PReCedeNT Trial: Phase III Randomised Controlled Open Label Trial of Lutetium 177 PRRT Plus Chemotherapy Versus PRRT Aalone in FDG Avid Well Differentiated Gastroenteropancreatic Neuroendocrine Tumors
Phase: PHASE3
Conditions: Neuroendocrine Neoplasia's (NENs), Neuroendocrine Tumor GEP Grade 1-3, Neuroendocrine Gastroenteropancreatic Tumour
Sponsor: Tata Memorial Hospital

1 
 
Title of Study: 
PReCedeNT trial: Phase III randomised-controlled open-label trial of Lutetium - 177 
Peptide Receptor Radionuclide Therapy (PRRT) Plus Chemotherapy Versus PRRT 
alone in FDG-avid, Well-Differentiated Gastro-Entero-Pancreatic Neuroendocrine 
Tumors (GEP-NETs) 
 
Date: 21.02.2024 
 
 
Clinical trial protocol Version 1.6 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Table of contents 
 
 
Serial 
numbe
r 
Protocol component 
Page 
numbe
r 
1 
Table of contents 
1-5 
2 
Study title 
6 
3 
Study synopsis 
Scientific background and rationale 
●​ Classification of GEP-NET 
●​ Current management 
strategies in 
unresectable/metastatic 
GEP-NET 
●​ Rationale of proposed study 
●​ Translational aspect 
7-9 
Study objectives and endpoints 
●​ Primary endpoint 
●​ Secondary endpoints and objectives 
●​ Translational objectives 
9 
Study design 
10 
 
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●​ Type of study 
●​ Patient number 
●​ Time schedule 
●​ Number of centres 
Patient selection 
●​ Inclusion criteria 
●​ Exclusion criteria 
11 
Treatment 
Overview 
PRRT 
Pre-requisites 
Formulation, dispensing, handling precautions, 
possible adverse effects 
Dose modifications 
Chemotherapy - 
Capecitabine-Temozolamide Distribution 
of study medications 
●​ General information of individual drugs 
13-24 
 
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●​ Capecitabine– formulation, dispensing, 
handling precautions, possible adverse 
effects 
●​ ​Temozolamide– formulation, dispensing, 
handling precautions, possible adverse effects 
Modifications of therapy and dosage 
●​ Overview and general principles 
●​ Baseline dose modification of drugs 
●​ Dose modifications in case of side-effects 
➢​ Dose adjustments in case of myelosuppression 
➢​ Dose adjustments in case of diarrhoea/mucositis 
➢​ Dose adjustments in case of nephrotoxicity 
➢​ Dose modifications for other toxicities 
Patient status before starting a new cycle of 
chemotherapy Guidelines for therapy post 
progression 
Emergency management 
25 
Enrolment 
25 
Premature withdrawal of an individual subject 
25 
Premature study termination by primary investigator and 
ethics committee 
25 
Study assessments (Baseline and efficacy) 
26 
 
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●​ Schedule of study assessments 
●​ Baseline assessment 
●​ Assessment during and after study 
●​ Documentation at follow up 
●​ Criteria for efficacy evaluation 
➢​ Tumor evaluation 
➢​ Progression free survival 
➢​ Overall survival 
Study assessments (safety) 
●​ Assessment of adverse events 
●​ Definitions 
➢​ Adverse events 
➢​ Serious adverse events (SAE)/SUSAR 
●​ Procedure for reporting serious adverse events 
●​ Pregnancy reporting 
●​ Monitoring of subjects with adverse events 
●​ Overdose 
29 
Assessment of quality of life 
1.​ Scales used in study 
2.​ Schedule for assessing quality of life 
32 
Data management and statistics 
33 
 
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●​ Data management 
●​ Biostatistical aspects 
●​ Design of study 
➢​ Sample size calculation 
➢​ Statistical methods 
➢​ Final analysis 
Documentation and archives 
●​ Documentation and information flow 
●​ Data archiving 
33 
Financing of study 
33 
Ethical considerations 
●​ Ethical considerations of study 
●​ Declaration of Helsinki 
●​ Informed consent of patient 
●​ Protocol amendments 
●​ Reimbursement and compensation 
34-36 
References 
36-38 
 
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Synopsis 
 
Scientific background and rationale 
Neuroendocrine tumors (NETs) are a heterogeneous group of malignancies ranging from well- 
differentiated, slowly growing tumors to poorly differentiated neoplasms, which are aggressive 
and less frequent (1). Neuroendocrine cells have the ability to express several peptide 
receptors in high volumes, especially somatostatin receptors, which are heptahelical 
G-protein–coupled glycoprotein transmembrane receptors. In the most recent SEER register 
(SEER-17), more than half of all NETs, i.e. 61%, were gastroenteropancreatic neuroendocrine 
tumors (GEP-NETs), with the highest frequency being found in the rectum (17.7%), the small 
intestine (17.3%), and the colon (10.1%) [2]. The tumor biology varies with the location of the 
primary tumors as well as with the grade and staging of the tumors. The malignant potential 
ranges from the most benign types of tumor to small intestinal tumors and up to 
neuroendocrine carcinoma (NEC) with very malignant behavior [3]. The tumors are graded 
according to the classification system of the World Health Organization (WHO), wherein a 
new classification system is just being accepted. The tumors are divided into grade 1 NET 
(NET-G1), with a proliferation <3%, NET-G2 with a proliferation between 3 and 20%, NET-G3, 
which is a new group with a Ki-67 >20%, and finally NEC-G3, exhibiting a Ki-67 of >20% as 
well (unpublished data). Of note, the difference between NET-G3 and NEC-G3 is mainly the 
degree of differentiation. NET-G3 are well-differentiated tumors, often with expression of 
somatostatin receptors. NEC-G3 are poorly differentiated tumors that usually lack expression 
of somatostatin receptors. 
NETs are characterized by a general lack of symptoms until they are in advanced phase, and 
early biomarkers are not as available and useful as required. Heterogeneity is an intrinsic, 
pivotal feature of NETs that derives from diverse causes and ultimately shapes tumor fate. (4) 
The different layers that conform NET heterogeneity include a wide range of distinct 
characteristics, from the mere location of the tumor to its clinical and functional features, and 
from its cellular properties, to the core signaling and (epi)genetic components defining the 
molecular signature of the tumor. The importance of this heterogeneity resides in that it 
translates into a high variability among tumors and, hence, patients, which hinders a more 
precise diagnosis and prognosis and more efficacious treatment of these diseases. 
Heterogeneity can be assessed objectively by molecular imaging techniques. Patients with 
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well- differentiated GEP NETs undergo imaging with Ga-68-DOTATOC PET/CT (DOTA 
PET/CT), which is a somatostatin-receptor (SSTR)-specific imaging tracer. PET/CT with 
68Ga-DOTA-peptides has been reported to present a higher sensitivity for the detection of 
well-differentiated, less aggressive NETs than 
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well tolerated with negligible grade 3/4 toxicities. After a median follow-up period of 36 months, 
the median OS was not achieved with a median PFS of 48 months. At 3 months after 
completion of combination of PRRT and chemotherapy, 2% of patients showed a complete 
anatomical response, 28% a partial response, 68% stable disease, and only 2% progression. 
On FDG PET/CT, 27% achieved a complete metabolic response during the follow-up period. A 
biochemical response (>25% fall in chromogranin-A levels) was seen in 45%. (16) These 
results established the effectiveness of the combination of PRRT and chemotherapy which is 
now practiced routinely. However, there is no prospective study to establish this treatment 
regime. We therefore propose to prospectively evaluate the combination of PRRT and 
chemotherapy in patients with well-differentiated NETs, in a systematic manner to generate 
reliable conclusions with regards to this treatment regimen for intermediate to high grade 
NETs.CT or scintigraphy (5,6). On the other hand, 18F-FDG PET/CT is preferred for more 
aggressive, less differentiated NETs as there is emerging evidence that the presence of 
increased expression of GLUT (glucose-transporter) receptors in NETs highlights an increased 
propensity for invasion and metastasis, and an overall poorer prognosis (7). In fact, a strong 
association has recently been shown between higher 18F-FDG uptake and worse outcome 
even in patients with well-differentiated or low-grade tumors, with provision of prognostic 
information independently of the mitotic rate (8). Accordingly, 18F-FDG has an important role 
in managing patients with NETs because of its high prognostic value and its higher sensitivity 
in delineating disease extent, especially in aggressive and high-grade and aggressive 
intermediate-grade tumors (9). While DOTA PET avidity is a feature of well-differentiated 
disease, FDG avidity tends to be associated with more aggressive, de-differentiated disease 
(10). Grade 1 NET tends to be DOTA-avid but negative on FDG PET, whereas grade 3 NEC 
generally shows the opposite imaging phenotype. Grade 2 NET may demonstrate uptake of 
both tracers. Irrespective of pathological grade, the distribution of these tracers may not be 
spatially concordant, with some lesions having either DOTA or FDG avidity, but not both. This 
highlights the limitations of relying on histopathological grade from a single biopsy site to 
predict disease behaviour. Despite the prognostic utility of pathological grading, FDG PET 
positivity has been consistently shown to be independently associated with a poor prognosis. 
(11) SSTR expression on the surface of NET enables the use of somatostatin analogues 
labelled with particle-emitting radionuclides for targeted peptide receptor radionuclide therapy 
(PRRT) NETTER-1 trial has established Lu-177 PRRT (Peptide Receptor Radionuclide 
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Therapy) as standard of care in treatment of metastatic well-differentiated GEP NETs. (12) 
However, FDG positivity in these tumors suggests presence of aggressive phenotypes and 
warrants simultaneous use of chemotherapy. (13) Strosberg et.al, have shown exceptionally 
high and durable response rate with combination of Capecitabine and temozolamide in 
metastatic well, or moderately differentiated pancreatic neuroendocrine tumor. Combination of 
PRRT and chemotherapy, that is, temozolomide-capecitabine (CAP-TEM) has been therefore 
effective in patients showing SSTR and GLUT receptor expression on Ga-68 DOTA PET and 
FDG PET respectively. (15) Kong et al studied a retrospective cohort of 52 patients selected 
for treatment on the basis of somatostatin-receptor imaging without spatially discordant 
FDG-avid disease. All patients received conventional PRRT regimen, in addition oral 
capecitabine was added after every PRRT cycle. Clinical, biochemical and imaging response 
was assessed after completion of induction. 
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treatment of combination of PRRT and chemotherapy. Combination of PRRT and 
chemotherapy was  
 
