Protocol
`
`This trial protocol has been provided by the authors to give readers additional information about their work.
`
`Protocol for: Strosberg J, El-Haddad G, Wolin E, et al. Phase 3 trial of 177Lu-Dotatate for midgut neuroendocrine
`tumors. N Engl J Med 2017;376:125-35. DOI: 10.1056/NEJMoa1607427
`
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`
`This supplement contains the following items: 
`
`1. Original protocol, final protocol, summary of changes. 
`
`2. Original statistical analysis plan, final statistical analysis plan, summary of changes. 
`
` 
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`Protocol N° AAA-III-01/FINAL version 1.0, November 14th, 2011
`
`
`
`
`
`
`STUDY PROTOCOL
`
`TITLE
`
` A
`
`STUDY
`
`EudraCT N°
`
`
`DATE
`
`
`SPONSOR
`
`
` multicentre, stratified, open, randomized, comparator-controlled, parallel-
`group phase III study comparing treatment with 177Lu-DOTA0-Tyr3-Octreotate to
`Octreotide LAR in patients with inoperable, progressive, somatostatin receptor
`positive, midgut carcinoid tumours.
`
`Phase III
`
`PROTOCOL N° AAA-III-01/FINAL version 1.0
`
`2011-005049-11
`
`
`November 14th, 2011
`
`
`Advanced Accelerator Applications SA
`20 rue Diesel
`01630 Saint Genis Pouilly
`France
`Tel: +33450993070
`www.adacap.com / info@adacap.com
`
`
`
`
`
`
`
`
`
`
`
`Property of Advanced Accelerator Applications SA
`Confidential
`May not be used, divulged, published or otherwise
`disclosed without the consent of Advanced Accelerator
`Applications SA
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`Protocol N° AAA-III-01/FINAL version 1.0, November 14th, 2011
`
`
`
`HEAD OF RESEARCH &
`DEVELOPMENT
`
`
`
`
`STUDY MANAGER
`
`
`
`
`
`SCIENTIFIC ADVISOR CHAIRS
`
`
`
`
`
`
`INDEPENDENT DATA SAFETY
`MONITORING BOARD CHAIR
`
`
`
`
`CONTACTS FOR SAFETY
`REPORTING
`
`
`
`
`
`CLINICAL RESEARCH
`ORGANIZATION (CRO)
`
`
`Maurizio Franco Mariani, M.D., Ph.D., D.A.B.T
`Advanced Accelerator Applications SA
`Tel:+39 0125 561206; Fax:+39 0125 561212
`E-mail: mailto:maurizio.mariani@adacap.com
`
`
`Paola Santoro
`Advanced Accelerator Applications SA
`Tel:+39 0125 561221; Fax:+39 0125 561212
`E-mail: paola.santoro@adacap.com
`
`
`Eric P. Krenning, M.D., Ph.D., F.R.C.P.
`Dik J. Kwekkeboom, M.D., Ph.D.
`Department of Nuclear Medicine
`Erasmus Medical Center, University Hospital Rotterdam
`Rotterdam, The Netherlands
`
`
`David Paul Kelsen, M.D.
`Gastrointestinal Oncology Service
`Memorial Sloan-Kettering Cancer Center
`New York
`
`
`Philippe Dasse
`Advanced Accelerator Applications SA
`Tel:+39 450 993070; Fax: +39 450 993070
`Mobile : +33 6 27 75 16 00;
`E-mail: pharmacovigilance@adacap.com
`
`
`Pierrel Research Italy SPA
`Medical Director: Piergiorgio Galletti, M.D.
`Via Alberto Falck, 15
`20099 Sesto San Giovanni (MI)
`Phone: +39 02 24134 208; Fax: +39 02 24862 961
`Mobile: +39 340 9188485
`Email: p.galletti@pierrelgroup.com
`
`
`
`
`
`
`
`GOOD CLINICAL PRACTICE AND CONFIDENTIALITY STATEMENT
`
`This trial will be conducted in compliance with the protocol, the principles of Good Clinical Practice
`(GCP), and applicable regulatory requirements.
`This confidential document is property of the Sponsor. No information contained in this document
`may be disclosed without prior written approval of the Sponsor.
