Conditions: Small Cell Lung Cancer Small Cell Lung Cancer Extensive Stage
Keywords: nivolumab 177Lu-DOTA0-Tyr3-Octreotate Lutathera
Allocation: RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 9
Healthy volunteers: no

Brief summary:
This research study is being done to assess the safety and tolerability of study drugs, 177Lu-DOTA0-Tyr3-Octreotate (Lutathera) and nivolumab in subjects with small cell lung cancer or advanced or inoperable neuroendocrine tumor of the lung that has overexpressed somatostatin receptors (SSRT). Lutathera is an investigational radioactive agent that targets tumor cells that express SSRT. Nivolumab is an investigational agent that targets and inhibits a pathway that prevents your immune system from effectively fighting your cancer. The combination of these 2 study drugs is investigational. The term "Investigational" in this context means that the drugs have not been approved for clinical use by the US Food and Drug Administration (FDA).

Giving Lutathera and nivolumab together may increase the effectiveness of this therapy. We first need to find out the highest dose of Lutathera that can be given safely together with nivolumab. This study will be the first study to test giving Lutathera together with nivolumab. Once we have found the highest dose of Lutathera that can be given with nivolumab, we will treat more patients with this combination to determine how effective it is.

The purposes of this study are:

To find the highest doses of Lutathera that can be given with nivolumab without causing severe side effects.

To find out the side effects seen by giving Lutathera at different dose levels with nivolumab.

To determine if the amount of something in your tumor called PD-L1 makes you more likely to have a response to the combination of Lutathera and nivolumab.

Detailed description:
The purpose of this project to see if the combination of 177Lu-DOTA0-Tyr3-Octreotate and nivolumab is safe and tolerable, and provides PFS benefit compared to observation alone in the maintenance setting in patients with ES-SCLC and no disease progression after first-line platinum-based chemotherapy.

Treatment will be administered on an outpatient basis. A standard dose-escalation phase I design will be used. Three subjects will be enrolled at each dose level in the absence of DLT.

Selection of the starting dose of 177Lu-DOTA0-Tyr3-Octreotate and nivolumab is based on the results from previous clinical studies with each compound used as single agent and the fact that the combination has not been tested in clinical trials. The first dose of 177Lu-DOTA0-Tyr3-Octreotate will be given two weeks after the first administration of nivolumab. Studies have shown that intravenous administration of amino acids has a renal protective effect \[46\]. An infusion of amino acids (lysine 2.5% and arginine 2.5% in 1 L 0.9% NaCl; 250 mL/h) will be started 30 minutes before the administration of 177Lu-DOTA0-Tyr3-Octreotate and last 4 hours.

Nivolumab will be administered as a fixed dose of 240 mg as an intravenous infusion over 30 minutes every 2 weeks. Nivolumab will be given until progressive disease, patient withdrawal or toxicities.

The phase II portion will consist of patients with ES-SCLC who completed platinum based standard first-line chemotherapy (e.g. 4-6 cycles of platinum plus etoposide or irinotecan) without disease progression (responders plus stable disease) at the time of initiation of the combination therapy with 177Lu-DOTA0-Tyr3-Octreotate and nivolumab. Eligible patients will then be randomly allocated in two arms: one will be treated with the combination of 177Lu-DOTA0-Tyr3-Octreotate and nivolumab, and the other arm will continue be followed (observation) after completion the standard chemotherapy treatment.

Randomization:

Patients who do not receive radiotherapy after chemotherapy

* The randomization must occur within 6 weeks of the last chemotherapy cycle.
* The study treatment must start within 2 weeks from randomization. Patients who receive radiotherapy (including prophylactic cranial radiation and/or thoracic radiation) after chemotherapy
* The randomization must occur within 9 weeks of the last chemotherapy cycle but at least 2 weeks after completion of radiotherapy.
* The first dose of 177Lu-DOTA0-Tyr3-Octreotate cannot be given within 8 weeks of radiotherapy.

Randomization process:

* Randomization will be stratified according to NETSPOT® PET tumor uptake score (Grade 2, 3 and 4).
* OnCore will be used as statistical center and the randomization algorithm will be developed by the study biostatistician.
* The project management department will be the first point of contact for assessment through email.

Courses are defined as 56 days of dosing. Nivolumab will be given until progressive disease, patient withdrawal, or toxicities. For patients randomized to the observation group, cross-over at the time of disease progression will be allowed, since the primary endpoint is PFS and not OS.

Arms:
arm 1: Nivolumab will be administered 240mg every 2 weeks. Nivolumab will be given until progressive disease, patient withdrawal, or toxicities.

The Phase II dose of 177Lu-DOTA0-Tyr3-Octreotate will be the maximum tolerated dose as determined in the Phase I portion. arm 2: Nivolumab will be administered 240mg every 2 weeks. Nivolumab will be given until progressive disease, patient withdrawal, or toxicities.

177Lu-DOTA0-Tyr3-Octreotate dose will be 3.7 GBq (100 mCi) every 8 weeks for 4 doses. arm 3: Nivolumab will be administered 240mg every 2 weeks. Nivolumab will be given until progressive disease, patient withdrawal, or toxicities.

177Lu-DOTA0-Tyr3-Octreotate dose will be 7.4 GBq (200 mCi) every 8 weeks for 4 doses. arm 4: Patients randomized to this arm will be followed (observation). Cross-over to Phase II Arm 1 at the time of disease progression will be allowed

Interventions: intervention 1: Nivolumab intervention 2: 177Lu-DOTA0-Tyr3-Octreotate
Intervention descriptions: intervention 1: Nivolumab is administered intravenously intervention 2: 177Lu-DOTA0-Tyr3-Octreotate will be administered every 8 weeks. The first dose of 177Lu-DOTA0-Tyr3-Octreotate will be given two weeks after the first administration of nivolumab. Each dose is infused over 30 minutes. On the day of 177Lu-DOTA0-Tyr3-Octreotate infusion, an intravenous bolus of anti-emetics will be given (suggested options: ondansetron (8 mg), granisetron (3 mg), or tropisetron (5 mg)). Administration of 177Lu-DOTA0-Tyr3-Octreotate may be given one day earlier or delayed up to 1 week due to holidays, inclement weather, conflicts, or similar reasons.

Concurrent amino acids are given with each dose of 177Lu-DOTA0-Tyr3-Octreotate since co-infusion of amino acids leads to a significant reduction (47%) in the mean radiation dose to the kidneys. The amino acid solution and 177Lu-DOTA0-Tyr3-Octreotate are administered in parallel by peripheral vein infusion

Protocol document:
Prot_SAP_001.pdf: 
Renee Webb 
LCCC  [Company address] 
TITLE: Phase I/II trial of anti-PD-1 checkpoint inhibitor nivolumab and 177Lu-DOTA0-Tyr3-
Octreotatefor Patients with Extensive-Stage Small Cell Lung Cancer 
 
NCT03325816  
 
Version 1.07: October 3, 2018 
 
 
 


Georgetown Lombardi Comprehensive Cancer Center 
 
 
Page 1 of 89 (Version 1.07) 
 
TITLE: Phase I/II trial of anti-PD-1 checkpoint inhibitor nivolumab and 177Lu-DOTA0-Tyr3-Octreotate 
for Patients with Extensive-Stage Small Cell Lung Cancer 
 
Principal Investigator:  
Giuseppe Giaccone, M.D. Ph.D. 
Georgetown Lombardi Comprehensive Cancer Center 
3970 Reservoir Road NW Washington DC 20007 
Phone: 202-687-7072; Fax: 202-687-0313; E-mail: gg496@georgetown.edu 
 
Sub-Investigator(s):  
 
Chul Kim, M.D. M.P.H., Georgetown Lombardi Comprehensive Cancer Center 
Deepa Subramanian, M.D., Georgetown Lombardi Comprehensive Cancer Center 
Stephen Liu, M.D., Georgetown Lombardi Comprehensive Cancer Center 
Giuseppe Esposito, M.D., Division of Nuclear Medicine at Georgetown University Hospital 
Martin E. Gutierrez, M.D., Hackensack University 
Christina Brzezniak, D.O., Walter Reed National Military Medical Center 
Lisa Bodei, M.D., Ph.D., Memorial Sloan Kettering Cancer Center 
Jonathan Lehman, M.D., Ph.D., Vanderbilt University Medical Center 
Randy R. Hecht, M.D., University of California, Los Angeles 
Jonathan W. Goldman, M.D., University of California, Los Angeles 
Thomas Hope, M.D., University of California, San Francisco 
 
Biostatistician:  
 
Ming T. Tan, Ph.D. 
Department of Biostatistics, Bioinformatics, and Biomathematics 
Georgetown University, Basic Science 255 
Phone: 202-687-0197; E-mail: mtt34@georgetown.edu 
 
Pathologist: 
Bhaskar Kallakury, M.D. 
Department of Pathology 
Georgetown University 


Georgetown Lombardi Comprehensive Cancer Center 
 
 
Page 2 of 89 (Version 1.07) 
Phone: 202) 687-3444; E-mail: KALLAKUB@gunet.georgetown.edu 
 
Study Drugs: Nivolumab, 177Lu-DOTA0-Tyr3-Octreotate 
 
Funding Source: Bristol-Myers Squibb for Nivolumab, Advanced Accelerator Applications for 
177Lu-DOTA0-Tyr3-Octreotate 
 
 
Version 1.07: 
 October 3, 2018 
 
  
 
 
Signature Page 
 
The signature below constitutes the approval of this protocol and the attachments, and provides the 
necessary assurances that this trial will be conducted according to all stipulations of the protocol, 
including all statements regarding confidentiality, and according to local legal and regulatory 
requirements and applicable U.S. federal regulations and ICH guidelines. 
 
Principal Investigator (PI) Name:_______________________ 
 
PI Signature: ___________________ 
 
Date:____________________ 
 


 
Page 3 of 89 (Version 1.07) 
TABLE OF CONTENTS 
1.0 
PRÉCIS.................................................................................................................................. 6 
2.0 
BACKGROUND AND RATIONALE .............................................................................. 10 
2.1 
Small cell lung cancer (SCLC) ....................................................................................... 10 
2.2 
Nivolumab ...................................................................................................................... 10 
2.3 
177Lu-DOTA0-Tyr3-Octreotate ........................................................................................ 14 
2.4 
Rationale for the combination of 177Lu-DOTA0-Tyr3-Octreotate and nivolumab .......... 17 
3.0 
STUDY HYPOTHESIS AND OBJECTIVES .................................................................. 18 
3.1 
Hypothesis ...................................................................................................................... 18 
3.2 
Primary objectives .......................................................................................................... 18 
3.3 
Secondary objectives ...................................................................................................... 18 
4.0 
PATIENT ELIGIBILITY .................................................................................................. 19 
4.1 
Phase I ............................................................................................................................ 19 
4.2 
Phase II ........................................................................................................................... 21 
4.3 
WOCBP/MOCBP ........................................................................................................... 23 
5.0 
TREATMENT PLAN ......................................................................................................... 24 
5.1 
Treatment Dosage and Administration ........................................................................... 24 
5.2 
Drug Administration ....................................................................................................... 26 
5.3 
Dose Delays/Dose Modifications and Management of Toxicities Associated with 177Lu-
DOTA0-Tyr3-Octreotate and nivolumab ..................................................................................... 27 
5.4 
Concomitant Medications/Treatments ............................................................................ 38 
5.5 
Off-treatment criteria ...................................................................................................... 38 
5.6 
Off-study criteria ............................................................................................................ 38 
5.7 
Duration of Follow-Up ................................................................................................... 39 
6.0 
STUDY PROCEDURES .................................................................................................... 39 


 
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6.1 
Screening/Baseline Procedures ...................................................................................... 39 
6.2 
Procedures During Treatment ......................................................................................... 40 
6.3 
Follow-up ....................................................................................................................... 40 
6.4 
Study Calendar ............................................................................................................... 41 
7.0 
Measurement of Effect ....................................................................................................... 41 
7.1 
Antitumor Effect- Solid Tumors .................................................................................... 41 
8.0 
ADVERSE EVENTS .......................................................................................................... 46 
8.1 
Definitions ...................................................................................................................... 46 
8.2 
Adverse Event Monitoring ............................................................................................. 48 
8.3 
Reporting Requirements for Adverse Events ................................................................. 48 
9.0 
DRUG INFORMATION .................................................................................................... 50 
9.1 
177Lu-DOTA0-Tyr3-Octreotate ........................................................................................ 50 
9.2 
Nivolumab ...................................................................................................................... 52 
10.0 CORRELATIVES/SPECIAL STUDIES .......................................................................... 53 
10.1 
Pathology correlative studies .......................................................................................... 53 
10.2 
Specimen Banking .......................................................................................................... 54 
11.0 STATISTICAL CONSIDERATIONS .............................................................................. 54 
11.1 
Study Design .................................................................................................................. 55 
11.2 
Sample Size and Accrual ................................................................................................ 55 
11.3 
Data Analyses Plans ....................................................................................................... 56 
12.0 STUDY MANAGEMENT.................................................................................................. 56 
12.1 
Institutional Review Board (IRB) Approval and Consent .............................................. 56 
12.2 
Required Documentation ................................................................................................ 57 
12.3 
Registration Procedures .................................................................................................. 57 
12.4 
Data Management and Monitoring/Auditing ................................................................. 58 


 
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12.5 
Adherence to the Protocol .............................................................................................. 59 
12.6 
Amendments to the Protocol .......................................................................................... 60 
12.7 
Record Retention ............................................................................................................ 60 
12.8 
Obligations of Investigators ........................................................................................... 60 


 
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1.0 
PRÉCIS 
Background 
 
Small cell lung cancer (SCLC), which accounts up to 15% of all new cases of lung cancer, is a 
lethal cancer with a poor prognosis. About 60% of patients present with extensive-stage disease.  
 
The mainstay of treatment for extensive-stage SCLC (ES-SCLC) is systemic chemotherapy 
comprising platinum and etoposide. Despite initial sensitivity to chemotherapy, patients with ES-
SCLC relapse quickly and their tumors become refractory to treatment within months. Novel 
systemic treatment options are needed for this highly aggressive cancer.  
 
Somatostatin receptors (SSTR) are expressed in neuroendocrine tumors (NETs) including SCLC. 
Peptide receptor radionuclide therapy (PRRT) utilizes radiolabeled SSTR2 analogs to treat NETs. 
177Lu-DOTA0-Tyr3-Octreotate (Lutathera) is a novel 177Lutetium-labeled somatostatin analog. 
Lutathera is under investigation in a number of different NETs and has an established safety 
profile. 
 
The clinical efficacy of immune checkpoint blockade targeting the programmed death 1 (PD-1) 
pathway has been shown in various cancers including SCLC. Nivolumab is a fully human IgG4 
monoclonal antibody that targets PD-1. Preliminary data from studies of nivolumab monotherapy 
or nivolumab/ipilimumab combination therapy show activity and durable responses in patients 
with progressive SCLC. 
 
Given the positive effects of radiation on immunogenic response (e.g. release of tumor antigens, 
induction of chemokines promoting the recruitment of T cells into the tumor, upregulation of 
MHC class I proteins and costimulatory molecules on tumor cells), we hypothesize that Lutathera 
and nivolumab will interact synergistically to provide increased therapeutic activity in patients 
with ES-SCLC. 
 
Primary objectives 
 
The primary objective of the phase I portion of the study is to determine the recommended phase 
II dose (RP2D) of 177Lu-DOTA0-Tyr3-Octreotate when given in combination with anti-PD-1 
checkpoint inhibitor nivolumab in patients with small-cell lung cancer or advanced or inoperable 
grade I-II pulmonary NETs. 
 
 
The primary objective of the randomized phase II portion of the study is to compare the 
progression-free survival (PFS) in patients with ES-SCLC who were not progressing to first-line 
treatment with platinum-based therapy, after receiving combination treatment of 177Lu-DOTA0-
Tyr3-Octreotate and nivolumab as a maintenance therapy versus observation.  
 
Secondary objectives 
 
To characterize the safety profile of 177Lu-DOTA0-Tyr3-Octreotate in combination with 
nivolumab. [Applicable to both phase 1 and 2 portions] 
 
In patients who were not progressing before initiating combination therapy: [applicable to the 
phase 2 portion] 


 
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o 
To assess the disease control rate (DCR) and objective response rate (ORR) after treatment 
with 177Lu-DOTA0-Tyr3-Octreotate plus nivolumab. 
o 
To assess overall survival (OS). 
o 
To assess whether the metabolic response seen on a NETSPOT® PET scan obtained on cycle 2 
day 1 will predict response to study treatment.  
 
Eligibility 
Abbreviated Eligibility Criteria 
1 
For the phase I part, patients must have cytologically or histologically confirmed relapsed or 
refractory extensive-disease small-cell lung cancer (ES-SCLC) or non-progressing ES-SCLC 
after first line chemotherapy, or advanced or inoperable grade I-II pulmonary NETs.  
2 
For the randomized phase II part, patients must have cytologically or histologically confirmed 
ES-SCLC and must not have progressed after first line platinum-based chemotherapy regimen 
before randomization. 
3 
Toxicities of prior therapy must be resolved to grade 1 or less as per Common Terminology 
Criteria for Adverse Events (CTCAE) version 4.03. 
4 
Patients with tumor tissue uptake during NETSPOT® PET that is equal to or higher than that 
in normal hepatic tissue (grade ≥2) will be eligible. It is recommended that NETSPOT® PET 
be obtained before initiation of chemotherapy, but NETSPOT® PET obtained during or after 
completion of chemotherapy could be used for screening purpose. Only for the phase I 
portion, at the discretion of the principal investigator, patients with SCLC whose tumors have 
lower levels of uptake than liver during NETSPOT® PET may be eligible for the study. 
5 
Patients with a history of autoimmune disease or other diseases requiring systemic 
glucocorticoid or immunosuppressive therapy, previous therapy with T-cell modulating 
antibodies (including anti-CTLA-4, anti-PD-1, anti-PD-L1), human immunodeficiency virus 
(HIV) infection, or active hepatitis B or C virus infection will be excluded. 
6 Subjects with symptomatic brain metastases will be excluded. However, subjects who have 
had treatment for their brain metastasis and are asymptomatic without steroid therapy for at 
least 2 weeks may be enrolled. 
7 
ECOG performance status of 0-1. 
8 
Adequate organ and bone marrow function (hemoglobin > 9 g/dL; absolute neutrophil count > 
1.5 x 109/L; platelet counts > 100 x 109/L; serum bilirubin < 2 x ULN (except subjects with 
Gilbert Syndrome who must have total bilirubin < 3.0 mg/dL); alanine aminotransferase 
(ALT) and aspartate aminotransferase (AST) < 2.5 x ULN or < 5 x ULN if liver metastases; 
calculated creatinine clearance > 50 mL/min). 
9 
Life expectancy of at least 3 months. 
10 Age > 18 years.  


 
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11 Ability to understand and willingness to sign a written informed consent document. 
12 Patients who received prior anti-tumoral radionuclide therapy (with unsealed sources) are not 
eligible for the study. 
 
Design 
 
Open-label, prospective phase I/II trial 
 
A randomized phase II study


 
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Schema 
 
 
CTX: chemotherapy 
ES-SCLC: Extensive-stage small cell lung cancer 
Pts: Patients 
RP2D: Recommended phase II dose 
 


 
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2.0 
BACKGROUND AND RATIONALE 
2.1 
Small cell lung cancer (SCLC) 
2.1.1 
Overview of SCLC 
Neuroendocrine tumors (NETs) are a heterogeneous group of solid tumors that arise from 
neuroendocrine cells throughout the body. Neuroendocrine tumors of the lung represent a wide 
spectrum of disease from low-grade typical carcinoid and intermediate-grade atypical carcinoid to 
high-grade groups of large-cell neuroendocrine carcinoma and small-cell carcinoma (SCLC) [1]. 
SCLC makes up about 15% of all lung cancers and about 60% of patients with SCLC present with 
ES-SCLC [2]. Patients with SCLC often present with rapid onset of symptoms and significant 
symptoms due to rapid intrathoracic tumor growth, distant metastasis, paraneoplastic syndromes, 
or a combination of these features [3]. Patients with SCLC have a poor prognosis. The 5-year 
survival rate for limited-stage SCLC is 12%, and 1.6% for ES-SCLC [4, 5]. 
2.1.2 
Treatment for SCLC 
Treatment options for SCLC are limited. Platinum-based chemotherapy regimens have been the 
standard of care for a long time [6]. While the combination of platinum-based chemotherapy and 
thoracic radiotherapy (RT) for limited-stage SCLC produces response rates close to 90%, the 
duration of response is relative short, and most patients relapse after completion of treatment, 
although approximately 20% of patients can be cured with concomitant chemo-radiation [7, 8]. 
For patients with ES-SCLC, chemotherapy is the mainstay of treatment, but objective response 
rates (ORRs) are lower at 45-60%, with infrequent complete responses and median PFS and OS of 
around 5 months and 10 months, respectively [9, 10]. Second-line chemotherapy for the treatment 
of relapsed SCLC is less effective than the initial treatment. Topotecan is the only drug that was 
approved by the US Food and Drug Administration (FDA) for the treatment of relapsed SCLC in 
1996 [11]. Topotecan yields objective response rates of 20-24% [12, 13]. The response rate in 
patients refractory to prior chemotherapy (6%) is lower than (37%) in those sensitive to first-line 
chemotherapy [12]. Prognosis for patients with relapsed SCLC is grim with a median overall 
survival of 5.4 months [12]. There is an urgent need to develop more effective therapies for 
patients with SCLC.  
2.2 
Nivolumab 
Recent additions to the therapeutic armamentarium for cancer treatment are the immune 
checkpoint inhibitors. The programmed death-1 (PD-1)/programmed death-1 ligand (PD-L1) 
pathway is implicated in the mechanisms whereby tumors limit the host immune response [14]. 
Nivolumab is a humanized anti-PD-1 monoclonal antibody that inhibits the binding of PD-L1 to 
PD-1 and as a result, potentiates antitumor immune responses[15]. Emerging evidence indicates 
that patients whose tumors overexpress PD-L1 have improved clinical outcomes with anti-PD-L1 
antibody therapy [16]. Nivolumab has been approved by the FDA in patients with melanoma, 
NSCLC, renal cell carcinoma, Hodgkin’s lymphoma, head and neck cancer, and urothelial 
carcinoma[17].  


