A Proof of Concept Study to Explore Safety and Efficacy of Tri-therapy Approach in Advanced/Metastatic NSCLC and Retrospectively Assess the Ability of Integrated Genomics and Transcriptomics to Match Patients to the Combination
Phase: PHASE1
Conditions: Non-small Cell Lung Cancer Metastatic, Non-small Cell Lung Cancer Stage IIIB
Sponsor: Worldwide Innovative Network Association

SPRING Protocol version 2.0 May 20th 2019                       CONFIDENTIAL 
Page 1 of 99 
 
 
 
SPRING protocol 
 
Survival Prolongation by Rationale INnovative Genomics (SPRING): 
A proof of concept study to explore safety and efficacy of tri-therapy approach in 
advanced/metastatic NSCLC and retrospectively assess the ability of integrated 
genomics and transcriptomics to match patients to the combination 
 
 
Version 2.0, May 20th 2019 
 
Protocol WIN001 - EudraCT number 2017-001455-32 – IND 131601 
 
NCT #03386929 
 
 
 
 
Sponsor of the study 
Signature of the sponsor 
Worldwide Innovative Network (WIN) 
Association 
(WIN Consortium) 
9 Rue Guy Môquet,  
94800 Villejuif,  
France 
 
 
 
 
Dr Vladimir Lazar, MD PhD 
Chief Scientific and Operating Officer 
 
 
 

SPRING Protocol version 2.0 May 20th 2019                       CONFIDENTIAL 
Page 2 of 99 
PRINCIPAL INVESTIGATORS 
 
Razelle Kurzrock, MD – Global Coordinator 
Chief, Division of Hematology and Oncology, UCSD School of Medicine, 
Senior Deputy Director, Clinical Science, 
Director, Center for Personalized Cancer Therapy, 
Director, Clinical Trials Office, 
UCSD Moores Cancer Center 
3855 Health Sciences Drive, MC #0987 
La Jolla, California, 92093-0658, USA 
 
Lyudmila Bazhenova, MD 
Clinical Professor of Medicine, Lung Cancer Team Leader 
Associate Director Hematology Oncology Training program 
UC San Diego Moores Cancer Center 
3855 Health Sciences Drive, MC 0698 
La Jolla, California, 92093-0698, USA 
 
Enriqueta Felip, MD, PhD – Co-Global Coordinator 
Head Thoracic Oncology Unit, Oncology Department 
Vall d'Hebron University Hospital 
Vall d'Hebron Institute of Oncology (VHIO) 
P. Vall d'Hebron, 119-129 
08035 Barcelona, Spain 
 
Jair Bar, MD 
Institute of Oncology 
Sheba Medical Center, Tel Hashomer, Israel, 52621 
 
Benjamin Solomon, MD 
Avera Cancer Institute 
University of South Dakota Sanford School of Medicine 
1000 E 23rd Street, Suite 200, Sioux Falls, SD 57105, USA 
 
Eric Raymond, MD, PhD 
Hôpital Saint Joseph 
185 Rue Raymond Losserand, 75014 Paris, France 
 
Pierre Saintigny, MD 
Centre Anticancéreux Léon Bérard 
28 rue Laennec 
69373, Lyon, France 
 
 
 

SPRING Protocol version 2.0 May 20th 2019                       CONFIDENTIAL 
Page 3 of 99 
Nicolas Girard, MD 
Institut Curie 
26 rue d’Ulm 
75231 Paris, France 
 
Guy Berchem, MD, PhD 
Centre Hospitalier de Luxembourg  
Service National d’Hémato-Oncologie  
4, rue Barblé, L-1210, Luxembourg, Luxembourg  
 
 
 
TRIAL TEAM 
 
Biostatistician coordinator of the study: 
Prof. J. Jack Lee, Ph.D. Professor, Department of Biostatistics,  
The University of Texas M.D. Anderson Cancer Center, 1400 Pressler Street,  
Houston, Texas 77030, USA 
 
 
IT team coordinator: Eitan Rubin, PhD 
The Shraga Segal Dept, Faculty of Health Sciences, 
Ben-Gurion University of the Negev, 
Beer-Sheva, 84105, Israel 
 
 
Central Genomics and Transcriptomic Laboratory Platform coordinators: 
 
Central Genomics Platform coordinator: 
Brandon Young, PhD 
Bowden WIN Laboratory,  
26442 Beckman Court, Murrieta, CA, 92562,USA 
 
Scientific and operational coordination: 
Vladimir Lazar MD, PhD, Chief Scientific and Operating Officer 
Worldwide Innovative Network (WIN) Association - (WIN Consortium) 
9 Rue Guy Môquet, 94800 Villejuif, France,  
Email: vladimir.lazar@winconsortium.org 
 
Covance Pharmacovigilance Unit: 
206 Carnegie Center Blvd 
Princeton, NJ 08540, USA 
 
 
 
 

SPRING Protocol version 2.0 May 20th 2019                       CONFIDENTIAL 
Page 4 of 99 
SIGNATURE PAGE 
 
Protocol title: 
Survival Prolongation by Rationale Innovative 
Genomics (SPRING) 
A proof of concept study to explore safety and efficacy 
of tri-therapy approach in advanced/metastatic NSCLC 
and retrospectively assess the ability of integrated 
genomics and transcriptomics to match patients to the 
combination 
WIN ID 
WIN001 
IND Nr. : 
131601 
EudraCT Nr.: 
2017-001455-32 
Sponsor: 
Worldwide Innovative Network (WIN) Association 
9 Rue Guy Môquet 
94800 Villejuif, France 
Version Nr.: 
2.0 of May, 20th 2019 
Name and address of 
the center: 
___________________________________________ 
___________________________________________ 
___________________________________________ 
___________________________________________ 
___________________________________________ 
___________________________________________ 
Principal Investigator 
(PI) Name of the site: 
___________________________________________ 
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. 
 
PI signature: 
 
 
Date: 
(dd/mm/yyyy) 
__ __ / __ __ / 20  __ __ 
 

SPRING Protocol version 2.0 May 20th 2019                       CONFIDENTIAL 
Page 5 of 99 
TABLE OF CONTENTS 
 
 
 
TABLE OF CONTENTS .............................................................................................................. 5 
LIST OF ABBREVIATIONS ....................................................................................................... 8 
1. 
KEYNOTES AND STUDY OVERVIEW ........................................................................... 10 
1.1. 
KEYNOTES - SPRING PROJECT AT A GLANCE .................................................................................10 
1.2. 
STUDY OVERVIEW ..................................................................................................................................12 
1.2.1. 
The first goal of the SPRING protocol is to test the safety and the activity of the selected tri-therapy in 
patients with metastatic NSCLC patients in first therapeutic line for the phase 2 portion of the trial (for the phase 
1 patients with a maximum of 2 prior lines will be accepted). .................................................................................. 12 
1.2.2. 
The second goal of the SPRING protocol is to validate retrospectively the SIMS (1) algorithm enabling 
matching patients to the best therapy (mono, dual or triple). .................................................................................. 13 
1.3. 
GLOBAL AIMS IN RELATION TO CLINICAL CANCER .....................................................................14 
1.4. 
SPRING STUDY SCHEMA ........................................................................................................................14 
2. 
BACKGROUND AND RATIONALE ................................................................................. 17 
2.1. 
LUNG CANCER .........................................................................................................................................17 
2.2. 
TARGETED THERAPY IN LUNG CANCER ...........................................................................................17 
2.3. 
LIMITATIONS OF CURRENT TARGETED THERAPY APPROCHES ................................................17 
2.4. 
COMBINATION THERAPY AND CANCER ...........................................................................................18 
2.5. 
PREVIOUS EXPERIENCE - WINTHER STUDY.....................................................................................18 
2.6. 
THE SPRING STRATEGY.........................................................................................................................19 
2.7. 
CONSIDERATIONS CONCERNING THE BIOPSIES IN SPRING TRIAL ...........................................20 
2.8. 
SUMMARY OF RATIONALE BACKGROUND AND STRATEGY ........................................................21 
3. 
SPRING OBJECTIVES AND DESIGN ............................................................................. 23 
3.1. 
PRIMARY OBJECTIVES ..........................................................................................................................23 
3.2. 
SECONDARY OBJECTIVES .....................................................................................................................23 
3.3. 
SPRING STUDY DESIGN ..........................................................................................................................24 
3.3.1. 
The Phase 1 ................................................................................................................................................ 24 

SPRING Protocol version 2.0 May 20th 2019                       CONFIDENTIAL 
Page 6 of 99 
3.3.2. 
The Phase 2 ................................................................................................................................................ 33 
4. 
ENROLLMENT OF PATIENTS ........................................................................................ 34 
4.1. 
ELIGIBILITY CRITERIA .........................................................................................................................34 
4.2. 
EXCLUSION CRITERIA ...........................................................................................................................35 
5. 
STUDY PROCEDURES ...................................................................................................... 38 
5.1. 
INFORMED CONSENT .............................................................................................................................38 
5.2. 
MOLECULAR PROFILING OF TUMOR AND NORMAL BIOPSIES AND BLOOD SPECIMENS ....39 
5.2.1. 
Collecting/processing methods of tissue biopsies .................................................................................... 39 
5.2.2. 
Control of variability and reduction of noise.......................................................................................... 39 
5.2.3. 
Molecular profiling of tissue biopsies ...................................................................................................... 40 
5.2.4. 
Blood specimens for research purpose .................................................................................................... 40 
5.2.5. 
Blood specimens for pharmacokinetics (PK) monitoring purpose ....................................................... 41 
5.3. 
BIOINFORMATICS AND DATA MANAGEMENT .................................................................................43 
5.4. 
PROCEDURES DURING TREATMENT ..................................................................................................43 
5.5. 
FOLLOW-UP PROCEDURES ...................................................................................................................44 
5.6. 
SAFETY REPORTING ...............................................................................................................................44 
5.6.1. 
Adverse events ........................................................................................................................................... 44 
5.6.1.1. 
Definition of adverse events ................................................................................................................. 44 
5.6.1.2. 
Definition of serious adverse events .................................................................................................... 45 
5.6.2. 
Recording of adverse events ..................................................................................................................... 46 
5.6.2.1. 
Time period for collection of adverse events ...................................................................................... 46 
5.6.2.2. 
Follow-up of unresolved adverse events ............................................................................................. 46 
5.6.2.3. 
Variables................................................................................................................................................ 46 
5.6.2.4. 
Causality collection ............................................................................................................................... 47 
5.6.2.5. 
Adverse events based on signs and symptoms .................................................................................... 47 
5.6.2.6. 
Adverse events based on examinations and tests ............................................................................... 47 
5.6.2.7. 
Disease progression .............................................................................................................................. 47 
5.6.2.8. 
New cancers ........................................................................................................................................... 48 
5.6.2.9. 
Handling of deaths ................................................................................................................................ 48 
5.6.2.10. 
Handling of exposure during breastfeeding ................................................................................... 48 
5.6.2.11. 
Handling of exposure during pregnancy ........................................................................................ 48 
5.6.2.12. 
Occupational exposure ..................................................................................................................... 49 
5.6.2.13. 
Potential drug-induced liver injury (Hy’s law cases) .................................................................... 50 
5.6.3. 
Reporting of Serious Adverse Events ...................................................................................................... 50 
5.7. 
REMOVAL OF SUBJECTS FROM STUDY .............................................................................................52 
5.8. 
EFFICACY EVALUATION .......................................................................................................................52 
5.9. 
DATA COLLECTION ................................................................................................................................53 
5.10. 
ETHICAL AND REGULATORY REGULATIONS ..................................................................................53 
5.10.1. 
Rules and regulation ................................................................................................................................. 53 
5.10.2. 
Ethic Committee – Competent Authorities ............................................................................................. 53 
5.10.3. 
Withdrawal of consent for continued study participation ..................................................................... 54 

SPRING Protocol version 2.0 May 20th 2019                       CONFIDENTIAL 
Page 7 of 99 
5.10.4. 
Data handling and record keeping .......................................................................................................... 54 
6. 
QUALITY CONTROL AND QUALITY ASSURANCE ................................................... 55 
7. 
STATISTICAL CONSIDERATIONS ................................................................................ 57 
7.1. 
SEAMLESS PHASE 1/ 2 TRIALS FOR THE TRIPLE COMBINATION THERAPY ............................58 
7.2. 
PHASE 2 EFFICACY EVALUATION .......................................................................................................58 
7.2.1. 
Statistical analysis of the primary efficacy end point ............................................................................ 58 
7.2.2. 
Statistical analysis of the secondary efficacy end point and other endpoints ...................................... 59 
7.3. 
SAFETY AND TOXICITY EVALUATIONS .............................................................................................59 
7.4. 
STATISTICAL ANALYSES OF THE SECONDARY OBJECTIVES ......................................................60 
7.5. 
INTERIM ANALYSIS ................................................................................................................................60 
7.6. 
FINAL ANALYSIS ......................................................................................................................................60 
8. 
DATA OWNERSHIP / PUBLICATION POLICIES ......................................................... 61 
9. 
REFERENCES .................................................................................................................... 62 
10. 
APPENDIXES .................................................................................................................. 64 
10.1. 
APPENDIX 1: The Simplified Interventional Mapping System (SIMS) Paper Reference ........................64 
10.2. 
APPENDIX 2: SIMS Explained ..................................................................................................................65 
10.3. 
APPENDIX 3: Drug Information ................................................................................................................69 
10.4. 
APPENDIX 4: Gene Expression Tumor vs. Normal ...................................................................................71 
10.5. 
APPENDIX 5: Clinical Flowchart ...............................................................................................................73 
10.6. 
APPENDIX 6: Safety Related Items for Avelumab ....................................................................................76 
10.7. 
APPENDIX 7: Protocols for PK ..................................................................................................................90 
10.8. 
APPENDIX 8: Global View on Toxicity Profiles ........................................................................................93 
10.9. 
APPENDIX 9: Modulators of CYP3A4 .......................................................................................................99 
 
 
 
 
 
 

SPRING Protocol version 2.0 May 20th 2019                       CONFIDENTIAL 
Page 8 of 99 
LIST OF ABBREVIATIONS 
 
 
 
ADL 
Activities of daily living 
ADR 
Adverse drug reaction 
AE 
Adverse event 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
ANC 
Absolute neutrophil count 
CBC 
Complete blood count 
CDER 
Center for drug evaluation and research 
CDK 
Cyclin-dependent kinases 
CMC 
Clinical monitoring committee  
CMP 
Complete metabolic profile 
CNS 
Central Nervous System 
CR 
Complete response 
CRF 
Case report form 
CT  
Computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
DILI 
Drug-induced liver injury 
DLT 
Dose limiting toxicity 
DNA 
Ribonucleic acid 
DSMB 
Independent safety and data monitoring committee 
ECG 
Electrocardiogram 
EGFR 
Endothelial growth factor receptor 
EMA 
European medicines agency 
FFPE 
Formalin-fixed paraffin-embedded 
GDPR 
General Data Protection Regulation 
HAV 
Hepatitis A virus 
HBV 
Hepatitis B virus 
HCV 
Hepatitis C virus 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
Human immunodeficiency virus 
ICF 
Informed Consent Form 
IDE 
Investigational device exemption 
IEC 
Institutional ethics committee 
IRB 
Institutional review board 
irAE 
Immune-related adverse event 
IV 
Intravenous 
LD 
Longest diameter 
MRI 
Magnetic resonance imagery 

SPRING Protocol version 2.0 May 20th 2019                       CONFIDENTIAL 
Page 9 of 99 
MTD 
Maximal tolerated dose 
NCI 
National Cancer Institute 
NSCLC 
Non-small cell lung cancer  
OS 
Overall survival 
PCR 
Polymerase chain reaction 
PD 
Progressive disease 
PET 
Positron emission tomography 
PFS 
Progression-free survival 
PFS1 
Progression-free survival on the immediate line prior SPRING 
PFS2 
Progression-free survival on the matched or unmatched SPRING therapy 
PK 
Pharmacokinetics 
PR 
Partial response 
PS 
Performance status 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RNA 
Ribonucleic acid 
RP2D 
Recommended Phase 2 Dose 
RPLS 
Reversible posterior leukoencephalopathy syndrome 
RR 
Response Rate 
SAE 
Serious Adverse Event 
SD 
Stable disease 
SIMS 
Simplified interventional mapping system  
SOP 
Standard operating procedure 
SPRING 
Survival Prolongation by Rationale Innovative Genomics 
SUSAR 
Suspected unexpected serious adverse reaction 
TBili 
Total bilirubin 
TKI 
Tyrosine kinase inhibitor 
TTP 
Time to progression 
TSH 
Thyroid-stimulating hormone 
ULN 
Upper Limit of Normal 
VEGFR 
Vascular endothelial growth factor receptor 
WBC 
White blood cells 
WIN 
Worldwide Innovative Network 
 
 
 
 
 
 
 
 
 

SPRING Protocol version 2.0 May 20th 2019                       CONFIDENTIAL 
Page 10 of 99 
1. KEYNOTES AND STUDY OVERVIEW 
 
1.1. KEYNOTES - SPRING PROJECT AT A GLANCE 
 
Survival Prolongation by Rationale Innovative Genomics (SPRING) clinical trial is pursuing two 
goals: 
(i) Establish the safety and clinical activity of triple targeted combination therapies following the 
historical model of this approach in AIDS. SPRING is a proof of concept study that will test only 
one combination of three targeted agents: avelumab - Bavencio /anti PD-L1 (PFIZER/MERCK), 
palbociclib – Ibrance / CDK4/6 inhibitor (PFIZER) and axitinib - Inlyta / anti VEGFR (PFIZER): 
− Avelumab is a fully human IgG1 monoclonal antibody (mAb) that targets programmed 
deathligand 1 (PD-L1) with the ability to mediate antibody-dependent cell-mediated cytotoxicity 
(ADCC). It is FDA-approved for the treatment of metastatic Merkel cell carcinoma and locally 
advanced or metastatic urothelial carcinoma. 
− Axitinib is a selective inhibitor of vascular endothelial growth factor receptors (VEGFR-1, -2, 
and -3) that is FDA-approved for the second-line treatment for advanced renal cell carcinoma 
(RCC). 
− Palbociclib is an oral, small molecule kinase inhibitor which is active against cyclin-dependent 
kinase (CDK) 4 and 6 which play a critical role in facilitating the gap 1 (G1) to synthesis (S) 
phase transition. Palbociclib received accelerated approval for use, in combination with letrozole, 
and for use, in combination with fulvestrant, for the treatment of patients with ER positive, HER2-
negative, breast cancer who had not received previous systemic treatment. 
− This trial will not evaluate the individual contribution of each of the tested drugs.  
− First, the safe dose of the combination of the three agents will be determined in a phase 1 study. 
It is important to outline that the dual combination avelumab and axitinib was already tested in a 
phase 1 trial, and the recommended phase 2 dose (RP2D) has been established. This dose for the 
dual combination avelumab and axitinib is currently used in the study JAVELIN Renal 101, a 
randomized phase 3 trial referenced at  
https://clinicaltrials.gov/ct2/show/NCT02684006?term=avelumab+and+axitinib&rank=1. 
For the triple combination, the starting dose of each agent of the dual combination will be reduced 
in order to add the third agent. Doses will then be progressively increased with, at each dose 
escalation, 3 new patients being added. Patients will be closely monitored to detect any adverse 
event until the MTD of the triple combination is determined or reaching the highest dose level of 
each agent, whichever occurs first. Note that if the MTD is reached, this dose combination is the 
RP2D. 
− Specific safety measures related to administration of avelumab will be implemented in each 
participating center: specific inclusion/exclusion criteria, safety assessments (pregnancy testing, 
monitoring of free T4 and TSH), premedication in order to mitigate avelumab infusion-related 
reactions, administration of avelumab in a facility that enable immediate access to emergency 
care unit, extended follow up to 90 days following the last administration of avelumab, monitoring 
of all specific adverse events, and reporting to the Pharmacovigilance Unit of the sponsor, within 
24 hours of any serious adverse events. For simultaneous administration with palbociclib and 
axitinib, other specific safety measures will be implemented (for example careful monitoring of 
arterial tension, bleeding, assessment of risk of arterial and venous thromboembolic events 

SPRING Protocol version 2.0 May 20th 2019                       CONFIDENTIAL 
Page 11 of 99 
relating to administration of axitinib, and careful monitoring of hematologic toxicities relating to 
administration of palbociclib). These specific measures are presented in a detailed manner in this 
protocol, at each concerned section/chapter; as well as in a specific appendix 6. 
− The study will then be expanded to a phase 2 in order to confirm the safety profile and assess the 
clinical utility of the tri-therapy approach in the treatment of metastatic NSCLC. All patients 
included in phase 2 will be receiving the tri-therapy combination at the RP2D, and will be 
followed up to determine clinical response, duration of the response and overall survival. Patients 
enrolled in the phase 1 study who receive the RP2D will also be included in the phase 2 efficacy 
assessment.  
 
(ii) Validate the clinical utility of a new tool/algorithm enabling matching of advanced/metastatic 
NSCLC patients with the tested combination of three targeted agents. The Simplified 
Interventional Mapping System (SIMS) algorithm enable a new approach in treating metastatic 
lung cancers using tri-therapy approach, following the historical success in AIDS, and was 
awarded Success Story of the European Community EUFP7 program.  
 
The tool SIMS (1) is based on integrated genomics and transcriptomics from tumor/metastasis 
tissue and normal matched tissue and was designed to predict efficacy of any mono, dual or triple 
therapy. In this study, all patients enrolled will receive the triple therapy combination and the 
SIMS (1) algorithm will only be used for preplanned retrospective correlations. 
 
To this aim patients will need to have adequate biopsy material to enable investigations of the 
DNA and RNA: 
− Tumor tissue from the primary tumor or from the metastatic lesion. For this purpose patients will 
have to consent to a biopsy.  
− Normal matched tissue, which in this case will be the bronchial mucosa. To this aim, patients will 
consent to the normal tissue biopsy obtained through bronchoscopy under video guidance, using 
a minimum of 2.5 mm3 forceps.  
 
Tumor/metastasis and normal tissue biopsies will be controlled for cellularity content with a threshold 
at 50% of tumor or 30% to 50% normal epithelial cells respectively, and will be used for genomic 
and transcriptomic analyses to generate the SIMS scoring. SIMS provides a 1 to 10 score indicating 
the activation of the targets (interventional points) of each specific drug. The threshold to consider an 
interventional point activated is >5. This threshold applies for each of the interventional point, 
including the PDL1. SIMS score for each patient will then be retrospectively correlated with the 
patients’ clinical outcome in order to assess its predictive value and ability to match patient’s tumor 
biology with the tri-therapy combination. SIMS will not be used for treatment decision. All patients 
will receive the tri-therapy combination.  
 
SPRING trial will aim to enroll patients who are usually offered first line platinum-based 
chemotherapy.  Patients with documented targetable driver alterations (EGFR mutations, ALK 
rearrangements, ROS1 and MET exon 14 skipping mutations) will be excluded. This population 
currently, without actionable oncogenic driver mutations, envisioned for the enrollment in SPRING 
trial represents the majority of patients with metastatic NSCLC (~80% in the Caucasian population).  

SPRING Protocol version 2.0 May 20th 2019                       CONFIDENTIAL 
Page 12 of 99 
Although the triple combination includes an immunomodulator (avelumab, anti PD-L1), patients will 
be included regardless of their PD-L1 expression status. Nevertheless, all molecular data available at 
enrollment will be recorded including PD1 and PD-L1 testing using any of the available IHC tests. 
Subsequently, the activation status of PD1 or PD-L1 will be assessed through the 1 to 10 SIMS 
scoring (where 5 is the cut-off), and will be used retrospectively for correlations with clinical outcome 
and any previous PD1 or PD-L1 tests. 
We estimate that overall 85% of the patients treated in the trial will have a profile that is matched to 
at least one out of the three drugs: 10% matched with three drugs, 36% matched with two drugs and 
39% matched with one drug.   
SPRING trial phase 2 is intended in first therapeutic line of metastatic NSCLC.  Indeed, due to the 
current extensive use of checkpoint inhibitors (e.g. anti-PD-1, anti-PD-L1) in first line of metastatic 
NSCLC, any testing of the tri-therapy in subsequent lines would make the enrollment extremely 
difficult, if not impossible. In addition, following the analogy with AIDS and tuberculosis for which 
only tri-therapy demonstrated long term efficacy, it would be conceptually difficult to prescribe first 
an immunomodulator as a monotherapy followed in second line by the tri-therapy, including the 
immunomodulator. Indeed, we can hypothesize that monotherapy will likely select for resistant 
clones that would hamper the treatment efficacy and compromise the clinical outcome.  
Nevertheless, patients with one to a maximum of 2 prior systemic regimens in the metastatic setting 
will be accepted for enrollment in phase 1.  
 
SPRING clinical trial is intended to open in a limited number of cancer centers of the WIN 
Consortium (2 centers in USA, 5 in Europe and 1 in Israel) enabling a rapid enrollment and follow-
up of patients. It is expected that 130 patients will be enrolled over an 18-month period (phase 1, 6 
to 8 months – phase 2, 8-12 months). With an additional 12/24 months of follow up, the total study 
duration will be 3 to 4 years. 
 
 
1.2. STUDY OVERVIEW 
 
1.2.1. The first goal of the SPRING protocol is to test the safety and the activity of the 
selected tri-therapy in patients with metastatic NSCLC patients in first therapeutic 
line for the phase 2 portion of the trial (for the phase 1 patients with a maximum of 
2 prior lines will be accepted).  
 
The trial will start with a Phase 1 safety study to establish the dose of each of the three agents.  This 
part of the study will require about 30 patients treated (~40 patients enrolled). The Phase 1 will be 
followed by a first extension Phase 2 to test efficacy on up to 100 patients who will all receive the tri-
therapy (100 patients treated/ ~120 patients enrolled (~20 patients screen failures)).  All patients will 
have the necessary biopsies performed to ensure that adequate biopsy material is available before 
starting treatment. For ethical reasons, patients whose biopsies fail to produce interpretable data will 
still be treated with the tri-therapy. Pending clinical activity, the study may be extended by an 
additional 100 patients treated (total = 200 patients on the phase 2 portion) in order to firm up the 
initial efficacy assessment and identify the potential subgroups of patients with clinically meaningful 
efficacy. 

SPRING Protocol version 2.0 May 20th 2019                       CONFIDENTIAL 
Page 13 of 99 
Patients with specific documented oncogenic aberrations (EGFR mutations, ALK translocations, 
ROS1 if available and MET exon 14 skipping mutation if available) will be excluded from the trial. 
The study cohort will aim to include patients who are not generally treated with specific targeted 
therapeutics. Patients will be included in the study regardless of their PD1 or PD-L1 expression status. 
In the case of patients already treated on SPRING protocol who are later determined to have EGFR 
mutation or ALK translocation or ROS1 or MET exon 14 skipping mutations after SIMS analyses, 
amenable to treatment with an approved therapy, they will be given the option to continue 
investigational treatment in the SPRING trial after obtaining appropriate re-consent or discontinue 
treatment. 
 
Early futility stopping rules will be applied in the phase 2 study should the tri-therapy have less than 
the expected efficacy to guard against patients being enrolled in ineffective treatment.  
We estimate that overall 85% of the patients treated in the trial will have a profile that is matched to 
at least one out of the three drugs: 10% matched with three drugs, 36% matched with two drugs and 
39% matched with one drug. 
 
1.2.2. The second goal of the SPRING protocol is to validate retrospectively the SIMS 
(1) algorithm enabling matching patients to the best therapy (mono, dual or triple). 
 
For this purpose, patients enrolled in each of the selected participating cancer center will undergo a 
dual biopsy for tissue collection and biomarker analysis, that are part of the study protocol. Adequate 
material from fresh frozen biopsies from NSCLC metastasis or primary tumor and normal bronchial 
mucosa tissue (by bronchial bronchoscopy) are necessary to the study. FFPE biopsies from both 
tumor and normal tissues will also be collected if possible. The samples will be processed for 
histology quality control and comprehensive omics analyses (including genome sequencing and 
transcriptomics (mRNA and miRNA)). Tumor/metastasis and matched normal tissue biopsies are 
necessary for investigations of the transcriptome in order to subtract the noise induced by the genetic 
variability between individuals. Both biopsies (of the tumor tissue and normal tissue) have proven to 
be well accepted by patients and safe in the WINTHER study (246 patients biopsied for both normal 
and tumor tissues) (http://clinicaltrials.gov/show/NCT01856296). 
 
