`
`This appendix has been provided by the authors to give readers additional information about their work.
`
`Supplement to: Strosberg J, El-Haddad G, Wolin E, et al. Phase 3 trial of 177Lu-Dotatate for midgut neuroendo-
`crine tumors. N Engl J Med 2017;376:125-35. DOI: 10.1056/NEJMoa1607427
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`177LU‐DOTATATE PHASE 3 TRIAL IN MIDGUT NEUROENDOCRINE TUMORS
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`SUPPLEMENTARY APPENDIX
`
`TABLE OF CONTENTS
`
`Acknowledgements ………………………………………………………….……………….……. 2
`
`Supplementary Table S1. Demographic and Baseline Clinical
`Characteristics of the Patients at Enrollment (Full Analysis Set) ……………… 3
`
`Supplementary Table S2. 177Lu‐DOTATATE Exposure. ………………….………….. 4
`
`Safety Assessments ………………………………………………………………………………… 6
`
`Supplementary Figure 1. CONSORT Flow Diagram. ………………..………….…… 12
`
`Supplementary Figure 2. Relative Change from Baseline in
`(a) Leukocyte Count. ….…………………………………………………………………………. 13
`
`Supplementary Figure 2. Relative Change from Baseline in
`(b) Lymphocyte Count. …………………………………………………………………………. 13
`
`Supplementary Figure 2. Relative Change from Baseline in
`(c) Neutrophil Count. …………………….…………………………………………………..…. 13
`
`Supplementary Figure 2. Relative Change from Baseline in
`(d) Platelet Count. …………………………………………………………….…………….……. 14
`
`Supplementary Figure 3.
`Creatinine Clearance Over Time in the Study. ……………………………………….. 14
`
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`Acknowledgements
`
`We thank the participating patients and their families, as well as the global network of
`
`research nurses, trial coordinators, and operations staff for their contributions, and the
`
`investigators whose patients were enrolled in this trial, including: Belgium: Eric Van Cutsem;
`
`France: Catherine Ansquer, Eric Baudin, Frederic Courbon, Francesco Giammarile, Philippe
`
`Ruszniewski, David Taieb; Germany: Richard P. Baum, Marianne Pavel, Klemens
`
`Scheidhauer, Matthias Weber; Italy: Lisa Bodei, Ernesto Brianzoni, Gianfranco Delle Fave,
`
`Maria Chiara Grana, Giuliano Mariani, Guido Rindi, Ettore Seregni, Stefano Severi; Portugal:
`
`Isabel Azevedo; Spain: Enrique Grande, Jaime Mora; Sweden: Kjell Öberg, Anders Sundin;
`
`United Kingdom: Adil Al‐Nahhas, Martyn Caplin, Nick Freemantle, Ashley Grossman,
`
`Prakash Manoharan, Nicholas Reed, Rajaventhan Srirajaskanthan; USA: Lowell Anthony, Al
`
`B. Benson, Jordan Berlin, David Bushnell, Ebrahim Delpassand, Stanley Garbus, Andrew
`
`Hendifar, Timothy Hobday, Matthew Kulke, Larry Kvols, David Metz, Erik Mittra, Michael
`
`Morse, Meike Schipper, Jonathan Strosberg, Edward Wolin, James Yao.
`
`Funded by Advanced Accelerator Applications; ClinicalTrials.gov number NCT01578239;
`
`EudraCT number 2011‐005049‐11.