Study objectives and endpoints 
 
Primary endpoint 
1.​ Progression-free survival (PFS) is defined as the time duration from the date of 
randomization to the tumor progression or death from any cause. Patients alive at last 
follow-up will be censored at the date of last follow-up visit 
Secondary endpoints and objectives 
2.​ Objective Tumor Response (complete + partial response) based on a Ga-68-DOTATOC 
PET/CT scan compared to baseline (pre-treatment) evaluation, and graded by RECIST 
1.1 criteria and by Metabolic Criteria (EORTC) as defined below. This evaluation will be 
performed earlier in case of a suspected progression. 
3.​ Quality of Life parameters using EORTC QLQ C-30 and EORTC G.I.NET-21 
Overall Survival (OS) is defined as the time duration from the date of randomization to the 
date of death from any cause. Patients alive at last follow-up will be censored at the date of 
last follow-up visit 
Study design 
 
Type of study - Prospective, randomized, 
open-label Patient number - 162 
Time schedule - 8 years 
   Number of centres - Single Center, Tata Memorial Center, Mumbai 
 
Histopathologically proven well-differentiated gastro-entero-pancreatic NEN patients who 
have been deemed inoperable on the basis of initial work-up, either in the form of 
cross-sectional imaging or ultrasonography and by consensus of multi-disciplinary NET 
Clinic will undergo Ga-68 DOTATOC PET/CT (if not done previously) and 18F-FDG PET/CT 
imaging which are as per the standard institutional protocol. Ga-68 DOTATOC PET/CT 
studies done elsewhere shall be uploaded on PACS and reviewed by the Dept of Nuclear 
Medicine at Tata Memorial Hospital. 
Ga-68-DOTATOC PET/CT: Gallium-68 is a GMP-compliant generator produced isotope which 
is an in-house Hospital Radiopharmacy preparation in Department of Nuclear Medicine, Tata 
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Memorial Hospital. It is labeled to octreotide analogs (TOC/NOC/TATE) with a chelator - DOTA 
(tetraazacyclododecane - tetraacetic acid). Images are acquired on a PET/CT scanner after 
injection of 3- 4 mCi of radiotracer at 45-60 minutes after injection, from skull base to 
mid-thigh. Dedicated triphasic CT scan shall be performed with the abdomen in the field of 
view during arterial and portal phases, whereas venous phase shall be acquired from skull 
base to mid-thigh. Fused PET/CT Images will be evaluated. Krennings score will be assessed 
using a visual scale on MIP (Maximum Intensity Projection) image of Ga-68 PET. 
 
Ga-DOTATOC PET/CT Image Interpretation based on Krennings score 
 
1 
Uptake < Liver 
2 
Uptake = Liver 
3 
Uptake > Liver < 
Spleen/kidneys 
4 
Uptake > spleen or kidneys 
 
Score more than 3 will be interpreted as ‘positive’ study and these patients will 
undergo FDG PET/CT imaging. 
FDG PET/CT: After 6 hours fasting, patients will be injected with 3-5 MBq/kg body weight of 
18F- FDG intravenously and images will be acquired on a dedicated PET/CT scanner at 
45-60 minutes, from skull base to mid-thigh. 
FDG PET Image interpretation: 
 
1 
Uptake < liver 
2 
Uptake = liver 
3 
Uptake > liver 
 
Score 3 uptake will be considered as positive FDG PET study. 
All patients with positive Ga-68 DOTANOC and 18F-FDG PET/CT imaging will be recruited 
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in the study. 
 