The algorithm (SIMS) (1, Appendix 1 and Appendix 2) will integrate the genomics and 
transcriptomics data from paired tumor/metastasis and normal tissue performed on fresh frozen 
biopsies’ material from patients. SIMS will identify activated pathways and so-called intervention 
points that are druggable targets. This information will be used retrospectively to assess how well the 
algorithm predicted the response to the triple therapy tested (druggable targets anti-PD-L1, CDK 4/6 
and anti VEGFR). SIMS will identify for each patient how many intervention points are activated out 
of the three tested. The hypothesis is that clinical outcome will be correlated to the number of targets 
activated as predicted by SIMS (1, 2 or 3).  
Based on previously published data on SIMS (1) we estimate that PD-L1-positive patients will 
represent 50% of the enrolled patients with metastatic NSCLC.  
 
In this study, we estimate that we will treat up to 100 patients in the first part of phase 2 (overview in 
Figure 1) with futility early stopping rules. If the trial is not stopped early after the first 100 patients, 
the study could be extended to an additional 100 patients treated.  

SPRING Protocol version 2.0 May 20th 2019                       CONFIDENTIAL 
Page 14 of 99 
Main outcome variables for the expansion phase will include response rate (RR) by RECIST 1.1, 
duration of response, progression-free survival (PFS), and overall survival (OS).  
 
 
 
 
Figure 1: Overview of SPRING Phase 2 
 
1.3. GLOBAL AIMS IN RELATION TO CLINICAL CANCER 
 
1. Safely and significantly improve treatment outcome in patients with advanced/metastatic NSCLC 
through drug combinations of molecular/immune targeted agents. 
2. Explore the clinical utility of SIMS for matching patients with combination therapy in the advanced 
NSCLC setting.  
 
 
1.4. SPRING STUDY SCHEMA  
 
Refer to Figure 2 below. 
 
The trial design is a two-part, multiple parallel cohort, dose-finding and activity-estimating study. 
The study will enroll patients with metastatic NSCLC that have no targetable alterations (EGFR 
mutations or ALK translocation) and for whom targeted therapies are not recommended. In the first 
Phase 1 portion of the trial, patients may have received a maximum of two prior therapies for 

SPRING Protocol version 2.0 May 20th 2019                       CONFIDENTIAL 
Page 15 of 99 
metastatic NSCLC but in the second portion of the trial, ONLY patients who have not received prior 
systemic therapy in the metastatic setting will be included. All patients included must be ECOG 0-1. 
All patients must consent to a dual biopsy of the tumor tissue obtained from a metastatic lesion under 
radiologic guidance or from the primary tumor, and of normal matched tissue (bronchial mucosa), 
obtained through bronchoscopy under video guidance. The paired biopsy samples will be processed 
in a centralized facility for comprehensive analyses including genome sequencing and 
transcriptomics (mRNA and miRNA). 
The primary objectives of the Phase 1 portion of the trial will be to establish the safety, tolerability, 
dose-limiting toxicities (DLTs), maximum tolerated doses (MTDs), and RP2Ds of the three drugs, 
administered concurrently, through enrollment in sequential dose-escalating. 
 
 
 
Figure 2: Study design and planned retrospective analysis of the clinical utility of the SIMS 
algorithm and integrated genomic/transcriptomic analysis. 
 
 
The statistical design of the trial has been performed by Prof. J. Jack Lee, University of Texas MD 
Anderson Cancer Center, Adjunct Professor of Statistics, Associate Vice Provost, Adjunct Professor 
of Biostatistics, Professor of Biostatistics, Biostatistics, Regular Member of the Graduate Faculty. 

SPRING Protocol version 2.0 May 20th 2019                       CONFIDENTIAL 
Page 16 of 99 
We estimate that we will treat up to 100 patients in the first part of phase 2 with futility early stopping 
rules.  
For the first cohort of 100 patients it is expected that half of the patients will be PD-L1 positive and 
half of the patients will be PD-L1 negative. The hypothesized 6-month response rate in Arm A (fully 
matched) is 50%; in Arms B1, B2, and C1 (partially matched with two targets) is 40%; in Arm B3 
(matched with PD-L1 only) is 30%; in Arms C2 and C3 (partially matched with VEGFR or CDK4/6) 
is 20%; and in Arm C4 (non-matched group) is 10%.  The expected 6-month response rate is 30% in 
the entire group assume the triple therapy works.  
• The first futility early stopping rule will be applied after treating 14 patients with the tri-
therapy at the RP2D level.  If none of the 14 patients has 6-month response (CR or PR), the 
patient enrollment will be halted and the trial can be stopped for futility.  
• The second futility early stopping rule will be evaluated every 10 patients after 20 patients are 
treated at the RP2D by applying the predictive probability. The trial will be stopped early if 
we see the following 6-month responses or less: 2 in 20, 3 in 30, 5 in 40, 6 in 50, 7 in 60, 9 in 
70, 11 in 80, or 12 in 90 patients.  
If the trial is not stopped early after the first 100 patients, the study could be extended to an additional 
100 patients treated with an amendment.  Two possible scenarios can then be envisioned: 
 Repeat identically all investigations for additional 100 patients, (exactly as for the first cohort), 
with the purpose to have a final cohort of 200 patients, which would give good statistical power 
for the study. With 5% one- sided type I error, we need to treat 20 patients to demonstrate the 
usefulness of the tri-therapy approach to achieve and 86% power based on the exact binomial test. 
With an expected 10% of patients who will be fully matched, we need to enroll 200 patients in 
the study. 
 For the second cohort, use SIMS to stratifying patients and select only the subgroups with the 
highest efficacy as demonstrated after the study of the first cohort. This statistical model will be 
much more powerful to demonstrate usefulness of the tri-therapy approach. This scenario is also 
the most appropriate from an ethical perspective.  
 
It is planned that after collecting data on about 50 patients, a meeting with the FDA will be organized 
in order to assess which scenario of design is recommended and to ask for a risk determination for 
need for IDE. 
 
 
 
 
 
 
 
 
 
 
 
 
 

SPRING Protocol version 2.0 May 20th 2019                       CONFIDENTIAL 
Page 17 of 99 
2. BACKGROUND AND RATIONALE 
 
 
Today, most malignancies (including lung cancer) are detected at a late stage (i.e., metastatic setting), 
and despite all recent progress in the field of personalized therapy, almost all patients will die of their 
disease. One reason behind this slow progress is that targeted and immune therapies have been 
typically tested and used as monotherapies. 
 
2.1. LUNG CANCER 
 
Lung cancer is one of the most prevalent and deadly malignancies, contributing a staggering 1.6 
million cases diagnosed per year and about 21% of cancer deaths to the global cancer burden (2, 3). 
The majority of individuals with non-small cell lung cancer (NSCLC) present at the metastatic stage, 
and most patients with localized disease will relapse. The standard of care in advanced disease–
mainly cytotoxic chemotherapy and targeted agents for selected subsets– has had modest impact on 
mortality as even responders inevitably develop resistance and succumb to their disease. Only about 
half of all patients diagnosed (regardless of stage) are alive at one year, and there are dismal one- and 
five-year survival rates of around 15% and 4%, respectively, for those with metastatic disease (2, 3, 
4). For patients who have failed first-line therapy, the median survival is only about seven months.  
 
More importantly, in the majority of patients with Stage IV NSCLC, chemotherapy remains 
the standard first-line treatment option, despite modest benefit. Targeted monotherapies can produce 
excellent response rates in small subsets of patients, but responders inevitably develop resistance and 
succumb to their disease. Combination of drugs may overcome such resistance, but a scientific 
methodology for determining individualized therapy combinations that can be used to treat lung 
cancer or other deadly malignancies does currently not exist. 
 
 
2.2. TARGETED THERAPY IN LUNG CANCER 
 
Targeted therapies implemented in standard care are directed at the activated products of mutated 
epidermal growth factor receptor (EGFR) (5) or ALK translocation (6). Such therapies have shown 
high response rates, and improved progression-free survival (PFS). However, these monotherapies 
apply to only small subsets of oncogene-driven patients, and virtually all develop resistance and 
succumb to their disease (7). Relapse occurs mostly as a consequence of the Darwinian selection of 
tumor clones harboring genomic variants that lead to the activation of additional signaling pathways 
and, hence, resistance. This is perhaps not unexpected, as tumors often exhibit a large variety of 
molecular abnormalities (7, 8), even at diagnosis. Heterogeneity across tumor clones is amplified in 
metastases, and in response to therapeutic pressure. 
 
 
2.3. LIMITATIONS OF CURRENT TARGETED THERAPY APPROCHES 
 
As mentioned, in NSCLC, as well as in many cancer types, molecular characterization of the tumors 
has resulted in segmentation of nosological classifications, based previously on the organ of origin 
and histology, into a variety of molecular subtypes, often characterized by one specific driver 
molecular genetic alteration (5, 9).  However, this strategy has several limitations: (i) only a portion 

SPRING Protocol version 2.0 May 20th 2019                       CONFIDENTIAL 
Page 18 of 99 
of tumors have an identified driver mutation, and many of these simple models may have been already 
described (10, 11); (ii) there is no recognized strategy to efficiently pinpoint unrecognized drivers 
within the complex and multiple genomic alterations observed in most tumors; (iii) targeted 
treatments are not uniformly efficient even in these selected subgroups;  (iv) the majority of tumors 
are actually driven by multiple aberrant genes (9, 12, 13), making the monotherapy paradigm 
unsuitable for most metastatic cancers; and (v) resistance uniformly emerges in a Darwinian manner 
in patients treated with a single targeted therapy. 
 
 
2.4. COMBINATION THERAPY AND CANCER 
 
Combination of cytotoxic therapies has been demonstrated to be effective where single agents provide 
only moderate benefits, as illustrated in Hodgkin’s lymphoma. Whether this paradigm applies to 
targeted therapy remains unclear for most diseases. However, recently, combinations targeting the 
same pathway in BRAF-mutant melanoma (14) (using trametinib (MEK inhibitor) together with 
dabrafenib (BRAF inhibitor)), or resistance pathways (combining PIK3CA and MEK inhibitors) (15) 
showed some efficacy, either pre-clinically and/or in the clinic.  
 
With the aim of further enhancing clinical benefit and increasing survival, we intend to explore 
the efficacy of triple regimen therapy, following the historical success in diseases such as acquired 
immunodeficiency syndrome. The major challenges for this effort are delineating the scientific 
rationale for matching agents with patients’ tumors, while being cognizant of potential toxicity for 
multi-drug regimens.   
 
 
2.5. PREVIOUS EXPERIENCE - WINTHER STUDY 
 
The study workflow and the use of dual biopsies were previously investigated in the WINTHER trial 
(http://clinicaltrials.gov/show/NCT01856296) of the Worldwide Innovative Networking (WIN) 
Consortium (www.winconsortium.org) for personalized cancer therapy (PI: JC Soria; Co-PI: R 
Kurzrock). WINTHER was built as a molecularly driven navigation trial. It was developed on the 
shoulders of previous trials:  
(i) 
The biomarker-driven trial pioneered by Dr. Von Hoff, which was one of the first to show that 
using biomarkers was feasible, and that, by using patients as their own controls (looking at 
PFS2 on matched therapy versus prior PFS), improved outcomes could be demonstrated 
without randomization (16). 
(ii) 
BATTLE study (17), which proved definitively that molecular profiling on fresh biopsies in 
lung cancer was feasible and safe.    
(iii) 
PREDICT, a navigation trial that showed that molecular matching (albeit non-randomized) 
was associated with substantially increased response rates PFS, OS, and PFS2/PFS1 ratio, 
even in the Phase I setting (18).  
(iv) 
NCI-Match, which started in 2015 and uses a similar molecularly driven, non-randomized 
strategy (19, 20).   
(v) 
Lung-Map in USA and CR-UK Matrix Lung in UK. 
 
To date, the WINTHER study has been activated in 6 cancer centers (Gustave Roussy, Centre 
Léon Bérard, Chaim Sheba Medical Center, Val d’Hebron, MD Anderson Cancer Center and McGill 
Segal Cancer Center) across 5 countries (France, Spain, Israel, Canada, USA). The study has accrued 

SPRING Protocol version 2.0 May 20th 2019                       CONFIDENTIAL 
Page 19 of 99 
more than 300 patients (study ongoing). The WINTHER study includes dual biopsies from both 
normal and tumor tissues and stratifies patients in different arms, i.e. Arm A (genomics, Next 
Generation Sequencing, Foundation Medicine) and Arm B (transcriptomic data, which uses the dual 
biopsies to compare the transcript levels in tumor to corresponding normal tissue) has been used to 
direct matched therapy. Specifically, patients who harbor a targetable genomic alteration are stratified 
to Arm A; patients with no targetable genomic alteration are stratified to Arm B and the choice of 
therapy is based on mRNA expression profiling analyzed by an algorithm. In the WINTHER trial, 
weekly Clinical Monitoring Committees (CMC) were successfully established (with calls occurring 
each Monday evening and allowing patients presentation, review of -omics data, and therapy 
suggestions by the participating physicians from the five countries). There have been no serious safety 
signals to date, and the dual biopsies have proven safe and feasible.    
 
The following elements have been established for WINTHER and will be used by the SPRING 
trial:  
• 
Dual biopsies of tumor and normal matched tissue in solid tumors (including lung) patients. No 
significant safety issue encountered, with 246 patients having undergone dual biopsies.  
• 
Use of both genomics and transcriptomics in the clinical setting was possible, under stringent 
quality control.  
• 
Multi-country trial across 6 centers and 5 countries (France, Spain, Israel, Canada and USA) - 
approved by IRB and regulatory authorities. 
• 
Information technology structure with web portal to support principal investigators (PIs) to make 
their therapeutic choice. 
• 
Weekly clinical monitoring committee with investigators from multiple countries convening to 
present and discuss patients, and assist with decision-making, was immensely successful.  
• 
Trial funded by a highly competitive peer-review European EU-FP7 grant of 3 million euros 
(funding only 2% of submitted grants) and also by philanthropy (2 million euros) and industry 
(1.5 million euros). 
 
 
2.6.  THE SPRING STRATEGY 
 
The SPRING trial will build on the established infrastructure from the WINTHER trial. It will, 
however, be a strategic second-generation trial, incorporating the following additional approaches:  
• Tri-therapy combinations instead of monotherapy will be tested 
• Immunotherapy will be incorporated  
• Genomics and transcriptomics will be integrated for correlation purposes at the end of the study 
• The SIMS algorithm will be incorporated (1) for correlation purposes at the end of the study. 
 
The simplified interventional mapping system (SIMS) algorithm will be applied to integrate 
genomic and transcriptomic data (1).  SIMS merges knowledge about existent drugs and their impact 
on the hallmarks of cancer. Our integrative approach and new mathematical modeling converts 
thousands of genomic and other “omics” measurements into a simple result that enables selection of 
individualized rational therapies including combinations of targeted therapies (1). 
 
More specifically, the use of SIMS can allow identification and scoring (from 1 to 10) of 
specific interventional points/nodes for drugs based on the pathways deregulated in each patient’s 
cancer. This approach for prioritizing intervention points for a patient is simple and easy to interpret. 

SPRING Protocol version 2.0 May 20th 2019                       CONFIDENTIAL 
Page 20 of 99 
The basic premise is that, when the genes associated with an intervention point are more disturbed 
(in terms of sequence and/or expression level), the intervention point is assigned a higher score and 
thus is more likely to be crucial to the tumor. From this, it follows that the more disturbed the genes 
of an intervention point are, the more likely it is that therapeutics targeting that point will benefit the 
patient. This new therapeutic approach of combination therapies aims to simultaneously block 
different biologic pathways and reduce the chance of developing secondary resistance. SIMS 
identifies within the hallmarks of cancer (11) only signaling and regulatory pathways that can be 
targeted with available therapeutic agents.  
Our work suggests that using the SIMS algorithm to orient therapeutic decision would benefit from 
several major assets: The interrogation of dual biopsies of tumor/metastasis and its normal 
counterpart, combined with a comprehensive systems biology investigation and innovative 
bioinformatics and scoring systems, may enable matching each individual patient with the most 
appropriate treatment. One of the cornerstones of this new methodology is use of dual matched tumor 
tissue and normal tissue biopsies from the same patient, enabling the subtraction of transcriptomic 
background noise in each patient (9, 21).   
 
We propose to test this novel SIMS algorithm retrospectively on the cohort of patients who will be 
treated with the tested tri-therapy.  The concept of SIMS was published in a peer-reviewed journal (1 
and appendix 1). SIMS enabled to estimate the frequency of occurrence of the activation of each 
target of the three drugs used in the combination. 
 
 
2.7. CONSIDERATIONS CONCERNING THE BIOPSIES IN SPRING TRIAL 
 
A cornerstone of the SPRING strategy is the interrogation of tumor tissue (from metastatic tissue or 
primary tumor) and matched normal tissue (namely bronchial mucosa) by bronchoscopy in order to 
investigate DNA and RNA and run the SIMS algorithm. In doing so, our utmost concern will be the 
safety of the procedures.  
In a majority of cases, percutaneous core needle biopsy is a standard part of initial work-up. In order 
to perform standard molecular testing (EGFR, ALK) more than one biopsy (bronchoscopic and 
percutaneous) is often required in clinical practice and is supported by NCCN (Diag-A 1 of 2). A 
second biopsy at time of progression is also supported by NCCN in select cases for further molecular 
characterization (NSCL 16-17). Repeat biopsies for cancer progressing after initial treatment is a 
common practice.  
In the SPRING trial, the additional biopsy of normal tissue is integral to the SIMS algorithm and the 
hypothesis is that it will improve precision oncologic therapy selection.  
In our previous experience in the WINTHER study where 303 patients were registered, 246 
underwent a dual biopsy of the tumor tissue and normal matched tissue of which 55 were dual biopsies 
in lung cancer patients. From the 55 lung cancer dual biopsied patients, 45 had CT-guided lung tumor 
core needle biopsies.  4 patients were observed in the hospital for 24 hours because they developed a 
small pneumothorax that resolved rapidly (among which 2 required chest tubes). There were no life-
threatening complications.  

SPRING Protocol version 2.0 May 20th 2019                       CONFIDENTIAL 
Page 21 of 99 
Research biopsies are a frequent component of current clinical trials. In MD Anderson’s experience 
in Oncologist 2011, a total of 281 research biopsies on 155 distinct patients and 42 lung biopsies had 
been done and 2 patients had a pneumothorax for rate of 4.8% (22). 
Furthermore, a meta-analysis performed in April 2016 reported 8,133 CT-guided core needle biopsy 
procedures. The pooled rate of pneumothorax requiring intervention was 5.6% (23) (e.g., clinically 
relevant pneumothorax requiring placement of chest tube). The published complication rate of 
endobronchial forceps biopsy is 4% rate of minor bleeding with endobronchial forceps biopsy (24) 
and 1.5% rate of pneumothorax (25). 
The following measures implemented in WINTHER will be applied to SPRING in order to mitigate 
any risk: 
• Biopsy of lowest risk lesion performed by experienced interventional radiologist, 
• As often as possible, biopsy of a liver lesion or lymph node (very low risk) to be chosen. 
An Independent safety and data monitoring committee (DSMB) will review the overall patient safety 
during the trial. 
In addition, the Informed Consent will be very detailed and clear about the risks of biopsy and the 
rationale for the dual biopsy approach. The interventional risk will be discussed with the patients in 
the context of the overall risk of their disease, the mortality risk of which is extremely high in lung 
cancer and will be juxtaposed to the potential benefits: Biopsies are a crucial component of the SIMS 
algorithm. 
 
 
2.8. SUMMARY OF RATIONALE BACKGROUND AND STRATEGY 
 
The standard of care in advanced disease—mainly cytototoxics or matched targeted monotherapies 
—has had modest impact on mortality as even responders inevitably develop resistance and succumb 
to their disease (7). Indeed, the fact that tumors are driven by multiple aberrant genes (9, 12, 13), and 
that resistance uniformly emerges in a Darwinian manner in patients treated with a single targeted 
therapy render the monotherapy paradigm unsuitable for most metastatic cancers.  
 
With the aim of further enhancing clinical benefit and increasing survival, we propose to test 
a triple therapy combination of novel targeted drugs in NSCLC. This mirrors the approach that has 
been so successful in treating AIDS and select cancer types, such as certain leukemias and malignant 
lymphomas.  
 
In the SPRING proof of concept trial, we selected three agents based on multiple criteria: 
− To limit the toxicity profile of the combination, we selected a modulator of immune check point 
(anti PD-L1) in association with two small molecule tyrosine kinase inhibitors (TKI): anti CDK 
4/6 (selective dual inhibitor of CDK 4/6) and an anti – VEGFR. The anti PD-L1 selected is 
avelumab, co-developed by MERCK and PFIZER. It demonstrated, so far, a good safety profile 
and is currently tested in various phase 3 programs (see Appendix 3). 
− The selected TKIs, palbociclib and axitinib (PFIZER), are approved in other indications and have 
individually also a safe toxicity profile (see Appendix 3). 
− Our data suggests a strong activation of these targets in a significant proportion of advanced 
NSCLC (see Appendix 4). 

SPRING Protocol version 2.0 May 20th 2019                       CONFIDENTIAL 
Page 22 of 99 
− We estimate that overall 85% of the patients treated in the trial will have a profile that is matched 
to at least one out of the three drugs: 10% matched with three drugs, 36% matched with two drugs 
and 39% matched with one drug.   
− The three agents were made available for combination by PFIZER. 
− Specific safety measures related to the administration of avelumab will be implemented in each 
participation center. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

SPRING Protocol version 2.0 May 20th 2019                       CONFIDENTIAL 
Page 23 of 99 
3. SPRING OBJECTIVES AND DESIGN 
 
 
3.1. PRIMARY OBJECTIVES 
 
• To determine the safety of the tested 3-drug combination therapy based on NCI CTCAE v4.03; 
June 14, 2010.  
 
• To assess activity parameters, including response rate (RR) by RECIST 1.1, duration of response, 
progression-free survival (PFS), overall survival (OS),  
 
• To correlate clinical outcome with the predicted SIMS matching through a retrospective study. 
 
Criteria of success: 
 
• We will document best response in all patients.  Patients shall be followed for at least six months 
on treatment (providing their tumors do not progress earlier) in order to document best response: 
The trial will be considered as meeting its primary endpoint if a 6-month response rate (% of 
patients achieving RECIST 1.1 complete or partial response within 6 months of treatment start) 
of 50% is achieved for patients who are fully matched according to the SIMS retrospective 
analysis and is superior to the partially matched arms. With a type I error of 10% and a power of 
94%, 20 patients fully matched will be enough to demonstrate the usefulness of the approach 
assuming a null response rate of 20% based on the one-sided Fisher’s exact test.  This would 
require a cohort of 200 patients treated. Nevertheless, we intend to treat an initial cohort of 100 
patients as an exploratory observational study. Pending clinical activity, the study could be 
extended to an additional 100 patients treated in order to attain sufficient statistical power to 
support the validity of the approach. 
 
• SIMS will show clinical utility: 
−  If the proportion of patients fully matched to the combination versus partially matched 
estimated using SIMS (20/80) is similar to the observed proportion in the SPRING cohort 
(maximum coefficient variability allowed 20%), 
− If fully matched patients show significantly better clinical outcomes than the partially 
matched ones and the fully or partially matched ones show significantly better clinical 
outcomes than the non-matched ones.  
 
 
3.2. SECONDARY OBJECTIVES 
 
• Describe any safety issues related to biopsy acquisition or drug combinations, 
 
• Describe genomic/transcriptomic aberrations seen in NSCLC. 
 
 
 

SPRING Protocol version 2.0 May 20th 2019                       CONFIDENTIAL 
Page 24 of 99 
3.3. SPRING STUDY DESIGN 
 
For the triple combination tested, we will conduct a seamless Phase 1/2 trial to establish the safety of 
the regimen and to identify the recommended Phase 2 dose.  
 
 
3.3.1. The Phase 1 
 
A Phase 1 study will be conducted to assess the safety of the triple combination and establish 
concentration of each of the agents: 
 
All patients enrolled in the Phase 1 of the study will be treated with the tested combination until 
progression unless toxicity occurs earlier. Eligible patients will be those with advanced/metastatic 
disease NSCLC with a maximum of two prior lines of treatment. Patients with already documented 
druggable oncogenic aberrations (EGFR mutations, ALK rearrangements, ROS1 or MET exon 14 
skipping mutations if available) will be excluded from the trial. All patients with adenocarcinoma 
histology must have documentation of results for druggable oncogenic aberrations (EGFR mutations, 
ALK rearrangements, and ROS1 when available) prior to enrollment on the study. 
In the case of patients already treated on SPRING protocol who are later determined to have EGFR 
mutation or ALK translocation or ROS1 or MET exon 14 skipping mutations after SIMS analyses, 
they will be asked to re-consent.  
Patients enrolled in the phase 1 study who receive the RP2D will also be included in the phase 2 
efficacy assessment.  All patients will undergo a tumor and normal tissue biopsy in order to obtain 
correlative genomic and transcriptomic data. 
 
 
Safety assessments for administration of avelumab in combination with palbociclib and axitinib 
 Blood chemistry and hematology assessments:  must be performed at baseline, every week 
during the first cycle and then prior to each avelumab dose, at end of treatment visit and at 30 
days post-treatment safety follow-up (+/- 3 days). 
 Monitor carefully proteinuria 
 Urine or blood pregnancy test for women of childbearing potential must be performed at 
baseline and at least every month during treatment. 
 Free T4 and TSH must be performed at baseline and at least every 8 weeks during treatment 
and at end of treatment or 30 days post-treatment safety follow-up (if not performed in the 
previous 8 weeks). Treat hypothyroidism and hyperthyroidism according to standard medical 
practice to maintain euthyroid state. 
 Blood pressure should be carefully monitored prior to initiating axitinib and after onset of 
the treatment, in particular after 4 days. 
 Monitor carefully all risk to arterial or venous thromboembolic event. 
 Monitor carefully active gastrointestinal bleeding. If any bleeding requires medical 
intervention, temporarily interrupt axitinib. 
 Monitor symptoms of gastrointestinal perforation or fistula periodically throughout treatment 
with axitinib. 
 ECG will be performed at the beginning of each treatment cycle (+/- 3 days). 

SPRING Protocol version 2.0 May 20th 2019                       CONFIDENTIAL 
Page 25 of 99 
During the phase 1, patients will be closely monitored as follows: 
− Within one week before day 1 of administration of the drugs, a full clinical examination will be 
performed, 
− During the first month, patients will be seen about every week, 
− Afterwards about every two weeks, 
− Extended safety follow-up: Given the potential risk for delayed immune-related toxicities, safety 
follow-up must be performed up to 90 days after the last dose of avelumab administration. The 
extended safety follow-up beyond 30 days after last study drug administration may be performed 
either via a site visit or via a telephone call with subsequent site visit requested in case any 
concerns noted during the telephone call. 
 
Treatment Plan: 
 
 
The phase 1 of the dual combination avelumab and axitinib has been done and RP2D of the 
combination has already been assessed (avelumab (10 mg/kg IV every two weeks -1/+3 days) and 
axitinib (5 mg po bid). These doses are used in the study JAVELIN Renal 101, a randomized phase 
3 trial, referenced at US Clinical Trials website: 
https://clinicaltrials.gov/ct2/show/NCT02684006?term=avelumab+and+axitinib&rank=1 
In order to add the third agent palbociclib, the dual drug combination dose will be reduced and the 
third drug will be added:  n ~ 30 patients.  
 