 
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2.2.1 
Non-clinical studies of Nivolumab (from the Nivolumab Investigator’s Brochure, 
version 15, June, 2016) 
Detailed information on all nonclinical studies performed to date can be found in the Investigator’s 
Brochure (IB). The ability of nivolumab to bind to the human PD-1 receptor has been 
demonstrated using Biacore, ELISA, FACS, and Scatchard analyses. Nivolumab has also been 
shown to inhibit the engagement of PD-1 with its ligands, PD-L1 and PD-L2. For example, the 
IC50 values for nivolumab-mediated inhibition of PD-1 (expressed on CHO/PD-L1 cells) binding 
to PD-L1 or PD-L2 was 1.04 and 0.97 nmol/L, respectively, in a study using FACS.  
PD-1 blockade with nivolumab results in enhanced T-cell reactivity and proliferation and 
augmentation of interferon-gamma (IFN- γ) in vitro, which was demonstrated in assays using an 
allogeneic mixed lymphocyte reaction (MLR), stimulation of human peripheral blood 
mononuclear cells (PBMCs) by the superantigen staphylococcal enterotoxin B (SEB), and antigen-
specific stimulation of T cells from cytomegalovirus (CMV)-responsive donors[18].  
In cynomolgus monkeys receiving single intravenous (IV) administration of nivolumab ranging 
from 1 mg/kg to 50 mg/kg, the apparent elimination half-life estimates were 124 to 148 hours after 
1 mg/kg doses and 223 to 267 hours after 10 or 50 mg/kg doses. Extravascular distribution of 
nivolumab was low as evidenced by the low volume of distribution in cynomolgus monkeys 
(0.046 L/kg to 0.071 L/kg). No metabolism studies with nivolumab have been performed in 
animals. Nivolumab is not predicted to induce or inhibit cytochrome P450 or other drug 
metabolizing enzymes.  
In a toxicity study in cynomolgus monkeys, nivolumab administration was well tolerated at doses 
up to 50 mg/kg, administered weekly for 5 weeks, and at doses up to 50 mg/kg, administered twice 
weekly for 27 doses, with no observed effect on body weight, cardiac, respiratory, or macroscopic 
or histologic pathology findings. In a 3-month IV injection toxicity study of nivolumab in 
cynomolgus monkeys, there was a reversible 28% decrease in T3 at week 13 in females treated 
with 50 mg/kg, but T4 and TSH were unchanged[18].  
In an enhanced pre- and postnatal development study performed in pregnant cynomolgus 
monkeys, nivolumab administration at up to 50 mg/kg twice weekly was well tolerated. However, 
in the offspring, maternal nivolumab administration at both doses was associated with 
fetal/neonatal mortality including dose-dependent increases in third trimester fetal losses and 
increased neonatal mortality. 
In cynomolgus monkeys, immune responses to SK-MEL-3 melanoma cell vaccine were elevated 
with administration of nivolumab, while nivolumab did not have an effect on HBsAg levels after 
HBsAg vaccine. 
2.2.2 
Clinical studies of Nivolumab 
Clinical Pharmacodynamics 
The pharmacodynamics (PD) effects of nivolumab were assessed by investigating assessing 
receptor occupancy (RO), peripheral immune cell population modulation, systemic cytokine 
modulation, and change in absolute lymphocyte count (ALC). These studies have demonstrated 
that 1) peripheral RO of PD-1 was saturated at doses ≥ 0.3 mg/kg dose levels, 2) no meaningful 


 
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changes were seen in activated T-cells in peripheral blood, 3) response to nivolumab was not 
associated with baseline select immune cell subsets, 4) ALC levels did not change with nivolumab 
at any dose levels, and 5) median percent increase in CXCR9 and CXCR10 was observed after 
treatment with nivolumab.  
Clinical Pharmacokinetics 
The mean T-HALF of single-dose nivolumab ranged from 17 to 25 days across the dose range of 
0.3 mg/kg to 10 mg/kg. The multi-dose pharmacokinetics (PK) of nivolumab was tested using 
various dose levels (0.1 to 20 mg/kg every 2 to 3 weeks). The geometric mean (% CV%) clearance 
(CL) was 9.5 mL/h (49.7%), geometric mean volume of distribution at steady state (Vss) was 8.0 
L (30.4%), and geometric mean elimination half-life (t1/2) was 26.7 days (101%). When 
nivolumab was administered at 3 mg/kg every two weeks, steady-state was reached by 12 weeks. 
Several clinical factors such as ECOG performance status, renal function, albumin, body weight, 
and hepatic function affected nivolumab CL, but the effect was not deemed clinically significant. 
In an analysis using a population pharmacokinetics (PPK) model, the overall distributions of 
nivolumab exposures (Cavgss, Cminss, Cmaxss, and Cmin1) were comparable between treatment 
with nivolumab 3 mg/kg and flat-dose 240 mg. There were no clinically meaningful changes in 
cytokines that are known to affect CYP enzymes across all dose levels of nivolumab (0.3, 2 and 10 
mg/kg). 
Clinical Safety 
The safety of nivolumab has been assessed in a number of clinical trials of single-agent nivolumab 
and nivolumab in combination with other agents involving approximately 12,300 patients. Overall 
the toxicity profile of nivolumab is manageable and consistent across clinical trials with no 
maximum tolerated dose (MTD) reached at any dose levels up to 10 mg/kg. Most adverse events 
(AEs) were low grade (grade 1 or 2) with few grade 3 or 4 AEs.  
In a phase I/II study of nivolumab and nivolumab plus ipilimumab in patients with recurrent 
SCLC, patients were treated with nivolumab 3 mg/kg every 2 weeks or nivolumab plus 
ipilimumab (1 mg/kg plus 1 mg/kg, 1 mg/kg plus 3 mg/kg, or 3 mg/kg plus 1 mg/kg, 
intravenously) every 3 weeks for four cycles, followed by nivolumab 3 mg/kg every 2 weeks[19]. 
The incidence of grade 3 or 4 treatment related AEs was 13% (13 of 98 patients) in the nivolumab 
3 mg/kg cohort, 30% (18 of 61 patients) in the nivolumab 1 mg/kg plus ipilimumab 3 mg/kg 
cohort, and 19% (10 of 54 patients) in the nivolumab 3 mg/kg plus ipilimumab 1 mg/kg cohort. 
There were no patients in the nivolumab 1 mg/kg plus ipilimumab 1 mg/kg cohort who had a 
grade 3 or 4 treatment-related adverse event. The most common grade 3 or 4 treatment-related 
AEs included increased lipase (none vs 5 [8%] vs none) and diarrhea (none vs 3 [5%] vs 1 [2%]). 
Only 4% of patients in the nivolumab 3 mg/kg group had dose delays due to treatment-related 
AEs, but dose delays occurred in 30% of patients in the nivolumab 1 mg/kg plus ipilimumab 3 
mg/kg and 15% of patients in the nivolumab 3 mg/kg plus ipilimumab 1 mg/kg cohort. The most 
frequently observed serious adverse events (SAEs) included 1) dyspnea which was experienced by 
five (5%) patients in the nivolumab 3 mg/kg cohort, two (3%) in the nivolumab 1 mg/kg plus 
ipilimumab 3 mg/kg cohort, and four (7%) in the nivolumab 3 mg/kg plus ipilimumab 1 mg/kg 
cohort, and 2) diarrhea, experienced by two (2%) patients in the nivolumab 3 mg/kg cohort, four 
(7%) in the nivolumab 1 mg/kg plus ipilimumab 3 mg/kg cohort, and two (4%) patients in the 


 
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nivolumab 3 mg/kg plus ipilimumab 1 mg/kg cohort. Select immune-related AEs are summarized 
in Table 1. 
Table 1. Select Immune Related Adverse Events Observed in CheckMate 032 
Adverse event 
Nivolumab 3 mg/kg (n=98) 
Nivolumab 3 mg/kg/ipilimumab 1 
mg/kg (n=61) 
Nivolumab 1 mg/kg/ipilimumab 3 
mg/kg (n=54) 
Grade 1/2 
Grade 3 
Grade 4 
Grade 1/2 
Grade 3 
Grade 4 
Grade 1/2 
Grade 3 
Grade 4 
Pneumonitis 
2 (2%) 
1 
0 
1 (2%) 
1 (2%) 
0 
2 (4%) 
0 
1 (2%) 
Hypothyroidism 
3 (3%) 
0 
0 
9 (15%) 
1 (2%) 
0 
4 (7%) 
0 
0 
Hyperthyroidism 
2 (2%) 
0 
0 
7 (11%) 
0 
0 
3 (6%) 
0 
0 
Adrenal 
insufficiency  
0 
0 
0 
1 (2%) 
0 
0 
1 (2%) 
1 (2%) 
0 
Aseptic 
meningitis 
0 
0 
0 
0 
0 
0 
0 
0 
1 (2%) 
Encephalitis 
0 
0 
1 (1%) 
1 (2%) 
0 
0 
0 
0 
0 
Myasthenia 
gravis 
0 
0 
0 
0 
1 (2%) 
0 
0 
0 
0 
Rash 
2 (2%) 
0 
0 
10 (16%) 
2 (3%) 
0 
4 (7%) 
0 
0 
Rash, 
maculopapular 
1 (1%) 
0 
0 
6 (10%) 
2 (3%) 
0 
2 (4%) 
0 
0 
Diarrhea  
7 (7%) 
0 
0 
10 (16%) 
3 (5%) 
0 
8 (15%) 
1 (2%) 
0 
Colitis 
0 
0 
0 
1 (2%) 
1 (2%) 
0 
0 
0 
0 
Drug-induced 
liver injury 
0 
1 (1%) 
0 
0 
0 
0 
0 
0 
0 
Increased 
aspartate 
aminotransferase 
3 (3%) 
0 
0 
3 (5%) 
0 
0 
0 
1 (2%) 
0 
Increased alanine 
aminotransferase 
2 (2%) 
1 (1%) 
0 
2 (3%) 
0 
0 
0 
1 (2%) 
0 
 
Clinical Efficacy 
According to a recent study that examined 99 cases of SCLC, 82 cases (82.8%) showed PD-L1 
expression [20]. Given the finding that PD-L1 expression was associated with better treatment 
outcomes with anti-PD-L1 antibody, the observed high frequency of PD-L1 expression in patients 
with SCLC provides a rationale to evaluate the efficacy of anti-PD-1 antibody in the management 
of SCLC. Recent evidence comes from trials combining CTLA-4 and PD1 blockade. ORRs in the 
Checkmate 032 trial were: 23% in the combination (CTLA-4 & PD-1) using nivolumab at 1 mg/kg 
and ipilimumab at 3 mg/kg, 19% when using nivolumab at 3mg/kg and ipilimumab at 1 mg/kg, 
and 10% in the nivolumab arm only[19]. While the combination of nivolumab and ipilimumab 
provided higher ORRs compared to nivolumab alone, there were more grade 3 or 4 treatment 


 
Page 14 of 89 (Version 1.07) 
 
related adverse events in the combination arms compared to the nivolumab alone arm (30% and 
19% vs. 13%). There results suggest that combining nivolumab with a therapeutic without 
overlapping toxicities may enhance the safety and efficacy of nivolumab. 
2.3 
177Lu-DOTA0-Tyr3-Octreotate 
For grade 1-2 NETs of pulmonary origin, a new treatment modality is peptide receptor 
radionuclide therapy (PRRT) with radiolabeled somatostatin analogs [21]. In PRRT, octreotide, a 
somatostatin analog, is coupled with a radionuclide. Since most NETs overexpress somatostatin 
receptors, they are targets for radionuclide coupled to octreotide [22]. Tumors expressing 
somatostatin receptors can be readily visualized using radiolabeled somatostatin analogs such as 
[111In-DTPA0]-octreotide (OctreoScan®; Mallinckrodt, St Louis, MO) [22] or 68Gallium 
DOTATATE (NETSPOT®) [23]. NETSPOT® is a significant improvement over OctreoScan®, 
with a higher sensitivity, rapid image acquisition, higher spatial resolution, higher affinity to 
SSTR2, less effective dose per Mbq injected, and lower radiation exposure. Several radiolabeled 
somatostatin analogs have been introduced with therapeutic purposes, and one of them is 177Lu-
DOTA0-Tyr3-Octreotate, a novel somatostatin analog DOTATATE, labeled with the ɣ (gamma) 
and beta particle-emitting radioisotope 177Lutetium [24]. 
2.3.1 
Non-clinical studies of Lutathera (from the Lutathera Investigator’s Brochure)  
Safety pharmacology, Biodistribution, Pharmacokinetics and Metabolism 
177Lu-DOTA0-Tyr3-Octreotate has been shown to bind with high affinity to the somatostatin 
receptors in vitro. In vivo animal studies demonstrate that the peptide has generally low uptake in 
non-receptor expressing tissues such as muscle and spleen, while it demonstrates a high specific 
uptake in pancreas which is a high somatostatin receptors expressing organ and medium unspecific 
uptake in the kidneys, which is the main excretion organ. 
The Irwin test performed in rats after single IV administration showed that 175Lu-DOTA0-Tyr3-
Octreotate, the non-radioactive compound, has no neurobehavioral effects and no effect on body 
temperature at any dose tested. The no observed effect level (NOEL) in this study was 20,000 
µg/kg (700 fold the intended human dose, scaled to rat based on body surface area). The absence 
of any effect on the cardiac conduction times was confirmed in vivo in Beagle dogs, in which the 
effects of 175Lu-DOTA0-Tyr3-Octreotate on blood pressure, heart rate, body temperature and 
electrocardiogram (duration of PR, PQ, QT and QRS) after single IV administration were 
investigated. The results showed that 175Lu-DOTA0-Tyr3-Octreotate does not affect cardiac 
conduction times or body temperature, and does not cause arrhythmia at the tested doses (from 80 
up to 800 µg/kg, that is 10 to 100 fold the intended human dose, scaled to dog based on body 
surface area), indicating that the compound does not have any effect on the cardiac conduction 
tissue.  
In vivo biodistribution/metabolic studies in tumor-bearing rats showed that the majority of 
radiolabelled Tyr3-Octreotate analogs was excreted mainly via the renal system, mostly as intact 
compound. In vitro serum stability studies indicated that 177Lu-DOTA0-Tyr3-Octreotate remains 
intact in serum for at least 24 hours. 


 
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The assessment of the potential for 175Lu-DOTA0-Tyr3-Octreotate to inhibit or induce human 
CYP450 enzymes showed that the compound does not act as an inhibitor or an inducer of the 
tested enzymes in the concentration range tested, which includes the expected compound plasma 
levels in human. Also, studies on P-gp mediated interactions using Caco-2 cell line indicated that 
175Lu-DOTA0-Tyr3-Octreotate does not show any potential for P-gp specific interaction, either as a 
substrate or as an inhibitor. 
Toxicology 
Both acute and delayed radiotoxicity evaluation of 177Lu-DOTA0-Tyr3-Octreotate were performed 
in rats. In the acute study (doses up to 4,550 MBq/kg) blood chemistry and blood counts of RBCs 
and platelets were normal at all time points. WBC counts showed a dose-dependent decrease at 
doses above 163 MBq/kg, but in all cases returned to normal after 1 month post-injection. The 
maximum tolerated irradiation dose was not reached. Delayed toxicity evaluation showed that 
injection of high doses of the labelled peptide (555 MBq/rat, 2,220 MBq/kg), without co-injection 
of amino acids, resulted in severe renal damage in rats, as indicated by proteinuria, elevated serum 
creatinine and histological damage. This damage was activity-dependent and became overt 
between 100 and 200 days after treatment. Fractionation of the dose (278 MBq/rat, or 1,110 
MBq/kg, twice with one-week interval, instead of 555 MBq/rat, or 2,220 MBq/kg once) 
significantly reduced the frequency of kidney damage. Moreover, lysine co-injection successfully 
prevented functional damage. 
2.3.2 
Clinical studies of Lutathera (from the Lutathera Investigator’s Brochure, Version 
15, June 2015) 
Biodistribution and metabolism 
The distribution pattern of 177Lu-DOTA0-Tyr3-Octreotate was comparable to that of 111In-DOTA0-
Tyr3-Octreotide, with rapid visualization of the kidneys and with visualization of the liver, spleen, 
kidneys, and in part of the patients the pituitary, thyroid, and tumors 4 hours post injection[25]. 
Comparisons between 86Y-DOTA0-Tyr3-Octreotide, 177Lu-DOTA0-Tyr3-Octreotate, and 111In-
DOTA0-Tyr3-Octreotide showed that the uptake in physiological target organs (liver, spleen and 
kidneys) is not significantly different, whereas uptake in somatostatin receptor subtype 2 
expressing neuroendocrine tumors is about 2 times higher for 86Y-DOTA0-Tyr3-Octreotide 
(Barone R et al., 2008) and 3-4 times higher for 177Lu-DOTA0-Tyr3-Octreotate[25, 26]. 
Safety and Efficacy in NETs 
At the Erasmus MC in the Netherlands, 504 patients with gastroenteropancreatic neuroendocrine 
tumors (GEP-NETs) were enrolled in a non-randomized, single-arm trial of 177Lu-DOTA0-Tyr3-
Octreotate and received up to 4 doses of 177Lu-DOTA0-Tyr3-Octreotate (7.4 GBq at 6- to 13-week 
intervals)[27]. Among the evaluable 310 patients, 5 (2%) and 86 (28%) achieved a complete 
response (CR) and a partial response (PR), respectively. Median PFS and OS were 33 months and 
46 months, respectively. In the 504 patients evaluated for toxicity, acute AEs after administration 
of 177Lu-DOTA0-Tyr3-Octreotate included nausea, vomiting and abdominal pain. These acute AEs 
occurred in about 25% of patients and were mild and transient. Six patients were admitted to the 
hospital within 2 days of the administration of 177Lu-DOTA0-Tyr3-Octreotate due to hormone-


 
Page 16 of 89 (Version 1.07) 
 
related crises. 3.6% of patients had grade 3 or 4 hematologic toxicity. Temporary hair loss (mostly 
grade 1) was seen in 62% of patients. SAEs that were possibly related to the treatment were 
myelodysplastic syndrome in three patients, and temporary, nonfatal, liver toxicity in two patients. 
Recently, Strosberg et al. reported the results of a randomized phase III comparing 177Lu-DOTA0-
Tyr3-Octreotate plus best supportive care including octreotide long-acting repeatable (LAR) or 
octreotide LAR alone in patients with well-differentiated, metastatic midgut neuroendocrine 
tumors[28]. Patients were treated at a dose of 7.4 GBq every 8 weeks up to four infusions. For 
renal protection, an IV amino acid solution was administered for at least 4 hours, starting 30 
minutes prior to infusion of 177Lu-DOTA0-Tyr3-Octreotate. 65.2% (95% confidence interval (CI), 
50.0 to 76.8) of patients in the 177Lu-DOTA0-Tyr3-Octreotate group had progression free survival 
vs. 10.8% (95% CI, 3.5. to 23.0) in the control group. The ORRs were significantly different 
between the two groups (18% vs. 3%) favoring treatment with 177Lu-DOTA0-Tyr3-Octreotate 
(p<0.001). 
177Lu-DOTA0-Tyr3-Octreotate was in general well tolerated with grade 3 or 4 toxicities occurring 
in 41% of patients. The most common AEs included nausea, vomiting, abdominal pain, fatigue, 
and cytopenia, which were mostly low grade. Grade 3 or 4 neutropenia, thrombocytopenia, and 
lymphopenia happened in 1%, 2%, and 9% of patients, respectively in the 177Lu-DOTA0-Tyr3-
Octreotate group vs. no patients in the control group. No evidence of renal toxic effects was 
observed with a median duration of follow-up of 14 months.  
Safety and Efficacy in pulmonary NETs 
A number of studies have assessed 177Lu-DOTA0-Tyr3-Octreotate for the treatment of NETs, and 
demonstrated its safety and efficacy. In a study of 22 patients with bronchial carcinoid tumors 
treated with 177Lu-DOTA0-Tyr3-Octreotate (4 intended administrations at 3 monthly intervals; 
mean activity per infusion, 7.8 GBq), there were 5 partial responses (22.7%), 2 minor responses 
(9.1%), and 8 patients with stable disease (36.4%) [29]. Median progression-free survival (PFS) 
was 31 months, and median overall survival was 42 months. 177Lu-DOTA0-Tyr3-Octreotate was 
well tolerated; reversible grade 3 or 4 hematotoxicity occurred in three patients (13.6%) and there 
was no grade 3 or greater nephrotoxicity. In another case series of 9 patients with bronchial 
carcinoid tumors treated with 177Lu-DOTA0-Tyr3-Octreotate, there were 5 partial responses (56%), 
which is comparable to that in patients with GEP-NETs [30]. The median time to progression 
(TTP) was 31 months, similar to the aforementioned study. In a phase II study of 177Lu-DOTA0-
Tyr3-Octreotate in 34 patients with typical and atypical carcinoids, 1 (3%) patient experienced a 
CR, 4 (12%) PR and 16 (47%) stable disease, with a disease control rate (DCR) of 62% [31]. All 
responders had TC. The median PFS was 18.5 months and the median OS was 48.6 months. No 
grade 3 or 4 toxicities were observed. A retrospective analysis of 114 patients treated with various 
PRRT regimens (90Y-DOTATOC vs. 177Lu-DOTA0-Tyr3-Octreotate vs. 90Y-DOTATOC + 177Lu-
DOTA0-Tyr3-Octreotate) was reported[32]. The regimens containing 177Lu-DOTA0-Tyr3-
Octreotate produced the highest 5-year (61.4%). Partial and minor responses were seen in 26.5% 
of the patients. Patients who received the 90Y-DOTATOC + 177Lu-DOTA0-Tyr3-Octreotate 
regimen had the highest ORR 38.1%, followed by those treated with 177Lu-DOTA0-Tyr3-
Octreotate (ORR: 29.2%). Common acute events included nausea during infusion and mild 
transient asthenia. Patients treated with 177Lu-DOTA0-Tyr3-Octreotate did not experience any 