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`Supplementary Table S1. Demographic and Baseline Clinical Characteristics of the
`Patients at Enrollment (Full Analysis Set)
`
`
`Characteristic
`
`Gender— no. (%)
`
`Female
`Male
`Mean age (SD) — yr
`Mean BMI (±SD) — kg/m2
`Continent of origin— no. (%)
`USA
`EU
`Median time since diagnosis — yr
`Mean KPS (SD)
`Primary tumor site — no. (%)
`Jejunum
`Ileum
`Small intestine
`Appendix
`Right colon
`Midgut (not otherwise specified)
`
`Site of metastasis — no. (%)
`Liver
`Lymph nodes
`Mesentery
`Bone
`Lungs
`Peritoneum
`Ovaries
`Other
`
`3
`
`177Lu‐DOTATATE
`(N = 116)
`
`53 (46)
`63 (54)
`63 (±9)
`25 (±5)
`
`66 (57)
`50 (43)
`3.8
`88.6 (±9.32)
`
`6 (5)
`86 (74)
`11 (9)
`1 (1)
`3 (3)
`9 (8)
`
`
`97 (84)
`77 (66)
`17 (15)
`13 (11)
`11 (9)
`7 (6)
`1 (1)
`15 (13)
`
`Octreotide LAR
`60 mg (N = 113)
`
`60 (53)
`53 (47)
`64 (±10)
`26 (±7)
`
`69 (61)
`44 (39)
`4.8
`88.0 (±9.56)
`
`9 (8)
`82 (73)
`12 (11)
`2 (2)
`1 (1)
`7 (6)
`
`
`94 (83)
`65 (58)
`8 (7)
`12 (11)
`5 (4)
`10 (9)
`9 (8)
`10 (9)
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`Ki67 index — no. (%)
`Grade 1/2
`SRS, Krenning scale — no. (%)†
`Grade 2
`Grade 3
`Grade 4
`Median chromogranin A (quartiles) — µg/l$
`Median 5‐HIAA (quartiles)‡— mg/24hr$
`Median serum alkaline phosphatase
`(quartiles) — U/l$
`Previous treatments—no. (%)*
`Surgery
`Tumor resection
`Tumor ablation
`Targeted therapy**
`Embolization#
`Chemotherapy
`Interferon
`Angiogenesis inhibitor
`Radiotherapy (external beam radiation)
`PRRT
`Investigational drug
`131I MIBG
`
`
`76/40 (66/35)
`
`11 (10)
`34 (29)
`71 (61)
`604 (247–2626)
`36 (17‐126)
`99 (74‐160)
`
`
`81/32 (72/28)
`
`12 (11)
`34 (30)
`67 (59)
`648 (290 – 2674)
`44 (21‐92)
`106 (75‐152)
`
`
`93 (80)
`90 (78)
`6 (5)
`19 (16)
`18 (16)
`11 (9)
`8 (7)
`6 (5)
`4 (3)
`1 (1)
`1 (1)
`0 (0)
`
`
`93 (82)
`93 (82)
`11 (10)
`17 (15)
`13 (12)
`14 (12)
`7 (6)
`2 (2)
`6 (5)
`0 (0)
`1 (1)
`2 (2)
`
`5‐HIAA denotes 5‐hydroxyindoleacetic acid, BMI body mass index, PRRT peptide receptor
`radionuclide therapy, SD standard deviation, and SRS somatostatin receptor scintigraphy.
`
`†Highest grade.
`‡Available in 82 and 84 patients, in 177Lu DOTATATE and Octreotide LAR 60 mg group,
`respectively
`*Other than somatostatin analogs (100% at study entry, inclusion criteria)
`**Includes everolimus, temsirolimus, sunitinib, imatinib, sorafenib, pazopanib, axitinib
`and gefitinib
`#Includes chemo‐embolization, radio‐embolization and trans‐arterial embolization
`$Normal range: CgA, 19.4 to 98.1 μg/l; 5HIAA, 0 to 15 mg/24hrs; AP, 0 to 150 U/l.
`
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`Supplementary Table S2. 177Lu‐DOTATATE Exposure.*
`
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`Patients who completed treatment phase
`(N=103†)
`Number of administrations
`
`4
`
`3
`
`2
`
`1
`
`0
`All treated patients (N=111)
`No DMT
`DMT
`
`* DMT denotes dose‐modifying toxicity.
`
`no. (%)
`
`79 (77)
`6 (6)
`12 (12)
`5 (5)
`1 (1)
`
`103 (93)
`8 (7)
`
`† Excluding pa(cid:415)ents s(cid:415)ll under treatment (n=8) or no treatment (n = 5).
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`SAFETY ASSESSMENTS
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`In both arms, safety assessment was performed every 12±1 weeks from the randomization
`date. In the active arm, during 177Lu‐DOTATATE treatment phase, additional safety visits
`were conducted every 2 to 4 weeks approximately. All adverse events (AEs), whether or not
`spontaneously reported by the patient, were recorded starting from the signing of the
`informed consent form (ICF) until the last study‐related visit. Furthermore, a Data Safety
`Monitoring Board evaluated patient safety throughout the study. An AE was defined as any
`untoward medical occurrence in a patient and which did not necessarily have a causal
`relationship with the study medication. AEs were reported from the time the ICF was signed
`onwards until the progression‐free survival (PFS) primary endpoint occurred, or until Week
`76 post randomization if the PFS primary endpoint had been reached, or until early
`termination.