Dose level -1 
3 patients receiving avelumab (10 mg/kg IV every two weeks -1/+3 
days) and axitinib (2 mg po bid) and palbociclib at 75 mg po daily (7 
days off; 21 days on) 
Dose level 1 
3 patients receiving avelumab (10 mg/kg IV every two weeks -1/+3 
days) and axitinib (3 mg po bid) and palbociclib at 75 mg po daily (7 
days off; 21 days on)  
Dose level 2 
3 patients receiving avelumab (10 mg/kg IV every two weeks -1/+3 
days) and axitinib (5 mg po bid) and palbociclib at 75 mg po daily (7 
days off; 21 days on)  
Dose level 3 
3 patients receiving avelumab (10 mg/kg IV every two weeks -1/+3 
days) and axitinib (5 mg po bid) and palbociclib at 100 mg po daily (7 
days off; 21 days on)  
Dose level 4 
3 patients receiving avelumab (10 mg/kg IV every two weeks -1/+3 
days) and axitinib (5 mg po bid) and palbociclib at 125 mg po daily (7 
days off; 21 days on)  

SPRING Protocol version 2.0 May 20th 2019                       CONFIDENTIAL 
Page 26 of 99 
Important note (1) 
A new escalation will be performed after 4 weeks of observation of at 
least three patients at the previous level if no dose-limiting toxicity 
(DLT) is observed. 
If there is DLT at a dose level (clinically relevant, grade 3 or 4 toxicity 
or inability to complete 50% of treatment administration due to AEs) in 
the first four weeks, three new patients will be included at the same 
level. If a second patient has dose limiting toxicity at that dose level, the 
dose level will be declared above the MTD and the next lower dose 
level will be expanded to six patients from three patients. The next 
lower dose level will be declared the MTD providing that no more than 
1 patient of six has dose limiting toxicity (or < one third of patients have 
DLTs).  Once the presumed MTD is found, this dose will be set as the 
RP2D and the first part of the phase 2 study begins. Bayesian toxicity 
monitoring will be performed throughout the phase 2 study to ensure 
that the DLT for the tri-therapy is no more than 33% with high 
confidence.  If greater than or equal to one third of patients have DLT, 
then next lower dose is MTD and that dose will be expanded in the same 
way. 
Important note (2) 
The Clinical Monitoring Committee (CMC) constituted by all principal 
investigators will meet at least monthly by teleconference to discuss the 
patients included in the study, with the purpose of monitoring and 
managing any toxicity related issue. 
Important note (3) 
A key point will be to understand the contribution of each of the drugs 
in generating toxicities. To this purpose, the CMC will specifically 
investigate whether observed toxicities relate to overlapping effects 
(such as fatigue, nausea diarrhea) or specific toxicities (such as febrile 
neutropenia – palbociclib) or low platelets level (axitinib). Appendix 8 
describes all observed toxicities and outlines common or specific 
toxicities. Main toxicities specific to each drug are summarized in 
Important note (5). 
 
Rules in case of toxicity/dose modifications: 
For any Grade 3 dose-limiting toxicity (see page 32 for dose-limiting 
toxicity definitions) that is deemed to be drug specific, that drug will be 
held until resolution to <Grade 1. The drug will then be restarted with 
the dose at the next lowest level.  If Grade 3 or greater toxicity recurs, 
the drug will be permanently stopped. Exception is hematologic toxicity 
which may be handled as in Important note (5), palbociclib section or 
Important note (6). 
If a toxicity has been deemed to be due to a single drug, but persists 
at > grade 3 level after stopping the drug, all drugs will be stopped. 
 
If it is unclear as to the drug that is causing a toxicity, all three drugs 
will be held. 
 

SPRING Protocol version 2.0 May 20th 2019                       CONFIDENTIAL 
Page 27 of 99 
Toxicities that may be clearly attributable to avelumab include immune 
toxicities such as immune mediated pneumonitis, hepatitis, colitis and 
nephritis, and infusion related reactions. 
Toxicities clearly attributable to axitinib include hypertension and 
proteinuria. 
Toxicities clearly attributable to palbociclib include lowering of white 
blood cells (WBC) or platelet counts. 
For Grade 4 dose limiting toxicities, the drug to which it is attributable 
will be permanently stopped.  If it is not clear as to which drug is 
associated with the toxicity, all drugs will be permanently stopped.  
 
A Clinical Monitoring Committee (that includes site PIs) may be 
convened to help decide to which drug the toxicity is attributable. 
 
Important note (4) 
For dose interruption and reduction events, accurate medical 
administration records will be maintained to capture changes in dosing 
regimens, including concomitant medications. 
 
Important note (5):   
Below are the AEs specific to each drug, warnings/precautions and guidance for dose 
modifications/interruption of drugs. 
Palbociclib (IBRANCE): (reference USPI- IBRANCE) 
1. Capsules should be taken with food. Patients should be encouraged to take their dose of 
palbociclib at approximately the same time each day.  
2. If the patient vomits or misses a dose, an additional dose should not be taken. The next prescribed 
dose should be taken at the usual time. Palbociclib capsules should be swallowed whole (do not 
chew, crush or open them prior to swallowing). Capsules should not be ingested if they are 
broken, cracked, or otherwise not intact. 
3. It is known there is a potential for palbociclib to increase the exposure of axitinib through a time-
dependent CYP3A4 mediated drug-drug interaction. As a weak time-dependent CYP3A4 
inhibitor, palbociclib may reduce the clearance of axitinib, which may increase its exposure-
related toxicities. Therefore, it is advised to: Exclude patients currently taking strong CYP3A4 
inducers and inhibitors if an alternative concomitant medication cannot be used because they will 
increase the variability in PK for both axitinib and palbociclib, See Appendix 9. 
4. Exclude patients with moderate hepatic impairment from the dose escalation phase of the study or 
until the MTD for the combination regimen has been determined. The combined effect of 
CYP3A4 inhibition by palbociclib along with the reduced clearance observed in patients with 
moderate hepatic impairment on the PK of axitinib is unknown. See US package insert (PI) for 
axitinib for further details, 
5. Exclude patients currently taking proton pump inhibitors from the study due to their impact on the 
disposition of palbociclib during the dose escalation phase. Patients taking H2-receptor blockers 
and local antacids can be included in the dose escalation portion of the study as these classes of 
agents do not alter the PK of palbociclib. 
6. Grapefruit or grapefruit juice intake during the whole duration of the treatment should be avoided 
as it may increase concentration of the drug in blood. 
 

SPRING Protocol version 2.0 May 20th 2019                       CONFIDENTIAL 
Page 28 of 99 
Toxicity management 
The most common (≥2%) Grade ≥3 adverse reactions of palbociclib were neutropenia, leukopenia, 
anaemia, fatigue, and infections 
1. Monitor complete blood counts prior to starting palbociclib therapy and at the beginning of each 
cycle, as well as on Day 14 of the first 2 cycles, and as clinically indicated 
2. Dose interruption, dose reduction or delay in starting treatment cycles is recommended for 
patients who develop Grade 3 or 4 neutropenia 
3. Special warning is febrile neutropenia has been reported in about 1% of patients exposed to 
palbociclib. 
4. Guidelines for dose adjustments for hematologic toxicities attributable to palbociclib  
 Grade 3: No dose adjustment is required. Consider repeating complete blood count 
monitoring one week later. Withhold initiation of next cycle until recovery to Grade ≤ 2.  
 Grade 3 ANC (<1000 to 500 mm3) + Fever ≥ 38.5oC and/or infection: Withhold 
palbociclib and initiation of next cycle until recovery to Grade ≤ 2 (≥ 1000/mm3). Resume 
at next lower dose.  
 Grade 4: Withhold palbociclib and initiation of next cycle until recovery to Grade ≤ 2. 
Resume at next lower dose 
 
Axitinib (INLYTA) (reference USPI-INLYTA) 
1. Administer axitinib doses approximately 12 hours apart with or without food. Axitinib should be 
swallowed whole with a glass of water.  
2. If the patient vomits or misses a dose, an additional dose should not be taken. The next prescribed 
dose should be taken at the usual time. 
3. It is known there is a potential for palbociclib to increase the exposure of axitinib through a time-
dependent CYP3A4 mediated drug-drug interaction. As a weak time-dependent CYP3A4 
inhibitor, palbociclib may reduce the clearance of axitinib, which may increase its exposure-
related toxicities. Therefore, it is advised to: Exclude patients currently taking strong CYP3A4 
inducers and inhibitors if an alternative concomitant medication cannot be used because they will 
increase the variability in PK for both axitinib and palbociclib, see Appendix 9. 
4. Exclude patients with moderate hepatic impairment from the dose escalation phase of the study or 
until the MTD for the combination regimen has been determined. The combined effect of 
CYP3A4 inhibition by palbociclib along with the reduced clearance observed in patients with 
moderate hepatic impairment on the PK of axitinib is unknown 
5. Grapefruit or grapefruit juice intake during the whole duration of the treatment should be avoided 
as it may increase concentration of the drug in blood. 
Toxicity management 
The most common (≥20%) adverse reactions are diarrhea, hypertension, fatigue, decreased appetite, 
nausea, dysphonia, palmar-plantar erythrodysesthesia (hand-foot) syndrome, weight decreased, vomiting, 
asthenia, and constipation.  
1. Blood pressure should be well-controlled prior to initiating axitinib. Patients should be monitored 
for hypertension and treated as needed with standard anti-hypertensive therapy. The median onset 
time for hypertension (systolic blood pressure >150 mmHg or diastolic blood pressure >100 

SPRING Protocol version 2.0 May 20th 2019                       CONFIDENTIAL 
Page 29 of 99 
mmHg) was within the first month of the start of axitinib treatment and blood pressure increases 
have been observed as early as 4 days after starting. In the case of persistent hypertension despite 
use of anti-hypertensive medications, reduce the axitinib dose. Discontinue axitinib if 
hypertension is severe and persistent despite anti-hypertensive therapy and dose reduction of 
axitinib, and discontinuation should be considered if there is evidence of hypertensive crisis. If 
axitinib is interrupted, patients receiving antihypertensive medications should be monitored for 
hypotension 
2. Use axitinib with caution in patients who are at risk for, or who have a history of, arterial 
thromboembolic events (including transient ischemic attack, cerebrovascular accident, myocardial 
infarction, and retinal artery occlusion). Axitinib has not been studied in patients who had an 
arterial thromboembolic event within the previous 12 months.  
3. Use axitinib with caution in patients who are at risk for, or who have a history of venous 
thromboembolic events. Axitinib has not been studied in patients who had a venous 
thromboembolic event within the previous 6 months.  
4. Axitinib should not be used in patients with recent active gastrointestinal bleeding. If any bleeding 
requires medical intervention, temporarily interrupt the axitinib dose. 
5. Monitor for symptoms of gastrointestinal perforation or fistula periodically throughout treatment 
with axitinib.  
6. Monitor thyroid function before initiation of, and periodically throughout, treatment with axitinib. 
Treat hypothyroidism and hyperthyroidism according to standard medical practice to maintain 
euthyroid state. 
7. Discontinue axitinib in patients developing Reversible Posterior Leukoencephalopathy Syndrome 
RPLS is a neurological disorder which can present with headache, seizure, lethargy, confusion, 
blindness and other visual and neurologic disturbances. Mild to severe hypertension may be 
present. Magnetic resonance imaging is necessary to confirm the diagnosis of RPLS. The safety of 
reinitiating axitinib therapy in patients previously experiencing RPLS is not known.  
8. Monitoring for proteinuria before initiation of, and periodically throughout, treatment with 
axitinib is recommended. For patients who develop moderate to severe proteinuria, reduce the 
dose or temporarily interrupt axitinib treatment.  
9. Monitor ALT, aspartate aminotransferase (AST) and bilirubin before initiation of and periodically 
throughout treatment with axitinib. 
10. Monitor for cavitation apparition throughout the treatment with axitinib.  
 
Avelumab (BAVENCIO) 
Premedication: Premedication for the first four doses of avelumab is mandatory. An antihistamine and 
paracetamol (acetaminophen) 30 to 60 minutes prior to the first 4 doses of avelumab is preferred (for 
example, 25-50 mg diphenhydramine and 500-650 mg paracetamol IV or oral). Equivalents of these drugs 
can be used in case of allergy or other contraindication. Premedication should be administered for 
subsequent avelumab doses based upon clinical judgment and presence/severity of prior infusion 
reactions. 
Premedication may be modified based on local treatment standards and guidelines, as appropriate. 
Examples of premedication options include but are not limited to nonsteroidal anti-inflammatory drugs as 
well as non-sedating anti-histamines like Zyrtec (cetirizine hydrochloride). 
Setting: Avelumab should be administered in a setting that allows for immediate access to an intensive 
care unit or equivalent environment and administration of therapy for anaphylaxis, such as the ability to 

SPRING Protocol version 2.0 May 20th 2019                       CONFIDENTIAL 
Page 30 of 99 
implement immediate resuscitation measures. Steroids (dexamethasone 10 mg), epinephrine 
(1:1,000 dilution), allergy medications (IV antihistamines), bronchodilators, or equivalents, and oxygen 
should be available for immediate access.  
Instructions for Storage: Avelumab drug product must be stored at 2 °C to 8 °C until use and protected 
from light. Avelumab stored at higher temperatures for extended periods of time might be subject to 
degradation. Avelumab drug product must not be frozen. Rough shaking of the solution must be avoided. 
Instruction for Preparation: Avelumab drug product must be diluted with 0.9% saline solution (sodium 
chloride injection) supplied in an infusion bag; alternatively a 0.45% saline solution can be used if needed. 
The diluted solution is stable 8h at room temperature and up to 24h at 2–8 °C. 
Prior to the preparation of the dilution for final infusion, allow each vial to equilibrate to room 
temperature. Use a disposable syringe equipped with a needle of suitable size to remove a volume of 
sodium chloride solution to be replaced by avelumab from the infusion bag and discard the removed 
solution. Use a new disposable syringe equipped with a needle of suitable size to inject a volume of 
avelumab drug product identical to the discarded volume of sodium chloride solution into the infusion 
bag. Gently invert the mixture 10 times. Infusion bags must not be shaken, in order to avoid foaming or 
excessive shearing of the protein solution. The preparation must be carefully inspected as it should result 
in a homogeneous looking clear solution, free of visible particles. 
Avelumab should be administered as an approximately 90 to 120 minutes infusion for the first 
administration to avoid infusion-related reactions. For subsequent doses, it can be administered as a 60 
min or longer infusion. 
 
Toxicity Management (see Table 2, Table 3 and Table 4, in appendix 6): 
Adverse Drug Reactions requiring avelumab discontinuation or modification (Table 2) 
Treatment Modification for Symptoms of Infusion-Related Reactions (Table 3) 
Management of immune-mediated adverse reactions (Table 4) 
Understanding contribution of each of the three drugs in observed toxicities, and manage dose reductions. 
 
Observation period:  Following avelumab infusions, patients must be observed for 30 minutes 
post-infusion for potential infusion-related reactions. 
 
ADVERSE DRUG REACTIONS REQUIRING AVELUMAB DISCONTINUATION OR 
MODIFICATION 
Dose escalation or reduction is not recommended. Dosing delay or discontinuation may be required based 
on individual safety and tolerability (refer to Appendix 6). Resume avelumab in patients whose adverse 
reactions recover to Grade 1 or resolved. 
Any Grade 4 ADRs require permanent treatment discontinuation with avelumab except for 
single laboratory values out of normal range that are unlikely related to study treatment as 
assessed by the Investigator, do not have any clinical correlate, and resolve within 7 days with 
adequate medical management and endocrinopathies controlled with hormone replacement. 

SPRING Protocol version 2.0 May 20th 2019                       CONFIDENTIAL 
Page 31 of 99 
Any Grade 3 ADRs require treatment discontinuation with avelumab except for any of the 
following:  
• Transient (≤ 6 hours) Grade 3 flu-like symptoms or fever, which is controlled with medical 
management 
• Transient (≤ 24 hours) Grade 3 fatigue, local reactions, headache, nausea, emesis that resolves 
to Grade ≤ 1  
• Single laboratory values out of normal range (excluding Grade ≥ 3 liver function test increase) 
that are unlikely related to study treatment according to the Investigator, do not have any 
clinical correlate, and resolve to Grade ≤ 1 within 7 days with adequate medical management 
• Tumor flare phenomenon defined as local pain, irritation, or rash localized at sites of known 
or suspected tumor 
• Change in ECOG PS to ≥ 3 that does resolve to ≤ 2 within 14 days (infusions should not be 
given on the following cycle, if the ECOG PS is ≥ 3 on the day of study drug administration) 
 
Recurrent Grade 3 ADRs and Grade 3 infusion-related reaction require permanent 
discontinuation. 
Any Grade 2 ADR should be managed as follows: 
• If a Grade 2 ADR resolves to Grade ≤ 1 by the last day of the current cycle, treatment may 
continue. 
• If a Grade 2 ADR does not resolve to Grade ≤ 1 by the last day of the current cycle, infusions 
should not be given on the following cycle.  If at the end of the following cycle the event has 
not resolved to Grade 1, it should be treated as a Grade 3 or 4 (except for hormone 
insufficiencies, that can be managed by replacement therapy; for these hormone 
insufficiencies, up to 2 subsequent doses may be omitted). 
• Upon the second occurrence of the same Grade 2 ADR (except for hormone insufficiencies 
that can be managed by replacement therapy) in the same subject, treatment with avelumab 
has to be permanently discontinued. 
Important note (6): 
Specific protocol dose modification for toxicity management 
related to palbociclib: 
- 
In case of recurrent grade 3 hematologic toxicities, palbociclib 
may be reduced to 75 mg po daily one week off and one week 
on. 
 
- 
In case of other severe (≥ grade 3) toxicity related to 
palbociclib, consider holding palbociclib until toxicity is grade 
1 or less, then resume at the alternate schedule of 2 weeks 
OFF / 2 weeks ON. 
 
 
 

SPRING Protocol version 2.0 May 20th 2019                       CONFIDENTIAL 
Page 32 of 99 
• DLT will be defined as: 
Any of the following events that are considered to be clinically significant and meaningful as per 
evaluation of the attending physicians and confirmed by CMC and at least possibly related to 
drug. DLTs for the purposes of dose-escalation will be evaluated during the 28-day period 
following the first dose of study treatment. Each treatment cycle is four weeks. Toxicities will be 
graded and documented according the NCI CTCAE (v4.03).  
 
• Non-hematological dose-limiting toxicity is defined as: 
- 
Persistent Grade 3 or 4 hypertension despite treatment with anti-hypertensive drugs. 
- 
Grade 3 or 4 Gastrointestinal bleeding. 
- 
Grade 3 or 4 Gastrointestinal perforation or fistula. 
- 
Development of Reversible Posterior Leukoencephalopathy Syndrome. 
- 
Persistent Grade 3 or 4 proteinuria. 
- 
Grade 3 or 4 arterial or venous thromboembolic events. 
- 
Any other Grade 3 or Grade 4 non-hematological toxicity that are considered at least 
possibly related to a study drug and clinically significant after discussion at CMC with 
exceptions listed below: 
grade 3 nausea, vomiting, diarrhea, that responds to maximal supportive treatment(s) within 
3 days, grade 3 liver enzyme elevation, including ALT/AST/GGT that returns to Grade ≤1 
or baseline prior to the time for the next treatment cycle. 
− Allergic reactions that necessitate discontinuation of the study drug responsible for the 
reaction. 
− Any Grade > 2 pneumonitis of any duration. 
 
• Hematological dose-limiting toxicity is defined as:  
− Grade 4 neutropenia (absolute neutrophil count, ANC) for > 7 days 
− Platelet count <10.000/mm3 one time or bleeding requiring transfusion  
− Toxicity that causes a delay of >14 days between treatment cycles 
− Febrile neutropenia despite G-CSF secondary prophylaxis 
− Either isolated or recurrent (i.e., cardiac, renal, neurologic) toxicity that is judged by the 
Investigator to be a DLT. 
 
• Further evaluation of the combination’s toxicity at a dose level: 
Up to 3 additional patients could be added at a dose level to explore the toxicity on an occasional 
basis after discussion with the CMC. All additional patients will be included in the study’s 
assessment.  
 
• To decide for dose-escalation cohort at a higher dose level, the CMC that includes the study 
investigators and the sponsor clinical study team, will review available data (e.g. safety profile). 
Subsequent safety reviews by the CMC will be conducted prior to enrollment of patients in a new 
cohort and to establish the RP2D. 
 
• Intra-patient dose escalation:   
Patients will be permitted to have a dose escalation to the highest dose shown to be safe at the time 
of escalation, provided they have no clinically relevant drug-related toxicity > Grade 1 at the dose 

SPRING Protocol version 2.0 May 20th 2019                       CONFIDENTIAL 
Page 33 of 99 
level they are on and that both they and their physician deem a dose escalation to be in their interest.   
For a dose level to be considered proven safe, there must be at least three patients treated at that 
dose level for at least four weeks, and the clinical monitoring committee must have deemed that 
dose level to be at or below the MTD.  
 
• Dose reduction 
Patients who have a dose limiting toxicity and it is unclear as to which drug may have caused the 
toxicity, may restart drugs at the next lower dose level once toxicity returns to < Grade I. If the 
investigator deems the toxicity to be due to one of the drugs in the regimen, only that drug may 
need to be reduced to the next lower dose level.  A second dose reduction of this type may occur 
if toxicity recurs. For a patient who is responding (PR or CR) the investigator may continue to 
reduce the dose to the lowest dose level tolerable; for these responding patients, if one drug is 
deemed responsible for recurring serious toxicity, it may be stopped and the other two drugs 
continued after review by the clinical monitoring committee. 
 
 
 
3.3.2. The Phase 2 
 
When the recommended Phase 2 dose is reached, there will be a first expansion of the study to explore 
efficacy of the tested triple combination. In the expansion, only patients with unresectable or 
metastatic NSCLC with no prior treatment line will be treated.  Up to 100 patients will be treated with 
the combination (~120 patients enrolled*) until progression. For ethical reasons, even patients who 
failed biopsy(ies) will be treated with the triple-therapy. Pending clinical activity, the study may be 
extended (with a study amendment) to an additional 100 patients treated in phase 2 in order to attain 
sufficient statistical power to support the validity of the approach. 
Study participation will be offered to patients with locally advanced or metastatic disease. 
  
Patients with documented oncogenic aberrations (EGFR, ALK, ROS1 if available, MET exon 14 
skipping if available) at enrollment will be excluded from the trial. In the case of patients already 
treated on SPRING protocol who are later determined to have EGFR mutation or ALK translocation 
or ROS1 or MET exon 14 skipping mutations after SIMS analyses, they will be asked to re-consent.  
Patients will be included in the study regardless of their PD1 or PD-L1 expression status.  
Main outcome variables will include response rate (RR), progression-free survival (PFS), and overall 
survival (OS). 
 
 
 
 
 
 
 
 
 
 
 

SPRING Protocol version 2.0 May 20th 2019                       CONFIDENTIAL 
Page 34 of 99 
4. ENROLLMENT OF PATIENTS 
 
 
Patients will be identified as potential candidates for the SPRING trial and may consent to enrollment 
in SPRING and to related study procedures including biopsies from the tumor tissue (metastatic lesion 
or primary tumor), and from its histologically matched normal tissue (bronchial mucosa). 
Biopsies will be processed and investigations performed (i) to detect genomic alterations (in the case 
that this information is not already available from the patient’s file) in order to exclude the patient 
from the tested tri-therapy trial if such aberrations are detected, (ii) to generate the SIMS scoring. 
However, the scoring will not be used other than to establish correlations retrospectively between 
biological data and clinical outcome. All eligible patients will receive the triple combination. 
 
 
4.1. ELIGIBILITY CRITERIA 
 
Note: Eligibility criteria should be verified between consent and registration (28 days maximum 
window). 
For phase 1 and phase 2:    
 
• Age: Men and women aged >18 years, 
• Signed written informed consent, 
• Any histologic type of locally advanced or metastatic NSCLC,  
• Life expectancy of ≥ 12 weeks, 
• Measurable or evaluable (cytologically or radiologically detectable disease such as ascites, 
peritoneal deposits, or lesions which do not fulfill RECIST 1.1 criteria for measurable disease) 
lesions according to RECIST 1.1 criteria for phase 1 portion.    For phase 2, all patients must have 
RECIST 1.1 measurable disease, 
• PHYSIOLOGIC FUNCTION: 
 Hematologic:  Absolute neutrophil count (ANC) ≥ 1.5 × 109/L, platelet count ≥ 100 × 109/L, 
and hemoglobin ≥ 9 g/dL (may have been transfused), 
 Hepatic: Total bilirubin level ≤ 1.5 × the upper limit of normal (ULN) range and AST and 
ALT levels ≤ 2.5 × ULN, 
 Renal: Estimated creatinine clearance ≥ 30 mL/min according to the Cockcroft-Gault formula 
(or local institutional standard method). 
• PREGNANCY AND CONTRACEPTION: 
 Pregnancy test: Negative serum or urine pregnancy test at screening for women of 
childbearing potential.  
 Contraception: Highly effective contraception for both male and female subjects throughout 
the study and for at least 90 days after last treatment administration if the risk of conception 
exists.  
• Ability to comply with protocol requirements, 
• Willingness to consent and ability to undergo a trucut biopsy to obtain a fresh metastasis or primary 
tumor biopsy, and to undergo bronchoscopy to obtain a biopsy from normal bronchial mucosa, 

SPRING Protocol version 2.0 May 20th 2019                       CONFIDENTIAL 
Page 35 of 99 
• No serious or medically uncontrolled concomitant conditions that are likely to make the patient 
unfit for SPRING combination therapy, as per investigator assessment, 
• ECOG performance status of 0 to 1. 
 
 
4.2. EXCLUSION CRITERIA 
 
Note: Exclusion criteria should be verified between consent and registration (28 days maximum 
window). 
 
• Patients with documented oncogenic aberrations at enrollment: EGFR, ALK, ROS1 when 
available, MET exon 14 skipping when available. For squamous undifferentiated cell carcinoma, 
documentation of these aberrations is not mandatory. 
Note: For Phase 1 portion, all patients with adenocarcinoma histology must have documentation 
of results for druggable oncogenic aberrations (EGFR mutations, ALK rearrangements, and ROS1 
when available) prior to enrollment on the study. 
• For Phase 1 portion, >2 lines of prior therapy in the metastatic setting.  
• For the dose escalation phase of the study or until the MTD for the combination regimen has been 
determined, patients with moderate hepatic impairment defined as AST, ALT, ALP >5 times ULN, 
which would be grade 3 or higher. However, patients with liver metastases with AST/ALT ≤ 5 x 
ULN can be included in the study.  
• For Phase 2 portion, any prior therapy in the metastatic setting. 
 
