Conditions: Metastatic Breast Cancer
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 20
Healthy volunteers: no

Brief summary:
This is an open-label, single arm, multicenter phase II study evaluating treatment with pembrolizumab in combination with paclitaxel in patients with locally advanced or metastatic non-luminal hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) (hereafter referred to as HR+/HER2-) breast cancer who had recurrence or progression while receiving previous therapy with a cyclin-dependent kinase (CDK) inhibitor in the adjuvant setting or to treat advanced disease (or both).

Detailed description:
The study will utilize a 2-stage, single arm, Simon's 2-stage design with one (efficacy) interim and a final analysis. The interim analysis will be conducted when 15 patients are evaluable for Overall Response Rate (ORR) as determined locally by the investigator through the use of Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v.1.1). If 5 or fewer responses are observed in up to 15 patients of the evaluable population (EP), the trial will be terminated in favor of the null for futility. Otherwise, up to a further 31 patients may be evaluated, for a maximum total of 46 evaluable patients. If a total of 19 or more responses are seen at the end of the second stage, then the null will have been rejected in favor of the alternative; and further investigation of the combination is warranted.

Recruitment will not be halted during the interim analysis period. Therefore, no interruption in the accrual will be done during the interim analysis in order to maintain the dynamic of accrual in the trial.

After confirmation of all eligibility criteria, eligible patients will receive pembrolizumab 200 mg every 3 weeks (on Day 1 \[D1\] of each 21-day cycle, beginning in Cycle 1) in combination with paclitaxel 80 mg/m² administered at Days 1, 8, and 15 of each 21-day cycle beginning at Cycle 2. Treatment will continue until disease progression, the development of unacceptable toxicity, withdrawal of consent, 24 months from the date of the first dose of pembrolizumab, or end of study, whichever occurs first.

All patients will be followed for survival from screening until the last patient recruited has been followed for 12 months, has progressed, or has died, whichever occurs first. The patient will be followed for survival approximately every 3 months (± 21 days) until death, withdrawal of consent, loss to follow-up, or study termination by the sponsor. In addition, information regarding use of subsequent anti-cancer agents for metastatic hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) during the survival follow-up period will be collected.

Tumor assessments per RECIST v.1.1 and Immune-Related Response Evaluation Criteria in Solid Tumors (iRECIST) will be performed every 9 weeks (63 days ± 5 days) until disease progression, treatment discontinuation, the start of new anti-cancer treatment, withdrawal of consent, death, or the end of the study, whichever occurs first. Tumor assessments will be performed on the specified schedule regardless of treatment delays.

Safety assessments will include the incidence, nature, and severity of adverse events (AEs) and laboratory abnormalities graded per the National Cancer Institute Common Terminology Criteria for Adverse Events version 5 (NCI CTCAE v.5).

Laboratory safety assessments will include the regular monitoring of hematology, blood chemistry, and pregnancy test.

Arms:
arm 1: Pembrolizumab 200 mg every 3 weeks (on Day 1 \[D1\] of each 21-day cycle, beginning in Cycle 1) in combination with paclitaxel 80 mg/m² administered at Days 1, 8, and 15 of each 21-day cycle beginning at Cycle 2.

Interventions: intervention 1: Pembrolizumab intervention 2: Paclitaxel
Intervention descriptions: intervention 1: Pembrolizumab 200 mg will be administered as a 30-minute intravenous (IV) infusion every 3 weeks beginning in Cycle 1 intervention 2: Paclitaxel will be administered at the 80 mg/m2 dose via 1-hour intravenous (IV) infusion on Days 1, 8, and 15 of every 21-day cycle (beginning in Cycle 2). On days of scheduled infusions of pembrolizumab and paclitaxel (i.e., Day 1 of every cycle), paclitaxel is to be administered after infusion of pembrolizumab

Protocol document:
Prot_000.pdf: 
PROTOCOL TATEN SOLTI-1716 
 
Version 2 dated 10-May-2021  
 
 
1 
 
 
 
 
 
 
SPONSOR: SOLTI 
 
TITLE: Targeting non-Luminal disease by PAM50 with pembrolizumab + paclitaxel in 
Hormone Receptor-positive/HER2-negative advanced/metastatic breast cancer, who have 
progressed on or after CDK 4/6 inhibitor treatment (TATEN trial) 
IND NUMBER: SOLTI-1716 
 
EudraCT NUMBER: 2018-003367-58 
 
 
 
Principal investigators 
 
 
Sponsor: 
SOLTI 
Version number 
Version 2 dated 10-May-2021  
Trial phase 
Phase II 
Document status 
Final 
 
 
 
 
 
 
 
PPD
PPD


PROTOCOL TATEN SOLTI-1716 
 
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Contact Addresses 
 
 
 
 
 
Writing Committee: 
 
Study Coordinator 
or Chairman: 
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Sponsor details: 
Pharmacovigilance: 
 PPD
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PROTOCOL TATEN SOLTI-1716 
 
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Traslational Research: 
Statistician Data 
management: 
 
 
 
 
 
 
PPD
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PROTOCOL TATEN SOLTI-1716 
 
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PROTOCOL APPROVAL SIGNATURES 
 
Title: Targeting non-Luminal disease by PAM50 with pembrolizumab + paclitaxel in 
Hormone Receptor-positive/HER2-negative advanced/metastatic breast cancer, who have 
progressed on or after CDK 4/6 inhibitor treatment (TATEN trial) 
 
Approval: 
PI Signature (Name and Title) 
 
Date 
PI Signature (Name and Title) 
 
Date 
Chief Scientific Officer  Signature (Name and Title) 
 
Date 
 
This confidential information about an investigational product is provided for the exclusive use of 
investigators of this product and is subject to recall at any time. The information in this document 
may not be disclosed unless federal or state law or regulations require such disclosure.  Subject to the 
foregoing, this information may be disclosed only to those persons involved in the study who have a 
need to know, with the obligation not to further disseminate this information.   
PPD
PPD
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PROTOCOL TATEN SOLTI-1716 
 
Version 2 dated 10-May-2021  
 
 
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PROTOCOL AGREEMENT - SITE PRINCIPAL INVESTIGATOR 
 
I have read the protocol specified below. In my formal capacity as Investigator, my duties include 
ensuring the safety of the study subjects enrolled under my supervision and providing SOLTI with 
complete and timely information, as outlined in the protocol.  It is understood that all information 
pertaining to the study will be held strictly confidential and that this confidentiality requirement 
applies to all study staff at this site. Furthermore, on behalf of the study staff and myself, I agree 
to maintain the procedures required to carry out the study in accordance with accepted GCP 
principles and to abide by the terms of this protocol. 
 
Protocol Number:  SOLTI-1716 
 
Protocol Date:  10-May 2021 
Investigator Signature  
 
Date 
 
Print Name and Title 
Site # 
Site Name 
Address 
 
Phone Number 
 
 
PPD
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PROTOCOL TATEN SOLTI-1716 
 
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INDEX 
1. 
TRIAL SUMMARY.................................................................................................... 1 
2. 
TRIAL DESIGN.......................................................................................................... 1 
 
Trial design .............................................................................................................. 1 
 
Trial diagram .......................................................................................................... 3 
3. 
OBJECTIVE(S) & HYPOTHESIS(ES) .................................................................... 4 
 
Primary objective(s) & hypothesis(es) .................................................................. 4 
 
Secondary objective(s) & hypothesis(es) ............................................................... 4 
 
Exploratory objective ............................................................................................. 5 
4. 
BACKGROUND & RATIONALE ............................................................................ 6 
 
Background ............................................................................................................. 6 
 Breast cancer ......................................................................................................... 6 
 Background on HR+/HER2- metastatic breast cancer and treatment ................... 6 
 The importance of intrinsic subtyping in HR+/HER2- breast cancer ................... 7 
 The main molecular features of the HER2-enriched and Basal-like subtypes ..... 8 
 Identification of non-luminal subtypes within HR+/HER2- disease .................... 8 
 Non-luminal subtypes in HR+/HER2- advanced/metastatic disease .................... 9 
 Prognostic value of non-luminal subtypes in HR+/HER2- ................................. 10 
 Anti-estrogen sensitivity of the HER2-E subtype ............................................... 11 
 Anti-CDK4/6 sensitivity of the non-luminal subtypes within HR+ disease ....... 12 
 Chemotherapy sensitivity of the non-luminal subtypes within HR+ disease ..... 12 
 Immune infiltration of non-luminal subtypes within HR+/HER2- disease ........ 12 
 
Pharmaceutical and therapeutic background .................................................... 13 


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 Paclitaxel ............................................................................................................. 13 
 Immunoncology .................................................................................................. 14 
 Immunotherapy in breast cancer ......................................................................... 14 
 Combination of PD1/PD-L1 inhibition and chemotherapy in breast cancer ...... 18 
 Pembrolizumab ................................................................................................... 19 
 
Rationale ................................................................................................................ 21 
 Rationale for the trial and selected population.................................................... 21 
 Justification for dose ........................................................................................... 22 
 Rationale for endpoints ....................................................................................... 23 
5. 
METHODOLOGY ................................................................................................... 24 
 
Study population ................................................................................................... 24 
 Participant inclusion criteria ............................................................................... 24 
 Participant exclusion criteria ............................................................................... 27 
 Lifestyle restrictions ............................................................................................ 29 
 Pregnancy ............................................................................................................ 29 
 Use in nursing women ........................................................................................ 30 
 
Trial treatments .................................................................................................... 30 
 Timing of dose administration ............................................................................ 30 
 Dose modification and toxicity management: general considerations................ 32 
 Dose modification and toxicity management for immune-related AEs associated 
with pembrolizumab ........................................................................................... 32 
 Dose modification and toxicity management for AEs associated with paclitaxel38 
 
Concomitant medications/vaccinations (allowed & prohibited) ...................... 41 
 Acceptable concomitant medications.................................................................. 41 
 Prohibited concomitant medications ................................................................... 42 


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 Rescue medications & supportive care ............................................................... 43 
 
Participant withdrawal/discontinuation criteria ............................................... 43 
 
Participant replacement strategy ........................................................................ 44 
 
Clinical criteria for early trial termination ........................................................ 44 
6. 
TRIAL FLOW CHART ........................................................................................... 46 
 
Study flow chart .................................................................................................... 46 
7. 
TRIAL PROCEDURES ........................................................................................... 50 
 
Trial procedures .................................................................................................... 50 
 Administrative procedures .................................................................................. 50 
 Clinical procedures/assessments ......................................................................... 53 
 Laboratory procedures/assessments .................................................................... 59 
 Other procedures ................................................................................................. 62 
 Visit requirements ............................................................................................... 62 
 
Assessing and recording adverse events ............................................................. 64 
 Definition of an overdose for this protocol and reporting of overdose to SOLTI 
and to Merck ....................................................................................................... 65 
 Reporting of pregnancy and lactation to SOLTI and to Merck .......................... 66 
 SOLTI immediate reporting of adverse events to SOLTI and to Merck ............ 67 
 Evaluating adverse events ................................................................................... 69 
 Sponsor responsibility for reporting adverse events ........................................... 73 
8. 
STATISTICAL ANALYSIS PLAN ........................................................................ 73 
 
Statistical and analysis plan summary ................................................................ 73 
 Analysis populations ........................................................................................... 73 
 Statistical analysis ............................................................................................... 74 
 
Sample size calculations ....................................................................................... 74 


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Primary objective .................................................................................................. 75 
 
Secondary objectives ............................................................................................. 75 
9. 
TRANSLATIONAL RESEARCH .......................................................................... 78 
 
Biological specimens .............................................................................................. 78 
 Tumor tissue samples .......................................................................................... 79 
 
Gene expression signatures .................................................................................. 79 
 The nCounter platform ........................................................................................ 80 
 RNA extraction ................................................................................................... 81 
 Technical procedures and data analysis .............................................................. 81 
 Immunohistochemistry ....................................................................................... 82 
 
Circulant tumor DNA ........................................................................................... 82 
 
Sample repository ................................................................................................. 82 
10. 
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES ................................................................................................................. 83 
 
Investigational product ......................................................................................... 83 
 
Packaging and labeling information ................................................................... 83 
 
Clinical supplies disclosure .................................................................................. 83 
 
Storage and handling requirements .................................................................... 83 
 
Returns and reconciliation ................................................................................... 84 
11. 
ADMINISTRATIVE AND REGULATORY DETAILS ....................................... 84 
 
Ethical and regulatory standards ......................................................................... 84 
 Independent Ethics Committee ........................................................................... 84 
 Ethical conduct of the study ................................................................................ 84 
 Subject information and consent ......................................................................... 85 
 
Subject records and source data .......................................................................... 85 


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 Study documentation and storage of records ...................................................... 86 
 
Access to source data and documentation ........................................................... 87 
 
Study monitoring ................................................................................................... 87 
 Responsibilities of the investigators .................................................................... 87 
 Responsibilities of SOLTI and monitoring.......................................................... 88 
 Source document requirements ........................................................................... 89 
 Use and completion of case report forms and additional requests ...................... 89 
 Use of computerized systems .............................................................................. 89 
 
Data management .................................................................................................. 90 
 
Confidentiality ....................................................................................................... 90 
 Patient records ..................................................................................................... 90 
 Study documentation and related data ................................................................. 90 
 
Property rights ....................................................................................................... 91 
 
Clinical trial protocol amendments ...................................................................... 91 
 
Protocol  deviations ................................................................................................ 92 
 Insurance ............................................................................................................... 92 
 Study committees ................................................................................................... 92 
 
Steering Committee ...................................................................................... 92 
 Premature discontinuation of the study or close- out of a site ........................... 92 
 Report and publication ......................................................................................... 93 
12. 
REFERENCES .......................................................................................................... 94 
13. 
APPENDICES ......................................................................................................... 104 
Appendix 1: ECOG performance status ....................................................................... 104 
Appendix 2: Common Terminology Criteria for Adverse Events V5.0 (CTCAE) ... 105 
Appendix 3: Contraceptive guidance and pregnancy testing ..................................... 106 


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Appendix 4: Description of the iRECIST process for assessment of disease progression
 .............................................................................................................................. 109 
Appendix 5: Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 
criteria for evaluating response in solid tumors .............................................. 113 
 


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1. TRIAL SUMMARY 
Abbreviated Title 
Targeting 
non-Luminal 
disease 
by 
PAM50 
with 
pembrolizumab + paclitaxel in Hormone Receptor-
positive/HER2-negative 
advanced/metastatic 
breast 
cancer 
Trial Phase 
Phase II 
Clinical Indication 
Pre and post-menopausal women with locally advanced or 
metastatic HR+/HER2-negative endocrine resistant breast 
cancer 
Trial Type 
Single arm 
Type of control 
- 
 
Route of administration 
I.V. 
Trial Blinding 
No 
Treatment Groups  
Pembrolizumab in combination with paclitaxel 
Number 
of 
trial 
participants 
46 evaluable patients (Approximately 184 screened) 
Estimated 
enrollment 
period 
Approximately 18 months  
Estimated duration of trial Approximately 56 months 
Duration of Participation 
Approximately 2 years or PD or discontinuation for any other 
reason whichever occurs first 
Estimated average length 
of treatment per patient 
Approximately 10 months 
 
 
 
2. TRIAL DESIGN 
 Trial design 
This is an open-label, single arm, multicenter phase II study evaluating treatment with 
pembrolizumab in combination with paclitaxel in patients with locally advanced or metastatic non-
luminal Hormone receptor-positive, HER2-negative (hereafter referred to as HR+/HER2-) breast 
cancer who had recurrence or progression while receiving previous therapy with a CDK inhibitor 
in the adjuvant setting or to treat advanced disease (or both). 
The study will utilize the optimal Simon’s two-stage design1 with one interim and a final 
analysis. The interim analysis will be conducted when 15 patients are evaluable for ORR as 
determined locally by the investigator through the use of RECIST v.1.1. If 5 or fewer responses 
are observed in up to 15 patients of evaluable population (EP), the trial will be terminated in favor 
of the null for futility. Otherwise, up to a further 31 patients may be evaluated, for a maximum 


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total of 46 evaluable patients. If a total of 19 or more responses are seen at the end of the second 
stage, then the null will have been rejected in favor of the alternative; and further investigation of 
the combination is warranted. 
Recruitment will not be halted during the interim analysis period. Therefore, no interruption in 
the accrual will be done during the interim analysis in order to maintain the dynamic of accrual in 
the trial. 
Before signing the main study informed consent form, patients who meet all clinical selection 
criteria will sign the pre-screening study informed consent form which will allow the patient to be 
pre-screened under SOLTI’s biomarker program. Estrogen Receptor (ER), Progesterone Receptor 
(PR) and epidermal growth factor receptor 2 (HER2) immunohistochemistry (IHC)/fluorescence 
in situ hybridization (FISH) will be determined locally and PAM50 standardized subtyping will 
be centrally determined to confirm the non-luminal status prior to starting the study treatment. If 
non-luminal disease (i.e. HER2-enriched [HER2-E] or basal-like) is identified, patients will be 
eligible for the trial and screening procedures will start (i.e. blood test, imaging…). Imaging will 
be performed prior to Day 1 of treatment and target lesions will be identified. Remaining tissue 
will be kept for future biomarker studies at the Central Laboratory. The study population consists 
of male or female patients age ≥ 18 years with advanced HR+/HER2- breast cancer who have 
received a CDK4/6 inhibitor containing regimen for locally recurrent and/or metastatic disease or 
in the adjuvant setting. Patients have to be CDK4/6 refractory, defined as progression while on, or 
within 6 months of ending CDK4/6 inhibition for locally advanced or metastatic breast cancer, or 
relapse during or after adjuvant with CDK4/6 inhibitors. Previous PI3K-pathway-targeted 
therapies (including PI3K, mTOR and AKT inhibitors) are permitted.  
After confirmation of all eligibility criteria, eligible patients will receive pembrolizumab 200 mg 
every 3 weeks (on D1 of each 21-day cycle, beginning in Cycle 1) in combination with paclitaxel 
80 mg/m2 administered at days 1, 8, 15 of each 21-day cycle beginning at cycle 2. Treatment will 
continue until disease progression, the development of unacceptable toxicity, withdrawal of 
consent, 24 months from the date of the first dose of pembrolizumab or end of study, whichever 
occurs first. 
Tumor assessments per Response Evaluation Criteria in Solid Tumors (RECIST) v.1.1 (see 
Appendix 5) and Immune-Related Response Evaluation Criteria In Solid Tumors (iRECIST) (see 
Appendix 4) will be performed every 9 weeks (63 days ± 5 days) until disease progression, 
treatment discontinuation, the start of new anti-cancer treatment, withdrawal of consent, death, or 
the end of the study, whichever occurs first. Tumor assessments will be performed on the specified 
schedule regardless of treatment delays.  
 
For estimation of overall response rate (ORR), clinical benefit rate (CBR), duration of response 
(DoR) and progression-free survival (PFS), tumor response will be based on RECIST v.1.1 (see 
Appendix 5). In patients who continue treatment beyond radiographic disease progression per 
RECIST v.1.1, tumor response (ORR and PFS) may continue to be assessed using iRECIST 
criteria (see Appendix 4) until study treatment discontinuation. 


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All patients will be followed for survival from screening until the last patient recruited has been 
followed for 12 months, has progressed or has died, whichever occurs first. The patient will be 
followed for survival approximately every 3 months (± 21 days) until death, withdrawal of consent, 
loss to follow-up, or study termination by SOLTI. In addition, information regarding use of 
subsequent anti-cancer agents for metastatic HR+/HER2- during the survival follow-up period will 
be collected. 
 
Safety assessments will include the incidence, nature, and severity of adverse events (AEs) and 
laboratory abnormalities graded per the NCI CTCAE v.5. Laboratory safety assessments will 
include the regular monitoring of hematology, blood chemistry and pregnancy test. A schedule of 
assessments is provided in section 6.1. 
 
 Trial diagram 
  
   
 
 
 
 
 


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3. OBJECTIVE(S) & HYPOTHESIS(ES) 
 Primary objective(s) & hypothesis(es) 
 
Primary objective 
Primary endpoint 
To assess the efficacy of 
pembrolizumab in 
combination with paclitaxel 
in HR+/HER2- non-luminal 
subtype advanced breast 
cancer defined by the PAM50 
assay. 
Overall Response rate (ORR) defined as the 
proportion of patients with best overall response of 
complete response (CR) or partial response (PR), as 
per local investigator´s assessment and according to 
Response Evaluation Criteria in Solid Tumors 
(RECIST) version 1.1 criteria (see Appendix 5). 
 
 Secondary objective(s) & hypothesis(es) 
Secondary objectives 
Secondary endpoints 
1. To determine the clinical 
benefit of pembrolizumab 
and paclitaxel in terms of: 
 
1.1. Clinical Benefit Rate (CBR) defined as the 
proportion of patients with a best overall response 
of CR, PR or an overall lesion response of Stable 
Disease (SD) or Non-PR/Non-progression disease 
(PD) lasting ≥ 24 weeks, based on local 
investigator´s assessment according to RECIST 
v1.1. 
1.2. Progression free survival (PFS) defined as the 
time from allocation to the first occurrence of 
disease progression, as determined locally by the 
investigator through the use of RECIST v.1.1, or 
death from any cause, whichever occurs first.  
1.3.  Duration of response (DoR) defined as the time 
from the first occurrence of a documented 
objective response to disease progression, as 
determined locally by the investigator through use 
of RECIST v.1.1, or death from any cause, 
whichever occurs first 
1.4. Time to response (TtR) defined as the time from 
allocation to the first objective tumor response 
(tumor shrinkage of ≥30%) observed for patients 
who achieved a CR or PR.  
1.5. Overall survival (OS) defined as the time from 
allocation to death from any cause (OS will be 
determined at the end of the study). 


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1.6. PFS on study treatment compared to PFS on prior 
line of therapy (pre-PFS). 
1.7. ORR according to PD1 mRNA expression. 
1.8. ORR according to early dynamic changes in 
ctDNA between baseline and after 1 cycle of 
pembrolizumab.  
1.9. PFS according to early dynamic changes in 
ctDNA between baseline and after 1 cycle of 
pembrolizumab. 
2. To assess the safety and 
tolerability 
of 
the 
combination 
of 
pembrolizumab 
with 
paclitaxel: 
2.1. Incidence, duration and severity of Adverse 
Events (AEs) assessed by the NCI Common 
Terminology for Classification of Adverse Events 
(CTCAE) version 5, including dose reductions, 
delays and treatment discontinuations. 
 
 Exploratory objective 
• To determine the ORR based on iRECIST. 
• To determine the PFS, DoR, TtR based on iRECIST. 
• To determine ORR according to PD-L1 protein expression by IHC.  
• To evaluate ORR according to stromal TILs. 
• To identify a new gene signature predictive of pembrolizumab and paclitaxel 
therapy benefit. 
Mandatory tumor samples collected during the pre-screening phase of the study will be used 
to investigate potential value of current and future RNA- and DNA-based biomarkers to predict 
response to the study drug(s). The following correlative science studies are planned: 
• Evaluation of gene expression 
To identify new biomarkers of response to the combination treatment, we aim to further 
evaluate the expression of 752 genes that encompass important genomic signatures and 
individual genes. The nCounter® Breast Cancer 360 Panel includes 752 genes that cover 
established breast cancer diagnostic and research signatures as well as key pathways at 
the interface of the tumor, tumor microenvironment and immune response. Special 
attention will be given to innate immune response genes as well as markers of antigen 
presentation, which are expected to be determinant for this combination treatment. The 
following genes/signatures will be evaluated among others: PAM50 genes and signatures, 
risk of recurrence (ROR) score, ER signaling biology, immune cell marker (e.g. BCL2; 


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CD163; CD68; CD84; CD8A; CD8B; CHIT1), chemo-endocrine score (CES), immune 
infiltration (e.g. CCL5; CD27; CD274; CD276; CD8A; CMKLR1; CXCL9) or 
proliferation. 
 
4. BACKGROUND & RATIONALE 
 Background 
 Breast cancer 
Breast cancer is a life-threatening disease and is the second leading cause of cancer death 
among women.  Although metastatic breast cancer is diagnosed in only 5% of cases at presentation, 
nearly one third of breast cancer patients with non-metastatic tumors will eventually develop 
metastases2.  
Breast cancer is considered a genetically heterogeneous and biologically diverse disease. 
Endocrine therapies that target estrogen receptor (ER) signaling pathways for ER-positive disease 
and human epidermal growth factor receptor 2 (HER2)-targeted therapies for HER2-positive 
disease play a critical role in the treatment of most patients with breast cancer3–5, but not every 
breast tumor responds equally to a specific agent. 
Hormone receptor-positive, HER2-negative breast cancer (hereafter referred to as 
HR+/HER2-) accounts for approximately 60-70% of all early stage breast cancer cases6. For this 
type of cancer, all patients are recommended for adjuvant endocrine therapy (ET) for 5-10 years. 
In the case of patients with intermediate/high risk, a chemotherapy regimen that generally 
contains anthracyclines and taxanes 
is also recommended7. However, in spite of this 
combination, these patients have a substantial relapse risk as shown by the large adjuvant 
studies GEICAM/9906 and CALGB/97418–10. A 
similar situation occurs in locally 
recurrent/metastatic HR+/HER2- disease, with a median overall survival not exceeding 30-35 
months in the post-aromatase inhibitors setting11,12. Therefore, new therapies and treatment 
strategies to improve the prognosis of patients with HR+/HER2- breast cancer are of great 
importance. 
 
 Background on HR+/HER2- metastatic breast cancer and treatment 
 Patients with metastatic HR+/HER2- breast cancer are treated with endocrine therapy; 
premenopausal patients often undergo additional ovarian ablation/suppression. Chemotherapy is 
indicated in patients with symptomatic visceral disease (visceral crisis) or in patients with disease 
progression after demonstration of endocrine resistance13,14.  
In the last 5 years, incorporation of novel drugs in combination with endocrine therapy is 
improving patient outcomes in HR+/HER2- advanced disease. The first success is exemplified by 
the 2012 approval of the mTOR inhibitor everolimus in combination with exemestane based on 
the BOLERO-2 study, setting a new standard for the second-line treatment of patients with 


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advanced HR+/HER2- breast cancer. Everolimus plus exemestane showed a median progression-
free survival (PFS) of 11 months versus 4.1 months for exemestane alone. In addition, 3 CDK4/6 
inhibitors are currently in late-stage commercialized for metastatic HR+/HER2- breast cancer: 
palbociclib, abemaciclib and ribociclib. All 3 of them are orally bioavailable and have similar 
mechanisms of action (Table 1). Palbociclib and ribociclib recently received FDA/EMA approval 
for the treatment of postmenopausal women with ER+/HER2- advanced breast cancer in 
combination with letrozole/fulvestrant as endocrine-based therapy for their metastatic disease.  
 
Table 1: Summary of recent trials using combination of CDK 4/6 inhibitors plus endocrine therapy 
in HR+/HER2- metastatic breast cancer. 
 
PALOMA  
215 
MONALEESA  
216 
MONALEESA 
717 
MONARCH  
318 
PALOMA 
 319 
MONARCH 
 220 
MONALEESA 
321 
Study 
design 
LTZ/Pbo vs 
LTZ/Palbo 
LTZ/Pbo vs 
LTZ/Ribo 
LTZ/ GnRh/Pbo 
Vs 
LTZ/GnRh/Ribo 
LTZ/Pbo 
Vs 
LTZ/Abema 
FVT/Pbo vs 
FVT/palbo 
FVT/Pbo vs 
FVT/ abema 
FVT/Pbo vs FVT/ 
Ribo 
No. of 
pts 
666 
668 
672 
493 
521 
699 
726 
Setting 
No 
progression 
on AIs 
No progression 
on AIs 
No progression 
on AIs (allow 1L 
prior CT) 
No 
progression 
on AIs 
Progression 
on AIs (allow 
1L prior CT) 
Progression 
on AIs 
No or progression 
on AIs 
PFS 
14.5 vs 24.8 
mo 
HR 0.58 
16 vs 25.3 mo 
HR 0.556 
13 vs 23.8mo 
HR 0.55 
NR vs 14.7 
HR 0.54 
4.6 vs 11.2 
mo 
HR 0.5 
9.3 vs 16.4 
mo 
HR 0.55 
12.8 vs 20.5 mo 
HR 0.59 
Pbo: Placebo; LTZ: letrozole; FVT: Fulvestrant Palbo: plabociclib; Ribo: ribociclib; Abema: abemaciclib; AIs: Aromatase 
inhibitors; mo: months; HR: hazard ratio.  
 
 The importance of intrinsic subtyping in HR+/HER2- breast cancer 
Breast cancer is a clinically and biologically heterogeneous disease. In terms of global gene 
expression, 4 main molecular subtypes (Luminal A, Luminal B, HER2-enriched [HER2-E] and 
Basal-like) have been identified and intensively studied in the last 15 years22–25. Known as the 
‘intrinsic subtypes of breast cancer, these groups of tumors have revealed critical differences in 
incidence26,27, survival28–30, and response to treatment31,32. Importantly, the information provided 
by the intrinsic subtypes complements and expands the information provided by classical clinical 
parameters (e.g. age, node status, tumor size, histological grade) and pathological markers 
(estrogen receptor [ER], progesterone receptor [PR] and HER2)8,30, all of which are routinely used 
today in the clinic to stratify patients for prognostic predictions and to select treatments. Although 
once thought that HR+/HER2- breast cancer was composed of Luminal disease, recent studies  
have shown that 5-20% of HR+/HER2- primary tumors do not fall into the Luminal A or B 
subtypes but rather fall into the HER2-E or Basal-like phenotype8,33,34(section 4.1.5)  
 


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The importance of intrinsic subtyping in breast cancer has been highlighted in one of the most 
complete molecular characterization studies that have ever been performed in breast cancer22. In 
this study, led by The Cancer Genome Atlas Project (TCGA), more than 500 primary breast cancer 
were extensively profiled at the DNA (i.e. methylation, chromosomal copy-number changes and 
somatic and germline mutations), RNA (i.e. miRNA and mRNA expression) and protein (i.e. 
protein and phosphor-protein expression) levels using the most recent technologies22. In a 
particular analysis of over 300 primary tumors (i.e. shown in Fig. 2 of that publication 
https://www.nature.com/articles/nature1141222, 5 different data-types (i.e. all except DNA 
mutations) were combined together in a cluster of clusters in order to identify how many biological 
homogenous groups of tumors one can identify in breast cancer. The consensus clustering results 
showed the presence of 4 main entities of breast cancer but, more importantly, these 4 entities were 
found to be very well recapitulated by the 4 main intrinsic subtypes (Luminal A, Luminal B, 
HER2-E and Basal-like) as defined by mRNA expression only35. Overall, these results suggest 
that intrinsic subtyping captures the vast majority of the biological diversity occurring in breast 
cancer.  
 