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`Protocol N° AAA-III-01/FINAL version 1.0, November 14th, 2011
`
`Objectives
`
`Study centres
`Sponsor
`Indication
`
`
`
`
`PROTOCOL SYNPOSIS
`Clinical Study Protocol Synopsis
`November 14th, 2011 Version
`FINAL version 1.0
`Version date
`AAA-III-01
`Clinical phase
`III
`Study number
`177Lu-DOTA0-Tyr3-Octreotate
`EudraCT number 2011-005049-11
`Drug substance
`Title of the study A multicenter, stratified, open, randomized, comparator-controlled, parallel-
`group phase III study comparing treatment with 177Lu-DOTA0-Tyr3-Octreotate to
`Octreotide LAR in patients with inoperable, progressive, somatostatin receptor
`positive midgut carcinoid tumours.
`Centres in EU and USA (approximately 28 EU sites and 13 USA sites)
`Advanced Accelerated Applications SA
`Patients with inoperable, progressive, OctreoScan® positive, well-differentiated
`neuroendocrine tumours of the small bowel (midgut carcinoid tumours), who are
`treated with 20 mg or 30 mg Octreotide LAR every 3-4 weeks at a fixed dose for
`at least 12 weeks prior to enrolment in the study.
`Primary objective:
`• To compare Progression Free Survival (PFS) after treatment with 177Lu-
`DOTA0-Tyr3-Octreotate plus best supportive care (30 mg Octreotide LAR) to
`treatment with high dose (60 mg) Octreotide LAR in patients with inoperable,
`progressive (as determined by RECIST Criteria), somatostatin receptor
`positive, well-differentiated neuroendocrine tumours of the small bowel
`(midgut carcinoid tumours).
`Secondary objective(s):
`• To compare the Objective Response Rate (ORR) between the two study arms;
`• To compare the Overall Survival (OS) between the two study arms;
`• To compare the Time to Tumour Progression (TTP) between the two study
`arms;
`• To evaluate the safety and tolerability of 177Lu-DOTA0-Tyr3-Octreotate;
`• To evaluate the health related quality of life (QoL) as measured by the
`EORTC QLQ-G.I.NET21 questionnaire;
`• To explore the correlation of toxicity outcomes and administered radiation
`doses corrected for body weight and body surface area;
`• To explore the correlation of clinical efficacy outcomes with the levels of the
`biomarkers Chromogranin-A (CgA) in the serum and 5-Hydroxyindoleacetic
`acid (5-HIAA) in the urine;
`• To evaluate dosimetry, pharmacokinetics (PK) and ECG in a subset of 20
`patients;
`
`
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`Protocol N° AAA-III-01/FINAL version 1.0, November 14th, 2011
`• To explore the correlation of clinical efficacy outcomes with OctreoScan®
`tumour uptake score;
`• To explore the correlation of clinical outcomes with serum levels of Alkaline
`Phosphatase (AP).
`A multicenter, stratified, open, randomized, comparator-controlled, parallel-
`group phase III study. In this study, treatment with 177Lu-DOTA0-Tyr3-Octreotate
`plus best supportive care (30 mg Octreotide LAR) will be compared to treatment
`with high dose (60 mg) Octreotide LAR in patients with inoperable, somatostatin
`receptor positive, histologically proven midgut carcinoid tumours; these patients
`should be progressive under Octreotide LAR. In case patients in either arm
`experience clinical symptoms (i.e. diarrhoea and flushing) associated with their
`carcinoid tumours, Octreotide s.c. rescue injections are allowed.
`Objective tumour response in both arms will be assessed every 12±1 weeks from
`the first treatment date according to RECIST Criteria. The baseline CT scan/MRI
`must not be older than 4 weeks before the projected randomization date.
`Patients will be evaluated for safety and tolerability in accordance with the Visit
`Schedules for the 177Lu-DOTA0-Tyr3-Octreotate arm and the Octreotide LAR
`arm as indicated in Table 1 and Table 2, respectively (see pages 10-13).
`177Lu-DOTA0-Tyr3-Octreotate arm:
`30 mg Octreotide LAR treatment for symptom control will continue until
`the end of study, unless the patient progresses or dies;
`Treatment will consist of a cumulative dose of 29.6 GBq (800 mCi) 177Lu-
`DOTA0-Tyr3-Octreotate;
`Four administrations of 7.4 GBq (200 mCi) 177Lu-DOTA0-Tyr3-Octreotate;
`Concomitant amino acids will be given with each administration for kidney
`protection;
`177Lu-DOTA0-Tyr3-Octreotate will be administered at 8±1-week intervals,
`which can be extended up to 16 weeks to accommodate resolving acute
`toxicity (see Dose Modifying Toxicity (DMT) below); in case patients
`experience clinical symptoms (i.e. diarrhoea and flushing) associated with
`their carcinoid tumours, Octreotide s.c. rescue injections are allowed.