Clinical criteria for phase 1 and phase 2 studies: 
• Patients with treated brain metastases are eligible as are patients with new, active untreated brain 
metastasis. 
• Participants with a history of myocardial infarction within the last 2 years or with significant 
cardiac arrhythmias uncontrolled by medication or pacemaker, 
• Participants with any history of interstitial lung disease, 
• Prior clinically significant toxicities from anticancer agents or radiotherapy which have not 
regressed to Grade ≤ 1 severity (NCI-CTCAE version 4.03) apart from peripheral neuropathy and 
alopecia, 
• History of any second malignancy in the last two years; patients with prior history of in-situ cancer 
or basal or squamous cell skin cancer are eligible.  Patients with a history of other malignancies 
are eligible if they have been continuously disease-free for at least two years, 
• Autoimmune condition requiring medical intervention, 
• Uncontrolled concomitant illness, active infection requiring i.v. antibiotics, 
• Patients who have had a thromboembolic event within six months are excluded, as are patients 
on anticoagulants, except for low dose aspirin (<100 mg/day) and low doses of anticoagulants 
meant to keep line access open;  
• Patients with Grade 3 or 4 (serious) gastrointestinal bleeding within the last six months are 
excluded. 
• Prior > G3 hemoptysis, major blood vessel involvement (specifically including aorta, superior 
and inferior vena cave, main pulmonary arteries and veins, subclavian arteries and veins and other 

SPRING Protocol version 2.0 May 20th 2019                       CONFIDENTIAL 
Page 36 of 99 
large blood vessels that in the investigator's opinion places the patients at high risk for major 
bleeding), and/or central cavitations,  
• Known or suspected drug hypersensitivity to any drug used in the combination, 
• Difficulty swallowing, malabsorption or other chronic gastrointestinal disease, or conditions that 
may hamper compliance and/or absorption of the oral drugs, 
• Any condition (e.g., known or suspected poor compliance, psychological instability, geographical 
location, etc.) that, in the judgment of the investigator may affect the patient’s ability to sign the 
informed consent and undergo study procedures, 
• Taking another experimental drug within 28 days prior to day 1 of the protocol medications in 
this study, 
• Pregnant or breast-feeding women, 
• Both male and female patients of reproductive potential must agree to use highly effective 
contraception, during the study and for 3 months following the last dose of study drug, 
• Patients currently taking strong CYP3A4 inducers and inhibitors, See Appendix 9. 
• Patients currently taking proton pump inhibitors due to their impact on the disposition of 
palbociclib during the phase 1.  
• Patients taking other anticancer agents with the exception of denosumab or equivalent medication 
for bone metastases. 
• A time period of at least three weeks (including radiotherapy) or five drug half-lives, whichever 
is shorter must have elapsed from last non-investigational therapy before first day of treatment on 
this study, 
• A time period of at least 10 days must have elapsed from last palliative radiotherapy before the 
first day of treatment on this study, 
• Specific exclusion criteria for administration of avelumab, in combination: 
 IMMUNOSUPRESSANTS:  Current use of immunosuppressive medication, EXCEPT for 
the following: a. intranasal, inhaled, topical steroids, or local steroid injection (e.g., intra-
articular injection); b. Systemic corticosteroids at physiologic doses ≤ 10 mg/day of 
prednisone or equivalent; c. Steroids as premedication for hypersensitivity reactions (e.g., CT 
scan premedication). 
 AUTOIMMUNE DISEASE:  Active autoimmune disease that might deteriorate when 
receiving an immuno-stimulatory agent.  Patients with diabetes type I, vitiligo, psoriasis, or 
hypo- or hyperthyroid diseases not requiring immunosuppressive treatment are eligible. 
 ORGAN TRANSPLANTATION:  Prior organ transplantation including allogenic stem-cell 
transplantation. 
 INFECTIONS: Active infection requiring IV (Intra venous) therapy.  
 HIV/AIDS: Known history of testing positive for HIV or known acquired immunodeficiency 
syndrome. 
 HEPATITIS: Hepatitis B virus (HBV) or hepatitis C virus (HCV) infection at screening 
(positive HBV surface antigen or HCV RNA if anti-HCV antibody screening test positive). 
 VACCINATION: Vaccination within 4 weeks of the first dose of avelumab and while on 
trials is prohibited except for administration of inactivated vaccines. 
 HYPERSENSITIVITY TO STUDY DRUG:  Known prior severe hypersensitivity to 
investigational product or any component in its formulations, including known severe 
hypersensitivity reactions to monoclonal antibodies (NCI CTCAE v4.03 Grade ≥ 3). 

SPRING Protocol version 2.0 May 20th 2019                       CONFIDENTIAL 
Page 37 of 99 
 CARDIOVASCULAR DISEASE:  Clinically significant (i.e., active) cardiovascular disease: 
cerebral vascular accident/stroke (< 6 months prior to enrollment), myocardial infarction (< 6 
months prior to enrollment), unstable angina, congestive heart failure (≥ New York Heart 
Association Classification Class II), or serious cardiac arrhythmia inadequately controlled by 
medication. 
 OTHER PERSISTING TOXICITIES:  Persisting toxicity related to prior therapy (NCI 
CTCAE v. 4.03 Grade > 1); however, alopecia, sensory neuropathy Grade ≤ 2, or other Grade 
≤ 2 not constituting a safety risk based on investigator’s judgment are acceptable. 
 Other severe acute or chronic medical conditions including colitis, inflammatory bowel 
disease, pneumonitis, pulmonary fibrosis or psychiatric conditions including recent (within 
the past year) or active suicidal ideation or behavior; or laboratory abnormalities that may 
increase the risk associated with study participation or study treatment administration or may 
interfere with the interpretation of study results and, in the judgment of the investigator, would 
make the patient inappropriate for entry into this study. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

SPRING Protocol version 2.0 May 20th 2019                       CONFIDENTIAL 
Page 38 of 99 
5. STUDY PROCEDURES 
 
 
5.1. INFORMED CONSENT 
 
Subjects will be asked to provide written consent using an IRB/EC-approved consent form. 
The investigator or study coordinator will obtain informed consent in a language understood by the 
prospective participant or their legally authorized representative, using certified translations of study 
documents and qualified translators, where applicable. Freely given informed consent will be 
obtained and documented for all subjects under this protocol (or a subject’s legal representative, if 
the subject is unable to provide informed consent) in accordance with ethical principles that have 
their origin in the Declaration of Helsinki and are consistent with the ICH guidelines on GCP, any 
applicable laws and requirements, and any conditions required by a Regulatory Authority and/or 
IRB/IEC. The investigator with assistance from the study coordinator will describe the study, 
including detailed information about risks, benefits, and voluntary nature of the study, to potential 
subjects. Subjects will be given ample time to read the consent form at the same visit or may take it 
with them to read at another time. Potential study subjects will be given the opportunity to ask any 
questions they may have about the study, including its risks and benefits, or about the consent form 
itself before signing the consent form. Each subject’s signed informed consent form(s) must be kept 
on file by the investigator for possible inspection by the sponsor or its designated monitors, auditors, 
or regulatory agency representatives. The patient or patient’s legal representative should receive a 
copy of the signed and dated written informed consent form(s) and any other written information 
provided to the subject, and should receive copies of any signed and dated consent form updates and 
any amendments to the written information provided to subjects. 
Patients who fulfill the eligibility criteria will be offered further participation in this study.  
Participants will also be requested to sign a separate authorization for the use of protected 
health information (i.e., HIPAA or other applicable privacy rules as per provisions of countries in 
which sites are active). Only patients who have consented and provided HIPAA authorization will 
have identifiers or linked information (e.g., study numbers, etc.) recorded on the 
Screening/Enrollment Log. 
 
Patients will be informed of the difference between receiving the combination of avelumab 
/anti PD-L1 (PFIZER/MERCK), palbociclib – Ibrance / CDK4/6 inhibitor (PFIZER) and axitinib - 
Inlyta / anti VEGFR (PFIZER) and the standard of care treatments that they could be receiving if they 
were not electing to participate in this study. Potential risks vs. potential benefits will be clearly 
presented so that patients can make an informed choice regarding their treatment. In particular, risks 
relating to any additional intervention (biopsy) than the standard of care will be detailed in the context 
of the overall risk of their disease.    
Patients with specific documented oncogenic aberrations (EGFR mutations, ALK translocations, 
ROS1 if available and MET exon 14 skipping mutation if available) will be excluded from the trial.  
Patients with unknown ROS 1 or MET exon 14 skipping mutation status at the time of enrollment 
who are later determined to have an actionable mutation amenable to treatment with an approved 
therapy can then be given the option to continue investigational treatment in the SPRING trial after 
obtaining appropriate re-consent or discontinue treatment. 

SPRING Protocol version 2.0 May 20th 2019                       CONFIDENTIAL 
Page 39 of 99 
5.2. MOLECULAR PROFILING OF TUMOR AND NORMAL BIOPSIES AND BLOOD 
SPECIMENS 
  
  
5.2.1. Collecting/processing methods of tissue biopsies 
Tissue biopsies will be collected and/or processed using WIN Consortium Standard Operating 
Procedures’ Manual. To summarize:    
 
1. The patient shall undergo a new tumor tissue biopsy. A minimum of 3 (but preferably 5) 
metastasis (or primary tumor) tissue samples from the patient will be obtained using 18 (or 20) 
gauges trucut biopsies under radiology control. The metastatic lesion chosen for the biopsy must 
be non-necrotic and preferably with a > 2 cm diameter. The needle will be placed at the periphery 
of the lesion so that the trucut (measuring 1.5 cm) remains within the metastasis in order to 
maximize tumor content and avoid contamination with surrounding stroma and normal tissues. 
The appropriate selection of the metastatic lesion biopsied is the most essential criteria to ensure 
success of the biopsies, 
2. A minimum of 3 (but preferably 5) random tissue samples from the patient’s normal bronchial 
mucosa will be obtained using minimum of 2.5 mm3 forceps under bronchoscopy. The normal 
bronchial mucosa biopsies can be done on any normal-appearing bronchial mucosa, with the 
safest location selected at the discretion of the pulmonologist performing the procedure. 
3. Up to 3 tumor biopsy specimens will be fresh frozen and if possible up to 2 stored in formalin-
fixed paraffin-embedded (FFPE) block.  
4. Normal tissue biopsy specimens up to 3 will be fresh frozen and if possible up to 2 stored in FFPE 
block.  
5. The tissue samples obtained from tumor/metastatic tissue and normal tissue will be used for 
histology control and preparation of nucleic acids (DNA and RNA) either at the cancer center or 
in the appointed central laboratory(ies) according to Standard Operating Procedures Manual. 
Histological control performed will determine the percentage of tumor cells and characterize the 
content of other components of the specimen (stroma, immune infiltrate, etc.) Acceptable 
tumor/metastasis and normal tissue biopsies will reach a threshold of 50% of tumor content and 
30% to 50% normal epithelial cells respectively, for performance of the genomic and 
transcriptomic analyses to generate the SIMS scoring. 
For FFPE specimens, macrodissection can be performed, if necessary, to ensure that 
tumor/metastatic tissue specimens reach the threshold of 50% tumor cells content. 
 
5.2.2. Control of variability and reduction of noise 
 
• The use of tumor/metastasis and normal matched tissue biopsies from the same patient will 
attenuate noise related to variability between individuals. The same applies for blood samples 
obtained from the same patient before and after treatment, 
• The use of dual biopsies enables the reduction by 16 folds the variance of micro arrays measuring 
gene expression in normal and tumor/metastasis tissues, 
• Strict control of histological preparations discards/minimizes inter-organ variability, 
• As much as possible, biopsies will be investigated in the same conditions. Genomic investigations 
will be performed by centralized laboratories in order to avoid inter-platform variability, 

SPRING Protocol version 2.0 May 20th 2019                       CONFIDENTIAL 
Page 40 of 99 
• Raw genomic data and clinical biological and pathology data will be merged into a single 
database. 
 
5.2.3. Molecular profiling of tissue biopsies 
 
Central genomics and transcriptomic platform(s) will be used. 
The following investigations will be done in the selected central platform(s): 
(i) Sequencing: A panel of 270 genes that will at least include the 183 cancer relevant genes of SIMS 
selected by capture will be sequenced using Illumina technology with a deep reading of at least 
1000x, according to Standard Operating Procedures (SOP) of WIN Consortium. The purpose is 
detection of mutations and all known translocations.  
Whilst only the sequencing data obtained on 183 SIMS genes will contribute to the evaluation of the 
2nd goal of the study (evaluation of the SIMS scoring), the sequencing will include other genes. This 
additional information will be used for other correlative studies, including an extensive study to 
predict efficacy to immunomodulators. 
(ii) Differential expression from tumor/metastatic tissue and normal tissue: 
Direct comparison of tumor/metastasis and normal mRNA will be performed to determine the 
differential expression levels between the two tissues for the 183 genes of the SIMS panel. 
Nevertheless, we will be using a large panel of probes (25,000) enabling the investigation of gene 
expression for almost all genes. 
Similarly, the top interacting 5 microRNA for each of the SIMS 183 genes will be investigated using 
the same method.  
Transcriptomic investigations (mRNA and MIR) for the purpose of validation of SIMS algorithm 
will be performed on RNA preparations from fresh frozen biopsies. Such investigations will be 
performed with validated technologies such as microarrays or RNAseq. 
FFPE biopsies might be used for ancillary analysis. Transcriptomic investigations might be done on 
FFPE samples with the objective to explore their correlation with frozen specimens and potentially 
determine if FFPE biopsies can indeed be used in the clinical setting and replace in the future frozen 
samples for RNA investigations. Also, will be explored the possibility to do proteomics correlative 
researches. 
 
 
5.2.4. Blood specimens for research purpose 
 
Blood specimens will be collected for each patient enrolled at baseline (before starting the treatment 
at Day 1 Cycle 1), one week after onset of the treatment and about every 8 weeks thereafter (Day 1 
before treatment of every odd cycles). Whilst data collected from blood will not be used for the 
therapeutic 
decision, 
they 
will 
be 
essential 
for 
further 
research 
into 
specific 
genomic/transcriptomic/proteomic markers that relate to predicting outcomes.  
− 10 ml blood will be collected. Blood specimens will be processed and stored locally in each 
participating center. Processing will consist in high speed centrifugation (4500g) collection of 
serum, and generation of 500 µl aliquots that will be stored at -80°C, 
− Requisition forms will be kept for record, 

SPRING Protocol version 2.0 May 20th 2019                       CONFIDENTIAL 
Page 41 of 99 
− Blood aliquots will be stored for further research, 
− Testing performed will be for research purpose only. 
 
 
5.2.5. Blood specimens for pharmacokinetics (PK) monitoring purpose 
 
The PK profile is known for each of the three drugs separately, as well as for the dual combination 
avelumab-axitinib.  
− The monitoring of PK in SPRING study has three purposes: 
1. Assess the simultaneous PK profile of the three drugs in combination and compare 
with known PK profiles, 
2. Determine if the PK profile of the three drugs in combination is stable across at least 
4 cycles, 
3. Monitor the apparition of auto-antibodies against avelumab (long term survey, after 4 
cycles). 
 
− To this aim, the blood collections will be performed on Day 15 visit of each cycle during phase 
1, for each dose level and every two cycles during the phase 2. The accurate monitoring will 
require that at each blood drawn we utilize a specific tube and conditions for processing, storage, 
shipment. The specific processing conditions and detailed protocols for each type of analyte, are 
described in appendix 7 and PK manuals. Briefly, monitoring of avelumab will require obtaining 
serum, whilst monitoring of palbociclib and axitinib will require obtaining plasma. Handling of 
tubes for axitinib will require protection from light. In addition, it is known that there is a potential 
for palbociclib to increase the exposure of axitinib through a time-dependent CYP3A4 mediated 
drug-drug interaction. As a weak time-dependent CYP3A4 inhibitor, palbociclib may reduce the 
clearance of axitinib, which may increase its exposure-related toxicities.  As a direct consequence, 
it will be mandatory to obtain PK blood samples at +0h45 and +1h15 after intake of palbociblib 
and axitinib, that is reflected in the PK steps below. Measurement of analytes will be performed 
in central laboratory(ies), based on suggestion made by Pfizer.  
 
− In order to have a maximal insight, we suggest the following blood draws for the day 15 of each 
cycle (as detailed in Table1): 
 
 Step 1 Time 0 – in the morning of day 15, obtain blood for baseline PK samples, 
 Step 2 Intake of palbociclib and axitinib with meal/food, 
 Step 3 Time 0h45 - Obtain PK samples, after intake of axitinib and palbociclib, 
 Step 4 Time 1h15 - Obtain PK samples, after intake of axitinib and palbociclib, 
 Step 5 Time 2h – Obtain PK samples, after intake of axitinib and palbociclib, 
 Step 6 Premedicate 30 to 60 minutes prior the avelumab infusion (in a facility with easy 
access to intensive care unit) 
 Step 7 Obtain PK samples 4h after intake of axitinib and palbociclib and immediately prior 
to start of the infusion with avelumab 
 Step 8 Administer avelumab for one hour, 
 Step 9 Obtain PK samples immediately at the end of the avelumab infusion,  
 Step 10 Obtain PK Samples 1 h, 2h, 3h, 4h and 5h after infusion with avelumab 

SPRING Protocol version 2.0 May 20th 2019                       CONFIDENTIAL 
Page 42 of 99 
Note that PK samplings must be recorded in PK requisition form. 
All PK samples are allowed to be drawn with a +/- 5 minutes window. 
Table 1: Overview of PK sampling 
Step 
Time 
Action 
Time points 
axitinib 
Time points 
palbociclib 
Time points 
avelumab 
1 
0 
PK blood drawn (separate tubes 
4 ml: one for each analyte axitinib 
and palbociclib) 
Baseline (0) 
(pre-dose) 
Baseline (0) 
(pre-dose) 
 
2 
 
Oral intake of palbociclib and 
axitinib with meal 
 
 
 
3 
+ 0h45 
PK blood drawn (separate tubes 
4 ml: one for each analyte axitinib 
and palbociclib) 
+ 0h45 
+ 0h45 
 
4 
+ 1h15 
PK blood drawn (separate tubes 
4 ml: one for each analyte axitinib 
and palbociclib) 
+ 1h15 
+ 1h15 
 
5 
+ 2h 
PK blood drawn (separate tubes 
4 ml: one for each analyte axitinib 
and palbociclib) 
+ 2h 
+ 2h 
 
6 
 
Premedication for avelumab 
 
 
 
7 
+ 4h 
PK blood drawn for all 3 analytes 
+ 4h 
+ 4h 
Baseline (0) 
before infusion 
8 
 
Infusion with avelumab (1h) 
 
 
 
9 
+ 5h 
PK blood drawn Immediately 
after the end of avelumab 
infusion for avelumab 
 
 
Immediately 
at the end of 
the infusion 
10 
+6h 
PK blood drawn for each of the 3 
analytes  
+ 6h 
+ 6h 
+1h after the 
end avelumab 
infusion 
10 
+7h 
PK blood drawn for avelumab  
 
 
+2h 
10 
+8h 
PK blood drawn for each of the 3 
analytes  
+ 8h 
+ 8h 
+3h 
10 
+9h 
PK blood drawn for avelumab  
 
 
+4h 
10 
+10h 
PK blood drawn for avelumab 
 
 
+5h 
 
The apparition of auto-antibodies against avelumab will be monitored during the phase 2: 1 
blood sample of 4 mL will be collected on Day 15 at baseline every two months. 
 
 
 
 
 

SPRING Protocol version 2.0 May 20th 2019                       CONFIDENTIAL 
Page 43 of 99 
5.3. BIOINFORMATICS AND DATA MANAGEMENT 
 
A centralized IT structure will be set up to support the data collection and analyses. 
 
(i) Central Bioinformatics platform will collect and will enable analysis of all data related to the study: 
− Clinical data through CRF or eCRF generated by each participating cancer center,  
− Quality Controls at all steps of the biological workflow generated by local and central 
laboratories, 
− Raw biological data generated by both genomics/transcriptomics and proteomics platforms. 
 
(ii) The bioinformatics platform will also run the SIMS scoring algorithm. The SIMS report including 
a comprehensive list of co-activated interventional points for the patient will be issued.  
IT infrastructure, database and tools/algorithms will be coordinated by IT team coordinator.  
 
 
5.4. PROCEDURES DURING TREATMENT 
 
Refer to study Flow Chart in Appendix 5 and study assessment manual for further directions at the 
discretion of the investigator. 
 
As dictated by standard of care, tumor assessments are to be done approximately every 8 weeks (+/- 
7 days).  
 
Safety assessments 
 Blood chemistry and hematology assessments:  must be performed at baseline, every week 
during the first cycle and then prior to each avelumab dose, at end of treatment visit and at 30 
days post-treatment safety follow-up (+/- 3 days). Complete Blood Count (CBC), Complete 
Metabolic Profile (CMP), amylase, lipase, and urine protein by dipstick are recommended. 
 Monitor carefully proteinuria. If the patient has 3+ proteinuria on dipstick, this should trigger 
a 24-hour urine to quantify the proteinuria so that it can be graded. 
 Urine or blood pregnancy test for women of childbearing potential must be performed at 
baseline and at least every month during treatment. 
 Free T4 and TSH must be performed at baseline and at least every 8 weeks during treatment 
and at end of treatment or 30 days post-treatment safety follow-up (if not performed in the 
previous 8 weeks). Treat hypothyroidism and hyperthyroidism according to standard medical 
practice to maintain euthyroid state. 
 Blood pressure should be carefully monitored prior to initiating axitinib and after onset of 
the treatment, in particular after 4 days. 
 Monitor carefully all risk to arterial or venous thromboembolic event. 
 Monitor carefully active gastrointestinal bleeding. If any bleeding requires medical 
intervention, temporarily interrupt axitinib. 
 Monitor symptoms of gastrointestinal perforation or fistula periodically throughout treatment 
with axitinib. 
 ECG will be performed at the beginning of each treatment cycle (+/- 3 days). 

SPRING Protocol version 2.0 May 20th 2019                       CONFIDENTIAL 
Page 44 of 99 
Other minor modifications of scheduled visits or medication administration for medical, personal, or 
logistical reasons may be done after CMC discussion providing that CMC determines that 
modifications do not impact patient safety. 
 
 
5.5. FOLLOW-UP PROCEDURES 
 
Extended safety follow-up 
 The Clinical Monitoring Committee (CMC) constituted by all principal investigators will 
meet at least monthly by teleconference to discuss all the patients included in the study, with 
the purpose of monitoring and managing any toxicity related issue.  
 Given the potential risk for delayed immune-related toxicities, safety follow-up must be 
performed up to 90 days after the last dose of avelumab administration. The last patient 90-
day follow-up visit is defined as the last patient last visit. 
 The extended safety follow-up beyond 30 days after last study drug administration may be 
performed either via a site visit or via a telephone call with subsequent site visit requested in 
case any concerns noted during the telephone call.  
 
After the patient comes off study, follow up to determine survival will be done for 2 years every 6 
months. Follow-up will consist of survival contacts via medical record review, telephone call, or 
review of the Social Security Index. 
 
 
 
5.6. SAFETY REPORTING 
 
5.6.1. Adverse events 
 
The Principal Investigator is responsible for ensuring that all staff involved in the study is 
familiar with the content of this section. 
 
5.6.1.1. 
Definition of adverse events 
 
 
An adverse event (AE) is any untoward medical occurrence or worsening of a pre-existing 
medical condition in a patient or clinical investigation subject. An AE can therefore be any 
unfavorable and unintended symptoms (eg, nausea, chest pain), signs (eg, tachycardia, enlarged liver) 
or the abnormal results of an investigation (eg, laboratory findings, electrocardiogram), whether or 
not a causal relationship (i.e related/not related) with investigational medicinal products and/or the 
study procedures is suspected.  In clinical studies, an AE can include an undesirable medical condition 
occurring at any time, including run-in or washout periods, even if no study treatment has been 
administered. 
 
The term AE is used to include both serious and non-serious AEs. 
 

SPRING Protocol version 2.0 May 20th 2019                       CONFIDENTIAL 
Page 45 of 99 
5.6.1.2. 
Definition of serious adverse events 
 
For detailed definition and example, refer to the Pfizer Safety Report Reference Manual. 
 
A serious adverse event (SAE) is an AE occurring during any study phase (i.e., run-in, treatment, 
washout, follow-up), that fulfills one or more of the following criteria: 
− Results in death 
− Is immediately life-threatening: An adverse event is life-threatening if the subject was at 
immediate risk of death from the event as it occurred i.e. does not include a reaction that might 
have caused death if it had occurred in a more serious form. For instance, drug induced 
hepatitis that resolved without evidence of hepatic failure would not be considered life 
threatening even though drug induced hepatitis can be fatal.  
− Requires in-patient hospitalization (even if for less than 24 hours) or prolongation of existing 
hospitalization (any extension beyond the anticipated/required stay for the original reason for 
admission or beyond the length of stay described in the protocol) 
− Results in persistent or significant disability/incapacity or substantial disruption of the ability 
to conduct normal life functions 
− Results in a congenital abnormality or birth defect 
or 
− Is an important medical event that may not result in death, be life-threatening, or require 
hospitalization 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 medical events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home, blood 
dyscrasias or convulsions that do not result in inpatient hospitalization, or the development of 
drug dependency or drug abuse. 
An important medical event also includes suspected transmission via avelumab, axitinib, 
palbociclib or another Pfizer product of an infectious agent, pathogenic or non-pathogenic, or 
development of drug dependency or drug abuse of any product (whether avelumab, axitinib, 
palbociclib, another Pfizer product or any non-Pfizer product). 
 
The following are not considered to be serious adverse events (SAE): 
− A visit to the emergency room or other hospital department for less than 24 hours that does 
not result in admission  
− Outpatient or same-day or ambulatory procedures 
− Observation or short-stay units without an AE 
− Hospitalization due to diagnostic procedures or standard supportive care (e.g. implant of 
central venous catheter) 
− A pre-planned hospitalization for a condition which existed at the start of study drugs and 
which is not associated with the development of a new AE or which do not worsen during the 
course of study drugs treatment 
− Social admission (e.g., subject has no place to sleep; hospice facilities) 
− Administrative admission (e.g., for yearly physical examinations) 

SPRING Protocol version 2.0 May 20th 2019                       CONFIDENTIAL 
Page 46 of 99 
− Protocol-specified admission during a clinical trial (e.g., for a procedure required by the study 
protocol or for clinical research) 
− Optional admission not associated with a precipitating clinical AE (e.g., for elective cosmetic 
surgery) 
 
 
5.6.2. Recording of adverse events 
 
5.6.2.1. 
Time period for collection of adverse events 
 
AEs will be collected throughout the study, from informed consent until the end of the follow-
up period. The follow-up period is defined as 90 +/-7 days after study treatment is discontinued. 
SAEs occurring in the follow-up period should be reported to the sponsor as described on 
section 5.6.3. 
 
5.6.2.2. 
Follow-up of unresolved adverse events 
 
AEs that are unresolved at the patient’s last visit in the study are followed up by the 
investigator for as long as medically indicated, but without further recording in the CRF. 
Covance pharmacovigilance unit retains the right to request additional information for any 
patient with ongoing AE(s) at the end of the study, if judged necessary. 
 
If an investigator learns of any SAEs, including death, at any time after a patient has completed 
the study and he/she considers there is a reasonable possibility that the event is related to axitinib, 
avelumab and palbociclib, the investigator should notify the pharmacovigilance unit of the sponsor.  
 
5.6.2.3. 
Variables 
 
The following variables will be collected for each AE: 
− AE diagnosis/description 
− The date when the AE started and stopped 
− CTCAE grade maximum intensity 
− Whether the AE is serious or not 
− Investigator causality rating against the investigational product 
− Action taken with regard to investigational product 
− Outcome 
 
The grading scales found in the current National Cancer Institute CTCAE version 4.03 will 
be used for all events with an assigned CTCAE grading. For those events without assigned CTCAE 
grades, the recommendation in the CTCAE criteria that converts mild, moderate and severe events 
into CTCAE grades should be used. A copy of the current CTCAE version can be downloaded from 
the Cancer Therapy Evaluation Program website (http://ctep.cancer.gov). 
 
 
 

SPRING Protocol version 2.0 May 20th 2019                       CONFIDENTIAL 
Page 47 of 99 
5.6.2.4. 
Causality collection 
 
The causal relationship between the study medication and the AE must be characterized as 
not related, unlikely, possible/probable, or definitely by the investigator. Drug-related events will be 
defined as those with a possible/probable or definite classification. 
 
 
5.6.2.5. 
Adverse events based on signs and symptoms 
 
All AEs spontaneously reported by the patient or care provider or reported in response to the 
open question from the study personnel: ‘Have you had any health problems since the previous 
visit/you were last asked?’, or revealed by observation will be collected and recorded in the CRF. 
 
 
When collecting AEs, recording of diagnoses is preferred (when possible) to recording a list 
of signs and symptoms. However, if a diagnosis is known and there are other signs or symptoms that 
are not generally part of the diagnosis, the diagnosis and each sign or symptom will be recorded 
separately. 
 
5.6.2.6. 
Adverse events based on examinations and tests 
 
The results from protocol mandated laboratory tests, vital signs, ECGs and other safety 
assessments will be summarized in the Clinical Study Report. Deterioration as compared to baseline 
in these parameters will therefore only be reported as AEs if they fulfill any of the criteria for a SAE, 
a DLT or are the reason for discontinuation of treatment with the investigational product(s) unless 
clearly due to progression of disease under study (section 5.6.2.7). 
 
If deterioration in a laboratory value, vital sign, ECG or other safety assessment is associated 
with clinical signs and symptoms, the sign or symptom will be reported as an AE and the associated 
laboratory result or other finding will be considered as additional information. 
 