 
Page 17 of 89 (Version 1.07) 
 
grade 3 or 4 hematological and renal AEs. 177Lu-DOTA0-Tyr3-Octreotate improves the quality of 
life in patients with NETs. In a study from the Netherlands in 265 patients with GEP-NETs or 
bronchial carcinoid tumors, 177Lu-DOTA0-Tyr3-Octreotate was significantly associated with 
improvement in Global health status/Quality of life scores and Karnofsky Performance Scores 
(KPS) [33].  
Based on the previous demonstration of somatostatin receptor subtype 2 (SSTR2) expression in 
SCLC cells and the common expression of SSTR2 in patients with SCLC (grade 2 or 3 close to 
70%) [34-36], a few studies evaluating the efficacy of PRRT in high-grade NETs have been 
reported. A preclinical study that investigated the efficacy of targeted peptide receptor 
chemoradiation therapy using an NCI-H69 SCLC xenograft mouse model demonstrated that the 
combination of 177Lu-DOTA0-Tyr3-Octreotate and carboplatin/etoposide chemotherapy was 
associated with improved survival compared to 177Lu-DOTA0-Tyr3-Octreotate or chemotherapy 
alone [37]. A single-center study in patients with ES-SCLC with either 177Lu-DOTA0-Tyr3-
Octreotate or 90Y-DOTATATE showed that there was no objective response among the 11 patients 
who received at least one dose of PRRT [38]. Four (36%) of 11 patients received 177Lu-DOTA0-
Tyr3-Octreotate. Three (27.3%) patients had grade 2 or 3 hematologic toxicity. One of the 
limitations of this study was that 7 patients (64%) received only one PRRT administration. van 
Essen et al. reported the efficacy of 177Lu-DOTA0-Tyr3-Octreotate (intended cumulative dose of 
22.2 – 29.6 GBq) in patients with metastasized or inoperable paragangliomas, meningiomas, 
SCLC, and melanomas[39]. Among three patients with SCLC, no objective response to 177Lu-
DOTA0-Tyr3-Octreotate was observed. Taken together, these data suggest that PRRT as a single 
treatment modality for high-grade NETs may be limited and combining PRRT with other 
treatment modalities is necessary for the treatment of high-grade NETs. 
2.4 
Rationale for the combination of 177Lu-DOTA0-Tyr3-Octreotate and 
nivolumab  
The role of combination therapy using radiotherapy and cancer immunotherapy is emerging in 
cancer treatment [40]. Radiation therapy can cause the release of tumor antigens and convert 
tumors into an in situ vaccine [41]. It can also induce the expression of chemokines promoting the 
recruitment of T cells into the tumor and increase the expression of death receptors, MHC class I 
proteins, and costimulatory molecules on tumor cells [41]. These responses augment antitumor 
effects of anti-PD-1 monoclonal antibody. Previous work also reported on radiotherapy resulting 
in a significant upregulation of immune effectors and cancer-testis antigens and concomitant 
downregulation of immune suppressors after radiotherapy in sarcomas[42]. Clinically, this 
synergistic effect has been observed as an abscopal effect that refers to a regression of non-
irradiated lesions in patients treated with concurrent radiotherapy and immunotherapy [43]. The 
synergistic effects of radiation and checkpoint inhibitor therapy have also been tested in various 
studies as in colon cancer and glioma, where the synergistic effect of combination of anti-PD-1 or 
PD-L1 antibody and external beam radiation was shown with regard to tumor control and increase 
in PD-L1 antigen expression after radiation [44, 45]. In light of the shared features of SCLC with 
neuroendocrine tumors, the use of checkpoint inhibitors in SCLC, and the positive effects of 
radiation on immunogenic response, we believe the combination of 177Lu-DOTA0-Tyr3-Octreotate 
in combination with nivolumab might lead to powerful positive interactions. Since there is no 


 
Page 18 of 89 (Version 1.07) 
 
effective maintenance therapy for patients with ES-SCLC, this population is suitable for our 
investigational phase I/II study. Here we propose a phase I/II study of 177Lu-DOTA0-Tyr3-
Octreotate and nivolumab in patients with ES-SCLC to assess the safety and efficacy of the 
combination. Since SSTR2 is moderately overexpressed in many tumors (e.g. breast, lymphoma, 
glioma, prostate, meningioma), this phase I/II trial might be pivotal to subsequently explore the 
combination of PRRT and checkpoint inhibitors treatment in a broader variety of tumors. 
3.0 
STUDY HYPOTHESIS AND OBJECTIVES 
3.1 
Hypothesis 
We hypothesize that the combination of 177Lu-DOTA0-Tyr3-Octreotate and nivolumab is safe and 
tolerable, and provides PFS benefit compared to observation alone in the maintenance setting in 
patients with ES-SCLC and no disease progression after first-line platinum-based chemotherapy.  
3.2 
Primary objectives 
3.2.1 
The primary objective of the phase I portion of the study is to determine the RP2D of 
177Lu-DOTA0-Tyr3-Octreotate when given in combination with anti-PD-1 checkpoint 
inhibitor nivolumab in patients with small-cell lung cancer or advanced or inoperable 
grade I-II pulmonary NETs. 
3.2.2 
The primary objective of the phase II portion of the study is to compare the PFS in 
patients with ES-SCLC who were not progressing to first-line treatment with platinum-
based therapy, after receiving combination treatment of 177Lu-DOTA0-Tyr3-Octreotate and 
nivolumab as a maintenance therapy versus observation.  
3.3 
Secondary objectives 
3.3.1 
To characterize the safety profile of 177Lu-DOTA0-Tyr3-Octreotate in combination with 
nivolumab. [Applicable to both phase 1 and 2 portions] 
3.3.2 
In patients who were not progressing before initiating combo therapy: [Applicable to the 
phase 2 portion] 
o To assess DCR and ORR after treatment with 177Lu-DOTA0-Tyr3-Octreotate plus 
nivolumab.  
o To assess OS 
o To assess whether the metabolic response seen on a NETSPOT® PET scan obtained 
on cycle 2 day 1 will predict response to study treatment.  


 
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4.0 
PATIENT ELIGIBILITY 
4.1 
Phase I  
4.1.1 
Inclusion Criteria  
4.1.1.1 
Patients must have cytologically or histologically confirmed relapsed or refractory 
extensive-disease small-cell lung cancer (ES-SCLC) or non-progressing ES-SCLC after 
first line chemotherapy, or advanced or inoperable grade I-II pulmonary NETs.  
4.1.1.2 
Patients with tumor tissue uptake during NETSPOT® PET that is equal to or higher than 
that in normal hepatic tissue (grade ≥2) will be eligible. At the discretion of the principal 
investigator, patients with SCLC whose tumors have lower levels of uptake than liver 
during NETSPOT® PET may be eligible for the study. 
4.1.1.3 
Toxicities of prior therapy must be resolved to grade 1 or less as per Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.03 with the exception of 
alopecia and grade 2, prior platinum-therapy related neuropathy. 
4.1.1.4 
Prior chemotherapy, radiotherapy or radiosurgery (including prophylactic cranial 
radiation and/or thoracic radiation) must have been completed at least 2 weeks prior to 
study treatment.  
4.1.1.5 
ECOG performance status of 0-1. 
4.1.1.6 
Adequate organ and bone marrow function (hemoglobin > 9 g/dL; absolute neutrophil 
count > 1.5 x 109/L; platelet counts > 100 x 109/L; serum bilirubin < 2 x ULN (except 
subjects with Gilbert Syndrome who must have total bilirubin < 3.0 mg/dL); alanine 
aminotransferase (ALT) and aspartate aminotransferase (AST) < 2.5 x ULN or < 5 x 
ULN if liver metastases; calculated creatinine clearance > 50 mL/min). 
4.1.1.7 
Life expectancy of at least 3 months. 
4.1.1.8 
Age > 18 years.  
4.1.1.9 
Women of childbearing potential (WOCBP) must use appropriate method(s) of 
contraception for 23 weeks after the last dose of investigational drug. Men who are 
sexually active with WOCBP must use any contraceptive method(s) with a failure rate 
of less than 1% per year for 31 weeks after the last dose of investigational drug. Women 
who are not of childbearing potential (i.e., who are postmenopausal or surgically sterile 
as well as azoospermic men) do not require contraception. Should a woman become 
pregnant or suspect she is pregnant while she or her partner is participating in this study, 
she should inform her treating physician immediately. See Section 4.3 for the definition 
of WOCBP. 


 
Page 20 of 89 (Version 1.07) 
 
4.1.1.10 Women of childbearing potential must have a negative serum or urine pregnancy test 
(minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropic 
[HCG]) within 24 hours prior to the start of the study drug.  
4.1.1.11 Women must not be pregnant or breastfeeding. 
4.1.1.12 Ability to understand and willingness to sign a written informed consent document. 
4.1.2 
Exclusion Criteria 
4.1.2.1 
Subjects with active, known or suspected autoimmune disease. Subjects with vitiligo, 
type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only 
requiring hormone replacement, psoriasis not requiring systemic treatment, or 
conditions not expected to recur in the absence of an external trigger are permitted to 
enroll. 
4.1.2.2 
Subjects with a condition requiring systemic treatment with either corticosteroids (> 10 
mg daily prednisone equivalents) or other immunosuppressive medications within 14 
days of study drug administration. Inhaled or topical steroids, and adrenal replacement 
doses > 10 mg daily prednisone equivalents are permitted in the absence of active 
autoimmune disease. 
4.1.2.3 
Subjects with symptomatic brain metastases will be excluded. However, subjects who 
have had treatment for their brain metastasis and are asymptomatic without steroid 
therapy for at least 2 weeks may be enrolled. 
4.1.2.4 
Prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA-4 antibody, or 
any other antibody or drug specifically targeting T-cell costimulation or immune 
checkpoint pathways. 
4.1.2.5 
Treatment with investigational agents is prohibited from 30 days prior to the first dose 
of the study treatment, and throughout the study. 
4.1.2.6 
History of a previous malignancy within the last 2 years, with the exception of early 
stage cancers that are at very low risk of recurrence, such as non-melanoma skin cancer, 
papillary carcinoma of the thyroid, or carcinoma in situ of the prostate, cervix, or breast. 
4.1.2.7 
Patients with human immunodeficiency virus (HIV) infection, or active hepatitis B or C 
virus infection will be excluded. 
4.1.2.8 
Patients who received prior anti-tumoral radionuclide therapy (with unsealed sources) 
are not eligible for the study. 
4.1.2.9 
Prior major surgery within 12 weeks or prior major surgery from which the patient has 
not sufficiently recovered yet. 


 
Page 21 of 89 (Version 1.07) 
 
4.1.2.10 Logistical or psychological hindrance to participation in clinical research. 
4.1.2.11 Uncontrolled or significant cardiovascular disease, including any of the following: 
o Symptomatic congestive heart failure (New York Heart Association Classification Class 
II).  
o Cerebral vascular accident/stroke (< 6 months prior to enrollment), myocardial infarction 
(< 6 months prior to enrollment), or unstable angina. 
o Uncontrolled hypertension or uncontrolled cardiac arrhythmia. 
4.1.2.12 Any other medical condition that in the Investigator’s opinion would not make the 
patient a good candidate for the study. 
4.2 
Phase II 
4.2.1 
Inclusion Criteria  
4.2.1.1 
Patients must have cytologically or histologically confirmed ES-SCLC and must not 
have progressed after first line platinum-based chemotherapy regimen before 
randomization. 
4.2.1.2 
Patients with tumor tissue uptake during NETSPOT® PET that is equal to or higher than 
that in normal hepatic tissue (grade ≥2) will be eligible. It is recommended that 
NETSPOT® PET be obtained before initiation of chemotherapy, but NETSPOT® PET 
obtained during or after completion of chemotherapy could be used for screening 
purpose. 
4.2.1.3 
Toxicities of prior therapy must be resolved to grade 1 or less as per Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.03 with the exception of 
alopecia and grade 2, prior platinum-therapy related neuropathy. 
4.2.1.4 
Prior radiotherapy or radiosurgery (including prophylactic cranial radiation and/or 
thoracic radiation) must have been completed at least 2 weeks prior to randomization.  
4.2.1.5 
For patients who do not receive radiotherapy after chemotherapy, the randomization 
must occur within 6 weeks of the last chemotherapy cycle. The study treatment must 
start within 2 weeks from randomization and no less than 2 weeks from last 
chemotherapy dose. For patients who receive radiotherapy (including prophylactic 
cranial radiation and/or thoracic radiation) after chemotherapy, the randomization must 
occur at least 8 weeks after completion of radiation therapy but within 12 weeks after 
completion of radiation therapy. 
4.2.1.6 
ECOG performance status of 0-1. 


 
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4.2.1.7 
Adequate organ and bone marrow function (hemoglobin > 9 g/dL; absolute neutrophil 
count > 1.5 x 109/L; platelet counts > 100 x 109/L; serum bilirubin < 2 x ULN (except 
subjects with Gilbert Syndrome who must have total bilirubin < 3.0 mg/dL); alanine 
aminotransferase (ALT) and aspartate aminotransferase (AST) < 2.5 x ULN or < 5 x 
ULN if liver metastases; calculated creatinine clearance > 50 mL/min). 
4.2.1.8 
Life expectancy of at least 3 months. 
4.2.1.9 
Age > 18 years.  
4.2.1.10 Women of childbearing potential (WOCBP) must use appropriate method(s) of 
contraception for 23 weeks after the last dose of investigational drug. Men who are 
sexually active with WOCBP must use any contraceptive method(s) with a failure rate 
of less than 1% per year for 31 weeks after the last dose of investigational drug. Women 
who are not of childbearing potential (i.e., who are postmenopausal or surgically sterile 
as well as azoospermic men) do not require contraception. Should a woman become 
pregnant or suspect she is pregnant while she or her partner is participating in this study, 
she should inform her treating physician immediately. See Section 4.3 for the definition 
of WOCBP. 
4.2.1.11 Women of childbearing potential must have a negative serum or urine pregnancy test 
(minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropic 
[HCG]) within 24 hours prior to the start of the study drug.  
4.2.1.12 Women must not be pregnant or breastfeeding. 
4.2.1.13 Ability to understand and willingness to sign a written informed consent document. 
4.2.2 
Exclusion Criteria 
4.2.2.1 
Subjects with active, known or suspected autoimmune disease. Subjects with vitiligo, 
type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only 
requiring hormone replacement, psoriasis not requiring systemic treatment, or 
conditions not expected to recur in the absence of an external trigger are permitted to 
enroll. 
4.2.2.2 
Subjects with a condition requiring systemic treatment with either corticosteroids (> 10 
mg daily prednisone equivalents) or other immunosuppressive medications within 14 
days of study drug administration. Inhaled or topical steroids, and adrenal replacement 
doses > 10 mg daily prednisone equivalents are permitted in the absence of active 
autoimmune disease.  
4.2.2.3 
Subjects with symptomatic brain metastases will be excluded from trial secondary to 
poor prognosis. However, subjects who have had treatment for their brain metastasis 
and whose brain disease is stable without steroid therapy for 2 weeks may be enrolled. 


 
Page 23 of 89 (Version 1.07) 
 
4.2.2.4 
Prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA-4 antibody, or 
any other antibody or drug specifically targeting T-cell costimulation or immune 
checkpoint pathways.  
4.2.2.5 
Treatment with investigational agents is prohibited from 30 days prior to the first dose 
of the study treatment, and throughout the study. 
4.2.2.6 
History of a previous malignancy within the last 2 years, with the exception of early 
stage cancers that are at very low risk of recurrence, such as non-melanoma skin cancer, 
papillary carcinoma of the thyroid, or carcinoma in situ of the prostate, cervix, or breast. 
4.2.2.7 
Patients with human immunodeficiency virus (HIV) infection, or active hepatitis B or C 
virus infection will be excluded. 
4.2.2.8 
Patients who received prior anti-tumoral radionuclide therapy (with unsealed sources) 
are not eligible for the study. 
4.2.2.9 
Prior major surgery within 12 weeks or prior major surgery from which the patient has 
not sufficiently recovered yet. 
4.2.2.10 Logistical or psychological hindrance to participation in clinical research. 
4.2.2.11 Uncontrolled or significant cardiovascular disease, including any of the following: 
o Symptomatic congestive heart failure (New York Heart Association Classification Class 
II).  
o Cerebral vascular accident/stroke (< 6 months prior to enrollment), myocardial infarction 
(< 6 months prior to enrollment), or unstable angina. 
o Uncontrolled hypertension or uncontrolled cardiac arrhythmia. 
4.2.2.12 Any other medical condition that in the Investigator’s opinion would not make the 
patient a good candidate for the study. 
4.3 WOCBP/MOCBP 
Women of childbearing potential (WOCBP) is defined as any female who has experienced 
menarche and who has not undergone surgical sterilization (hysterectomy or bilateral 
oophorectomy) or is not postmenopausal. Menopause is defined clinically as 12 months of 
amenorrhea in a woman over age 45 in the absence of other biological or physiological causes. In 
additional, women under the age of 62 must have a documented serum follicle stimulating 
hormone, (FSH) level > 40 mIU/mL. Women treated with hormone replacement therapy (HRT) 
are likely to have artificially suppressed FSH levels and may require a washout period in order to 
obtain a physiologic FSH level. The duration of the washout period is a function of the type of 
HRT used:  
o 1-week minimum for vaginal hormonal products, (rings, creams, gels) 


 
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o 4-week minimum for transdermal products 
o 8-week minimum for oral products.  
Other parenteral products may require washout periods as long as 6 months. 
Women of childbearing potential (WOCBP) must agree to follow instructions for acceptable 
contraception from the time of signing consent, and for 23 weeks after their last dose of protocol-
indicated treatment.  
Men not azoospermic who are sexually active with WOCBP must agree to follow instructions for 
acceptable contraception from the time of signing consent, and for 31 weeks after their last dose of 
protocol-indicated treatment. 
5.0 
TREATMENT PLAN 
5.1 
Treatment Dosage and Administration 
5.1.1 
Phase I  
5.1.1.1 
Dose Limiting Toxicity (DLT) 
A DLT is defined as any toxicity not attributable to the disease or disease-related processes under 
investigation, which occurs from the first dose of study treatment (Day 1, Cycle 1) up to the last 
day of the cycle (Day 57). To be considered as DLT, it must be related to the study drugs 
(attributions: possible, probable, and definite) while fulfilling one of the following criteria as per 
the NCI Common Toxicity Criteria for Adverse Events (CTCAE) version 4.03: 
 
Toxicity grade 2 for platelets and any other grade 3 or 4 toxicity, excluding 
o Grade 3 diarrhea, nausea, or vomiting if it can be controlled with supportive therapy 
o Grade 3 endocrinopathy that is managed with or without systemic corticosteroid 
therapy and/or hormone replacement therapy and the patient is asymptomatic.  
 
Persistent (>21 days) non-hematologic grade 2 adverse events despite optimal medical 
management and treatment delay > 21 days 
 
Any other toxicity: 
o if worse than baseline value, documented, clinically relevant and/or unacceptable, and 
is judged to be a DLT by the investigators 
o if results in a protocol defined stopping criteria 
o if results in disruption of dosing schedule 
Patients experiencing DLT will be monitored weekly until toxicity stabilization, and then every 
two weeks until normalization. 
5.1.1.2 
Dose Escalation and Treatment Duration 
Treatment will be administered on an outpatient basis.  
A standard dose-escalation phase I design will be used. Three subjects will be enrolled at each 


 
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dose level in the absence of DLT. Please find the details in the dose escalation table below. 
Dose escalation table 
Number of Patients with DLT at 
a Given Dose Level 
Escalation Decision Rule 
0 out of 3 
Enter 3 patients at the next dose level. 
≥ 2 
Dose escalation will be stopped. This dose level will be declared 
the maximally administered dose (highest dose administered). 
Three additional patients will be entered at the next lowest dose 
level if only 3 patients were treated previously at that dose. 
1 out of 3 
Enter at least 3 more patients at this dose level. 
 If 0 of these 3 patients experience DLT, proceed to the 
next dose level. 
 If 1 or more of this group suffer DLT, then dose 
escalation is stopped, and this dose is declared the 
maximally administered dose. 
 Three additional patients will be entered at the next 
lowest dose level if only 3 patients were treated 
previously at that dose. 
≤2 out of 6 at highest DL  
This is generally the recommended phase 2 dose. At least 6 
patients must be treated at the recommended phase 2 dose. 
 