`Octreotide LAR arm:
`60 mg Octreotide LAR treatment every 4 weeks (i.m. injections) until the
`end of the study, unless the patient progresses or dies (see Dose Modifying
`Toxicity (DMT) below);
`In case patients experience clinical symptoms (i.e. diarrhoea and flushing)
`associated with their carcinoid tumours, s.c. Octreotide rescue injections are
`allowed.
`According to National Cancer Institute Common Terminology Criteria for
`Adverse Events Version 4.0, DMT is defined as a Grade 2 toxicity for blood
`platelet count, any Grade 3 or 4 haematological
`toxicity other
`than
`lymphocytopenia, a 40% increase over the baseline in serum creatinine value
`with a concomitant decrease of over 40% in creatinine clearance, or any other
`
`•
`
`•
`
`•
`
`•
`
`•
`
`•
`
`•
`
`Study design
`
`Treatment
`
`Dose modifying
`toxicity
`
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`5
`Protocol N° AAA-III-01/FINAL version 1.0, November 14th, 2011
`Grade 3 or 4 toxicity possibly related to study drug and regardless of its duration.
`If the patients experiences DMT during 177Lu-DOTA0-Tyr3-Octreotate
`1.
`therapy, the subsequent treatments of 177Lu-DOTA0-Tyr3-Octreotate are
`permissible, provided the DMT resolves within 16 weeks following the
`non-tolerated administration. After resolution of a DMT, a patient may
`receive his/her subsequent planned treatment(s) at 50% of the standard
`treatment dose. If the same DMT recurs after treatment with the reduced
`dose, the patient goes off-study. If the DMT event does not reoccur, the next
`treatment is at full dose.
`If the patient experiences DMT with the increased dose Octreotide
`LAR, the dose will be adjusted to the previous well-tolerated dose, to be
`increased again with the next treatment to 60 mg.
`32 months total: 14 months recruitment and 18 months treatment and
`assessments until the End of Study.
` Long-term toxicities suspected in relationship to the study drug (included
`haematology, biochemistry, urine analyses), PFS (based on local assessments),
`OS data will be collected every 6 months for 3 years after the End of Study
`(phone contact or visit at site).
`200 patients (considering the drop-out rate, 100 patients per treatment group will
`be randomly assigned to open-label treatment).
`1. Presence of inoperable (curative intent) at enrolment time, histologically
`proven, midgut carcinoid tumour.
`2. Ki67 index ≤ 20%.
`3. Patients on Octreotide LAR at a fixed dose of 20 mg or 30 mg at 3-4
`weeks intervals for at least 12 weeks prior to enrolment in the study.
`4. Patients ≥18 years of age.
`5. Patients must have progressive disease based on RECIST Criteria,
`Version 1.1 (Appendix 2) evidenced with CT scans/MRI obtained within
`3 years from enrolment; previous images must be centrally evaluated to
`confirm the disease progression under previous therapy: for the purpose
`of determining disease progression the oldest CT/MRI scan must not be
`older than 3 years and the most recent scan must not be older than 4
`weeks from the projected randomization date. The CT scan/MRI scan
`should be one that was performed while the patient was on a fixed dose
`of Sandostatin LAR.
`6. Confirmed presence of somatostatin receptors on all
`technically
`evaluable tumour lesions documented by CT/MRI scans, based on
`positive OctreoScan® imaging within 24 weeks prior to enrolment in the
`study.
`7. The tumour uptake observed using OctreoScan® must be ≥ normal liver
`uptake observed on planar imaging (Appendices 5 and 6).
`8. Karnofsky Performance Score (KPS) ≥60
`
`Study duration
`
`Planned number
`of patients
`Inclusion criteria
`
`
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`Protocol N° AAA-III-01/FINAL version 1.0, November 14th, 2011
`9. Presence of at least 1 measurable site of disease.
`1. Serum creatinine >150 µmol/L or 1.7 mg/dL, or a measured creatinine
`clearance (or measured glomerular filtration rate (GFR) using plasma
`clearance methods, not gamma camera-based) of <50 mL/min.