 The main molecular features of the HER2-enriched and Basal-like subtypes 
The HER2-E is characterized by high expression of growth factor receptor-related genes, such 
as HER2 and/or FGFR4, and of cell cycle-related genes, and low expression of estrogen-related 
genes such as estrogen and progesterone receptors, as well as low expression of basal-related genes 
(e.g. keratin 5 and FOXC1)22. At the DNA level, these tumors show the highest number of 
mutations across the genome, and 72% and 39% of HER2-E tumors are TP53 and PIK3CA 
mutated, respectively. Interestingly, the HER2-E subtype has been found uniquely enriched for 
tumors with high frequency of APOBEC3B-associated mutations36. APOBEC3B is subclass of 
APOBEC cytidine deaminases, which convert cytosine to uracil and has been implicated as a 
source of mutations in many cancer types37.  
The Basal-like is characterized by high expression of EGFR and cell cycle-related genes, and 
very low expression of estrogen-related genes such as estrogen and progesterone receptors, as well 
as ERBB2/HER2. At the DNA level, these tumors show high number of mutations across the 
genome, and 80% of Basal-like tumors are TP53 mutated22.  
 
 Identification of non-luminal subtypes within HR+/HER2- disease 
For many years, it has been thought that Basal-like tumors are always triple-negative by 
immunohistochemistry (IHC) and that HER2-E tumors have always ERBB2/HER2 
overexpression and/or amplification and do not express ER and PR by IHC. However, we now 
know this is not entirely correct. For example, HER2-E tumors are identified in 6.6-11.0% 
HR+/HER2-, 18.7% HR+/HER2+ and 9.1% triple-negative breast cancer (Table 2). In a previous 
study, we showed that, from a biological perspective, HER2-E tumors that are HER2+ are 
practically the same as HER2-E tumors that are HER2-negative, except for the 
amplification/overexpression of the ERBB2 DNA amplicon29. Thus, although HER2-E tumors 
might express HER2, ER or PR, the main biological features are maintained within this subtype. 


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Table 2. Distribution of the PAM50 intrinsic subtypes within the pathology-based groups in 
primary tumors*.  
 
 
 
 
 
 
 
 
 
 
 
*The table has been published previously38 and has been obtained from different publications. Several studies have performed a 
standardized version of the PAM50 assay (RT-qPCR-based or nCounter-based) from formalin-fixed paraffin-embedded tumor 
tissues8,28,30,39,40, while others have performed the microarray-based version of the PAM50 assay22,29,31,41–44. 
Based on the molecular features of the HER2-E and Basal-like subtypes, it is expected to 
identify these 2 subtypes in tumors that express low levels of ER by IHC. In fact, intrinsic 
subtyping in 25 tumor samples with 1-9% ER-positive tumor cells found that 48% and 32% were 
Basal-like and HER2-E45, respectively. Moreover, a combined analysis of 48 borderline cases (1-
10% ER+ tumor cells) from the MA.5, MA.12 and GEICAM9906 phase III clinical trials revealed 
that 31% and 18% were identified as HER2-E and Basal-like33,46, respectively. However, the 
HER2-E and Basal-like subtypes can also be identified in tumors that have very high expression 
of ER by IHC (i.e. Allred Score of 6-8) as exemplified by the identification of 6 HER2-E tumors 
and 1 Basal-like tumor in the Z1031 phase III trial (representing 2.9% of the entire cohort of 
HR+/HER2-). Thus, current IHC-based biomarkers cannot identify this biomarker. 
 
 Non-luminal subtypes in HR+/HER2- advanced/metastatic disease 
Although the incidence of the Basal-like and HER2-E subtypes in primary tumors is below 
10%, current evidence suggest that this frequency is much larger in the advanced/metastatic 
setting, specially following endocrine treatment. This increase in the HER2-E subtype in the 
metastatic setting may be due to setting selection, a change in the biology of the tumor due to the 
inherent evolution of the tumor or the effects of the treatment, or a combination of both. Current 
evidence supports this latter possibility. On the one hand, patients with early RH+/HER2-/HER2-
E breast cancer have a higher probability of relapse than luminal disease. Therefore, it is likely 
that a given population of patients with metastatic disease is more enriched for the HER2-E 
 
 
 
PAM50 Intrinsic Subtype Distribution 
IHC-based 
group 
References 
N 
Luminal A Luminal B 
HER2-enriched 
Basal-like 
HR+/HER2- 
(10, 12, 15, 20-25) 
4,295 60.3% 
31.9% 
6.6% 
1.2% 
Luminal A 
(10, 15, 21, 25) 
637 
62.2% 
27.0% 
10.2% 
0.6% 
Luminal B 
(10, 15, 21, 25) 
317 
34.1% 
51.1% 
11.0% 
3.8% 
HER2+ 
(4, 11, 13, 26, 27) 
831 
17.6% 
26.8% 
44.6% 
11.0% 
HER2+/HR+ 
(13, 27) 
182 
33.0% 
46.2% 
18.7% 
2.2% 
HER2+/HR- 
(13, 27) 
168 
19.0% 
4.2% 
66.1% 
10.7% 
TNBC 
(10, 11, 28, 29) 
868 
1.6% 
3.2% 
9.1% 
86.1% 


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subtype compared to patients with early breast cancer. On the other hand,  Cejalvo and colleagues47  
showed using 123 pairs of primary vs. metastatic tumor samples (70% being HR+/HER2-) that the 
HER2-E signature and HER2-E subtype are enriched in the metastatic samples compared to 
primary tumors. For example, 13% of primary Luminal A and B tumors were identified as HER2-
E in the relapsed tumor sample. Overall, the proportion of HER2-E tumors in primary vs. 
metastatic was 11.4% vs. 22%, respectively. Moreover, in a retrospective analysis of tumor 
samples from the BOLERO-2 study, where patients with HR+/HER2- advanced disease resistant 
to an aromatase inhibitor, the proportion of HER2-E in primary vs. metastatic tumors was 19% vs. 
32%48. 
Recently, data from the gene expression in the PALOMA 2 study have been presented in 
SABCS 201715. In this retrospective analysis, which included 68% (445/666) of the tumors (both 
primary and metastatic samples) of the clinical trial population, the HER2-E population 
represented 19% and the Basal-like population represented 1%. 
 
 Prognostic value of non-luminal subtypes in HR+/HER2- 
The prognostic value of the Basal-like and HER2-E intrinsic subtypes has been evaluated in 
various studies and cohorts. For example, intrinsic subtyping was performed in a cohort of 1,380 
patients with ER+ early breast cancer treated with 5 years of adjuvant tamoxifen-only28. Patients 
with HER2-E and Basal-like disease, which represented 7% of the entire cohort, showed a 
statistically significant worse outcome compared to Luminal A subtype.  
Moreover, the prognostic value of the HER2-E intrinsic subtype has been evaluated 
retrospectively in 3 studies of HR+/HER2-metastatic disease28,33,49. In the first one, intrinsic 
subtyping was performed in a cohort of 821 patients with HR-positive disease (644 HER2-negative 
and 157 HER2+) treated in the first-line metastatic setting with letrozole or letrozole plus lapatinib 
in the EGF30008 Phase III clinical trial49. Patients with HER2-E and Basal-like disease showed 
worse PFS and overall survival (OS) compared to Luminal A disease regardless of the HER2 status 
and treatment (Fig. 1). Median PFS with letrozole-only was 4-5 months in both subtypes. 
Figure 1. Overall survival based on intrinsic subtype in HR+/HER2-neg metastatic disease50. 
 


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In the second study, PAM50 was performed in 261 tumor samples from the BOLERO-2 phase 
III trial48. The subtype distribution was: 46.7% Luminal A, 21.5% HER2-E, 15.7% Luminal B, 
14.2% Normal-like and 1.9% Basal-like. Non-luminal disease was independently associated with 
poor PFS and OS compared to the rest of the subtypes.  
In the third study, PAM50 was performed in 465 tumor samples from the PALOMA-2 phase 
III trial15. Both non-luminal subtypes were associated with worse PFS compared to Luminal A 
subtype (Fig. 2). Thus, non-luminal HR+/HER2- tumors are aggressive and require novel 
therapeutic approaches. 
 
Figure 2. Median PFS based on intrinsic subtypes in PALOMA-2 study. 
 
 
 Anti-estrogen sensitivity of the HER2-E subtype  
The ability of the Basal-like and HER2-E subtype to predict benefit from anti-estrogen therapy 
has been evaluated in the neoadjuvant setting. In the Z1031 neoadjuvant trial42 within ER+/HER2-
negative disease, patients with HER2-E or Basal-like disease had persistently high surgical Ki67 
levels (20%) after 4-6 months of treatment with an aromatase inhibitor, consistent with high-level 
estrogen-independent growth. In another retrospective study41 of 112 postmenopausal women with 
stages I–IIIB ER+ early breast cancer before and after 2-weeks’ anastrozole treatment in a 
neoadjuvant trial, patients with HER2-E subtype (n=9 [8.0%]) or Basal-like subtype (n=3 [2.7%]) 
showed a poorer Ki67 response (mean Ki-67 change of -50.7% and +15.3%) compared to Luminal 
A or B subtypes (mean Ki-67 change of -75%)41. Interestingly, this study also profiled post-
treatment samples. As expected, the vast majority of Luminal A samples (31/32, 97%) continued 
being Luminal A41. However, although the majority of Luminal B tumors became Luminal A 
(9/17, 53%), 12% (2/17) became HER2-E41. Overall, this data, together with the poor PFS of the 
HER2-E subtype following endocrine therapy in EGF3000850, BOLERO-248 and PALOMA 2 
trials15, suggest that both non-luminal subtypes within HR-positive disease might not benefit 
substantially from anti-estrogen therapy. 
 


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 Anti-CDK4/6 sensitivity of the non-luminal subtypes within HR+ disease 
The ability of the Basal-like and HER2-E subtype to predict benefit from palbociclib has been 
recently evaluated in 465 samples of the PALOMA-2 study15. As shown in Fig. 2, the increase in 
median PFS in the HER2-E subtype was modest (2.8 months), compared to the increase in median 
PFS of 13.4 and 8.6 months in Luminal A and B subtypes, respectively. Regarding Basal-like, 
only 1 patient was identified and progressed at 6.4 months following letrozole + palbociclib. This 
data suggest that non-luminal subtypes do not benefit much from CDK4/6 inhibition. Further 
confirming this hypothesis, Ma and colleagues conducted the NEOPALANA neoadjuvant trial 
with anastrozole and palbociclib and identified by PAM50 analysis 2 patients with non-luminal 
disease (1 HER2-E and 1 Basal-like)51. Interestingly, none of the 2 patients responded to the 
combined treatment51. 
 
 Chemotherapy sensitivity of the non-luminal subtypes within HR+ disease 
The ability of the Basal-like and HER2-E subtype to predict chemotherapy sensitivity within 
HR+/HER2- disease has been evaluated in the neoadjuvant setting. In one study, 
 and 
colleagues evaluated the pathological complete response (pCR) rated in 451 patients with 
HR+/HER2- disease treated with standard multi-agent neoadjuvant chemotherapy52. The pCR 
rates in the non-luminal subtype was 23.2% compared to 15% in Luminal B and 5% in Luminal A 
tumors. In another neoadjuvant study, 
and colleagues evaluated the residual cancer burden 
(RCB) 0/1 rates of the intrinsic subtypes in 180 patients with HR+/HER2- disease treated with 
anthracycline/taxane-based chemotherapy53. Concordant with the first study, the RCB0/1 rates 
were higher in the non-luminal subtypes (38.1%) compared to Luminal B (20.0%) and Luminal A 
(9.3%). Overall, this data suggests that within HR+/HER2- disease, non-luminal tumors are highly 
chemo-sensitive. 
 
 Immune infiltration of non-luminal subtypes within HR+/HER2- disease 
Previous studies of the intrinsic subtypes have shown that Basal-like and HER2-E are 
associated with higher expression of immune-related genes or higher infiltration of stromal tumor 
infiltrating lymphocytes compared to the luminal subtypes54–56. However, this has not been 
specifically evaluated in HR+/HER2- disease until recently. For example, in a SOLTI cohort of 
101 patients with HR+/HER2- disease, the PAM50 intrinsic subtype was performed. As shown in 
Fig. 3 (unpublished), both non-luminal subtypes showed higher stromal TILs than luminal 
subtypes. Similar data has been observed using gene expression of PD1 (PDCD1), PD-L1 
(CD274), CD8A and CD4 in another cohort of 261 tumor samples from 
 laboratory (Fig. 
4; unpublished). 
PPD
PP
P


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Figure 3. Stromal TILs across the intrinsic subtypes in HR+/HER2- disease. 
Figure 4. Expression of immune-related genes in 261 tumor samples. 
 Pharmaceutical and therapeutic background 
 Paclitaxel 
Taxane-based regimens are considered a standard of care (SoC) option in first-line therapy for 
patients with metastatic breast cancer13. No standard approach exists for second- or further-line 
CCI
CCI


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treatment, and options for HR+/HER2- patients of cytotoxic chemotherapy are the same as those 
for other subtypes. Single-agent cytotoxic chemotherapeutic agents are generally regarded as the 
primary option for patients with metastatic breast cancer, although combination chemotherapy 
may be used when there is aggressive disease and visceral involvement.  
 
The role of paclitaxel in the treatment of breast cancer is well established. The response rates 
for paclitaxel administered as a single agent to patients with metastatic breast cancer are 
approximately 25% in first-line treatment57–60.  
 
Weekly paclitaxel (80–90 mg/m2) is currently considered the most effective schedule for 
delivering paclitaxel, and was found to be associated with higher overall survival (OS) and lower 
incidence of serious adverse events (AEs), neutropenia, neutropenic fever, and peripheral 
neuropathy compared with the three-weekly taxane schedules in advanced breast cancer58,61.  
 
 Immunoncology 
The importance of intact immune surveillance function in controlling outgrowth of neoplastic 
transformations has been known for decades62.  The modern era of cancer immunology has focused 
on using immunotherapy to “boost” the immune system through vaccination, adoptive cellular 
immunotherapy or inhibiting immune checkpoints63. All these strategies aim to enable the patient’s 
immune system to specifically recognize and kill cancer cells. 
Cancer is characterized by the accumulation of different genetic and epigenetic alterations 
which lead to the expression of different tumor antigens, which are displayed on the surface of 
cancer cells. At the same time, cancer cells have developed sophisticated ways of escaping from 
immune attack, which has been a major limitation of cancer immunotherapy64,65. To date, many 
immune escape mechanisms have been identified, including expression of endogenous “immune 
checkpoints” that normally terminate immune responses after antigen activation64,66,67. These 
observations have resulted in the development of immune checkpoint-pathway inhibitors such as 
anti-programmed death 1 (PD1) or anti-CTL antigen-4 (CTLA4). 
Durable monotherapy responses are currently consistently being reported for a broad range of 
human cancers with several different agents68–70; providing a compelling argument that cancer 
immunotherapy is active in a range of indications beyond melanoma, a disease often thought to be 
atypically immunogenic71. Many of this studies are now demonstrating long-terms events as 
increases in OS in particularly immunotherapy, that use monoclonal antibodies that block 
inhibitory immune checkpoint molecules72–75. As a consequence, several immunotherapies have 
been approved by the US Food and Drug Administration (FDA) and other regulatory agencies 
worldwide for the treatment of various tumors. 
 Immunotherapy in breast cancer 
PD1 receptor/ PD1 ligand (PD-L1) interaction is a key immune checkpoint that is overridden 
by malignant tumors to escape from the immune surveillance76. PD1 receptors are normally 
expressed during the initial activation of T-cell to suppress the unnecessary or excessive immune 
response that can precipitate autoimmune reactions. The PD1/PD-L1 pathway is engaged by 


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cancer cells to undergo immune evasion. PD1 receptors suppress T-cell activation upon the 
interaction of PD1 with PD-L1 ligand proteins. PD1 is expressed on activated T lymphocytes and 
myeloid cells, while PD-L1 is mostly expressed on antigen-presenting cells together with other 
hematopoietic, non-hematopoietic cells and some epithelial cells77. Tumor immune evasion occurs 
because of the upregulated expression of PD-L1 on tumor cells and on other components of tumor 
microenvironment78.  
The PD1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress 
immune control. The normal function of PD1, expressed on the cell surface of activated T-cells 
under healthy conditions, is to down-modulate unwanted or excessive immune responses, 
including autoimmune reactions. PD1 (encoded by the gene PDCD1) is an immunoglobulin (Ig) 
superfamily member related to cluster of differentiation 28 (CD28) and cytotoxic T-lymphocyte-
associated protein 4 (CTLA-4) that has been shown to negatively regulate antigen receptor 
signaling upon engagement of its ligands (PD-L1 and/or PD-L2)79,80.  
The structure of murine PD1 has been resolved81.  PD1 and its family members are type I 
transmembrane glycoproteins containing an Ig-variable–type (IgV-type) domain responsible for 
ligand binding and a cytoplasmic tail responsible for the binding of signaling molecules.  The 
cytoplasmic tail of PD1 contains 2 tyrosine-based signaling motifs, an immunoreceptor tyrosine-
based inhibition motif, and an immunoreceptor tyrosine-based switch motif.  Following T-cell 
stimulation, PD1 recruits the tyrosine phosphatases, SHP-1 and SHP-2, to the immunoreceptor 
tyrosine-based switch motif within its cytoplasmic tail, leading to the dephosphorylation of 
effector molecules such as CD3 zeta (CD3ζ), protein kinase C-theta (PKCθ), and zeta-chain-
associated protein kinase (ZAP70), which are involved in the CD3 T-cell signaling cascade80,82–
84.  The mechanism by which PD1 down-modulates T-cell responses is similar to, but distinct 
from, that of CTLA-4, because both molecules regulate an overlapping set of signaling 
proteins82,85.  As a consequence, the PD1/PD-L1 pathway is an attractive target for therapeutic 
intervention in several malignancies.  
Monoclonal antibodies targeting PD1/PD-L1 immune checkpoints are an evolving approach 
for the management of cancer. These immune checkpoint inhibitors include PD1 antibodies such 
as pembrolizumab and nivolumab or PD-L1 antibodies as durvalumab, avelumab and 
atezolizumab86. The favorable clinical outcomes in patients receiving PD1/PD-L1 immune 
checkpoint inhibitors are mostly associated with upregulated expression of PD-L1. Nonetheless, 
some studies reported clinical outcomes in patients with tumors that lack PD-L1 expression87. 
Tumor infiltrating lymphocytes (TILs) enriched tumor microenvironment is a feature associated 
with higher response rates to immune checkpoint inhibitors88.  Such tumors are called hot or 
inflamed tumors. Accumulating evidence shows a correlation between TILs in cancer tissue and 
favorable prognosis in various malignancies.  In particular, the presence of CD8+ T-cells and the 
ratio of CD8+ effector T-cells/FoxP3+ regulatory T-cells (T-regs) correlates with improved 
prognosis and long-term survival in solid malignancies, such as ovarian, colorectal, and pancreatic 
cancer; hepatocellular carcinoma; malignant melanoma; and renal cell carcinoma. TILs can be 
expanded ex vivo and reinfused, inducing durable objective tumor responses in cancers such as 
melanoma89,90. 


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It is noteworthy that breast tumors, which exhibit poor prognostic criteria such as ER-negative 
or PR-negative status and lymph node positivity were shown to have higher levels of TILs91,92. 
Outcomes from clinical trials highlighted that a higher percentage of CD8+ TILs is a feature 
associated with higher response rates to immune check point inhibitors in TNBC patients87,93. 
Thus, immunotherapy is considered a promising therapeutic option for TNBC which has poor 
response to conventional therapies and does not have any specific targeted therapy options. The 
response of TNBC to immunotherapy is higher than the response rate of ER- positive breast 
cancer94,95. Several studies have characterized the immune landscape of ER-positive/HER2-
negative breast cancer. ER-positive/HER2-negative breast cancer is associated with lower rate of 
lymphocytic infiltration96, especially by CD8+ T cells97. In a study that included 2009 samples, 
the median infiltration by lymphocytes was 10 in ER-positive/HER2-negative breast cancer as 
compared to 20 in TNBC. In a pooled analysis of four studies, ER-positive/HER2-negative breast 
cancer presented a lower rate of infiltration by CD8+ T cells. Interestingly, while associated with 
lower infiltration of T cell, 71% of ER- positive/HER2-negative breast cancer presented expression 
of PD-L198. Although the presence of TILs and PD-L1 expression is less common in the 
HR+/HER2- subtype than in TNBC, patients with ER-positive/HER2-negative tumors represent a 
considerable proportion of PD-L1-positive tumors given their high prevalence.  
Since advanced TNBC is among the tumors that exhibit high recurrence rate and resistance to 
the common chemotherapies, clinical trials are in process to evaluate the potential merit of immune 
checkpoint inhibitors in an effort to find a successful approach for treatment of such hard to treat 
tumors  Four phase I studies have evaluated the antitumor activity of pembrolizumab (anti-PD1), 
atezolizumab (anti-PD-L1) (alone or in combination with chemotherapy), and avelumab (anti-PD-
L1) in patients with advanced TNBC. Some of these trials included HR+/HER2- patients. (Table 
3). 
Table 3. Targeting the PD1/PD-L1 pathway in breast cancer. 
Antibody 
Trial 
Study type 
Target 
Subtype 
n 
ORR 
(%) 
Avelu 
JAVELIN94  
Phase 1  stratified 
for PD-L1 solid 
tumor 
PD-L1 
All 
168 
4.8 
PD-L1+ All 
12 
33.3 
TNBC 
58 
8.6 
PD-L1+ TNBC 
9 
44.4 
Pembro 
KEYNOTE-01299  
Phase 1b for PD-L1 
positive solid tumors 
PD1 
PD-L1+ TNBC 
27 
18.5 
KEYNOTE-028100  
Phase 1b for PD-L1 
positive solid tumors 
PD-L1+ 
HR+/HER2- 
25 
12 
KEYNOTE-086101  
Phase 2 for TNBC 
TNBC 
170 
4.7  


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PD-L1+ TNBC 
105 
4.8  
Atezo 
NCT01375842102  
Phase 1 stratified 
PD-L1 for solid 
tumors 
PD-L1 
TNBC 
112 
10 
PD-L1+ TNBC 
71 
13 
 
While the response was relatively low, it is still promising because of the observation that the 
patients who respond to treatment with immune checkpoint blockade have favorable prognosis 
and often show a significant increase in the overall survival with extended anti-tumor immunity 
(Fig. 5). Therefore, the main challenge is to find ways to enhance the tumor response to such 
therapy and to convert the non-responders to responders, and more important to further select the 
patients who are more likely to benefit. This will consequently help to decrease deaths tolls and 
open new hopes for patients with advanced stage/metastatic breast cancer.  
Immune checkpoint inhibitors have been studied in the neoadjuvant and adjuvant space in 
combination with chemotherapy as well. Currently 13 clinical trials with pembrolizumab are being 
studied in early breast cancer in all the subtypes (9 in TNBC and 4 HER2-negative), all setting (9 
neoadjuvant and 4 adjuvant) and in combination with different SoC agents. 
Figure 5. Kaplan-Meier overall survival analysis based on clinical response in TNBC patients 
treated with pembrolizumab in (A) KEYNOTE-086 and in (B) NCT01375842. 
 
(A) 
 
 
 
 


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(B) 
 
 
 Combination of PD1/PD-L1 inhibition and chemotherapy in breast cancer 
In early breast cancer, preliminary results from KEYNOTE-173 evaluating pembrolizumab in 
combination with chemotherapy as neoadjuvant treatment for TNBC were presented at ASCO 
2017103. Data on 10 patients treated in cohort A and B, respectively, were reported. Treatment in 
cohort A consisted of 4 cycles of pembrolizumab + nab-paclitaxel followed by four cycles of 
pembrolizumab + doxorubicin + cyclophosphamide; treatment in cohort B was the same as in A 
but with carboplatin added to pembrolizumab and nab-paclitaxel. ORR in cohort A and B was 80% 
and 100%, respectively [42]. The ypT0/Tis ypN0 (noninvasive cancer and non in-situ cancer in 
the breast) pCR rate was 60% in cohort A and 90% in B. Using a Bayesian design, Nanda et al104 
used the I-SPY platform to compare preoperative pembrolizumab in combination with standard 
treatment with paclitaxel followed by doxorubicin + cyclophosphamide with standard treatment in 
HER2-negative early breast cancer. Addition of pembrolizumab increased pCR in HR+/HER2- 
patients from 14.8% to 28% and in TNBC patients from 19.3% to 71.4%. 
In metastatic breast cancer, a phase Ib study of atezolizumab in combination with nab-
paclitaxel in 32 pretreated patients with TNBC, of whom 24 were evaluable, have shown a 
confirmed ORR of 42% and an ORR of 71% with 4% CR. Notably, responses occurred both in 
tumors with high and little to no PD-L1 expression. The DoR was not reported105.  
Recently, the results of IMpassion130 have been reported. The Phase III IMpassion130 study 
met its co-primary endpoint of PFS. Results demonstrated that the combination of atezolizumab 
plus nab-paclitaxel, as a first-line treatment, significantly reduced the risk of disease worsening or 
death (PFS) in the intention-to treat and PD-L1 positive population with metastatic or unresectable 
locally advanced TNBC. 
Treatment with the combination of pembrolizumab and eribulin demonstrated a 26.4% ORR 
for 
patients 
with 
metastatic 
(TNBC, 
according 
to 
updated 
findings 
from 
the 
ENHANCE1/KEYNOTE-150 phase Ib/II study presented at the 2017 San Antonio Breast Cancer 


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Symposium). 
A range of studies have been initiated including several phase II/III studies evaluating in 
particular pembrolizumab and atezolizumab in combination with different chemotherapeutic 
compounds routinely used in breast cancer.  
 Pembrolizumab 
 Preclinical and clinical trial data 
Although breast cancer has historically been considered immunologically silent, several 
preclinical and clinical studies suggest that immunotherapy has the potential to improve clinical 
outcomes for patients with breast cancer106,107. Breast cancer is one of the most commonly studied 
tumors for the presence of immune system cells in the lesion and scores of ongoing clinical trials are 
evaluating the role of immunotherapy in breast cancer treatment and prevention. 
 
 Preclinical studies with PD1 immune checkpoint inhibitors  
Preclinical data from mouse models have shown that administration of antibodies blocking 
PD1/PD-L1 interaction increases infiltration of tumor-specific CD8-positive T cells and finally 
guides to tumor rejection, either as a monotherapy or in combination with other treatment 
modalities108,109. 
Pembrolizumab potently blocks binding to both ligands, PD-L1 and PD-L2, with IC50 values 
below 1 nM. Pembrolizumab binds to human and Cynomolgus monkey PD1 with comparable 
affinity and blocks the binding of human and Cynomolgus monkey PD1 to PD-L1 and PD-L2 with 
comparable potency. Pembrolizumab does not cross-react with dog, rat, or mouse PD1. 
 
Pembrolizumab enhances T-cell responses in human donor blood cell cultures, with a half-
maximal effective concentration of approximately 0.1 to 0.3 nM. Pembrolizumab strongly 
enhances T-lymphocyte immune responses in cultured blood cells from healthy human donors, 
cancer patients, and Cynomolgus monkeys. The antibody potentiates existing immune responses 
only in the presence of antigen-receptor stimulation and does not nonspecifically activate all T-
cells. 
Pembrolizumab does not bind Ig superfamily members CD28, CTLA-4, or ICOS. In in vitro 
PBMC and whole blood cytokine release assays, the cytokine levels induced by pembrolizumab 
were low, and comparable to those induced by trastuzumab. Pembrolizumab does not induce 
ADCC or CDC. 
 
Safety pharmacology evaluations conducted as part of the 1- and 6-month toxicity and TK 
studies in Cynomolgus monkeys showed no pembrolizumab–related effects on any parameter 
evaluated (ECGs, general veterinary and physical examinations with body temperature and blood 
pressure, clinical observations, and histopathology of tissues from the cardiovascular, respiratory, 
renal, and nervous systems). 
 


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 Clinical studies with pembrolizumab in various cancer types. 
Pembrolizumab is a potent and highly selective humanized monoclonal antibody of the 
IgG4/kappa isotype designed to directly block the interaction between PD1 and its ligands, PD-L1 
and PD-L2. Many clinical studies have been conducted to evaluate the efficacy of pembrolizumab 
to treat various cancers. Pembrolizumab has demonstrated robust, substantial, and clinically 
meaningful benefit in the treatment of melanoma, non-small cell lung cancer (NSCLC), head and 
neck squamous cell cancer (HNSCC), urothelial carcinoma (UC), microsatellite instability-high 
(MSI-H) tumors, and gastric or esophagogastric junction adenocarcinoma based on RECIST 1.1 
criteria and iRECIST recommendation. For classical Hodgkin lymphoma (cHL), demonstration of 
clinically meaningful benefit was based on Revised Response Criteria for Malignant Lymphoma 
(2007) from the IWG (For study details please refer to the pembrolizumab Investigator’s 
Brochure.).  
 
 
Pembrolizumab is indicated in Europe for the treatment of:  
 
• 
In combination with pemetrexed and platinum chemotherapy, is indicated for the first-line 
treatment of metastatic NSCLC in adults whose tumors have no EGFR or ALK positive 
mutations. 
 
• 
As monotherapy is indicated for the treatment of recurrent or metastatic HNSCC in adults 
whose tumors express PD-L1 with a ≥50% tumor proportion score (TPS) and progressing on 
or after platinum-containing chemotherapy.  
 
• 
As monotherapy is indicated for the treatment of advanced (unresectable or metastatic) 
melanoma in adults. 
 
• 
As monotherapy is indicated for the first-line treatment of metastatic NSCLC in adults whose 
tumors express PD-L1 with a ≥50% TPS with no EGFR or ALK positive tumour mutations. 
 