Selection of the starting dose of 177Lu-DOTA0-Tyr3-Octreotate and nivolumab is based on the 
results from previous clinical studies with each compound used as single agent and the fact that the 
combination has not been tested in clinical trials. The first dose of 177Lu-DOTA0-Tyr3-Octreotate 
will be given two weeks after the first administration of nivolumab. Studies have shown that 
intravenous administration of amino acids has a renal protective effect [46]. An infusion of amino 
acids will be started 30 minutes before the administration of 177Lu-DOTA0-Tyr3-Octreotate and 
last 4 hours (Table 3). 
 
Patient Replacement 
Three patients within a dose level must be observed for one cycle (56 days) before accrual to the 
next higher dose level may begin. If a patient is withdrawn from the study prior to completing 56 
days of therapy without experiencing a DLT prior to withdrawal, an additional patient may be 
added to that dose level. 
5.1.2 
Phase II 
The phase II portion will consist of patients with ES-SCLC who completed platinum based 
standard first-line chemotherapy (e.g. 4-6 cycles of platinum plus etoposide or irinotecan) without 
disease progression (responders plus stable disease) at the time of initiation of the combination 
therapy with 177Lu-DOTA0-Tyr3-Octreotate and nivolumab. Eligible patients will then be 
randomly allocated in two arms: one will be treated with the combination of 177Lu-DOTA0-Tyr3-


 
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Octreotate and nivolumab, and the other arm will continue be followed (observation) after 
completion the standard chemotherapy treatment.  
Randomization: 
Patients who do not receive radiotherapy after chemotherapy 
 
The randomization must occur within 6 weeks of the last chemotherapy cycle.  
 
The study treatment must start within 2 weeks from randomization, but no less than 2 
weeks from last dose of chemotherapy.  
Patients who receive radiotherapy (including prophylactic cranial radiation and/or thoracic 
radiation) after chemotherapy 
 
Randomization must occur at least 8 weeks after completion of radiation therapy but 
within 12 weeks after completion of radiation therapy. 
Randomization process: 
 
OnCore will be used as statistical center and the randomization algorithm will be 
developed by the study biostatistician.  
 
The project management department will be the first point of contact for assessment 
through email. 
Courses are defined as 56 days of dosing. Nivolumab will be given until progressive disease, 
patient withdrawal, or toxicities. For patients randomized to the observation group, cross-over at 
the time of disease progression will be allowed, since the primary endpoint is PFS and not OS. 
5.2 
Drug Administration  
5.2.1 
177Lu-DOTA0-Tyr3-Octreotate 
177Lu-DOTA0-Tyr3-Octreotate will be administered every 8 weeks. The first dose of 177Lu-DOTA0-
Tyr3-Octreotate will be given two weeks after the first administration of nivolumab. Each dose is 
infused over 30 minutes. On the day of 177Lu-DOTA0-Tyr3-Octreotate infusion, an intravenous 
bolus of anti-emetics will be given (suggested options: ondansetron (8 mg), granisetron (3 mg), or 
tropisetron (5 mg)). Administration of 177Lu-DOTA0-Tyr3-Octreotate may be given one day earlier 
or delayed up to 1 week due to holidays, inclement weather, conflicts, or similar reasons. 
Prednisone should be avoided as preventive anti-emetic treatment due to potential negative effect 
on anti-PD-1 therapy. In case of nausea or vomiting despite the use of aforementioned anti-emetic, 
patients can be treated with other anti-emetic medications at the discretion of the treating 
physician.  
Concurrent amino acids are given with each dose of 177Lu-DOTA0-Tyr3-Octreotate since co-
infusion of amino acids leads to a significant reduction (47%) in the mean radiation dose to the 
kidneys. The amino acid solution and 177Lu-DOTA0-Tyr3-Octreotate are administered in parallel 
by peripheral vein infusion.   


 
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Table 2. 177Lu-DOTA0-Tyr3-Octreotate Administration Schedule. 
Preparation 
Starting time (h) 
Infusion Rate (ml/h) 
Duration (h) 
Granisetron 3 mg (or alternative) 
0 
Bolus 
- 
Amino acids: 1-2.2 L solution* 
0 
250 to 550** 
4 
177Lu-DOTA0-Tyr3-Octreotate 
0.5 
50 
0.5 
Saline solution 25 mL – (two pump 
method)1 
1 
50 
0.5 
1When the two-pump method is used, 177Lu-DOTA0-Tyr3-Octreotate is pumped directly into the 
infusion line. The infusion line must be flushed with at least 25 ml of sodium chloride 9 mg/ml 
(0.9%) solution for injection after the infusion of 177Lu-DOTA0-Tyr3-Octreotate. 
* For specifications of the recommended commercial amino acid solution for coinfusion, please 
refer to the investigator brochure.  
** The infusion rate may be reduced at the discretion of the investigator. 
5.2.2 
Nivolumab 
Nivolumab will be administered once every 2 weeks until disease progression, patient withdrawal 
or toxicities. Nivolumab is administered intravenously and is administered first in combination 
studies. Wait 30 minutes before the next compound is administered (regardless of route of 
administration). Administer the infusion over 30 minutes (+/- 5 minutes) through an intravenous 
line containing a sterile, non-pyrogenic, low protein binding in-line filter (polyethersulfone with 
pore size of 0.2 micrometer to 1.2 micrometer). Do not coadminister other drugs through the same 
intravenous line. Nivolumab infusions are compatible with PVC or polyolefin containers and 
infusion sets, and glass bottles. Flush the intravenous line at end of infusion with appropriate 
amount of diluent (15-20 ml) to ensure that the total dose is administered. Administration of 
nivolumab may be given one day earlier or delayed up to 1 week due to holidays, inclement 
weather, conflicts, or similar reasons. The timing of subsequent administrations is then adjusted to 
maintain a 14 days-interval. 
5.3 
Dose Delays/Dose Modifications and Management of Toxicities Associated with 
177Lu-DOTA0-Tyr3-Octreotate and nivolumab 
5.3.1 
General Recommendations for Evaluation of Toxicities and Dose 
Delays/Modifications 
Any patient who receives treatment on this protocol will be evaluable for toxicity. Toxicity will be 
assessed according to the NCI Common Toxicity Criteria for Adverse Events (CTCAE), version 
4.03. Dose delays or dose modifications should be made according to the system showing the 
greatest degree of toxicity. Once the patient has a dose reduction due to toxicity, the dose will not 


 
Page 28 of 89 (Version 1.07) 
 
be re-escalated. Dose delays and dose modifications will be made using the following 
recommendations. At the discretion of the investigator, the study drugs may be held or dose 
modified independently if the observed AE is attributed to only one of the study drugs, while the 
patient continued to receive the drug not associated with the observed AE. For example, if the 
patient develops immune-related adverse events, nivolumab may be held following guidelines in 
section 5.3.5 while the patient continues to receive 177Lu-DOTA0-Tyr3-Octreotate. If the patient 
develops hematologic adverse events that are frequently associated with 177Lu-DOTA0-Tyr3-
Octreotate, but rarely associated with nivolumab (e.g. thrombocytopenia), 177Lu-DOTA0-Tyr3-
Octreotate may be held while the patient continues on nivolumab. If the observed toxicity is 
attributable to both drugs, both drugs will be held.  
 
Dose modifications for 177Lu-DOTA0-Tyr3-Octreotate are permitted according to the table below. 
Dose Level 
(DL) 
177Lu-DOTA0-Tyr3-Octreotate (IV) 
Level 1 
3.7 GBq (100 mCi) every 8 weeks 
Level 2 
7.4 GBq (200 mCi) every 8 weeks 
No dose modifications are allowed for nivolumab. 
5.3.2 
Hematologic Toxicities 
Table 3. General Recommendations for Dose Modifications and Management of 
Hematological Toxicities 
Adverse Event or Observation 
Management 
ANC*  1,000/mm3 
AND  
Platelets**  75,000/mm3 
AND 
Hemoglobin***  8 g/dL 
Maintain dose 
ANC < 1,000/mm3 
OR 
Platelets <75,000/mm3 
OR 
Hemoglobin <8 g/dL 
On first occurrence, hold the drug(s) causing the toxicity up to 
21 days until ANC  1,000/mm3, platelets  75,000/mm3, 
hemoglobin  9 g/dL.  
The subinvestigator and/or PI will determine whether one or 
both drugs are responsible for an observed toxicity and will 
initiate appropriate medical therapy and no change in dose 
upon re-initiation. 


 
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On second occurrence, hold the drug(s) causing the toxicity up 
to 21 days until ANC  1,000/mm3, platelets  75,000/mm3, 
hemoglobin  9 g/dL. Treatment with 177Lu-DOTA0-Tyr3-
Octreotate may be restarted one dose level lower.  
Patient who have not recovered to ANC  1,000/mm3, 
platelets  75,000/mm3, hemoglobin  9 g/dL after 21 days 
should be removed from the drug causing the toxicity. 
Grade 4 hematologic AE 
On first occurrence, hold the drug(s) causing the toxicity up to 
21 days until ANC  1,000/mm3, platelets  75,000/mm3, 
hemoglobin  9 g/dL. Treatment with 177Lu-DOTA0-Tyr3-
Octreotate may be restarted one dose level lower.  
On second occurrence, discontinue the drug(s) causing the 
toxicity. Follow patient until resolution and/or stabilization of 
toxicity.  
Patient who have not recovered to ANC  1,000/mm3, 
platelets  75,000/mm3, hemoglobin  9 g/dL after 21 days 
should be removed from the drug causing the toxicity. 
*ANC: Absolute neutrophil count. Growth factors to prevent neutropenia will not be administered 
prophylactically, but can be used during a drug hold to assist the recovery.  
** Thrombocytopenia will be treated conservatively. In the absence of bleeding, or a necessary 
invasive procedure, platelet transfusions should be given for a platelet count ≤ 10,000/mm3. If 
invasive procedure(s) is (are) planned, or the patient develops bleeding, platelet transfusions 
should be administered in accordance with the standard of practice, usually maintaining a platelet 
count above 50,000/mm3.  
*** Red blood cell transfusion and is recommended if the hemoglobin falls below 8 g/dL or the 
patient is symptomatic. The initiation of erythropoietic therapy for the management of 
chemotherapy-induced anemia follows the American Society of Hematology/ASCO clinical 
practice guidelines (http://www.asco.org). 
5.3.3 
Non-hematologic Toxicities 
 
The management of general AEs not otherwise specified in the following sections should be as 
per Table 5.  
 
Dose modifications for nausea, vomiting, and diarrhea will be made only if they are refractory 
to treatment. The time a given drug is held should not exceed 21 days.  
Table 4. General Recommendations for Dose Modification and Management of Non-
Hematological Toxicities 
Observation 
Management 


 
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Grade 1 non-hematologic AE 
Maintain dose level.  
Any grade 2 non-hematologic AE related 
to study drug(s) lasting >7 days despite 
maximal intervention  
Hold study drug(s)** for up to 21 days until toxicity 
resolves to  grade 1. 
Treatment with 177Lu-DOTA0-Tyr3-Octreotate may be 
restarted one dose level lower. 
Any ≥ grade 3 non-hematologic*  
Hold study drug(s)** for up to 21 days until toxicity 
resolves to  grade 1 or baseline. 
Treatment with 177Lu-DOTA0-Tyr3-Octreotate may be 
restarted one dose level lower. 
Grade 3 or 4 non-hematologic AE related 
to drugs* that does not resolve to grade 1 
or less within 21 days despite maximum 
supportive care after treating patient at the 
lowest reduced DL. 
Remove patient from study regimen. 
* Excluding 1) Grade 3 fatigue/asthenia < 2 weeks in duration, or grade 3 asymptomatic 
electrolytes imbalance with optimal and continuing repletion that downgrades to grade 1 or better 
within 7 days after onset of the event; 2) Grade 3 asymptomatic increase in gamma glutamyl 
transferase (GGT). 
** For patients on combination therapy, if the observed AE is specifically attributed to only 1 of 
the drugs, that drug may be held while the patient continues to receive the drug not associated with 
the observed AE. The time a given drug is held should not exceed 21 days. 
5.3.4 
Management of Infusion-Related Reactions  
Table 5. Dose Modifications and Management of Infusion-Related Reactions 
Observation 
Management 
Grade 1 or 2 AE 
The infusion rate of study drug(s) may be decreased by 50% or 
temporarily interrupted until resolution of the event. 
Acetaminophen and/or antihistamines may be administered per 
institutional standard at the discretion of the investigator. 
Consider premedication prior to subsequent doses. 
Grade 3 or 4 AE 
Discontinue study drug(s). 
Manage severe infusion-related reactions (e.g., IM epinephrine, 
followed by IV diphenhydramine and ranitidine, and IV 
glucocorticoid).  
 


 
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5.3.5 
Management of Immune-Related Toxicities 
Treatment of immune-related adverse events (irAEs) should follow guidelines set forth in the 
following tables. Also, please refer to Appendix B for details. 
Table 6. Dose Modification and Management of irAEs 
Gastrointestinal irAEs (e.g. diarrhea, colitis) 
Observation 
Management 
Follow-up 
Grade 1 AE 
 
Continue nivolumab therapy. 
Consider symptomatic treatment (e.g. 
loperamide, hydration, electrolyte 
replacement). 
Close monitoring for worsening 
symptoms. 
Educate patient to report worsening 
immediately. 
If worsens: Treat as Grade 2 or 3/4 
Grade 2 AE 
Delay nivolumab therapy. 
Symptomatic treatment. 
If improves to Grade 1: Resume 
nivolumab therapy. 
If no improvement within 5-7 days or 
recur: Consider starting IV 
methylprednisolone 0.5-1.0 mg/kg/day or 
oral equivalent. Once improving, taper 
steroids over ≥1 month and consider 
prophylactic antimicrobials for 
opportunistic infections, and consider 
resuming nivolumab. 
If the event is not responsive within 3-5 
days or worsens despite steroid: Treat as 
Grade 3/4. 
Grade 3 to 4 AE 
Discontinue nivolumab therapy. 
1.0 to 2.0 mg/kg/day methylprednisolone 
IV or equivalent. 
Consider urgent GI consult and imaging 
and/or colonoscopy as appropriate. 
 
Once improving, taper steroids over ≥ 1 
month and consider prophylactic 
antimicrobials for opportunistic 
infections. 
 
If still no improvement within 3-5 days 
or recurs after improvement despite 
steroid: consider adding further 
immunosuppressives (e.g. infliximab at 
5mg/kg once every 2 weeks if no 
contraindication). Caution: Consider GI 


 
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consult to rule out bowel perforation and 
refer to infliximab label for general 
guidance before using infliximab. 
Infliximab should not be used in cases of 
perforation or sepsis. 
 
Dermatological irAEs 
Observation 
Management 
Follow-up 
Grade 1-2 AE 
Symptomatic therapy (e.g. oral 
antihistamines, topical steroids). 
Continue nivolumab therapy. 
If persists > 1-2 weeks or recurs: 
Consider delaying nivolumab. Consider 
skin biopsy. Consider 0.5-1.0 mg/kg/day 
methylprednisolone IV or oral 
equivalent. Once improving, taper 
steroids over ≥ 1month, consider 
prophylactic antimicrobials for 
opportunistic infections, and resume 
nivolumab. 
If worsens: Treat as Grade 3-4. 
Grade 3-4 AE 
Delay or discontinue nivolumab therapy. 
1.0 to 2.0 mg/kg/day methylprednisolone 
IV or equivalent. 
Consider dermatology consult and/or skin 
biopsy.  
If improves to Grade 1: taper steroids 
over ≥ 1 month and consider 
prophylactic antimicrobials for 
opportunistic infections and consider 
resuming nivolumab. 
 
Pulmonary irAEs 
Observation 
Management 
Follow-up 
Grade 1 AE 
Consider delay of nivolumab therapy. 
Monitor for symptoms at least every 2-3 
days. 
Re-image at least every 3 weeks. 
If worsens: Treat as Grade 2 or Grade 3-
4. 


 
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Consider Pulmonary and Infectious 
Disease consults. 
Grade 2 AE 
Delay nivolumab therapy. 
Consider Pulmonary and Infectious 
Disease consults. 
Monitor symptoms daily, consider 
hospitalization. 
1.0 mg/kg/day methyl-prednisolone IV or 
oral equivalent. 
Consider bronchoscopy, lung biopsy. 
Re-image every 1-3 days. 
If improves: When symptoms return to 
near baseline, taper steroids over ≥1 
month, resume nivolumab therapy, and 
consider prophylactic antimicrobials.  
If not improving after 2 weeks or 
worsening: Treat as Grade 3 to 4. 
Grade 3 or 4 AE 
Discontinue nivolumab therapy. 
Hospitalize. 
Pulmonary and Infectious Disease 
consults. 
2 to 4 mg/kg/day methylprednisolone IV or 
IV equivalent. 
Add prophylactic microbials for 
opportunistic infections. 
Consider bronchoscopy, lung biopsy.  
If improves to baseline: Taper steroids 
over at least 6 weeks. 
If not improving within 48 hours or 
worsening: Add additional 
immunosuppression (e.g. infliximab, 
cyclosporine, tacrolimus, 
cyclophosphamide, intravenous 
immunoglobulin, or mycophenolate 
mofetil). 
 
Hepatic irAEs 
Observation 
Management 
Follow-up 
Grade 1 AE 
Continue nivolumab therapy. 
Continue liver function monitoring. 
If worsens: Treat as Grade 2 or 3-4. 
Grade 2 AE 
Delay nivolumab therapy. 
Regular and frequent checking (e.g. every 
3 days) of LFTs until elevations of these 
are improving or resolved. 
If returns to baseline: Resume routine 
monitoring, resume nivolumab therapy. 


 
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If elevations persist > 5-7 days or 
worsen: 0.5 to 1 mg/kg/day 
methylprednisolone or oral equivalent 
and when LFT returns to Grade 1 or 
baseline, taper steroids over ≥ 1 month, 
consider prophylactic antimicrobials for 
opportunistic infections, and resume 
nivolumab therapy. 
Grade 3 to 4 AE 
Discontinue nivolumab therapy* 
Regular and frequent checking of LFTs 
(e.g. every 1-2 days) until elevations of 
these are improving or resolved. 
1.0 to 2.0 mg/kg/day methylprednisolone 
IV or IV equivalent** 
Add prophylactic antimicrobials for 
opportunistic infections. 
Consult gastroenterologist. 
If returns to Grade 2 or better: Taper 
steroids over ≥ 1 month. 
If does not improve in > 3 to 5 days, 
worsens or rebounds: Add 
mycophenolate mofetil 1 gram (g) twice 
daily. If no response within an additional 
3 to 5 days, consider other 
immunosuppressants per local 
guidelines. 
*Nivolumab therapy may be delayed rather than discontinued if AST/ALT <= 8 x ULN and Total 
bilirubin <= 5 x ULN. 
**The recommended starting dose for grade 4 hepatitis is 2 mg/kg/day methylprednisolone IV. 
Endocrine irAEs 
Endocrine 
Disorder 
Management 
Follow-up 
Asymptomatic 
TSH elevation  
Continue nivolumab therapy.   
 If TSH < 0.5 x LLN, or TSH > 2 x ULN, or consistently out of range in 2 subsequent 
measurements: include free T4 at subsequent cycles as clinically indicated; consider 
endocrinology consult.  
Symptomatic 
endocrinopathy  
Evaluate endocrine function.  
Consider pituitary scan.  
If improves (with or without hormone 
replacement): Taper steroids over ≥1 
month and consider prophylactic 
antimicrobials for opportunistic 
infections. 
Resume nivolumab therapy. 


 
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Symptomatic with abnormal lab / pituitary 
scan: Delay nivolumab therapy. 1 to 2 
mg/kg/day methylprednisolone IV or by 
mouth equivalent. Initiate appropriate 
hormone therapy. 
No abnormal lab / pituitary MRI scan but 
symptoms persist: Repeat labs in 1 to 3 
weeks / MRI in 1 month  
Subjects with adrenal insufficiency may 
need to continue steroids with 
mineralocorticoid component. 
Suspicion of 
adrenal crisis 
(e.g. severe 
dehydration, 
hypotension, 
shock out of 
proportion to 
current illness  
Delay or discontinue nivolumab therapy. 
Rule out sepsis. 
Stress dose of IV steroids with mineralocorticoid activity.  
IV fluids. 
Consult endocrinologist. 
If adrenal crisis ruled out, then treat as above for symptomatic endocrinopathy. 
 