`2. Hb concentration <5.0 mmol/L (<8.0 g/dL); WBC <2x109/L (2000/mm3);
`platelets <75x109/L (75x103/mm3).
`3. Total bilirubin >3 x ULN.
`4. Serum albumin <3.0 g/dL unless prothrombin time is within the normal
`range.
`5. Pregnancy (see protocol Appendix 7).
`6. For female patients of childbearing potential (defined as < 2 years after
`last menstruation and not surgically sterile) and male patients, who are
`not surgically sterile or with female partners of childbearing potential:
`absence of effective, non-hormonal means of contraception (intrauterine
`contraceptive device, barrier method of contraception in conjunction with
`spermicidal gel) as defined in Appendix 7.
`7. Treatment with >30 mg Octreotide LAR at 3-4 weeks intervals within 12
`weeks prior to enrolment in the study.
`8. Peptide receptor radionuclide therapy (PRRT) at any time prior to
`enrolment in the study.
`9. Targeted
`(external beam), chemotherapy,
`surgery,
`radiotherapy
`embolization, interferons, mTOR-inhibitors or other investigational
`therapy within 12 weeks prior to enrolment in the study.
`10. Known brain metastases, unless these metastases have been treated and
`stabilized for at least 24 weeks, prior to enrolment in the study. Patients
`with a history of brain metastases must have a head CT with contrast to
`document stable disease prior to enrolment in the study.
`11. Uncontrolled congestive heart failure (NYHA II, III, IV).
`12. Uncontrolled diabetes mellitus as defined by a fasting blood glucose >2
`ULN.
`13. Any patient who has both OctreoScan® positive and negative tumours.
`14. Any patient receiving treatment with short-acting Octreotide, which
`cannot be interrupted for 24 h before and 24 h after the administration of
`177Lu-DOTA0-Tyr3-Octreotate, or any patient receiving treatment with
`Octreotide LAR, which cannot be interrupted for at least 6 weeks before
`the administration of 177Lu-DOTA0-Tyr3-Octreotate, unless the tumour
`uptake observed by OctreoScan® imaging during continued Octreotide
`treatment is at least as high as normal liver uptake observed by planar
`imaging (Appendices 5 and 6).
`15. Patients with any other significant medical, psychiatric, or surgical
`condition, currently uncontrolled by treatment, which may interfere with
`completion of the study.
`
`Exclusion criteria
`
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`Protocol N° AAA-III-01/FINAL version 1.0, November 14th, 2011
`16. Prior external beam radiation therapy to more than 25% of the bone
`marrow.
`17. Urinary incontinence.
`18. Other known co-existing malignancies except non-melanoma skin cancer
`and carcinoma in situ of the uterine cervix, unless definitively treated and
`proven no evidence of recurrence for 5 years.
`19. Patients who have not provided a signed an informed consent form to
`participate in the study, obtained prior to the start of any protocol related
`activities.
`
`The End of Study is defined as the moment that the last enrolled patient has
`completed 72 weeks of assessments (unless early termination) after the patient’s
`first treatment in either arm of the study.
`Long-term toxicity to critical organs (bone marrow and kidney) suspected in
`relationship to the study drug (including haematology, biochemistry, urine
`analyses) will be monitored every 6 months for 3 years after the End of Study.
`PFS (based on local assessments) and OS data will be recorded every 6 months
`for 3 years after the End of Study.
`Phone contacts or visits at site can be performed during the 3 years follow-up
`after end of the study.
`
`End of Study
`
`Long-term follow-
`up after End of
`Study
`
`Treatment
`
`Dosage
`
`Duration of
`treatment
`
`Form/dosing route A ready-to-use radioactive liquid solution for intravenous infusion.
`Investigational
`[Lutetium-177]-N-[(4,7,10-Tricarboxymethyl-1,4,7,10-tetraazacyclododec-1-
`drug
`yl)acetyl]-D-phenylalanyl-L-cysteinyl-L-tyrosyl-D-tryptophanyl-L-lysyl-L-
`threoninyl-L-cysteinyl-L-threonine-cyclic(2-7)disulfide.
`Abbreviated: 177Lu-DOTA0-Tyr3-Octreotate.
`In total 29.6 GBq (800 mCi) 177Lu-DOTA0-Tyr3-Octreotate administered in four
`equally divided doses.