• 
In combination with pemetrexed and platinum chemotherapy, is indicated for the first-line 
treatment of metastatic non-squamous NSCLC in adults whose tumors have no EGFR or 
ALK positive mutations. 
 
• 
As monotherapy is indicated for the treatment of locally advanced or metastatic NSCLC in 
adults whose tumors express PD-L1 with a ≥1% TPS and who have received at least one 
prior chemotherapy regimen. Patients with EGFR or ALK positive tumor mutations should 
also have received targeted therapy before receiving Pembrolizumab. 
 
• 
As monotherapy is indicated for the treatment of adult patients with relapsed or refractory 
classical cHL who have failed autologous stem cell transplant and brentuximab vedotin 
(BV), or who are transplant-ineligible and have failed BV. 
 


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• 
As monotherapy is indicated for the treatment of locally advanced or metastatic UC in adults 
who have received prior platinum-containing chemotherapy. 
 
• 
As monotherapy is indicated for the treatment of locally advanced or metastatic UC in adults 
who are not eligible for cisplatin-containing chemotherapy and whose tumors express PD-
L1 with a combined positive score ≥10 
 
 PD-L1PD-L1Clinical studies of pembrolizumab inhibitor in HR+/HER2 disease 
Pembrolizumab has been evaluated in patients with HR+/HER2- metastatic breast cancer 
and in triple-negative disease99,100. Of the 248 patients with ER+/HER2-negative breast cancer 
who had evaluable tumor samples screened for PD-L1 expression, 48 (19%) had PD-L1-positive 
tumors. Of these, 25 patients were enrolled100. The overall response rate (ORR) observed was 14% 
and responses seemed to be long-lived. Overall tolerance was acceptable and no new concerns 
regarding auto-immune toxicity have emerged. In the triple-negative phase IB study (KEYNOTE-
012), 111 heavily pre-treated patients with PD-L1-positive (defined as >1% expression in tumor or 
stromal cells) disease were included and received 10 mg/kg of pembrolizumab every 2 weeks as 
monotherapy99. Twenty-seven patients were evaluable for response and had an ORR of 18.5% 
with duration of 15 weeks to more than 47 weeks. Grade 3 or higher toxicity was observed in 
15.6% of patients and there was one treatment-related death from disseminated intravascular 
coagulation in a patient with rapidly progressive disease not responding to three previous lines 
of therapy99. Findings presented during the 2017 San Antonio Breast Cancer Symposium (SABCS) 
showed the combination of eribulin and pembrolizumab resulted in an objective response rate 
(ORR) of 26.4% (95% CI: 18.3 – 35.9), the primary efficacy endpoint of the study. Three complete 
responses were observed; one of which was in a patient with a PD-L1-negative tumor 
(ENHANCE1/KEYNOTE-150). 
 Rationale 
 Rationale for the trial and selected population 
Breast cancer is a clinically and biologically heterogeneous disease. In terms of global gene 
expression, 4 main molecular subtypes (Luminal A, Luminal B, HER2-E and Basal-like) have 
been identified and intensively studied in the last 15 years22–25. Known as the ‘intrinsic subtypes 
of breast cancer’, these groups of tumors have revealed critical differences in incidence26,27, 
survival28–30, and response to treatment31,32. Although the incidence of the non-luminal subtypes 
(i,e. Basal-like and HER2-E) in primary tumors is below 10%, current evidence suggest that this 
frequency is much larger in the advanced/metastatic setting, specially following endocrine 
treatment, 15-25% approximately15,47,110.  
The rationale to assess the anti-tumor effect (efficacy) of pembrolizumab and paclitaxel in 
PAM50 non-luminal disease within HR+/HER2- advanced breast cancer is as follows: 
1. The prognostic value of the Basal-like and HER2-E intrinsic subtypes in metastatic breast 
cancer has been evaluated in four studies and cohorts. In all these studies15,50,111 both non-


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luminal subtypes were associated with worse PFS compared to Luminal subtypes. Thus, 
non-luminal HR+/HER2- tumors are aggressive and require novel therapeutic approaches.  
2. Several studies15,50 suggest that both non-luminal subtypes within HR-positive disease 
might not benefit substantially neither from anti-estrogen therapy and CDK4/6 or mTOR 
inhibitors. On the other hand, some studies52,53 had shown that within HR+/HER2- disease, 
non-luminal tumors are highly chemo-sensitive. 
3. Previous studies of the intrinsic subtypes have shown that Basal-like and HER2-E are 
associated with higher expression of immune-related genes or higher infiltration of stromal 
tumor infiltrating lymphocytes compared to the luminal subtypes54–56. Immune infiltration 
in breast cancer is associated with chemo-responsiveness and potentially benefit from anti-
PD1/PD-L1 inhibitors101,102,112–114. 
4. In addition, one emerging biomarker of response to anti-PD1 therapy is the tumor 
mutational burden (I.e. the total number of mutations per coding area of a tumor genome). 
The HER2-E and Basal-like profiles have been associated with high mutational burden112. 
5. Immune checkpoint inhibitors given in monotherapy in advanced breast cancer have shown 
modest benefit in first-line, and very limited efficacy in later lines. However, response 
following anti-PD1/PD-L1 monotherapy is associated with large survival benefit in the 
advanced setting. Thus combination therapies are needed101,102,114. 
6. A range of studies have been initiated including several phase II/III studies evaluating in 
particular pembrolizumab in combination with different chemotherapeutic compounds 
routinely used in breast cancer, but none with predefined biomarker.  
 
 Justification for dose  
The planned dose of pembrolizumab for this study is 200 mg every 3 weeks (Q3W).  Based on 
the totality of data generated in the Keytruda development program, 200 mg Q3W is the 
appropriate dose of pembrolizumab for adults across all indications and regardless of tumor type.  
As outlined below, this dose is justified by: 
• Clinical data from 8 randomized studies demonstrating flat dose- and exposure-efficacy 
relationships from 2 mg/kg Q3W to 10 mg/kg every 2 weeks (Q2W),  
• Clinical data showing meaningful improvement in benefit-risk including overall survival 
at 200 mg Q3W across multiple indications, and 
• Pharmacology data showing full target saturation in both systemic circulation (inferred 
from pharmacokinetic [PK] data) and tumor (inferred from physiologically-based PK 
[PBPK] analysis) at 200 mg Q3W 
Among the 8 randomized dose-comparison studies, a total of 2262 participants were enrolled 
with melanoma and non-small cell lung cancer (NSCLC), covering different disease settings 
(treatment naïve, previously treated, PD-L1 enriched, and all-comers) and different treatment 
settings (monotherapy and in combination with chemotherapy). Five studies compared 2 mg/kg 
Q3W versus 10 mg/kg Q2W (KN001 Cohort B2, KN001 Cohort D, KN002, KN010, and KN021), 
and 3 studies compared 10 mg/kg Q3W versus 10 mg/kg Q2W (KN001 Cohort B3, KN001 Cohort 
F2 and KN006). All of these studies demonstrated flat dose- and exposure-response relationships 


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across the doses studied representing an approximate 5- to 7.5-fold difference in exposure. The 2 
mg/kg (or 200 mg fixed-dose) Q3W provided similar responses to the highest doses studied. 
Subsequently, flat dose-exposure-response relationships were also observed in other tumor types 
including head and neck cancer, bladder cancer, gastric cancer and classical Hodgkin Lymphoma, 
confirming 200 mg Q3W as the appropriate dose independent of the tumor type.  These findings 
are consistent with the mechanism of action of pembrolizumab, which acts by interaction with 
immune cells, and not via direct binding to cancer cells. 
Additionally, pharmacology data clearly show target saturation at 200 mg Q3W. First, PK data 
in KN001 evaluating target-mediated drug disposition (TMDD) conclusively demonstrated 
saturation of PD1 in systemic circulation at doses much lower than 200 mg Q3W. Second, a PBPK 
analysis was conducted to predict tumor PD1 saturation over a wide range of tumor penetration 
and PD1 expression.  This evaluation concluded that pembrolizumab at 200 mg Q3W achieves full 
PD1 saturation in both blood and tumor. 
Finally, population PK analysis of pembrolizumab, which characterized the influence of body 
weight and other participant covariates on exposure, has shown that the fixed-dosing provides 
similar control of PK variability as weight based dosing, with considerable overlap in the 
distribution of exposures from the 200 mg Q3W fixed dose and 2 mg/kg Q3W dose.  Supported 
by these PK characteristics, and given that fixed-dose has advantages of reduced dosing 
complexity and reduced potential of dosing errors, the 200 mg Q3W fixed-dose was selected for 
evaluation across all pembrolizumab protocols. 
 
 Rationale for endpoints 
 
Efficacy endpoint 
ORR is based on criteria related to changes in tumor size (e.g., RECIST) and is generally 
defined as the sum of partial and complete responses. ORR is a robust indicator of antitumor 
activity in many agents including anti-PD1 and is considered to be an established surrogate marker 
for clinical benefit. Significant antitumor activity of anti-PD1 agent in combination with 
chemotherapy, has been reported in patients with advanced TNBC101. Preliminary data with 
pembrolizumab in refractory ER-positive/HER2-negative metastatic breast cancer patients have 
shown promising antitumor activity, resulting in response rates practically similar to those 
observed with the best chemotherapy agents used in this setting100. However, no data are available 
so far with anti-PD1 and anti-PD-L1 agents in combination with chemotherapy in this non-luminal 
subtype. 
The patients who respond to treatment with immune checkpoint blockade have favorable 
prognosis and often show a significant increase in the overall survival with extended anti-tumor 
immunity (Fig. 5) and also acceptable safety profile in early phase trials in metastatic setting.  


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 Biomarker research  
 Biomarkers to predict benefit of anti-PD1 
Anti-PD1 drugs such as pembrolizumab have demonstrated unprecedented clinical efficacy 
in more than 15 cancer-types115. Patients responding to these therapies usually gain a large survival 
benefit, leading to impressive outcomes. Thus, pre-selecting patients most likely to respond to anti-
PD1 is necessary. 
 
Recent studies support the role of PD-L1 expression by immunohistochemistry (IHC) as a 
potential biomarker for pembrolizumab in non-small cell lung cancer (NSCLC)116. However, its 
predictive value in other cancer-types is controversial. Moreover, IHC-based detection of PD-L1 
has important limitations, such as different sensitivities of the antibodies used,  its subjectivity in 
scoring and cut-off determination, and varying tissue sources assayed for expression (archived or 
fresh, primary or metastatic tumor)116. Therefore, identification of reproducible biomarkers that 
can be applied to predict benefit of anti-PD1 might be of clinical value.  
It is abundantly clear that robust biomarkers are needed to determine which breast cancer 
patients may or may not respond to checkpoint blockade. Response to checkpoint blockade has 
been associated with several biomarkers, including PD-L1 expression on tumor cells and/or 
associated immune cells, tumor-infiltrating lymphocytes (TILs), tumor mutational burden (TMB), 
and PD1 mRNA expression. All these biomarkers will be detected in the TATEN study samples.  
In addition, the first cycle is given without paclitaxel to be able to analyze the early dynamics 
changes of ctDNA after 1 cycle of pembrolizumab and the relationship with efficacy of the 
treatment. 
 
5. METHODOLOGY 
 
Study population 
 Participant inclusion criteria 
Patient eligibility will be reviewed and documented by a suitable member of the Investigator’s 
study team before the patients are enrolled in the study (section 7.1.1.2) 
Any asterisked* are also applicable as an exclusion criterion prior to perform the prescreening 
PAM50 testing. To perform the PAM50 assay, investigator judgement of patient’s potential 
eligibility to the study should be assessed as per TRIAL FLOW CHART (section 6). 
Participants are eligible to be included in the study only if all of the following criteria apply: 
1. *Male/female participants who are at least 18 years of age on the day of signing informed 
consent with histologically confirmed diagnosis of locally advanced or metastatic, 
histologically documented hormone receptor positive (ER and/or PR expression >1%) and 


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HER2- breast cancer by local testing, not amenable to surgical therapy will be enrolled in 
this study. 
a) HER2 negativity is defined as either of the following by local laboratory assessment: 
IHC 0, IHC 1+ or IHC2+/in situ hybridisation (ISH) negative as per American Society 
of Clinical Oncology (ASCO)-College of American Pathologists Guideline (CAP) 
guideline (ISH negative is defined as a ratio of HER2 to CEP17 <2.0)117.  
b) ER and/or PR positivity are defined as >1% of cells expressing HR via IHC analysis as 
per ASCO-CAP guideline118 
 
2. The participant (or legally acceptable representative if applicable) provides written 
informed consent for the trial.   
 
3. * Eligible for taxane therapy. 
 
4. * No prior chemotherapy for inoperable locally advanced or metastatic breast cancer.  
5. Prior radiation therapy for metastatic disease is permitted. Subjects who were treated with 
radiation therapy may participate as long as at least 2 weeks have elapsed since the last 
dose of radiation therapy or have recovered from the effects of radiation before allocation 
whichever is the latest.   
6. Disease refractory to CDK4/6 inhibitors, defined as recurrence during or within 12 months 
after the end of adjuvant treatment or progression during or within 6 months after the end 
of treatment for advanced/metastatic disease.  
Notes: CDK4/6 inhibitors do not have to be the last treatment prior to randomization. Other 
prior anticancer endocrine therapy, e.g. aromatase inhibitors, fulvestrant or tamoxifen, are 
also allowed.  
7. * Previous chemotherapy with a taxane for early breast cancer (neoadjuvant or adjuvant 
setting) is permitted. 
8. * Availability of formalin-fixed paraffin-embedded (FFPE) tumor block, collected during 
advanced/metastatic disease, with an associated pathology report. The tumor tissue should 
be of good quality based on total and viable tumor content and must be evaluated centrally 
for PAM50 analysis prior to enrollment. Patients whose tumor tissue is not evaluable for 
central testing are not eligible. If PAM50 analysis of tumor sample has alredy been 
performed at central lab (i.e analysis from other SOLTI clinical trial) PAM50 result can be 
valid for this study. 
a) Acceptable samples include core needle biopsies for deep tumor tissue or excisional, 
incisional, punch, or forceps biopsies for cutaneous, subcutaneous, or mucosal lesions 
or biopsies from bone metastases. 
b) Fine needle aspiration, brushing, cell pellet from pleural effusion and lavage samples 
are not acceptable. 


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9. Non-Luminal subtype as per PAM50 analysis (i.e. HER2-enriched or Basal-like). 
10. * Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1. 
Evaluation of ECOG is to be performed within 10 days prior to the date of 
allocation/randomization.   
11. * Life expectancy ≥ 12 weeks 
12. * Measurable disease, as defined by RECIST v1.1. (Note: Previously irradiated lesions can 
be considered as measurable disease only if disease progression has been unequivocally 
documented at that site since radiation.) 
13.  Adequate hematologic and end-organ function, defined by the following laboratory results 
(Table 4) obtained within 10 days prior to the first study treatment (Cycle 1, Day 1): 
Table 4. Adequate organ function laboratory values 
System 
Laboratory Value 
Hematological 
 
Absolute neutrophil count (ANC) 
≥1500/µLa 
Platelets 
≥100 000/µLb 
Hemoglobin 
≥9.0 g/dL or ≥5.6 mmol/Lc 
Renal 
 
Creatinine OR 
Measured or calculated d creatinine clearance 
(MDRD GFR can also be used in place of 
creatinine or CrCl) 
≤1.5 × ULN OR 
≥30 mL/min for participant with creatinine 
levels >1.5 × institutional ULN 
Hepatic 
 
Total bilirubin 
≤1.5 ×ULN OR direct bilirubin ≤ULN for 
participants 
with 
total 
bilirubin 
levels 
>1.5 × ULN 
AST (SGOT) and ALT (SGPT) 
≤2.5 × ULN (≤5 × ULN for participants with 
liver metastases) 
Coagulation 
 
International normalized ratio (INR) OR 
prothrombin time (PT) 
Activated partial thromboplastin time (aPTT) 
≤1.5 × ULN unless participant is receiving 
anticoagulant therapy as long as PT or a PTT is 
within therapeutic range of intended use of 
anticoagulants 
ALT (SGPT)=alanine aminotransferase (serum glutamic pyruvic transaminase); AST (SGOT)=aspartate 
aminotransferase (serum glutamic oxaloacetic transaminase); GFR=glomerular filtration rate; ULN=upper 
limit of normal. 


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Male participants: 
14. A male participant must agree to use contraception as detailed in Appendix 3 of this 
protocol during the treatment period and for at least 180 days after the last dose of paclitaxel 
and 120 days form the last doses of pembrolizumab and refrain from donating sperm during 
this period. 
Female participants: 
 
15. A female participant is eligible to participate if she is not pregnant (see Appendix 3), not 
breastfeeding, 
and 
at 
least 
one 
of 
the 
following 
conditions 
applies:  
a.) Not a woman of childbearing potential (WOCBP) as defined in Appendix 3  
OR  
b.) A WOCBP who agrees to follow the contraceptive guidance in Appendix 3 during the 
treatment period and for at least 180 days after the last dose of paclitaxel and 120 days 
from the last dose of pembrolizumab. 
 
 Participant exclusion criteria 
Participants are excluded from the study if any of the following criteria apply: 
1. A WOCBP who has a positive urine pregnancy test within 72 hours prior to C1D1 (see 
Appendix 3). If the urine test is positive or cannot be confirmed as negative, a serum 
pregnancy test will be required. 
 
2. * Has received prior therapy with an anti-PD1, anti-PD-L1, or anti-PD-L2 agent or with an 
agent directed to another stimulatory or co-inhibitory T-cell receptor (eg, CTLA-4, OX-40, 
CD137). 
 
3. * History of hypersensitivity reactions to paclitaxel or other drugs formulated in the same 
solvent as paclitaxel (polyoxyethylated castor oil). 
 
4. Resolution of all acute toxic effects of prior anti-cancer therapy or major surgical 
procedures to NCI CTCAE version 5.0 Grade ≤ 1 (except alopecia or other toxicities not 
considered a safety risk for the patient at investigator´s discretion).  
Note: Placement of central venous access catheter(s) (e.g., port or similar) is not considered 
a major surgical procedure and is therefore permitted. 
 
a Criteria must be met without granulocyte colony stimulating factor [G-CSF] support within 2 weeks prior to 
Cycle 1, Day 1. 
b Criteria must be met without transfusion within 2 weeks prior to Cycle 1, Day 1. 
c Criteria must be met without erythropoietin dependency and without packed red blood cell (pRBC) 
transfusion within 2 weeks prior to Cycle 1, Day 1.  
d Creatinine clearance (CrCl) should be calculated per institutional standard. 
 


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5. Has received a live vaccine within 30 days prior to the first dose of study drug.  Examples 
of live vaccines include, but are not limited to, the following:  measles, mumps, rubella, 
varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette–Guérin (BCG), and 
typhoid vaccine.  Seasonal influenza vaccines for injection are generally killed virus 
vaccines and are allowed; however, intranasal influenza vaccines (eg, FluMist®) are live 
attenuated vaccines and are not allowed.  
 
Note: It is not recommended the use of live or attenuated COVID-19 vaccines within 30 
days of initiation or during study treatment. However, if vaccination with these vaccines 
is required, please ask for advice on how to proceed the Medical Monitor.  
 
6. Uncontrolled pleural effusion, pericardial effusion, or ascites (Note: patients with 
indwelling catheters, such as PleurX® are allowed). 
 
7. Uncontrolled hypercalcemia (>1.5 mmol/L [>6 mg/dL] ionized calcium or serum calcium 
[uncorrected for albumin] >3 mmol/L [>12 mg/dL] or corrected serum calcium >ULN) or 
clinically significant (symptomatic) hypercalcemia 
 
8. * Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in 
dosing exceeding 10 mg daily of prednisone equivalent) or any other form of 
immunosuppressive therapy within 7 days prior to the first dose of study drug. 
 
 
9. * Has a known additional malignancy that is progressing or has required active treatment 
within the past 3 years.  Note:  Participants with basal cell carcinoma of the skin, squamous 
cell carcinoma of the skin or carcinoma in situ (e.g. breast carcinoma, cervical cancer in 
situ) that have undergone potentially curative therapy are not excluded. 
 
10. Has known active CNS metastases and/or carcinomatous meningitis.  Participants with 
previously treated brain metastases may participate provided they are radiologically stable, 
i.e. without evidence of progression for at least 4 weeks by repeat imaging (note that the 
repeat imaging should be performed during study screening), clinically stable and without 
requirement of steroid treatment for at least 14 days prior to first dose of study treatment. 
 
11. * Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients. 
 
12. * Has active autoimmune disease that has required systemic treatment in the past 2 years 
(i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). 
Replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid replacement 
therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic 
treatment. 
 
13. * Has a history of (non-infectious) pneumonitis/interstitial lung disease that required 
steroids or has current pneumonitis/interstitial lung disease. 
 
14. * Prior allogeneic stem cell or solid organ transplantation 


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15. Has an active infection requiring systemic therapy. 
 
16. * Has a known history of Human Immunodeficiency Virus (HIV).   
 
17. * Has a known history of Hepatitis B (defined as Hepatitis B surface antigen [HBsAg] 
reactive) or known active Hepatitis C virus (defined as HCV RNA [qualitative] is detected) 
infection. Note: no testing for Hepatitis B and Hepatitis C is required unless mandated by 
local health authority.  
 
18. * Has a known history of active TB (Bacillus Tuberculosis).   
 
19. Has a history or current evidence of any condition, therapy, or laboratory abnormality that 
might confound the results of the study, interfere with the subject’s participation for the 
full duration of the study, or is not in the best interest of the subject to participate, in the 
opinion of the treating investigator.   
 
20. * Has known psychiatric or substance abuse disorders that would interfere with cooperation 
with the requirements of the trial. 
 
21. Is pregnant or breastfeeding or expecting to conceive or father children within the projected 
duration of the study, starting with the screening visit through 120 days after the last dose 
of pembrolizumab or 180 days after the last dose of paclitaxel. 
 
 Lifestyle restrictions 
 Meals and dietary restrictions 
Participants should maintain a normal diet unless modifications are required to manage an AE 
such as diarrhea, nausea or vomiting. 
 Contraception 
Pembrolizumab and paclitaxel may have adverse effects on a fetus in utero. Refer to Appendix 
3 for approved methods of contraception. 
For this study, male participants will be considered to be of non-reproductive potential if they 
have azoospermia (whether due to having had a vasectomy or due to an underlying medical 
condition).   
 Pregnancy 
If a participant inadvertently becomes pregnant while on treatment with pembrolizumab or 
paclitaxel, the participant will be immediately discontinued from study treatment.  The site will 
contact the participant at least monthly and document the participant’s status until the pregnancy 


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has been completed or terminated.  The outcome of the pregnancy will be reported to Merck within 
2 working days if the outcome is a serious adverse experience (eg, death, abortion, congenital 
anomaly, or other disabling or life-threatening complication to the mother or newborn).  The study 
Investigator will make every effort to obtain permission to follow the outcome of the pregnancy 
and report the condition of the fetus or newborn to Merck.  If a male participant impregnates his 
female partner, the study personnel at the site must be informed immediately and the pregnancy 
must be reported to Merck and followed as described in Section 7.2.2. 
 Use in nursing women 
It is unknown whether pembrolizumab is excreted in human milk. Since many drugs are 
excreted in human milk, and because of the potential for serious adverse reactions in the nursing 
infant, participants who are breast-feeding are not eligible for enrollment. 
 Trial treatments 
The treatment to be used in this trial is outlined below in Table 5 
Table 5. Trial treatment 
Drug 
Dose/Potency 
Dose 
Frequency 
Route of 
Administration 
Regimen/Treatment 
Period 
Use 
Pembrolizumab 200 mg 
Q3W 
IV infusion 
Day 1 of each 3 week 
cycle 
Experimental 
Paclitaxel 
80 mg/m2 
Q1W 
IV infusion 
Day 1,8,15 of each 3 
week cycle 
(beginning in cycle 
2) 
Standard of 
care 
 
Trial treatment should begin on the day of inclusion or up to 3 days after the scheduled Day 1. 
 Timing of dose administration 
Trial treatment should be administered on Day 1 of each cycle after all procedures/assessments 
have been completed as detailed on the Trial Flow Chart (Section 6.1).  Trial treatment may be 
administered up to 3 days after the scheduled Day 1 of each cycle due to administrative reasons. 
All trial treatments will be administered on an outpatient basis. 
Pembrolizumab 200 mg will be administered as 30 minutes IV infusion every 3 weeks 
beginning in Cycle 1.  Sites should make every effort to target infusion timing to be as close to 30 
minutes as possible.  However, given the variability of infusion pumps from site to site, a window 
of -5 minutes and +10 minutes is permitted (i.e., infusion time is 30 minutes: -5 min/+10 min). 
For the first infusion of pembrolizumab, no premedication will be administered. However, 
should the patient experience infusion-related reaction(s) during any infusion, premedication with 


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antihistamines will be administered for subsequent infusions at the discretion of the treating 
physician. 
Administration of pembrolizumab will be performed in a setting with emergency medical 
facilities and staff who are trained to monitor for and respond to medical emergencies. 
Pembrolizumab infusions will be administered per the instructions outlined in Table 6. 
On day 1 cycle 2 (C2D1) when paclitaxel and pembrolizumab are given, pembrolizumab will 
be given first and patients will be observed for 1 hour for infusion and other AEs. Paclitaxel may 
then be administered. 
Paclitaxel will be administered at the 80 mg/m2 dose via 1-hour IV infusion on Days 1, 8, and 
15 of every 21-day cycle (beginning in Cycle 2). On days of scheduled infusions of pembrolizumab 
and paclitaxel (i.e., Day 1 of every cycle), paclitaxel is to be administered after infusion of 
pembrolizumab. Doses of paclitaxel should not be administered more frequently than every 7 days. 
To reduce the risk of severe hypersensitivity reactions, all patients should be premedicated 
prior to paclitaxel administration. Prior to receiving the first two study infusions of paclitaxel, all 
patients will receive corticosteroids (8-10 mg dexamethasone or equivalent) as part of either the 
institutional SoC or the following premedication: 
• Dexamethasone 8-10 mg (or equivalent) administered orally approximately 12 and 6 hours 
prior to the paclitaxel infusion. Patients may be treated with dexamethasone ≤10 mg IV 
within 1 hour prior to the paclitaxel infusion if the patient did not take the oral 
dexamethasone. 
• Diphenhydramine 50 mg IV (or equivalent) 30-60 minutes prior to the paclitaxel infusion 
• Cimetidine 300 mg IV or ranitidine 50 mg IV (or equivalent) 30-60 minutes prior to 
paclitaxel infusion. 
Because the effects of corticosteroids on T-cell proliferation have the potential to ablate early 
pembrolizumab-mediated anti-tumor immune activity, it is recommended that the dose of 
dexamethasone (or equivalent) is minimized to the extent that is clinically feasible. For example, 
if paclitaxel is well tolerated during the first two weekly infusions without apparent 
hypersensitivity reaction, a reduction in the dose of dexamethasone premedication (or equivalent) 
should be considered for subsequent cycles if permitted by institutional SoC. This approach has 
been reported to be successful in the literature119. 
 
In the absence of unacceptable toxicity, paclitaxel will be administered until PD or until the 
end of the study, whichever occurs earlier. Paclitaxel and pembrolizumab may be discontinued for 
toxicity independently of each other in the absence of disease progression. 
Any overdose or incorrect administration of paclitaxel should be noted on the Paclitaxel 
Administration eCRF. AEs associated with an overdose or incorrect administration of paclitaxel 
should be recorded on the AE eCRF. 


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The Pharmacy Manual contains specific instructions for the preparation of the pembrolizumab 
infusion fluid and administration of infusion solution. 
 Dose modification and toxicity management: general considerations 
Reasons for dose modifications or delays, the supportive measures taken, and the outcomes 
will be documented in the patient's chart and recorded on the eCRF.  
When several toxicities with different grades of severity occur at the same time, the dose 
interruptions or modifications should be according to the highest grade observed. If, in the opinion 
of the investigator, a toxicity is considered to be due solely to one component of the study treatment 
(i.e., pembrolizumab or paclitaxel) and the dose of that component is delayed or modified in 
accordance with the guidelines below, the other component may be administered if there is no 
contraindication. 
When treatment is temporarily interrupted because of toxicity caused by pembrolizumab or 
paclitaxel, the treatment cycles will be restarted such that the pembrolizumab and paclitaxel 
infusions remain synchronized. 
If it is anticipated that paclitaxel will be delayed by >1 week, then pembrolizumab should be 
given without the chemotherapy, as long as there is no contraindication.  
In general, the start of a cycle may be delayed allowing recovery from toxicities, but there 
should be no delays within cycles. Cycle length is fixed at 21 days, and dosing on days 8 and 15 
of a cycle may be skipped but should not be delayed outside of the +1 days window. 
The treating physician may use discretion in accelerating the dose modification guidelines 
described below depending on the severity of toxicity and an assessment of the risk versus benefit 
for the patient. 
 Dose modification and toxicity management for immune-related AEs associated 
with pembrolizumab 
AEs associated with pembrolizumab exposure may represent an immunologic etiology. These 
immune-related AEs (irAEs) may occur shortly after the first dose or several months after the last 
dose of pembrolizumab treatment and may affect more than one body system simultaneously. 
Therefore, early recognition and initiation of treatment is critical to reduce complications.  Based 
on existing clinical study data, most irAEs were reversible and could be managed with 
interruptions of pembrolizumab, administration of corticosteroids and/or other supportive care. 
For suspected irAEs, ensure adequate evaluation to confirm etiology or exclude other causes. 
Additional procedures or tests such as bronchoscopy, endoscopy, skin biopsy may be included as 
part of the evaluation. Based on the severity of irAEs, withhold or permanently discontinue 
pembrolizumab and administer corticosteroids. Dose modification and toxicity management 
guidelines for irAEs associated with pembrolizumab are provided in Table 6. 