Renal irAEs 
Observation 
Management 
Follow-up 
Grade 1 AE 
Continue nivolumab therapy. 
Monitor creatinine weekly. 
If returns to baseline: resume routine 
creatinine monitoring per protocol. 
If worsens: Treat as Grade 2 or 3/4. 
Grade 2-3 AE 
Delay nivolumab therapy. 
Regular and frequent checking of 
Creatinine (e.g. every 2-3 days) until 
Creatinine elevation is improving or 
resolved. 
0.5 to 1 mg/kg/day methylprednisolone IV 
or oral equivalent. 
Consider renal biopsy with nephrology 
consult.  
If returns to grade 1: Taper steroids over ≥ 
1 month, consider prophylactic 
antimicrobials for opportunistic infections, 
and resume nivolumab therapy and routine 
creatinine monitoring per protocol. 
If elevations persist > 7 days or worsen: 
Treat as Grade 4. 


 
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Grade 4 AE 
Discontinue nivolumab therapy. 
Regular and frequent checking of 
Creatinine until Creatinine elevation is 
improving or resolved. 
1 to 2 mg/kg/day methylprednisolone iv or 
iv equivalent. 
Consult nephrologist. 
Consider renal biopsy. 
If returns to Grade 1: Taper steroids over 
≥1 month, consider prophylactic 
antimicrobials for opportunistic infections.  
 
Neurological irAEs 
Observation 
Management 
Follow-up 
Grade 1 AE 
 
Continue nivolumab therapy. 
Continue to monitor the patient. 
If worsens: Treat as Grade 2 or 3/4. 
Grade 2 AE  
Delay nivolumab therapy. 
Treat symptoms per local guidelines. 
Consider 0.5 to 1 mg/kg/day 
methylprednisolone iv or oral equivalent. 
If improves to baseline or grade 1: 
Resume nivolumab therapy per protocol 
when improved to baseline. 
If worsens: Treat as Grade 3-4. 
Grade 3-4 AE 
 
Discontinue nivolumab therapy.  
Obtain neurology consult. 
Treat symptoms per local guidelines. 
1 to 2 mg/kg/day methylprednisolone IV or 
equivalent. 
Add prophylactic antibiotics for opportunistic 
infections. 
If improves to grade 2: Taper steroids 
over ≥1 month. 
If worsens or atypical presentation: 
consider IVIG or other 
immunosuppressive therapies per local 
guidelines. 
 


 
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Other irAEs 
Observation 
Dose Modifications 
Toxicity management 
Grade 1 AE 
 
Continue nivolumab therapy. 
Consider appropriate symptomatic 
treatment.  
Subjects should be evaluated to identify 
any alternative etiology. 
Symptomatic and/or topical therapy 
should be considered for low grade 
events. 
Systemic corticosteroids should be 
considered for a persistent low-grade 
event or for a more severe event. Patients 
on IV steroids may be switched to an 
equivalent dose of oral corticosteroids 
(e.g. prednisone) at start of tapering or 
earlier, once sustained clinical 
improvement is observed. Lower 
bioavailability of oral corticosteroids 
should be taken into account when 
switching to the equivalent dose of oral 
corticosteroids. 
More potent immunosuppressive agents 
should be considered for events not 
responding to systemic steroids (e.g., 
infliximab, mycophenolate, etc.).  
Discontinuation of study drug is not 
mandated for Grade 3 / Grade 4 
inflammatory reactions attributed to local 
tumor response (e.g., inflammatory 
reaction at sites of metastatic disease, 
lymph nodes etc.). Continuation of study 
drug in this situation should be based 
upon a benefit/risk analysis for that 
patient. 
 
Grade 2 AE 
Hold nivolumab until grade 2 resolution to 
≤ grade 1.  
If toxicity worsens, then treat as grade 3 or 
grade 4.  
If toxicity improves to baseline, then 
consider restarting nivolumab. 
Grade 3 AE** 
Depending on the individual toxicity, may 
permanently discontinue nivolumab* 


 
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Grade 4 AE** 
Permanently discontinue nivolumab.  
 
 
* In addition to the criteria for permanent discontinuation of study drug/regimen based on CTC 
grade/severity, permanently discontinue study drug/study regimen for the following conditions: 1) 
Inability to reduce corticorsteroid to a dose of ≤10 mg of prednisone per day (or equivalent) within 
12 weeks after last dose of study drug/regimen, 2) Recurrence of a previously experienced Grade 3 
treatment-related AE following resumption of dosing. 
** For Grade 3 and above asymptomatic amylase or lipase levels, hold study drug/regimen and if 
complete work up shows no evidence of pancreatitis, may continue or resume study drug/regimen 
Abbreviations: ADL=activities of daily living, ALT=alanine aminotransferase, AST=aspartate 
aminotransferase, irAE=immune-related adverse event, IV=intravenous, LLN=lower limit of 
normal, MRI=magnetic resonance imaging, NSAIDs=nonsteroidal anti-inflammatory drugs, 
T4=thyroxine, TSH=thyroid-stimulating hormone, ULN=upper limit of normal, IVIG=intravenous 
immunoglobulins, CPK=creatine phosphokinase. 
5.4 
Concomitant Medications/Treatments 
Concomitant use of chemotherapy or investigational agents are not allowed. Palliative radiation to 
limited areas is allowed during the study, unless this is required because of progression of the 
disease. 
5.5 
Off-treatment criteria 
Treatment may continue until one of the following criteria applies: 
 
Disease progression and investigator determination that the subject is no longer benefiting 
from study treatment* 
 
Any AE that meets criteria for discontinuation as defined in section 5.3.  
 
Patient decides to withdraw from the study. 
 
General or specific changes in the patient’s condition render the patient unfit for further 
treatment in the judgment of the investigator. 
 
Patient is non-compliant with the protocol guidelines. 
* Patients are allowed to stay on treatment beyond progression if the investigator thinks that the 
patient is still benefiting from the treatment. 
5.6 
Off-study criteria 
 
Death 
 
Patient decides to withdraw consent from the study. 
 
Lost to follow-up 


 
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 
Completed study follow-up period 
 
Investigator discretion 
5.7 
Duration of Follow-Up 
Patients will be followed either with clinic visits or phone interviews yearly for two years. Patients 
removed from treatment for unacceptable adverse event(s) will be followed clinically until 
resolution or stabilization of the adverse event, and then via clinic visits or phone interviews yearly 
for two years.   
The following information will be collected:  
 
Date of follow up  
 
Is patient dead or alive?  
 
If dead, document exact date of death.  
 
Further treatment(s), if any  
 
Document date of disease progression  
6.0 
STUDY PROCEDURES 
6.1 Screening/Baseline Procedures 
Subjects who meet all eligibility criteria will be enrolled in the study. Assessments performed 
exclusively to determine eligibility for this study will be done after obtaining informed consent. 
Assessments performed for clinical indications (not exclusively to determine study eligibility) may 
be used for baseline values even if the studies were done before informed consent was obtained. 
All screening procedures must be performed within 4 weeks prior to starting study drugs, unless 
otherwise stated. The screening procedures include: 
 
Complete history and physical examination including vital signs, height, weight and ECOG 
performance score (see appendix C). 
 
Baseline imaging studies: Patients should have a baseline radiographical evaluation with 
computed tomography (CT) scan of the chest/abdomen/pelvis, MRI or CT of the brain, and 
FDG-PET (skull base to mid-thigh). Two NETSPOT® PET scans will be performed, the first 
one within 4 weeks before the start of chemotherapy (preferable) or as soon as possible after 
initiation of chemotherapy. This scan will be used to evaluate SSTR2 expression and the 
patient’s eligibility for the study. The second NETSPOT® PET scan will be conducted as far 
as possible from the end of chemotherapy (ideally within 1 week before the start of study 
treatment). This scan will be used for exploratory analysis on eventual SSTR2 expression 
modification with chemotherapy. If a patient presents after completion of chemotherapy and 
did not have a NETSPOT® PET scan performed before or during chemotherapy, a NETSPOT® 
PET scan will be obtained to determine the patient’s eligibility. The participating centers of 
the proposed study will follow the approved reconstitution and quality control procedures for 
[68Ga]-DOTATE, and will use the qualified Ge-68/Ga-68 generator. Outside imaging studies 
will be accepted at the discretion of the PI. 
 
Electrocardiogram (EKG) 


 
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 
Laboratory evaluation (baseline tests to be obtained within two weeks prior to starting 
treatment unless otherwise noted) 
o Hematological Profile: Complete blood count (CBC) with differential and platelet 
count, prothrombin time/international normalized ratio (PT/INR), activated partial 
thromboplastin time (aPTT). 
o Biochemical Profile: Sodium, potassium, calcium, phosphorous, magnesium, blood urea 
nitrogen (BUN), creatinine, glucose, aspartate aminotransferase (AST), alanine 
aminotransferase (ALT), alkaline phosphatase, lactic acid dehydrogenase (LDH), 
bilirubin, albumin. 
o Baseline glomerular filtration rate (GFR) calculation. 
o Serum or urine beta-hCG for female patients of childbearing age within 24 hours prior 
to the start of study drug. 
o Viral Markers: HBsAg (hepatitis B surface antigen), anti-HCV antibody, anti-HIV 
antibody within 3 months prior to starting treatment. 
o Amylase, lipase, thyroid function test (TSH, free T3, free T4). 
6.2 
Procedures During Treatment 
Patients receiving study treatment will be followed every 2 weeks and the following will be done 
(unless otherwise indicated). 
 
History and physical exam (± 3 days). 
 
Laboratory evaluation (± 3 days): Hematologic profile (CBC with differential). Biochemical 
profile. Does not need to repeat for C1D1 if performed within 7 days.  
 
Thyroid function testing will be done every cycle on day 1 (± 3 days) and day 29 (± 3 days) 
for subjects receiving nivolumab. Does not need to repeat on C1D1. 
 
Tumor imaging will be performed every 8 weeks (± 7 days). 
 
NETSPOT® PET scan on cycle 2 day 1 (± 3 days) to assess the metabolic response. 
 
Serum or urine beta-hCG for female patients of childbearing age within 24 hours prior to the 
administration of 177Lu-DOTA0-Tyr3-Octreotate. 
Patients randomized to observation will be followed every 4 weeks and the following will be done.  
 
History and physical exam (± 3 days). 
 
Laboratory evaluation (± 3 days): Hematologic and biochemical profile. Laboratory evaluation 
can be performed within 3 days prior to clinic visit. 
 
Tumor imaging will be performed every 8 weeks (± 7 days). 
After 30 days (± 7 days) from treatment termination, the following will be obtained if the patient is 
available: 
 
History and physical exam. 
 
Laboratory evaluation: Hematologic and biochemical profile. Thyroid function testing.  
6.3 
Follow-up 
Patients will be followed either with clinic visits or phone interviews yearly for two years.  
Patients removed from treatment for unacceptable adverse event(s) will be followed clinically until 


 
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resolution or stabilization of the adverse event, and then via clinic visits or phone interviews yearly 
for two years. 
The following information will be collected: 
 
Date of follow up 
 
Is patient dead or alive? 
 
If dead, document exact date of death. 
 
Further treatment(s), if any  
 
Document date of disease progression 
 
Long-term myelosuppression, myelodysplasia, and occurrence of secondary malignancies. 
6.4 
Study Calendar 
Please refer to Appendix D. 
7.0 
Measurement of Effect 
7.1 Antitumor Effect- Solid Tumors 
Response and progression will be evaluated in this study using the international criteria proposed 
by the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 [47]. Changes in only 
the largest diameter (unidimensional measurement) of the tumor lesions and the shortest diameter 
in the case of malignant lymph nodes are used in the RECIST version 1.1 criteria. 
7.1.1 
Definitions 
Evaluable for toxicity: All patients will be evaluable for toxicity from the time of their first 
treatment with 177Lu-DOTA0-Tyr3-Octreotate and nivolumab. 
Evaluable for objective response: Only those patients who have received at least one cycle of 
therapy, and have had their disease re-evaluated will be considered evaluable for response.  These 
patients will have their response classified according to the definitions stated below. (Note:  
Patients who exhibit objective disease progression prior to the end of cycle 1 will also be 
considered evaluable.) 
Evaluable Non-Target Disease Response: Patients who have lesions present at baseline that are 
evaluable but do not meet the definitions of measurable disease, have received at least one cycle of 
therapy, and have had their disease reevaluated will be considered evaluable for non-target 
disease. The response assessment is based on the presence, absence, or unequivocal progression of 
the lesions. 
7.1.2 
Disease Parameters 
Measurable disease: Measurable lesions are defined as those that can be accurately measured in at 
least one dimension (longest diameter to be recorded) as ≥20 mm by chest x-ray, as ≥10 mm with 
CT scan, or 10 mm with calipers by clinical exam. All tumor measurements must be recorded in 
millimeters (or decimal fractions of centimeters). 


 
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Note: Tumor lesions that are located in a previously irradiated area might or might not be 
considered measurable at the discretion of the PI.  
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a lymph node 
must be ≥15 mm in short axis when assessed by CT scan (CT scan slice thickness recommended to 
be no greater than 5 mm). At baseline and in follow-up, only the short axis will be measured and 
followed. 
Non-measurable disease: All other lesions (or sites of disease), including small lesions (longest 
diameter <10 mm or pathological lymph nodes with ≥ 10 to <15 mm short axis), are considered 
non-measurable disease. Bone lesions, leptomeningeal disease, ascites, pleural/pericardial 
effusions, lymphangitis cutis/pulmonis, inflammatory breast disease, abdominal masses (not 
followed by CT or MRI), and cystic lesions are all non-measurable. 
Note: Cystic lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor nonmeasurable) since they are, by 
definition, simple cysts.  
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable lesions, if 
they meet the definition of measurability described above. However, if non-cystic lesions are 
present in the same patient, these are preferred for selection as target lesions. 
Target lesions:  All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in 
total, representative of all involved organs, should be identified as target lesions and recorded and 
measured at baseline. Target lesions should be selected on the basis of their size (lesions with the 
longest diameter), be representative of all involved organs, and their suitability for accurate 
repeated measurements (either by imaging techniques or clinically). A sum of the diameters 
(longest for non-nodal lesions, short axis for nodal lesions) for all target lesions will be calculated 
and reported as the baseline sum diameters.  If lymph nodes are to be included in the sum, then 
only the short axis is added into the sum. The baseline sum diameters will be used as reference to 
further characterize any objective tumor regression in the measurable dimension of the disease. 
Non-target lesions.  All other lesions (or sites of disease) including any measurable lesions over 
and above the 6 target lesions should be identified as non-target lesions and should also be 
recorded at baseline.  Measurements of these lesions are not required, but the presence or absence 
of each should be noted throughout follow-up.  
7.1.3 
Methods for Evaluation of Measurable Disease 
All measurements should be taken and recorded in metric notation using a ruler or calipers.  All 
baseline evaluations should be performed as closely as possible to the beginning of treatment and 
never more than 28 days before the beginning of the treatment. 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging-based evaluation is 
preferred to evaluation by clinical examination unless the lesion(s) being followed cannot be 
imaged but are assessable by clinical exam. 


 
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Clinical lesions: Clinical lesions will only be considered measurable when they are superficial 
(e.g., skin nodules and palpable lymph nodes) and ≥10 mm diameter as assessed using calipers 
(e.g., skin nodules). In the case of skin lesions, documentation by color photography, including a 
ruler to estimate the size of the lesion, is recommended. 
Conventional CT and MRI: CT and MRI - CT and MRI are the best currently available and 
reproducible methods to measure target lesions selected for response assessment. For this study 
helical multidetector CT will be performed with cuts of 5 mm in slice thickness for chest, 
abdomen and pelvis lesions and 2-3 mm thickness for head and neck lesions. For consistency, it is 
recommended that investigators use the same imaging modality for follow-up of tumors for a 
given patient. 
Cytology, Histology: These techniques can be used to differentiate between partial responses (PR) 
and complete responses (CR) in rare cases. 
The cytological confirmation of the neoplastic origin of any effusion that appears or worsens 
during treatment when the measurable tumor has met criteria for response or stable disease is 
mandatory to differentiate between response or stable disease (an effusion may be a side effect of 
the treatment) and progressive disease. 
FDG-PET: New lesions on the basis of FDG-PET imaging can be identified according to the 
following algorithm. Negative FDG-PET at baseline, with a positive FDG-PET at follow-up may 
be a sign of progressive disease. If the positive FDG-PET at follow-up corresponds to a new site of 
disease confirmed by CT, this is progressive disease (PD). If the positive FDG-PET at follow-up is 
not confirmed as a new site of disease on CT, additional follow-up CT scans are needed to 
determine if there is truly progression occurring at that site. If so, the date of PD will be the date of 
the initial abnormal FDG-PET scan. If the positive FDG-PET at follow-up corresponds to a pre-
existing site of disease on CT that is not progressing on the basis of the anatomic images, this is 
not PD.  
Note: A positive FDG-PET scan lesion means one which is FDG avid with an uptake greater than 
twice that of the surrounding tissue on the attenuation corrected image. 
7.1.4 
Response Criteria 
7.1.4.1 
Evaluation of Target Lesions 
Response and progression will be evaluated in this study using the international criteria proposed 
by the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. 
Complete Response (CR): Disappearance of all target lesions. There can be no appearance of new 
lesions. Any pathological lymph nodes must have reduction in short axis to <10 mm. 
Partial Response (PR): At least a 30% decrease in the sum of target lesions, taking as reference the 
baseline sum diameters. There can be no appearance of new lesions. 
Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions, 
taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest 
on study). The appearance of one or more new lesions is also considered progression). 


 
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Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum diameters while on study. 
7.1.4.2 
Evaluation of Non-Target Lesions 
Complete Response (CR): Disappearance of all non-target lesions and normalization of tumor 
marker level. All lymph nodes must be non-pathological in size (<10 mm short axis). 
Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or maintenance of tumor 
marker level above the normal limits. 
Progressive Disease (PD): Appearance of one or more new lesions and/or unequivocal progression 
of existing non-target lesions. Unequivocal progression should not normally trump target lesion 
status. It must be representative of overall disease status change, not a single lesion increase. 
Although a clear progression of “non-target” lesions only is exceptional, the opinion of the treating 
physician should prevail in such circumstances, and the progression status should be confirmed at 
a later time by the review panel (or Principal Investigator). 
7.1.4.3 
Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the treatment until disease 
progression/recurrence (taking as reference for progressive disease the smallest measurements 
recorded since the treatment started).  The patient's best response assignment will depend on the 
achievement of both measurement and confirmation criteria. 
Table 7. Evaluation of patients with measureable disease. 
Target 
Lesions 
Non-Target Lesions 
New Lesions* 
Overall Response 
CR 
CR 
No 
CR 
CR 
Non-CR/Non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non-PD/not 
evaluated 
No 
PR 
SD 
Non-CR/Non-PD/not 
evaluated 
No 
SD 
PD 
Any 
Yes or No 
PD 
Any 
PD** 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
* See RECIST 1.1 manuscript for further details on what is evidence of a new lesion.  


 
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** In exceptional circumstances, unequivocal progression in non-target lesions may 
be accepted as disease progression.  
Note: Patients with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should be 
reported as “symptomatic deterioration”.  Every effort should be made to document 
the objective progression even after discontinuation of treatment. 
 
Table 8. Evaluation of patients with non-measureable disease 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated  
No 
Not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
*  ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target 
disease since SD is increasingly used as an endpoint for assessment of 
efficacy in some trials so to assign this category when no lesions can be 
measured is not advised. 
7.1.5 
Duration of Response 
Duration of overall response:  The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first date that 
recurrent or progressive disease is objectively documented (taking as reference for progressive 
disease the smallest measurements recorded since the treatment started). 
The duration of overall CR is measured from the time measurement criteria are first met for CR 
until the first date that recurrent disease is objectively documented.  
Duration of stable disease:  Stable disease is measured from randomization until the criteria for 
progression are met, taking as reference the smallest measurements recorded since the treatment 
started.  
7.1.6 
Progression-Free Survival 
PFS is defined as the duration of time from randomization to time of progression or death, 
whichever occurs first. 
7.1.7 
Overall Survival 
Overall survival is defined as the duration of time from randomization to death from any cause. 


 
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8.0 
ADVERSE EVENTS 
8.1 Definitions 
8.1.1 
Definition of Adverse Event 
An adverse event (AE) is any untoward medical occurrence in a patient receiving study treatment 
and which does not necessarily have a causal relationship with this treatment. An AE can therefore 
be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or 
disease temporally associated with the use of an experimental intervention, whether or not related 
to the intervention.  For this study, AEs will include events reported by the patient, as well as 
clinically significant abnormal findings on physical examination or laboratory evaluation. A new 
illness, symptom, sign or clinically significant laboratory abnormality or worsening of a pre-
existing condition or abnormality is considered an AE. All AEs must be recorded on the AE case 
report form. 
AEs should be reported up to 30 days following the last dose of study drug. All AEs, including 
clinically significant abnormal findings on laboratory evaluations, regardless of severity, will be 
followed until satisfactory resolution. AEs should be reported up to 30 days following the last dose 
of study drug. 
An abnormal laboratory value will be considered an AE if the laboratory abnormality is 
characterized by any of the following: 
 
Results in discontinuation from the study 
 
Is associated with clinical signs or symptoms 
 
Requires treatment or any other therapeutic intervention 
 
Is associated with death or another serious adverse event, including hospitalization. 
 