 
 
Patient selection 
 
Inclusion criteria 
 
●​ Male or female, age greater than 18 years 
●​ Histopathological diagnosis of GEP-NET, necessarily satisfying all the the criteria below 
●​ Well differentiated G2 (Ki67 : ≥3-20%) OR G3 (ki67- greater than 20-55%), 
OR 
Well-differentiated G1 (<3%) with disease progression in last 6 months  
                                                         
●​ Positive Ga-68-DOTANOC PET/CT, Krennings score >/=3 
●​ Positive FDG PET imaging, grade 3 or 4 uptake 
●​ Locally advanced/inoperable disease or metastatic disease 
●​ Karnofsky performance-status score of at least 60 or ECOG performance status </= 2 
●​ Life expectancy greater than 6 months 
Exclusion criteria 
 
●​ Serum creatinine level of more than 1.6 mg/dl or a creatinine 
clearance of less than 50 ml/min 
●​ Hemoglobin level of less than 8.0 g per deciliter 
●​ Red blood cell count noty less than 300,000/cubic millimeter 
●​ White cell count of less than 2000 per cubic millimeter 
●​ Platelet count of less than 75,000 per cubic millimetre 
●​ Total bilirubin level of more than 3 times the upper limit of the normal range 
●​ Serum albumin level < 3.0 g/dl 
●​ Treatment with more than 30 mg of octreotide LAR within 4 weeks before randomisation. 
●​ Peptide receptor radionuclide therapy at any time before randomisation 
●​ Pregnancy and Lactation 
●​ Patients with concurrent malignancies 
 
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Treatment 
 
Overview 
 
Peptide Receptor Radionuclide Therapy involves use of beta-emitting radio-isotopes like 
Lutetium-177 (Lu-177) and Yttrium-90 (Y-90) labeled to somatostatin receptor specific peptide 
- DOTATATE. DOTA-TATE is a compound containing Tyrosine3-octreotate, a somatostatin 
receptor (SSTR) antagonist, and the bifunctional chelator (BFC) DOTA. SSTRs are found with 
high density in numerous malignancies, including CNS, breast, lung, and lymphatics.The role 
of SSTR antagonists (i.e. somatostatin and its analogs such as octreotide, somatuline and 
vapreotide) in neuroendocrine tumours (NETs) is well established, and massive SSTR 
overexpression is present in several NETs. (Tyr3)- octreotate binds the transmembrane 
receptors of NETs with highest activity for SSTR2 and is actively transported into the cell via 
endocytosis, allowing trapping of the radioactivity and increasing the probability of the desired 
double-strand DNA breakage (for tumour control). Trapping improves the efficacy of this effect 
due to the relatively short range of the beta particles emitted by Lu-177, which have a 
maximum range in tissue of <2 mm. Bystander effects include cellular damage by free radical 
formation. 
Combination of PRRT with oral chemotherapy is popularly known as PRCRT (Peptide 
Receptor Chemo-radionuclide Therapy). CAPTEM (Capecitabine-Temozolomide) is 
one of the suggested 
treatment regimens for progressive well-differentiated neuroendocrine tumors. Capecitabine is 
a prodrug that is converted from fluoropyrimidine to 5-fluorouracil upon oral intake. 
5-Fluorouracil has anticancer activity that induces damage to DNA by inhibiting thymidylate 
synthase. Temozolomide is a lipophilic methylator derived from dacarbazine—an alkylating 
agent used as a chemotherapy drug. The pharmacologic rationale for Cap/Tem emerged from 
the hypothesis that slow-growing NETs might be more sensitive to cytotoxic drugs that have an 
extended G0 phase cycle. Consequently, a lipophilic methylator such as temozolomide under 
continuous exposure to an antimetabolite such as capecitabine could be beneficial. 
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Our study involves randomisation of patients into the PRRT Arm (Arm - A) and 
PRRT plus Chemotherapy arm 
●​ Arm A (PRRT Arm) 
 
Peptide Receptor Radionuclide Therapy with Lu-177-DOTATATE, 180-200 mCi 
administered intravenously for 4 cycles, at interval duration of 8-12 weeks 
●​ Arm B (PRRT plus Chemotherapy Arm) 
 
Peptide Receptor Radionuclide Therapy with Lu-177-DOTATATE, 180-200 mCi 
administered intravenously for 4 cycles, at interval duration of 6-8 weeks 
Plus 
 
CAP-TEM Protocol: 
 
Day 1: Oral Capecitabine 1500 mg/m2, per oral, twice daily within 15 min of food for 
14 days, followed by 2 weeks rest period 
Day 10-D14: Oral Temozolamide 200 mg/m2 per oral, daily dose for 5 days as a single 
dose with a glass of water at bed time. To be taken empty stomach at least 30 min 
before or 2 hours after meal. 
Distribution of study medications 
 
All the radiopharmaceuticals and drugs used in this study will be considered as standard 
of care. Drugs will be prescribed by the treating physician, as this prescription is within 
the framework of standard usage. 
Arm A (PRRT Arm): 
 
●​ Overview and general principles 
Lutetium-1777-DOTATATE is FDA approved radiopharmaceutical produced by Board 
of Radiation and Isotope technology (BRIT). It is supplied in doses of 180-200 mCi 
and injected intravenously under radiation safety precautions. 4 cycles of PRRT are 
administered at an interval of 8-12 weeks. 
Patient status before starting a new cycle of therapy 
●​ Serum creatinine level should not be more than 1.6 mg/dl or a creatinine 
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clearance of less than 50 ml/min 
●​ Hemoglobin level should not be less than 8.0 g per deciliter 
●​ Red blood cell count not less than 300,000/cubic millimeter 
●​ White cell count should not be less than 2000 per cubic millimeter 
●​ Platelet count should not be less than 75,000 per cubic millimetre 
●​ Total bilirubin level of should not be more than 3 times the upper limit of the normal range 
●​ Serum albumin level should not be more than 3.0 g/dl 
●​ Patient should not have been treated with more than 30 mg of octreotide LAR within 12 
weeks 
General Precautions 
 
During the administration of the radiopeptide, a physician must remain nearby. A resuscitation 
cart as well as a trained emergency team must be available. 
The radiopharmaceutical should be diluted with saline to a final volume of 100 ml. 
 
The radiopharmaceutical should be administered via an indwelling catheter to ensure safe 
intravenous administration and prevent paravascular infiltration, and should be administered 
over 30 minutes· 
The line should be flushed with saline after completion of radiopeptide infusion. PRRT may 
reproduce the syndromes of the respective functional tumours due to the sudden massive 
release of the hormones and stimulation of their corresponding receptors. The clinical 
manifestation is dependent on the specific hormone involved. 
The following measures are therefore recommended. Vital signs (at least blood pressure and 
pulse) should be monitored before and after therapy infusion in symptomatic patients. 
Amino Acid Infusion: 
Renal uptake of radiolabelled somatostatin analogues can in part be attributed to the 
receptor-mediated endocytic renal transporter system involving megalin-mediated cubilin 
dependent endocytosis across the proximal epithelium.To counteract and reduce the high 
kidney retention of radiopeptides, positively charged amino acids, such as L-lysine and 
L-arginine, are co-infused to competitively inhibit the proximal tubular reabsorption of the 
radiopeptide. The coadministration of these amino acids leads to a significant reduction in the 
renal absorbed dose. 
For renal protection, an intravenous amino acid solution 25g of lysine and 25g of arginine 
diluted in 2 liters of normal saline administered concomitantly for at least 4 hours, starting 30 
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minutes before infusion of radiopharmaceutical. 
 