Wherever possible the reporting investigator uses the clinical, rather than the laboratory term 
(eg, anemia versus low hemoglobin value). In the absence of clinical signs and symptoms, clinically 
relevant deteriorations in non-mandated parameters should be reported as AE(s). 
Deterioration of a laboratory value that is unequivocally due to disease progression should not 
be reported as an AE. 
Any new or aggravated clinically relevant abnormal medical finding at a physical examination 
as compared with the baseline assessment will be reported as an AE. 
 
 
5.6.2.7. 
Disease progression 
 
Disease progression can be considered as a worsening of a patient’s condition attributable to 
the disease for which the investigational products are being studied. It may be an increase in the 
severity of the disease under study and/or increases in the symptoms of the disease. The development 
of new, or progression of existing metastasis to the primary cancer under study should be considered 

SPRING Protocol version 2.0 May 20th 2019                       CONFIDENTIAL 
Page 48 of 99 
as disease progression and not an AE. Events that are unequivocally due to disease progression should 
not be reported as AEs/SAEs during the study. 
Progression of the disease under the study is reportable only if the patient dies of the disease 
progression within the study reporting period. Hospitalization due to signs and symptoms of 
malignancy progression should not be reported. 
 
 
5.6.2.8. 
New cancers 
 
The development of a new cancer should be regarded as an AE and will generally meet at 
least one of the serious criteria. New cancers are those that are not the primary reason for the 
administration of the study treatment and have been identified after the patient’s inclusion in this 
study. They do not include metastases of the original cancer. 
 
 
5.6.2.9. 
Handling of deaths 
 
All deaths that occur during the study, or within the follow-up period after the administration 
of the last dose of investigational product, should be reported as follows: 
 
− Death, which is unequivocally due to disease progression within the study reporting period 
should  be reported as a SAE. 
− Where death is not clearly due to disease progression of the disease under study the AE 
causing the death should be reported to the sponsor as an SAE immediately upon awareness. 
The report should contain a comment regarding the co-involvement of progression of disease, 
if appropriate, and should assign a single primary cause of death together with any 
contributory causes. 
− Deaths with an unknown cause should always be reported to the sponsor as a SAE but every 
effort should be made to establish a cause of death. Include a summary of autopsy findings, if 
available. 
 
5.6.2.10. Handling of exposure during breastfeeding 
 
An exposure during breastfeeding occurs if an infant or child may have been exposed through breast 
milk to the Pfizer/Merck product during breastfeeding by a female taking the Pfizer/Merck product. 
Exposure during breastfeeding is reportable to the pharmacovigilance unit regardless of whether there 
is an associated SAE in the infant or child. 
 
 
5.6.2.11. Handling of exposure during pregnancy 
 
Exposure during pregnancy occurs when a fetus (from pre-embryo to birth) may have been exposed 
at any time during the pregnancy to a Pfizer/Merck product. Exposure during pregnancy is reportable 
to the pharmacovigilance unit regardless of whether there is an associated SAE. 

SPRING Protocol version 2.0 May 20th 2019                       CONFIDENTIAL 
Page 49 of 99 
The specific details that need to be included in the report of an Exposure during Pregnancy depend 
on whether the exposure was maternal or paternal. The anticipated date of delivery should be included 
in the report, for both maternal and paternal exposures. The principal investigator must then follow 
the subject through the pregnancy and is to notify the sponsor and Pfizer/Merck of the outcome as a 
follow-up to the initial exposure during the pregnancy report. 
An Exposure During Pregnancy Occurs Through Either: 
- 
Maternal exposure 
A female subject becomes, or is found to be, pregnant either while receiving or having been exposed 
to a medicinal product, or the female becomes, or is found to be, pregnant after discontinuing or 
being exposed to the medicinal product 
A pregnant woman may have an environmental exposure involving direct contact with a 
Pfizer/Merck product (e.g., a nurse reports that she is pregnant and has been exposed to 
chemotherapeutic products by inhalation or spillage) 
 
OR 
- 
Paternal exposure 
A male subject has been exposed, either due to treatment or environmental exposure, to a medicinal 
product prior to or around the time of conception of his child or during his partner’s pregnancy. 
 
If the outcome of the pregnancy meets any of the criteria for seriousness, report it to 
the pharmacovigilance unit as an SAE.  
 
Examples of pregnancy outcomes that are SAEs: 
− Spontaneous abortion (includes miscarriage and missed abortion) 
− Stillbirth 
− Congenital anomaly (including in an aborted fetus,  a stillborn infant, or neonate that 
dies shortly after birth) 
− Neonatal death 
 
In the case of neonatal death: 
− Any neonatal death that occurs within 1 month of birth should be reported, without 
regard to causality, as an SAE 
 
In the case of infant death: 
− Any infant death that is assessed as possibly related to the in utero exposure to the Pfizer 
product or blinded therapy should be reported as an SAE. 
 
 
5.6.2.12. Occupational exposure 
 
An occupational exposure is an exposure to a Pfizer/Merck product for human use as a result of one’s 
occupation. An occupational exposure is reportable regardless of whether there is an associated SAE. 
 
 
 
 

SPRING Protocol version 2.0 May 20th 2019                       CONFIDENTIAL 
Page 50 of 99 
5.6.2.13. Potential drug-induced liver injury (Hy’s law cases) 
 
For Pfizer investigational (non-authorized) medicinal products and Pfizer products that are 
investigational in the United States (irrespective of being authorized elsewhere), interventional 
clinical study reports with elevations in aspartate aminotransferase (AST) and/or alanine 
aminotransferase (ALT) in addition to and/or preceding total bilirubin (TBili) elevations (>2 x ULN) 
are considered potential drug-induced liver injury (DILI- assessed per Hy’s law criteria) cases and 
should always be considered important medical events and should be reported as SAEs, even before 
all other possible causes of liver injury have been excluded.   
 
The threshold of laboratory abnormalities for a potential DILI case depends on the subject’s 
individual baseline values and underlying conditions.  Subjects who present with the following 
laboratory abnormalities should be evaluated further as potential DILI (Hy’s law) cases to definitively 
determine the etiology of the abnormal laboratory values: 
 
• Subjects with AST/ALT and TBili baseline values within the normal range who 
subsequently present with AST or ALT values >3 x ULN and a TBili value >2 × ULN with 
no evidence of hemolysis and an alkaline phosphatase value <2 × ULN or not available. 
• For subjects with baseline AST or ALT or TBili values above the ULN, the following 
threshold values are used in the definition mentioned above, as needed, depending on which 
value(s) are above the ULN at baseline. 
• Preexisting AST or ALT baseline values above the normal range: AST or ALT values >2 
times the baseline values and >3 × ULN; or >8 × ULN (whichever is smaller). 
• Preexisting values of TBili above the normal range: TBili level increased from baseline value 
by an amount of at least 1 × ULN or if the value reaches >3 × ULN (whichever is smaller). 
 
Rises in AST/ALT and TBili separated by more than a few weeks are assessed individually based on 
clinical judgment; any case where uncertainty remains as to whether it might represent a potential 
DILI case is reviewed with the sponsor.  The investigator coordinator is informed if such a situation 
occurs during the study and she will inform the HIC that will provide the necessary support for an 
appropriate evaluation. 
 
 
5.6.3. Reporting of Serious Adverse Events 
 
Any SAE which occurs or comes to the attention of the investigator at any time during the 
study since consent is given and within 90 days (+/-7 days) after the last dose of study drugs, have to 
be reported to the sponsor's appointed pharmacovigilance unit without delay and in no circumstances 
later than 24 hours after first awareness by the investigator, whether or not considered causally related 
to the investigational product, or to the study procedure(s), by fax/email via a SAE report form 
according to the study procedure. 
 
 
 
 
 

SPRING Protocol version 2.0 May 20th 2019                       CONFIDENTIAL 
Page 51 of 99 
Fax number: +1.888.887.8097 
Phone: +1.888.724.4908 
E-mail: SAEIntake@Covance.com 
(9 a.m. - 6 p.m. from Monday to Friday, except on bank holidays) 
Pharmacovigilance unit address: 
Covance 
206 Carnegie Center Blvd 
Princeton, NJ 08540, USA  
All late Serious Adverse Events (occurring after this period of 90 days) considered to be 
reasonably related to the IMPs or the protocol must be reported (no time limit). 
 
Information collected in the SAE form is crucial to assess the case. For this reason, diligence 
in collecting as much verifiable and reliable information is needed: both, quality and timeliness are 
key factors. If known, the diagnosis of the underlying illness or disorder should be recorded, rather 
than its individual symptoms. The following information should be captured for all SAEs: onset, 
duration, intensity, seriousness, relationship to study drugs and/or to the protocol, action taken and 
corrective treatment required. 
The investigator must also attach the following to the serious adverse event report form, 
wherever possible: 
 A copy of the summary of hospitalization or prolongation of hospitalization 
 A copy of the post-mortem report (if applicable) 
 A copy of all relevant laboratory examinations and the dates on which these examinations 
were carried out, including relevant negative results, as well as normal laboratory ranges. 
 All other document that he judges useful and relevant. 
 
All these documents will remain anonymous. 
Further information can be requested (by fax, telephone, email or when visiting) by the monitor and/or 
the safety manager. 
 
 
 
Follow-up information 
− The investigator is responsible for the appropriate medical follow-up of patients until 
resolution or stabilization of the adverse event or until the patient's death. This may mean that 
follow-up should continue once the patient has left the trial. 
− Follow up information about a previously reported serious adverse event must be reported by 
the investigator to the Pharmacovigilance Unit within 24 hours of receiving it (on the serious 
adverse event report form, by ticking the box marked Follow-up Nr). The investigator also 
transmits the final report at the time of resolution or stabilization of the SAE. 
− The investigator retains the documents concerning the supposed adverse event so that 
previously transmitted information can be completed if necessary. 
All SAEs will be recorded in the CRF. 
 
The Sponsor is responsible for meeting all local regulatory safety reporting requirements and 
obligations in all countries participating in this trial.  This includes expedited reporting of all serious, 

SPRING Protocol version 2.0 May 20th 2019                       CONFIDENTIAL 
Page 52 of 99 
unexpected and possibly study-drug-related SAEs (SUSARs) from the study to the local Regulatory 
Authority and IEC/IRB, as required and to the EMA pharmacovigilance database (Eudravigilance).   
 
All SAEs information will be transferred to Pfizer. 
 
 
5.7. REMOVAL OF SUBJECTS FROM STUDY 
 
Patients can be taken off the study at any time at their own request, or they may be withdrawn at the 
discretion of the investigator for behavioral or administrative reasons. The reason(s) for 
discontinuation will be documented and may include: 
• Patient withdraws consent, 
• Patient is unable to comply with protocol requirements, 
• Treating physician judges continuation on the study would not be in the patient’s best interest. 
 
 
5.8. EFFICACY EVALUATION 
 
Efficacy evaluation will be primarily based on investigator assessment: 
 
• Best Overall Response: Best response is the maximal response recorded from the start of a 
treatment until the end of treatment taking into account any requirement for confirmation. 
• 6-month Response: The primary endpoint of the study is defined as the 6-month response rate 
(proportion of patients with complete or partial response based on the RECIST 1.1 criteria) 
from the start of treatment.  
• Progression-Free Survival: Progression-free survival (PFS) is defined as the duration of time 
from the start of treatment until tumor progression or death, 
• Overall Survival: Overall survival (OS) is defined as the duration of time from the start of 
treatment to death. 
 
PFS may include review of CT images. CT or MRI scans will be performed as per routine 
institutional practice. Patients will be considered evaluable if they received at least one cycle of 
treatment and had their baseline scan within 28 days of the start of therapy and follow-up scans about 
every 8 weeks (+/- 7 days) thereafter. The same imaging technology (i.e., CT or MRI as preferred by 
the physician) as used at baseline will be required at all follow up examinations. Since previous 
studies suggest that early radiographic response assessment of patients receiving immunotherapy may 
initially meet RECIST criteria for progressive disease only to demonstrate response or stable disease 
on a subsequent scan, the investigator may consider performing a confirmatory scan 4 weeks after 
progression to confirm this finding if clinically indicated. If the disease is confirmed to meet RECIST 
criteria for progression, the patient will no longer be treated on the study. However, if criteria are not 
met for progression, the patient may continue on the study, and radiographic assessment will continue 
on 8 week intervals thereafter. 
 
 
Target lesions will be selected on the basis of their size (lesions with the longest diameter) 
and their suitability for accurate repeated measurements (either by imaging techniques or clinical 

SPRING Protocol version 2.0 May 20th 2019                       CONFIDENTIAL 
Page 53 of 99 
assessment). Target lesions at screening/baseline must have a unilateral tumor measurement of at 
least 2 times the size of the CT/MRI scan interval cut. The longest diameters for all target lesions will 
be recorded and a sum of the longest diameter (LD) for all target lesions will be calculated and 
reported as the baseline sum LD. At baseline, all measurable lesions up to a maximum of 5 lesions 
per organ systems and 10 lesions in total should be identified as target lesions, ideally representative 
of all involved organs. 
 
5.9. DATA COLLECTION 
 
This study will require analysis of all data generated on all patients for whom the biomarker molecular 
analysis was performed. Data will include, but will not be limited to, information about side effects, 
efficacy and patient demographics as well as any biological monitoring performed during the 
treatment. 
 
 
5.10. 
ETHICAL AND REGULATORY REGULATIONS 
 
5.10.1. Rules and regulation 
 
This study will be conducted in accordance with applicable laws and regulations including, but not 
limited to: 
− The US Code of Federal Regulations, Title 21, 50, 54, 56, 201 and 312. 
− The French Public Healthcare Law (n° 2004-806) of August 9, 2004, a partial adaptation of 
the European Directive (2001/20/EC) and Jardé law (n° 2012-300) of March, 5th 2012 on the 
conduct of clinical trials, modified by the ordinance No. 2016-800 of June 16 2016 and its 
implemented decree n° 2016-1537 of November 16th 2016. 
− The European Directive (2001/20/EC and 2005/28/EC). 
− The Informatics and Liberties Law (n° 78-17) of January 6, 1978, modified by Law n° 2004-
801 of August 6, 2004, the EU regulation 2016/679 (General Data Protection Regulation – 
“GDPR”) repealing the EU Directive 95/46 CE and the HIPAA 1996 on the protection of 
individuals with regard to the processing of personal data and on the free movement of such 
data.  
− Law n° 2002-303 of March 4, 2002 relative to patients’ rights and to the quality of the 
healthcare system. 
− Annex 13 of the E. U. Guide to Good Manufacturing Practices (revised and adopted in January 
2010 by the European Commission). 
− The Good Clinical Practices guidelines (International Conference on Harmonization (ICH E6) 
and Statistical Principles for Clinical Trials (ICH E9). 
 
 
5.10.2. Ethic Committee – Competent Authorities 
 
The institutional review board (IRB)/independent ethics committee (IEC) must review and approve 
the protocol and informed consent form before any subjects are enrolled.  Before any protocol-

SPRING Protocol version 2.0 May 20th 2019                       CONFIDENTIAL 
Page 54 of 99 
required procedures are performed, the subject must sign and date the IRB/IEC-approved informed 
consent form.  
 
This protocol was submitted to the Ethic Committee/IRB/CPP which gave its approval on the 
dd/mmm/yyyy.  
This protocol has also been approved by the Competent Authority on the dd/mmm/yyyy. 
The sponsor(s) has taken out a legal liability insurance policy (Nr. xxxxxx). 
A final report on the trial will be written at the latest, 1 year after the end of the trial and sent to the 
competent authority and to the Ethic Committee/IRB/CPP.  
The sponsor(s) will maintain records of essential trial documentation in the Sponsor file for a 
minimum duration of 15 years after the end of the trial.  
 
 
5.10.3. Withdrawal of consent for continued study participation 
 
Study data are protected by the use of a subject identification number, which is a number specific to 
the subject. The investigator is in control of the information that is needed to connect a study sample 
to a subject. A subject’s consent to the use of data does not have a specific expiration date, but the 
subject may withdraw consent at any time by notifying in written the investigator. If consent is 
withdrawn, any data collected prior to that time may still be given to and used by the sponsor but no 
new data or samples will be collected unless specifically required to monitor safety of the subject. 
 
 
5.10.4. Data handling and record keeping 
 
To maintain confidentiality, all laboratory specimens, evaluation forms, reports, and other records 
transmitted outside the clinical site will be identified by a subject’s identification number or coded 
number and age. All study records, source medical records, and code sheets or logs linking a subject’s 
name to an SID number will be kept in a secure location. Studies records such as CRFs may be 
maintained electronically and require the same security and confidentiality as paper. Clinical 
information will not be released without written permission of the subject/legal representative, except 
as specified in the informed consent form(s) (eg, necessary for monitoring by regulatory authorities 
or the sponsor of the clinical study). The investigator must also comply with all applicable privacy 
regulations (eg, HIPAA 1996, GDPR 2016/679). Study documents (including subject records, copies 
of data submitted to the sponsor, study notebook, and pharmacy records) must be kept secured in 
accordance with the specific data retention periods that are described in the clinical study site 
agreement and based upon local requirements. Study documents must not be destroyed without prior 
written approval of the sponsor. 
 
 
 
 
 
 
 
 

SPRING Protocol version 2.0 May 20th 2019                       CONFIDENTIAL 
Page 55 of 99 
6.  QUALITY CONTROL AND QUALITY ASSURANCE 
 
 
Direct Access to Source Documents  
The study will be monitored by the sponsor on a regular basis throughout the study period. During 
monitoring visits, the investigator will provide direct access to all source documentation relevant to 
the subject’s participation in the study. Source documentation includes, but is not limited to, the 
subject’s clinic and/or office chart, hospital chart, ICFs, treatment notes, laboratory reports, pharmacy 
records, radiographs, recorded data from automated instruments, and any other records maintained to 
conduct and evaluate the clinical study. The investigator must also ensure that direct access to study 
documents be made available for study-related audits, IRB/IEC review, or regulatory inspection. 
 
Data Collection  
As part of the responsibilities assumed by participating in the study, the investigator agrees to 
maintain adequate and accurate case histories for the subjects treated under this protocol. Case 
histories include CRFs and supporting data including, but not limited to, signed and dated ICFs, 
progress notes, hospital charts, nurse’s notes, diary cards or other worksheets provided to subjects, 
laboratory reports, ECG strips, etc. 
Subject demographics and key/essential disease baseline characteristics thought to affect outcome, 
ie, stratification variables and other prognostic factors, may be collected, as available, for all subjects 
who provide written informed consent. For subjects who provided informed consent and were not 
entered into the study, the reason the subject was not entered, ie, did not meet one or more inclusion 
criteria, met one or more exclusion criteria, or other (eg, lost to follow-up, consent withdrawn), may 
also be collected. 
 
Study Monitoring  
In order to guarantee the authenticity and the credibility of the data in conformity with good clinical 
practices, the sponsor has installed a quality assurance system which includes: 
- Trial management in accordance with the procedures at WIN,  
- Quality control of data at the investigating site,  
- Possible auditing of investigating centers,  
Quality control includes verification that the investigator’s file exists and that it is updated, 
verification of the consent forms, that subjects fulfill eligibility criteria, the validity of evaluation 
criteria and treatment toxicity with the help of source documents (and others to be specified and 
adapted according to the study), 
Drug accountability will also be checked and the drug accountability forms will need to be validated 
and signed by the in-house pharmacist before any request for destruction. 
 
Audit and Inspection of the Study  
During and after the study, the sponsor or its representative may conduct audits of any data and any 
facility participating in the study. The investigator and institutions involved in the study will permit 
such study-related audits and provide direct access to all study records and facilities. The investigator 
must maintain a comprehensive and centralized filing system of all study-related documentation that 
is suitable for inspection by the sponsor or its designated monitors, auditors, or regulatory agency 
representatives. The investigator agrees to participate in audits conducted at a convenient time in a 

SPRING Protocol version 2.0 May 20th 2019                       CONFIDENTIAL 
Page 56 of 99 
reasonable manner. Government regulatory authorities may also perform inspections either during or 
after the study. In the event of an inspection by any regulatory authority, the investigator should 
promptly notify the sponsor. The investigator agrees to cooperate fully with inspections conducted 
by regulatory authorities and to allow representatives of the regulatory authority access to all study 
records. The investigator will forward to the sponsor a copy of any inspection records received 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

SPRING Protocol version 2.0 May 20th 2019                       CONFIDENTIAL 
Page 57 of 99 
7. STATISTICAL CONSIDERATIONS 
 
 
The statistical design of the trial has been performed by Prof. J.Jack Lee, University of Texas MD 
Anderson Cancer Center Adjunct Professor of Statistics, Associate Vice Provost, Adjunct Professor 
of Biostatistics, Professor of Biostatistics, Biostatistics, Regular Member of the Graduate Faculty. 
The proposed study is a proof of concept protocol to evaluate the outcome of patients who 
receive triple therapy and to evaluate through a retrospective analysis, the clinical utility of the SIMS 
algorithm and integrated genomic/transcriptomic analysis. For the selected triple combination 
therapy, we will incorporate a seamless Phase 1/2 design with a limited Phase 1 run-in to determine 
the recommended Phase 2 dose for the regimen. Patients enrolled in the phase 1 study who receive 
the RP2D will also be included in the phase 2 efficacy assessment. In the first part of the phase 2 
study, up to 100 patients will receive the triple combination therapy and all will have dual biopsies in 
order to obtain the full set of genomic and transcriptomics data resulting from the investigation of 
matched tumor and normal biopsies. The population for analysis of response (evaluable patients) will 
be those that received at least one cycle of treatment. The SIMS algorithm will not be used 
prospectively to assign patients to treatment.  However, it is expected that the SIMS score for each 
patient will be available within 3 months after the treatment start date. SIMS algorithm will be used 
retrospectively for defining patient subgroups and correlation correlating with treatment outcome.  
Patients will be stratified into the fully matched group (Arm A) with all three interventional points 
activated, or partially matched group, with one or two interventional points activated (Arms B1-B3, 
C1-C3) or the non-matched group (Arm C4) (see study schema). In addition, after completion of the 
clinical trial, a correlation study will be performed between patients’ clinical outcomes and the 
predicted match determined by SIMS and all potential prognostic and predictive variables. The 
primary endpoint for this study is defined as the 6-month objective response rate (by RECIST 1.1 
criteria as percent of patients achieve complete response, or partial response). We choose the 6-month 
response rate for an early efficacy read of the triple therapy.  Other efficacy endpoints may include 
best overall response rate, progression-free survival (PFS), overall survival (OS). The expected result 
is a better clinical outcome in the fully matched patients arm (arm A) as compared to the partially 
matched or the non-matched patients’ arms.  
Also we will compare the estimated numbers of patients in each of the arms as predicted by SIMS 
versus the observed distribution in the patients treated. Based on previous data published (1), the 
estimated match in PD-L1 positive (50 patients) is: 
− Arm A: Fully matched group, with all three activated targets, will be seen in 10 patients. 
− Arms B1 or B2: Partially matched group, with two activated targets (anti PD-L1 + CDK4/6 or 
anti PD-L1 + anti VEGFR), will be seen in 13 patients and 12 patients respectively. 
− Arm B3: Remaining 15 patients will only be matched to anti PD-L1.  
 
For the PD-L1 negative patients (50 Patients), they are further grouped into the following 4 
subgroups: 
− Arm C1: Partially matched group with two activated targets (CDK4/6 and VEGFR), will be seen 
in 11 patients. 

SPRING Protocol version 2.0 May 20th 2019                       CONFIDENTIAL 
Page 58 of 99 
− Arm C2 or C3: Partially matched group with one activated targets (VEGFR or CDK4/6), will be 
seen in 8 and 16 patients, respectively. 
− Arm C4: Non-matched group, with none of the three activated target matched, will be seen in 15 
of patients. 
 
It is expected that half of the patients will be PD-L1 positive and half of the patients will be PD-L1 
negative. The hypothesized 6-month response rate in Arm A (fully matched) is 50%; in Arms B1, 
B2, and C1 (partially matched with two targets) is 40%; in Arm B3 (matched with PD-L1 only) is 
30%; in Arms C2 and C3 (partially matched with VEGFR or CDK4/6) is 20%; and in Arm C4 (non-
matched group) is 10%.  The expected 6-month response rate is 30% in the entire group assuming the 
triple therapy works. 
 
 
7.1. SEAMLESS PHASE 1/ 2 TRIALS FOR THE TRIPLE COMBINATION THERAPY 
 
For the triple combination therapy we will conduct a seamless Phase 1/2 trial to establish the safety 
of the regimen and to identify the recommended Phase II dose. Efficacy and safety will be assessed 
throughout both Phase 1 and 2. The starting dose for phase 2 will depend on the drugs administered.  
The target toxicity level is no more than one-third (33%) of patients experiencing dose DLT defined 
as Grade 3 non-hematological or Grade 4 hematological toxicities under the NCI CTCAE version 
4.03.  
 
 
7.2. PHASE 2 EFFICACY EVALUATION 
 
The Phase 2 study will be conducted in two parts.  In the first part of the Phase 2 study, we expect to 
enroll approximately 120 patients in order to obtain 100 patients eligible for the study treatment.  
Futility early stopping rule will be implemented to ensure that the treatment has met the minimum 
efficacy requirements.  If not meeting the minimum efficacy requirement, the trial will be stopped 
early.  If the trial is not stopped early after the first 100 patients, the study could be extended, (with 
an amendment) to the second part of the Phase 2 study in order to reach a total of 200 patients treated.  
 
7.2.1. Statistical analysis of the primary efficacy end point 
 
The primary efficacy evaluation for measuring a clinical meaningful improvement is defined as 
demonstrating an improvement of the primary efficacy endpoint of 6-month objective response rate 
from 20% (under the null hypothesis) to 50% (under the alternative hypothesis) in the fully matched 
arm.  With 5% one-sided type I error, we need to treat 20 patients to demonstrate the usefulness of 
the tri-therapy approach to achieve and 86% power based on the exact binomial test.  With an 
expected 10% of patients who will be fully matched, we need to enroll 200 patients in the study.  All 
inevaluable patients will be replaced. To ensure that patients will not receive ineffective 
treatments after sufficient evidence, two efficacy futility early stopping rules will be 
implemented.   

SPRING Protocol version 2.0 May 20th 2019                       CONFIDENTIAL 
Page 59 of 99 
• The first futility early stopping rule will be applied after treating 14 patients with the tri-
therapy at the RP2D level.  If none of the 14 patients has 6-month response (CR or PR), the 
patient enrollment will be halted and the trial can be stopped for futility. This futility early 
stopping rule coincides with the first stage of the Gehan’s design targeting 20% response rate 
with 95% confidence (26). 
• The second futility early stopping rule will be evaluated every 10 patients after 20 patients are 
treated at the RP2D by applying the predictive probability (27). The trial can be stopped early 
if we see the following 6-month responses or less: 2 in 20, 3 in 30, 5 in 40, 6 in 50, 7 in 60, 9 
in 70, 11 in 80, or 12 in 90 patients. The design has 5% type I error rate and 95% power with 
a null response rate of 10% and a target response rate of 30% at 6 months in the whole group. 
The probability of early stopping is 0.95, 0.31, and 0.04 if the response rate in the whole group 
is 10%, 20%, and 30%, respectively.  
• In addition to the futility analysis for early stopping of the trial if the triple therapy does not 
show minimum efficacy in the whole group, we will also look for efficacy signal in the 
subgroups. The triple therapy will be considered potentially effective if the posterior 
probability of response rate greater than 0.3 is larger than 60% in any of the predefined 
subgroups (Arm A, Arms B1-B3, Arms C1-C3, or any of the combined groups). Assuming a 
weak prior of Beta (0.1, 0.9), the treatment will be considered potentially efficacious if we see 
4 responses in 10 patients, 7 responses in 20 patients, or 10 responses in 30 patients.  
• In rare occasions that the early futility stopping criterion is met but the treatment shows 
potential efficacy in predefined subgroups, further discussions will be conducted among study 
PIs, sponsors, and regulatory agencies to determine whether study will be terminated or 
extended in specific subgroups.   
These cohort size estimates are based on in silico data generated by SIMS using an independent set 
of data obtained from investigation of tumor and matched normal biopsies from the same patient.  
SIMS model will be considered clinically meaningful if the observed matches are similar to estimated 
matches, with a maximal tolerated coefficient of variability of 20%, and if fully matched group shows 
better outcome than partially matched groups. 
 
