's protocol code number

START-01

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Region Skåne
B.1.3.4	Country	Sweden
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Region Skåne
B.4.2	Country	Sweden
B.4.1	Name of organisation providing support	Region Uppsala
B.4.2	Country	Sweden
B.4.1	Name of organisation providing support	Västra Götalandsregionen
B.4.2	Country	Sweden
B.4.1	Name of organisation providing support	Fru Berta Kamprads Stiftelse
B.4.2	Country	Sweden
B.4.1	Name of organisation providing support	Gunnar Nilssons Cancerstiftelse
B.4.2	Country	Sweden
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Region Skåne
B.5.2	Functional name of contact point	Pernilla Asp
B.5.3	Address:
B.5.3.1	Street Address	Skånes Universitetssjukhus
B.5.3.2	Town/ city	Lund
B.5.3.3	Post code	22185
B.5.3.4	Country	Sweden
B.5.4	Telephone number	+4646177877
B.5.6	E-mail	Pernilla.P.Asp@skane.se

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Xeloda
D.2.1.1.2	Name of the Marketing Authorisation holder	Roche Registration GmbH
D.2.1.2	Country which granted the Marketing Authorisation	Germany
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Xeloda
D.3.4	Pharmaceutical form	Film-coated tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Capecitabine
D.3.9.1	CAS number	154361-50-9
D.3.9.3	Other descriptive name	CAPECITABINE
D.3.9.4	EV Substance Code	SUB12474MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg/m2 milligram(s)/square meter
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	825
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 2
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	Yes
D.2.5.1	Orphan drug designation number	EU/3/14/1269
D.3 Description of the IMP
D.3.1	Product name	177Lu-Edotreotide
D.3.2	Product code	177Lu-DOTATOC
D.3.4	Pharmaceutical form	Solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	177Lu-Edotreotide
D.3.9.1	CAS number	321835-55-6
D.3.9.3	Other descriptive name	LUTETIUM (177LU) EDOTREOTIDE
D.3.9.4	EV Substance Code	SUB192518
D.3.10	Strength
D.3.10.1	Concentration unit	GBq gigabecquerel(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	7.5
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	Yes
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Patients with SSTR+, advanced, progressive NET Grade 1-3 of any origin for whom Peptide-receptor radionuclide therapy, PRRT, is considered the most
appropriate treatment option in relation to other approved or available investigational agents for the specific tumor subtype.

Patienter med spridd, neuroendokrin tumör med ett kraftigt upptag på Gallium-PET

E.1.1.1

Medical condition in easily understood language

Patients with neuroendocrine tumours

Patienter med neuroendokrina tumörer

E.1.1.2

Therapeutic area

Diseases [C] - Cancer [C04]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	21.0
E.1.2	Level	LLT
E.1.2	Classification code	10062476
E.1.2	Term	Neuroendocrine tumor
E.1.2	System Organ Class	10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

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.

E.2.2

Secondary objectives of the trial

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

E.2.3

Trial contains a sub-study

Yes

E.2.3.1

Full title, date and version of each sub-study and their related objectives

1. START-NET translational substudy
To perform longitudinal collection of biomaterial from patients with NETs undergoing 177Lu-DOTATOC therapy in order to fuel translational research studies focusing on
a) Characterizing the biology of advanced NETs, and
b) Identifying novel predictive and prognostic biomarkers.

2. Bonemarrow dosimetry
To assess bone marrow dosimetry and the correlation to bone marrow toxicity.

E.3

Principal inclusion criteria

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 ≤ 3 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.

E.4

Principal exclusion criteria

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

E.5 End points

E.5.1

Primary end point(s)

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

E.5.1.1

Timepoint(s) of evaluation of this end point

Radiological evaluation will be performed at screening to confirm progressive disease within the last 24 months. This examination will serve as the baseline evaluation and must therefore be performed within four weeks of randomization. During the treatment phase disease status will be re-evaluated radiologically after every two cycles, and shortly before the EOT visit. During LTFU radiological evaluation will be performed every 3 months during the first year, and every three to six months thereafter, until progression, death, or withdrawal from the trial for any reason. All patients included in the trial will be followed for overall survival every 6 months until End of Trial.

E.5.2

Secondary end point(s)

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.

E.5.2.1

Timepoint(s) of evaluation of this end point

Continuously: Rate of AEs, survival
Every two cycles during treatment phase and every 3-6 months during LTFU: RECIST evaluations of radiological response (CR, PR, SD, PD, PFS, SLD)
Every two cycles, and in EOT and EOS visit: QoL
In every treatment cycle: AD and BED to tumor and kidneys, resource utilization

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

E.8.2.3

Other

Yes

E.8.2.3.1

Comparator description

Personalized treatment is compared with non-personalized treatment

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.7

Trial has a data monitoring committee

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

The study ends 18 months after the last administered treatment within the trial, at which point all patients that are still in LTFU will have an EOS visit. After study finalization patients will be followed up according to clinical routine.

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

220

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

300

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

According to clinical standard

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2021-12-22

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2022-01-20

P. End of Trial
P.	End of Trial Status	Trial now transitioned

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