Is judged by the Investigator to be of significant clinical impact 
 
If any abnormal laboratory result is considered clinically significant, the investigator will 
provide details about the action taken with respect to the test drug and about the patient’s 
outcome. 
8.1.2 
Suspected Adverse Reaction 
Suspected adverse reaction means any adverse event for which there is a reasonable possibility 
that the drug caused the adverse event. The term ‘reasonable possibility’ means there is evidence 
to suggest a causal relationship between the drug and the adverse event. A suspected adverse 
reaction implies a lesser degree of certainty about causality than adverse reaction, which means 
any adverse event caused by a drug. 
8.1.3 
Unexpected Adverse Reaction 
An adverse event or suspected adverse reaction is considered “unexpected” if it is not listed in the 
investigator brochure or is not listed at the specificity or severity that has been observed; or, if an 
investigator brochure is not required or available, is not consistent with the risk information 
described in the general investigational plan or elsewhere in the current application. "Unexpected”, 
also refers to adverse events or suspected adverse reactions that are mentioned in the investigator 


 
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brochure as occurring with a class of drugs or as anticipated from the pharmacological properties 
of the drug, but are not specifically mentioned as occurring with the particular drug under 
investigation. 
8.1.4 
Serious Adverse Events  
An adverse event or suspected adverse reaction is considered serious if in the view of the 
investigator or the sponsor*, it results in any of the following:  
 
Death. 
 
A life-threatening adverse drug experience. 
 
NOTE: The term “life-threatening” in this definition refers to an event in which the subject is 
at risk of death at the time of the event; it does not refer to an event that hypothetically might 
cause death if it were more severe. 
 
Inpatient hospitalization or prolongation of existing hospitalization, excluding hospitalizations 
done to facilitate research studies or for non-medical reasons (to facilitate completion of 
protocol-directed requirements, i.e. biopsy, imaging, desensitization for platinum). 
 
Persistent or significant incapacity or substantial disruption of the ability to conduct normal 
life functions. 
 
A congenital anomaly/birth defect. 
 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse drug experience when, based upon 
appropriate medical judgment, they may jeopardize the patient or subject and may require 
medical or surgical intervention to prevent one of the outcomes listed in this definition. 
Examples of such events include, but are not limited to, intensive treatment in an emergency 
room or at home for allergic bronchospasm; blood dyscrasias or convulsions that do not result 
in hospitalization. 
 
Potential drug induced liver injury (DILI)** 
 
Suspected transmission of an infectious agent (e.g. pathogenic or nonpathogenic) via the study 
drug is a serious adverse event. 
*Dr. Giuseppe Giaccone is the sponsor of this trial. 
**Potential Drug Induced Liver Injury 
Wherever possible, timely confirmation of initial liver-related laboratory abnormalities should 
occur prior to the reporting of a potential DILI event. All occurrences of potential DILIs, meeting 
the defined criteria, must be reported as potential drug induced liver injury is defined as: 
1) ALT or AST elevation > 3 times upper limit of normal (ULN) 
AND 
2) Total bilirubin > 2 times ULN, without initial findings of cholestasis (elevated serum alkaline 
phosphatase) 


 
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AND 
3) No other immediately apparent possible causes of AST/ALT elevation and hyperbilirubinemia, 
including, but not limited to, viral hepatitis, pre-existing chronic or acute liver disease, or the 
administration of other drug(s) known to be hepatotoxic. 
8.1.5 
Severity of Adverse Events 
All non-hematologic adverse events will be graded according to the NCI Common Terminology 
Criteria for Adverse Events (CTCAE) version 4.0. The CTCAE v4.0 is available at 
http://ctep.cancer.gov/reporting/ctc.html 
Attribution categories are as follows: 
 
Definite – The AE is clearly related to the study treatment. 
 Probable – The AE is likely related to the study treatment. 
 Possible – The AE may be related to the study treatment. 
 Unlikely – The AE is doubtfully related to the study treatment.  
 Unrelated – The AE is clearly NOT related to the study treatment. 
8.2 Adverse Event Monitoring 
Adverse event data collection and reporting, which are required as part of every clinical trial, are 
done to ensure the safety of Subjects enrolled in the studies as well as those who will enroll in 
future studies using similar agents. Adverse events are reported in a routine manner at scheduled 
times during a trial.  Additionally, certain adverse events must be reported in an expedited manner 
to allow for optimal monitoring of patient safety and care.  
8.3 Reporting Requirements for Adverse Events 
Participating investigators (all sites) must report all serious adverse events to the Sponsor-
Investigator within 24 hours of discovery or notification of the event. The participating 
investigator must also provide follow-up information on the SAE until final resolution. The 
Sponsor-Investigator can be contacted at Giuseppe Giaccone, E-mail: gg496@georgetown.edu, 
phone: 202-687-7072 with CC to Multi-Site-AEReports@georgetown.edu and CC to sub-
investigator Chul Kim, E-mail: chul.kim@gunet.georgetown.edu. 
The Sponsor-Investigator will review the SAE and report the event to the FDA, external 
collaborator(s), IND manufacturer, and IRB as applicable as described below. 
It is the Sponsor-Investigator’s responsibility (e.g. lead site PI) to ensure that all serious adverse 
events that occur on the study (e.g. all SAEs that occur at each enrolling institution) are reported to 
all participating sites. 
*After informed consent has been obtained but prior to initiation of study treatment, only serious 
adverse events caused by a protocol-mandated intervention (e.g., invasive procedures such as 
biopsies) should be reported.  


 
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**After initiation of study treatment, all adverse events will be reported until 30 days after the last 
dose of study treatment or last observation follow-up visit or until initiation of new systemic anti-
cancer therapy, whichever occurs first, and serious adverse events will continue to be reported 
until 90 days after the last dose of study treatment or last observation follow-up visit or until 
initiation of new systemic anti-cancer therapy, whichever occurs first. 
8.3.1 
Expedited IRB Reporting 
The institutional officials must be notified within 10 business days of “any unanticipated problems 
involving risk to subjects or others” (UPR). UPRs are defined as any problem or event that is 
considered: 1) serious, 2) unexpected, and 3) at least possibly related to study participation. 
8.3.2 
FDA Reporting Criteria  
8.3.2.1 
IND Safety Reports to the FDA (Refer to 21 CFR 312.32) 
The Sponsor will notify the FDA of any unexpected fatal or life-threatening suspected adverse 
reactions as soon as possible but no later than 7 calendar days of initial receipt of the information 
using the MedWatch Form 3500a.  
The Sponsor is also responsible for reporting any:  
 
suspected adverse reaction that is both serious and unexpected  
 
any findings from clinical, epidemiological, or pooled analysis of multiple studies or any 
findings from animal or in vitro testing that suggest a significant risk in humans exposed to the 
drug  
 
clinically important increase in the rate of a serious suspected adverse reaction over that listed 
in the protocol or investigator brochure  
to the FDA and to all investigators no later than 15 calendar days after determining that the 
information qualifies for reporting using the MedWatch Form 3500a. If FDA requests any 
additional data or information, the sponsor must submit it to the FDA as soon as possible, but no 
later than 15 calendars days after receiving the request. 
SAEs should be reported on MedWatch Form 3500A, which can be accessed at: 
http://www.accessdata.fda.gov/scripts/medwatch/ 
MedWatch SAE forms should be sent to the FDA at: 
MEDWATCH 
5600 Fishers Lane 
Rockville, MD 20852-9787 
Fax: 1-800-FDA-0178 (1-800-332-0178) 
http://www.accessdata.fda.gov/scripts/medwatch/ 


 
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8.3.2.2 
FDA Annual Reports (Refer to 21 CFR 312.32) 
The study Sponsor will submit a brief report annually of the progress of the trial within 60 days of 
the anniversary date that the IND went into effect as indicated in 21CFR 312.33, and any 
associated FDA correspondences regarding the IND annual report. 
8.3.3 
IND Manufacturer Reporting 
8.3.3.1 
Reporting of Adverse Events (SAEs) to Advanced Accelerator Applications (AAA) 
A copy of the MedWatch/AdEERs report must be faxed to AAA at the time the event is reported 
to the FDA.  It is the responsibility of the investigator to compile all necessary information and 
ensure that the FDA receives a report according to the FDA reporting requirement timelines and to 
ensure that these reports are also submitted to AAA at the same time. 
* Send SAE report and accompanying cover page by way of email to 
Pharmacovigilance@adacap.com (email is the preferred method) 
OR 
* Send SAE report and accompanying cover page by way of fax to line: 1-212-235-2381  
8.3.3.2 
Reporting of Adverse Events (SAEs) to Bristol-Myers Squibb (BMS) 
See Appendix E for mandatory adverse event reporting information. All serious adverse events 
must be reported to BMS Worldwide Safety. 
9.0 
DRUG INFORMATION 
9.1 
177Lu-DOTA0-Tyr3-Octreotate  
9.1.1 
Investigational Drug Product: 177Lu-DOTA0-Tyr3-Octreotate 
177Lu-DOTA0-Tyr3-Octreotate is a radiopharmaceutical solution for infusion supplied as a ready-
to-use product. No manipulation of the product in needed at the clinical site. The only Quality 
Control (QC) tests that must be performed at the clinical site are; 1) confirm correct product 
certificate; 2) determine total radioactivity; 3) confirm visual appearance. Since 177Lu-DOTA0-
Tyr3-Octreotate is manufactured in centralized GMP facilities, the majority of required QC tests 
are performed before product shipment. A batch release certificate of the product will be sent to 
the investigational centers. This batch release certificate is provided by the Qualified Person (QP) 
of the manufacturing site to ensure that the product is suitable for administration and that it meets 
the specifications indicated in the Investigational Medicinal Product Dossier (IMPD). 
The product is manufactured and supplied to the clinical sites in monodose vials. One vial, for one 
administration, contains 3.7 GBq (100 mCi) or 7.4 GBq (200 mCi) of 177Lu-DOTA0-Tyr3-
Octreotate at calibration time (the time of infusion). The variability of the volume depends on the 
time between the calibration date and the production date. The product will be shipped and 
calibrated for use at 24h or 48h after production in a centralized GMP facility. The calibration time 
of a dose depends on the distance from the manufacturing facility to the clinical sites. The amount 


 
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of administered radioactivity is specified at the time of infusion. Additional information on 
recommendations for treated patients are provided in Appendix F. 
Chemical-physical properties of each dose are listed in the Table 10. 
Table 9. 177Lu-DOTA0-Tyr3-Octreotate Infusion Solution Composition. 
Component 
Composition (one vial) 
Function 
177Lu-DOTA0-Tyr3-Octreotate 
7.4 GBq / 200 mCi 
Active Pharmaceutical Ingredient 
X-DOTA0-Tyr3-Octreotate 
10 μg/mL 
Total peptide content 
177Lu-DOTA0-Tyr3-Octreotate 
4.57 μg/mL* 
Active Pharmaceutical Ingredient 
DOTA0-Tyr3-Octreotate 
5.92 μg/mL* 
Active Pharmaceutical Ingredient 
Precursor 
Volume 
From 22-25 mL 
 
Specific Activity 
(GBq/Total peptide) 
53 GBq/μmol (at EOP)* 
 
Radioconcentration 
370 MBq/mL (at EOP) 
 
Other Constituents/Excipients 
Acetic Acid 
Sodium Acetate 
Gentisic Acid 
Ascorbic Acid 
DTPA 
NaCl 
Water for Injection 
mg/mL 
0.48* 
0.66* 
0.63* 
2.80 
0.05 
6.85 
- 
 
pH adjuster 
pH adjuster 
Radiation Stability Enhancer 
Radiation Stability Enhancer 
Masking Agent 
Blood isotonic solution 
Solvent 
*Values calculated assuming 177Lu specific activity of 740 GBq/mg at labelling time and a mean 
synthesis yield of 80% and radiochemical purity ≥97%. 
Treatment with 177Lu-DOTA0-Tyr3-Octreotate will consist of a cumulative dose of 14.8 GBq (400 
mCi) or 29.6 GBq (800mCi) with the dosing equally divided among 4 administrations of 177Lu-
DOTA0-Tyr3-Octreotate at 8±1-weeks intervals. 
9.1.2 
Handling  
177Lu-DOTA0-Tyr3-Octreotate must be administered at the investigational site. The study 
medication must be stored, handled and administered only by qualified/authorized personnel and 
must be prepared in accordance with pharmaceutical quality requirements, and radiation safety 
regulations for 177Lu-DOTA0-Tyr3-Octreotate. 


 
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9.1.3 
Packing and Labeling  
177Lu-DOTA0-Tyr3-Octreotate will be prepared, packaged, labelled, and released under the 
responsibility of Advanced Accelerated Application´s Standard Operating Procedures (SOPs), 
Good Manufacturing Practice (GMP) guidelines, ICH Good Clinical Practice (GCP) guidelines, 
and applicable local laws/regulations. Instructions for shipment, storage and handling of the 177Lu-
DOTA0-Tyr3-Octreotate Solution of Infusion are provided in Appendix G. 
9.1.4 
Destruction  
The used/unused medications, except for 177Lu-DOTA0-Tyr3-Octreotate, which will be locally 
discarded, will be returned to the proper local depot for destruction at the study completion or 
upon expiration, according to IPM/Sponsor decision and approval. 
9.2 
Nivolumab  
9.2.1 
Description 
Product name  
Nivolumab Injection, 100 mg/vial (10 mg/mL) 
Product description and Packaging 
Packaging: Vials assembled into dispensing boxes containing 
5 vials of 100 mg Nivolumab 
Vials: 10 cc Type I glass vial, 20 mm stopper and seal 
Appearance: Clear to opalescent, colorless to pale yellow 
liquid, light (few) particulates may be present. 
Product Ingredients 
Each vial contains Nivolumab 100 mg active 
9.2.2 
Handling and Dose preparation 
As with all injectable drugs, care should be taken when handling and preparing nivolumab. 
Whenever possible, nivolumab infusions should be prepared in a laminar flow hood, glovebox, or 
safety cabinet using standard procedures for the safe handling of intravenous agents applying 
aseptic techniques. Gloves are required. If nivolumab solution comes in contact with the skin or 
mucosa, immediately and thoroughly wash with soap and water. 
9.2.3 
Dose Preparation and administration 
Visually inspect drug product solution for particulate matter and discoloration prior to 
administration. Nivolumab is a clear to opalescent, colorless to pale-yellow solution. Discard the 
vial if the solution is cloudy, discolored, or contains extraneous particulate matter other than a few 
translucent-to-white, proteinaceous particles. Do not shake the vial. 
Preparation 
 
Withdraw the required volume of nivolumab and transfer into an intravenous container. 


 
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 
Dilute nivolumab with either 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, 
USP to prepare an infusion with a final concentration ranging from 1 mg/mL to 10 mg/mL. 
For dilution, nivolumab injection may either be added to an empty infusion container and then 
further diluted by addition of NS or D5W, or the nivolumab injection may be added directly to 
an appropriate volume of NS or D5W in a pre-filled infusion container. 
 
Mix diluted solution by gentle inversion. Do not shake. 
 
Discard partially used vials or empty vials of nivolumab according to protocol section 9.2.4. 
Storage of Infusion 
The product does not contain a preservative. After preparation, store the nivolumab infusion 
either: 
 
at room temperature for no more than 4 hours from the time of preparation. This includes 
room temperature storage of the infusion in the IV container and time for administration of the 
infusion 
OR 
 
under refrigeration at 2°C to 8°C (36°F to 46°F) for no more than 24 hours from the time of 
infusion preparation.  
Do not freeze. 
9.2.4 
Study Drug Destruction 
Study drugs (those supplied by BMS or sourced by the site/investigator) can to be destroyed on 
site if local policies allow to do so. It is the Investigator’s responsibility to ensure that 
arrangements have been made for the disposal, procedures for proper disposal have been 
established according to applicable regulations, guidelines and institutional procedures, and 
appropriate records of the disposal have been documented. The unused study drugs can only be 
destroyed following BMS approval and after being inspected and reconciled by the responsible 
site manager (SMN). If required by local country/hospital regulations drug can be returned to an 
off-site drug destruction vendor, but should only be completed with your SMN while they are on 
site. All drug destruction whether performed on or off site should be documented using the 
Investigational Product Return Form or local form as provided by SMN. 
10.0 
CORRELATIVES/SPECIAL STUDIES  
Contribution to correlative studies by each site is recommended and encouraged by the Sponsor, 
but is optional for the participating sites. 
10.1 
Pathology correlative studies 
PD-L1 protein expression in pretreatment tumor biopsy samples will be evaluated using a 
validated automated immunohistochemistry (IHC) assay (Dako, Carpinteria, CA, USA) that uses a 
rabbit monoclonal PD-L1 antibody (clone 28-8; Epitomics Inc, Burlingame, CA, USA). We will 
assess whether PD-L1 expression is associated with the clinical outcome following administration 
of 177Lu-DOTA0-Tyr3-Octreotate and nivolumab. PD-L1 expression will be categorized as positive 


 
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if ≥ 1% of tumor cells in a section that includes ≥100 evaluable tumor cells display PD-L1. 
Different cut-off values will also be assessed retrospectively. 
Acknowledging the difficulties in obtaining fresh tumor samples in SCLC, utilization of archival 
tumor material will be allowed. Optional tumor biopsies from consenting patients will also be 
performed at the following times. 
 
Prior to treatment 
 
At the time of progression 
If sufficient material is available, in addition to PD-L1, other biomarkers in the tumor and stromal 
compartments including SSTR2, TIM-3, VISTA, FOXP3, LAG3, and IDO-1 may be analyzed. 
Expression of downstream signaling molecules of SSTR2 (e.g. AKT, MYC) may also be 
investigated. 
Each patient sample set will be assigned a unique patient identifier. The protocol scientific 
investigator(s) handling the samples will be blinded as to the patient identification, patient data 
and outcome. 
10.2 
Specimen Banking 
Patient samples collected at Georgetown University and sent from an outside institution will be 
retained in the Dr. Giaccone’s lab.  
Giuseppe Giaccone, M.D., Ph.D. 
Research Building, Room W503 
Georgetown University 
3970 Reservoir Road NW Washington DC 20007 
Specimens will be stored indefinitely or until they are used up. If future use is denied or withdrawn 
by the patient, best efforts will be made to stop any additional studies and to destroy the 
specimens. 
Dr. G. Giaccone will be responsible for reviewing and approving requests for clinical specimen 
from potential research collaborators outside of Georgetown University Medical Center. 
Collaborators will be required to complete an agreement (a Material Transfer Agreement or 
recharge agreement) that states specimens will only be released for use in disclosed research. 
The following information obtained from the subject's medical record may be provided to research 
collaborators when specimens are made available:   
 
Diagnosis  
 Collection time in relation to study treatment 
 Clinical outcome – if available 
 Demographic data 
11.0 
STATISTICAL CONSIDERATIONS 


 
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11.1 
Study Design 
This is a phase I/II clinical trial of 177Lu-DOTA0-Tyr3-Octreotate and nivolumab, in patients with 
ES-SCLC. The primary endpoint of the phase I portion is to determine the recommended phase II 
doses of 177Lu-DOTA0-Tyr3-Octreotate when given in combination with nivolumab. Patients with 
relapsed or refractory ES-SCLC and patients with advanced or inoperable grade I-II pulmonary 
NETs are also eligible for the phase I portion. For all patients participating in this phase I/II study, 
a positive SRI (Somatostatin Receptor Imaging) scan showing overexpression of SSTR2 will be 
mandatory for inclusion (NETSPOT®). The phase II portion will consist of patients with ES-
SCLC that completed standard first-line chemotherapy with a platinum-based regimen, without 
disease progression (responders plus stable disease) at the time of initiation the combination 
therapy with 177Lu-DOTA0-Tyr3-Octreotate and nivolumab. Patients will be randomly allocated in 
two arms: one will be treated with the combination of 177Lu-DOTA0-Tyr3-Octreotate and 
nivolumab, and the other arm will continue be followed (observation) after completion the 
standard chemotherapy treatment. Cross-over will be permitted at the time of disease progression.  
11.2 
Sample Size and Accrual 
ES-SCLC (i.e. SCLC that has spread beyond the supraclavicular areas or with distant metastases) 
remains incurable with current management options, and patients are treated with combination 
chemotherapy. Several chemotherapy combinations are active in SCLC, but usually a platinum-
containing regimen is chosen. The ORR of platinum-based therapy administered to patients with 
ES-SCLC ranges from 40 to 80%, and the median PFS ranges from 5 to 7 months in patient series 
treated in a clinical trial setting (phase-II/III studies) [9, 10, 48-55]. A placebo-controlled 
randomized phase II study of maintenance sunitinib shows that median PFS was 2.1 months in the 
placebo group[56]. 
Based on historic average clinical outcomes, we propose a clinical study that will be integrated by 
a dose finding approach followed by a randomized phase II study with PFS as the primary 
endpoint, designed to have 80% power for a two-sided 0.05 level test. The completion of the first 
part of the study will require approximately 8-9 months for accrual assuming 9 to 12 patients will 
be required for the completion of the phase I portion with the participation of 7 institutions 
(Georgetown Lombardi comprehensive Cancer Center, Memorial Sloan Kettering Cancer Center, 
University of California, Los Angeles, University of California, San Francisco, Vanderbilt 
University, Hackensack University Medical Center, and Walter Reed National Military Medical 
Center).  
For the phase II portion, assuming a median PFS of 2 months following completion of first-line 
therapy with a platinum-based chemotherapy for ES-SCLC in the control arm, and an expected 
median PFS of 5 months for the maintenance therapy with 177Lu-DOTA0-Tyr3-Octreotate and 
nivolumab in the experimental arm (hazard ratio 0.4), it will be required to document 40 PFS 
events from a total population of 44 patients enrolled during a period of 18 month, including a 
minimum follow up of 10 months, with an expected accrual rate of 3-4 patients per month and the 
participation of 6-7 institutions. Assuming a potential 15% dropout, the total number of patients to 
recruit will be 52 [57-59].  