 
7.2.2. Statistical analysis of the secondary efficacy end point and other endpoints 
 
In addition to analyze response rate (RR), and PFS, we will measure other efficacy endpoints 
including best overall response rate, and overall survival (OS), etc.  Kaplan-Meier estimate and Cox 
proportional hazards model will be applied to analyze time-to-event data such as PFS and OS.  Our 
goal is to achieve OS ≥ 60% at 1.5 years for the matched patients. 
 
7.3. SAFETY AND TOXICITY EVALUATIONS 
 
The toxicity profile of each patient and each treatment regimen will be documented using the NCI 
CTCAE version 4.03. Severe adverse events will be reported to the study IRB and regulatory 
agencies. To ensure the safety of study patients, we will also implement the Bayesian toxicity 

SPRING Protocol version 2.0 May 20th 2019                       CONFIDENTIAL 
Page 60 of 99 
monitoring to alert the study investigators when the probability of unacceptable toxicity (DLT rate ≥ 
33%) is higher than 50%.  The corresponding toxicity stopping boundaries is to stop the trial if we 
see DLT in number of patients as follows: at least 4 in 10, 7 in 20, 10 in 30, 14 in 40, 17 in 50, 20 in 
60, 24 in 70, 27 in 80, and 30 in 90 patients.  
 
 
7.4. STATISTICAL ANALYSES OF THE SECONDARY OBJECTIVES 
 
Descriptive statistics will be generated, standard statistical methods will be applied, and exploratory 
data analysis will be performed to achieve the goals for the secondary objectives.  For example, the 
success rate of biopsy acquisition and the frequency and severity of biopsy related adverse incidence 
will be recorded and analyzed.  The frequency and distribution of genomic/transcriptomic aberrations 
including DNA mutations/amplifications, RNA gene expression, and microRNA profiling in NSCLC 
will be estimated and analyzed.  In addition, we will fine tune the SIMS algorithm using cumulative 
data and updated knowledge with the goal of enhance the overall performance of the predictive 
method. For example, available data both inside and outside the trial will be acquired to correlate 
genomic scores with treatments and the efficacy outcomes to improve the predictive algorithm. The 
institution variation will be estimated and efforts will be made to reduce the institution-to-institution 
variation.   
 
 
7.5. INTERIM ANALYSIS 
 
As described earlier toxicity and efficacy monitoring will be conducted throughout the first 100 
patients. A descriptive interim analysis will be performed for this study after enrollment, treatment, 
and follow up of the first 50 patients, during which enrollment will continue. The PFS ratio will be 
estimated in all groups. No hypothesis testing will be performed and no early stopping rules will be 
implemented.  The sample size re-estimation may be carried out should the observed improvements 
rates be much different from the estimated rates. This analysis will be share with FDA CDER in order 
to assess whether SIMS will be used prospectively or retrospectively in the second part of the phase 
2 (=100) and if applicable there is need for an IDE application.  
 
 
7.6. FINAL ANALYSIS 
 
It is expected that 130 patients will be enrolled over an 18-month period (phase 1, 6 to 8 months – 
phase 2, 8-12 months). With an additional 12/24 months of follow up, the total study duration will be 
3 to 4 years. Final analysis will be performed after enrollment, treatment, and follow-up of all patients 
enrolled in the study.  Both intent-to-treat and per-treatment analyses will be performed. Due to the 
nature of the Phase 2 study, no multiplicity adjustment will be made.  All study findings will need to 
be validated by future studies.  
 
 
 
 

SPRING Protocol version 2.0 May 20th 2019                       CONFIDENTIAL 
Page 61 of 99 
8. DATA OWNERSHIP / PUBLICATION POLICIES 
 
 
The investigator promises, on his/her behalf as well as that of all the persons involved in the 
conduct of the trial, to guarantee the confidentiality of all the information related to the SPRING trial 
until the publication of the results of the trial.  
All publications, abstracts or presentations including the results of the trial require prior approval of 
the investigators and sponsor. All oral presentations, manuscripts must include a rubric mentioning 
the sponsor, the investigators / institutions and all other institutions or companies that participated or 
contributed to the conduct of the trial and the bodies which funded the research. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

SPRING Protocol version 2.0 May 20th 2019                       CONFIDENTIAL 
Page 62 of 99 
9. REFERENCES 
 
 
(1) 
Lazar V, Rubin E, Depil S, Pawitan Y, Martini J-F, Gomez-Navarro J, et al. A simplified 
interventional mapping system (SIMS) for the selection of combinations of targeted 
treatments in non-small cell lung cancer. Oncotarget. 2015 Apr 3.  
(2) 
Siegel R. Cancer of the Lung and Bronchus - SEER Stat Fact Sheets [Internet]. Available 
from: http://seer.cancer.gov/statfacts/html/lungb.html 
(3) 
American Lung Association.  Lung Cancer Fact Sheet. [Internet]. Available from: 
http://www.lung.org/lung-health-and-diseases/lung-disease-lookup/lung-cancer/learn-about-
lung-cancer/lung-cancer-fact-sheet.htm 
(4) 
Sequist LV, Martins RG, Spigel D, Grunberg SM, Spira A, Jänne PA, et al. First-line gefitinib 
in patients with advanced non-small-cell lung cancer harboring somatic EGFR mutations. J 
Clin Oncol Off J Am Soc Clin Oncol. 2008 May 20;26(15):2442–9.  
(5) 
Kwak EL, Bang Y-J, Camidge DR, Shaw AT, Solomon B, Maki RG, et al. Anaplastic 
Lymphoma Kinase Inhibition in Non-Small-Cell Lung Cancer. N Engl J Med. 2010 Oct 
28;363(18):1693–703.  
(6) 
Lovly CM, Shaw AT. Molecular pathways: resistance to kinase inhibitors and implications 
for therapeutic strategies. Clin Cancer Res Off J Am Assoc Cancer Res. 2014 May 
1;20(9):2249–56.  
(7) 
Gerlinger M, Rowan AJ, Horswell S, Larkin J, Endesfelder D, Gronroos E, et al. Intratumor 
Heterogeneity and Branched Evolution Revealed by Multiregion Sequencing. N Engl J Med. 
2012;366(10):883–92.  
(8) 
Wheler JJ, Parker BA, Lee JJ, Atkins JT, Janku F, Tsimberidou AM, et al. Unique molecular 
signatures as a hallmark of patients with metastatic breast cancer: Implications for current 
treatment paradigms. Oncotarget. 2014 May 2.  
(9) 
Lazar V, Suo C, Orear C, van den Oord J, Balogh Z, Guegan J, et al. Integrated molecular 
portrait of non-small cell lung cancers. BMC Med Genomics. 2013;6:53.  
(10) 
Vogelstein B, Papadopoulos N, Velculescu VE, Zhou S, Diaz LA, Kinzler KW. Cancer 
Genome Landscapes. Science. 2013 Mar 29;339(6127):1546–58.  
(11) 
Hanahan D, Weinberg RA. Hallmarks of Cancer: The Next Generation. Cell. 2011 Mar 
4;144(5):646–74.  
(12) 
The Cancer Genome Atlas Research Network. Comprehensive molecular profiling of lung 
adenocarcinoma. Nature. 2014 Jul 31;511(7511):543–50.  
(13) 
Davoli T, Xu AW, Mengwasser KE, Sack LM, Yoon JC, Park PJ, et al. Cumulative 
Haploinsufficiency and Triplosensitivity Drive Aneuploidy Patterns and Shape the Cancer 
Genome. Cell. 2013 Jul 11;155(4):948–62.  
(14) 
Menzies AM, Long GV. Dabrafenib and Trametinib, alone and in combination for BRAF-
mutant metastatic melanoma. Clin Cancer Res. 2014 Feb 28;clincanres.2054.2013.  

SPRING Protocol version 2.0 May 20th 2019                       CONFIDENTIAL 
Page 63 of 99 
(15) 
Shimizu T, Tolcher AW, Papadopoulos KP, Beeram M, Rasco DW, Smith LS, et al. The 
clinical effect of the dual-targeting 
strategy 
involving 
PI3K/AKT/mTOR and 
RAS/MEK/ERK pathways in patients with advanced cancer. Clin Cancer Res Off J Am Assoc 
Cancer Res. 2012 Apr 15;18(8):2316–25.  
(16) 
Von Hoff DD, Stephenson JJ Jr, Rosen P, Loesch DM, Borad MJ, Anthony S, et al. Pilot study 
using molecular profiling of patients’ tumors to find potential targets and select treatments for 
their refractory cancers. J Clin Oncol Off J Am Soc Clin Oncol. 2010 Nov 20;28(33):4877–
83.  
(17) 
Kim ES, Herbst RS, Wistuba II, Lee JJ, Blumenschein GR Jr, Tsao A, et al. The BATTLE 
trial: personalizing therapy for lung cancer. Cancer Discov. 2011 Jun;1(1):44–53.  
(18) 
Tsimberidou A-M, Iskander NG, Hong DS, Wheler JJ, Falchook GS, Fu S, et al. Personalized 
medicine in a phase I clinical trials program: the MD Anderson Cancer Center initiative. Clin 
Cancer Res Off J Am Assoc Cancer Res. 2012 Nov 15;18(22):6373–83.  
(19) 
National Cancer Institute’s Precision Medicine Initiatives for the New National Clinical Trials 
Network. 
J 
Clin 
Oncol 
[Internet]. 
[cited 
2015 
Apr 
9]; 
Available 
from: 
http://meetinglibrary.asco.org/content/114000071-144 
(20) 
NCI-match  [Internet]. Available from: 
http://deainfo.nci.nih.gov/advisory/ncab/164_1213/Conley.pdf 
(21) 
Koscielny S. Why most gene expression signatures of tumors have not been useful in the 
clinic. Sci Transl Med. 2010 Jan 13;2(14):14ps2.  
(22) 
El-Osta et al. The Oncologist. 2011;16:1292–1298. 
(23) 
Heerink WJ et al. Complication rates of CT-guided transthoracic lung biopsy: meta-analysis. 
Eur Radiol. 2016 Apr 23. [Epub ahead of print]  
(24) 
Shital P, et al. J Cancer Res Clin Oncol. 2014 May;140(5):809-15. Epub 2014 Feb 16. 
Transbronchial needle aspiration cytology (TBNA) in endobronchial lesions: a valuable 
technique during bronchoscopy in diagnosing lung cancer and it will decrease repeat 
bronchoscopy. 
(25) 
Wang Memoli et al. Chest. 2012 Aug;142(2):385-93. Meta-analysis of guided bronchoscopy 
for the evaluation of the pulmonary nodule. 
(26) 
Gehan EA et al. J Chronic Dis 1961;13:346–53. The determination of the number of patients 
required in a preliminary and a follow-up trial of a new chemotherapeutic agent.  
(27) 
Lee JJ and Liu DD. Clin Trials. 2008;5(2):93-106. A predictive probability design for phase 
II cancer clinical trials. 
 
 
 
 
 
 
 
 

SPRING Protocol version 2.0 May 20th 2019                       CONFIDENTIAL 
Page 64 of 99 
10. APPENDIXES 
 
 
10.1. 
APPENDIX 1: The Simplified Interventional Mapping System (SIMS) Paper 
Reference 
 
A simplified interventional mapping system (SIMS) for the selection of combinations of 
targeted treatments in non-small cell lung cancer 
Lazar, V., Rubin, E., Depil, S., Pawitan, Y., Martini, J., Gomez-Navarro, J., Yver, A., Kan, Z., Dry, 
J., Kehren, J., Validire, P., Rodon, J., Vielh, P., Ducreux, M., Galbraith, S., Lehnert, M., Onn, A., 
Berger, R., Pierotti, M., Porgador, A., Pramesh, C., Ye, D., Carvalho, A., Batist, G., Chevalier, T., 
Morice, P., Besse, B., Vassal, G., Mortlock, A., Hansson, J., Berindan-Neagoe, I., Dann, R., Haspel, 
J., Irimie A, A., Laderman, S., Nechushtan, H., Al Omari, A., Haywood, T., Bresson, C., Soo, K., 
Palmer, G., Lacroix, L., Koscielny, S., Eterovic, K., Blay, J., Buller, R., Eggermont, A., Schilsky, R., 
Mendelsohn, J., Soria, J., Rothenberg, M., Scoazec, J., Hong, W., & Kurzrock, R.  
Retrieved from  
http://www.impactjournals.com/oncotarget/index.php?journal=oncotarget&page=article&op=view
&path%5B%5D=3741&path%5B%5D=7940 
 
Oncotarget: Received: January 19, 2015 Accepted: March 02, 2015 Published: April 03, 2015. 
 
ABSTRACT 
Non-small cell lung cancer (NSCLC) is a leading cause of death worldwide. Targeted monotherapies 
produce high regression rates, albeit for limited patient subgroups, who inevitably succumb. We 
present a novel strategy for identifying customized combinations of triplets of targeted agents, 
utilizing a simplified interventional mapping system (SIMS) that merges knowledge about existent 
drugs and their impact on the hallmarks of cancer. Based on interrogation of matched lung tumor and 
normal tissue using targeted genomic sequencing, copy number variation, transcriptomics, and 
miRNA expression, the activation status of 24 interventional nodes was elucidated. An algorithm was 
developed to create a scoring system that enables ranking of the activated interventional nodes for 
each patient. Based on the trends of co-activation at interventional points, combinations of drug 
triplets were defined in order to overcome resistance. This methodology will inform a prospective 
trial to be conducted by the WIN consortium, aiming to significantly impact survival in metastatic 
NSCLC and other malignancies. 
 
 
 
 
 
 
 

SPRING Protocol version 2.0 May 20th 2019                       CONFIDENTIAL 
Page 65 of 99 
10.2. 
APPENDIX 2: SIMS Explained 
 
 
Table 1. Summary of the interventional points or nodes (N=24) defined by the genes involved (N = 
183) and examples of drugs that can impact these nodes 
Interventional points are defined by (genes/group of genes) that, when activated, could be blocked by 
a customized therapy combination. 
 
 
 
 

SPRING Protocol version 2.0 May 20th 2019                       CONFIDENTIAL 
Page 66 of 99 
 
 
 
Figure 1. The framework for combinatorial personalized cancer medicine. The SIMS strategy has 
three steps:  
A: Mapping therapeutic efficacy to cellular components and identification of interventional nodes. 
The example outlines the HER interventional point, constituted by four receptors (EGFR, Her2, Her3 
and Her4) and their major ligands (EGF, TGFA, NRG1, NRG2, NRG4 and NRG4). Activation of 
this node can be induced by receptor mutations or overexpression of receptors and or ligands in tumor 
as compared with the normal counterpart, and this activation can be efficiently blocked by a panHer 
inhibitor, such as afatinib; B: Scoring the status of specific nodes in the interventional maps defined 
and predicting combination efficacy. Interventional points scored over 5 (6 to 10) are high priority. 
C. Finding the most frequent co-existing interventional nodes and hence suggesting combinations. 
Frequently co-occurring, high priority interventional points are determined, and cognate drugs are 
identified based on literature reviews.   
 
 
 

SPRING Protocol version 2.0 May 20th 2019                       CONFIDENTIAL 
Page 67 of 99 
 
 
Figure 2:  A:  Flowchart of the scoring system: The principles of the score are the followings: A 
Score is designed to correlate with the likelihood that an interventional node is abnormally active in 
the tumor. It ranges from 1 to 10. The score combines evidence from 3 data sources: mutations, 
meanfold change in gene over expression (mRNA and miRNA) in the tumor versus normal and copy 
number variation. Different data sources will trigger different weights in the score: i) activating 
mutations (e.g. KRAS in the RAS path) have decisive weight. The maximal score of 10 is given to 
every node with an activating mutation; ii) in the absence of a mutation, the score is based on weighted 
sum of the mRNA meanfold changes corrected by an adjustment based on miRNAs and to a lesser 
extent on CNV abnormalities. B:  Principle of the calibrator: In Y: Fold change (Fc) of differential 
gene expression between tumor (T) and normal (N) in each patient. In X: number of patients (NB): 
for each graph, the order of patients is different. This series serve as a calibrator for calculation of 
deciles. For every new measurement in each patient, the meanfold change for mRNA is plotted 
against the calibrator curve, and the deciles partition of the curve enables assignment of a score from 
1 to 10. The score obtained based on the mRNA is corrected by miRNA, and is considered in the 
absence of mutations. 
 
 
 
 
 

SPRING Protocol version 2.0 May 20th 2019                       CONFIDENTIAL 
Page 68 of 99 
 
 
 
 
Figure 4.  3D representation of the scoring system. Axis Z shows score from 1 to 10 of each 
interventional point.  Axis X represents examples of interventional points. Axis Y represents each 
patient.  Four subjects are shown to demonstrate the complexity of co-activation of interventional 
points. Abbreviations used to designate interventional points are described in Table 1.  Each patient’s 
tumor shows numerous activations, suggesting multiple possibilities for combinations. S1, S2, S3, 
and S4 each represent an individual patient. 
 
 
 
 
 
 
 
 
 
 
 
 

SPRING Protocol version 2.0 May 20th 2019                       CONFIDENTIAL 
Page 69 of 99 
10.3. 
APPENDIX 3: Drug Information 
 
• Bavencio - avelumab: has been approved in March 2017 for the treatment of metastatic 
Merkel Cell Carcinoma and in May 2017 for the treatment of locally advanced or metastatic 
urothelial carcinoma. Avelumab is an immune checkpoint inhibitor, directed against 
programmed cell death ligand 1 (PD-L1). Signals from PD-L1 help tumors avoid detection 
by the immune system. Avelumab blocks these signals, countering the tumor’s immune-
evading tactics. As an anti–PD-L1 antibody, avelumab binds to PD-L1, allowing T-cells to 
recognize and kill tumor cells. It exhibits no immunogenicity that impacts pharmacokinetics 
or pharmacodynamics at 10 mg/kg. The most common any-grade Adverse events (Aes) in 
patients receiving all doses of avelumab were fatigue (7%), nausea (5%), vomiting (5%), 
arthralgia (4%), and rash (4%). 
 
• Ibrance - palbociclib: Approved in February 2015 for the treatment of ER positive HER2 
negative breast cancers. Palbociclib is an orally available pyridopyrimidine derived cyclin 
dependent kinase inhibitor. Palbociclib is a very selective dual inhibitor of cyclin-dependent 
kinase (CDK) 4 and 6. It blocks progression of cells from G1 into S phase. In particular, it 
shows activity in presence of high levels of Cyclin A. MTD is 125 mg orally daily for 21 
consecutive days, followed by 7 days off treatment. If the patient vomits or misses a dose, an 
additional dose should not be taken that day. The next prescribed dose should be taken at the 
usual time. Ibrance capsules should be swallowed whole (do not chew, crush or open them 
prior to swallowing). No capsule should be ingested if it is broken, cracked, or otherwise not 
intact. Palbociclib capsules should be taken with food. Grapefruit or grapefruit juice intake 
during the whole duration of the treatment should be avoided as it may increase concentration 
of the drug in blood. Most common adverse reactions (greater than or equal to 10%) is 
neutropenia, leukopenia, fatigue, anemia, upper respiratory infection, nausea, stomatitis, 
alopecia, diarrhea, thrombocytopenia, decreased appetite, vomiting, asthenia, peripheral 
neuropathy, and epistaxis. The most frequently reported serious adverse event were 
pulmonary embolism (4%) and severe diarrhea (2%). Avoid concomitant use of strong and 
moderate CYP3A inducers.).  
 
• Inlyta - axitinib: approved in January 2012 for the treatment of advanced renal carcinoma 
Inlyta is a kinase inhibitor. It has been shown to inhibit receptor tyrosine kinases including 
vascular endothelial growth factor receptors (VEGFR)-1, VEGFR-2, and VEGFR-3. These 
receptors are implicated in pathologic angiogenesis, tumor growth, and cancer progression. 
Inlyta is supplied as a tablet for oral administration. The recommended starting dose of Inlyta 
is 5 mg twice daily. Doses should be administered approximately 12 hours apart with or 
without food. The tablet should be swallowed whole with a glass of water. If the patient vomits 
or misses a dose, an additional dose should not be taken. The next prescribed dose should be 
taken at the usual time. Side effects include: diarrhea, fatigue, decreased appetite, nausea, 
hypertension, dysphonia, palmar-plantar erythrodysesthesia (hand-foot) syndrome, weight 
decreased, vomiting, asthenia, constipation. 
The Dual combination avelumab + axitinib is currently referenced in two clinical trials: 

SPRING Protocol version 2.0 May 20th 2019                       CONFIDENTIAL 
Page 70 of 99 
 A Study Of Avelumab In Combination With Axitinib In Advanced Renal Cell Cancer 
(JAVELIN Renal 100). This is a Phase 1b, open-label, multi-center, multiple-dose trial 
designed to estimate the maximum tolerated dose (MTD) and select the recommended phase 
2 dose (RP2D) of avelumab (MSB0010718C) in combination with axitinib (AG-013736). 
Once the MTD of avelumab administered in combination with axitinib is estimated (dose 
finding portion), the dose expansion phase will be opened to further characterize the 
combination 
in 
term 
of 
safety 
profile, 
anti-tumor 
activity, 
pharmacokinetics, 
pharmacodynamics and biomarker modulation.  
https://clinicaltrials.gov/ct2/show/NCT02493751?term=avelumab+and+axitinib&rank=2 
 
 A Study of Avelumab With Axitinib Versus Sunitinib In Advanced Renal Cell Cancer 
(JAVELIN Renal 101). This is a phase 3 randomized trial evaluating the anti-tumor activity 
and safety of avelumab in combination with axitinib and of sunitinib monotherapy, 
administered as first-line treatment, in patients with advanced renal cell carcinoma. 
https://clinicaltrials.gov/ct2/show/NCT02684006?term=avelumab+and+axitinib&rank=1 
 
The doses for avelumab in combination with axitinib used in the study JAVELIN Renal A01 are: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

SPRING Protocol version 2.0 May 20th 2019                       CONFIDENTIAL 
Page 71 of 99 
10.4. 
APPENDIX 4: Gene Expression Tumor vs. Normal 
 
 
GENE EXPRESSION TUMOR vs. NORMAL SUPPORTING THE CHOICE OF 
INDIVIDUAL AGENTS  
Gene Expression intensities of Tumor tissue (Y axis) and Normal (X axis) tissue for relevant genes 
targeted by the selected agents were obtained from the retrospective data from Chemores cohort. Red 
circles represent patients with no differential expression T/N (cut off of the Fold change is 2). Green 
circles represent patients with differential T/N expression.   Correlation of intensities demonstrates 
the necessity of using dual biopsies. 
 
Expression data Tumor vs. Normal supporting the use of palbociclib in NSCLC 
 
 
 
 
 
 
 
 
 
 

SPRING Protocol version 2.0 May 20th 2019                       CONFIDENTIAL 
Page 72 of 99 
Gene Expression data Tumor vs. Normal supporting the use of axitinib in NSCLC and showing 
that the main contributor to neoangiogenesis is VEGFA  
 
 
The frequencies of activation of actionable interventional points in three groups of NSCLC patients: 
 
 
 
 
 
 

SPRING Protocol version 2.0 May 20th 2019                       CONFIDENTIAL 
Page 73 of 99 
10.5. 
APPENDIX 5: Clinical Flowchart 
 
 
 
 
Screening / 
Baseline 
Biopsies 
Cycle 112 
Cycle 2 
Cycle n 
Discontinuation 
(for progression or 
toxicity, etc.) 
Follow-up 
 
D-28 to 
registration 
 
D1 
D8 
D15 
D22 
D1 
D8 
D15 
D22 
D1 
D15 
 
D30 after last 
treatment 
administration 
D90 after last 
treatment 
administration11 
WRITTEN INFORMED 
CONSENT 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
INCLUSION/EXCLUSION 
CRITERIA VERIFICATION1 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ASSIGNMENT OF STUDY 
IDENTIFICATION NUMBER 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
DEMOGRAPHIC DATA 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PREVIOUS MEDICAL 
HISTORY 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CONCOMITANT 
MEDICATION 
X 
 
CONTINUOUS MONITORING 
PHYSICAL EXAMINATION 
X 
 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
HEIGHT 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
WEIGHT 
X 
 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
 
 
ECOG PERFORMANCE 
STATUS 
X 
 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
VITAL SIGN 
X 
 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
ELECTROCARDIOGRAM 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
BLOOD TEST FOR VIRAL 
INFECTION (HEPATITIS 
A, B, AND C) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PREGNANCY TEST2 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
X 
 
 
THYROID FUNCTION 
TESTS (FREE T4 AND 
TSH)3 
X 
 
X 
 
 
 
 
 
 
 
X 
 
X 
X 
 

SPRING Protocol version 2.0 May 20th 2019                       CONFIDENTIAL 
Page 74 of 99 
Study Assessments 
Screening / 
Baseline 
Biopsies 
Cycle 112 
Cycle 2 
Cycle n 
Discontinuation 
(for progression or 
toxicity, etc.) 
Follow-up 
 
D-28 to 
registration 
 
D1 
D8 
D15 
D22 
D1 
D8 
D15 
D22 
D1 
D15 
 
D30 after last 
treatment 
administration 
D90 after last 
treatment 
administration11 
HEMATOLOGY, 
CHEMISTRY AND URINE 
TESTS 4 
X 
 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
 
COAGULATION PROFILE 
(PROTHROMBIN TIME) 
X 
 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
 
RADIOLOGIC TUMOR 
ASSESSMENT AS 
PREFERRED BY THE 
PHYSICIAN - USUALLY 
CT (BUT COULD BE 
PET/CT OR MRI OR 
OTHER IMAGING AS 
CLINICALLY 
APPROPRIATE) RECIST 
1.15 
X 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
 
TUMOR AND NORMAL 
BIOPSIES  
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
AVELUMAB 
ADMINISTRATION6  
 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
 
 
 
AXITINIB 
ADMINISTRATION7  
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
PALBOCICLIB 
ADMINISTRATION8  
 
 
off 
X 
X 
X 
off 
X 
X 
X 
off 
X 
 
 
 
AES/SAES 
X 
 
CONTINUOUS MONITORING 
BLOOD SAMPLE 
COLLECTION FOR 
TUMOR MARKERS9 
 
 
X 
X 
 
 
 
 
 
 
X 
 
 
 
 
PK BLOOD SAMPLE 
COLLECTION10 
 
 
 
 
X 
 
 
 
X 
 
 
X 
 
 
 
MUTATION STATUS 
(EGFR, ALK) IF NOT 
ALREADY DOCUMENTED.  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

SPRING Protocol version 2.0 May 20th 2019                       CONFIDENTIAL 
Page 75 of 99 
1 Eligibility criteria should be verified between consent and registration (28 days maximum window).  
2Urine or blood pregnancy test for women of childbearing potential must be performed at baseline and every month during treatment. 
3Free T4 and TSH must be performed at baseline and at least every 8 weeks during treatment and at end of treatment or 30 days post-treatment safety follow-up (if not 
performed in the previous 8 weeks). 
4Hematology and Chemistry tests and urinalysis (see section 5.4) should be performed every week +/- 3 days during the first cycle and then every 2 weeks +/- 3 days 
prior the avelumab infusion. 
5 Baseline scan within 28 days of the start of therapy and follow-up scans about every 8 weeks (+/- 7 days): end of C2, C4, C6, etc. 
6 Avelumab is administered at the study site at D1 (-1/+3 days) and D15 (-1/+3 days) of each cycle. Premedication in order to mitigate infusion-related reactions, with 
an antihistamine and with paracetamol (acetaminophen) should be given 30 to 60 minutes prior to avelumab infusion for at least the 4 first doses. Following avelumab 
infusions, patients must be observed for 30 minutes post-infusion for potential infusion-related reactions.   
7 Axitinib is taken every day orally at home. Treatment diary should be provided to the patient to record treatment intake and side effects. 
8 Palbociclib is taken orally from day 8 to day 28 every cycle at home. Treatment diary should be provided to the patient to record treatment intake and side effects. 
9 Blood specimens will be collected for each patient enrolled at base line, before starting the treatment, one week after onset of the treatment and about every 8 weeks 
thereafter. 
10 PK Blood specimens will be collected for each patient at day 15 of each cycle (-1/+3 days according to the 2nd avelumab injection) at the following time +/- 5 
minutes: before intake of axitinib and palbociclib, after 0h45, 1h15 and 2h of axitinib and palbociclib intake, 4h after axitinib and palbociclib intake and before 
avelumab IV, at the end of avelumab infusion, after 1h, 2h, 3h and 5h of avelumab infusion. 
11 The extended safety follow-up beyond 30 days after last study drug administration may be performed either via a site visit or via a telephone call with subsequent 
site visit requested in case any concerns noted during the telephone call. 
12 1 cycle = 28 days  
 
Other minor modifications of scheduled visits or medication administration for medical, personal, or logistical reasons may be done after CMC discussion providing 
that CMC determines that modifications do not impact patient safety.   