`Four administrations of 177Lu-DOTA0-Tyr3-Octreotate (each treatment 7.4 GBq
`(200 mCi)) at 8±1-week intervals, which can be extended to 16 weeks for
`resolving acute toxicity.
`Patients are scheduled to continue to receive study treatment until any of the
`following occurs:
`1. Unacceptable toxicity;
`2. Progressive disease as determined by RECIST Criteria;
`3. Inability or unwillingness of the patient to comply with study procedures;
`4. Patient withdrawing consent to participate.
`Assessments (see accompanying Visit Schedules)
`
`Objective CT/MRI tumour assessment in both arms will be performed every
`12±1 weeks from the first treatment date until End of Study.
`
`Efficacy
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`Safety
`
`8
`Protocol N° AAA-III-01/FINAL version 1.0, November 14th, 2011
`Safety assessments will be performed 2 weeks before and 4 weeks after each
`177Lu-DOTA0-Tyr3-Octreotate treatment and every 12±1 weeks from the first
`treatment date in both study arms.
`Long-term toxicity to critical organs suspected in relationship to the study drug
`will be monitored every 6 months for 3 years after the End of Study.
`Overall Survival OS will be calculated from randomization until the day of death due to any cause;
`OS will not be censored if a patient receives other anti-tumour treatments after
`study medication.
`Survival data will be recorded at the End of Study, and every 6 months for 3
`years after the End of Study.
`Statistical methods
`
`POWER Procedure Log-Rank Test for Two Survival Curves (SAS 9.2) based on
`the following assumptions:
`Median PFS for group 1 (Octreotide LAR): 14 months
`Median PFS for group 2 (177Lu-DOTA0-Tyr3-Octreotate): 30 months
`Nominal Power: 90%
`Alpha: 0.05
`Accrual period: 0 months (patients enrolled over 14 month period but follow-up
`for each patients is fixed at 72 weeks)
`Follow-up period: 18 months (72 weeks)
`Based on the above median PFS assumptions, a sample size of 162 patients in
`total with an expected number of 75 events is obtained. Controlling for a drop-
`out rate of approximately 20% a total of 200 patients (100 patients per treatment
`group) will be randomized and treated. This sample size also provides the
`availability of sufficient safety data.
`1. Centre
`2. OctreoScan® tumour uptake score (Grade 2, 3 and 4); see Appendix 5
`3. The length of time that patients have been on the most recent constant dose
`of Octreotide prior to enrolment (≤6 and >6 months).
`The primary efficacy variable of this study is PFS.
`The median point estimate and 95% Confidence Interval (CI) for the PFS will be
`provided using the Kaplan-Meier method, and the log-rank test will be used
`to compare the PFS between the two treatment groups.
`The secondary efficacy variables are: Objective Response Rate (ORR), Time to
`Tumour Progression (TTP) and OS.
`Response rates and 95% CIs will be calculated for the ORR by treatment group.
`Frequencies in the two treatment groups will be compared by Fisher’s exact
`test.
`OS and TTP will be similarly analyzed as the primary efficacy variable.
`
`Sample size
`
`Stratification
`before
`randomization
`
`
`Statistical
`Analysis
`
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`Protocol N° AAA-III-01/FINAL version 1.0, November 14th, 2011
`Survival curves will be compared by the log-rank test. The null hypothesis will
`be investigated, that the survival experience in the two groups is the same,
`i.e. there is no difference between the treatment groups in the probability of
`PFS, TTP, and OS at any time point (i.e.: S1=S2), against the two sided
`alternative hypothesis that the survival experience in the two treatment
`groups is different (i.e.: S1≠S2).
`The comparison of ORR by Fisher’s exact test investigates the null hypothesis
`that the two treatment group proportions are equal (i.e.: p1=p2) against the
`two sided alternative hypothesis that the two treatment group proportions
`are not equal (i.e.: p1≠p2).