 
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After the dose finding of the phase 1 portion is concluded, the phase 2 will start. The major end of 
the phase I is the safety and tolerability. Activity will not be adequately assessed in the phase I 
portion. The total number of patients required for the whole study will be 61-64 (phase I: 9-12 
patients, phase II: 52 patients).  
11.3 
Data Analyses Plans 
PFS will be defined as the time from random assignment to disease progression or death from any 
cause, whichever comes first. OS will be defined as the time from random assignment to death 
from any cause; living patients will be censored at the date of last follow-up. Survival will be 
estimated and plotted by the Kaplan–Meier method. In addition, the median progression-free and 
overall survival times will be reported along with the 95% confidence intervals. The cox 
proportional hazards regression model will be used to obtain hazard ratios (HRs) and the log-rank  
test will be utilized to compare survival estimates between the maintenance group and the control 
observation group. Secondary endpoints will be analyzed when the required number of events for 
the primary endpoint (PFS) has been met. The DCR is defined as the proportion of patients with a 
best overall response of CR, PR, or SD. The ORR is defined as the proportion of patients with a 
best overall response of CR or PR. All randomized subjects will consist of the safety population. 
This population will be used for all summaries of safety data (AEs, concomitant medications, 
laboratory data). P-values less than 0.05 will be considered significant. All statistical analyses will 
be performed using SAS (Version 9.4; SAS Institute, Cary, NC). Dr. Ming T. Tan will serve as the 
study statistician.  
12.0 
STUDY MANAGEMENT 
12.1 
Institutional Review Board (IRB) Approval and Consent 
It is expected that the IRB will have the proper representation and function in accordance with 
federally mandated regulations.  The IRB should approve the consent form and protocol. In 
obtaining and documenting informed consent, the investigator should comply with the applicable 
regulatory requirement(s), and should adhere to Good Clinical Practice (GCP) and to ethical 
principles that have their origin in the Declaration of Helsinki. 
Before recruitment and enrollment onto this study, the patient will be given a full explanation of 
the study and will be given the opportunity to review the consent form. Each consent form must 
include all the relevant elements currently required by the FDA Regulations and local or state 
regulations. Once this essential information has been provided to the patient and the investigator is 
assured that the patient understands the implications of participating in the study, the patient will 
be asked to give consent to participate in the study by signing an IRB-approved consent form. 
Prior to a patient’s participation in the trial, the written informed consent form should be signed 
and personally dated by the patient and by the person who conducted the informed consent 
discussion. 


 
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12.2 
Required Documentation 
Before the study can be initiated at any site, the following documentation must be provided to the 
Research office. 
 
A copy of the official IRB approval letter for the protocol and informed consent 
 
IRB membership list 
 
CVs and medical licensure for the principal investigator and any associate investigators who 
will be involved in the study 
 
Form FDA 1572 appropriately filled out and signed with appropriate documentation (NOTE: 
this is required if UNC holds the IND.  Otherwise, the affiliate Investigator’s signature on the 
protocol is sufficient to ensure compliance) 
 
A copy of the IRB-approved consent form 
 
CAP and CLIA Laboratory certification numbers and institution lab normal values 
 
Executed clinical research contract 
12.3 
Registration Procedures  
 The study site coordinator or physician is responsible to screen potential subjects using the 
eligibility criteria, obtain informed consent and HIPAA authorization forms from each consenting 
subject, and to provide the Eligibility Packet (defined below) to the Quality Assurance Office 
(QAO) for review. The QAO is responsible to verify eligibility of all subjects screened to 
investigator initiated or multi-site clinical research trials, to assign subject IDs to each eligible 
patient, and to inform the study site of the assigned subject ID or any eligibility issues within one 
business day.  
 
Subjects may not begin treatment until eligibility is confirmed and subject ID is assigned by 
QAO.  
 
Procedures: 
1. Patient signs Informed Consent Form (ICF) and HIPAA authorization form.  
 
ICF is administered by site coordinator or treating physician.  
2. Site screens subject for eligibility criteria  
 
Site coordinator or treating physician completes eligibility checklist  
 
If patient does not meet eligibility criteria, stop and report screen failure.  
3. Site faxes the eligibility packet to QAO at 202-687-9361 or emails the packet to 
LCCCQAO@georgetown.edu  
 
Eligibility Packet to include:  
o Completed QAO Registration Form  
o Signed and dated Eligibility Checklist, completely filled out  
o Signed and dated ICF  
o Signed and dated HIPAA authorization form  
o All source documents required for verification of eligibility 
4. QAO verifies eligibility using Eligibility Packet  


 
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 
If eligibility is not verified, stop and inform site of eligibility issues or questions  
5. If eligibility is verified, QAO does the following:  
 
Assigns Subject ID  
 
Registers the patient in the study and in the CTMS  
 
Emails the Subject ID to the study site within one business day of receiving the Eligibility 
Packet  
12.4 
Data Management and Monitoring/Auditing 
The Georgetown Lombardi Comprehensive Cancer Center (LCCC) will be responsible for the data 
and safety monitoring of this trial. As this study is an investigator initiated Phase I/II study it is 
considered a high risk study which requires real-time monitoring by the PI and study team and 
quarterly reviews by the LCCC Data and Safety Monitoring Committee (DSMC). 
 
 
The Study Chairs and Associate Investigators will review the data including safety monitoring at 
their monthly teleconferences of participating sites.  
 
All “reportable” (defined above) Severe Adverse Events (SAEs) are required to be reported to the 
local and to the Georgetown IRB, as detailed above, and to the chair of the DSMC. Based on SAEs, 
the IRB retains the authority to suspend further accrual pending more detailed reporting and/or 
modifications to further reduce risk and maximize the safety of participating patients. 
 
Progress on the trial and the toxicities experienced will be reviewed by the LCCC Data and Safety 
Monitoring Committee every three months from the time the first patient is enrolled on the study. 
Results of the DSMC meetings will be forwarded to the IRB with recommendations regarding need 
for study closure. 
 
DSMC recommendations should be based not only on results for the trial being monitored as well 
as on data available to the DSMC from other studies. It is the responsibility of the Study Chair to 
ensure that the DSMC is kept apprised of non-confidential results from related studies that become 
available. It is the responsibility of the DSMC to determine the extent to which this information is 
relevant to its decisions related to the specific trial being monitored. 
 
A written copy of the DSMC recommendations will be given to the trial Study Chair and the IRB. 
If the DSMC recommends a study change for patient safety or efficacy reasons the Study Chair must 
act to implement the change as expeditiously as possible. In the unlikely event that the Study Chair 
does not concur with the DSMC recommendations, then the LCCC Associate Director of Clinical 
Research must be informed of the reason for the disagreement. The Study Chair, DSMC Chair, and 
the LCCC AD for Clinical Research will be responsible for reaching a mutually acceptable decision 
about the study and providing details of that decision to the IRB. Confidentiality must be preserved 
during these discussions. However, in some cases, relevant data may be shared with other selected 
trial investigators and staff to seek advice to assist in reaching a mutually acceptable decision. 
 
If a recommendation is made to change a trial for reasons other than patient safety or efficacy the 
DSMC will provide an adequate rationale for its decision. If the DSMC recommends that the trial 
be closed for any reason, the recommendation will be reviewed by the Associate Director for Clinical 
Research at GU-LCCC. Authority to close a trial for safety reasons lies with the IRB, with the above 
described input from DSMC and the AD for Clinical Research.  
 


 
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Of note, the DSMC will also review the safety data of the patients enrolled outside of Georgetown 
University. The multi-institutional coordinator will be tasked with the job of collecting all primary 
source documentation for patients enrolled outside of Georgetown University. In addition, the data 
managers at each site will be entering data into the Georgetown database, so that all data will be 
available for the DSMC at Georgetown to review. Faxed records should be sent to Gabriela Gomez 
with an email to the multi-institutional coordinator and Dr. Giaccone to confirm receipt of those 
records. 
12.5 
Adherence to the Protocol 
Except for an emergency situation in which proper care for the protection, safety, and well-being 
of the study patient requires alternative treatment, the study shall be conducted exactly as 
described in the approved protocol.   
12.5.1 Emergency Modifications 
Investigators may implement a deviation from, or a change of, the protocol to eliminate an 
immediate hazard(s) to trial subjects without prior IRB approval. For any such emergency 
modification implemented, an IRB modification form must be completed within five (5) business 
days of making the change.   
12.5.2 Single Patient/Subject Exceptions 
Any request to enroll a single subject who does not meet all the eligibility criteria of this study 
requires the approval of the Principal Investigator and the IRB.  
12.5.3 Other Protocol Deviations/Violations 
All other planned deviations from the protocol must have prior approval by the Principal 
Investigator and the IRB. According to the IRB, a protocol deviation is any unplanned variance 
from an IRB approved protocol that:  
 
Is generally noted or recognized after it occurs. 
 Has no substantive effect on the risks to research participants. 
 
Has no substantive effect on the scientific integrity of the research plan or the value of the data 
collected.  
 Did not result from willful or knowing misconduct on the part of the investigator(s). 
An unplanned protocol variance is considered a violation if the variance: 
 
Has harmed or increased the risk of harm to one or more research participants. 
 
Has damaged the scientific integrity of the data collected for the study. 
 
Results from willful or knowing misconduct on the part of the investigator(s). 
 Demonstrates serious or continuing noncompliance with federal regulations, State laws, or 
University policies. 
If a deviation or violation occurs without prior approval from the Principal Investigator, please 
follow the guidelines below: 


 
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Protocol Deviations: Personnel will report to any sponsor or data and safety monitoring 
committee in accordance with their policies.  Deviations should be summarized and reported to the 
IRB at the time of continuing review. 
Protocol Violations: Violations should be reported by study personnel within one (1) week of the 
investigator becoming aware of the event using the same IRB online mechanism used to report 
Unanticipated Problems.   
12.6 
Amendments to the Protocol 
Should amendments to the protocol be required, the amendments will be originated and 
documented by the Principal Investigator.  It should also be noted that when an amendment to the 
protocol substantially alters the study design or the potential risk to the patient, a revised consent 
form might be required. The written amendment, and if required the amended consent form, must 
be sent to the IRB for approval prior to implementation.   
12.7 
Record Retention 
Study documentation includes all Case Report Forms, data correction forms or queries, source 
documents, Sponsor-Investigator correspondence, monitoring logs/letters, and regulatory 
documents (e.g., protocol and amendments, IRB correspondence and approval, signed patient 
consent forms). Source documents include all recordings of observations or notations of clinical 
activities and all reports and records necessary for the evaluation and reconstruction of the clinical 
research study. Government agency regulations and directives require that all study documentation 
pertaining to the conduct of a clinical trial must be retained by the study investigator. In the case of 
a study with a drug seeking regulatory approval and marketing, these documents shall be retained 
for at least two years after the last approval of marketing application in an International 
Conference on Harmonization (ICH) region.  In all other cases, study documents should be kept on 
file until three years after the completion and final study report of this investigational study. 
12.8 
Obligations of Investigators 
The Principal Investigator is responsible for the conduct of the clinical trial at the site in 
accordance with Title 21 of the Code of Federal Regulations and/or the Declaration of Helsinki.  
The Principal Investigator is responsible for personally overseeing the treatment of all study 
patients.  The Principal Investigator must assure that all study site personnel, including sub-
investigators and other study staff members, adhere to the study protocol and all FDA/GCP/NCI 
regulations and guidelines regarding clinical trials both during and after study completion. The 
Principal Investigator at each institution or site will be responsible for assuring that all the required 
data will be collected and entered onto the Case Report Forms. Periodically, monitoring visits will 
be conducted and the Principal Investigator will provide access to his/her original records to 
permit verification of proper entry of data. At the completion of the study, all case report forms 
will be reviewed by the Principal Investigator and will require his/her final signature to verify the 
accuracy of the data. 
 
 
 


 
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Safety Notifications. 2017  [cited 2017 February 27]; Available from: 
http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm279174. 
18. 
Wang, C., et al., In vitro characterization of the anti-PD-1 antibody nivolumab, 
BMS-936558, and in vivo toxicology in non-human primates. Cancer Immunol 
Res, 2014. 2(9): p. 846-56. 
19. 
Antonia, S.J., et al., Nivolumab alone and nivolumab plus ipilimumab in recurrent 
small-cell lung cancer (CheckMate 032): a multicentre, open-label, phase 1/2 
trial. Lancet Oncol, 2016. 17(7): p. 883-95. 
20. 
Komiya, T. and R. Madan, PD-L1 expression in small cell lung cancer. Eur J 
Cancer, 2015. 51(13): p. 1853-5. 
21. 
Modlin, I.M., et al., Gastroenteropancreatic neuroendocrine tumours. Lancet 
Oncol, 2008. 9(1): p. 61-72. 
22. 
Kwekkeboom, D.J., et al., Radiolabeled somatostatin analog [177Lu-
DOTA0,Tyr3]octreotate in patients with endocrine gastroenteropancreatic tumors. 
J Clin Oncol, 2005. 23(12): p. 2754-62. 
23. 
Geijer, H. and L.H. Breimer, Somatostatin receptor PET/CT in neuroendocrine 
tumours: update on systematic review and meta-analysis. Eur J Nucl Med Mol 
Imaging, 2013. 40(11): p. 1770-80. 
24. 
Bodei, L., et al., The joint IAEA, EANM, and SNMMI practical guidance on 
peptide receptor radionuclide therapy (PRRNT) in neuroendocrine tumours. Eur J 
Nucl Med Mol Imaging, 2013. 40(5): p. 800-16. 
25. 
Kwekkeboom, D.J., et al., [177Lu-DOTAOTyr3]octreotate: comparison with 
[111In-DTPAo]octreotide in patients. Eur J Nucl Med, 2001. 28(9): p. 1319-25. 
26. 
Barone, R., et al., Therapy using labelled somatostatin analogues: comparison of 
the absorbed doses with 111In-DTPA-D-Phe1-octreotide and yttrium-labelled 
DOTA-D-Phe1-Tyr3-octreotide. Nucl Med Commun, 2008. 29(3): p. 283-90. 
27. 
Kwekkeboom, D.J., et al., Treatment with the radiolabeled somatostatin analog 
[177 Lu-DOTA 0,Tyr3]octreotate: toxicity, efficacy, and survival. J Clin Oncol, 
2008. 26(13): p. 2124-30. 


 
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28. 
Strosberg, J., et al., Phase 3 Trial of 177Lu-Dotatate for Midgut Neuroendocrine 
Tumors. N Engl J Med, 2017. 376(2): p. 125-135. 
29. 
Sabet, A., et al., First data on efficacy of PRRT in bronchial NET: Experience from 
a dual-centre analysis. J NUCL MED MEETING ABSTRACTS, 2014. 
55(1_MeetingAbstracts): p. 394-. 
30. 
van Essen, M., et al., Peptide receptor radionuclide therapy with 177Lu-octreotate 
in patients with foregut carcinoid tumours of bronchial, gastric and thymic origin. 
Eur J Nucl Med Mol Imaging, 2007. 34(8): p. 1219-27. 
31. 
Ianniello, A., et al., Peptide receptor radionuclide therapy with (177)Lu-
DOTATATE in advanced bronchial carcinoids: prognostic role of thyroid 
transcription factor 1 and (18)F-FDG PET. Eur J Nucl Med Mol Imaging, 2016. 
43(6): p. 1040-6. 
32. 
Mariniello, A., et al., Long-term results of PRRT in advanced bronchopulmonary 
carcinoid. Eur J Nucl Med Mol Imaging, 2016. 43(3): p. 441-52. 
33. 
Khan, S., et al., Quality of life in 265 patients with gastroenteropancreatic or 
bronchial neuroendocrine tumors treated with [177Lu-DOTA0,Tyr3]octreotate. J 
Nucl Med, 2011. 52(9): p. 1361-8. 
34. 
Kwekkeboom, D.J., et al., The value of octreotide scintigraphy in patients with 
lung cancer. Eur J Nucl Med, 1994. 21(10): p. 1106-13. 
35. 
Reubi, J.C., et al., Somatostatin receptors are present in small-cell but not in non-
small-cell primary lung carcinomas: relationship to EGF-receptors. Int J Cancer, 
1990. 45(2): p. 269-74. 
36. 
Fujita, T., et al., Gene expression of somatostatin receptor subtypes, SSTR1 and 
SSTR2, in human lung cancer cell lines. Life Sci, 1994. 55(23): p. 1797-806. 
37. 
Lewin, J., et al., Peptide receptor chemoradionuclide therapy in small cell 
carcinoma: from bench to bedside. Eur J Nucl Med Mol Imaging, 2015. 42(1): p. 
25-32. 
38. 
Sollini, M., et al., Brief report on the use of radiolabeled somatostatin analogs for 
the diagnosis and treatment of metastatic small-cell lung cancer patients. J Thorac 
Oncol, 2013. 8(8): p. 1095-101. 
39. 
van Essen, M., et al., Effects of therapy with [177Lu-DOTA0, Tyr3]octreotate in 
patients with paraganglioma, meningioma, small cell lung carcinoma, and 
melanoma. J Nucl Med, 2006. 47(10): p. 1599-606. 
40. 
Formenti, S.C. and S. Demaria, Combining radiotherapy and cancer 
immunotherapy: a paradigm shift. J Natl Cancer Inst, 2013. 105(4): p. 256-65. 
41. 
Le, Q.T., et al., Emerging Treatment Paradigms in Radiation Oncology. Clin 
Cancer Res, 2015. 21(15): p. 3393-401. 
42. 
Sharma, A., et al., Radiotherapy of human sarcoma promotes an intratumoral 
immune effector signature. Clin Cancer Res, 2013. 19(17): p. 4843-53. 


 
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43. 
Golden, E.B., et al., An abscopal response to radiation and ipilimumab in a patient 
with metastatic non-small cell lung cancer. Cancer Immunol Res, 2013. 1(6): p. 
365-72. 
44. 
Zeng, J., et al., Anti-PD-1 blockade and stereotactic radiation produce long-term 
survival in mice with intracranial gliomas. Int J Radiat Oncol Biol Phys, 2013. 
86(2): p. 343-9. 
45. 
Dovedi, S.J., et al., Acquired resistance to fractionated radiotherapy can be 
overcome by concurrent PD-L1 blockade. Cancer Res, 2014. 74(19): p. 5458-68. 
46. 
Valkema, R., et al., Long-term follow-up of renal function after peptide receptor 
radiation therapy with (90)Y-DOTA(0),Tyr(3)-octreotide and (177)Lu-DOTA(0), 
Tyr(3)-octreotate. J Nucl Med, 2005. 46 Suppl 1: p. 83S-91S. 
47. 
Eisenhauer, E.A., et al., New response evaluation criteria in solid tumours: revised 
RECIST guideline (version 1.1). Eur J Cancer, 2009. 45(2): p. 228-47. 
48. 
Noda, K., et al., Irinotecan plus cisplatin compared with etoposide plus cisplatin 
for extensive small-cell lung cancer. N Engl J Med, 2002. 346(2): p. 85-91. 
49. 
Kim, S.J., et al., A multicenter phase II study of belotecan, new camptothecin 
analogue, in patients with previously untreated extensive stage disease small cell 
lung cancer. Lung Cancer, 2010. 68(3): p. 446-9. 
50. 
Hong, J., et al., Phase II study of combined belotecan and cisplatin as first-line 
chemotherapy in patients with extensive disease of small cell lung cancer. Cancer 
Chemother Pharmacol, 2012. 69(1): p. 215-20. 
51. 
Lim, S., et al., Phase II study of camtobell inj. (belotecan) in combination with 
cisplatin in patients with previously untreated, extensive stage small cell lung 
cancer. Lung Cancer, 2013. 80(3): p. 313-8. 
52. 
Ohe, Y., et al., Phase I-II study of amrubicin and cisplatin in previously untreated 
patients with extensive-stage small-cell lung cancer. Ann Oncol, 2005. 16(3): p. 
430-6. 
53. 
Yana, T., et al., Phase II study of amrubicin in previously untreated patients with 
extensive-disease small cell lung cancer: West Japan Thoracic Oncology Group 
(WJTOG) study. Invest New Drugs, 2007. 25(3): p. 253-8. 
54. 
Kobayashi, M., et al., Phase II study of sequential triplet chemotherapy, irinotecan 
and cisplatin followed by amrubicin, in patients with extensive-stage small cell 
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55. 
O’Brien, M.E., et al., Randomised phase II study of amrubicin as single agent or in 
combination with cisplatin versus cisplatin etoposide as first-line treatment in 
patients with extensive stage small cell lung cancer–EORTC 08062. European 
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57. 
Hunsberger, S., Y. Zhao, and R. Simon, A comparison of phase II study strategies. 
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Rubinstein, L.V., et al., Design issues of randomized phase II trials and a proposal 
for phase II screening trials. Journal of Clinical Oncology, 2005. 23(28): p. 7199-
7206. 