SPRING Protocol version 2.0 May 20th 2019                       CONFIDENTIAL 
Page 76 of 99 
10.6. 
APPENDIX 6: Safety Related Items for Avelumab 
 
 
1. Safety relevant inclusion and exclusion criteria (see Table 1): 
Minimum required safety-related inclusion and exclusion criteria for avelumab are described in Table 
1. Additional inclusion and exclusion criteria should be considered based on requirements related to 
other drugs used in combination treatments, target population or study objectives as well as based on 
Sponsor (investigator) judgment. 
 
2. Safety assessments 
 
− Blood chemistry and hematology assessments:  must be performed at baseline, prior to each 
avelumab dose, at end of treatment visit and at 30 days post-treatment safety follow-up. 
− Urine pregnancy test for women of childbearing potential must be performed at baseline and 
at least every month during treatment. 
− Free T4 and TSH must be performed at baseline and at least every 8 weeks during treatment 
and at end of treatment or 30 days post-treatment safety follow-up (if not performed in the 
previous 8 weeks). 
 
3. Extended safety follow-up 
Given the potential risk for delayed immune-related toxicities, safety follow-up must be performed 
up to 90 days after the last dose of avelumab administration. 
The extended safety follow-up beyond 30 days after last study drug administration may be performed 
either via a site visit or via a telephone call with subsequent site visit requested in case any concerns 
noted during the telephone call. 
 
4. Special Precautions for Administration: 
 
− Premedication: In order to mitigate infusion-related reactions, a premedication with an 
antihistamine and with paracetamol (acetaminophen) 30 to 60 minutes prior to the avelumab 
infusion is mandatory for at least the first 4 infusions (for example, 25-50 mg 
diphenhydramine and 500-650 mg paracetamol IV or oral). Premedication should be 
administered for subsequent avelumab doses based upon clinical judgment and 
presence/severity of prior infusion reactions. This may be modified based on local treatment 
standards and guidelines, as appropriate.  
 
− Setting: Avelumab should be administered in a setting that allows for immediate access to an 
intensive care unit or equivalent environment and administration of therapy for anaphylaxis, 
such as the ability to implement immediate resuscitation measures.  Steroids (dexamethasone 
10 mg), 
epinephrine 
(1:1,000 dilution), 
allergy 
medications 
(IV antihistamines), 
bronchodilators, or equivalents, and oxygen should be available for immediate access. 
 
 

SPRING Protocol version 2.0 May 20th 2019                       CONFIDENTIAL 
Page 77 of 99 
− Observation period:  Following avelumab infusions, patients must be observed for 30 
minutes post-infusion for potential infusion-related reactions.   
 
5. Toxicity Management (see Table 2, Table 3 and Table 4): 
 
− Adverse Drug Reactions requiring avelumab discontinuation or modification (Table 2) 
− Treatment Modification for Symptoms of Infusion-Related Reactions (Table 3) 
− Management of immune-mediated adverse reactions (Table 4) 
 
TABLE 1. SAFETY RELATED INCLUSION AND EXCLUSION CRITERIA 
INCLUSION CRITERIA 
1. AGE: Male or female subjects aged ≥ 18 years.   
2. PHYSIOLOGIC FUNCTION: 
Hematologic:  Absolute neutrophil count (ANC) ≥ 1.5 × 109/L, platelet count ≥ 100 × 109/L, and 
hemoglobin ≥ 9 g/dL (may have been transfused) (Applicable for solid tumors. 
Hepatic: Total bilirubin level ≤ 1.5 × the upper limit of normal (ULN) range and AST and ALT levels 
≤ 2.5 × ULN or AST and ALT levels ≤ 5 x ULN (for subjects with documented metastatic disease to 
the liver). 
Renal: Estimated creatinine clearance ≥ 30 mL/min according to the Cockcroft-Gault formula (or 
local institutional standard method). 
3. PREGNANCY AND CONTRACEPTION: 
Pregnancy test: Negative serum or urine pregnancy test at screening for women of childbearing 
potential.  
Contraception: Highly effective contraception for both male and female subjects throughout the 
study and for at least 60 days after last avelumab treatment administration if the risk of conception 
exists.  
 
EXCLUSION CRITERIA 
1. IMMUNOSUPRESSANTS: “Current use of immunosuppressive medication, EXCEPT for the 
following: a. intranasal, inhaled, topical steroids, or local steroid injection (e.g., intra-articular 
injection); b. Systemic corticosteroids at physiologic doses ≤ 10 mg/day of prednisone or equivalent; 
c. Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication).” 
2. AUTOIMMUNE DISEASE: “Active autoimmune disease that might deteriorate when receiving an 
immuno-stimulatory agent.  Patients with diabetes type I, vitiligo, psoriasis, or hypo- or hyperthyroid 
diseases not requiring immunosuppressive treatment are eligible.”  
3. ORGAN TRANSPLANTATION: “Prior organ transplantation including allogenic stem-cell 
transplantation.”  
4. INFECTIONS: “Active infection requiring systemic therapy. “ 
5. HIV/AIDS: “Known history of testing positive for HIV or known acquired immunodeficiency 
syndrome.” 

SPRING Protocol version 2.0 May 20th 2019                       CONFIDENTIAL 
Page 78 of 99 
6. HEPATITIS: “Hepatitis B virus (HBV) or hepatitis C virus (HCV) infection at screening (positive 
HBV surface antigen or HCV RNA if anti-HCV antibody screening test positive)” 
7. VACCINATION: “Vaccination within 4 weeks of the first dose of avelumab and while on trials is 
prohibited except for administration of inactivated vaccines “ 
8. HYPERSENSITIIVTY TO STUDY DRUG: “Known prior severe hypersensitivity to investigational 
product or any component in its formulations, including known severe hypersensitivity reactions to 
monoclonal antibodies (NCI CTCAE v4.03 Grade ≥ 3)” 
9. CARDIOVASCULAR DISEASE: “Clinically significant (i.e., active) cardiovascular disease: cerebral 
vascular accident/stroke (< 6 months prior to enrollment), myocardial infarction (< 6 months prior to 
enrollment), unstable angina, congestive heart failure (≥ New York Heart Association Classification 
Class II), or serious cardiac arrhythmia requiring medication.” 
10. OTHER PERSISTING TOXICITIES: “Persisting toxicity related to prior therapy (NCI CTCAE v. 
4.03 Grade > 1); however, alopecia, sensory neuropathy Grade ≤ 2, or other Grade ≤ 2 not constituting 
a safety risk based on investigator’s judgment are acceptable.” 
11. Other severe acute or chronic medical conditions including colitis, inflammatory bowel disease, 
pneumonitis, pulmonary fibrosis or psychiatric conditions including recent (within the past year) or 
active suicidal ideation or behavior; or laboratory abnormalities that may increase the risk associated 
with study participation or study treatment administration or may interfere with the interpretation of 
study results and, in the judgment of the investigator, would make the patient inappropriate for entry 
into this study. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

SPRING Protocol version 2.0 May 20th 2019                       CONFIDENTIAL 
Page 79 of 99 
TABLE 
2. 
ADVERSE 
DRUG 
REACTIONS 
REQUIRING 
AVELUMAB 
DISCONTINUATION OR MODIFICATION 
Dose escalation or reduction is not recommended. Dosing delay or discontinuation may be required 
based on individual safety and tolerability (refer to Appendix 6). Resume avelumab in patients whose 
adverse reactions recover to Grade 1 or resolved. 
Any Grade 4 ADRs require permanent treatment discontinuation with avelumab except for 
single laboratory values out of normal range that are unlikely related to study treatment as assessed 
by the Investigator, do not have any clinical correlate, and resolve within 7 days with adequate 
medical management and endocrinopathies controlled with hormone replacement. 
Any Grade 3 ADRs require treatment discontinuation with avelumab except for any of the following:  
• Transient (≤ 6 hours) Grade 3 flu-like symptoms or fever, which is controlled with medical 
management 
• Transient (≤ 24 hours) Grade 3 fatigue, local reactions, headache, nausea, emesis that resolves 
to Grade ≤ 1  
• Single laboratory values out of normal range (excluding Grade ≥ 3 liver function test increase) 
that are unlikely related to study treatment according to the Investigator, do not have any clinical 
correlate, and resolve to Grade ≤ 1 within 7 days with adequate medical management 
• Tumor flare phenomenon defined as local pain, irritation, or rash localized at sites of known or 
suspected tumor 
• Change in ECOG PS to ≥ 3 that does not resolve to ≤ 2 within 14 days (infusions should not be 
given on the following cycle, if the ECOG PS is ≥ 3 on the day of study drug administration) 
 
Recurrent Grade 3 ADRs and Grade 3 infusion-related reaction require permanent 
discontinuation. 
Any Grade 2 ADR should be managed as follows: 
• If a Grade 2 ADR resolves to Grade ≤ 1 by the last day of the current cycle, treatment may 
continue. 
• If a Grade 2 ADR does not resolve to Grade ≤ 1 by the last day of the current cycle, infusions 
should not be given on the following cycle.  If at the end of the following cycle the event has 
not resolved to Grade 1, it should be treated as a Grade 3 or 4 (except for hormone 
insufficiencies, that can be managed by replacement therapy; for these hormone insufficiencies, 
up to 2 subsequent doses may be omitted). 
• Upon the second occurrence of the same Grade 2 ADR (except for hormone insufficiencies that 
can be managed by replacement therapy) in the same subject, treatment with avelumab has to 
be permanently discontinued. 
 
 

SPRING Protocol version 2.0 May 20th 2019                       CONFIDENTIAL 
Page 80 of 99 
TABLE 3. TREATMENT MODIFICATION FOR SYMPTOMS OF INFUSION-RELATED 
REACTIONS  
NCI-CTCAE Grade  
Treatment Modification for avelumab 
Grade 1 – mild 
Mild transient reaction; infusion interruption 
not indicated; intervention not indicated. 
Decrease the study drug infusion rate by 50% 
and monitor closely for any worsening. 
 
Grade 2 – moderate 
Therapy or infusion interruption indicated but 
responds promptly to symptomatic treatment 
(for example, antihistamines, NSAIDs, 
narcotics, IV fluids); prophylactic 
medications indicated for ≤ 24 h. 
Temporarily discontinue avelumab infusion. 
Resume infusion at 50% of previous rate once 
infusion-related reaction has resolved or 
decreased to at least Grade 1 in severity, and 
monitor closely for any worsening. 
Grade 3 or Grade 4 – severe or 
life-threatening 
Grade 3: Prolonged (for example, not rapidly 
responsive to symptomatic medication and/or 
brief interruption of infusion); recurrence of 
symptoms following initial improvement; 
hospitalization indicated for clinical sequelae. 
Grade 4: Life-threatening consequences; 
urgent intervention indicated. 
Stop avelumab infusion immediately and 
disconnect infusion tubing from the subject. 
Subjects have to be withdrawn immediately 
from avelumab treatment and must not 
receive any further avelumab treatment. 
IV = intravenous; NCI-CTCAE = National Cancer Institute-Common Terminology Criteria for 
Adverse Event; NSAIDs = nonsteroidal anti-inflammatory drugs. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

SPRING Protocol version 2.0 May 20th 2019                       CONFIDENTIAL 
Page 81 of 99 
 TABLE 4.  MANAGEMENT OF IMMUNE-MEDIATED ADVERSE REACTIONS 
 
Since inhibition of PD-L1 stimulates the immune system, immune-related AEs (irAEs) may occur.  
Treatment of irAEs is mainly dependent upon severity (NCI-CTCAE version 4.03 grade) 
Grade 1 to 2:  treat symptomatically or with moderate dose steroids, more frequent monitoring 
Grade 1 to 2 (persistent):  manage similar to high grade AE (Grade 3 to 4) 
Grade 3 to 4:  treat with high dose corticosteroids 
Treatment of gastrointestinal, dermatological, pulmonary, hepatic, renal, cardiac, endocrine or 
other irAEs should follow guidelines set forth in the table below. 
Gastrointestinal irAEs 
Severity of Diarrhea / 
Colitis 
Initial Management 
Follow-up Management 
Grade 1 
Diarrhea: < 4 stools/day 
over Baseline 
Colitis: asymptomatic  
Continue avelumab therapy 
Symptomatic treatment (for 
example, loperamide) 
Close monitoring for worsening 
symptoms 
Educate subject to report 
worsening immediately 
If worsens: 
Treat as Grade 2 or 3/4  
Grade 2 
Diarrhea:  4 to 6 stools per 
day over Baseline; IV 
fluids indicated < 24 
hours; not interfering with 
ADL 
Colitis:  abdominal pain; 
blood in stool  
Withhold avelumab therapy 
Symptomatic treatment 
If improves to Grade ≤1:  
Resume avelumab therapy. 
 
If persists > 5 to 7 days or recur: 
Treat as Grade 3 to 4 
Grade 3 to 4 
Diarrhea (Grade 3): ≥ 7 
stools per day over 
Baseline; incontinence; IV 
fluids ≥ 24 hrs.; interfering 
with ADL 
Colitis (Grade 3):  severe 
abdominal pain, medical 
intervention indicated, 
peritoneal signs 
Withhold avelumab for Grade 
3. 
 
Permanently discontinue 
avelumab for Grade 4 or 
recurrent Grade 3. 
 
1.0 to 2.0 mg/kg/day 
prednisolone IV or equivalent 
If improves:  
Continue steroids until Grade ≤1, 
then taper over at least 1 month; 
resume avelumab therapy 
following steroids taper (for 
initial Grade 3). 
 
 
If worsens, persists > 3 to 5 days, 
or recurs after improvement: 

SPRING Protocol version 2.0 May 20th 2019                       CONFIDENTIAL 
Page 82 of 99 
Grade 4:  life-threatening, 
perforation 
Add prophylactic antibiotics for 
opportunistic infections  
Consider lower endoscopy  
Add infliximab 5 mg/kg (if no 
contraindication). 
Note: Infliximab should not be 
used in cases of perforation or 
sepsis.  
Dermatological irAEs 
Grade of Rash 
Initial Management 
Follow-up Management 
Grade 1 to 2  
Covering ≤ 30% body 
surface area  
Continue avelumab therapy 
Symptomatic therapy (for 
example, antihistamines, 
topical steroids) 
If persists > 1 to 2 weeks or 
recurs:  
Withhold avelumab therapy 
Consider skin biopsy  
 
Consider 0.5 to 1.0 mg/kg/day 
prednisolone or equivalent. Once 
improving, taper steroids over at 
least 1 month, consider 
prophylactic antibiotics for 
opportunistic infections, and 
resume avelumab therapy 
following steroids taper. 
If worsens:  
Treat as Grade 3 to 4.  
Grade 3 to 4 
Grade 3: Covering > 30% 
body surface area; 
Grade 4: life threatening 
consequences  
Withhold avelumab for Grade 
3. 
Permanently discontinue for 
Grade 4 or recurrent Grade 3. 
Consider skin biopsy  
Dermatology consult  
1.0 to 2.0 mg/kg/day 
prednisolone or equivalent  
Add prophylactic antibiotics for 
opportunistic infections. 
If improves to Grade ≤1:  
Taper steroids over at least 1 
month; resume avelumab therapy 
following steroids taper (for 
initial Grade 3) 
Pulmonary irAEs 
Grade of Pneumonitis 
Initial Management 
Follow-up Management 
Grade 1 
Consider withholding avelumab 
therapy  
Re-assess at least every 3 weeks 
If worsens:  

SPRING Protocol version 2.0 May 20th 2019                       CONFIDENTIAL 
Page 83 of 99 
Radiographic changes 
only  
Monitor for symptoms every 
2 to 3 days  
Consider Pulmonary and 
Infectious Disease consults  
Treat as Grade 2 or Grade 3 to 4.  
Grade 2 
Mild to moderate new 
symptoms  
Withhold avelumab therapy 
Pulmonary and Infectious 
Disease consults 
Monitor symptoms daily, 
consider hospitalization  
1.0 to 2.0 mg/kg/day 
prednisolone or equivalent 
followed by a corticosteroid 
taper. 
Add prophylactic antibiotics for 
opportunistic infections 
Consider bronchoscopy, lung 
biopsy  
Re-assess every 1 to 3 days  
If improves:  
When symptoms return to Grade 
≤ 1, taper steroids over at least 1 
month and then resume avelumab 
therapy following steroids taper  
If not improving after 2 weeks or 
worsening:  
Treat as Grade 3 to 4.  
Grade 3 to 4 
Grade 3: Severe new 
symptoms; New / 
worsening hypoxia;  
Grade 4: life-threatening  
Permanently discontinue 
avelumab therapy 
Hospitalize.  
Pulmonary and Infectious 
Disease consults. 
1.0 to 2.0 mg/kg/day 
prednisolone or equivalent 
followed by a corticosteroid 
taper 
Add prophylactic antibiotics for 
opportunistic infections  
Consider bronchoscopy, lung 
biopsy  
If improves to Grade ≤ 1:  
Taper steroids over at least 1 
month. 
If not improving after 48 hours or 
worsening:  
Add additional 
immunosuppression (for example, 
infliximab, cyclophosphamide, IV 
immunoglobulin, or 
mycophenolate mofetil)  
Hepatic irAEs 
Grade of Liver Test 
Elevation 
Initial Management 
Follow-up Management 
Grade 1 
Grade 1 AST or ALT > 
ULN to 3.0 x ULN and/or 
total bilirubin > ULN to 
1.5 x ULN  
Continue avelumab therapy 
Continue liver function 
monitoring  
If worsens:  
Treat as Grade 2 or 3 to 4  
Grade 2 
Withhold avelumab therapy 
If returns to Grade ≤ 1:  

SPRING Protocol version 2.0 May 20th 2019                       CONFIDENTIAL 
Page 84 of 99 
AST or ALT > 3.0 to ≤ 5 x 
ULN and / or total 
bilirubin > 1.5 to ≤ 3 x 
ULN  
Increase frequency of 
monitoring to every 3 days  
Resume routine monitoring, 
resume avelumab therapy 
If elevations persist > 5 to 7 days 
or worsen:  
Treat as Grade 3 to 4. 
Grade 3 to 4 
AST or ALT > 5 x ULN 
and/or total bilirubin > 3 x 
ULN  
Permanently discontinue 
avelumab therapy  
Increase frequency of 
monitoring to every 1 to 2 days  
1.0 to 2.0 mg/kg/day 
prednisolone or equivalent, 
followed by a corticosteroid 
taper 
Add prophylactic antibiotics for 
opportunistic infections  
Consult 
gastroenterologist/hepatologist 
Consider obtaining MRI/CT 
scan of liver and liver biopsy if 
clinically warranted. 
If returns to Grade ≤ 1:  
Taper steroids over at least 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  
Renal irAEs 
Grade of Creatinine 
Increased 
Initial Management 
Follow-up Management 
Grade 1 
Creatinine increased > 
ULN to 1.5 x ULN  
Continue avelumab therapy 
Continue renal function 
monitoring  
If worsens:  
Treat as Grade 2 or 3 to 4.  
 Grade 2 to 3 
Creatinine increased > 1.5 
and ≤ 6 x ULN 
Withhold avelumab therapy. 
Increase frequency of 
monitoring to every 3 days. 
1.0 to 2.0 mg/kg/day 
prednisone or equivalent 
Add prophylactic antibiotics for 
opportunistic infections. 
Consider renal biopsy. 
 If resumes to Grade ≤ 1: 
Taper steroids over at least 1 
month, and resume avelumab 
therapy following steroids taper. 
If worsens: 
Treat as Grade 4. 
 Grade 4 
Creatinine increased > 6 x 
ULN 
Permanently discontinue 
avelumab therapy 
Monitor Creatinine daily. 
 If resumes to Grade ≤ 1: 
Taper steroids over at least 1 
month. 

SPRING Protocol version 2.0 May 20th 2019                       CONFIDENTIAL 
Page 85 of 99 
1.0 to 2.0 mg/kg/day 
prednisone or equivalent 
Add prophylactic antibiotics for 
opportunistic infections. 
Consider renal biopsy. 
Nephology consult. 
Cardiac irAEs 
Myocarditis 
Initial Management 
Follow-up Management 
New onset of cardiac signs 
or symptoms and / or new 
laboratory cardiac 
biomarker elevations (e.g. 
troponin, CK-MB, BNP) 
or cardiac imaging 
abnormalities suggestive 
of myocarditis.  
Withhold avelumab therapy. 
 
Hospitalize. 
 
In the presence of life 
threatening cardiac 
decompensation, consider 
transfer to a facility 
experienced in advanced heart 
failure and arrhythmia 
management. 
 
Cardiology consult to establish 
etiology and rule-out immune-
mediated myocarditis. 
 
Guideline based supportive 
treatment as per cardiology 
consult. 
 
Consider myocardial biopsy if 
recommended per cardiology 
consult. 
If symptoms improve and 
immune-mediated etiology is 
ruled-out, re-start avelumab 
therapy. 
 
If symptoms do not 
improve/worsen, viral myocarditis 
is excluded, and immune-
mediated etiology is suspected or 
confirmed following cardiology 
consult, manage as immune-
mediated myocarditis. 
Immune-mediated 
myocarditis 
Permanently discontinue 
avelumab. 
Guideline based supportive 
treatment as appropriate as per 
cardiology consult. 
1.0 to 2.0 mg/kg/day 
prednisone or equivalent. 
Add prophylactic antibiotics for 
opportunistic infections. 
Once improving, taper steroids 
over at least 1 month. 
 
If no improvement or worsening, 
consider additional 
immunosuppressants (e.g. 
azathioprine, cyclosporine A) 

SPRING Protocol version 2.0 May 20th 2019                       CONFIDENTIAL 
Page 86 of 99 
Endocrine irAEs 
Endocrine disorder 
Initial Management 
Follow-up Management 
Grade 1 or Grade 2 
endocrinopathies 
(hypothyroidism, 
hyperthyroidism, adrenal 
insufficiency, type I 
diabetes mellitus) 
Continue avelumab therapy 
Endocrinology consult if 
needed 
 
Start thyroid hormone 
replacement therapy (for 
hypothyroidism), anti-thyroid 
treatment (for 
hyperthyroidism), 
corticosteroids (for adrenal 
insufficiency) or insulin ( for 
type I diabetes mellitus) as 
appropriate. 
 
Rule-out secondary 
endocrinopathies (i.e. 
hypopituitarism / hypophysitis) 
Continue hormone 
replacement/suppression and 
monitoring of endocrine function 
as appropriate. 
Grade 3 or Grade 4 
endocrinopathies 
(hypothyroidism, 
hyperthyroidism, adrenal 
insufficiency, type I 
diabetes mellitus) 
Withhold avelumab therapy 
Consider hospitalization 
Endocrinology consult  
 
Start thyroid hormone 
replacement therapy (for 
hypothyroidism), anti-thyroid 
treatment (for 
hyperthyroidism), 
corticosteroids (for adrenal 
insufficiency) or insulin (for 
type I diabetes mellitus) as 
appropriate. 
 
Rule-out secondary 
endocrinopathies (i.e. 
hypopituitarism / hypophysitis) 
Resume avelumab once 
symptoms and/or laboratory tests 
improve to Grade ≤ 1 (with or 
without hormone 
replacement/suppression) 
 
Continue hormone replacement/ 
suppression and monitoring of 
endocrine function as appropriate. 

SPRING Protocol version 2.0 May 20th 2019                       CONFIDENTIAL 
Page 87 of 99 
Hypopituitarism / 
hypophysitis (secondary 
endocrinopathies) 
If secondary thyroid and/or 
adrenal insufficiency is 
confirmed (i.E. subnormal 
serum FT4 with inappropriately 
low TSH and/or low serum 
cortisol with inappropriately 
low ACTH): 
• Refer to endocrinologist 
for dynamic testing as 
indicated and 
measurement of others 
hormones (FSH, LH, 
GH/IGF-1, PRL, 
testosterone in men, 
estrogens in women) 
• Hormone 
replacement/suppressive 
therapy as appropriate 
• Perform pituitary MRI 
and visual field 
examination as 
indicated. 
 
If hypophysitis confirmed: 
• Continue avelumab if 
mild symptoms with 
normal MRI. Repeat the 
MRI on 1 month. 
• Withhold avelumab if 
moderate, severe or life-
threatening symptoms 
of hypophysitis and/or 
abnormal MRI. 
Consider 
hospitalization. Initiate 
corticosteroids (1 to 2 
mg/kg/day prednisone 
or equivalent) followed 
by corticosteroids taper 
during at least 1 month. 
• Add appropriate 
antibiotics for 
opportunistic infections. 
Resume avelumab once 
symptoms and hormone tests 
improve to Grade ≤ 1 (with or 
without hormone replacement) 
 
In addition, for hypophysitis with 
abnormal MRI, resume avelumab 
only once shrinkage of the 
pituitary gland on MRI/CT scan is 
documented. 
 
Continue hormone replacement/ 
suppression therapy as 
appropriate. 

SPRING Protocol version 2.0 May 20th 2019                       CONFIDENTIAL 
Page 88 of 99 
Other irAES 
Grade of other irAEs 
Initial Management 
Follow-up Management 
 Grade 2 or Grade 3 
clinical signs of 
symptoms suggestive of a 
potential irAE 
Withhold avelumab therapy 
pending clinical investigation. 
 
 If irAE is rled-out, manage as 
appropriate according to the 
diagnosis and consider re-starting 
avelumab therapy. 
If irAE is conforme, treat as 
Grade 2 or 3 irAE. 
 Grade 2 irAE or first 
occurrence of Grade 3 
irAE 
Withhold avelumab therapy.  
1.0 to 2.0 mg/kg/day 
prednisone or equivalent. 
Add prophylactic antibiotics for 
opportunistic infections. 
Specialty consult as 
appropriate. 
If improves to Grade ≤ 1: 
Taper steroids over at least 1 
month, and resume avelumab 
therapy following steroids taper. 
 
 Recurrence of same 
Grade 3 irAE 
Permanently discontinue 
avelumab therapy.  
1.0 to 2.0 mg/kg/day 
prednisone or equivalent. 
Add prophylactic antibiotics for 
opportunistic infections. 
Specialty consult as 
appropriate. 
If improves to Grade ≤ 1: 
Taper steroids over at least 1 
month. 
 
 Grade 4 
Permanently discontinue 
avelumab therapy.  
1.0 to 2.0 mg/kg/day 
prednisone or equivalent and/or 
other immunosuppressant as 
needed. 
Add prophylactic antibiotics for 
opportunistic infections. 
Specialty consult. 
 If improves to Grade ≤ 1: 
Taper steroids over at least 1 
month. 
 
Requirement for 10 mg 
per day or greater 
prednisone or equivalent 
for more than 12 weeks 
for reasons other than 
hormonal replacement 
for adrenal insufficiency. 
Permanently discontinue 
avelumab therapy.  
Specialty consult. 
  