PRRT administration protocol: (in sequence) 
 
One-day 
prior (Day 0) 
Tablet Dexamethasone 4 mg BD oral 
Day of 
therapy (Day 
1) 
Premedication 
Tablet Aprepitant 125 mg oral 
Intravenous Dexamethasone 8 
mg 
Intravenous Palonosetron 0.25 mg 
Amino Acid Infusion to 
be started 
(1 hour after premedication) 
Intravenous infusion of lysine 
and arginine diluted in 500 ml of 
normal saline over 1 hour 
PRRT 
Intravenous infusion of 200 mCi of 
Lu- 177 DOTATATE diluted in 100 
ml normal saline over 30 minutes 
After PRRT infusion is 
over, start amino acid 
infusion 
Intravenous infusion of lysine and 
arginine diluted in 1500 ml of 
normal saline over 3 hours 
Day 2 
Tablet Aprepitant 80 mg oral, in 
morning Oral Dexamethasone 4 mg 
BD 
Day 3 
Tablet Aprepitant 80 mg oral, in 
morning Oral Dexamethasone 4 mg 
BD 
  
 
 Post-therapy scanning 
Lutetium-177 being a gamma-emitting radio-isotope as well, patients can be imaged following 
administration of therapeutic dose of Lu-177. This is done to confirm localisation of tracer at the 
targeted sites. Post-therapy scans shall be acquired at 24, 48 and 96 hours after administration 
of therapy under Dual-head SPECT/CT Gamma Camera at Dept of Nuclear Medicine, Tata 
Memorial Hospital. 
 
Radiation Safety Precautions 
Therapy will be administered in a Isotope Therapy Facility located in Tata Memorial Center 
Complex that is, either at the 3rd floor or 9th floor of Annexe Building. Trained nursing 
personnel will be instructed in radiation safety. Any serious or life-threatening medical condition 
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will be noted and contingency plans put in place in case radiation precautions need to be 
breached to allow emergency medical care. 
In a medical emergency, concerns about radiation exposure will not hinder the prompt delivery 
of appropriate medical care to the patient. 
During the first 12 hours, patients will be advised to observe rigorous hygiene to avoid 
contaminating persons using the same toilet facilities. A double toilet flush will be followed after 
urination. Incontinent patients will be catheterized prior to PRRT and the catheter will be kept 
for 2 days thereafter. Urine bags will be emptied frequently. Standard Radiation Protection 
protocol will be followed. 
Patient shall be discharged at 24 hours after the therapy, after documenting the exposure 
levels. No specific radiation safety precautions need to be followed thereafter. 
Patients would undergo 48 and 96 hour post therapy scanning on an outpatient basis. 
 
 
Arm B (PRRT plus chemotherapy) 
 
PRRT will be administered as previously detailed with similar precautions. Post 
approximately 14-21 days of PRRT, patients will be started on chemotherapy with 
Capecitabine-Temozolomide. 
Chemotherapy -Capecitabine-Temozolomide 
 
Capecitabine 
 
Formulation 
 
Capecitabine is available as an oral tablet with a strength of 500mg 
per tablet. Dispensing and handling 
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The tablets should be swallowed whole with water within 30 minutes after a meal. Capecitabine 
tablets should not be crushed or cut for administration. 
Possible side effects 
 
Nausea/vomiting, diarrhea, leukopenia, thrombocytopenia, anemia, increase of liver enzymes, 
hand-foot syndrome are common side effects seen. 
Temozolamid
e 
Formulation 
Temozolamide is available as an oral capsule with a strength of 5 mg, 20 mg, 100 mg, 140 
mg, 180 mg, 250 mg per tablet. 
Dispensing 
 
Temozolamide capsules are swallowed with a glass of water. Temozolamide capsules should 
not be opened or chewed. 
Possible side effects 
 
Fatigue,​ headache,​alopecia,​ skin​ rash,​ nausea,​vomiting,​ constipation,​ anorexia,​
diarrhea, lymphocytopenia, thrombocytopenia, neutropenia, leukopenia are common side 
effects seen. 
Modifications of therapy and dosage 
 
Overview and general principles 
 
Toxicity will be graded according to NCI CTCAE, version 5.0; the therapy modifications 
described below are applied according to this severity grading. Toxicities of severity grade 1 
only will not lead to any dose reduction or cycle delay. The same holds for adverse reactions 
without any potential of serious or life- threatening complications according to the judgment of 
the physician (e.g. alopecia). If the toxicity is unequivocally caused by only one drug, a dosage 
modification of the other drugs is not required. 
If more than one different type of toxicity occurs concurrently, the most severe grade will 
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determine the modification. In case of a necessary dose reduction the lower dose level will be 
applied throughout the rest of the therapy without re-escalation, if not stated otherwise. 
In case of acute allergic reactions of grade 3 or 4, the respective agent should be discontinued 
permanently; in case of grade 1 or 2, it is up to the physician to continue treatment without 
dose modification, if this is in the best interest of the patient. Each dose modification or 
treatment delay has to be documented in the CRF, including the respective reason. 
Due to logistic reasons arising out of non-availability of Lu-177-DOTATATE (PRRT), 
CAP-TEM regimen can be started till the availability of radio-pharmaceutical. 
Baseline 
dose 
modification 
of 
chemotherapy 
– 
combination 
chemotherapy 
(Capecitabine-Temozolamide) 
 
The following factors can be used for upfront dose modification (up to a maximum of 25% 
reduction) at discretion of treating physician - 
·​
Albumin levels 3.0 – 3.5 mg% 
 
·​
Creatinine clearance 40 ml/min – 50 ml/min 
 
·​
ECOG PS 2 
 
·​
Age > = 65 
 
Modifications 
of 
chemotherapy 
– 
combination 
chemotherapy 
(Capecitabine 
and 
Temezolamide) from Cycle 2 of chemotherapy onwards 
Dose adjustment/delay in case of myelosuppression 
 
In case of myelosuppression persisting on the planned day 1 of the next cycle, the following 
measures should be taken: 
ANC < 1.500/μL Therapy delay for at least 1 week 
 
Platelets < 100.000/μL Differential blood counts at least weekly 
 
In case of febrile neutropenia (despite secondary prophylaxis with G-CSF or peg GCSF as 
explained later) or thrombocytopenia with bleeding, temezolamide will be reduced to 75% of 
the initial dose. If these toxicities are observed again, a second reduction to 50% of the full 
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dose has to be performed. If the toxicity re-occurs, capecitabine will be reduced to 75% of the 
initial dose. If the toxicity still re-occurs, these 2 drugs will have to stop permanently. 
Use of growth factors (GCSF or peg-GCSF) is allowed as per institution/physician choice. 
GCSF or peg- GCSF should not be used concurrently with capecitabine or temezolamide. 
GCSF or peg-GCSF may be used as an emergent measure during neutropenia or febrile 
neutropenia post cessation of oral chemotherapy. 
Dose adjustment in case of febrile neutropenia 
 
Occurrence of 
Febrile Neutropenia 
Temezolamide 
dose reduction 
Capecitabine 
dose 
reduction 
1st appearance 
75% 
2nd appearance 
50% 
3rd appearance 
50% 
75% 
4th appearance 
50% 
50% 
5th appearance 
Drug​
stopped 
permanently 
Drug​
stopped 
permanently 
 
 
Dose adjustment in case of diarrhoea / mucositis 
 
In case of diarrhoea and/or mucositis ≥ grade 3, capecitabine have to be reduced to 75% of 
the initial dose. If these toxicities are observed again, a second reduction to 50% of the full 
dose has to be performed. If these toxicities are observed again, temezolamide have to be 
reduced to 75% of the initial dose. If these toxicities are observed again, a second reduction to 
50% of the full dose has to be performed. If the toxicity re-occurs, these 2 drugs will have to 
stop permanently. 
 