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Table 6. Dose modification and toxicity management guidelines for immune-related AEs associated with pembrolizumab  
 
General instructions: 
1. Corticosteroid taper should be initiated upon AE improving to Grade 1 or less and continue to taper over at least 4 weeks. 
2. For situations where pembrolizumab has been withheld, pembrolizumab can be resumed after AE has been reduced to Grade 1 or 0 and 
corticosteroid has been tapered. Pembrolizumab should be permanently discontinued if AE does not resolve within 12 weeks of last dose or 
corticosteroids cannot be reduced to ≤10 mg prednisone or equivalent per day within 12 weeks.  
3. For severe and life-threatening irAEs, IV corticosteroid should be initiated first followed by oral steroid. Other immunosuppressive treatment 
should be initiated if irAEs cannot be controlled by corticosteroids. 
 
Immune-related 
AEs 
Toxicity grade or 
conditions 
(CTCAEv5.0) 
Action taken to 
pembrolizumab 
irAE management with 
corticosteroid and/or other 
therapies  
Monitor and follow-up  
Pneumonitis  
Grade 2 
Withhold  
• Administer corticosteroids (initial 
dose of 1-2 mg/kg prednisone or 
equivalent) followed by taper 
 
• 
Monitor participants for signs and 
symptoms of pneumonitis 
• 
Evaluate participants with suspected 
pneumonitis with radiographic imaging and 
initiate corticosteroid treatment 
• 
Add prophylactic antibiotics for 
opportunistic infections 
Grade 3 or 4, or 
recurrent Grade 2 
Permanently 
discontinue 
Diarrhea / Colitis  Grade 2 or 3 
Withhold 
• Administer corticosteroids (initial 
dose of 1-2 mg/kg prednisone or 
equivalent) followed by taper 
 
• 
Monitor participants for signs and symptoms 
of enterocolitis (ie, diarrhea, abdominal 
pain, blood or mucus in stool with or 
without fever) and of bowel perforation 
(ie, peritoneal signs and ileus). 


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Recurrent Grade 3 
or Grade 4 
Permanently 
discontinue 
• 
Participants with ≥ Grade 2 diarrhea 
suspecting colitis should consider GI 
consultation and performing endoscopy to 
rule out colitis.  
• 
Participants with diarrhea/colitis should be 
advised to drink liberal quantities of clear 
fluids.  If sufficient oral fluid intake is not 
feasible, fluid and electrolytes should be 
substituted via IV infusion. 
AST / ALT 
elevation or 
Increased 
bilirubin 
Grade 2 
Withhold 
• Administer corticosteroids (initial 
dose of 0.5- 1 mg/kg prednisone or 
equivalent) followed by taper 
• 
Monitor with liver function tests (consider 
weekly or more frequently until liver 
enzyme value returned to baseline or is 
stable 
Grade 3 or 4  
Permanently 
discontinue 
• Administer corticosteroids (initial 
dose of 1-2 mg/kg prednisone or 
equivalent) followed by taper 
Type 1 diabetes 
mellitus (T1DM) 
or 
Hyperglycemia 
 
Newly onset 
T1DM or  
Grade 3 or 4 
hyperglycemia 
associated with 
evidence of -cell 
failure 
Withhold 
• Initiate insulin replacement 
therapy for participants with 
T1DM  
• Administer anti-hyperglycemic in 
participants with hyperglycemia  
 
• 
Monitor participants for hyperglycemia or 
other signs and symptoms of diabetes. 
Hypophysitis 
Grade 2 
Withhold 
• Administer corticosteroids and 
initiate hormonal replacements as 
clinically indicated.   
 
• 
Monitor for signs and symptoms of 
hypophysitis (including hypopituitarism and 
adrenal insufficiency)  
Grade 3 or 4  
Withhold or 
permanently 
discontinue1  
Hyperthyroidism  
Grade 2 
Continue  
• Treat with non-selective beta-
blockers (eg, propranolol) or 
thionamides as appropriate  
• 
Monitor for signs and symptoms of thyroid 
disorders.  
 
Grade 3 or 4  
Withhold or  
permanently 
discontinue1 
Hypothyroidism 
Grade 2-4 
Continue  
• Initiate thyroid replacement 
hormones (eg, levothyroxine or 
liothyroinine) per standard of care 
• 
Monitor for signs and symptoms of thyroid 
disorders.  
 


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Nephritis  
grading 
according to 
increased 
creatinine or 
acute kidney 
injury 
Grade 2 
Withhold  
• Administer corticosteroids 
(prednisone 1-2 mg/kg or 
equivalent) followed by taper. 
• 
Monitor changes of renal function 
 
Grade 3 or 4  
Permanently 
discontinue 
Neurological 
Toxicities 
Grade 2 
Withhold 
•  Based on severity of AE administer 
corticosteroids 
•  Ensure adequate evaluation to confirm 
etiology and/or exclude other causes 
Grade 3 or 4 
Permanently 
discontinue 
Myocarditis 
Grade 1 
Withhold 
• Based on severity of AE 
administer corticosteroids 
• 
Ensure adequate evaluation to confirm 
etiology and/or exclude other causes 
 
Grade 2, 3 or 4 
Permanently 
discontinue 
Exfoliative 
Dermatologic 
Conditions 
Suspected SJS, 
TEN, or DRESS 
Withhold 
• Based on severity of AE 
administer corticosteroids 
• 
Ensure adequate evaluation to confirm 
etiology or exclude other causes 
Confirmed SJS, 
TEN, or DRESS 
Permanently 
discontinue 
All other 
immune-related 
AEs 
Intolerable/ 
persistent Grade 2 
Withhold 
• Based on type and severity of AE 
administer corticosteroids  
• 
Ensure adequate evaluation to confirm 
etiology and/or exclude other causes 
 
Grade 3 
Withhold or 
discontinue based 
on the type of 
event.  Events that 
require 
discontinuation 
include and not 
limited to:  
Gullain-Barre 
Syndrome, 
encephalitis 
Grade 4 or 
recurrent Grade 3  
Permanently 
discontinue 


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1. Withhold or permanently discontinue pembrolizumab is at the discretion of the investigator or treating physician.   
NOTE:  
For participants with Grade 3 or 4 immune-related endocrinopathy where withhold of pembrolizumab is required, pembrolizumab may be resumed 
when AE resolves to ≤ Grade 2 and is controlled with hormonal replacement therapy or achieved metabolic control (in case of T1DM).   
 
Dose modification and toxicity management of infusion-reactions related to pembrolizumab 
Pembrolizumab may cause severe or life threatening infusion-reactions including severe hypersensitivity or anaphylaxis. Signs and 
symptoms usually develop during or shortly after drug infusion and generally resolve completely within 24 hours of completion of 
infusion. Dose modification and toxicity management guidelines on pembrolizumab associated infusion reaction are provided in Table 
7.  


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Table 7.  Pembrolizumab infusion reaction dose modification and treatment guidelines 
NCI CTCAE Grade 
Treatment 
Premedication at 
Subsequent Dosing 
Grade 1 
Mild reaction; infusion 
interruption not 
indicated; intervention 
not indicated 
Increase monitoring of vital signs as medically 
indicated until the participant is deemed medically 
stable in the opinion of the investigator. 
None 
Grade 2 
Requires therapy or 
infusion interruption 
but responds promptly 
to symptomatic 
treatment (e.g., 
antihistamines, 
NSAIDs, narcotics, IV 
fluids); prophylactic 
medications indicated 
for ≤24 hrs 
Stop Infusion. 
Additional appropriate medical therapy may include 
but is not limited to: 
IV fluids 
Antihistamines 
NSAIDs 
Acetaminophen 
Narcotics 
Increase monitoring of vital signs as medically 
indicated until the participant is deemed medically 
stable in the opinion of the investigator. 
If symptoms resolve within 1 hour of stopping drug 
infusion, the infusion may be restarted at 50% of the 
original infusion rate (e.g. from 100 mL/hr to 50 
mL/hr).  Otherwise dosing will be held until 
symptoms resolve and the participant should be 
premedicated for the next scheduled dose. 
Participants who develop Grade 2 toxicity despite 
adequate premedication should be permanently 
discontinued from further study drug treatment 
Participant may be 
premedicated 1.5h (± 30 
minutes) prior to infusion 
of pembrolizumab with: 
Diphenhydramine 50 mg 
po (or equivalent dose of 
antihistamine). 
Acetaminophen 500-1000 
mg po (or equivalent dose 
of analgesic). 
Grades 3 or 4 
Grade 3: 
Prolonged (i.e., not 
rapidly responsive to 
symptomatic 
medication and/or brief 
interruption of 
infusion); recurrence of 
symptoms following 
initial improvement; 
hospitalization 
indicated for other 
clinical sequelae (e.g., 
renal impairment, 
pulmonary infiltrates) 
Grade 4: 
Life-threatening; 
pressor or ventilatory 
support indicated 
Stop Infusion. 
Additional appropriate medical therapy may include 
but is not limited to: 
Epinephrine** 
IV fluids 
Antihistamines 
NSAIDs 
Acetaminophen 
Narcotics 
Oxygen 
Pressors 
Corticosteroids 
Increase monitoring of vital signs as medically 
indicated until the participant is deemed medically 
stable in the opinion of the investigator. 
Hospitalization may be indicated. 
**In cases of anaphylaxis, epinephrine should be 
used immediately. 
Participant is permanently discontinued from 
further study drug treatment. 
No subsequent dosing 
Appropriate resuscitation equipment should be available at the bedside and a physician readily available during the period 
of drug administration. 
For further information, please refer to the Common Terminology Criteria for Adverse Events v5.0 (CTCAE) at 
http://ctep.cancer.gov 
 


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Other allowed dose interruption for pembrolizumab  
Pembrolizumab may be interrupted for situations other than treatment-related AEs such 
as medical / surgical events or logistical reasons not related to study therapy. Participants 
should be placed back on study therapy within 3 weeks of the scheduled interruption, unless 
otherwise discussed with SOLTI. The reason for interruption should be documented in the 
patient's study record. 
 
 Dose modification and toxicity management for AEs associated with paclitaxel 
Paclitaxel infusion should be discontinued immediately in case of severe hypersensitivity 
reactions, such as hypotension requiring treatment, dyspnea requiring bronchodilators, 
angioedema, or generalized urticaria; these events should be treated with aggressive 
symptomatic therapy. Patients who have developed severe hypersensitivity reactions should 
not be rechallenged with paclitaxel. In addition, paclitaxel should be permanently discontinued 
upon ruling out infectious etiology (using routine microbiological and/or immunologic 
methods) and making a diagnosis of pneumonitis. Consideration may be given to performing 
pulse oximetry and pulmonary function tests to confirm respiratory and ventilation 
compromise in patients with suspected pneumonitis. 
Other events that required discontinuation of paclitaxel in clinical trials include cases of 
severe neurotoxicity, such as peripheral neuropathies (1% of all patients). Occasionally 
paclitaxel infusions must be interrupted or discontinued because of initial or recurrent 
hypertension. Frequent vital sign monitoring, particularly during the first hour of paclitaxel 
infusion, is recommended. 
Refer to the local paclitaxel prescribing information for further details 
Hematologic Toxicities 
Absolute neutrophil count (ANC) must be ≥1500/µL (≥1500 cells/mm3) and platelet count 
must be ≥100,000/µL (≥100,000 cells/mm3) for the patient to receive paclitaxel 80mg/m2 on 
any treatment day (Day 1, 8, 15 of any 21-day cycle). 
Dose modifications should be made according to the following Table 8: 
 
 
 
 
 


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Table 8. Hematological dose modifications 
ANC 
 
Platelets 
Paclitaxel Dose 
≥1,500/µL       
(≥1,500 cells/mm3) 
and 
≥100,000/µL 
(≥100,000 
cells/mm3) 
80 mg/m2 
1,000-1,499/µL 
(1,000-1,499 
cells/mm3) 
or 
75,000-
99,999/µL 
(75,000-99,999 
cells/mm3) 
65mg/m2 
<1,000/µL 
(<1,000 cells/mm3) 
or 
<75,000/µL 
(<75,000 
cells/mm3) 
Hold(1)  
(1) If treatment is held, the CBC should be repeated until ANC ≥1500/µL (≥1500 cells/mm3) 
and platelets ≥100,000/µL (≥100,000 cells/mm3). If paclitaxel therapy must be held for > 3 
weeks to allow for resolution of haematologic toxicity, the patient will discontinue paclitaxel 
treatment but may continue receiving pembrolizumab. 
For any patient experiencing any of the following haematologic toxicities, the paclitaxel 
dose should be reduced to 65 mg/m² for all subsequent cycles: 
• 
Fever (>38.5°C) associated with ANC <1,000/µL (<1,000 cells/mm3) 
• 
Absolute granulocyte count <500/µL (<500 cells/mm3) for > 5 days 
• 
Significant bleeding associated with a platelet count <40,000/µL (<40,000      
cells/mm3) 
• 
Any platelet count <20,000/µL (<20,000 cells/mm3). 
If these severe hematologic toxicities recur in subsequent cycles despite dose reduction, 
paclitaxel should be discontinued, however the patient may continue receiving 
pembrolizumab. 
If the start of a cycle is delayed (i.e. both pembrolizumab and paclitaxel are held) for low 
counts, Day 1 will be postponed, and dosing resumed when ANC recovers to ≥1500/µl (≥1500 
cells/mm3) and platelet count returns to ≥100,000/µl (≥100,000 cells/mm3). 
In certain situations, a cycle may begin with the administration of pembrolizumab alone 
(without paclitaxel on Day 1). If paclitaxel cannot be administered on Day 8 of the cycle, it 
may be administered on Day 15 if counts have recovered to permissible levels. If paclitaxel 
cannot be administered on Day 15 of the cycle, the next dose of paclitaxel should be 


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administered on Day 1 of the following cycle when ANC and platelets counts have recovered 
to permissible levels. 
Hepatic Toxicities 
In case of hepatic toxicities, dose modifications should be made according to the following 
Table 9: 
 
Table 9: Hepatic dose modifications 
AST 
 
Bilirubin 
Paclitaxel dose 
≤ 5 x ULN 
And 
≤ 1.5 mg/dL (≤ 
25.65 μmol/L) 
80mg/m2 
> 5 but ≤ 10 x ULN 
Or 
1.6 - 2.5 mg/dL 
(27.36 
- 
42.75 
μmol/L) 
65mg/m2 
> 10 x ULN 
Or 
≥ 2.6 mg/dL (≥ 
44.46 μmol/L) 
Hold(1) 
AST: aspartate aminotransferase; ULN: upper limit of normal  
(1) Hold therapy until AST < 10 x ULN and bilirubin < 2.5 mg/dL. If paclitaxel must be held 
for > 3 weeks to allow for resolution of hepatic toxicity, the patient will discontinue paclitaxel 
treatment but may continue receiving pembrolizumab. 
Patients requiring a delay in paclitaxel therapy due to hepatic toxicity should be evaluated 
for possible progressive hepatic metastases. 
Peripheral Neuropathy 
If grade 3 toxicity develops, paclitaxel treatment should be withheld until the neuropathy 
recovers to < grade 1 (pembrolizumab treatment should continue as scheduled). When 
treatment is resumed, the paclitaxel dose should be reduced permanently to 65 mg/m². If grade 
3 neuropathy persists for > 3 weeks or recurs after dose reduction, the patient will discontinue 
paclitaxel treatment but may continue receiving pembrolizumab. 
Gastrointestinal Toxicity 
Nausea and/or vomiting should be controlled with standard antiemetics and will not result 
in dose modification. 
 
 


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Anaphylaxis/Hypersensitivity 
• 
Mild symptoms (e.g., mild flushing, rash pruritus): No treatment needed. Supervise at 
bedside and complete paclitaxel infusion. 
• 
Moderate symptoms (moderate flushing, rash, mild dyspnea, chest discomfort): Stop 
paclitaxel infusion. Administer diphenhydramine 25 mg (or equivalent) and 
dexamethasone 10 mg IV (or equivalent). After recovery of symptoms, resume infusion 
at half the previous rate for 15 minutes. If no further symptoms occur, complete the 
infusion at the full dose rate. If symptoms recur, the reaction should be reported as an 
AE and the patient will discontinue paclitaxel treatment but may continue 
pembrolizumab. 
• 
Severe life-threatening symptoms (e.g., hypotension requiring pressor therapy, 
angioedema, respiratory distress requiring bronchodilators, generalized urticaria): Stop 
the infusion and administer diphenhydramine 25 mg (or equivalent) and 
dexamethasone 10 mg IV (or equivalent). Add epinephrine or bronchodilators if 
needed. The reaction should be reported as an AE and the patient will discontinue 
paclitaxel treatment but may continue pembrolizumab. 
Other Toxicity 
If the patient develops any other grade 3 or 4 toxicity considered related to paclitaxel, 
paclitaxel should be held until symptoms resolve to grade 1 or less (pembrolizumab treatment 
should continue as scheduled). When treatment is resumed, the paclitaxel dose should be 
reduced permanently to 65 mg/m². If grade 3 toxicity persists for >3 weeks or recurs after dose 
reduction, the patient will discontinue paclitaxel treatment but may continue pembrolizumab. 
Refer to the local paclitaxel prescribing information for further details. 
 Concomitant medications/vaccinations (allowed & prohibited) 
Medications or vaccinations specifically prohibited in the exclusion criteria are not 
allowed during the ongoing trial.  If there is a clinical indication for one of these or other 
medications or vaccinations specifically prohibited during the trial, discontinuation from trial 
therapy or vaccination may be required.  The final decision on any supportive therapy or 
vaccination rests with the investigator and/or the participants's primary physician.  
 Acceptable concomitant medications 
All treatments that the investigator considers necessary for a participant’s welfare may be 
administered at the discretion of the investigator in keeping with the community standards of 
medical care.  All concomitant medication will be recorded on the case report form (CRF) 
including all prescription, over-the-counter (OTC), herbal supplements, and IV medications 
and fluids.  If changes occur during the trial period, documentation of drug dosage, frequency, 
route, and date may also be included on the CRF. 


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All concomitant medications received within 28 days before the first dose of trial treatment 
and 30 days after the last dose of trial treatment should be recorded.  Concomitant medications 
administered after 30 days after the last dose of trial treatment should be recorded for SAEs 
and ECIs as defined in Section 7.2. 
 Prohibited concomitant medications 
Participants are prohibited from receiving the following therapies during the Screening 
and Treatment Phase (including retreatment for post-complete response relapse) of this trial: 
• 
Antineoplastic systemic chemotherapy or biological therapy  
• 
Immunotherapy not specified in this protocol 
• 
Chemotherapy not specified in this protocol 
• 
Investigational agents other than pembrolizumab 
• 
Radiation therapy  
• 
Live vaccines within 30 days prior to the first dose of study treatment and while 
participating in the study.  Examples of live vaccines include, but are not limited to, the 
following: measles, mumps, rubella, varicella/zoster, yellow fever, rabies, BCG, and 
typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus 
vaccines and are allowed; however, intranasal influenza vaccines (eg, FluMist®) are 
live attenuated vaccines and are not allowed.  
• 
Systemic glucocorticoids for any purpose other than to modulate symptoms from an 
event of clinical interest of suspected immunologic etiology.  The use of physiologic 
doses of corticosteroids may be approved after consultation with SOLTI. 
 
Participants who, in the assessment by the investigator, require the use of any of the 
aforementioned treatments for clinical management should be removed from the study.  All 
treatments that the Investigator considers necessary for a participant’s welfare may be 
administered at the discretion of the Investigator in keeping with the community standards of 
medical care.   
Medications or vaccinations specifically prohibited in the exclusion criteria are not 
allowed during the ongoing study.  If there is a clinical indication for any medication or 
vaccination specifically prohibited during the study, discontinuation from study therapy may 
be required.  The final decision on any supportive therapy or vaccination rests with the 
investigator and/or the participant's primary physician.  However, the decision to continue the 
participant on study treatment requires the mutual agreement of the investigator, SOLTI and 
the participant. 
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 Rescue medications & supportive care 
Participants should receive appropriate supportive care measures as deemed necessary by 
the treating investigator.  Suggested supportive care measures for the management of AEs with 
potential immunologic etiology are outlined along with the dose modification guidelines in 
Section 5.2.2, [Table 6].  Where appropriate, these guidelines include the use of oral or IV 
treatment with corticosteroids, as well as additional anti-inflammatory agents if symptoms do 
not improve with administration of corticosteroids.  Note that several courses of steroid 
tapering may be necessary as symptoms may worsen when the steroid dose is decreased.  For 
each disorder, attempts should be made to rule out other causes such as metastatic disease or 
bacterial or viral infection, which might require additional supportive care.  The treatment 
guidelines are intended to be applied when the Investigator determines the events to be related 
to pembrolizumab.  
Note: If after the evaluation of the event, it is determined not to be related to pembrolizumab, 
the Investigator does not need to follow the treatment guidance.  Refer to [Table 6] in Section 
5.2.2 for guidelines regarding dose modification and supportive care.  
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, 
or skin photography as part of evaluation of the event.  
 Participant withdrawal/discontinuation criteria 
Participants may discontinue study treatment at any time for any reason or be dropped 
from the study treatment at the discretion of the investigator should any untoward effect occur.  
In addition, a participant may be discontinued from study treatment by the investigator or 
SOLTI if study treatment is inappropriate, the trial plan is violated, or for administrative and/or 
other safety reasons.  Specific details regarding procedures to be performed at study treatment 
discontinuation are provided in Section 7.1.4 – Other Procedures. 
A participant must be discontinued  
from study treatment but continue to be monitored in the study for any of the following reasons: 
• 
The participant or participant’s legally acceptable representative requests to 
discontinue study treatment. 
• 
Confirmed radiographic disease progression outlined in Section 7.1.2.6. 
• 
Any progression or recurrence of any malignancy, or any occurrence of another 
malignancy that requires active treatment. 
• 
Unacceptable adverse experiences as described in Section 5.2.2. 
• 
The participant has a medical condition or personal circumstance which, in the opinion 
of the investigator and/or sponsor, placed the participant at unnecessary risk from 
continued administration of study treatment. 


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• 
The participant has a confirmed positive serum pregnancy test. 
• 
Noncompliance with study treatment or procedure requirements. 
• 
Recurrent Grade 2 pneumonitis. 
• 
Discontinuation of treatment may be considered for participants who have attained a 
confirmed complete response (CR) and have been treated for at least 8 cycles (at least 
24 weeks), receiving 2 cycles of the combination including 2 doses of 
pembrolizumab and at least 80% of the planned doses of paclitaxel beyond the date 
when the initial CR was declared.  
• 
The participant is lost to follow-up. 
• 
Completion of 35 treatments (approximately 2 years) with pembrolizumab. 
Note: The number of treatments is calculated starting with the first dose.   
• 
Administrative reasons 
 Participant replacement strategy 
Patients will be replaced if they are considered to be non-evaluable. An evaluable patient is 
one that has received at least one combination dose, has measurable disease according to the 
Investigator site assessment and has at least one postbaseline tumor assessment.  
 
Patients who have failed screening (usually because they have failed one or more of the 
inclusion or exclusion criteria) will not receive study treatments and are considered not to be 
evaluable 
 
 Clinical criteria for early trial termination 
Early trial termination will be the result of the criteria specified below: 
1. Quality or quantity of data recording is inaccurate or incomplete 
2. Poor adherence to protocol and regulatory requirements 
3. Incidence or severity of adverse drug reaction in this or other studies indicates a potential 
health hazard to participants 
4. Plans to modify or discontinue the development of the study drug 
SOLTI, as Sponsor, may decide to put an end to the study at any time for safety reasons, 
due to slow patient recruitment or due to the emergence of new data that could alter the 
relevance of the study objectives. The steering committee (SC) will provide their counsel. 
Ethics committees and health authorities will be informed about all decisions in this respect. 
The decision to terminate the study early will be binding for all investigators at all study sites. 


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In the event of early termination, all investigators must inform their patients as soon as 
possible and they will be responsible for the follow-up and subsequent therapeutic 
management as appropriate and in accordance with recommended standard practice. 
Investigators may be informed of additional procedures to be performed to ensure the safety 
and better care of their patients. 


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6. TRIAL FLOW CHART 
 Study flow chart 
Trial Period: 
Screening Phase 
Treatment Cyclesb 
End of 
Treatme
nt 
Post-Treatment 
Treatment Cycle/Title: 
Pre-
screening 
(Visit 1) 
Main Study 
Screeninga 
(Visit 2) 
1 
2 
All Cycles 
Discon 
Safety 
Follow-
upc 
Follow-Up  
Survival 
Follow-
Up 
Scheduling Window (Days): 
 
-28 to -1 
1+ 3 
8± 1 
15± 1 1+3 8± 1 
15± 1 1+ 3 
8± 1 
15± 1 
At time 
of 
Discon 
30 days 
post 
discon 
Every 9 
weeks post 
discon 
Every 
12 
weekst  
(±21 
days) 
 
Administrative Procedures 
Pre-screening Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed Consent 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics and Medical Historyd 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior and Concomitant Medication 
Reviewe 
 
X 
X 
 
 
X 
 
 
X 
 
 
X 
X 
 
 
Pembrolizumab Administration 
 
 
X 
 
 
X 
 
 
X 
 
 
 
 
 
 
Paclitaxelf 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
Post-study anticancer therapy status 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Survival Status 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Clinical Procedures/Assessments 
Review Adverse Events 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
X 
 
Full Physical Examinationg 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Directed Physical Examinationh 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
Height 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Trial Period: 
Screening Phase 
Treatment Cyclesb 
End of 
Treatme
nt 
Post-Treatment 
Treatment Cycle/Title: 
Pre-
screening 
(Visit 1) 
Main Study 
Screeninga 
(Visit 2) 
1 
2 
All Cycles 
Discon 
Safety 
Follow-
upc 
Follow-Up  
Survival 
Follow-
Up 
Scheduling Window (Days): 
 
-28 to -1 
1+ 3 
8± 1 
15± 1 1+3 8± 1 
15± 1 1+ 3 
8± 1 
15± 1 
At time 
of 
Discon 
30 days 
post 
discon 
Every 9 
weeks post 
discon 
Every 
12 
weekst  
(±21 
days) 
Vital Signs and Weighti 
 
X 
X 
 
 
X 
 
 
X 
 
 
 
 
 
 
ECOG Performance Statusj  
 
X 
X 
 
 
X 
 
 
X 
 
 
X 
X 
X 
 
12- Lead Electrocardiogram (Locally 
performed) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Laboratory Procedures/Assessments: analysis performed by LOCAL laboratory 
Pregnancy Test – Urine or Serum -HCGk 
 
X 
X 
 
 
X 
 
 
X 
 
 
 
 
 
 
PT/INR and aPTT 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
CBC with Differentiall 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
 
Comprehensive Serum Chemistry Panelm 
 
X 
X 
 
 
X 
 
 
X 
 
 
 
X 
 
 
Urinalysisn 
 
X 
X 
 
 
X 
 
 
X 
 
 
 
X 
 
 
T3 (free or total), Free T4 and TSH 
 
 
Every 2 cycles 
 
X 
 
 
 
Efficacy Measurements 
Tumor Imagingo 
 
 
Every 9 weeks (63 + 5 days) 
Xp 
 
Xq 
 
 
Tumor Biopsies/Archival Tissue Collection/Correlative Studies Blood 
Archival or Newly Obtained Tissue 
Collectionr 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood Collections 
 
 
X 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
Confirmation of PAM50 eligibility & inclusion criteria 
Medical monitor eligibity confirmation 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 


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a) Written informed consent is required before performing any study-specific tests or procedures. Signing of the Informed Consent Form can occur outside the 28-day 
screening period. All screening evaluations must be completed and reviewed to confirm that patients meet all eligibility criteria before randomization. Results of standard-
of-care tests or examinations performed prior to obtaining informed consent and within 28 days prior to study entry (except where otherwise specified) may be used for 
screening assessments rather than repeating such tests. The investigator will maintain a screening log to record details of all patients screened and to confirm eligibility 
or record reasons for screening failure, as applicable. 
b) Assessment window of + 3 days for Cycles ≥2, Day 1. If scheduled dosing is precluded because of a holiday, then dosing may be postponed to the soonest following 
date, with subsequent dosing continuing on the specified schedule. If treatment was postponed for fewer than 2 days, the patient can resume the original schedule. If 
scheduled study assessments cannot be obtained because of a holiday, these assessments should then be obtained at the soonest following date, provided that the soonest 
following date is not within 2 days of other regularly scheduled study assessments. Assessments scheduled on the day of study treatment administration (Day 1) of each 
cycle should be performed prior to study treatment infusion unless otherwise noted. 
c) Patients will be asked to return to the clinic not more than 30 days after the decision to discontinue treatment for a treatment discontinuation visit. The visit at which the 
decision is made to discontinue treatment (e.g., disease progression is determined or confirmed) may be used as the treatment discontinuation visit. If a participant initiates 
a new anti-cancer therapy within 30 days after the last dose of trial treatment, the 30 day Safety Follow-up visit must occur before the first dose of the new therapy.   
d) Cancer history includes stage, date of diagnosis, and prior anti-tumor treatment. Demographic information includes age and self-reported race/ethnicity. Reproductive 
status and smoking history should also be captured. 
e) Concomitant medications include any prescription medications or over-the-counter medications. At screening, any medications the patient has used within the 28 days 
prior to Cycle 1, Day 1. At subsequent visits, changes to current medications or medications used since the last documentation of medications will be recorded. 
Concomitant medications administered after 30 days after the last dose of trial treatment should be recorded.  
f) 
Weekly paclitaxel beginning in Cycle 2.  
g) A complete physical examination should include an evaluation of the head, eyes, ears, nose, and throat, and the cardiovascular, dermatological, musculoskeletal, 
respiratory, gastrointestinal, genitourinary, and neurological systems as well as weight (in kilograms) and height (in centimeters; height is measured at the screening visit 
only).  Symptom-directed physical exam after baseline assessment. 
h) Directed physical examination should include, symptom-directed examination or as clinically indicated. Limited physical examination will be performed monthly every 
treatment cycle, with additional examinations as clinically indicated at baseline. 
i) 
Vital signs include heart rate, blood pressure, and temperature. 
j) 
Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, as assessed within 10 days prior to the start of study treatment 
k) Serum/urine pregnancy test within 72 hours before Cycle 1, Day 1. Afterward, perform every cycle. A positive urine test must be confirmed with a serum test 
l) 
Hematology consists of CBC, including RBC count, hemoglobin, hematocrit, WBC count with differential (neutrophils, eosinophils, lymphocytes, monocytes, basophils, 
and other cells), and platelet count. A manual differential can be done if clinically indicated. Local laboratory assessments from each cycle must be reviewed prior to 
study treatment administration for each cycle. Laboratory tests for screening should be performed within 10 days prior to the first dose of treatment.  After Cycle 1, pre-
dose laboratory procedures can be conducted up to 72 hours prior to dosing. 
m) Serum chemistry includes creatinine, sodium, potassium, magnesium, calcium, glucose, total bilirubin, ALT, AST, alkaline phosphatase, Lactate dehydrogenase (LDH). 
Local laboratory assessments from each cycle must be reviewed prior to study treatment administration for each cycle. Screening results may be valid for Cycle 1, Day 
1 if performed within 10 days prior to Week 1, Day 1. 
n) Urinalysis (specific gravity, pH, glucose, protein, ketones, and blood). Screening results may be valid for Week 1, Day 1 if performed within 10 days prior to Week 1, 
Day 1. 