 
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Appendix A. GUIDANCE ON CONTRACEPTION 
ACCEPTABLE METHODS FOR PROTOCOLS WITH A TERATOGENIC DRUG OR WHEN 
THERE IS INSUFFICIENT INFORMATION TO DETERMINE TERATOGENICITY 
(CHOOSE ONE OF THE FOLLOWING 3 OPTIONS)a 
 
OPTION 1: Any TWO of the following methods 
o 
Hormonal methods of contraceptionb, c, d 
o 
IUDc, d, e 
o 
Vasectomyd, f 
o 
Tubal Ligationd 
o 
A Barrier method (Female or Male Condom with spermicide, Cervical Cap with 
spermicide, Diaphragm with spermicide) 
 
OPTION 2: Male condom (with spermicide) and diaphragmg 
 
OPTION 3: Male condom (with spermicide) and cervical capg 
a The theoretical failure rate for any of the options listed is considerably less than 1% per year 
b Excludes progestin-only pills 
c Hormonal contraceptives may not be used for contraception unless a drug-drug interaction study 
has demonstrated that the pharmacokinetics of the hormone based contraceptive has not been 
adversely affected by the investigational drug in the protocol or there is compelling evidence to 
substantiate that investigational product(s) or con-meds will not adversely affect contraception 
effectiveness. The use of hormone based contraceptives is not otherwise restricted. 
d A highly effective method of birth control with a failure rate less than 1% per year. 
e IUDS used should have a failure rate less than 1% (highly effective method), such as Mirena 
and ParaGard. 
f Must be at least 90 days from date of surgery with a semen analysis documenting azoospermia. 
g These 2 barrier methods together are acceptable for a teratogenic drug. 
 
UNACCEPTABLE METHODS OF CONTRACEPTION 


 
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 
No method 
 
Withdrawal 
 
Rhythm 
 
Vaginal Sponge 
 
Any barrier method without spermicide 
 
Spermicide 
 
Progestin only pills 
 
Concomitant use of female and male condom 


 
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Appendix B.  Immune-related toxicity management algorithms. 
These general guidelines constitute guidance to the Investigator and may be supplemented by 
discussions with the Medical Monitor representing the Sponsor. The guidance applies to all 
immuno-oncology agents and regimens. 
 
A general principle is that differential diagnoses should be diligently evaluated according to 
standard medical practice. Non-inflammatory etiologies should be considered and appropriately 
treated. 
 
Corticosteroids are a primary therapy for immuno-oncology drug-related adverse events. The oral 
equivalent of the recommended IV doses may be considered for ambulatory patients with low-
grade toxicity. The lower bioavailability of oral corticosteroids should be taken into account when 
switching to the equivalent dose of oral corticosteroids. 
 
Consultation with a medical or surgical specialist, especially prior to an invasive diagnostic or 
therapeutic procedure, is recommended. 
 
The frequency and severity of the related adverse events covered by these algorithms will depend 
on the immuno-oncology agent or regimen being used. 
 


 
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Appendix C. ECOG Performance Status Score  


 
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ASSESSMENT/EVENT 
Screening 
Treatment Period* 
  
  
Study Visit 
C1 
C1 
C1 
C1 
C2 and 
beyond 
C2 and 
beyond 
C2 and 
beyond 
C2 and 
beyond 
EOT 
Follow-
up 
  
  
D1 
D15 
D29 
D43 
D1 
D15 
D29 
D43 
  
  
Informed consent  
X 
  
  
  
  
  
  
  
  
  
  
ECOG PS 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
History and physical examination  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
Adverse event assessments 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
Height and weight 
X 
  
  
  
  
  
  
  
  
  
  
Concomitant Medications 
Collection 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
12 Lead ECG 
X 
  
  
  
  
  
  
  
  
  
  
Tumor imaginga 
X 
  
  
  
  
X 
  
  
  
  
  
Brain imaging (MRI or CT) 
X 
To be performed as clinically indicated at the discretion of the investigator  
  
FDG-PET 
X 
To be performed as clinically indicated at the discretion of the investigator 
 
NETSPOT PETb 
X 
  
  
  
  
Xc 
  
  
  
  
  
CBC with differential 
X 
Xj 
X 
X 
X 
X 
X 
X 
X 
X 
  
PT/aPTT 
X 
  
  
  
  
  
  
  
  
  
  
Comprehensive Metabolic Panel 
X 
Xj 
X 
X 
X 
X 
X 
X 
X 
X 
  
Thyroid function testd 
X 
  
  
X 
  
X 
  
X 
  
X 
  
LDH 
X 
Xj 
X 
X 
X 
X 
X 
X 
X 
X 
  
Magnesium 
X 
Xj 
X 
X 
X 
X 
X 
X 
X 
X 
  
Phosphorus 
X 
Xj 
X 
X 
X 
X 
X 
X 
X 
X 
  
Amylase 
X 
  
  
  
  
  
  
  
  
  
  
Lipase 
X 
  
  
  
  
  
  
  
  
  
  
HBsAge 
X 
  
  
  
  
  
  
  
  
  
  
anti-HCVe 
X 
  
  
  
  
  
  
  
  
  
  
anti-HIVe 
X 
  
  
  
  
  
  
  
  
  
  
Pregnancy testf 
X 
  
Xf 
  
  
  
Xf 
  
  
  
  
Tumor biopsy 
Xg 
Optional at the time of progression 
  
Nivolumabh 
  
X 
X 
X 
X 
X 
X 
X 
X 
  
  
177Lu-DOTA0-Tyr3-Octreotate 
  
  
X 
  
  
  
Xh 
  
  
  
  
Long-term follow up including 
survival 
  
  
  
  
  
  
  
  
  
  
XI 
  


 
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Appendix D. Study Calendar
a: Initial tumor assessment will be performed at C2 D1 (± 7 days) and every 8 weeks (± 7 days) thereafter. 
b: Refer to section 6.1 for details 
c: On treatment Netspot only on cycle 2 day 1 (± 3 days) 
d: Thyroid function testing will be done every cycle on day 1 (± 3 days) and day 29 (± 3 days). Does not need to repeat on C1D1. 
e: Within three months prior to starting study treatment 
f: Only for women of child bearing potential (WOCBP). Within 24 hours prior to the administration of 177Lu-DOTA0-Tyr3-Octreotate.  
g: Optional. Utilization of archival tissue will be allowed. 
h: May be given one day earlier or delayed up to 1 week. 177Lu-DOTA0-Tyr3-Octreotate will only be given for 4 cycles. 
i: Annually for two years 
j: C1D1 laboratory tests do not need to be repeated if the screening laboratory tests were done within 7 days from C1D1. 
* Refer to section 6.2 for details about time windows within which each procedure should be performed. 
 


 
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Appendix E. Mandatory Adverse Event Reporting Information for Nivolumab 
 
All Serious Adverse Events (SAEs) that occur following the subject’s written consent to 
participate in the study through 30 days of discontinuation of dosing must be reported to 
BMS Worldwide Safety. 
 
If the BMS safety address is not included in the protocol document (e.g. multicenter studies 
where events are reported centrally), the procedure for safety reporting must be 
reviewed/approved by the BMS Protocol Manager.  Procedures for such reporting must be 
reviewed and approved by BMS prior to study activation. 
 
The BMS SAE form should be used to report SAEs. If the BMS form cannot be used, another 
acceptable form (i.e CIOMS or Medwatch) must be reviewed and approved by BMS.  The 
BMS protocol ID number must be included on whatever form is submitted by the 
Sponsor/Investigator. 
 
Following the subject’s written consent to participate in the study, all SAEs, whether related 
or not related to study drug, are collected, including those thought to be associated with 
protocol-specified procedures. The investigator should report any SAE occurring after these 
time periods that is believed to be related to study drug or protocol-specified procedure. 
 
In accordance with local regulations, BMS will notify investigators of all reported SAEs that 
are suspected (related to the investigational product) and unexpected (i.e., not previously 
described in the IB). In the European Union (EU), an event meeting these criteria is termed a 
Suspected, Unexpected Serious Adverse Reaction (SUSAR). Investigator notification of these 
events will be in the form of an expedited safety report (ESR).  
 
Other important findings which may be reported by the as an ESR include: increased 
frequency of a clinically significant expected SAE, an SAE considered associated with study 
procedures that could modify the conduct of the study, lack of efficacy that poses significant 
hazard to study subjects, clinically significant safety finding from a nonclinical (eg, animal) 
study, important safety recommendations from a study data monitoring committee, or sponsor 
decision to end or temporarily halt a clinical study for safety reasons. 
 
Upon receiving an ESR from BMS, the investigator must review and retain the ESR with the 
IB. Where required by local regulations or when there is a central IRB/IEC for the study, the 


 
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sponsor will submit the ESR to the appropriate IRB/IEC. The investigator and IRB/IEC will 
determine if the informed consent requires revision. The investigator should also comply with 
the IRB/IEC procedures for reporting any other safety information.  
 
In addition, suspected serious adverse reactions (whether expected or unexpected) shall be 
reported by BMS to the relevant competent health authorities in all concerned countries 
according to local regulations (either as expedited and/or in aggregate reports). 
 
If the investigator believes that an SAE is not related to study drug, but is potentially related 
to the conditions of the study (such as withdrawal of previous therapy or a complication of a 
study procedure), the relationship should be specified in the narrative section of the SAE 
Report Form. 
 
If only limited information is initially available, follow-up reports are required. (Note: 
Follow-up SAE reports should include the same investigator term(s) initially reported.) 
 
If an ongoing SAE changes in its intensity or relationship to study drug or if new information 
becomes available, a follow-up SAE report should be sent within 24 hours to BMS using the 
same procedure used for transmitting the initial SAE report. All SAEs should be followed to 
resolution or stabilization.  All SAEs should be followed to resolution or stabilization. 
 
SAEs, whether related or not related to study drug, and pregnancies must be reported to BMS 
within 24 hours. SAEs must be recorded on BMS or an approved form; pregnancies on a 
Pregnancy Surveillance Form.  
SAE Email Address:  Worldwide.Safety@BMS.com 
SAE Facsimile Number:  609-818-3804 
SAEs should be reported on MedWatch Form 3500A, which can be accessed at: 
http://www.accessdata.fda.gov/scripts/medwatch/ 
MedWatch SAE forms should be sent to the FDA at: 
MEDWATCH 
5600 Fishers Lane 
Rockville, MD 20852-9787 


 
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Fax: 1-800-FDA-0178 (1-800-332-0178) 
http://www.accessdata.fda.gov/scripts/medwatch/ 
A nonserious adverse event is an AE not classified as serious.  
Nonserious Adverse Event Collection and Reporting 
The collection of nonserious AE information should begin at initiation of study drug. All 
nonserious adverse events (not only those deemed to be treatment-related) should be collected 
continuously during the treatment period and for a minimum of 100 days following the last dose 
of study treatment. Nonserious AEs should be followed to resolution or stabilization, or reported 
as SAEs if they become serious. Follow-up is also required for nonserious AEs that cause 
interruption or discontinuation of study drug and for those present at the end of study treatment as 
appropriate.  
Laboratory Test Abnormalities 
All laboratory test results captured as part of the study should be recorded following institutional 
procedures. Test results that constitute SAEs should be documented and reported as such. The 
following laboratory abnormalities should be documented and reported appropriately: 
 
Any laboratory test result that is clinically significant or meets the definition of an SAE 
 
Any laboratory abnormality that required the subject to have study drug discontinued or 
interrupted 
 
Any laboratory abnormality that required the subject to receive specific corrective therapy.  
Pregnancy 
If, following initiation of the investigational product, it is subsequently discovered that a study 
subject is pregnant or may have been pregnant at the time of investigational product exposure, 
including during at least 6 half lives after product administration, the investigational product will 
be permanently discontinued in an appropriate manner (e.g. dose tapering if necessary for subject 
safety). The investigator must immediately notify Worldwide Safety @BMS of this event via the 
Pregnancy Surveillance Form in accordance with SAE reporting procedures. Follow-up 
information regarding the course of the pregnancy, including perinatal and neonatal outcome and, 
where applicable, offspring information must be reported on the Pregnancy Surveillance Form 


 
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[provided upon request from BMS]. Any pregnancy that occurs in a female partner of a male 
study participant should be reported to BMS. Information on this pregnancy will be collected on 
the Pregnancy Surveillance Form. 
Overdose 
An overdose is defined as the accidental or intentional administration of any dose of a product 
that is considered both excessive and medically important. All occurrences of overdose must be 
reported as an SAE. 
Other Safety Considerations 
Any significant worsening noted during interim or final physical examinations, 
electrocardiograms, x-rays, and any other potential safety assessments, whether or not these 
procedures are required by the protocol, should also be recorded as a nonserious or serious AE, as 
appropriate, and reported accordingly. 


 
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Appendix F. Recommended Precautions for Patients Treated with 177Lu-DOTA0-Tyr3-
Octreotate (Lutathera) 
In accordance with the medical staff, you have agreed to receive a treatment using a radioactive 
medicine. We think that the potential activity of this medicine in treating your tumor is due to the 
radioactivity of this medicine; it is also for this reason that it is necessary to follow certain 
precautions in order to limit the exposure of the people around you and to avoid contaminating 
them with radioactivity. 
Because of knowledge and experience in the field, it is estimated that the health risks to your 
family members and the general public are low because of the physical and radiopharmaceutical 
properties and the metabolism of the radiopharmaceutical. You must adhere to the following rules 
to maximize the safety of other persons. They are the result of many years of experience in the 
use of radioactivity in medicine, and they include recommendations by international 
organizations. 
1. General rule 
You must avoid close contact with people who live with you, and should try to keep a distance of 
at least one meter for 7-days after you receive Lutathera. 
2. Use of toilets 
Toilets must be used in a seated position, even for men. It is absolutely necessary to use toilet 
paper each time. It is equally important to wash your hands to avoid contaminating the door 
handles. It is strongly recommended to move your bowels every day and use a laxative if you 
need help. Furthermore, empty your bladder (urinate) frequently, every hour for example, on the 
day you received treatment and for two days after. Follow your doctor’s advice on how much 
fluid to drink. After expelling fluids, drink a glass of water. You can substitute juice or a sports 
drink as a means to replace expelled fluids. Follow any additional advice that your doctor 
provides on how much to drink. 
3. Contact with children (less than 10 years old) 
Because of the high sensitivity of children to radioactivity, it is strongly advised to limit contact 
to them to less than 15 minutes for each day while keeping a distance of at least 1-2 meters. It is 
strongly recommended that there be no contact with children who are less than 10 years old for 7-
days after the administration of Lutathera. 
4. The spouse and people in the family circle 


 
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It is strongly advised to sleep in separate beds at a distance of at least 1 meter. Embraces and 
sexual activity are not advised for eight days after the administration of Lutathera. 
5. Seniors 
Older people are less sensitive to radioactivity (between 3 and 10 times less than a middle-aged 
person). Therefore, the previous recommendations can be followed with a little more flexibility in 
the presence of the elderly.  
6. Contact with pregnant women 
Contact with pregnant women should follow the same restrictions recommended for children less 
than 10 years old. 
7. Breastfeeding 
Breastfeeding should be stopped because it is not compatible with a treatment using a radioactive 
product. 
8. Pregnancy 
Pregnancy must be excluded before the start of treatment. Any woman who has missed a period 
must be assumed to be pregnant until proven otherwise and alternative therapies which do not 
involve ionizing radiation must be then considered. 
There is a potential risk that ionizing radiation by Lutathera could cause toxic effects on female 
and male gonads. Due to the nature of the compound, women of child-bearing potential, as well 
as males, must abstain from procreation (using effective contraceptive measures) during and up to 
6 months after treatment with Lutathera. 
9. People who need extra assistance 
People who are confined to the bed or have reduced mobility will preferably receive assistance by 
a care provider. It is recommended that when providing assistance in the bathroom, the care 
provider wear disposable gloves for 2-3 days after administration. In the case of the use of special 
medical equipment such as catheters, colostomy bags bedpan, water nozzle, or anything that 
could be contaminated by your body fluids they must be emptied immediately in the toilet and 
then cleaned. If anyone helps you clean up vomit, blood, urine, or stool they should wear plastic 
gloves; the gloves should then be put in the specified trash plastic bag. 
10. Dishes and bathroom accessories 
For the first two days after your treatment wipes and/or toilet paper must be flushed down the 
toilet. Always wash your hands well after using the toilet. It is strongly recommended to shower 


 
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every day for at least the first 7 days after your treatment. Try to flush any tissues or any other 
items that contain anything from your body, such as blood, urine and faeces down the toilet (at 
least for two days after the therapy). Items that cannot be flushed, such as menstrual pads and 
bandages, must be placed in specified plastic trash bags. 
Wash your underwear, pajamas, sheets and any clothes that contain sweat, blood or urine 
separately from the laundry of others in your household. Wash your items two or three times; use 
a standard washing machine; you do not need to use bleach and do not need extra rinses. 
11. Trash recommendations 
Keep the specified plastic trash bags separate from other trash; keep the bags away from children 
and animals. A member of the Study Staff will tell you how and when to get rid of the specified 
plastic trash bag; you may be asked to bring the bag back to your treatment facility, or, after 70 
days, the bag may be removed as other trash bags.  
12. Professional activities 
Lutathera could affect your ability to drive and to use machines, as dizziness has been reported as 
a common side effect. If there is a risk of frequent contact and being in close vicinity to the public 
and/or with children, the activity must be temporarily suspended. 
13. Use of public transportation 
For short trips (less than 30 minutes), the precautions are minimum. If you ride with someone 
else, confirm she is not pregnant, and maintain a distance of >1 meter (use the back seat on 
opposite side of the driver). If you are able to do so, it is best to drive yourself. 
14. Public activities 
Avoid assisting in shows or public meetings which could expose third-parties for more than 30 
minutes in the first week after your treatment. 
Ask Your Doctor or a member of the Study Staff when: 
- It will be safe to eat out, go shopping and attend events such as religious services, parties and 
movies; 
- You will be able to return to work and to care for or teach others; 
- It would be safe to donate blood; 
- Special or longer distance travel is possible (Note: For up to 3 months or more following 
radioactive treatment you may set off radiation detectors at: national borders, airports, bus and 


 
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train stations, tunnels, bridges, trash collection sites and even your place of employment); a 
member of your Study Staff will issue you a letter or card describing the therapy and the phone 
number of a person knowledgeable about your treatment (usually at the treating facility) in case 
local law enforcement agents need to check on this information; you should keep the letter or card 
containing the information with you whenever you are travelling for at least 3 months. 
15. Hospitalization 
In the case that an unplanned hospitalization occurs, it is important to notify your doctor. There is 
a possibility that due to an excessive release of hormones following the administration of 177Lu-
DOTA0-Tyr3-Octreotate your doctor may request that you stay in hospital overnight for 
observation and treatment if necessary, normally consists of intravenous fluids, corticosteroids 
and the correction of any chemical imbalance in the blood. 
16. Domesticated animals 
The lifespan of domesticated animals is much less than that of humans. Therefore, the effect of 
the radioactivity is less. It is not necessary to take any particular precautions. But do not sleep 
with pets (ask your doctor for how long) since your secretions may be carried away by the pet. 
17. Emergency Care  
You will get an information card or letter at the time of your treatment that will show the date, 
type and amount of radioactivity that you were treated with; carry this card with you at all times 
for at least 3 months following your treatment. 
If you are in a traffic accident or any other medical emergency and require medical assistance 
during the first week after your treatment, you should show this card to the medical providers to 
let them know about the date and dose of your radioactive treatment. 
18. Important information for patients on risks of radiation 
Radiation exposure to others should always be As Low As Reasonably Achievable, a goal often 
abbreviated as ALARA. If you follow the above advice, the radiation from you to others is likely 
to be less than what they receive from radiation in nature over a year’s time. 
Please phone us if: 
 
you have any questions, and particularly if 
 
any of the above instructions cannot be followed and/or if 
 
you see anything that may have accidentally or unavoidably increased exposure of others to 


 
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 
radiation.  
19. Recommended Precautions after Lutathera treatments 
  


 
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Appendix G. Instructions for Shipment, Storage and Handling of 177Lu-DOTA0-Tyr3-
Octreotate (Lutathera) Solution for Infusion 
 
Name of the medicinal product 
Lutathera 7400 MBq, radiopharmaceutical solution for infusion 
 
Qualitative and quantitative composition  
Lutathera is supplied as a ready for use radiopharmaceutical solution for infusion. 
A vial contains 7400 MBq of 177Lu-DOTA0-Tyr3-Octreotate with a specific activity greater than 
53 GBq/umol and with a radioconcentration of 370 MBq/mL at end of production. 
 
Pharmaceutical form  
Sterile Solution for infusion. 
Clear, colorless or slightly yellow solution. 
 
Pharmaceutical components  
List of excipients 
Acetic Acid 
Sodium Acetate 
Gentisic Acid 
Ascorbic Acid 
DTPA 
NaCl 
Water for Injection 
 
Shelf life 
72 hours after end of production. 


 
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Special precautions for storage 
Store below 25°C. 
Store in the original package for radioprotection purposes. 
The product must be stored according to national regulations concerning radioactive products. 
Nature and contents of container 
A 30 mL vial, colorless Type I glass, closed by a rubber stopper and sealed by an aluminum cap. 
One vial contains 22 to 25 mL of solution. The vial is inserted into a lead shielded container 
protected by a plastic sealed container closed in a Type A package (according to the Accord 
Dangereuses Route agreement or ADR). 
 
Type A container 
  
Plastic container