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Dose adjustment in case of diarrhoea / mucositis 
 
Occurrence​
of 
diarrhoea 
Temezolamid
e dose 
reduction 
Capecitabine 
dose 
reduction 
 
and/or 
mucositis​
≥ 
grade 3, 
1st appearance 
75% 
2nd appearance 
50% 
3rd appearance 
75% 
4th appearance 
50% 
50% 
5th appearance 
Drug stopped 
Drug stopped 
 
 
Dose adjustment in case of nephrotoxicity 
 
During the course of chemotherapy, if creatinine clearance drop to the range below 40 mL/min, 
but > 30 mL/min, hydration for 48 hours will be performed with a subsequent reassessment of 
the clearance. Following dosing modifications to take place – 
Creatinine clearance 30 – 50 ml/min – Capecitabine to be continued at 75% doses; 
temezolamide can be continued at full doses or reduced doses as per physician decision. 
Creatinine clearance below 30 ml/min – All drugs to be stopped. 
 
 
 
 
 
 
 
Protocol Version 1.6 dated_21-02-2024 

23 
 
Dose adjustments for capecitabine in case of hand-foot-syndrome 
 
Grade of toxicity 
Dose Adjustment for Next 
Cycle (% of starting dose) 
Action 
during 
chemothera
py 
Grade 1 
Maintain dose level 
Maintain dose level 
 
Protocol Version 1.6 dated_21-02-2024 

24 
 
Grade 2 
1st appearance 
100
% 
Interrupt until 
resolved 
to grade 0-1 
2nd appearance 
75% 
Interrupt until 
resolved 
to grade 0-1 
3rd appearance 
50% 
Interrupt until 
resolved 
to grade 0-1 
4th appearance 
-- 
Discontinue 
treatment 
permanently 
Grade 3 
1st appearance 
75% 
Interrupt until 
resolved 
to grade 0-1 
2nd appearance 
50% 
Interrupt until 
resolved 
to grade 0-1 
3rd appearance, OR 
--- 
Discontinue 
treatment 
any evidence of 
permanently 
Stevens-Johnson 
syndrome or Toxic 
epidermal necrolysis 
 
 
Dose adjustment in case of other toxicities 
 
If other toxicities of NCI CTC grade 3 to 4 occur, a dose adjustment of the cytostatic drug most 
probably responsible for the event should be reduced. Consultation of the PI is recommended. 
Maximum doses 
Protocol Version 1.6 dated_21-02-2024 

25 
 
PRRT - 4 sessions maximum, in case the cumulative dose of 1000 MBq is not attained, 5th 
cycle can be given 
Chemotherapy - 15- 18 cycles of chemotherapy. Chemotherapy will continue for 2-3 cycles 
post last dose of PRRT, assuming patient is feasible and satisfies criteria for administration 
of chemotherapy 
 
Schedule of Events: 
 
Pre 
study 
Cycle 1 
15-21 
days after 
PRRT 
Pre 
therapy 
Cycle 
2 
15-21 
days after 
PRRT 
Pre 
therapy 
Cycle 3 
15-21 days 
after PRRT 
Pre 
therapy 
Cycle 4 
15-21 days 
after PRRT 
Follow 
up 
Lu-177 
DOTATATE 
therapy 
(PRRT) 
x 
x 
x 
x 
CAPTEM 
Chemotherapy 
x 
x 
x 
x 
Informed 
Consent 
x 
x 
x 
x 
x 
x 
x 
Demographics 
x 
Medical history 
x 
Concurrent 
meds 
x 
 
Protocol Version 1.6 dated_21-02-2024 

26 
 
 
Physical exam 
x 
x 
x 
x 
x 
Vital signs 
x 
x 
x 
x 
x 
Height/ 
Weight 
x 
x 
x 
x 
x 
Performance 
status 
x 
x 
x 
x 
x 
Hb 
x 
x 
x 
x 
x 
WBC 
x 
x 
x 
x 
x 
RBC 
x 
x 
x 
x 
x 
Platelet 
x 
x 
x 
x 
x 
GFR 
x 
x 
x 
x 
x 
DOTA PET 
x 
x 
x 
FDG PET 
x 
x 
x 
Pre 
study 
Cycle 1 
15-21 
days after 
PRRT 
Pre 
therapy 
Cycle 
2 
15-21 
days after 
PRRT 
Pre 
therapy 
Cycle 3 
15-21 days 
after PRRT 
Pre 
therapy 
Cycle 4 
15-21 days 
after PRRT 
Follow 
up 
Adverse event 
evaluation 
x 
x 
x 
x 
x 
EORTC QLQ- 
C30 
x 
X 
X 
X 
X 
EORTC 
GI.NET21 
x 
X 
X 
X 
X 
 
Protocol Version 1.6 dated_21-02-2024 

27 
 
Guidelines for therapy post progression 
 
Once the patient has ceased therapy (either Arm A or Arm B), due to progressive disease, 
intolerable side effects or patient choice, further therapy is as per physician choice. 
Patients who have temporarily ceased therapy (for a minimum of 2 months) (Arm A or Arm B) 
due to adverse events can be considered for restarting the same regimen after a delay/break 
based on discretion of the treating physician. The cessation of therapy will be labelled as an 
‘event’, even if not progression and the date of cessation will be taken for calculation of event 
free survival. 
Special situations: 
 
●​ In patients with reduced renal function the following additional interventions are used: 
(a)​Nephrourology consultation. 
(b)​Extensive hydration (e.g. 2–3 l of fluid intake, if clinically appropriate) prior to PRRT. 
(c)​Diuretics (e.g. furosemide) should be considered in case of dilated renal 
pelvis and delayed outflow. 
●​ In patients with reduced haematological values the following additional interventions are 
used: 
(a)​Haematologist consultation. 
(b)​When required, packed red blood cells or platelet concentrate support may 
be given following PRRT. 
●​ In patients randomized to the chemo-PRRT arm, in case there are certain unavoidable 
delays in administering PRRT, then patient may be started on chemotherapy as per 
plan and PRRT started at a later date based on PI decision. 
 
Emergency management 
In case of an emergency the principal investigator can be approached via phone or email. 
Serious adverse events or reactions observed during the conduct of the study, have to be 
reported to the IRB/IEC. 
 
Enrolment 
Subjects fulfilling all in- / exclusion criteria, having provided written informed consent on the 
approved informed consent form are eligible for participation in the study. 
Protocol Version 1.6 dated_21-02-2024 

28 
 
Premature withdrawal of an individual subject 
Patients will be taken off the protocol treatment for the following reasons - 
 
●​ Treatment delay more than three weeks post randomization. 
●​ administration of any other anti-neoplastic medication or any other 
●​ consent withdrawn by patient 
●​ investigator decision in the best interest of the patient 
●​ pregnancy or insufficient contraception 
●​ loss to follow-up 
 
The time point of and reason for removal of a patient must be documented on the case report 
form. The investigator will attempt to complete all discharge procedures at the time a patient is 
discontinued from study treatment and to record further follow-up data, if required. 
Premature study termination by primary investigator and ethics committee 
At any time, coordinating investigator of the study, or/and the ethics committee may terminate 
the trial participation of an individual patient, as well as the whole trial, provisionally or 
permanently, if this is required by stringent medical or legal reasons (including insufficient 
patient recruitment), especially if severe and/or frequent adverse events occur, requiring a new 
risk/benefit evaluation. 
Study assessments 
 