`A serious AE (SAE) was any untoward medical occurrence that at any dose:
` Resulted in death;
` Was life‐threatening;
` Resulted in persistent or significant disability/incapacity;
` Resulted in congenital anomaly or birth defect;
` Required inpatient hospitalization or leads to prolongation of hospitalization, with
`the exception of elective preplanned hospitalizations.
`If a patient became pregnant during treatment, this had to be reported to the Sponsor
`Safety Officer as if it were an SAE. According to protocol, during the long‐term follow‐up,
`only SAEs related to 177Lu‐DOTATATE had to be reported to the Sponsor Safety Officer. In
`general, the investigator was requested to indicate the probable cause of the specific SAE in
`the appropriate section(s) of the SAE Reporting Form. The National Cancer Institute
`Common Terminology for Adverse Events (Version 4.03) was used for determining the
`severity of AEs.
`In addition to the above‐defined SAE, a set of potential risks deserved special attention even
`if they do not fulfill any of the seriousness criteria. These non‐serious AEs of special interest
`(AESIs) occurring in patients enrolled in the investigational arm (177Lu‐DOTATATE) had to be
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`reported to the clinical trial pharmacovigilance department for safety analysis any time they
`occurred after enrollment including long term follow‐up. Owing to the drug mechanism of
`action, hematotoxicity, secondary hematologic malignancies, and nephrotoxicity and
`cardiovascular events were investigated as AESIs. As the AESIs were not intended as a
`specific category of AEs for analysis in the Statistical Analysis Plan, the AESI flags in the
`database were not fully reconciled. To account for possible AESI underreporting an
`additional post hoc analysis was also conducted to identify AESIs in the two arms among the
`AEs/SAEs and the laboratory data as follows:
` Hematotoxicity: all grade ≥2 thrombocytopenia or grade 3/4 anemia/leukopenia/
`neutropenia events not present at baseline were extracted from the laboratory
`dataset, as well as all the treatment‐emergent AEs/SAEs with the Preferred Term
`related to this toxicity category (different from thrombocytopenia, anemia,
`leukopenia, neutropenia, because already extracted from the laboratory data).
`Secondary hematologic malignancies: all the treatment‐emergent AEs/SAEs with the
`Preferred Term related to this toxicity category.
` Nephrotoxicity: all the treatment‐emergent AEs/SAEs with the Preferred Term
`related to this toxicity category.
` Cardiovascular events: all the treatment‐emergent AEs/SAEs with the Preferred
`Term related to this toxicity category.
`All AEs occurring during the study were to be followed up until resolved or judged to be
`no longer clinically significant, or until they became chronic to the extent that they could
`be fully characterized. An assessment had to be made at the last study‐related visit for
`each patient.
`Laboratory assessments required that blood samples were taken for hematology and
`blood chemistry, and a urine sample for urinalysis, as listed below. Laboratory
`assessments were performed at the investigational site, except for the evaluation of
`serum chromogranin A. At screening: all patients had screening laboratory assessments
`including hematology, blood chemistry, and urinalysis; the assessment could be
`combined with baseline evaluation if sampling was within 3 weeks (preferably 2 weeks
`in the 177Lu‐DOTATATE arm) before the first treatment date. If laboratory data were
`available from a date that was less than 2 weeks since the signature of the ICF, those
`data could be considered acceptable for the initial screening of the patient (as
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`acknowledged in the ICF), if the repetition of the same examinations was regarded as
`useless. During the study, in the 177Lu‐DOTATATE arm: within 2 weeks before and 4±1
`weeks after each 177Lu‐DOTATATE treatment. In addition, for the second, third, and
`fourth 177Lu‐DOTATATE treatment, an additional laboratory assessment was performed
`on the same day or within 1 day before treatment. Blood tests performed 4 weeks after
`any treatment could not serve as baseline values for the next treatment. A washout
`period was required between treatments. Patients were not eligible for their next
`treatment until a minimum of 7 weeks had passed since the last administration of study
`drug (maximum 16 weeks). Throughout the study, laboratory assessments were
`performed every 12±1 weeks since the first treatment date (Week 0). In the octreotide
`LAR 60 mg arm: throughout the study laboratory assessments were performed 4 weeks
`after the first treatment, and every 12±1 weeks since the first treatment date (Week 0).