SPRING Protocol version 2.0 May 20th 2019                       CONFIDENTIAL 
Page 89 of 99 
Persistent Grade 2 or 3 
irAE lasting 12 weeks or 
longer. 
ACTH = adrenocorticotropic hormone; ADL = activities of daily living; ALT = alanine 
aminotransferase; AST = aspartate aminotransferase; BNP = B-type natriuretic peptide; CK-MB = 
creatine kinase MB; CT = computed tomography; FSH = follicule-stimulating hormone; GH = growth 
hormone; IGF-1 = insulin-like growth factor 1; irAE = immune-related adverse event; 
IV=intravenous; LH = luteinizing hormone; LFT = liver function test; LLN = lower limit of normal; 
MRI = magnetic resonance imaging; NCI-CTCAE = National Cancer Institute-Common 
Terminology Criteria for Adverse Event; PRL = prolactin; T4 = free thyroxine; TSH = thyroid-
stimulating hormone; ULN = upper limit of normal. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

SPRING Protocol version 2.0 May 20th 2019                       CONFIDENTIAL 
Page 90 of 99 
10.7. 
APPENDIX 7: Protocols for PK 
 
Avelumab PK serum and ADA/Nab serum sampling, processing and storage instructions:  
 
PK Avelumab: MSB0010718C 
Use Yellow-Gold Top, Plastic, SST, 3.5mL and Cryovial, 2mL, screw cap w/o-ring sterile 
 
1. The entire blood processing to serum and placing the samples in the freezer described below 
should be completed within 90 minutes of blood collection. 
2. Collect a minimum of 3.5mL of whole blood per PK time point into an appropriately labeled 
yellow-gold top SST tubes.  
3. It is important to thoroughly mix the blood with the clotting activation agent by gently 
inverting the tube for at least five times (do not shake). 
4. Place the blood collection tube in the upright position and keep the tube at room temperature 
for at least 30 mins but no longer than 60 mins (tube standing upright) to allow for clotting 
the blood to serum.  
5. Centrifuge at approximately 1700 x g for 10 min or until serum is clearly separated from the 
clot. A refrigerated centrifuge is preferred but not essential. If a refrigerated centrifuge is not 
available, samples may be pre-chilled by refrigerating for 30 minutes prior to centrifuging 
and/or centrifuged in pre-chilled rotors. 
6. Using a separate clean disposable pipette or a tip for each blood collection tube, transfer 
serum in to the 1 appropriately labeled PK sample storage cryo vials.  
7. Store the sample cryo vials at approximately -70°C until shipment. If -70°C is not available, 
samples may be stored at -20°C. Once frozen, samples should not be allowed to thaw. 
8. Ship the serum samples on dry ice to Central Lab using sufficient dry ice to ensure that 
samples remain frozen for at least 72 hours. It is contemplated that shipment be performed 
by clinical site in one single batch with all phase 1 patients’ samples at a date that will be 
instructed by the sponsor for the analysis. Performance of the analysis on a single batch will 
avoid variability between assays done on different batches.  
 
Monitoring of Immunogenicity  
ADA: ANTI- MSB0010718C: Nab: NEUTRALIZING ANTI-MSB0010718C 
 
1. The entire blood processing to serum and placing the samples in the freezer described below 
should be completed within 90 minutes of blood collection. 
2.  Collect a minimum of 3.5mL of whole blood per ADA/NAB time point into an appropriately 
labeled yellow-gold top SST tubes.  
3.  It is important to thoroughly mix the blood with the clotting activation agent by gently 
inverting the tube for at least five times (do not shake).  
4.  Place the blood collection tube in the upright position and keep the tube at room temperature 
for at least 30 mins but no longer than 60 mins (tube standing upright) to allow for clotting 
the blood to serum. 
5. Centrifuge at approximately 1700 x g for 10 min or until serum is clearly separated from the 

SPRING Protocol version 2.0 May 20th 2019                       CONFIDENTIAL 
Page 91 of 99 
clot. A refrigerated centrifuge is preferred but not essential. If a refrigerated centrifuge is not 
available, samples may be pre-chilled by refrigerating for 30 minutes prior to centrifuging 
and/or centrifuged in pre-chilled rotors. 
6. Using a separate clean disposable pipette or a tip for each blood collection tube, transfer 
serum in to the 2 appropriately labeled ADA/NAB sample storage cryo vials. 
7. Store the sample cryo vials at approximately -70°C until shipment. If -70°C is not available, 
samples may be stored at -20°C. Once frozen, samples should not be allowed to thaw. 
8. Ship the serum samples on dry ice to Central Lab using sufficient dry ice to ensure that 
samples remain frozen for at least 72 hours. It is contemplated that shipment be performed 
by clinical site in one single batch with all phase 1 patients’ samples at a date that will be 
instructed by the sponsor for the analysis. Performance of the analysis on a single batch will 
avoid variability between assays done on different batches.  
 
Axitinib PK plasma sampling, processing, and storage instructions:  
Special precautions should be taken throughout sample collection, processing, storage, and 
shipment to minimize exposure to visible light, which will cause rapid degradation of 
Axitinib.  
1. Using a separate tube per timepoint, collect 3 mL blood per PK sampling timepoint into a 
commercially available 3-mL collection tube containing K3-EDTA anticoagulant. Samples 
should be processed as soon as possible after collection. Harvested plasma should be frozen 
preferably within 1 hour of collection. 
2. Each filled blood collection tube should be gently inverted at least 8-10 times to thoroughly 
mix the blood with the anticoagulant. 
3. Blood collection tubes should be protected from light (covered completely in aluminum foil 
or in black protection tubes) and placed at 2°C to 8°C (e.g., ice bath or under refrigerated 
conditions) during the interval between collection and centrifugation to harvest plasma. 
4. Centrifuge blood samples for at least 10 minutes at 1700 x g at 4°C or lower. Following 
centrifugation, the resulting plasma should be transferred to labeled amber cryovials using 
a different pipette for each timepoint to avoid cross-contamination. 
5. Plasma samples should be transferred to an opaque box to protect from light exposure and 
stored at - 20°C or lower in a non-defrosting freezer within 1 hour of collection. If a sample 
is inadvertently exposed to light (for 5 minutes or more), the sponsor should be notified so 
that the sample can be flagged for potentially spurious results. 
6. Once frozen, plasma samples should not be allowed to thaw, including during shipment. 
7. Frozen plasma samples should be shipped with a completed sample inventory form and 
sufficient dry ice to last for at least 2 to 3 days. Shipping schedule will be determined by 
the sponsor. It is contemplated that shipment be performed by clinical site in one single 
batch with all phase 1 patients’ samples at a date that will be instructed by the sponsor for 
the analysis. Performance of the analysis on a single batch will avoid variability between 
assays done on different batches.  
 
 

SPRING Protocol version 2.0 May 20th 2019                       CONFIDENTIAL 
Page 92 of 99 
Sample Handling, Processing and Storage Instructions for Palbociclib (PD- 0332991):  
Pharmacokinetics of Palbociclib  
1. Blood samples (3 or 4 mL, depending on the availability of the blood collection tube) 
to provide a minimum of 1.0 mL of plasma for pharmacokinetic analysis of Palbociclib 
will 
be 
collected 
into 
appropriately 
labeledtubes 
containing 
dipotassium 
ethylenediaminetetraacetic acid (K2EDTA) per time point.  
2. Upon collection of the blood PK samples, keep the samples on wet ice at all times prior 
to processing to plasma.  
3. The blood samples have to be processed to plasma and placed in a freezer at -20°C 
within 1 hour of collection.  
4. To process the blood samples to plasma, centrifuge the blood samples in a refrigerated 
centrifuge at approximately 4°C at about 1700 x g for approximately 10 minutes.  
5. Using a clean separate pipette for each time point, transfer the plasma samples into pre- 
labeled 4 or 5 mL polypropylene cryovials and store in the freezer at approximately – 
20°C until shipment. If a -20°C freezer is not available at the site the samples may be 
stored at - 80°C. Palbociclib is stable at -20°C and - 80°C for 439 days in frozen 
K2EDTA plasma.  
6. Ship the frozen samples on dry ice to the contract bioanalytical laboratory. It is 
contemplated that shipment be performed by clinical site in one single batch with all 
phase 1 patients’ samples at a date that will be instructed by the sponsor for the analysis. 
Performance of the analysis on a single batch will avoid variability between assays done 
on different batches.  
 
All information added to the labels should be written with an indelible marker; water-based 
inks will smear during thawing, making the label unreadable rendering the written 
information useless. Labels should be affixed only to DRY surfaces. Labels should contain, 
at a minimum, the following information: -Protocol # or Pfizer IIR Tracking #-Investigator 
Name-Subject ID-Sample Matrix (e.g. plasma) -Analyte (e.g. palbociclib)-Visit (e.g. 
C1D14)-Nominal Sampling Time (e.g. 1Hr).  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

SPRING Protocol version 2.0 May 20th 2019                       CONFIDENTIAL 
Page 93 of 99 
10.8. 
APPENDIX 8: Global View on Toxicity Profiles 
 
 
GLOBAL VIEW ON TOXICITY PROFILES (specific and overlapping) and SAE reported by 
Pfizer/Merck to date. 
The tables below show the most common and the most serious adverse events known about the 3 
drugs. There might be other side effects that researchers do not yet know about. If important new 
adverse events are found, the study investigator will discuss these with the patient. 
 
The frequency described in the following table must be understood as follow: 
1. Any event listed with a frequency of more than 10% are adverse events considered very 
common, some may be serious (in 100 people receiving at least one of the drug, more than 10 
and up to 100 may have the corresponding side effect) 
2. Any event listed with a frequency comprised between 1% and 10% are adverse events 
considered common, some may be serious (in 100 people receiving at least one of the drug, 
from 1 to 10 or less may have the corresponding side effect) 
3. Any event listed with a frequency comprised below 1% are adverse events considered 
uncommon, some may be serious (in 1000 people receiving at least one of the drug, from 1 to 
10 or less may have the corresponding side effect) 
 
The table indicates also if the adverse events listed is specific to one drug or common to 2 or all. 
 
 
Adverse Events 
Avelumab 
Axitinib 
Palbociclib 
Specificity 
Frequency 
Infusion-related reaction 
X 
- 
- 
Specific 
More than 10% 
Dysphonia (hoarse voice) 
- 
X 
- 
Specific 
More than 10% 
Hypertension 
- 
X 
- 
Specific 
More than 10% 
Haemorrhage 
- 
X 
- 
Specific 
More than 10% 
Palmar-plantar 
erythrodysaesthesia 
syndrome (Hand and Foot 
Syndrome) 
- 
X 
- 
Specific 
More than 10% 
Proteinuria 
- 
X 
  
Specific 
More than 10% 
Infection 
- 
- 
X 
Specific 
More than 10% 
Insomnia 
- 
- 
X 
Specific 
More than 10% 
Malaise 
- 
- 
X 
Specific 
More than 10% 
Ascites  
X 
- 
- 
Specific 
1% to 10% 
Autoimmune disorder 
X 
- 
- 
Specific 
1% to 10% 
Hypoxia 
X 
- 
- 
Specific 
1% to 10% 
Lymphocyte count decrease 
X 
- 
- 
Specific 
1% to 10% 
Pleural effusion 
X 
- 
- 
Specific 
1% to 10% 
Pneumonia, Pneumonitis 
X 
- 
- 
Specific 
1% to 10% 
Respiratory failure  
X 
- 
- 
Specific 
1% to 10% 
Pruritus 
X 
- 
- 
Specific 
1% to 10% 
Rash maculo-papular 
X 
- 
- 
Specific 
1% to 10% 
Sepsis 
X 
- 
- 
Specific 
1% to 10% 
Small intestinal obstruction 
X 
- 
- 
Specific 
1% to 10% 
Cardiac failure events 
- 
X 
- 
Specific 
1% to 10% 
Dehydration 
- 
X 
- 
Specific 
1% to 10% 
Erythema 
- 
X 
- 
Specific 
1% to 10% 

SPRING Protocol version 2.0 May 20th 2019                       CONFIDENTIAL 
Page 94 of 99 
Adverse Events 
Avelumab 
Axitinib 
Palbociclib 
Specificity 
Frequency 
Gastrointestinal perforation 
and fistula 
- 
X 
- 
Specific 
1% to 10% 
Glossodynia (burning mouth 
sensation) 
- 
X 
- 
Specific 
1% to 10% 
Haemorrhoids 
- 
X 
- 
Specific 
1% to 10% 
Hyperbilirubinemia 
- 
X 
- 
Specific 
1% to 10% 
Hypercalcaemia 
 
X 
- 
Specific 
1% to 10% 
Polycythaemia 
- 
X 
- 
Specific 
1% to 10% 
Potassium and sodium 
increase 
- 
X 
- 
Specific 
1% to 10% 
Renal failure 
- 
X 
- 
Specific 
1% to 10% 
Tinnitus 
- 
X 
- 
Specific 
1% to 10% 
Venous embolic and 
thrombotic events and 
arterial embolic and 
thrombotic events 
- 
X 
- 
Specific 
1% to 10% 
Abdominal distension and 
discomfort 
- 
- 
X 
Specific 
1% to 10% 
Blurred vision, Lacrimation 
increase, Eye dryness 
- 
- 
X 
Specific 
1% to 10% 
Dry mouth 
- 
- 
X 
Specific 
1% to 10% 
Epistaxis (nose bleeding) 
- 
- 
X 
Specific 
1% to 10% 
Febrile neutropenia 
- 
- 
X 
Specific 
1% to 10% 
Hypoaesthesia (reduced 
sense of touch or 
sensation) 
- 
- 
X 
Specific 
1% to 10% 
Hypotension 
- 
- 
X 
Specific 
1% to 10% 
Muscle spasms 
- 
- 
X 
Specific 
1% to 10% 
Muscular weakness 
- 
- 
X 
Specific 
1% to 10% 
Night sweats 
- 
- 
X 
Specific 
1% to 10% 
Pain and flank pain 
- 
- 
X 
Specific 
1% to 10% 
Palpitations 
- 
- 
X 
Specific 
1% to 10% 
Rhinorrhoea 
- 
- 
X 
Specific 
1% to 10% 
Adrenocortical insufficiency 
acute  
X 
- 
- 
Specific 
0.1% to 0.99% 
Acute hepatic failure, 
hepatic failure, hepatitis 
X 
- 
- 
Specific 
0.1% to 0.99% 
Anaphylactic reaction 
X 
- 
- 
Specific 
0.1% to 0.99% 
Autoimmune hepatitis 
X 
- 
- 
Specific 
0.1% to 0.99% 
Autoimmune 
hypothyroidism 
X 
- 
- 
Specific 
0.1% to 0.99% 
Blood creatinine 
phosphokinase increased  
X 
- 
- 
Specific 
0.1% to 0.99% 
Colitis (inflammation of the 
colon), autoimmune colitis 
and enterocolitis 
X 
- 
- 
Specific 
0.1% to 0.99% 
Dermatitis exfoliative 
X 
- 
- 
Specific 
0.1% to 0.99% 
Diabetes mellitus, type I 
diabetes mellitus 
X 
- 
- 
Specific 
0.1% to 0.99% 
Drug hypersensitivity, 
hypersensitivity and type I 
hypersensitivity 
X 
- 
- 
Specific 
0.1% to 0.99% 
Erythema multiforme 
X 
- 
- 
Specific 
0.1% to 0.99% 
Guillian-Barré syndrome 
X 
- 
- 
Specific 
0.1% to 0.99% 
Hypopituitarism 
X 
- 
- 
Specific 
0.1% to 0.99% 

SPRING Protocol version 2.0 May 20th 2019                       CONFIDENTIAL 
Page 95 of 99 
Adverse Events 
Avelumab 
Axitinib 
Palbociclib 
Specificity 
Frequency 
Myositis (muscle 
inflammation) 
X 
- 
- 
Specific 
0.1% to 0.99% 
Pemphigoid 
X 
- 
- 
Specific 
0.1% to 0.99% 
Pruritus generalised 
X 
- 
- 
Specific 
0.1% to 0.99% 
Rash generalised, pruritic, 
erythematous, macular and 
popular  
X 
- 
- 
Specific 
0.1% to 0.99% 
Thyroiditis and autoimmune 
thyroiditis 
X 
- 
- 
Specific 
0.1% to 0.99% 
Tubulointerstitial nephritis 
X 
- 
- 
Specific 
0.1% to 0.99% 
Transaminase increased  
X 
- 
- 
Specific 
0.1% to 0.99% 
Uveitis 
X 
- 
- 
Specific 
0.1% to 0.99% 
Posterior reversible 
encephalopathy syndrome 
- 
X 
- 
Specific 
0.1% to 0.99% 
Dry skin 
- 
X 
X 
Common to 2 
More than 10% 
Dyspepsia (indigestion) 
- 
X 
X 
Common to 2 
More than 10% 
Stomatitis (inflammation of 
the mouth) 
- 
X 
X 
Common to 2 
More than 10% 
Pyrexia (fever) 
X 
- 
X 
Common to 2 
More than 10% for 
Avelumab, 1% to 
10% for Palbociclib 
Back pain 
X 
- 
X 
Common to 2 
More than 10% for 
Avelumab, 1% to 
10% for Palbociclib 
Oedema peripheral 
X 
- 
X 
Common to 2 
More than 10% for 
Avelumab, 1% to 
10% for Palbociclib 
Dysgeusia (change of 
sense of taste) 
- 
X 
X 
Common to 2 
More than 10% for 
Axitinib, 1% to 10% 
for Palbociclib 
Mucosal inflammation 
  
X 
X 
Common to 2 
More than 10% for 
Axitinib, 1% to 10% 
for Palbociclib 
Pain in extremity 
- 
X 
X 
Common to 2 
More than 10% for 
Axitinib, 1% to 10% 
for Palbociclib 
Chills 
X 
- 
X 
Common to 2 
 1% to 10% for 
Palbociclib and 
Avelumab 
Blood creatinine increased 
- 
X 
X 
Common to 2 
1% to 10% for 
Axitinib, more than 
10% for Palbocyclib 
Hypothyroidism 
X 
X 
- 
Common to 2 
1% to 10% for 
Avelumab, more 
than 10% for 
Axitinib 
Neutropenia 
- 
X 
X 
Common to 2 
0.1% to 0.99% for 
Axitinib, more than 
10% for Palbocyclib 
Alanine aminotransferase 
increased 
X 
X 
- 
Common to 2 
0.1% to 0.99% for 
avelumab, 1% to 
10% for axitinib 
Hyperthyroidism  
X 
X 
- 
Common to 2 
1% to 10% for 
axitinib, 0.1% to 
0.99% for 
avelumab 
Hypokalaemia 
X 
X 
- 
Common to 2 
1% to 10% 

SPRING Protocol version 2.0 May 20th 2019                       CONFIDENTIAL 
Page 96 of 99 
Adverse Events 
Avelumab 
Axitinib 
Palbociclib 
Specificity 
Frequency 
Lipase and amylase 
increased 
X 
X 
- 
Common to 2 
1% to 10% 
Alopecia (hair loss) 
- 
X 
X 
Common to 2 
1% to 10% 
Dizziness 
- 
X 
X 
Common to 2 
1% to 10% 
Flatulence 
- 
X 
X 
Common to 2 
1% to 10% 
Oropharyngeal pain 
- 
X 
X 
Common to 2 
1% to 10% 
Constipation  
X 
X 
X 
Common to 3 
More than 10% 
Diarrhoea 
X 
X 
X 
Common to 3 
More than 10% 
Decreased appetite 
X 
X 
X 
Common to 3 
More than 10% 
Fatigue 
X 
X 
X 
Common to 3 
More than 10% 
Nausea 
X 
X 
X 
Common to 3 
More than 10% 
Vomiting 
X 
X 
X 
Common to 3 
More than 10% 
Weight decreased 
X 
X 
X 
Common to 3 
More than 10% for 
Avelumab, 1% to 
10% for Axitinib 
and Palbociclib 
Anaemia 
X 
X 
X 
Common to 3 
More than 10% for 
Avelumab and 
Palbociclib, 1% to 
10% for Axitinib 
Abdominal pain 
X 
X 
X 
Common to 3 
More than 10% for 
Avelumab and 
Axitinib, 1% to 10% 
for Palbociclib 
Cough 
X 
X 
X 
Common to 3 
More than 10% for 
Avelumab and 
Axitinib, 1% to 10% 
for Palbociclib 
Dyspnoea (shortness of 
breath) 
X 
X 
X 
Common to 3 
More than 10% for 
Avelumab and 
Axitinib, 1% to 10% 
for Palbociclib 
Arthralgia (join pain) 
X 
X 
X 
Common to 3 
More than 10% for 
Axitinib and for 
Avelumab, 1% to 
10% for Palbociclib,  
Headache  
X 
X 
X 
Common to 3 
1% to 10% for 
Avelumab and 
Palbociclib, more 
than 10% for 
Axitinib 
Rash  
X 
X 
X 
Common to 3 
1% to 10% for 
Avelumab and 
Palbociclib, more 
than 10% for 
Axitinib 
Weakness 
X 
X 
X 
Common to 3 
1% to 10% for 
Avelumab and 
Palbociclib, more 
than 10% for 
Axitinib 
Aspartate aminotransferase 
increased 
X 
X 
X 
Common to 3 
0.1% to 0.99% 
Avelumab, 1% to 
10% for Axitinib, 
more than 10% for 
Palbociclib 

SPRING Protocol version 2.0 May 20th 2019                       CONFIDENTIAL 
Page 97 of 99 
Adverse Events 
Avelumab 
Axitinib 
Palbociclib 
Specificity 
Frequency 
Blood alkaline phosphatase 
increased 
X 
X 
X 
Common to 3 
1% to 10% for 
Avelumab and 
Axitinib, more than 
10% for Palbociclib 
Itching 
X 
X 
X 
Common to 3 
1% to 10% 
Myalgia (muscle pain) 
X 
X 
X 
Common to 3 
1% to 10% 
 
 
 
 
The following table lists serious adverse events (SAE) that may require hospitalization or may be 
irreversible, long-term, or life-threatening. This list contains also fatal events related to single drug 
treatment axitinib (total of 27 to date), palbociclib (total of 7 to date), avelumab (total of 5 to date). 
 
Adverse events and Serious adverse events are reported from trials with the drug administered as a 
single drug for all types of cancer and all origins, for treatment-related only (not all-causality) and 
all clinical phases.  
 
 
Serious Adverse Events 
Avelumab 
Axitinib 
Palbociclib 
Specificity 
Acute liver failure, hepatitis and 
autoimmune hepatitis 
X 
- 
- 
Specific 
Adrenal insufficiency  
X 
- 
- 
Specific 
Anaemia 
X 
- 
- 
Specific 
Anaphylactic reaction 
X 
- 
- 
Specific 
Arthralgia 
X 
- 
- 
Specific 
Ascites  
X 
- 
- 
Specific 
Aspartate aminotransferase (AST) 
increased 
X 
- 
- 
Specific 
Blood creatinine phosphokinase 
increased 
X 
- 
- 
Specific 
Colitis (inflammation of the colon) 
X 
- 
- 
Specific 
Constipation 
X 
- 
- 
Specific 
Cougth 
X 
- 
- 
Specific 
Diabetes mellitus and Type 1 
diabetes mellitus 
X 
- 
- 
Specific 
Dyspnea 
X 
- 
- 
Specific 
Edema peripheral 
X 
- 
- 
Specific 
Guillian-Barré syndrome 
X 
- 
- 
Specific 
hyponatramia 
X 
- 
- 
Specific 
Hypothyroidism / hyperthyroidism / 
Thyroiditis 
X 
- 
- 
Specific 
Infusion-related reaction 
X 
- 
- 
Specific 
Myositis (muscle inflammation) 
X 
- 
- 
Specific 
Non-cardiac chest pain 
X 
- 
- 
Specific 
Pleural effusion 
X 
- 
- 
Specific 
Rash generalised 
X 
- 
- 
Specific 
Respiratory distress 
X 
- 
- 
Specific 
Small intestinal obstruction 
X 
- 
- 
Specific 
Transaminase increased 
X 
- 
- 
Specific 
Tubulointerstitial nephritis 
X 
- 
- 
Specific 
Type I hypersensitivity 
X 
- 
- 
Specific 

SPRING Protocol version 2.0 May 20th 2019                       CONFIDENTIAL 
Page 98 of 99 
Serious Adverse Events 
Avelumab 
Axitinib 
Palbociclib 
Specificity 
Weight decrease 
X 
- 
- 
Specific 
Aorto-duodenal fistula 
- 
X 
- 
Specific 
Arterial embolic and thrombotic 
events 
- 
X 
- 
Specific 
Cerebrovascular accident 
- 
X 
- 
Specific 
Circulatory collapse 
- 
X 
- 
Specific 
General health degradation 
- 
X 
- 
Specific 
Haemorrhage 
- 
X 
- 
Specific 
Hepatic cancer 
- 
X 
- 
Specific 
Hyperosmolar hyperglycaemic 
state 
- 
X 
- 
Specific 
Hypertension 
- 
X 
- 
Specific 
Metastatic renal cell carcinoma 
- 
X 
- 
Specific 
Myocardial infarction 
- 
X 
- 
Specific 
Pulmonary embolism 
- 
X 
- 
Specific 
Venous embolic and thrombotic 
events 
- 
X 
- 
Specific 
Weakness 
- 
X 
- 
Specific 
Alveolitis allergic 
- 
- 
X 
Specific 
Lung infection 
- 
- 
X 
Specific 
Abdominal pain 
X 
X 
- 
Common to 2 
Back pain  
X 
X 
- 
Common to 2 
Decrease appetite 
X 
X 
- 
Common to 2 
Dehydration 
- 
X 
X 
Common to 2 
Dyspnoea (shortness of breath) 
X 
X 
- 
Common to 2 
Fatigue 
X 
X 
- 
Common to 2 
Haemoptysis (coughing up blood) 
- 
X 
X 
Common to 2 
Hepatic failure 
X 
X 
- 
Common to 2 
Intestinal perforation 
- 
X 
X 
Common to 2 
Nausea  
X 
X 
- 
Common to 2 
Pneumonia / Pneumonitis 
X 
- 
X 
Common to 2 
Pyrexia (Fever) 
X 
X 
- 
Common to 2 
Respiratory failure 
X 
- 
X 
Common to 2 
Sepsis (general infection) 
X 
X 
- 
Common to 2 
Syncope 
- 
X 
X 
Common to 2 
Vomiting 
X 
X 
- 
Common to 2 
Cardiac arrest 
X 
X 
X 
Common to 3 
Diarrhoea 
X 
X 
X 
Common to 3 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

SPRING Protocol version 2.0 May 20th 2019                       CONFIDENTIAL 
Page 99 of 99 
10.9. 
APPENDIX 9: Modulators of CYP3A4 
 
 
Relevant strong inhibitors and inducers of CYP3A4 list. 
 
Strong CYP3A4 inhibitors or inducers are prohibited while on this protocol per Important Note (5). 
Moderate CYP3A4 inhibitors or inducers should be used with caution.   
 
*Note: This list is not exhaustive. It is expected that the patient’s medications’ list is reviewed by 
pharmacy to determine each medication potential effect on the CYP3A4 metabolism system. 
Medications that are used in disease states that are excluded by the SPRING protocol were 
specifically excluded from this list (HIV, hepatitis, etc.).  
 
Modulators of CYP3A4 
Strong Inhibitors 
Strong Inducers 
Clarithromycin 
Carbamazepine 
Itraconazole 
Fosphenytoin 
Ketoconazole 
Phenobarbital 
Mifepristone 
Phenytoin 
Nefazodone 
Primidone 
Posaconazole 
Rifampin 
Suboxone 
St John’s wort 
Telaprevir 
 
Telithromycin 
 
Voriconazole 
 
 
References: 
1. 
Lexi-comp drug information. UpToDate. Retrieved May 10, 2018 from https://www.uptodate.com/contents/search.   
2. 
Micromedex. Retrieved May 10, 2018 from http://www.micromedexsolutions.com/home/dispatch. 
3. 
P450 drug interaction table. Indiana University.  Retrieved May 10, 2018 from http://medicine.iupui.edu/clinpharm/ddis/main-table.  
4. 
Drug development and drug interactions: table of substrates, inhibitors and inducers. 11/17/2017. U.S. Food & Drug Administration. 
Retrieved May 10, 2018 from 
https://www.fda.gov/drugs/developmentapprovalprocess/developmentresources/druginteractionslabeling/ucm093664.htm.