●​ Baseline assessment 
In the experimental and standard arm, the following procedures/assessments will be 
carried out at baseline within 2 weeks prior to start of study treatment 
●​ Physical exam and vital parameters 
●​ Echocardiography/MUGA 
●​ Hb, CBC, Liver Function Test (LFT) 
●​ Renal function test 
●​ Serum electrolytes 
●​ GFR (sampling method)/e-GFR and tubular function by 99m Tc – EC Renogram 
●​ Assessment during and after study 
-​
Next day after conclusion of every cycle of 
PRRT: CBC, LFT and serum electrolytes 
-​
After 14 days: CBC, LFT and serum electrolytes 
-​
1 week before starting every subsequent cycle of PRRT: 
Protocol Version 1.6 dated_21-02-2024 

29 
 
○​ Physical exam and vital parameters 
○​ Echocardiography/MUGA 
○​ Hb, CBC, Liver Function Test (LFT) 
○​ Renal function test 
○​ Serum electrolytes 
○​ GFR (sampling method)/e-GFR and tubular function by 99m Tc – EC 
renogram 
 
●​ Documentation at follow up 
Patients will be followed up while on active treatment with cancer directed 
therapy as well as supportive care. Investigations likely to be conducted are as 
follows (not all inclusive) 
○​ Physical examination including: weight, ECOG performance status 
○​ Vital signs: blood pressure, pulse rate and oral temperature 
○​ Evaluation of prolonged side effects as per NCI CTCAE 
○​ 2 D Echo/MUGA (Multi-Gated Acquisition) 
○​ Ga-68-DOTANOC PET/CT and/or FDG PET/CT, if deemed necessary 
●​ Criteria for efficacy evaluation 
Tumor measurements are to be made using the same method at each protocol-defined 
assessment. If a patient has clinical signs of progression, then tumor evaluation can 
take place at that time. 
This tumor evaluation will be performed by the oncologist in collusion with radiologist 
as per the RECIST (Response Evaluation Criteria In Solid Tumors, V. 1.1, 2009) and 
EORTC criteria. 
RECIST 1.1 Criteria: 
 
Target Lesions: 
Complete Response (CR) 
Disappearance of all target lesions 
Partial Response (PR) 
≥ 30% decrease in the sum of the longest 
diameters of target lesions compared with 
baseline 
 
Protocol Version 1.6 dated_21-02-2024 

30 
 
Stable Disease (SD) 
Any case that does not qualify for PR or PD 
Progressive Disease (PD) 
≥ 20% increase in the sum of the longest 
diameter of target lesions compared with the 
smallest-sum longest diameter recorded or the 
appearance of one or more new lesions 
Non-Target Lesions 
Complete Response (CR) 
Disappearance of all non-target lesions 
and normalization of tumor marker 
level 
Incomplete Response, PD 
Persistence of one or more non-target lesions 
and/or the maintenance of tumor marker level 
above the normal limits 
Stable Disease (SD) 
Appearance of one or more new lesions and/or 
unequivocal progression of existing non-target 
lesions 
 
 
EORTC Criteria: 
 
Complete Metabolic Response (CMR) 
Complete resolution of all lesions 
Partial Metabolic Response (PMR) 
Greater than or equal to 25% 
decrease in SUVmax 
Stable Disease (SD) 
Less than 25% change in SUVmax 
Progressive Disease (PD) 
Greater than/equal to 25% 
increase in SUV max 
 
Protocol Version 1.6 dated_21-02-2024 

31 
 
Progression free survival (PFS) 
 
Progression-free survival (PFS) will be defined as the time from enrolment to the time of disease 
progression or death, or to the date of last tumor assessment without any such event (censored 
observation). 
Time to deterioration (TTD) of ECOG PS 
 
Time to deterioration (TTD) of ECOG PS is based on assessment of ECOG PS at baseline and 
then at every clinical visit while on active treatment. Worsening of ECOG-PS will be defined as 
an increase from 0 to ≥2, an increase from 1–2 to ≥3, or death (irrespective of cause). 
Overall survival (OS) 
 
The duration of overall survival (OS) will be determined by measuring the time interval from 
enrolment to the date of death or last observation (censored). 
Study assessments (safety) 
 
●​ At each visit, the investigator will evaluate the subject to determine whether any AEs 
have occurred. AEs may be directly observed, reported spontaneously by the subject or 
by questioning the subject at each study visit. All laboratory values will be evaluated by 
the Investigator as to clinical significance. All post-baseline abnormal laboratory values 
considered clinically significant by the Investigator will be recorded as an AE. 
●​ All clinical AEs occurring after the subject signs the ICF and up to 30 days after the 
patient is taken off the active portion of the trial, whether observed by the investigator or 
reported by the subject, will be recorded as an AE. Medical conditions that exist prior to 
the informed consent will be recorded as part of the medical history and will not be an 
AE. Diagnosis to be reported as the AE or SAE term; when the diagnosis is unavailable, 
signs and symptoms as individual entries of AE or SAE to be entered until the diagnosis 
becomes available. Pre-planned procedure/hospitalization for pre-existing conditions 
which do not worsen in severity should not be reported as SAEs. Progressive disease is 
waived from SAE reporting. In addition, death due to progressive disease does not have 
to be reported as an SAE. The investigator should follow subjects with AEs until the 
event has resolved or the condition has stabilized. In case of unresolved 
Protocol Version 1.6 dated_21-02-2024 

32 
 
AEs including significant abnormal laboratory values at the end of treatment 
assessment, these events will be followed up until resolution or until they become 
clinically not relevant. 
●​ The NCI Common Terminology Criteria for Adverse Events version 4 (NCI CTCAE 
v4.03) will be used to classify and grade the intensity of adverse events during and after 
each treatment cycle. CTCAE will be used to grade all events regardless of attribution, 
in order to ensure objective reporting, and in order to report trial data according to 
accepted international guidelines. The worst toxicity will be recorded. The results will be 
computed in a tabular form in which the proportion of people having their highest grade 
of toxicity will be charted. 
II. Definitions 
 
7.2.1 An ADVERSE EVENT (AE) is any untoward medical occurrence in a patient or 
clinical investigational subject administered a pharmaceutical product and which does 
not necessarily have a causal relationship with this treatment. An AE can therefore be 
any unfavourable or unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal investigational 
product, whether or not considered related to the medicinal product (see below). 
Adverse events include the following: 
 
1.​
All suspected adverse drug or device reactions 
 
2.​
Apparently unrelated illnesses, including the worsening (severity, frequency) of 
pre- existing illnesses 
3.​
Injury or accidents. 
 
4.​
Abnormalities in physiological testing or physical examination that require clinical 
intervention or further investigation (beyond ordering a repeat examination) 
5.​
Laboratory abnormalities that require clinical intervention or further investigation 
(beyond ordering a laboratory test). 
6.​
Any untoward event that occurs after the protocol-specified reporting period 
Protocol Version 1.6 dated_21-02-2024 

33 
 
which the Investigator believes may be related to the drug or device. 
AEs are not required to be reported unless they meet SAE 
criteria. Documented Adverse Events are as follows: 
CAP-TEM: The most common grade 3 or 4 hematological adverse events are 
thrombocytopenia (8–12%), lymphopenia (20-25%) and grade 1 or 2 neutropenia 
(~50%). Non-hematologic side effects, grade 1 or 2 palmar-plantar erythrodysesthesia is 
seen in approximately 12-15% with no treatment discontinuation, fatigue grade 1 or 2 
upto 50%, severe nausea in a few cases, and grade 3 or 4 diarrhea (3%). 
PRRT: The most common adverse events are nausea (30-40%) and vomiting 
(25-30%). Other common adverse events included fatigue or asthenia and diarrhea. 
Grade 3 or 4 neutropenia, thrombocytopenia, and lymphopenia is seen in 1%, 2%, 
and 9% of patients respectively. 
III.A SERIOUS ADVERSE EVENT (SAE) are expected in less than 1% of patients. 
 