`
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`Table 1: Visit Schedule: 177Lu-DOTA0-Tyr3-Octreotate Treatment Arm
`
`Visit Eligibility Baseline
`
`Treatments / Assessments
`
`Week
`
`Therapy
`
`Week -3
`
`0
`
`4
`
`6
`
`8
`
`12
`
`14
`
`16
`
`20
`
`22
`
`24
`
`28
`
`32
`
`36
`
`40
`
`44
`
`48
`
`52
`
`56
`
`60
`
`64
`
`68
`
`72
`
`(cid:170)(cid:134)
`
`(cid:170)(cid:134)
`
`(cid:170)(cid:134)
`
`(cid:170)(cid:134) (cid:134) (cid:134) (cid:134) (cid:134) (cid:134) (cid:134) (cid:134) (cid:134) (cid:134) (cid:134) (cid:134) (cid:134)
`
`EOS6 FOLLOW-UP7
`76 Every 6-months
`for 3-years
`
`10
`Protocol N° AAA-III-01/FINAL version 1.0, November 14th, 2011
`
`x
`< 24 weeks
`x
`x
`< 4 weeks
`x
`
`x
`
`x
`
`x
`
`x
`
`x
`
`x
`
`x
`
`x
`
`x
`
`x
`
`x
`
`x
`
`x
`
`x
`
`x
`
`x
`
`x
`
`x
`
`x
`
`x
`
`x
`
`x
`
`x
`
`
`
`Informed Consent
`OctreoScan®
`Histology and Ki671
`Diagnosis and Extent of Cancer
`CT/MRI Scan Confirming Disease Progression1
`Demographic Data
`Relevant Medical History
`Prior Therapy for Carcinoid Tumour
`Confirmation of Eligibility and Randomization
`Diary Delivery (Symptoms and Rescue Med)
`Cardiac Ejection Fraction
`ECG (at the end of 177Lu-DOTA0-Tyr3-Octreotate infusion)
`Physical Exam and Vital Signs
`Karnofsky Performance Status
`Quality of Life (EORTC GI-NET21; EORTC C30)
`Hematology2
`Blood Chemistry2
`Urinalysis2
`Pregnacy test2
`Serum CgA1
`Cancer Related Symptoms3
`Concomitant/Rescue Therapy
`Adverse Events5
`Disease Assessment RECIST (CT, MRI)1
`Survival Information
`
`Refer to Protocol Section 6 for further details on Visits Assessments
`
`x
`
`x
`
`x
`x
`
`x
`x
`x
`x
`
`x
`x
`x
`
`x
`
`x
`
`x
`
`x
`x
`
`x
`x
`x
`x
`
`x
`x
`x
`x
`x
`x
`
`x
`x
`
`x
`
`x
`
`x
`
`
`
`x
`x
`x
`
`x
`
`x
`x
`
`x
`x
`x
`x
`x
`
`
`
`x
`
`x
`
`x
`
`x
`x
`x
`
`x
`
`x
`
`x
`x
`x
`x
`x
`x
`
`x
`x
`
`x
`
`x
`x
`x
`x
`x
`x
`
`x
`x
`
`x
`
`x
`
`x
`
`x
`x
`x
`x
`x
`x
`
`x
`x
`
`x
`
`x
`
`x
`
`x
`x
`
`x
`x
`x
`
`x
`
`x
`x
`x
`x
`x
`x
`
`x
`x
`
`x
`
`x
`
`x
`
`
`
`
`x
`x
`x
`
`
`
`
`x
`
`
`
`x
`x
`(cid:98)
`(x)4
`x
`x
`x
`x
`x
`x
`x
`x
`x
`
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`x
`x
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`x
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`
`Table 1 Footnotes
`(cid:170) TREATMENT: 177Lu-DOTA0-Tyr3-Octreotate 4 administrations at 8±1-week intervals
`(cid:134) TREATMENT: 30 mg Sandostatin® LAR Depot injections to be administered the day after each 177Lu-DOTA0-Tyr3-Octreotate infusion
` Last Sandostatin® LAR Depot injection should have been administered at least 6 weeks before the next 177Lu-DOTA0-Tyr3-Octreotate treatment date
` IF REQUIRED, RESCUE TREATMENTS: Octreotide s.c. injections (to be stopped 24 h before each 177Lu-DOTA0-Tyr3-Octreotate administration)
`1Centrally evaluated until End Of Study
`Disease progression at inclusion to be confirmed centrally: the oldest CT/MRI scan must not be older than 3 years and the most recent scan must not be older than 4 weeks
`from the projected randomization date. The CT scan/MRI scan that is to be compared to the baseline CT scan/MRI scan should be one that was performed while the patient
`was on a fixed dose of Sandostatin LAR
`RECIST Disease Assessment during the 3 years follow-up will be performed locally
`2Tests included in the local laboratory assessments:
`- Haematology: WBC with differential, Platelets, Hb, MCV
`- Blood chemistry: Serum Creatinine, (Creatinine Clearance - Cockcroft-Gault formula), Uric Acid, Albumin, Total Bilirubin, AP, AST/ASAT, ALT/ALAT, Gamma-GT, Sodium,
`Potassium, LDH, GlycoHb, fT4
`- Urinalysis: RBC/hpf, WBC/hpf, Casts/lpf, Protein by dipstick test, 5-HIAA, Pregnancy test (the latter at baseline for female of childbearing potential and during 177Lu-DOTA0-
`Tyr3-Octreotate therapy within 7 days prior to each treatment)
`- At baseline it is preferable that laboratory tests will be performed within 2 weeks before treatment administration
`- During 177Lu-DOTA0-Tyr3-Octreotate treatment, laboratory tests will be performed within 2 weeks before and 4 weeks after each treatment. Then every 12±1 weeks
`- If a 40% increase over the baseline serum creatinine value occurs during the course of treatment, with a concomitant decrease of over 40% in creatinine clearance as
`calculated from serum creatinine concentrations according to Cockcroft-Gault formula, patients must also have a measured creatinine clearance (or GFR) performed.