`In the event of a significant laboratory abnormality, or if clinical or laboratory evidence
`of toxicity occurred, the investigator collected additional specimens for repeat or
`additional analyses, at intervals appropriate to the abnormality. The patient was closely
`followed until sufficient information was obtained to determine the cause or the value
`regressed. Appropriate remedial measures were taken and the response recorded. All
`safety laboratory results had to be evaluated by the investigator before administration
`of study medication. Any clinically relevant change from baseline onwards was recorded
`on the Adverse Event page of the electronic case report form (e‐CRF), possibly with a
`single diagnosis encompassing all changes supporting the single diagnosis. Laboratory
`assessments included the following:
` Hematology: white blood cell (WBC) count with differential (i.e. lymphocytes,
`monocytes, neutrophils, eosinophils, basophils), platelets, hemoglobin, mean
`corpuscular volume, and hematocrit.
` Blood chemistry: blood urea nitrogen, serum creatinine, uric acid, albumin, total
`bilirubin, alkaline phosphatase, aspartate aminotransferase, alanine
`aminotransferase, gamma‐glutamyltransferase, sodium, potassium, lactate
`dehydrogenase, chromogranin A (centralized assessment), glycosylated
`hemoglobin, free thyroxine, calcium, fasting blood glucose, and creatinine
`clearance (calculated by the Cockroft‐Gault formula).
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` Urinalysis: red blood cells per high‐power field, WBCs per high‐power field, casts
`per low‐power field, protein (dipstick test was accepted to assess protein),
`pregnancy test if applicable (the latter at baseline for women of childbearing
`potential and during 177Lu‐DOTATATE therapy within 7 days before each
`treatment; blood pregnancy test was accepted). 5‐hydroxyindoleacetic acid had
`to be done on 24‐hour urine collection only at eligibility or baseline visit, at
`Weeks 12, 24, 36, 48, 60, 72, or 76 (and following 3‐monthly laboratory
`assessments until the analysis of the PFS primary endpoint and at 6‐month
`follow‐up visits).
`Patients with uncontrolled congestive heart failure (New York Heart Association class
`II–IV) were not eligible. Patients with a history of congestive heart failure who did
`not violate the above exclusion criteria underwent an evaluation of their cardiac
`ejection fraction before baseline, preferably via gated equilibrium radionuclide
`ventriculography. The results from an earlier study (not exceeding 30 days) may have
`substituted the evaluation at the discretion of the investigator, if no clinical
`worsening was noted. It was recommended that the patient’s measured cardiac
`ejection fraction was >40% before randomization.
`Electrocardiograms (ECGs) were recorded at baseline, immediately after each 177Lu‐
`DOTATATE treatment procedure (following the completion of the 177Lu‐DOTATATE
`infusion), and at the end of study to measure the different ECG intervals (RR, PR,
`QRS, and a more extended QT evaluation according to International Conference on
`Harmonisation Guideline E14, and heart rate). ECGs were taken also in the
`octreotide LAR 60 mg arm at the same timepoints (before the octreotide LAR
`injection). Standard 12‐lead ECG was the preferred option, but if not possible, a 3‐
`lead ECG was acceptable. An ECG in triplicate (at least 5 minutes apart) was taken
`supine, after 5 minutes rest, and not immediately after a meal. The parameters were
`measured as a mean value of minimally 3 beats; the mean of each parameter had to
`be used for eCRF completion. The investigator/local cardiologist noted in the source
`documents (and in the e‐CRF) whether the ECG was normal or abnormal, as well as
`the clinical relevance of abnormal ECGs results and the different ECG interval
`measurements, calculated as the mean value of three measurements for each
`parameter. Relevant abnormalities at baseline were recorded in the Medical History
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`page, while changes during the study were recorded on the Adverse Event page of
`the e‐CRF.