SAE, if any, will be reported during the active period of the 
trial. NOTES: 
The term “life-threatening” in the definition of “serious” refers to an event in which the 
patient was at risk of death at the time of the event; it does not refer to an event which 
hypothetically might have caused death if it were more severe. 
Important medical events which may not be immediately life-threatening or result in 
death or hospitalization but which may jeopardize the patient or may require intervention 
to prevent one of the listed outcomes in the definition above should also be considered 
serious. 
A SUSPECTED UNEXPECTED SERIOUS ADVERSE REACTION (SUSAR) is an SAE 
that is 
related to the drug or device and is unexpected (i.e. not listed in the investigator 
brochure or approved Product Information; or is not listed at the specificity or severity 
that has been observed; or is not consistent with the risk information described in the 
Protocol Version 1.6 dated_21-02-2024 

34 
 
Subject Information Sheet and Informed Consent Form or elsewhere in the protocol. 
(FDA, Safety Reporting Requirements for INDs and BA/BE Studies, draft guidance, 
September 2010)). 
An event is causally related if there is a reasonable possibility that the drug 
[intervention] caused the AE, i.e. there is evidence to suggest a causal relationship 
between the drug and the event (FDA, Safety Reporting Requirements for INDs and 
BA/BE Studies, draft guidance, September 2010). 
For the purposes of this study, the following adverse events are not reported as SAEs: 
 
-hospitalization or death as a result of or related to disease 
progression. Procedure for reporting serious adverse events 
SAE reports will be forwarded to the IEC in the IEC approved format within 24 hours. 
 
●​ Pregnancy reporting 
Any pregnancy in a female subject diagnosed during the treatment period or within 6 
months after last study treatment administration must be reported unhesitatingly to the 
IEC. Follow-up information on the subject and her pregnancy outcome should be 
communicated by the Investigator to the IEC as soon as available. 
●​ Monitoring of subjects with adverse events 
Any AE that occurs in the course of the clinical study must be monitored and followed 
up until the end of treatment visits. It is the responsibility of the investigator that any 
necessary additional therapeutic measures and follow-up procedures are performed. 
●​ Overdose 
In case of a significant overdose of a study drug, this has to be reported as a serious 
adverse event. 
 
Assessment of quality of life 
 
QOL analysis will be conducted using the following tools (with appropriate language 
translations) 
 
·​
EORTC QLQ-30 
 
·​
EORTC G.I.NET-21 
Protocol Version 1.6 dated_21-02-2024 

35 
 
 
QOL analysis will be conducted at the following time intervals (approximate) 
 
●​ Baseline – 6-10 days before first cycle of PRRT, during pre-therapy work up (scheduled 
routine visit) 
●​ 6-10 days before start of next cycle of PRRT, when the patient comes for pre-therapy 
work-up, (scheduled routine visit). 
●​
3 months after last cycle when patient comes for routine follow-up 
 
It will be administered using the EORTC tools mentioned above through a face-to-face 
interview in language comfortable to the patient. Adequate time shall be given to patient to 
respond to questions. 
As per the EORTC QOL scoring manual instructions for domains with multiple questions, if 
greater than 50% but less than 100% of questions are completed at a visit, then that visit will 
be deemed evaluable for that domain, and the average of the remaining assessed questions 
will be used in the analysis. Visits with less than 50% of questions missing for a particular 
domain shall be excluded from the analyses. 
Data management and statistics 
 
Based on the NETTER-1 trial, we assumed that PRRT will give a 2 year PFS of 60%, the 
experimental arm will improve the 2 year PFS by an absolute value of 15%. With a type 1 error 
(one-sided) of 5% and 
Type 2 error of 20 %, with 10% lost to follow up, sample size of 162 
patients For any statistical test performed, significance level will be 
set to 5%. 
Documentation and archives 
 
Protocol Version 1.6 dated_21-02-2024 

36 
 
●​ All patient-related data are recorded in a pseudonymized way. Each patient is 
unequivocally identified by a trial subject number, attributed at recruitment into the study. 
The investigator will keep a complete patient identification log, including the full name, 
address etc. 
●​ Patients who were screened in order to be entered into the study, but who could not be 
recruited for whatever reason will be recorded in a "patient reject log" with the reason for 
non-inclusion in study being specified. All the data retrieved during the conduct of the 
study are entered into the case record forms (CRF) by the investigator or 
co-investigator. 
●​ All relevant forms and study documents including CRFs will be stored for 10 years at PI 
place with access to IEC, PI and designated personnel. 
Financing of study: 
Since both arms of the study are ‘standard-of-care’, there are no funding 
requirements Budgeting has been done only for personnel i.e. Trial Co-ordinator 
(Page 38) for the study. 
General ethics for the conduct of the study: 
●​ The study will be conducted in compliance with the ICMR Statement on Human 
Experimentation, and the Declaration of Helsinki principles. 
●​ Declaration of Helsinki: The trial will be performed in accordance with the Declaration of 
Helsinki, as decided upon by the 18th World Medical Assembly, Helsinki, Finland, June 
1964 (amended by subsequent World Medical Assembly Somerset West, South Africa, 
October 1996,). 
●​ Informed consent: The Investigator or a person designated by him/her will collect 
informed consent from all participants, prior to which the Investigator or co-investigator 
must inform each participant of the objectives, benefits, risks and requirements of the 
study. He/she will also provide the participant with an information sheet in clear, simple 
language. The study participant will be allowed ample time to inquire about details of the 
Protocol Version 1.6 dated_21-02-2024 

37 
 
study and to decide whether or not to participate in the study. Moreover, the patient will 
receive a written “patient information”, containing all relevant information for the patient's 
decision and the course of the study. The consent of the patient to participate must be 
obtained in writing before recruitment into the study. The informed consent form must be 
dated and signed by the patient. Thereby, he declares his voluntary consent to 
participate in the study and his willingness to comply with the requirements of the trial 
and the instructions of the treating investigator during the course of the study. There are 
two copies of the informed consent form: one for the patient and one to be kept by the 
investigator in his study documents. The informed consent is only valid after receiving 
the patient's signature. Thereafter, the patient can be entered into the study if he/she 
fulfils the selection criteria. The study will not commence until approval has been 
obtained from the Tata Memorial Hospital Human Ethics Committee. 
●​ Protocol amendments 
Any modifications to the protocol which may impact on the conduct of the study, 
potential benefit of the study, or may affect patient safety, including changes of study 
objectives, study design, patient population, sample sizes, study procedures, or 
significant administrative aspects will require a formal amendment to the protocol. Such 
amendment will be agreed upon by the investigators and then submitted to the IEC/IRB 
for acceptance. 
●​ Administrative or technical changes of the protocol such as minor corrections and/or 
clarifications that have no effect on the way the study is to be conducted, nor on the 
risk-benefit-ratio, will be agreed upon by all the investigators and will be documented in 
a memorandum to the protocol. The IEC may be notified of such changes at the 
discretion of the sponsor/coordinating investigator. The coordinating investigator has to 
assure, that all amendments have been added to the study documents at any site 
involved in the trial. 
●​ Reimbursement 
The patients receiving chemotherapy arm will have to pay for the chemotherapy, and for 
the blood investigations and imaging studies. For all patients, the cost of standard 
testing and therapy, like palliative radiation, stenting, analgesics, supportive 
medications, etc. will be borne by the patient. 
●​ Compensation: 
Protocol Version 1.6 dated_21-02-2024 

38 
 
It will be as per the Institutional IEC policy 
 
Evaluation of Benefits and Risks/Discomforts 
·​
There is potential benefit in the form of improved survival and quality of life 
from this study 
·​
No potential physical, psychological or social risks 
·​
There are no alternate treatment possible during the study 
Risks/Benefits Analysis 
The study poses minimal risk, i.e. the probability and magnitude of harm or discomfort 
anticipated in the research are not greater in and of themselves than those ordinarily 
encountered in daily life or during the performance of routine physical or psychological 
examinations or tests. 
 