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Trial Period: 
Screening Phase 
Treatment Cyclesb 
End of 
Treatme
nt 
Post-Treatment 
Treatment Cycle/Title: 
Pre-
screening 
(Visit 1) 
Main Study 
Screeninga 
(Visit 2) 
1 
2 
All Cycles 
Discon 
Safety 
Follow-
upc 
Follow-Up  
Survival 
Follow-
Up 
Scheduling Window (Days): 
 
-28 to -1 
1+ 3 
8± 1 
15± 1 1+3 8± 1 
15± 1 1+ 3 
8± 1 
15± 1 
At time 
of 
Discon 
30 days 
post 
discon 
Every 9 
weeks post 
discon 
Every 
12 
weekst  
(±21 
days) 
o) Tumor assessments performed as standard of care prior to obtaining informed consent and within 28 days prior to Cycle 1, Day 1 may be used rather than repeating tests. 
All measurable and evaluable lesions should be assessed and documented at the screening visit. Radiologic imaging performed during the screening period should consist 
of 1) CT and/or MRI of the chest/abdomen/pelvis 2) Bone scan or PET scan should be performed to evaluate for bone metastases and 3) any other imaging studies (CT 
neck, plain films, bone scan etc.) as clinically indicated by the treating physician. The same radiographic procedures and technique must be used throughout the study 
for each patient (e.g., if the patient had CT chest/abdomen/pelvis performed during screening, then she should subsequently undergo CT performed using the same 
radiologic protocol throughout the remainder of the study). Results must be reviewed by the investigator before dosing at the next cycle. Tumor assessments will be 
performed at baseline, every 9 weeks (63 days ± 5 days). All known sites of disease documented at screening should be re-assessed at each subsequent tumor evaluation. 
Tumor assessments performed after the screening period should consist of 1) CT and/or MRI of the chest/abdomen/pelvis, 2) bone scan or PET scan if there were osseous 
sites of disease identified or if these studies are felt to be clinically indicated by the treating physician, and 3) any other imaging studies felt to be clinically indicated by 
the treating physician. Tumor response will be evaluated using both RECIST v1.1 and immune-modified RECIST criteria. In the absence of disease progression, tumor 
assessments should continue regardless of whether patients discontinue study treatment, unless they withdraw consent or the study is terminated by SOLTI, whichever 
occurs first.  
p) If previous imaging was obtained within 4 weeks prior to the date of discontinuation, then imaging at treatment discontinuation is not mandatory. In participants who 
discontinue study treatment due to documented disease progression and the Investigator elects not to implement iRECIST, this is the final required tumor imaging. 
q) In subject who discontinue trial treatment without documented disease progression, every effort should be made to continue monitoring their disease status by radiologic 
imaging every 9 weeks (+ 5 days) until (1) the star of new anti-cancer treatment, (2) disease progression, (3) death, or (4) the end of the study, whichever occurs the first.  
r) 
Tumor tissue should be of good quality based on total and viable tumor. An FFPE block should be provided.  Fine-needle aspiration, brushing, cell pellets from pleural 
effusion, and lavage samples are not acceptable. Retrieval of archival tumor sample can occur outside the 28-day screening period (centrally perform PAM50 test). Tumor 
sample from metastatic disease period is mandatory.  
s) Plasma from 30 ml of blood will be collected and banked at C1D1 (samples may be extracted within the ten previous days to Week 1 Day1), C2D1 and at progression. 
t) 
Survival follow-up information will be collected via telephone calls, patient medical records, and/or clinic visits approximately every 3 months (±  21 days) until death, 
loss to follow-up, withdrawal of consent or until study termination by SOLTI. All patients will be followed for survival and new anti-cancer therapy (including targeted 
therapy and immunotherapy) information unless the patient requests to be withdrawn from follow-up; this request must be documented in the source documents and 
signed by the investigator. If the patient withdraws from study, the study staff may use a public information source (e.g., county records) to obtain information about 
survival status only. 
 


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7. TRIAL PROCEDURES 
 
Trial procedures 
The Trial Flow Chart - Section 6.0 summarizes the trial procedures to be performed at 
each visit.  Individual trial procedures are described in detail below.  It may be necessary to 
perform these procedures at unscheduled time points if deemed clinically necessary by the 
investigator. 
Furthermore, additional evaluations/testing may be deemed necessary by SOLTI and/or 
Merck for reasons related to participant safety. In some cases, such evaluation/testing may be 
potentially sensitive in nature (e.g., HIV, Hepatitis C, etc.), and thus local regulations may 
require that additional informed consent be obtained from the participant.  In these cases, such 
evaluations/testing will be performed in accordance with those regulations. 
 Administrative procedures 
 Informed consent 
The Investigator must obtain documented consent from each potential participant prior to 
participating in a clinical trial. 
 Molecular pre-screening 
After signing the molecular pre-screening consent, tumor tissue (archival or newly 
obtained or excisional biopsy of a tumor lesion not previously irradiated) will be sent to a 
central laboratory to analyze non-luminal subtype by PAM50 test. This will be conducted 
during a pre-screening phase prior to enrolling into the trial (≥ Day 1). For eligibility into the 
study, patients must be non-luminal by PAM50 test analyzed in the designated laboratory. 
Tumor tissue sample obtained during the advanced/metastatic setting is mandatory, it is 
recommended to provide a tumor sample collected after the most recent progression or 
recurrence. Tumor tissue requirements, along with shipping requirements, will be detailed in 
the sample management plan provided by SOLTI.  
To perform the PAM50 test, investigator judgement of patient’s potential eligibility to the 
study should be assessed as per inclusion/exclusion criteria (section 5.1) and TRIAL FLOW 
CHART (section 6.1). 
 General informed consent 
Consent must be documented by the participant’s dated signature or by the participant’s 
legally acceptable representative’s dated signature on a consent form along with the dated 
signature of the person conducting the consent discussion.  
A copy of the signed and dated consent form should be given to the participant before 
participation in the trial. 


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The initial informed consent form, any subsequent revised written informed consent form 
and any written information provided to the participant must receive the IRB/ERC’s 
approval/favorable opinion in advance of use.  The participant or his/her legally acceptable 
representative should be informed in a timely manner if new information becomes available 
that may be relevant to the participant’s willingness to continue participation in the trial.  The 
communication of this information will be provided and documented via a revised consent 
form or addendum to the original consent form that captures the participant’s dated signature 
or by the participant’s legally acceptable representative’s dated signature. 
Specifics about a trial and the trial population will be added to the consent form template 
at the protocol level.   
The informed consent will adhere to IRB/ERC requirements, applicable laws and 
regulations and Sponsor requirements. 
 Consent and collection of specimens for future biomedical research 
The investigator or qualified designee will explain the Future Biomedical Research 
consent to the participant, answer all of his/her questions, and obtain written informed consent 
before performing any procedure related to the Future Biomedical Research subtrial. A copy 
of the informed consent will be given to the participant. 
 Inclusion/exclusion criteria 
All inclusion and exclusion criteria will be reviewed by the investigator or qualified 
designee to ensure that the participant qualifies for the trial.  All screening evaluations must be 
completed and reviewed to confirm that patients meet all eligibility criteria before allocation. 
Results from evaluation will be sent together with a completed study-specific Patient 
Enrollment Form to the medical monitor for evaluation. Decision will be available within 24 
hours, confirming whether patient might be allocated. The investigator will maintain a 
screening log to record details of all patients screened and to confirm eligibility or record 
reasons for screening failure, as applicable. 
 Medical history 
A medical history will be obtained by the investigator or qualified designee.  Medical 
history will include all active conditions, and any condition diagnosed within the prior 10 years 
that are considered to be clinically significant by the Investigator.  Details regarding the disease 
for which the participant has enrolled in this study will be recorded separately and not listed 
as medical history.   


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 Prior and concomitant medications review 
 Prior medications 
The investigator or qualified designee will review prior medication use, including any 
protocol-specified washout requirement, and record prior medication taken by the participant 
within 28 days before starting the trial.  Treatment for the disease for which the participant has 
enrolled in this study will be recorded separately and not listed as a prior medication.  
 Concomitant medications 
The investigator or qualified designee will record medication, if any, taken by the 
participant during the trial.  All medications related to reportable SAEs and ECIs should be 
recorded as defined in Section 7.2. 
 Disease details and treatments 
 Disease details 
The investigator or qualified designee will obtain prior and current details regarding 
disease status.  
 Prior treatment details 
The investigator or qualified designee will review all prior cancer treatments including 
systemic treatments, radiation and surgeries. 
 Subsequent anti-cancer therapy status 
The investigator or qualified designee will review all new anti-neoplastic therapy initiated 
after the last dose of trial treatment. If a participant initiates a new anti-cancer therapy within 
30 days after the last dose of trial treatment, the 30 day Safety Follow-up visit must occur 
before the first dose of the new therapy.  Once new anti-cancer therapy has been initiated the 
participant will move into survival follow-up.  
 Assignment of screening number 
All consented participants will be given a unique screening number and will be done 
centrally through the eCRF that will be used to identify the participant for all procedures that 
occur prior to randomization. Each participant will be assigned only one screening number. 
Screening numbers must not be re-used for different participants. 
Any participant who is screened multiple times will retain the original screening number 
assigned at the initial screening visit. 


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 Assignment of randomization number 
Not applicable  
 Trial compliance (medication/diet/activity/other) 
Administration of trial medication(s) will be witnessed by the investigator and/or trial 
staff. The total volume of trial medication infused will be compared with the total volume 
prepared to determine compliance with each dose administered. 
Interruptions from the protocol specified treatment plan for greater than 3 weeks between 
pembrolizumab or paclitaxel doses for nondrug-related or administrative reasons require 
consultation between the investigator and SOLTI and written documentation of the 
collaborative decision on participant management. 
 Clinical procedures/assessments 
 Adverse event (AE) monitoring 
The investigator or qualified designee will assess each participant to evaluate for potential 
new or worsening AEs as specified in the Trial Flow Chart and more frequently if clinically 
indicated.  Adverse experiences will be graded and recorded throughout the study and during 
the follow-up period according to NCI CTCAE Version 5.0 (see Appendix 2).  Toxicities will 
be characterized in terms regarding seriousness, causality, toxicity grading, and action taken 
with regard to trial treatment.  
Please refer to section 7.2 for detailed information regarding the assessment and recording 
of AEs.   
 Full physical exam 
The investigator or qualified designee will perform a complete physical exam during the 
screening period.  Clinically significant abnormal findings should be recorded as medical 
history.  A full physical exam should be performed during screening. 
Complete physical examination: must include evaluation of the head, mouth, eyes, ears, 
nose and throat, neck (including thyroid), abdomen, back, extremities, lymph nodes, and 
cardiovascular systems, dermatological, locomotor, respiratory, digestive, genitourinary and 
neurological systems, weight (Kg) and height (cm). If no abnormal data are observed during 
selection, the full physical examination may be based on concurrent signs and / or symptoms. 
 


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 Directed physical exam 
For cycles that do not require a full physical exam per the Trial Flow Chart, the 
investigator or qualified designee will perform a directed physical exam as clinically indicated 
prior to trial treatment administration.   
 Vital signs 
The investigator or qualified designee will take vital signs at screening, at Day 1 of each 
cycle of treatment and at treatment discontinuation as specified in the Trial Flow Chart (Section 
6.1). Vital signs should include temperature, pulse, weight and blood pressure.  Height will be 
measured at screening only. 
 Eastern Cooperative Oncology Group (ECOG) performance scale 
The investigator or qualified designee will assess ECOG status (see Appendix 1) at 
screening, at Day 1 of each cycle of treatment and discontinuation of trial treatment as specified 
in the Trial Flow Chart.   
 Tumor imaging and assessment of disease 
Tumor imaging is strongly preferred to be acquired by computed tomography (CT).  For 
the abdomen and pelvis, contrast-enhanced magnetic resonance imaging (MRI) may be used 
when CT with iodinated contrast is contraindicated, or when local practice mandates it.  MRI 
is the strongly preferred modality for imaging the brain. The same imaging technique regarding 
modality, ideally the same scanner, and the use of contrast should be used in a participant 
throughout the study to optimize the reproducibility of the assessment of existing and new 
tumor burden and improve the accuracy of the assessment of response or progression based on 
imaging. 
Expedited confirmation of measurable disease based on RECIST 1.1 at screening should 
be used to determine participant eligibility. Confirmation that the participant’s imaging shows 
at least 1 lesion that is appropriate for selection as a target lesion per RECIST 1.1 is highly 
recommended prior to participant allocation.   
 Initial tumor imaging 
Initial tumor imaging at Screening must be performed within 28 days prior to the date of 
allocation.  The site study team must review screening images to confirm the participant has 
measurable disease per RECIST 1.1.  
Radiologic imaging performed during the screening period should consist of the following: 
1) Initial screening assessments must include computerized tomography (CT) scans (with 
oral/IV contrast unless contraindicated) and/or magnetic resonance imaging (MRI) of the 
chest/abdomen/pelvis. A spiral CT scan of the chest may be obtained but is not a requirement. 


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MRIs of the chest, abdomen, and pelvis with a non-contrast CT scan of the chest may be used 
in patients for whom CT scans with contrast are contraindicated (i.e., patients with contrast 
allergy or impaired renal clearance). If a CT scan for tumor assessment is performed using a 
positron emission tomography (PET)/CT scanner, the CT acquisition must be consistent with 
the standards for a full contrast diagnostic CT scan. 
2) Bone scan or PET scan should be performed to evaluate for bone metastases; 
3) CT scans of the neck should also be performed if clinically indicated during the screening 
period; 
4) At the investigator’s discretion, other methods of assessment of measurable disease per 
RECIST v1.1 may be used. 
5) Brain imaging, if performed to document the stability of existing metastases, should be by 
MRI if possible.  If MRI is medically contraindicated, CT with contrast is an acceptable 
alternative. 
 Tumor imaging during the study  
The first on-study imaging assessment should be performed at 9 weeks (63 days ± 5 days]) 
from the date of allocation.  Subsequent tumor imaging should be performed every 9 weeks 
(63 days ±5 days) or more frequently if clinically indicated.  Imaging timing should follow 
calendar days and should not be adjusted for delays in cycle starts. Imaging should continue to 
be performed until disease progression is identified by the Investigator.  
For each patient, the same radiographic procedures and technique used to assess disease 
sites at screening must be used throughout the study (e.g., the same contrast protocol for CT 
scans and/or magnetic resonance imaging [MRI]), and results must be reviewed by the 
investigator before dosing at the next cycle. All known sites of disease documented at 
screening/baseline should be re-assessed at each subsequent tumor evaluation. To the extent 
feasible, assessments should be performed by the same evaluator to ensure internal consistency 
across visits 
At the investigator’s discretion, CT or other clinically appropriate scans may be repeated 
at any time if progressive disease is suspected. If the initial screening bone scan or PET scan 
does not show evidence of bone metastases, then these procedures do not need to be repeated 
unless clinically indicated or at the treating physician’s discretion. 
Per iRECIST (Section 7.1.2.6.5), disease progression should be confirmed by the site 4 to 
8 weeks after first radiologic evidence of PD in clinically stable participants.  Participants who 
have unconfirmed disease progression may continue on treatment at the discretion of the 
Investigator until progression is confirmed by the site provided they have met the conditions 
detailed in Section 7.1.2.6.5  Participants who receive confirmatory imaging do not need to 
undergo the next scheduled tumor imaging if it is less than 4 weeks later; tumor imaging may 


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resume at the subsequent scheduled imaging time point, if clinically stable. Participants who 
have confirmed disease progression by iRECIST, as assessed by the site, will discontinue study 
treatment. Exceptions are detailed in Section 7.1.2.6.5. 
 End of treatment and follow-up tumor imaging 
In participants who discontinue study treatment, tumor imaging should be performed at 
the time of treatment discontinuation (every 9 weeks (+ 5 days)). If previous imaging was 
obtained within 4 weeks prior to the date of discontinuation, then imaging at treatment 
discontinuation is not mandatory. In participants who discontinue study treatment due to 
documented disease progression and the Investigator elects not to implement iRECIST, this is 
the final required tumor imaging. 
In participants who discontinue study treatment without documented disease progression, 
every effort should be made to continue monitoring their disease status by tumor imaging using 
the same imaging schedule used while on treatment (every 9 weeks(63 + 5 days)) to monitor 
disease status until the start of a new anticancer treatment, disease progression, pregnancy, 
death, withdrawal of consent, or the end of the study, whichever occurs first. 
 RECIST 1.1 assessment of disease 
RECIST 1.1 will be used as the primary measure for assessment of tumor response, date 
of disease progression, and as a basis for all protocol guidelines related to disease status (eg, 
discontinuation of study treatment).  Although RECIST 1.1 references a maximum of 5 target 
lesions in total and 2 per organ, SOLTI allows a maximum of 10 target lesions in total and 5 
per organ, if clinically relevant to enable a broader sampling of tumor burden.  
 iRECIST assessment of disease 
iRECIST is based on RECIST 1.1 but adapted to account for the unique tumor response 
seen with immunotherapeutic drugs.  When clinically stable, participants should not be 
discontinued until progression is confirmed by the Investigator, working with local radiology, 
according to the rules below.  This allowance to continue treatment despite initial radiologic 
PD takes into account the observation that some participants can have a transient tumor flare 
in the first few months after the start of immunotherapy, and then experience subsequent 
disease response. 
Evaluation of response will also be performed using iRECIST guidelines as an exploratory 
assessment. Additional details and definitions of iRECIST are found in Appendix 4, with 
additional detail in the iRECIST publication120. 
 
 
 


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Table 10. Imaging and treatment after first radiologic evidence of progressive disease. 
 
Clinically Stable 
Clinically Unstable 
Imaging 
Treatment 
Imaging 
Treatment 
First radiologic 
evidence of PD by 
RECIST 1.1  
Repeat imaging at 
4 to 8 weeks to 
confirm PD. 
May continue study 
treatment at the 
Investigator’s 
discretion while 
awaiting confirmatory 
tumor imaging by site 
by iRECIST. 
Repeat imaging at 
4 to 8 weeks to 
confirm PD per 
Investigator’s 
discretion only. 
Discontinue treatment 
Repeat tumor 
imaging confirms 
PD (iCPD) by 
iRECIST per 
Investigator 
assessment 
No additional 
imaging required. 
Discontinue treatment 
(exception is possible 
upon consultation with 
Sponsor). 
No additional 
imaging required. 
Not applicable 
Repeat tumor 
imaging shows 
iUPD by iRECIST 
per Investigator 
assessment 
Repeat imaging at 
4 to 8 weeks to 
confirm PD.  May 
occur at next 
regularly 
scheduled imaging 
visit. 
Continue study 
treatment at the 
Investigator’s 
discretion. 
Repeat imaging at 
4 to 8 weeks to 
confirm PD per 
Investigator’s 
discretion only. 
Discontinue treatment 
Repeat tumor 
imaging shows iSD, 
iPR, or iCR by 
iRECIST per 
Investigator 
assessment. 
Continue regularly 
scheduled imaging 
assessments. 
Continue study 
treatment at the 
Investigator’s 
discretion. 
Continue regularly 
scheduled imaging 
assessments. 
May restart study 
treatment if condition has 
improved and/or 
clinically stable per 
Investigator’s discretion.  
Next tumor image should 
occur according to the 
regular imaging schedule. 
iCPD = iRECIST confirmed progressive disease; iCR = iRECIST complete response; iRECIST = modified Response 
Evaluation Criteria in Solid Tumors 1.1 for immune-based therapeutics; iSD = iRECIST stable disease; iUPD = iRECIST 
unconfirmed progressive disease; PD = progressive disease; RECIST 1.1 = Response Evaluation Criteria in Solid Tumors 
1.1. 


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For this study in which ORR is the primary endpoint use the following figure: 
Figure 6. Imaging and Treatment for Clinically Stable Participants after First Radiologic 
Evidence of PD Assessed by the Investigator 
 
 
 Tumor tissue collection  
Tissue for PAM50 analysis should be obtained from an archival tissue sample or newly 
obtained core or excisional biopsy of a tumor lesion not previously irradiated. An archival 
tumor tissue sample must be obtained during the advanced/metastatic setting. Informed 
consent for the study must be taken prior to collection of a new biopsy. If the participant signs 
the Future Biomedical Research consent, any leftover tissue that would ordinarily be discarded 
at the end of the main study will be retained for Future Biomedical Research. Include a copy 
of the local pathology report with the tissue for PAM50 analysis. For a tumor biopsy to be 
considered newly obtained (fresh biopsy) the sample from a core or excisional biopsy must be 
obtained from the subject during the screening period. 
Plasma sampling will be obtained from all participants. All baseline plasma samples 
should be drawn in screening period, at Cycles 2 and at EOT.  
Sample collection, storage, and shipment instructions for serum samples will be provided 
in the study sample management plan. 


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 Laboratory procedures/assessments 
Details regarding specific laboratory procedures/assessments to be performed in this trial 
are provided below.  
Laboratory tests for hematology, chemistry, urinalysis, and others are specified in Table 
11.  


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Table 11. Laboratory tests 
Hematology 
Chemistry 
Urinalysis 
Other 
Hematocrit 
Alkaline phosphatase 
Blood 
Serum β-human chorionic gonadotropin† 
Hemoglobin 
Alanine aminotransferase (ALT) 
Glucose 
  (β-hCG)† 
Platelet count 
Aspartate aminotransferase (AST) 
Protein 
PT (INR) 
WBC (total and differential) 
Lactate dehydrogenase (LDH) 
Specific gravity  
aPTT 
Red Blood Cell Count 
Calcium 
Microscopic exam (If abnormal)  
Total thriiodothyronine (T3) or T3 free 
Absolute Neutrophil Count 
Glucose 
results are noted 
Free tyroxine (T4) 
Absolute Lymphocyte Count 
Potassium   
Urine pregnancy test † 
Thyroid stimulating hormone (TSH) 
 
Sodium 
 
Blood for correlative studies 
 
Magnesium 
 
 
 
Total Bilirubin 
 
 
 
Direct Bilirubin (If total bilirubin is 
elevated above the upper limit of 
normal) 
 
  
† Perform on women of childbearing potential only. If urine pregnancy results cannot be confirmed as negative, a serum pregnancy test will be required.   
 
Laboratory tests for screening (hematology and serum chemistry) should be performed within 10 days prior to the first dose of 
treatment. Pregnancy test must be performed within 72 hours before Cycle 1 Day1.  After Cycle 1, pre-dose laboratory procedures can 
be conducted up to 72 hours prior to dosing.  Results must be reviewed by the investigator or qualified designee and found to be 
acceptable prior to each dose of trial treatment. 


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 Other procedures 
 Withdrawal/discontinuation 
When a participant discontinues/withdraws prior to trial completion, all applicable 
activities scheduled for the final trial visit should be performed at the time of discontinuation.  
Any adverse events which are present at the time of discontinuation/withdrawal should be 
followed in accordance with the safety requirements outlined in Section 7.2 - Assessing and 
Recording Adverse Events.  Participants who a) attain a CR or b) complete 24 months of 
treatment with pembrolizumab may discontinue treatment with the option of restarting 
treatment if they meet the criteria specified in Section 5.2.3.  After discontinuing treatment 
following assessment of CR, these participants should return to the site for a Safety Follow-up 
Visit (described in Section 7.1.5.4.1) and then proceed to the Follow-Up Period of the study 
(described in Section 7.1.5.4.2). Every effort should be made to obtain information on patients 
who withdraw from the study. The primary reason for withdrawal from the study should be 
documented on the appropriate eCRF. However, patients will not be followed for any reason 
after consent has been withdrawn.  
Patients will be replaced if they are considered to be non-evaluable. An evaluable patient 
is one that has received at least one combination dose,  has measurable disease according to 
the Investigator site assessment and has at least one postbaseline tumor assessment. 
 
 Blinding/unblinding 
This is an open-label trial; therefore, SOLTI, investigator and participant will know the 
treatment administered. 
 Visit requirements 
Visit requirements are outlined in Section 6.1 - Trial Flow Chart. Specific procedure-
related details are provided above in Section 7 - Trial Procedures. 
 Pre-screening 
After signing the molecular pre-screening consent, tumor tissue (archival or newly 
obtained or excisional biopsy of a tumor lesion not previously irradiated) will be sent to a 
central laboratory to analyze non-luminal subtype by PAM50 test. This will be conducted 
during a pre-screening phase prior to enrolling into the trial. For eligibility into the study, 
patients must be non-luminal/ by PAM50 test analyzed in the central laboratory. Tumor tissue 
sample obtained during the advanced/metastatic setting is mandatory, it is recommended to 
provide a tumor sample collected after the most recent progression or recurrence. Tumor tissue 
requirements, along with shipping requirements, will be detailed in the sample manual 
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To perform PAM50 test, investigator judgement of patient’s potential eligibility to the 
study should be assessed as per inclusion/exclusion criteria (section 5.1) and TRIAL FLOW 
CHART (section 6). 
 Screening 
Within 28 days prior to treatment allocation, potential participants will be evaluated to 
determine that they fulfill the entry requirements as set forth in Section 6.1 Visit requirements 
are outlined in the Schedule of Activities (Flow Chart).  
Participants may be rescreened after consultation with SOLTI. Rescreening should include 
all screening procedures listed in the protocol Flow Chart, including consent review. Rescreen 
procedures cannot be conducted the day prior to treatment allocation if there are Day -1 
procedures planned per protocol. 
Written consent must be obtained prior to performing any protocol-specific procedure. 
Results of a test performed prior to the participant signing consent as part of routine clinical 
management are acceptable in lieu of a screening test if performed within the specified time 
frame. Screening procedures are to be completed within 28 days prior to the allocation for the 
following: 
• Evaluation of ECOG is to be performed within 10 days prior to the first dose of trial 
treatment. 
• For women of reproductive potential, a urine or serum pregnancy test will be performed 
within 72 hours prior to the first dose of trial treatment. If urine pregnancy results 
cannot be confirmed as negative, a serum pregnancy test will be required (performed 
by the local trial site laboratory).  
Participants may be rescreened after initially failing to meet the inclusion/exclusion 
criteria. Results from assessments during the initial screening period are acceptable in lieu of 
a repeat screening test if performed within the specified time frame and the corresponding 
inclusion/exclusion criteria is met. Participants who are rescreened will retain their original 
screening number. 
 Treatment period 
Visit requirements are outlined in the Section 6 – Schedule of Activities. Specific 
procedure related details are provided in Section 7 
 Post-treatment visits 
 Safety follow-up visit 
The mandatory Safety Follow-Up Visit should be conducted approximately 30 days after 
the last dose of study treatment or before the initiation of a new anti-cancer treatment, 
whichever comes first.  All AEs that occur prior to the Safety Follow-Up Visit should be 


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recorded.  Participants with an AE of Grade > 1 will be followed until the resolution of the AE 
to Grade 0-1 or until the beginning of a new anti-cancer therapy, whichever occurs first.  SAEs 
that occur within 90 days of the end of treatment or before initiation of a new anti-cancer 
treatment should also be followed and recorded.  Participants who are eligible for 
retreatment/crossover with pembrolizumab (as described in Section 5.2.3) may have up to two 
safety follow-up visits, one after the Initial Treatment Period and one after the Second Course 
Treatment. 
 Follow-up visits 
Discontinuation of study treatment does not represent withdrawal from the study. 
Participants who discontinue study treatment for a reason other than disease progression will 
move into the Follow-Up Phase and should be assessed every 9 weeks (63 ± 5 days) by 
radiologic imaging to monitor disease status.  Every effort should be made to collect 
information regarding disease status until the start of new anti-cancer therapy, disease 
progression, death, end of the study or if the participant begins retreatment with 
pembrolizumab as detailed in Section 5.2.3.  Information regarding post-study anti-cancer 
treatment will be collected if new treatment is initiated. 
Participants who are eligible to receive retreatment with pembrolizumab according to the 
criteria in Section 5.2.3 will move from the follow-up phase to the Second Course Phase when 
they experience disease progression.   
 Survival follow-up 
Participants who experience confirmed disease progression or start a new anticancer 
therapy, will move into the Survival Follow-Up Phase and should be contacted by telephone 
every 3 months (± 21 days) to assess for survival status until death, withdrawal of consent, loss 
to follow-up, or study termination by SOLTI , whichever occurs first. In addition, information 
regarding use of subsequent anti-cancer agents for metastatic breast cancer during the survival 
follow-up period will be collected. 
 Assessing and recording adverse events 
An adverse event is defined as any untoward medical occurrence in a patient or clinical 
investigation participant administered a pharmaceutical product and which does not 
necessarily have to have a causal relationship with this treatment. An adverse event can 
therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, 
for example), symptom, or disease temporally associated with the use of a medicinal product 
or protocol-specified procedure, whether or not considered related to the medicinal product or 
protocol-specified procedure. Any worsening (i.e., any clinically significant adverse change in 
frequency and/or intensity) of a preexisting condition that is temporally associated with the use 
of the pembrolizumab, is also an adverse event. 
Changes resulting from normal growth and development that do not vary significantly in 
frequency or severity from expected levels are not to be considered adverse events.  Examples 


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of this may include, but are not limited to, teething, typical crying in infants and children and 
onset of menses or menopause occurring at a physiologically appropriate time. 
Merck product includes any pharmaceutical product, biological product, device, 
diagnostic agent or protocol-specified procedure, whether investigational (including placebo 
or active comparator medication) or marketed, manufactured by, licensed by, provided by or 
distributed by Merck for human use. 
Adverse events may occur during the course of the use of Merck product in clinical trials, 
or as prescribed in clinical practice, from overdose (whether accidental or intentional), from 
abuse and from withdrawal. 
All AEs, SAEs and other reportable safety events that occur after the consent form is 
signed but before treatment allocation/randomization must be reported by the investigator if 
the participant is receiving treatment, if the event cause the participant to be excluded from the 
study, or is the result of a protocol-specified intervention, including but not limited to washout 
or discontinuation of usual therapy, diet, or a procedure.  
• All AEs from the time of treatment allocation/randomization through 30 days following 
cessation of study treatment must be reported by the investigator.  
• All AEs meeting serious criteria, from the time of treatment allocation through 90 days 
following cessation of study treatment, or 30 days following cessation of study 
treatment if the participant initiates new anticancer therapy, whichever is earlier must 
be reported by the investigator.  
• All pregnancies and exposure during breastfeeding, from the time of treatment 
allocation/randomization through 120 days following cessation of study treatment, or 
30 days following cessation of study treatment if the participant initiates new anticancer 
therapy must be reported by the investigator.  
• Additionally, any SAE brought to the attention of an investigator at any time outside of 
the time period specified above must be reported immediately by the investigator if the 
event is considered to be drug-related. 
Investigators are not obligated to actively seek AE or SAE or other reportable safety events 
in former study participants. However, if the investigator learns of any SAE, including a death, 
at any time after a participant has been discharged from the study, and he/she considers the 
event to be reasonably related to the study treatment or study participation, the investigator 
must promptly notify Merck. 
 Definition of an overdose for this protocol and reporting of overdose to SOLTI 
and to Merck 
For purposes of this study, an overdose of pembrolizumab will be defined as any dose of 
1,000 mg or greater (≥5 times the indicated dose).  No specific information is available on the 


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treatment of overdose of pembrolizumab. In the event of overdose, the participant should be 
observed closely for signs of toxicity.  Appropriate supportive treatment should be provided if 
clinically indicated. 
If an adverse event(s) is associated with (“results from”) the overdose of a Merck product, 
the adverse event(s) is reported as a serious adverse event, even if no other seriousness criteria 
are met. 
If a dose of Merck’s product meeting the protocol definition of overdose is taken without 
any associated clinical symptoms or abnormal laboratory results, the overdose is reported as a 
non-serious Event of Clinical Interest (ECI), using the terminology “accidental or intentional 
overdose without adverse effect.” 
All reports of overdose with and without an adverse event must be reported within 24 
hours to SOLTI and within 2 working days hours to Merck Global Safety.
 