`Measured creatinine clearance should be through two 24-h urine collections. Total urinary protein should also be measured
`3During the study, symptoms will be recorded in the e-CRF according to patient diary notes
`4Preferably via gated equilibrium radionuclide ventriculography (RVG), only in patients with history of congestive heart failure (patients with uncontrolled congestive heart failure
`(NYHA II, III, IV) aren't eligible according to exclusion criterium №-11)
`5AEs/SAEs will be reported from signing the informed consent form onwards until end of study. During the long-term 3 year follow-up only SAEs related to 177Lu-DOTA0-Tyr3-
`Octreotate must be reported to the Sponsor Safety Officer
`6EOS = End of Study Visit for each patient
`7Patient must be contacted every 6 months up to 3 years after the end of the study (phone contacts or visits at Site)
`Laboratory assessments (haematology, biochemistry, urinalysis), SAEs suspected in relationship to the study drug, progression free survival (local evaluation) and overall survival
`data will be reported
` Information to be collected during the entire study  
`
`                                                       
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`Table 2: Visit Schedule: Octreotide LAR Arm
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`Refer to Protocol Section 6 for further details on Visits Assessments
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`Table 2 Footnotes
`(cid:170)TREATMENT: 60 mg 4-week interval Octreotide LAR Depot injections
`
`IF REQUIRED, RESCUE TREATMENTS: Octreotide s.c injections
`1Centrally evaluated until End Of Study
`Disease progression at inclusion to be confirmed centrally: the oldest CT/MRI scan must not be older than 3 years, and the most recent scan must not be older than 4
`weeks from the projected randomization date. The CT scan/MRI scan that is to be compared to the baseline CT scan/MRI scan, should be one that was performed while
`the patient was on a fixed dose of Sandostatin LAR.
`RECIST Disease Assessment during the 3 year follow-up will be performed locally
`
`2Tests included in the local laboratory assessments:
`- Haematology: WBC with differential, Platelets, Hb, MCV
`- Blood chemistry: Serum Creatinine, (Creatinine Clearance - Cockcroft-Gault formula), Uric Acid, Albumin, Total Bilirubin, AP, AST/ASAT, ALT/ALAT, Gamma-GT,
`Sodium, Potassium, LDH, GlycoHb, fT4
`- Urinalysis: RBC/hpf, WBC/hpf, Casts/lpf, Protein by dipstick test, 5-HIAA, Pregnancy test (the latter only at baseline for female of childbearing potential)
`3During the study symptoms will be recorded in the e-CRF according patient diary notes
`4Preferably via gated equilibrium radionuclide ventriculography (RVG), only in patients with history of congestive heart failure (patients with uncontrolled congestive heart failure
`(NYHA II, III, IV) aren't eligible according to exclusion criterium №-11)
`5EOS= End of Study Visit for each patient
`
`6Patient must be contacted every 6 months up to 3 years after the end of the study (phone contacts or visits at Site)
`
` Laboratory assessments (haematology, biochemistry, urinalysis), progression free survival (local evaluation) and overall survival data will be reported
`
`Information to be collected during entire the study
`
` 
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`Protocol N° AAA-III-01/FINAL version 1.0, November 14th, 2011
`INVESTIGATOR APPROVAL SIGNATURE PAGE
`Protocol N°AAA III-01 / FINAL version 1.0, November 14th, 2011
`
`
`1. I have carefully read this protocol entitled “A multicenter, stratified, open, randomized,
`comparator-controlled, parallel-group phase III study comparing treatment with 177Lu-
`DOTA0-Tyr3-Octreotate to Octreotide LAR in patients with inoperable, progressive,
`somatostatin receptor positive midgut carcinoid tumours”, and agree that it contains all the
`necessary information required to conduct the study. I agree to conduct this study as outlined
`in the protocol.