Consent and Assent Process and Documentation 
Consent shall be taken after giving adequate time to the patient and Legally Accepted 
Representative to understand the study design 
Consent shall be signed and dated by the patient and countersigned by the investigator. 
A copy of the consent shall be handed over to patient and one copy shall be kept for 
records 
 
Impartial witness shall be present to overlook the consent administration 
process Participants right to refuse to participate in the trial shall be 
respected 
 
After the participant has entered into the trial, the clinician shall give alternative treatment to 
that specified in the protocol, at any stage, if he/she feels it to be in the best interest of the 
participant. The reason for doing so, shall be recorded; the participant will remain within the 
trial for the purpose of follow-up and for data analysis by the treatment option to which they 
have been allocated. 
Similarly, the participant must remain free to change their mind at any time about the protocol 
treatment and trial follow-up without giving a reason and without prejudicing his/her further 
treatment. 
Patients who are not able to give consent won’t be included in the study. 
In case a patient loses his/her ability to give consent during the study, he/she will be dropped 
out of the study. 
 
 
 
 
Protocol Version 1.6 dated_21-02-2024 

39 
 
Trial closure 
The trial will close when all patients have completed follow-up. 
Details about reporting of trial closure to the regulatory and ethical committees. 
 
 
References 
1.​ Klimstra DS, Modlin IR, Coppola D, Lloyd RV, Suster S. The pathologic 
classification of neuroendocrine tumors: a review of nomenclature, grading, and 
staging systems. Pancreas. 2010;39:707–12. 
 
2.​ Yao JC, Hassan M, Phan A, et al. One hundred years after “carcinoid”: 
epidemiology of and prognostic factors for neuroendocrine tumors in 35,825 cases 
in the United States. J Clin Oncol.2008;26:3063-72. 
 
3.​ Sorbye H, Welin S, Langer SW, Vestermark LW, Holt N, Osterlund P, et al. Predictive 
and prognostic factors for treatment and survival in 305 patients with advanced 
gastrointestinal neuroendocrine carcinoma (WHO G3): the NORDIC NEC study. Ann 
Oncol. 2013; 24:152–60. 
 
4.​ Oberg KE. The management of neuroendocrine tumours: current and future 
medical therapy options. Clin Oncol (R Coll Radiol). 2012;24:282–93. 
 
5.​ van Essen M, Sundin A, Krenning EP, Kwekkeboom DJ. Neuroendocrine tumours: 
the role of imaging for diagnosis and therapy. Nat Rev Endocrinol. 2014;10:102–14. 
 
6.​ Krenning EP, Kooij PP, Pauwels S, Breeman WA, Postema PT, De Herder WW, 
et al. Somatostatin receptor: scintigraphy and radionuclide therapy. Digestion. 
1996;57:57–61. 
7.​ Kayani I, Bomanji JB, Groves A, Conway G, Gacinovic S, Win T, et al. 
Functional imaging of neuroendocrine tumors with combined PET/CT using 
68Ga-DOTATATE (DOTA-DPhe1, Tyr3- octreotate) and 18F-FDG. Cancer. 2008; 
112:2447–55. 
 
8.​ Binderup T, Knigge U, Loft A, Federspiel B, Kjaer A. 18Ffluorodeoxyglucose positron 
emission tomography predicts survival of patients with neuroendocrine tumors. Clin 
Cancer Res. 2010;16:978–85. 
 
9.​ Pasquali C, Rubello D, Sperti C, Gasparoni P, Liessi G, Chierichetti F, et al. 
Neuroendocrine tumor imaging: can 18F-fluorodeoxyglucose positron emission 
tomography detect tumors with poor prognosis and aggressive behavior? World J 
Surg. 1998;22:588–92. 
Protocol Version 1.6 dated_21-02-2024 

40 
 
 
10.​Hofman MS, Hicks RJ. Changing paradigms with molecular imaging of neuroendocrine 
tumors. Discov Med. 2012;14:71–81. 
 
11.​Rinzivillo M, Partelli S, Prosperi D, Capurso G, Pizzichini P, Iannicelli E, et al. 
Clinical Usefulness of (18)F-Fluorodeoxyglucose Positron Emission Tomography 
in the Diagnostic Algorithm of Advanced Entero-Pancreatic Neuroendocrine 
Neoplasms. Oncologist. 2018 
;23:186-192. 
 
12.​Strosberg J, El-Haddad G, Wolin E, Hendifar A, Yao J, Chasen B, et al; NETTER-1 
Trial Investigators. Phase 3 Trial of (177)Lu-Dotatate for Midgut Neuroendocrine 
Tumors. N Engl J Med. 2017;376:125-135. 
 
13.​Barber TW, Hofman MS, Thomson BN, Hicks RJ. The potential for induction peptide 
receptor chemoradionuclide therapy to render inoperable pancreatic and duodenal 
neuroendocrine tumours resectable. Eur J Surg Oncol. 2012;38:64–71. 
 
14.​Strosberg JR, Fine RL, Choi J, Nasir A, Coppola D, Chen DT, et al, First-line 
chemotherapy with capecitabine and temozolomide in patients with metastatic 
pancreatic endocrine carcinomas. Cancer. 2011;117:268-75. 
 
15.​Kashyap R, Hofman MS, Michael M, Kong G, Akhurst T, Eu P, et al. Favourable 
outcomes of (177)Lu-octreotate peptide receptor chemoradionuclide therapy in 
patients with FDG-avid neuroendocrine tumours. Eur J Nucl Med Mol Imaging. 
2015;42:176-85. 
 
16.​Kong G, Callahan J, Hofman MS, Pattison DA, Akhurst T, Michael M, et al. High clinical 
and morphologic response using (90)Y-DOTA-octreotate sequenced with 
(177)Lu-DOTA-octreotate induction peptide receptor chemoradionuclide therapy 
(PRCRT) for bulky neuroendocrine tumours. Eur J Nucl Med Mol Imaging. 
2017;44:476-489. 
 
 
 
 
 
 
 
 
 
 
 
 
 
Protocol Version 1.6 dated_21-02-2024 

41 
 
Budget Sheet: 
 
 
 
Year 
1 
2 
3 
4 
5 
6 
7 
8 
Salary of 
Personnel 
(Co-ordinator) 
18000 
20000 
22000 
24000 
26000 
28000` 
30000 
32000 
 
Total Budget: Rs 24,00,000/- 
Protocol Version 1.6 dated_21-02-2024