 
 Reporting of pregnancy and lactation to SOLTI and to Merck 
Although pregnancy and infant exposure during breast feeding are not considered adverse 
events, it is the responsibility of investigators or their designees to report any pregnancy or 
lactation in a participant (spontaneously reported to them) that occurs during the study. 
Pregnancies and infant exposures during breastfeeding that occur after the consent form is 
signed but before treatment allocation/randomization must be reported by the investigator if 
they cause the participant to be excluded from the trial, or are the result of a protocol-specified 
intervention, including but not limited to washout or discontinuation of usual therapy, diet, 
placebo treatment or a procedure.   
Pregnancies and infant exposures during breastfeeding that occur from the time of 
treatment allocation/randomization through 120 days following cessation of Sponsor’s 
product, or 30 days following cessation of treatment if the participant initiates new anticancer 
therapy, whichever is earlier, must be reported by the investigator.  All reported pregnancies 
must be followed to the completion/termination of the pregnancy. Pregnancy outcomes of 
spontaneous abortion, missed abortion, benign hydatidiform mole, blighted ovum, fetal death, 
intrauterine death, miscarriage and stillbirth must be reported as serious events (Important 
Medical Events). If the pregnancy continues to term, the outcome (health of infant) must also 
be reported. 
To ensure patient safety, each pregnancy in a patient on study treatment must be reported to 
 within 24 hours of learning of its occurrence within 2 working 
days to SOLTI Project Manager and to Merck Global Safety. 
 
 
Pregnancy should be recorded on a Clinical Trial Pregnancy Form and send by email to 
 
. 
PPD
PPD
PPD
PPD
PPD
PPD
PPD


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In case of any problem, please contact under following phone number: 
 
Pregnancy follow-up should be recorded on the same form and should include an 
assessment of the possible relationship to the study treatment of any pregnancy outcome. Any 
SAE experienced during pregnancy must be reported on the SAE Report Form.  
Pregnancy outcomes must be collected for the female partners of any males who took 
study treatment in this study. Consent to report information regarding these pregnancy 
outcomes should be obtained from the mother. 
 SOLTI immediate reporting of adverse events to SOLTI and to Merck 
 Serious adverse events 
A serious adverse event is any adverse event occurring at any dose or during any use of 
Merck’s product that: 
• Results in death; 
• Is life threatening; 
• Results in persistent or significant disability/incapacity; 
• Results in or prolongs an existing inpatient hospitalization; 
• Is a congenital anomaly/birth defect; 
• Is an other important medical event  
• Note: In addition to the above criteria, adverse events meeting either of the below 
criteria, although not serious per ICH definition, are reportable to the Merck in the same 
timeframe as SAEs to meet certain local requirements. Therefore, these events are 
considered serious by Merck for collection purposes. 
• Is a new cancer (that is not a condition of the study); 
• Is associated with an overdose. 
 
Refer to Table 12 for additional details regarding each of the above criteria. 
For the time period beginning when the consent form is signed until treatment 
allocation/randomization, any serious adverse event, or follow up to a serious adverse event, 
including death due to any cause that occurs to any participant must be reported within 24 
hours of learning of its occurrence. within 2 working days to SOLTI Project Manager and to 
Merck Global Safety. 
 
SOLTI if it causes the participant to be excluded from the trial, or is the result of a protocol-
specified intervention, including but not limited to washout or discontinuation of usual therapy, 
diet, placebo treatment or a procedure. 
For the time period beginning at treatment allocation through 90 days following cessation 
of treatment, or 30 days following cessation of treatment if the participant initiates new 
anticancer therapy, whichever is earlier, any serious adverse event, or follow up to a serious 
PPD
PPD
PPD


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adverse event, including death due to any cause whether or not related to the Merck product, 
must be reported within 24 hours of learning of its occurrence. within 2 working days to SOLTI 
Project Manager and to Merck Global Safety.
 
SOLTI Additionally, any serious adverse event, considered by an investigator who is a 
qualified physician to be related to Merck product that is brought to the attention of the 
investigator at any time following consent through the end of the specified safety follow-up 
period specified in the paragraph above, or at any time outside of the time period specified in 
the previous paragraph also must be reported immediately to Merck Global Safety. 
All participants with serious adverse events must be followed up for outcome. 
SAE reports and any other relevant safety information are to be forwarded to within 
24 hours of learning of its occurrence within 2 working days to SOLTI Project Manager and 
to Merck Global Safety. 
 
A copy of all 15 Day Reports and Annual Progress Reports is submitted as required by 
FDA, European Union (EU), Pharmaceutical and Medical Devices agency (PMDA) or other 
local regulators. Investigators will cross reference this submission according to local 
regulations to the Merck Investigational Compound Number (IND, CSA, etc.) at the time of 
submission. Additionally investigators will submit a copy of these reports to Merck & Co., Inc. 
 at the time of submission to FDA. 
 Events of clinical interest 
Selected non-serious and serious adverse events are also known as Events of Clinical 
Interest (ECI) and must be reported within 24 hours of learning of its occurrence. within 2 
working days to SOLTI Project Manager and to Merck Global Safety. 
 
 
For the time period beginning when the consent form is signed until treatment 
allocation/randomization, any ECI, or follow up to an ECI, that occurs to any participant must 
be reported within within 24 hours of learning of its occurrence. within 2 working days to 
SOLTI Project Manager and to Merck Global Safety. 
 
 
 if it causes the participant to be excluded from the trial, or is the result of a 
protocol-specified intervention, including but not limited to washout or discontinuation of 
usual therapy, diet, placebo treatment or a procedure. 
For the time period beginning at treatment allocation/randomization through 90 days 
following cessation of treatment, or 30 days following cessation of treatment if the participant 
initiates new anticancer therapy, whichever is earlier, any ECI, or follow up to an ECI, whether 
or not related to Merck product, must be reported within 2 working days to Merck Global 
Safety. 
Events of clinical interest for this trial include: 
PPD
PP
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


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1.  an overdose of Merck product, as defined in Section 7.2.1 - Definition of an Overdose 
for This Protocol and Reporting of Overdose to SOLTI, that is not associated with 
clinical symptoms or abnormal laboratory results.  
2.  an elevated AST or ALT lab value that is greater than or equal to 3X the upper limit of 
normal and an elevated total bilirubin lab value that is greater than or equal to 2X the 
upper limit of normal and, at the same time, an alkaline phosphatase lab value that is less 
than 2X the upper limit of normal, as determined by way of protocol-specified laboratory 
testing or unscheduled laboratory testing.* 
*Note:  These criteria are based upon available regulatory guidance documents. The 
purpose of the criteria is to specify a threshold of abnormal hepatic tests that may require an 
additional evaluation for an underlying etiology.  
 
 Evaluating adverse events 
An investigator who is a qualified physician will evaluate all adverse events according to 
the NCI Common Terminology for Adverse Events (CTCAE), version 5.0. Any adverse event 
which changes CTCAE grade over the course of a given episode will have each change of 
grade recorded on the adverse event case report forms/worksheets. 
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Table 12. Evaluating adverse events 
An investigator who is a qualified physician, will evaluate all adverse events as to: 
V5.0 CTCAE 
Grading 
Grade 1 
Mild; asymptomatic or mid symptoms; clinical or diagnostic observations only; intervention not indicated. 
Grade 2 
Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental ADL. 
 
Grade 3 
Severe or medically significant but not immediately life-threatening; hospitalization or prolongation or hospitalization indicated; disabling; 
limiting self-care ADL. 
 
Grade 4 
Life threatening consequences; urgent intervention indicated. 
 
Grade 5 
Death related to AE 
Seriousness 
A serious adverse event is any adverse event occurring at any dose or during any use of Merck product that: 
 
†Results in death; or 
 
†Is life threatening; or places the participant, in the view of the investigator, at immediate risk of death from the event as it occurred (Note: This does not include an 
adverse event that, had it occurred in a more severe form, might have caused death.); or 
 
†Results in a persistent or significant disability/incapacity (substantial disruption of one’s ability to conduct normal life functions); or 
 
†Results in or prolongs an existing inpatient hospitalization (hospitalization is defined as an inpatient admission, regardless of length of stay, even if the 
hospitalization is a precautionary measure for continued observation. (Note: Hospitalization for an elective procedure to treat a pre-existing condition that has not 
worsened is not a serious adverse event.  A pre-existing condition is a clinical condition that is diagnosed prior to the use of a Merck product and is documented in the 
patient’s medical history.); or 
 
†Is a congenital anomaly/birth defect (in offspring of participant taking the product regardless of time to diagnosis);or 
 
Is a new cancer (that is not a condition of the study) (although not serious per ICH definition, is reportable to SOLTI within 24 hours and to Merck within 2 working 
days to meet certain local requirements); or 
 
Is an overdose (whether accidental or intentional).  Any adverse event associated with an overdose is considered a serious adverse event for collection purposes. An 
overdose that is not associated with an adverse event is considered a non-serious event of clinical interest and must be reported within 24 hours to SOLTI and to Merck 
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Other important medical events that may not result in death, not be life threatening, or not require hospitalization may be considered a serious adverse event when, 
based upon appropriate medical judgment, the event may jeopardize the participant and may require medical or surgical intervention to prevent one of the outcomes 
listed previously (designated above by a †). 
Duration 
Record the start and stop dates of the adverse event. If less than 1 day, indicate the appropriate length of time and units 
Action taken  
Did the adverse event cause Merck product to be discontinued? 
Relationship to 
Merck Product  
Did Merck product cause the adverse event? The determination of the likelihood that Merck  product caused the adverse event will be provided by an investigator who 
is a qualified physician. The investigator’s signed/dated initials on the source document or worksheet that supports the causality noted on the AE form, ensures that a 
medically qualified assessment of causality was done. This initialed document must be retained for the required regulatory time frame. The criteria below are intended 
as reference guidelines to assist the investigator in assessing the likelihood of a relationship between the test drug and the adverse event based upon the available 
information. 
The following components are to be used to assess the relationship between Merck product and the AE; the greater the correlation with the components and their 
respective elements (in number and/or intensity), the more likely Merck product caused the adverse event (AE): 
 
Exposure 
Is there evidence that the participant was actually exposed to Merck product such as: reliable history, acceptable compliance assessment (pill count, 
diary, etc.), expected pharmacologic effect, or measurement of drug/metabolite in bodily specimen? 
 
Time Course 
Did 
the 
AE 
follow 
in 
a 
reasonable 
temporal 
sequence 
from 
administration 
of 
Merck 
product?  
Is the time of onset of the AE compatible with a drug-induced effect (applies to trials with investigational medicinal product)? 
 
Likely Cause 
Is the AE not reasonably explained by another etiology such as underlying disease, other drug(s)/vaccine(s), or other host or environmental factors 
 


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Relationship 
The following components are to be used to assess the relationship between the test drug and the AE: (continued) 
to Merck 
Product 
(continued)  
Dechallenge 
Was Merck product discontinued or dose/exposure/frequency reduced? 
If yes, did the AE resolve or improve? 
If yes, this is a positive dechallenge. If no, this is a negative dechallenge. 
(Note: This criterion is not applicable if: (1) the AE resulted in death or permanent disability; (2) the AE resolved/improved despite continuation of 
SOLTI’s product; or (3) the trial is a single-dose drug trial); or (4) Sponsor’s product(s) is/are only used one time.) 
 
Rechallenge 
Was the participant re-exposed to Merck product in this study? 
If yes, did the AE recur or worsen? 
If yes, this is a positive rechallenge. If no, this is a negative rechallenge. 
(Note: This criterion is not applicable if: (1) the initial AE resulted in death or permanent disability, or (2) the trial is a single-dose drug trial); or (3) 
Sponsor’s product(s) is/are used only one time). 
NOTE: IF A RECHALLENGE IS PLANNED FOR AN ADVERSE EVENT WHICH WAS SERIOUS AND WHICH MAY HAVE BEEN 
CAUSED BY MERCK PRODUCT, OR IF REEXPOSURE TO MERCK PRODUCT POSES ADDITIONAL POTENTIAL SIGNIFICANT RISK 
TO THE PARTICIPANT, THEN THE RECHALLENGE MUST BE APPROVED IN ADVANCE BY SOLTI AS PER DOSE MODIFICATION 
GUIDELINES IN THE PROTOCOL. 
 
Consistency 
with Trial 
Treatment 
Profile 
Is the clinical/pathological presentation of the AE consistent with previous knowledge regarding Merck product or drug class pharmacology or 
toxicology? 
The assessment of relationship will be reported on the case report forms /worksheets by an investigator who is a qualified physician according to his/her best clinical judgment, including 
consideration of the above elements. 
Record one of the following 
Use the following scale of criteria as guidance (not all criteria must be present to be indicative of Merck product relationship). 
Yes, there is a reasonable 
possibility of Merck product 
relationship. 
There is evidence of exposure to Merck product.  The temporal sequence of the AE onset relative to the administration of Merck product is reasonable.  
The AE is more likely explained by Merck product than by another cause. 
No, there is not a reasonable 
possibility of Merck product 
relationship 
Participant did not receive the Merck product OR temporal sequence of the AE onset relative to administration of Merck product is not reasonable 
OR the AE is more likely explained by another cause than the Merck product.  (Also entered for a participant with overdose without an associated 
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 Sponsor responsibility for reporting adverse events 
Prompt notification (within 24 hours) by the investigator to SOLTI of SAE is essential so 
that legal obligations and ethical responsibilities towards the safety of participants and the 
safety of a study treatment under clinical investigation are met. 
• SOLTI has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study treatment under clinical investigation. 
All AEs will be reported to regulatory authorities, IRB/IECs and investigators in 
accordance with all applicable global laws and regulations, ie, per ICH Topic E6 (R2) 
Guidelines for GCP. 
•  Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSARs) according to local regulatory requirements and Sponsor policy and 
forwarded to investigators as necessary. 
• An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (eg, summary or listing of SAE) from SOLTI will file it 
along with the IB and will notify the IRB/IEC, if appropriate according to local 
requirements. 
8. STATISTICAL ANALYSIS PLAN 
 Statistical and analysis plan summary 
This is an open-label, single arm, multicenter phase II study evaluating treatment with 
paclitaxel in combination with pembrolizumab in patients with locally advanced or metastatic 
non-luminal HR+/HER2- breast cancer refractory to CDK inhibitors. This study will utilize a 
Simon’s two-stage design, single arm, with one interim and a final analysis. The interim 
analysis will be conducted when 15 patients are evaluable for Objective Response Rate (ORR) 
as determined locally by the investigator through the use of RECIST v.1.1. Recruitment will 
not be halted during the interim analysis period. Therefore, no interruption in the accrual will 
be done during the interim analysis in order to maintain the dynamic of accrual in the trial. 
Detailed statistical analysis information will be provided separately in the Statistical 
Analysis Plan (SAP). The SAP will be approved before the final close of database and will 
detail all data analyses and deviation to the final version of Protocol study. 
 Analysis populations 
All patients included into the study will be considered in the statistical report. 
Intent-to-Treat (ITT) population: includes all patients that are enrolled in the study. This 
population will be used for the efficacy analysis, with the exception of overall response 
rate and clinical benefit rate, which used the evaluable population. 


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Evaluable population (EP): includes all patients who have received at least one 
combination dose of pembrolizumab and paclitaxel who had measurable disease according to 
the Investigator site assessment at baseline and who had at least one postbaseline tumor 
assessment . This population will be used for overall response rate and cinical benefit rate 
analysis.  
Safety population (SP): includes the set of patients who received at least one (even 
incomplete) part of the study treatments. This population will be analyzed for the secondary 
endpoint of safety. 
 Statistical analysis 
The statistical analysis will be conducted following the principles as specified in 
International Conference on Harmonization (ICH) Topic E9 (CPMP/ICH/363/96). The 
significance level will be α=0.05 for all tests. As an exploratory study, multiple testing 
without adjustment of the significance level is considered acceptable. 
A summary of the general approach to statistical analysis is given below. A detailed 
statistical plan will be issued and approved prior to declaration of clean database. 
Quantitative variables will be summarized using descriptive statistics, including number 
of missing values, number of valid values and their observed range, median, mean, 
standard deviation and 95% confidence interval for the mean. The Kaplan-Meier method will 
be used to estimate the time to event function the median of time to event and the 95% 
confidence interval of the same will be calculated. These confidence intervals will be 
calculated based on the Greenwood method. 
Qualitative variables will be summarized presenting frequency and percentage of each 
level of the variable. In case of dichotomous variables, as ORR, estimation of proportions 
will be done by 95% confidence interval using the Wilson’s method. Ordinal variables will 
be described as both quantitative and qualitative variables. 
All safety analyses will be performed on the Safety Population. All AEs will be graded 
according to the NCI CTCAE v.5.0. Appropriate summary statistics will be provided for 
the analyses of vital signs (i.e., weight, blood pressure, heart rate, and body temperature), 
ECOG performance status, and ECGs. 
 
 Sample size calculations 
The primary endpoint, objective response rate (ORR) as determined locally by the investigator 
through the use of RECIST v.1.1. The rationale for a null hypothesis of p ≤ 0.30 is based on 
previously published analysis from a clinical trial with paclitaxel (BELLE-4) in 209 patients 
with metastatic disease with no prior chemotherapy for advanced disease, where an ORR of 
27.1% has been observed for paclitaxel monotherapy 121. The ORR of pembrolizumab in 
combination with paclitaxel is expected to be at least as high as this in patients unselected for 
PD-L1 positive disease.  Supposing a minimum increase of 20% in the ORR to be considered 


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the study successful, the ORR at the end of stage 2 should be ≥ 50%, to warrant further research 
of this treatment combination in this patient population.  
This study will utilize the optimal two-stage Simon’s design (1989)1. The null hypothesis 
that the true response rate is not more than 30% (p  0.3) versus the alternative hypothesis that 
the true response rate is at least 50% (p ≥ 0.50) will be tested. The first stage, will be conducted 
with 15 evaluable patients. If there are 5 or fewer responses in these 15 patients, the study will 
be stopped. Otherwise, 31 additional patients will be accrued for a total of 46. The null 
hypothesis will be rejected if 19 or more responses are observed in 46 patients of EP. This 
design yields a one-sided type I error rate of 0.05 (alpha) and power of 80%.  
 Up to 46 evaluable patients of EP may therefore be enrolled to this clinical trial. It is 
expected that approximately 184 patients will be screened in order to identify 51 patients who 
meet all the inclusion and exclusion criteria. Assuming a dropout rate of 10%, the study will 
aim to recruit 51 patients in total in order to have at least 46 evaluable patients of EP to attain 
80% power at nominal level of one-sided alpha of 0.05.  
 
Primary objective 
The primary objective of the study is to assess the proportion of patients with best overall 
response of CR or PR, as per local investigator’s assessment and according to RECIST v1.1 
(see Appendix 5 for details) with paclitaxel and pembrolizumab among patients with 
HR+/HER2-, non-luminal metastatic breast cancer who have progressed on or after CDK 4/6 
inhibitor. To be consistent with the sample size calculation, the primary hypothesis will be tested 
at 0.05 level of significance (one-sided) and a 90% confidence intervals will be reported. 
Additionally, the ORR will be reported along with associated 95% confidence interval. 
 
Secondary objectives 
The secondary objectives in this study are to evaluate the progression free survival (PFS), 
clinical benefit rate (CBR) and duration of response (DOR), Time to response (TtR), Pre-PFS, 
overall survival (OS) and safety. In addition of the calculation of 90% confidence intervals for 
efficacy secondary objectives, 95% confidence intervals may also be provided as needed. 
Progression free survival 
PFS is defined as the time from the date of allocation to the date of the first documented 
progression or death due to any cause occurring in the study. PFS will be assessed based on 
local investigator’s assessment according to RECIST v1.1 (see Appendix 5 for further details).  
PFS will be censored if no PFS event is observed before the cut-off date. The censoring date 
will be the date of last adequate tumor assessment before the cut-off date. If a PFS event is 
observed after two or more missing or non-adequate tumor assessments, then PFS will be 
censored at the last adequate tumor assessment. If a PFS event is observed after a single 
missing or non-adequate tumor assessment, the actual date of event will be used (see Appendix 


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5). It is not intended to censor patients for new anticancer therapy prior to documented disease 
progression in the primary analysis.  
The Kaplan-Meier estimate of the PFS survival function will be estimated and displayed. The 
resulting median PFS time will be given for each cohort with 95% confidence intervals, as 
well as 25th and 75th percentiles will be reported. 
Clinical benefit rate 
Clinical Benefit Rate is defined as the proportion of patients with a best overall response of 
CR or PR or an overall lesion response of stable disease (SD) or Non-CR or PR/ Non-PD 
lasting ≥ 24 weeks based on local investigator’s assessment according to RECIST v1.1. CBR 
will be calculated based on the mFAS. The CBR and its exact 90% confidence interval. 
Duration of response 
DOR is the time from the date of first documented response (confirmed CR or PR) to the date 
of first documented progression or death due to underlying cancer. DOR only applies to 
patients whose best overall response is CR or PR according to RECIST v1.1 based on tumor 
response data per local investigator’s assessment. The start date is the date of first documented 
response of CR or PR (i.e., the start date of response, not the date when response was 
confirmed), and the end date is defined as the date of the first documented progression or death 
due to underlying cancer. Patients continuing without progression or death due to underlying 
cancer will be censored at the date of their last adequate tumor assessment. 
Time to response  
TtR is defined as the time from the allocation to the first objective tumor response (tumor 
shrinkage of ≥30%) observed for patients who achieved a CR or PR.  TtR only applies to 
patients whose best overall response is CR or PR according to RECIST v1.1 based on tumor 
response data per local investigator’s assessment. 
Overall Survival 
OS is defined as the time from the date of allocation to the date of death due to any cause. Data 
for patients who are alive at the time of the analysis data cutoff will be censored at the last date 
they were known to be alive. Data from patients without post-baseline information will be 
censored at the date of allocation. 
The results from log-rank test will be provided. The OS curve will be estimated by the Kaplan-
Meier methodology, and the 95% CI will be estimated by the Cox proportional-hazards 
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PFS on study treatment compared to PFS on prior line of therapy (pre-PFS). 
PFS is defined as the time from the date of allocation to the date of the first documented 
progression or death due to any cause occurring in the study. PFS will be assessed based on 
local investigator’s assessment according to RECIST v1.1 (see Appendix 5 for further details).  
Pre-PFS is defined as the time from the date of first dose of the previous medication to the date 
of the first documented progression in the previously metastatic line. Pre-PFS only applies to 
patients whose received have previous treatment for metastatic disease 
ORR according to PD1 mRNA expression 
To evaluate the direct association of PD1 FFPE-based mRNA expression with ORR we 
evaluate the PD1 mRNA pre-established cutoff (median or tertiles) and as a continuous 
variable.  
Median: Cutoff points are calculated according to the median value for the mRNA expression. 
Samples with mRNA expression above or equal to the median were considered as samples 
with high expression, while those with value below the median as samples with low expression.  
Tertiles: Cutoff points are calculated according to the tertiles value for the mRNA expression. 
Samples with mRNA expression above or equal to the tertile-1 (PD1-high) were considered as 
samples with high expression, samples with mRNA expression above or equal to the tertile-2 
(PD1-high) were considered as samples with intermediate expression, while those with value 
below the tertile-2 as samples with low expression. 
To compare distribution of variables between two groups, we used Fisher's exact test. 
Proportions and 95% CI were also provided.  Univariate and multivariable logistic regression 
analyses are done to investigate the association of each variable with ORR. Odds ratios (ORs) 
and 95% CIs are calculated for each variable. All the laboratory analyses are performed 
blinding to the clinical data. 
ORR and PFS according to early dynamic changes in ctDNA between before the 
treatment and cycle 2 after one dose of pembrolizumab.  
The “circulating tumor DNA response” is defined as the ratio of mutant copies/ml of plasma 
at day 1 cycle 2 and day 1 cycle 1, subsequently denoted as CDR21. Aggregate totals 
of genes mutation copies/ml will be used where a sample exhibited polyclonality for these 
mutations. Paired day 1 cycle 2 and day 1 cycle 1 copies/ml and allele fractions will be 
compared using Wilcoxon signed-rank test. The distribution of copies/ml between selected 
genes will be compared using the Mann–Whitney test. Comparisons of CDR15 distributions 
will be treated similarly. Harrell’s c-index will be used to optimize the CDR21 cut-off. The test 
for an association between undetectable mutation at day 1 cycle 2 and end of treatment will be 
conducted with Fisher’s exact test. Proportions of patients with undetectable mutations at the 
end of treatment for selected genes will be    compared with a two-sample test of proportions. 
For all analyses, a p value of <0.05 will be considered statistically significant. 


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For analyses of PFS, Kaplan–Meier curves will be plotted, and groups compared using the log-
rank test. Hazard ratios and associated 95% CIs will be obtained from Cox proportional hazards 
regression models. In order to determine the optimal cut-point for CDR21 in relation to PFS, 
the maximally selected log-rank statistics will be used to selected the cut-off that better separate 
patients according CDR21 .  
9. TRANSLATIONAL RESEARCH 
Translational research data will be collected outside the clinical database; correlations 
with relevant clinical features will be performed by specialized scientists of 
 
 and reported in a 
separate ad-hoc report, which will integrate the results and findings described in the clinical 
study report. 
All the data analyses of the study will be under the responsibility of SOLTI and they will 
be based on a statistical plan according to the protocol specifications. 
 
 Biological specimens 
The tissue samples collected will be used to identify biomarkers that may be predictive 
of response or toxicity to the proposed treatments and/or prognostic for breast cancer. 
Since the knowledge of new markers that may correlate with disease activity and the 
efficacy or safety of the treatment is evolving, the analytes may change during the course of 
the study and may include determination of additional markers of tumorigenesis pathways 
and mechanisms of treatment response. The collected tumor tissue samples may also be used 
to develop and validate diagnostic assays and allow the generation of statistically meaningful 
biomarker data. 
Remaining sample materials after the completion of the initial biomarker assessments 
(e.g., aliquots of tumor RNA or DNA) may be used for further assessment of expanded 
marker panels. 
Samples will be stored at the 
 
 for up to 15 years after 
database closure, with the additional option of further long-term storage. They will be stored 
under the responsibility of the Dr 
. 
 