`2. I understand that this study will not be initiated without approval of the appropriate
`Institutional Review Committee/Ethics Committee and that all administrative requirements of
`the governing body of the institution will be complied with fully.
`3. I confirm that I will conduct the study in accordance with the International Conference on
`Harmonisation (ICH) Good Clinical Practice (GCP) guidelines and FDA requirements as
`specified in Title 21, Code of Federal Regulations, Part 50, 54, 56, 312 and the provisions of
`the Helsinki Declaration (Appendix 1); copies of these documents have been given to me by
`the Sponsor.
`4. I will also ensure that sub-investigator(s) and other relevant members of my staff have access
`to copies of this protocol, the ICH GCP guidelines, and the Helsinki Declaration to enable
`them to work in accordance with the provisions of these documents.
`5. Informed written consent will be obtained from all participating patients in accordance with
`institutional and ICH Guidelines for Good Clinical Practice.
`6. I will enrol patients who meet the protocol criteria for entry and who can be followed up in
`accordance with this protocol.
`7. I understand that my signature on each completed Case Report Form indicates that I have
`carefully reviewed each page and accept full responsibility for the contents thereof.
`8. I understand that the information presented in this study protocol is confidential and I hereby
`assure that no information based on the conduct of the study will be released without prior
`consent from the Sponsor unless this requirement is superseded by the Food and Drug
`Administration/European Medicines Agency, European Competent Authorities and Ethic
`Committees.
`
`
`
`Principal Investigator’s Signature
`
`
`Principal Investigator’s Printed Name
`
`
`Affiliation
`
`
`
`Date
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`Protocol N° AAA-HI-O1/FINAL version 1,0, November 14", 2011
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`15
`
`SPONSOR APPROVAL SIGNATURE PAGE
`
`Advanced Accelerator Applications SA, Head of Research & Development
`
`MaurizioFrancoMariani
`
`MAManis
`
`Signature
`
`al Hos [20
`
`Date
`
`Advanced Accelerator Applications SA, Clinical Study Manager
`
`Paola Santoro
`
`oQa. Aawons
`
`iy Nov 20h
`
`Signature
`
`Date
`
`Designated CRO Authorized Representative
`
`PieeqokGio GAtLLETTI
`(newCAL 0 LECTOi)
`
`At, |Kev | Cott
`Date
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`Protocol N° AAA-III-01/FINAL version 1.0, November 14th, 2011
`
`Table of Contents
`1- INTRODUCTION...................................................................................................................................... 23 
`1.1 BACKGROUND .................................................................................................................................. 23 
`1.2 PEPTIDE RECEPTOR RADIONUCLIDE THERAPY................................................................................. 23 
`1.3 RISK-BENEFIT ASSESSMENT ............................................................................................................. 24 
`1.3.1 Treatment Options ......................................................................................................................... 24 
`1.3.2 Efficacy of Sandostatin® LAR ....................................................................................................... 25 
`1.3.3 177Lu-DOTA0-Tyr3-Octreotate Phase I/II Study Data .................................................................... 25 
`1.3.3.1 Safety of 177Lu-DOTA0-Tyr3-Octreotate .................................................................................................. 25 
`1.3.3.2 Efficacy of 177Lu-DOTA0-Tyr3-Octreotate ............................................................................................... 27 
`2- STUDY OBJECTIVES.............................................................................................................................. 29 
`2.1 PRIMARY OBJECTIVE ....................................................................................................................... 29 
`2.2 SECONDARY OBJECTIVES ................................................................................................................. 29 
`3- STUDY DESIGN........................................................................................................................................ 30 
`3.1 STUDY OUTLINE ............................................................................................................................... 30 
`3.2 END OF STUDY.................................................................................................................................. 31 
`3.3 STUDY DESIGN RATIONALE ...................................................................................................