`Physical examinations were performed by the investigator or qualified designee. All
`body systems were examined and any relevant findings were documented in the
`source documents and e‐CRF. Physical examinations should have included heart rate,
`blood pressure, and weight measurement (height was only measured at baseline).
`Blood pressure and pulse rate measurements were performed after the patient
`rested for 5 minutes. For each patient, all blood pressure recordings should have
`been made using the same type of instrument (i.e., manual blood pressure recording
`vs. automatic digital vital signs monitor) on the same arm. Significant findings that
`were present before baseline were recorded in the Medical History page, while
`changes during the study (including significant changes of the symptoms due to the
`underlying disease vs. baseline, as reported in the diary card) were recorded on the
`Adverse Event page of the e‐CRF.
`Karnofsky performance score forms had to be completed by a medical professional
`at each treatment and follow‐up visit, and before any current clinical information
`was given to the patient.
`The serious adverse reactions (SARs) reported by the investigators in the 177Lu‐
`DOTATATE arm were:
` One patient suffered from a serious episode of hepatic encephalopathy which
`required hospitalization but resolved without sequelae within 1 week. This SAR
`was related to the amino acids administration according to the investigator.
` One patient had mild thrombocytopenia which lasted for 28 days and was
`assessed as medically significant and related to 177Lu‐DOTATATE by the
`investigator. This SAR did not require any hospitalization or specific
`treatment/action.
` One patient had grade 3 thrombocytopenia assessed by the investigator as
`medically significant and related to 177Lu‐DOTATATE which required no specific
`action but was still ongoing at the time of database lock.
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` One patient had grade 4 neutropenia assessed by the investigator as medically
`significant and related to 177Lu‐DOTATATE which required postponing next 177Lu‐
`DOTATATE infusion but resolved within 10 days.
` One patient suffered from an episode of syncope which was considered medically
`significant and related to amino acid infusion by the investigator. The SAR
`resolved spontaneously within few hours.
` One patient had an increase in creatinine levels (to 105 μmol/L, which was not
`abnormal per se, but was a 32% increase compared to baseline) which lasted for
`27 days and required postponing the subsequent cycle of 177Lu‐DOTATATE. This
`SAR was assessed as related to 177Lu‐DOTATATE and improved at database lock.
` One patient had a moderate increase in creatinine (up to 1.95 mg/dL) and
`decrease of creatinine clearance (down to 36 ml/min; baseline 76 ml/min) which
`were seen as medically significant and related to 177Lu‐DOTATATE by the
`investigator, and necessitated postponing the next investigational product
`administration. These SARs resolved without sequelae within about 6 months.
` One patient suffered from severe abdominal ascites, related to 177Lu‐DOTATATE
`according to the investigator, which lasted for several months and necessitated
`therapeutic paracentesis procedures and one TIPS procedure before resolving
`without sequelae.
` One patient suffered from mild proteinuria and renal dysfunction which were
`assessed as medically significant and related to 177Lu‐DOTATATE by the
`investigator. This SAR did not require any hospitalization or specific
`treatment/action, but was still ongoing at the time of database lock.
` One patient suffered from significant dehydration related to 177Lu‐DOTATATE
`according to the investigator, which necessitated hospitalization but resolved
`within 3 days.
`
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`Supplementary Figure 1
`
`
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`
`
`Enrolment
`
`Assessed for eligibility (n=316)
`
`Excluded due to screening
`
`failure (n=87)
`
`Randomized (n=229)
`
`Allocation
`
`
`
`Allocated to 177Lu-DOTATATE (n=116)
`
`Allocated to octreotide LAR (n=113)
`
`Received allocated intervention (n=111)
`
`Received allocated intervention (n=110)
`
`Analysis
`
`Full analysis set (n=116)*
`
`Safety set (n=111)
`
`Full analysis set (n=113)*
`
`Safety set (n=110)
`
`*At the time of the analysis cutoff date (July 2015), 15 patients in the 177Lu-DOTATATE
`
`arm and 13 patients in the Octreotide LAR arm had no follow-up scans
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`Supplementary Figure 2 – Hematological parameters mean relative change from
`baseline evolution over time (Error bars indicate standard deviations of the mean)
`2a.
`
`2b.
`
`2c.
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`2d.
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`Supplementary Figure 3
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