All patients will be consented for the collection and use of research blood and tissue 
samples. All samples will be linked anonymized and only identified by the trial ID and unique 
sample number allocated by the SOLTI SAMPLE TRACKER SYSTEM coordinating team. 
For sampling procedures and shipment see instructions in the appropriate sections of the 
study sample management manual 
 
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 Tumor tissue samples 
 
Collection of tumor biopsies is an essential part of this study. Paraffin-embedded and 
formalin-fixed tumor samples will be obtained from all patients. Quality of tumor samples 
even for pre-screening sample will be evaluated upon arrival to central laboratory. Pathological 
analysis includes hematoxylin and eosin (H&E) staining, identification of areas with greater 
amount of tumor cells and determination of their tumor cell percentage. Confirmation of 
eligibility criteria requires central assessment of an adequate quantity and quality of pre-
screening sample. If not available, the patient must agree to re-biopsy.  
 Gene expression signatures 
The study foresees the identification of the molecular intrinsic subtypes (Luminal A, 
Luminal B, HER2-E, basal-like) and the normal breast-like group using the PAM50 panel 
(non-commercial version). This panel measures the expression of 50 classifier genes and 5 
control genes, which classify the tumors into 5 intrinsic subtypes (luminal A, luminal B, HER2-
enriched and basal-like) and the normal breast-like group. 
Besides of PAM50 gene expression analysis at baseline and in order to identify new 
biomarkers of response to the combination treatment, we aim to further evaluate the expression 
of 702 additional genes that encompass important genomic signatures and individual genes of 
importance for breast cancer: The nCounter®Breast Cancer 360 Panel includes 752 genes 
across 23 key breast cancer pathways and processes (Table 13) as well as established breast 
cancer diagnostic and research signatures, tumor microenvironment, and immune response. 
Special attention will be given to innate immune response genes as well as markers of antigen 
presentation, which are expected to be determinant for this combination treatment. The 
following genes/signatures will be evaluated among others:  
• Intrinsic PAM50 subtypes (Basal-like, HER2-enriched, Luminal A, Luminal B, and 
Normal-like): 50 genes including probes for ER, PgR and HER2.  
• ROR score: Validated score for predicting risk of relapse in a cohort of node-negative 
patients with OR- and OR+ tumors who did not receive adjuvant systemic treatment. 
ROR-S (with subtype information) and ROR-P (using proliferation data separately)  
• EGFR-related genes: ERBB2, EGFR, ERBB4, GRB7, CRYAB  
• PI3K pathway genes: PIK3CA, PTEN.  
• Claudin-low subtype: Recently described subtype, enriched for stem cell and/or tumor 
initiating features, as well as metaplastic features, containing genes coding for of 
Vimentin, Claudins 3, 4 and 7, ZEB1.  
• VEFG signature: containing VEGF, adrenomedulin (ADM), angiopoietin 4-type 
(ANGPTL4) and likely indicative of hypoxia.  
• Proliferation: Multi-gene signature indicative of cell proliferation rate, containing genes 
such as MKI67, MYC, TOP2A, CCNB1, CCNE1, RB1 and p16.  
• Estrogen-responsive signature: ESR1, PGR, NAT1, FOXA1, BCL2, BAG1 and GATA3  
• Basal-luminal differentiation: keratin 5, 19, 14, 8 and 17  
• DNA replication genes: TYMS, CDC6, RRM2, ORC6L, CENPF, RAD51.  


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• Stroma-related genes: vimentin, CAV1, SFRP1  
• Immune Infiltration: CD27, CD274, CD276, CD8A, LAG3  
• Other genes: MLPH, CD24, EPCAM, DDR1, BIRC5, CDH3  
 
 
Table 13: Type of immune genes to be assayed. 
 
 
Pathway 
# 
Genes 
Adhesion and Migration 
83 
Angiogenesis 
34 
Antigen Presentation 
21 
Apoptosis 
9 
Cytokine and Chemokine Signaling 
50 
DNA Damage Repair 
140 
EMT 
85 
ER Signaling 
27 
Epigenetic Regulation 
18 
Hedgehog 
20 
Immune Infiltration 
33 
Internal Reference Gene 
18 
JAK-STAT 
47 
MAPK 
100 
Notch 
22 
PI3K 
96 
Proliferation 
142 
Stromal Markers 
6 
Subtypes 
70 
TGF-beta 
57 
Transcriptional Misregulation 
63 
Triple Negative Biology 
50 
Tumor Metabolism 
15 
Wnt 
51 
 
 The nCounter platform 
The NanoString nCounter Analysis System (http://www.nanostring.com/) delivers direct, 
multiplexed measurements of gene expression through digital readouts of the relative 
abundance of hundreds of mRNA transcripts. It uses gene-specific probe pairs that 
hybridize directly to the mRNA sample in solution eliminating any enzymatic reactions that 


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might introduce bias in the results. After hybridization, all of the sample processing steps are 
automated. 
 
 RNA extraction 
The PAM50 assay uses RNA from FFPE breast tumor tissue. A section of the FFPE breast 
tissue will first be examined with a hematoxylin and eosin (H&E) staining to determine 
percent tumor nuclei, percent normal nuclei, and percent necrosis per standard pathology 
processing. The slide will then be reviewed by a pathologist, who will identify and mark the 
region of the tissue that contains an adequate percentage of tumor for the gene expression test 
on the slide. RNA will be extracted from the FFPE tissue sample using an RNA isolation 
kit. Additional general-purpose laboratory reagents are required for deparaffinization. The 
extraction process includes a step for removing genomic DNA from the sample. Following 
extraction of total RNA and removal of genomic DNA, the optical density is measured at 
wavelengths of 260 nm and 280 nm to determine both yield and purity using a low volume 
spectrophotometer. RNA will be stored at –80ºC until time of testing. 
 
 Technical procedures and data analysis 
For each set of up to 10 RNA samples isolated from breast cancer tissue, the user will 
pipette a defined amount of RNA into separate tubes within a 12-reaction strip tube and add 
the CodeSet and hybridization buffer as specified within the assay protocol. A set 
concentration of reference sample is pipetted into the remaining two tubes with CodeSet and 
hybridization buffer. The CodeSet consists of probes for each gene that is targeted, additional 
probes for endogenous “housekeeping” normalization genes and positive and negative 
controls that are spiked into the assay. The reference sample consists of in vitro transcribed 
RNA for the targeted genes and housekeeping genes. Once the hybridization reagents are 
added to the respective tubes, the user transfers the strip tube into a specified heated-lid 
heat block and incubates for a defined period of time at a set temperature of 65ºC. 
Upon completing hybridization, the user will then transfer the strip tube containing the set 
of 10 assays and two reference samples into the nCounter Prep Station.  An automated 
purification process then removes excess capture and reporter probe through two successive 
hybridization-driven magnetic bead capture steps. The nCounter Prep Station then transfers 
the purified target/probe complexes into an nCounter cartridge for capture to a glass slide. 
Following completion of the run, the user removes the cartridge from the Prep Station and 
seals it with an adhesive film. 
The cartridge is then sealed and inserted into the nCounter Digital Analyzer. The analyzer 
counts the number of probes captured on the slide for each gene, which corresponds to the 
amount of target in solution. The signals of each sample will be normalized using the 
housekeeping genes to control for input sample quality. The signals are then normalized to the 
reference sample within each run to control for run-to-run variations. The resulting 
normalized data is input into the breast cancer-subtyping algorithm or gene signatures score 
algorithm. 
 


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 Immunohistochemistry 
Immunohistochemistry at a central laboratory will be used to measure the number of 
stromal tumor-infiltrating lymphocytes (TILs) and PD-L1 staining in immune cells and tumor 
cells. 
 
 Circulant tumor DNA  
Plasma samples will be collected at day 1 cycle 1, day 1 cycle 2, and end of treatment in 
EDTA blood collection tubes. Samples will be processed within 30 min of collection by 
centrifugation at 1500–2000 × g for 10 min. Plasma will be then separated and stored at −70 to 
−80 °C. Prior to DNA extraction plasma samples will be thawed and subjected to further 
centrifugation at 3000 × g for 10 min. 
 Sample repository 
All residual samples after protocol-defined studies are completed will be stored in a central 
sample repository as a collection. The samples in the study repository might be used for future 
biomarker research towards further understanding of treatment with study drugs, of breast 
cancer, related diseases, and adverse events, and for the development of potential, associated 
diagnostic assays, in accordance with the recommendations and approval of the Study Steering 
Committee. Samples will be stored up to 15 years or until they are exhausted, whatever 
happens first, in accordance with applicable local regulations (Law 14/2007 on Biomedical 
Research and the Royal Decree 1716/2011).  
A separate, specific signature will be required to document a patient's agreement to allow 
future biomarker research and storage in repository of any remaining samples. Labels of 
biological samples will not contain any clinical information of patients.  
Samples will be stored in the biorepository of the 
. 
Responsible for the samples custody is 
 of the Hospital Clínic of Barcelona and head of the research group 
. The repository is located in the
 
 Barcelona (Spain); Phone: 
  
Samples will be stored as a collection and registered in the National Registry of Biobanks, 
in agreement with article 37 of the Royal Decree 1716/2011.  
Results derived from the analysis of biological samples of a patient will not be provided 
to the Site Investigators, unless patient explicitly requests this information, in compliance with 
local and national law. Patient must be informed that those results are for investigational use 
only and should not be used for treatment decision. The final results deriving from 
investigation with these biological samples will be published in accordance with the Steering 
Committee charter of this study. 
 
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10. LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES 
 
Investigational product  
The investigator shall take responsibility for and shall take all steps to maintain 
appropriate records and ensure appropriate supply, storage, handling, distribution and usage of 
investigational product in accordance with the protocol and any applicable laws and 
regulations. 
Pembrolizumab will be provided by Merck as summarized in Table 14. 
Table 14. Product Descriptions 
Product Name & Potency 
Dosage Form 
Pembrolizumab 100 mg/ 4mL 
Solution for Infusion 
 
Paclitaxel is considered as SoC Treatment and will be supplied locally, and packaged, stored 
and administered according to their label. 
 
Packaging and labeling information 
Supplies will be labeled in accordance with regulatory requirements. 
Pembrolizumab will supplied by Merck or its designee. Storage conditions are described in the 
medication label. All prescribed and dispensed dosages must be recorded. 
Paclitaxel will be supplied locally, and packaged, stored and administered according to their 
label. All prescribed and dispensed dosages must be recorded. 
 
Clinical supplies disclosure 
This trial is open-label; therefore, the participant, the trial site personnel, SOLTI and/or 
designee are not blinded to treatment. Drug identity (name, strength) is included in the label 
text; random code/disclosure envelopes or lists are not provided. 
 
Storage and handling requirements 
Clinical supplies must be stored in a secure, limited-access location under the storage 
conditions specified on the label.   
Receipt and dispensing of trial medication must be recorded by an authorized person 
at the trial site. 
Clinical supplies may not be used for any purpose other than that stated in the protocol. 


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Returns and reconciliation 
The investigator is responsible for keeping accurate records of the clinical supplies 
received from Merck or designee, the amount dispensed to and the amount remaining at the 
conclusion of the trial. Upon completion or termination of the study, all unused and/or 
partially used investigational product will be destroyed at the site per institutional policy. It is 
the Investigator’s responsibility to arrange for disposal of all empty containers, provided that 
procedures for proper disposal have been established according to applicable federal, state, 
local and institutional guidelines and procedures, and provided that appropriate records of 
disposal are kept. 
 
11. ADMINISTRATIVE AND REGULATORY DETAILS 
 
Ethical and regulatory standards 
 Independent Ethics Committee 
This protocol and any amendments will be submitted to a properly constituted 
Independent Ethics Committee (IEC), in accordance with the International Conference on 
Harmonization (ICH) guidelines, the applicable European Directives and local legal 
requirements, for approval of the study. Approval must be obtained in writing before the first 
subject can be recruited. 
During the Clinical Trial, any amendment or modification to the Protocol should be 
submitted to the Ethics Committee (IRB/IEC) before implementation, unless the change is 
necessary to eliminate an immediate hazard to the patients, in which case the IRB/IEC should 
be informed as soon as possible. It should also be informed of any event likely to affect the 
safety of patients or the continued conduct of the Clinical Trial, in particular any change in 
safety. 
Principal Investigator will not be released at the study site and the Investigator will not 
start the study before the written and dated approval/favorable opinion is received by the 
Investigator and SOLTI. Before study start, the investigator must sign the Protocol 
signature page to confirm that he/she agrees to conduct the study in compliance with these 
documents and with all instructions and procedures described in the Protocol and to permit 
access to all relevant data and records to the study monitors, SOLTI auditors, representatives 
of SOLTI's clinical quality assurance department, designated SOLTI agents, IECs and health 
authorities upon request. 
A progress report is sent to the Ethics Committee (IRB/IEC) at least annually DSUR and 
a summary of the Clinical Trial’s outcome at the end of the Clinical Trial. 
 
 Ethical conduct of the study 
The Clinical Trial will be conducted in compliance with the Protocol, regulatory 


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requirements, the ICH guidelines for Good Clinical Practice (GCP) and the ethical 
principles of the latest revision of the Declaration of Helsinki as adopted by the World 
Medical Association. 
This Clinical Trial will be recorded in the public registry website clinicaltrials.gov and 
Registro Español de Ensayos Clinicos before the enrollment of the first patient. The registry 
will contain basic information about the trial sufficient to inform interested patients and their 
healthcare practitioners on how to enroll in the trial. 
 
 Subject information and consent 
All potential participants will receive verbal and written information on the study in 
a previous interview with the study doctor in their hospital. In this information, special 
emphasis will be placed on the fact that participation in the study is voluntary and that the 
patient may withdraw herself from the study at any time and for any reason, without this 
affecting her medical care. All patients will have the opportunity to ask questions about the 
study and they will be given sufficient time to decide if they wish to participate. 
 
The ICF must mention the specific data that will be recorded, collected, processed and that 
can be sent to countries pertaining to and outside of the European Economic Area (EEA). In 
accordance with the in accordance with the Regulation (EU) 2016/679 of the European 
Parliament and of the Council of 27 April 2016 and LOPD, the individuals participating in 
the study shall not be identified. 
Personal data will be managed in accordance with the applicable legislation in force at the 
time, and in particular, in accordance with Regulation (EU) No 2016/679 of 27 April 2016 on 
the protection of individuals with regard to the processing of their personal data (hereinafter, 
“GDPR”). 
The patient will be given a copy of the Patient Information Sheet, including the signed ICF. 
Eligible patients can only be included after granting their written informed consent (before 
witnesses, when required by laws or standards). The signature of the ICF must be obtained 
before performing any study-specific procedures (that is, any of the procedures described in 
the Protocol). The date on which the ICF is signed must be recorded in the eCRF. 
The investigators will be given an ICF approved by the IEC that is considered to be 
appropriate for the study and that satisfies the ICH GCP standards and legal requirements. 
Any modification to this ICF proposed by the investigator must be accepted by SOLTI and 
approved by the local IEC. A copy of the approved version must be provided to the trial 
monitor after IEC approval is obtained. 
 
 
Subject records and source data 
A current copy of the Curriculum Vitae describing the experience, qualification, and 
training of each Investigator and Sub-investigator will be signed, dated and provided to SOLTI 


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prior to the beginning of the Clinical Trial. 
It is the responsibility of the Investigator to record essential information in the medical 
records in accordance with national regulations and requirements. The following information 
should be included as a minimum: 
• 
A statement that the subject is in a clinical study 
• 
The identity of the study, e.g., Study code 
• 
Subject screening number and/or subject number 
• 
That IC was obtained and the date 
• 
Diagnosis 
• 
Dates of all visits during the study period 
• 
Any information relating to AEs 
• 
All treatments and medications prescribed/administered (including dosage) 
• 
Date of study termination 
• 
Subject health service identification number 
 
The Investigator is responsible for ensuring the accuracy, completeness, legibility, and 
timeliness of the data recorded on the e-CRFs. Data reported on the e-CRF that are derived 
from source documents should be consistent with the source documents or the discrepancies 
should be explained. Signed sections of CRFs will be monitored on a regular basis. 
 
 Study documentation and storage of records 
The investigator or the site must store the essential documents (as defined in Standard 
E6 of the ICH GCP, section 8) as required by the applicable administrative requirements. The 
investigator or the site will have to take measures to prevent the accidental or early destruction 
of said documents. 
After the study is closed, the investigator or the designated individual from the site must store 
all study records in a secure, protected area of the site, except where, according to local 
legislation, they must be stored by another person or institution. The records must be stored 
to enable their easy, timely recovery as needed (for example, audit or inspection) and, 
whenever possible, to allow any subsequent analysis of the data together with the site's 
assessment, the support systems and the personnel. When so permitted by local standards or 
legislation or the institution's policy, some or all of these records can be stored in a format 
other than hard copy (for example, microfile, scanned or electronic support); however, 
precaution must be exercised before adopting these measures. The investigator must make 
certain that all reproductions are legible, a true and exact copy of the original and that they 
comply with the standards for accessibility and recovery, including that of re-generating a 
printed copy if necessary. Moreover, the investigator must make certain that there is an 
acceptable backup copy of these reproductions and an acceptable quality control process for 
making said reproductions. 
SOLTI will inform the investigator of the period for storing these records for the purposes 
of complying with all current administrative requirements. The minimum storage period must 


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comply with the strictest standard applicable to the study at this site, as dictated by the 
institutional requirements, laws or local standards or SOLTI's procedures and standards; 
otherwise, the default storage period shall be at least 25 years after the finalization of the study. 
The investigator must notify SOLTI of any change in the availability of the files, for 
example: archived in an off-site facility or transfer of the ownership of the records in the event 
the investigator leaves the site. 
 
 
Access to source data and documentation 
For the purpose of ensuring compliance with the Clinical Trial Protocol, GCP, and 
applicable regulatory requirements, the Investigator should permit auditing by or on the 
behalf of SOLTI and by regulatory authorities. 
The Investigator agrees to allow the auditors/inspectors to have direct access to his/her 
study records for review, being understood that these personnel is bound by professional 
secrecy, and, as such, will not disclose any personal identity or personal medical 
information. 
The Investigator will make every effort to help with the performance of the audits and 
inspections, giving access to all necessary facilities, data, and documents. As soon as the 
Investigator is notified of a planned inspection by the authorities, he/she will inform SOLTI 
and authorize SOLTI to participate in this inspection. The confidentiality of the data verified 
and the protection of the patients should be respected during these inspections. Any 
results and information arising from the inspections by the regulatory authorities will be 
immediately communicated by the Investigator to SOLTI. 
The Investigator must take appropriate measures required by the SOLTI to take 
corrective actions for all problems found during the audit or inspections. 
 
 
Study monitoring 
 Responsibilities of the investigators 
The Investigators and delegated investigator staff undertakes to perform the Clinical Trial 
in accordance with this Clinical Trial Protocol, ICH guidelines for GCP, and the applicable 
regulatory requirements. 
The Investigator is required to ensure compliance with all procedures required by the 
Clinical Trial Protocol and with all study procedures provided by SOLTI (including security 
rules). The Investigator agrees to provide reliable data and all information requested by 
the Clinical Trial Protocol (with the help of the e-CRF, Discrepancy Resolution Form 
[DRF], or other appropriate instrument) in an accurate and legible manner according to 
the instructions provided and to ensure direct access to source documents by SOLTI 
representatives. 
If any circuit includes transfer of data, particular attention should be paid to the 
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The Investigator may appoint other individuals, as he/she may deem appropriate, as 
Sub-investigators to assist in the conduct of the Clinical Trial in accordance with the 
Clinical Trial Protocol. All Sub-investigators must be appointed and listed in a timely 
manner. The Sub-investigators will be supervised by and work under the responsibility of 
the Investigator. The Investigator will provide them with a copy of the Clinical Trial 
Protocol and all necessary information. 
 
 Responsibilities of SOLTI and monitoring 
The Sponsor of this Clinical Trial, SOLTI, is responsible to Health Authorities for taking 
all reasonable steps to ensure the proper conduct of the Clinical Trial Protocol as regards ethics, 
Clinical Trial Protocol compliance, and integrity and validity of the data recorded on the e-
CRFs. Thus, the main duty of the Monitoring Team is to help the Investigator and SOLTI 
maintain a high level of ethical, scientific, technical, and regulatory quality in all aspects of 
the Clinical Trial. 
At regular intervals during the Clinical Trial the site will be contacted through monitoring 
visits, letters, or telephone calls by a representative of the Monitoring Team to review study 
progress, Investigator and patient compliance with Clinical Trial Protocol requirements, 
and any emergent problems. 
The Monitor will visit the study site on a regular basis to ensure that the study is 
conducted and documented in accordance with this protocol, ICH GCP guidelines, 
regulatory requirements, and any study specific documents such as e-CRF completion 
guidelines. 
Monitoring visits will be conducted to confirm that: 
• 
The investigational team is adhering to the study protocol. 
• 
IC has been obtained from all participants. 
• 
AEs have been reported as required. 
• 
Data are being accurately recorded on the e-CRFs. 
• 
IMP is being stored correctly and drug accountability is being performed on an on-
going basis. 
• 
Facilities are, and remain, acceptable throughout the study. 
• 
The Investigator and the site are receiving sufficient information and support 
throughout the study. 
Moreover, during monitoring visits, the data recorded on the e-CRFs, source documents, 
and other study-related records will be compared against each other in order to ensure 
accurate data that reflect the actual existence of the subject in the study, i.e., source data 
verification. 
Detailed monitoring visit information will be provided separately in the Monitoring Plan 
(MP). The MP will be approved before the first patient is included. 
 


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 Source document requirements 
According to the ICH guidelines for GCP, the Monitoring Team must check the e-CRF 
entries against the source documents, except for the pre-identified source data directly 
recorded on the e-CRF. The IC Form will include a statement by which the patient allows 
SOLTI´s duly authorized personnel, the Ethics Committee (IRB/IEC), and the regulatory 
authorities to have direct access to original medical records, which support the data on the e-
CRFs (e.g., patient's medical file, appointment books, original laboratory records, etc.). 
These personnel, bound by professional secrecy, must maintain the confidentiality of all 
personal identity or personal medical information (according to confidentiality and personal 
data protection rules). 
 
 Use and completion of case report forms and additional requests 
It is the responsibility of the Investigator to maintain adequate and accurate Case Report 
Forms, which for this trial will be of electronic nature. The electronic Case Report Form (e-
CRF) is designed by SOLTI to record, according to SOLTI instructions, all observations and 
other data pertinent to the Study. All e-CRFs should be completed in their entirety in a neat, 
legible manner to ensure accurate interpretation of data. Should a correction be made, the 
corrected information will be entered in the e-CRF overwriting the initial information. An 
audit trail allows identifying the modification. 
Data are available to SOLTI as soon as they are entered in the e-CRF system. The 
computerized handling of the data by SOLTI when available in the e-CRF may generate 
additional requests (DRF) to which the Investigator is obliged to respond by confirming or 
modifying the data questioned. The requests along with their responses will be managed 
through the e-CRF. 
 
 Use of computerized systems 
Procedures shall be employed and controls designed to ensure the confidentiality of 
electronic records. Such procedures and controls must include validation of systems to ensure 
accuracy and reliability, ability to generate accurate and complete copies of records, 
protection of records to enable retrieval, use of secure, computer-generated, time-stamped 
entries, use of  operational system  checks,  use of device checks to determine validity of 
source data input, determination that those who develop, maintain, or use such systems have 
adequate education and training, the establishment and adherence of written policies to 
deter record falsification, the use of appropriate controls over systems documentation 
including the distribution or use of documentation for system operation and maintenance, 
and revision and change control procedures, which document time-sequenced development 
and modifications of systems documentation. For data management activities, the e-CRF will 
be built using e-Clinical SQL Server. 
 


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Data management 
Data management and handling will be conducted according to the study specific Data 
Management Plan in accordance with ICH guidelines and SAIL standard operating procedures 
(SOPs), which will be prepared and approved before the first patient is included. 
Data entry, validation, and data queries will be handled by the SAIL The data will be 
subjected to validation according to SAIL SOPs in order to ensure accuracy in the collected 
e-CRF data. 
Before database closure, reconciliation will be performed between the SAEs entered in 
the safety database and the study database. After database closure, the database will be 
exported as SAS® data sets. 
Any deviations, i.e., discrepancies and additions from the process defined in the Data 
Management Plan, will be described in a study-specific Data Management Report. 
 
 
Confidentiality 
 Patient records 
The investigator shall ensure that the anonymity of the patients and protection of her 
identity from unauthorized individuals are maintained. In the eCRFs or other documents sent 
to the data management department, patients shall not be identified by name, but by an 
identification code. The investigator must keep a patient inclusion log with their codes and 
full names. The investigator will have to store the documents that are not going to be sent 
to the data processing center, for example, original patient ICFs, in a strictly confidential 
manner. 
 
 Study documentation and related data 
All information disclosed or provided by SOLTI (or any company/institution acting on 
its behalf), or produced during the Clinical Trial, including, but not limited to, the Clinical 
Trial Protocol, the e-CRFs, the Summary of Product Characteristics and the results 
obtained during the course of the Clinical Trial, is confidential prior to the publication of the 
Clinical Trial results. The Investigator and any person under his/her authority agree to 
undertake to keep confidential and not to disclose the information to any third party without 
the prior written approval of SOLTI. However, the submission of this Clinical Trial Protocol 
and other necessary documentation to the Ethics Committee (IRB/IEC) is expressly 
permitted, the IRB/IEC members having the same obligation of confidentiality. 
The Sub-investigators are bound by the same obligations as the Investigator. The 
Investigator must inform the Sub-investigators of the confidential nature of the Clinical 
Trial. The Investigator and the Sub-investigators should use the information solely for the 
purposes of the Clinical Trial, to the exclusion of any use for their own or for a third party's 
account. Furthermore, the Investigator and SOLTI agree to adhere to the principles of 


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personal data confidentiality in relation to the patients, the Investigator, and the collaborators 
involved in the study. 
 
 
Property rights 
All information supplied by SOLTI in connection with this study will remain the 
sole property of SOLTI and is to be considered confidential information. No confidential 
information will be disclosed to others without obtaining prior written consent from SOLTI 
and will not be used except in the performance of this Study. SOLTI will retain ownership 
of all data. 
All information, documents, and intellectual property (IP) provided by Merck are and 
remain the sole property of Merck. The Investigator shall not mention any information 
or the Product in any application for a patent or for any other intellectual property rights. 
In terms of the results generated by the study, SOLTI will maintain ownership of all data 
and will allow Merck to make scientific and commercial use of it, if it considers it 
pertinent. Any reports, documents, publications and inventions directly or indirectly arising 
from this study shall be the immediate and exclusive property of SOLTI. SOLTI, as 
Sponsor, may use and exploit all the study results at its full discretion. 
As the case may be, the Investigator and/or the Sub-investigators should provide all 
assistance required by SOLTI, at SOLTI's expense, for obtaining and defending any patent, 
including signature of legal documents. 
 
 
Clinical trial protocol amendments 
All appendices attached hereto and referred to herein are made part of this Clinical Trial 
Protocol. 
The Investigator should not implement any deviation from, or changes to the Clinical Trial 
Protocol 
without 
agreement 
by 
SOLTI 
and 
prior 
review 
and 
documented 
approval/favorable opinion from the IRB/IEC of an substantial amendment, except where 
necessary to eliminate immediate hazard(s) to patients enrolled in the trial, or when the 
change(s) involves only logistical or administrative aspects of the trial (i.e. non substantial 
amendments). Any change agreed upon will be recorded in writing, the written amendment 
will be signed by the Investigator and by SOLTI, and the signed amendment will be filed 
with this Clinical Trial Protocol. 
Any substantial amendment to the Clinical Trial Protocol requires written 
approval/favorable opinion by the Ethics Committee (IRB/IEC) prior to its implementation, 
unless there are overriding safety reasons. 
In some instances, an amendment may require a change to the IC Form. In cases of 
substantial amendments the Investigator must receive an IRB/IEC approval/favorable opinion 
concerning the revised IC form prior to implementation of the change and patient signature 
should be recollected if necessary. 
 


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Protocol  deviations 
Deviations to the study protocol will be documented in a Protocol Deviation Log. 
The classification of subjects into protocol violators will be made during a meeting before 
database lock. Listings will indicate the allocation of subjects by analysis set and the 
number of subjects per analysis set will be recorded in the Clinical Study Report. 
 
 Insurance 
SOLTI should provide insurance or should indemnify (legal and financial coverage) the 
Investigator/the institution against claims arising from the study, except for claims that arise 
from malpractice, negligence, or non-compliance with the protocol. 
 
 Study committees 
 Steering Committee 
A SC will be created comprising SOLTI investigators associated with the design or 
conduct of the study, as well as non-SOLTI investigators, provided the Principal Investigator 
of the study deems it appropriate. They will review the main safety and efficacy data 
after the first 15 patients are evaluable for Objective Response Rate (ORR) at the time of 
primary analysis. 
The SC shall ensure that the management of the study is carried out in line with the 
Protocol and GCP guidelines. The SC may propose and must review and approve any 
necessary amendment to the Protocol. It will also make decisions regarding the publications 
generated from the study data. Information on members, responsibilities and frequency of 
steering committee meetings are specified in the SC statutes. 
The SC may be consulted for advice when needed, either in face-to-face meetings or via 
teleconference. 
 
 Premature discontinuation of the study or close- out of a site 
Decided by SOLTI in the following cases: 
• 
If new information on the product leads to doubt as to the benefit/risk ratio. 
• 
If the Investigator has received from SOLTI all IP, means, and information necessary 
to perform the Clinical Trial and has not included any patient after a reasonable 
period of time mutually agreed upon. 
• 
In the event of breach by the Investigator of a fundamental obligation under this 
agreement, including, but not limited to, breach of the Clinical Trial Protocol, 
breach of the applicable laws and regulations, or breach of the ICH guidelines for 
GCP. 


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• 
If the total number of patients are included earlier than expected. 
 
In any case, SOLTI will notify the Investigator of its decision by written notice. 
Decided by the Investigator 
The Investigator must notify (30 days' prior notice) SOLTI of his/her decision and give 
the reason in writing. In all cases (decided by SOLTI or by the Investigator), the appropriate 
Ethics Committee(s) (IRB/IEC) and Health Authorities should be informed according to 
applicable regulatory requirements. 
 
 Report and publication 
All publications and presentations of the study results must comply with the approved 
scientific practice and academic standards and comply with SOLTI's publication policy. This 
policy is available to all investigators and groups participating in the study. Every 
investigator who wishes to publish or present the study data must obtain the permission of the 
study SC. SOLTI must review and approve any article prior to it being submitted to journals, 
congresses or conferences. The authorship of the publications will be decided by the SC, 
which will follow the standard guidelines of peer-reviewed journals and will observe SOLTI's 
publication policy. 
Key design elements of this protocol will be posted in a publicly accessible database 
such as clinicaltrials.gov prior to enrolment of the first patient. 
Once the study has been completed, SOLTI will prepare a Clinical Study Report (CSR) 
in line with the ICH guidelines on the structure and content of clinical study reports (ICH E3). 
All publications and presentations must be based on the CSR. 
SOLTI agrees to communicate the results of the study, regardless of if they are positive 
or negative, in public access media, and shall particularly respect the dissemination of the 
results in scientific publications, assuming an active role in the preparation of articles or 
summaries, in line with the SC, and participating in its submission to the corresponding authors. 
All study communications must mention Merck’s economic support and supply of the drugs. 
In order to guarantee the protection of the industrial property arising from the study, Merck 
will have the right to review all articles prior to submission. 
SOLTI will have the right to use the results in internal presentations and for the external 
promotion of its interests. 
If an Investigator wishes to publish results from this clinical study, written permission to 
publish must be obtained from SOLTI in advance. 
 
 
 


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13. APPENDICES 
Appendix 1: ECOG performance status 
Grade 
Description 
0 
Normal activity. Fully active, able to carry on all pre-disease 
performance without restriction. 
1 
Symptoms, but ambulatory. Restricted in physically strenuous 
activity, but ambulatory and able to carry out work of a light or 
sedentary nature (e.g., light housework, office work). 
2 
In bed <50% of the time. Ambulatory and capable of all self-care, but 
unable to carry out any work activities. Up and about more than 50% 
of waking hours. 
3 
In bed >50% of the time. Capable of only limited self-care, confined 
to bed or chair more than 50% of waking hours. 
4 
100% bedridden. Completely disabled. Cannot carry on any self-care. 
Totally confined to bed or chair. 
5 
Dead. 
* As published in Am. J. Clin. Oncol.:  Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., 
McFadden, E.T., Carbone, P.P.: Toxicity And Response Criteria Of The Eastern Cooperative Oncology 
Group. Am J Clin Oncol 5:649-655, 1982. The Eastern Cooperative Oncology Group, Robert Comis 
M.D., Group Chair. 
 
 
 
 
 
 
 
 
 
 


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Appendix 2: Common Terminology Criteria for Adverse Events V5.0 (CTCAE) 
The descriptions and grading scales found in the revised NCI Common Terminology Criteria 
for Adverse Events (CTCAE) version 5.0 will be utilized for adverse event reporting. 
(http://ctep.cancer.gov/reporting/ctc.html) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Appendix 3: Contraceptive guidance and pregnancy testing 
Woman of Childbearing Potential (WOCBP) 
A woman is considered fertile following menarche and until becoming post-menopausal unless 
permanently sterile (see below)  
Women in the following categories are not considered WOCBP: 
● 
Premenarchal 
● 
Premenopausal female with 1 of the following: 
○ Documented hysterectomy 
○ Documented bilateral salpingectomy 
○ Documented bilateral oophorectomy 
Note:  Documentation can come from the site personnel’s review of the participant’s 
medical records, medical examination, or medical history interview. 
● 
Postmenopausal female 
○ A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause.  
▪ 
A high follicle stimulating hormone (FSH) level in the postmenopausal range may 
be used to confirm a postmenopausal state in women not using hormonal 
contraception or hormonal replacement therapy (HRT). However, in the absence of 
12 months of amenorrhea, confirmation with two FSH measurements in the 
postmenopausal range is required.  
○ 
Females on HRT and whose menopausal status is in doubt will be required to use one 
of the non-hormonal highly effective contraception methods if they wish to continue their HRT 
during the study. Otherwise, they must discontinue HRT to allow confirmation of 
postmenopausal status before study enrollment. 
Contraception requirements 
Male participants: 
Male participants with female partners of childbearing potential are eligible to participate if 
they agree to one of the following during the protocol defined time frame in section 5.1:  
● Be abstinent from penile-vaginal intercourse as their usual and preferred lifestyle (abstinent 
on a long term and persistent basis) and agree to remain abstinent 
● Use a male condom plus partner use of a contraceptive method with a failure rate of <1% 
per year as described in Table 15 when having penile-vaginal intercourse with a woman 
of childbearing potential who is not currently pregnant. 
○ Note: Men with a pregnant or breastfeeding partner must agree to remain abstinent 
from penile-vaginal intercourse or use a male condom during each episode of penile 
penetration. 
 
 


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Female participants: 
Female participants of childbearing potential are eligible to participate if they agree to use a 
highly effective method of contraception that has a low user dependency consistently and 
correctly as described in Table 15 during the protocol-defined time frame in Section 5.1.   
Table 15. Highly Effective Contraceptive Methods That Have Low User Dependency 
 
Highly 
Effective 
Methods 
That 
Have 
Low 
User 
Dependency 
Failure rate of <1% per year when used consistently and correctly. 
● Progestogen- only contraceptive implant a, b 
● Intrauterine hormone-releasing system (IUS) b 
● Intrauterine device (IUD) 
● Bilateral tubal occlusion 
 
● Vasectomized partner  
A vasectomized partner is a highly effective contraception method provided that the partner is the 
sole male sexual partner of the WOCBP and the absence of sperm has been confirmed. If not, an 
additional highly effective method of contraception should be used.  
● Sexual abstinence  
Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study treatment. The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the study and the 
preferred and usual lifestyle of the participant.  
Notes: 
Use should be consistent with local regulations regarding the use of contraceptive methods for 
participants of clinical studies. 
 
a) If locally required, in accordance with Clinical Trial Facilitation Group (CTFG) guidelines, 
acceptable contraceptive implants are limited to those which inhibit ovulation. 
b) If hormonal contraception efficacy is potentially decreased due to interaction with study treatment, 
condoms must be used in addition to the hormonal contraception during the treatment period and for 
at least [X days, corresponding to time needed to eliminate study treatment plus 30 days for study 
treatments with genotoxic potential]  after the last dose of study treatment.   
 
Pregnancy testing 
WOCBP should only be included after a negative highly sensitive urine or serum pregnancy 
test and in accordance with local requirements. When applicable this test should be repeated a 
maximum of 24-hours before the first dose/vaccination. 
Following initiation of treatment additional pregnancy testing will be performed at monthly 
intervals during the treatment period.  


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Pregnancy testing will be performed whenever an expected menstrual cycle is missed or when 
pregnancy is otherwise suspected. 


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Appendix 4: Description of the iRECIST process for assessment of disease progression 
Assessment at screening and prior to RECIST 1.1 progression 
Until radiographic progression based on RECIST 1.1, there is no distinct iRECIST assessment. 
Assessment and decision at RECIST 1.1 progression 
In participants who show evidence of radiological PD by RECIST 1.1 the Investigator will 
decide whether to continue a participant on study treatment until repeat imaging is obtained 
(using iRECIST for participant management (see Table 10 and Fig. 6).  This decision by the 
Investigator should be based on the participant’s overall clinical condition. 
Clinical stability is defined as the following:  
• Absence of symptoms and signs indicating clinically significant progression of disease 
• No decline in ECOG performance status  
• No requirements for intensified management, including increased analgesia, radiation, 
or other palliative care 
Any participant deemed clinically unstable should be discontinued from study treatment at 
site-assessed first radiologic evidence of PD, and is not required to have repeat tumor imaging 
for confirmation of PD by iRECIST. 
If the Investigator decides to continue treatment, the participant may continue to receive study 
treatment and the tumor assessment should be repeated 4 to 8 weeks later to confirm PD by 
iRECIST, per Investigator assessment.  I 
Tumor flare may manifest as any factor causing radiographic progression per RECIST 1.1, 
including: 
• Increase in the sum of diameters of target lesion(s) identified at baseline to ≥ 20% and 
≥ 5 mm from nadir 
o Please note: the iRECIST publication uses the terminology “sum of 
measurements”, but “sum of diameters” will be used in this protocol, consistent 
with the original RECIST 1.1 terminology. 
• Unequivocal progression of non-target lesion(s) identified at baseline 
• Development of new lesion(s) 
iRECIST defines new response categories, including iUPD (unconfirmed progressive disease) 
and iCPD (confirmed progressive disease).  For purposes of iRECIST assessment, the first visit 
showing progression according to RECIST 1.1 will be assigned a visit (overall) response of 
iUPD, regardless of which factors caused the progression. 


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At this visit, target and non-target lesions identified at baseline by RECIST 1.1 will be assessed 
as usual. 
New lesions will be classified as measurable or non-measurable, using the same size thresholds 
and rules as for baseline lesion assessment in RECIST 1.1.  From measurable new lesions, up 
to 5 lesions total (up to 2 per organ), may be selected as New Lesions – Target.  The sum of 
diameters of these lesions will be calculated, and kept distinct from the sum of diameters for 
target lesions at baseline.  All other new lesions will be followed qualitatively as New Lesions 
– Non-target. 
Assessment at the confirmatory imaging 
On the confirmatory imaging, the participant will be classified as progression confirmed (with 
an overall response of iCPD), or as showing persistent unconfirmed progression (with an 
overall response of iUPD), or as showing disease stability or response (iSD/iPR/iCR). 
Confirmation of Progression 
Progression is considered confirmed, and the overall response will be iCPD, if ANY of the 
following occurs: 
• Any of the factors that were the basis for the initial iUPD show worsening 
o For target lesions, worsening is a further increase in the sum of diameters of 
≥ 5 mm, compared to any prior iUPD time point 
o For non-target lesions, worsening is any significant growth in lesions overall, 
compared to a prior iUPD time point; this does not have to meet the “unequivocal” 
standard of RECIST 1.1 
o For new lesions, worsening is any of these: 
▪ An increase in the new lesion sum of diameters by ≥ 5 mm from a prior iUPD 
time point  
▪ Visible growth of new non-target lesions  
▪ The appearance of additional new lesions 
• Any new factor appears that would have triggered PD by RECIST 1.1 
Persistent iUPD 
Progression is considered not confirmed, and the overall response remains iUPD, if: 
• None of the progression-confirming factors identified above occurs AND 
• The target lesion sum of diameters (initial target lesions) remains above the initial PD 
threshold (by RECIST 1.1) 


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Additional imaging for confirmation should be scheduled 4 to 8 weeks from the scan on which 
iUPD is seen.  This may correspond to the next visit in the original visit schedule.  The 
assessment of the subsequent confirmation scan proceeds in an identical manner, with possible 
outcomes of iCPD, iUPD, and iSD/iPR/iCR. 
Resolution of iUPD 
Progression is considered not confirmed, and the overall response becomes iSD/iPR/iCR, if: 
• None of the progression-confirming factors identified above occurs, AND 
• The target lesion sum of diameters (initial target lesions) is not above the initial PD 
threshold.  
The response is classified as iSD or iPR (depending on the sum of diameters of the target 
lesions), or iCR if all lesions resolve. 
In this case, the initial iUPD is considered to be pseudo-progression, and the level of suspicion 
for progression is “reset”.  This means that the next visit that shows radiographic progression, 
whenever it occurs, is again classified as iUPD by iRECIST, and the confirmation process is 
repeated before a response of iCPD can be assigned. 
Management following the confirmatory imaging 
If repeat imaging does not confirm PD per iRECIST, as assessed by the Investigator, and the 
participant continues to be clinically stable, study treatment may continue and follow the 
regular imaging schedule.  If PD is confirmed, participants will be discontinued from study 
treatment. 
NOTE: If a participant has confirmed radiographic progression (iCPD) as defined above, but 
the participant is achieving a clinically meaningful benefit, an exception to continue study 
treatment may be considered.  In this case, if study treatment is continued, tumor imaging 
should continue to be performed following the intervals as outlined in Section 6. 
Detection of progression at visits after pseudo-progression resolves 
After resolution of pseudo-progression (ie, achievement of iSD/iPR/iCR), iUPD is indicated 
by any of the following events: 
• Target lesions 
o Sum of diameters reaches the PD threshold (≥ 20% and ≥ 5 mm increase from 
nadir) either for the first time, or after resolution of previous pseudo-progression.  
The nadir is always the smallest sum of diameters seen during the entire trial, either 
before or after an instance of pseudo-progression. 
• Non-target lesions 


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o If non-target lesions have never shown unequivocal progression, their doing so for 
the first time results in iUPD. 
o If non-target lesions had shown previous unequivocal progression, and this 
progression has not resolved, iUPD results from any significant further growth of 
non-target lesions, taken as a whole. 
• New lesions 
o New lesions appear for the first time 
o Additional new lesions appear 
o Previously identified new target lesions show an increase of ≥ 5 mm in the new 
lesion sum of diameters, from the nadir value of that sum 
o Previously identified non-target lesions show any significant growth 
If any of the events above occur, the overall response for that visit is iUPD, and the iUPD 
evaluation process (see Assessment at the Confirmatory Imaging above) is repeated.  
Progression must be confirmed before iCPD can occur. 
The decision process is identical to the iUPD confirmation process for the initial PD, except in 
one respect. If new lesions occurred at a prior instance of iUPD, and at the confirmatory scan 
the burden of new lesions has increased from its smallest value (for new target lesions, their 
sum of diameters is ≥5 mm increased from its nadir), then iUPD cannot resolve to iSD or iPR. 
It will remain iUPD until either a decrease in the new lesion burden allows resolution to iSD 
or iPR, or until a confirmatory factor causes iCPD. 
Additional details about iRECIST are provided in the iRECIST publication120 . 


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Appendix 5: Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 criteria 
for evaluating response in solid tumors  
RECIST v.1.1122 will be used in this study for assessment of tumor response. While either CT 
or MRI may be utilized, as per RECIST v.1.1, CT is the preferred imaging technique in this 
study.  
 
Patient eligibility 
Only patients with measurable disease at baseline should be included in this study. Changes in 
only the largest diameter (unidimensional measurement) of the tumor lesions are used in the 
RECIST v 1.1.  
Note: Lesions are either measurable or nonmeasurable using the criteria provided below. The 
term “evaluable” in reference to measurability provides neither additional meaning nor 
accuracy and will not be used. 
Measurable disease 
Tumor lesions: Must be accurately measured in at least one dimension (longest diameter in the 
plane of measurement is to be recorded) with a minimum size of: 
• 10 mm by CT scan (CT scan slice thickness no greater than 5 mm) 
• 10 mm caliper measurement by clinical exam (lesions which cannot be accurately 
measured with calipers should be recorded as non-measurable). 
• 20 mm by chest X-ray. 
Nonmeasurable disease 
All other lesions, including small lesions (longest diameter <10 mm or pathological lymph 
nodes with ≥10 to <15 mm short axis) as well as truly non-measurable lesions. Lesions 
considered truly non-measurable include: leptomeningeal disease, ascites, pleural or 
pericardial effusion, inflammatory breast disease, lymphangitic involvement of skin or lung, 
abdominal masses/abdominal organomegaly identified by physical exam that is not measurable 
by reproducible imaging techniques. 
Target lesions 
When more than one measurable lesion is present at baseline all lesions up to a maximum of 
five lesions total (and a maximum of two lesions per organ) representative of all involved 
organs should be identified as target lesions and will be recorded and measured at baseline 
(this means in instances where patients have only one or two organ sites involved a maximum 
of two and four lesions respectively will be recorded). Target lesions should be selected on the 
basis of their size (lesions with the longest diameter), be representative of all involved organs, 
but in addition should be those that lend themselves to reproducible repeated measurements. It 
may be the case that, on occasion, the largest lesion does not lend itself to reproducible 
measurement in which circumstance the next largest lesion which can be measured 
reproducibly should be selected. Lymph nodes merit special mention since they are normal 
anatomical structures which may be visible by imaging even if not involved by tumor. 


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Pathological nodes which are defined as measurable and may be identified as target lesions 
must meet the criterion of a short axis of ≥15 mm by CT scan. Only the short axis of these 
nodes will contribute to the baseline sum. The short axis of the node is the diameter normally 
used by radiologists to judge if a node is involved by solid tumor. Nodal size is normally 
reported as two dimensions in the plane in which the image is obtained (for CT scan this is 
almost always the axial plane; for MRI the plane of acquisition may be axial, sagittal or 
coronal). The smaller of these measures is the short axis. For example, an abdominal node 
which is reported as being 20 mm x 30 mm has a short axis of 20 mm and qualifies as a 
malignant, measurable node. In this example, 20 mm should be recorded as the node 
measurement. All other pathological nodes (those with short axis ≥10 mm but <15 mm) should 
be considered non-target lesions. Nodes that have a short axis <10 mm are considered non-
pathological and should not be recorded or followed. A sum of the diameters (longest for non-
nodal lesions, short axis for nodal lesions) for all target lesions will be calculated and reported 
as the baseline sum diameters. If lymph nodes are to be included in the sum, then as noted 
above, only the short axis is added into the sum. The baseline sum diameters will be used as 
reference to further characterize any objective tumor regression in the measurable dimension 
of the disease. 
Non-target lesions 
All other lesions (or sites of disease) including pathological lymph nodes should be identified 
as non-target lesions and should also be recorded at baseline. Measurements are not required 
and these lesions should be followed as ‘present’, ‘absent’, or in rare cases ‘unequivocal 
progression’ (more details to follow). In addition, it is possible to record multiple nontarget 
lesions involving the same organ as a single item on the case record form (eg, ‘multiple 
enlarged pelvic lymph nodes’ or ‘multiple liver metastases’). 
Guidelines for evaluation of measurable disease 
All measurements should be recorded in metric notation, using calipers if clinically assessed. 
All baseline evaluations should be performed as close as possible to the treatment start and 
never more than 28 days before the beginning of the treatment. 
Method of assessment 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging based evaluation 
should always be done rather than clinical examination unless the lesion(s) being followed 
cannot be imaged but are assessable by clinical exam. 
Clinical lesions: Clinical lesions will only be considered measurable when they are superficial 
and ≥10 mm diameter as assessed using calipers (eg, skin nodules). For the case of skin lesions, 
documentation by color photography including a ruler to estimate the size of the lesion is 
suggested. As noted above, when lesions can be evaluated by both clinical exam and imaging, 
imaging evaluation should be undertaken since it is more objective and may also be reviewed 
at the end of the study. 
Chest X-ray: Chest CT is preferred over chest X-ray, particularly when progression is an 
important endpoint, since CT is more sensitive than X-ray, particularly in identifying new 


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lesions. However, lesions on chest X-ray may be considered measurable if they are clearly 
defined and surrounded by aerated lung.  
CT, MRI: CT is the best currently available and reproducible method to measure lesions 
selected for response assessment. This guideline has defined measurability of lesions on CT 
scan based on the assumption that CT slice thickness is 5 mm or less. When CT scans have 
slice thickness greater than 5 mm, the minimum size for a measurable lesion should be twice 
the slice thickness. MRI is also acceptable in certain situations (eg, for body scans).  
Ultrasound: Ultrasound is not useful in assessment of lesion size and should not be used as a 
method of measurement. Ultrasound examinations cannot be reproduced in their entirety for 
independent review at a later date and, because they are operator dependent, it cannot be 
guaranteed that the same technique and measurements will be taken from one assessment to 
the next. If new lesions are identified by ultrasound in the course of the study, confirmation by 
CT or MRI is advised. If there is concern about radiation exposure at CT, MRI may be used 
instead of CT in selected instances. 
Endoscopy, laparoscopy: The utilization of these techniques for objective tumor evaluation is 
not advised. However, they can be useful to confirm complete pathological response when 
biopsies are obtained or to determine relapse in studies where recurrence following CR or 
surgical resection is an endpoint. 
Tumor markers: Tumor markers alone cannot be used to assess objective tumor response. If 
markers are initially above the upper normal limit, however, they must normalize for a patient 
to be considered in CR. Because tumor markers are disease specific, instructions for their 
measurement should be incorporated into protocols on a disease specific basis. Specific 
guidelines for both CA-125 response (in recurrent ovarian cancer) and PSA response (in 
recurrent prostate cancer), have been published. In addition, the Gynecologic Cancer 
Intergroup has developed CA125 progression criteria which are to be integrated with objective 
tumor assessment for use in first-line studies in ovarian cancer. 
Cytology, histology: These techniques can be used to differentiate between PR and CR in rare 
cases if required by protocol (for example, residual lesions in tumor types such as germ cell 
tumors, where known residual benign tumors can remain). When effusions are known to be a 
potential adverse effect of treatment (eg, with certain taxane compounds or angiogenesis 
inhibitors), the cytological confirmation of the neoplastic origin of any effusion that appears 
or worsens during treatment can be considered if the measurable tumor has met criteria for 
response or SD in order to differentiate between response (or SD) and PD. 
Evaluation of target lesions 
This section provides the definitions of the criteria used to determine objective tumor response 
for target lesions. 
Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to <10 mm. 
Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking 
as reference the baseline sum diameters. 


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Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions, 
taking as reference the smallest sum on study (this includes the baseline sum if that is the 
smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate 
an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also 
considered progression). 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum diameters while on study. 
Evaluation of non-target lesions 
This section provides the definitions of the criteria used to determine the tumor response for 
the group of non-target lesions. 
While some non-target lesions may actually be measurable, they need not be measured and 
instead should be assessed only qualitatively at the time points specified in the protocol. 
Complete Response (CR): Disappearance of all non-target lesions and normalization of tumor 
marker level. All lymph nodes must be non-pathological in size (<10 mm short axis). 
Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or maintenance of tumor 
marker level above the normal limits. 
Progressive Disease (PD): Unequivocal progression of existing non-target lesions. (Note: the 
appearance of one or more new lesions is also considered progression). 
Target Lesions 
Non-target Lesions 
New Lesions 
Overall Response 
CR 
CR 
No 
CR 
CR 
Non-CR/non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not all evaluated 
No 
PR 
SD 
Non-PD or not all evaluated 
No 
SD 
Not all evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
Abbreviations: CR: complete response; NE: not evaluated; PD: progressive disease; 
PR: partial response; SD: stable disease. 
Note: Patients with a global deterioration of health status requiring discontinuation of 
investigational product without objective evidence of disease progression at that time should 
be classified as having “symptomatic deterioration.” Every effort should be made to document 
the objective progression, even after discontinuation of investigational product. In some 
circumstances, it may be difficult to distinguish residual disease from normal tissue. When the 
evaluation of CR depends on this determination, it is recommended that the residual lesion be 
investigated (fine needle aspirate/biopsy) before confirming the CR status. 


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Confirmatory measurement/duration of response 
Confirmation 
In non-randomized studies where response is the primary endpoint, confirmation of PR and 
CR is required to ensure responses identified are not the result of measurement error. This will 
also permit appropriate interpretation of results in the context of historical data where response 
has traditionally required confirmation in such studies. However, in all other circumstances, 
ie, in randomized studies (phase 2 or 3) or studies where SD or progression are the primary 
endpoints, confirmation of response is not required since it will not add value to the 
interpretation of study results. However, elimination of the requirement for response 
confirmation may increase the importance of central review to protect against bias, in particular 
in studies which are not blinded. In the case of SD, measurements must have met the SD criteria 
at least once after study entry at a minimum interval (in general not less than 6–8 weeks) that 
is defined in the study protocol. 
Duration of overall response 
The duration of overall response is measured from the time measurement criteria are first met 
for CR/PR (whichever is first recorded) until the first date that recurrent or PD is objectively 
documented (taking as reference for PD the smallest measurements recorded on study). The 
duration of overall CR is measured from the time measurement criteria are first met for CR 
until the first date that recurrent disease is objectively documented. 
Duration of stable disease 
Stable disease is measured from the start of the treatment (in randomized studies, from date of 
randomization) until the criteria for progression are met, taking as reference the smallest sum 
on study (if the baseline sum is the smallest, this is the reference for calculation of PD). The 
clinical relevance of the duration of SD varies in different studies and diseases. If the 
proportion of patients achieving SD for a minimum period of time is an endpoint of importance 
in a particular study, the protocol should specify the minimal time interval required between 
two measurements for determination of SD. Note: The DoR and SD as well as the PFS are 
influenced by the frequency of follow-up after baseline evaluation. It is not in the scope of this 
guideline to define a standard follow-up frequency. The frequency should take into account 
many parameters including disease types and stages, treatment periodicity and standard 
practice. However, these limitations of the precision of the measured endpoint should be taken 
into account if comparisons between studies are to be made. 
 

SAP_001.pdf: 
STATISTICAL ANALYSIS PLAN (SAP) 
CONFIDENTIAL INFORMATION 
 
Statistical Analysis Plan (SAP) 
 
Version 1 
7th September 2021 
 
EudraCT Number 
2018-003367-58 
Protocol Number 
SOLTI-1716 
Protocol Version Date 
10-May-2021. Version number 2.0. 
Title 
TATEN trial 
Targeting non-Luminal disease by PAM50 with 
pembrolizumab + paclitaxel in Hormone 
Receptor-positive/HER2-negative 
advanced/metastatic breast cancer, who have 
progressed on or after CDK 4/6 inhibitor 
treatment. 
Sponsor 
 
 
 
 
 
 
 
 
PPD
PPD


Study Code: 2018-003367-58 (TATEN) 
Statistical Analysis Plan 
August 13, 2021 
2 
Final v1 
 
 
 
Signature Page 
EudraCT Number: 
2018-003367-58 
Protocol Number: 
SOLTI-1716 
Written by: 
Signature: 
 
Date: 
 
SAIL S.L. 
Barcelona, Spain 
 
 
 
Sponsor Signature: 
The undersigned hereby declare that they have examined the Statistical Analysis Plan document 
and agree to its form and content. 
Represented by: 
 
Signature:
 
 
Date: 
Date: 
 
 
 
 
Name:
Title:
Name: 
 
Title:
2021/09/07 
2021/09/09 
PPD
PPD
PPD
PPD
PPD
PPD
PPD


Study Code: 2018-003367-58 (TATEN) 
Statistical Analysis Plan 
August 13, 2021 
3 
Final v1 
 
 
 
SAP Revision History: 
 
Version 
Number 
Date 
Changes 
1.0 
New 


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LIST OF ABBREVIATIONS 
 
Abbreviation Definition 
AE Adverse event 
AESI Adverse Event of Special Interest 
ATC Anatomical Therapeutic Chemical 
CBR Clinical Benefit Rate 
CI Confidence Interval 
CR Complete Response 
CTCAE Common Terminology Criteria for Adverse Events 
ER Estrogen Receptor 
HER2 Human Epidermal Growth Factor Receptor 2 
ICH International Conference on Harmonization 
IHC Immunohistochemistry 
IQR Interquartile Range 
ISH In Situ Hybridization 
ITT Intention-To-Treat 
IV Intravenous 
BC Breast Cancer 
MEDDRA Medical Dictionary for Regulatory Activities 
MG Milligrams 
NYHA New York Heart Association 
ORR Objective Response Rate 
PD Progressive Disease 
PGR Progesterone Receptor 
PP Protocol Population 
PR Partial Response 
PT Preferred Term 
RDI Relative Dose Intensity 
SAE Serious Adverse Event 
SAP Statistical Analysis Plan 
SD Stable Disease 
SD Standard Deviation 
SI International System of Units 
SOC System Organ Class 
TEAE Treatment Emergent Adverse Event 
TLF Tables, Listings, Figures 


Study Code: 2018-003367-58 (TATEN) 
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TABLE OF CONTENTS 
1 
INTRODUCTION ____________________________________________________ 7 
1.1 
General __________________________________________________________________________ 7 
1.2 
Type of Study _____________________________________________________________________ 7 
1.3 
Study Population __________________________________________________________________ 7 
1.4 
Study Design _____________________________________________________________________ 7 
1.5 
Study Schedule ___________________________________________________________________ 8 
1.6 
Trial Diagram _____________________________________________________________________ 9 
1.7 
Sample Size _____________________________________________________________________ 10 
2 
STUDY OBJECTIVES ________________________________________________ 10 
2.1 
Primary objective _________________________________________________________________ 10 
2.2 
Secondary Objectives ______________________________________________________________ 10 
3 
DEFINITION OF ENDPOINTS _________________________________________ 10 
3.1 
Primary Endpoint _________________________________________________________________ 10 
3.2 
Secondary Endpoints ______________________________________________________________ 10 
3.3 
Safety Endpoints _________________________________________________________________ 11 
3.4 
Exploratory Endpoints _____________________________________________________________ 11 
4 
ANALYSIS POPULATIONS ___________________________________________ 11 
5 
STATISTICAL METHODS _____________________________________________ 12 
5.1 
General Methodology ______________________________________________________________ 12 
5.2 
Subject Disposition ________________________________________________________________ 12 
5.3 
Baseline Characteristics ____________________________________________________________ 13 
5.4 
Efficacy _________________________________________________________________________ 14 
5.4.1 
Response Efficacy Definitions _____________________________________________________ 14 
5.4.2 
Primary Efficacy Analysis _________________________________________________________ 15 
5.4.3 
Secondary Efficacy Analysis ______________________________________________________ 15 
5.4.4 
Handling of Missing Data ________________________________________________________ 16 
5.4.5 
Exploratory Analysis ____________________________________________________________ 16 
5.5 
Safety __________________________________________________________________________ 17 
5.5.1 
Duration and Extent of Exposure of Study Treatment __________________________________ 17 
5.5.2 
Concomitant Medications ________________________________________________________ 18 
5.5.3 
Adverse Events ________________________________________________________________ 18 
5.5.4 
Clinical Laboratory Parameters ____________________________________________________ 20 
5.5.5 
Vital Signs ____________________________________________________________________ 20 
5.5.6 
Physical Examination ____________________________________________________________ 20 
5.6 
Interim Analysis __________________________________________________________________ 20 
5.7 
Deviations from SAP ______________________________________________________________ 20 
6 
APPENDICES _____________________________________________________ 21 
6.1 
SAS Codes for Primary Endpoint _____________________________________________________ 21 
6.2 
List of Tables, Listings, Figures ______________________________________________________ 21 
 


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Study Code: 2018-003367-58 (TATEN) 
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1 
INTRODUCTION 
1.1 General 
The purpose of this statistical analysis plan (SAP) is to provide a protocol specific description of the statistical analysis 
that will be performed to produce an integrated clinical/statistical report. 
This SAP is based upon the following study documents: 
- 
Protocol version: 
10-May-2021, Version 2.0 
- 
electronic Case Report Form (eCRF) release version: 01-July-2020 
 
1.2 Type of Study 
This is an open-label, single arm, multicenter phase II study. 
Pembrolizumab in combination with paclitaxel. Route of administration I.V. 
1.3 Study Population 
Pre- and post-menopausal women with locally advanced or metastatic non-luminal HR+/HER2-negative endocrine 
resistant breast cancer who had recurrence or progression while receiving previous therapy with a CDK inhibitor in the 
adjuvant setting or to treat advanced disease. 
1.4 Study Design 
The study will utilize the optimal Simon’s two-stage design with one interim and a final analysis. The interim analysis 
will be conducted when 15 patients are evaluable for ORR as determined locally by the investigator using RECIST v.1.1. 
If 5 or fewer responses are observed in up to 15 patients of evaluable population (EP), the trial will be terminated in 
favor of the null for futility. Otherwise, up to a further 31 patients may be evaluated, for a maximum total of 46 
evaluable patients. If a total of 19 or more responses are seen at the end of the second stage, then the null will have 
been rejected in favor of the alternative; and further investigation of the combination is warranted. 
Recruitment will not be halted during the interim analysis period. Therefore, no interruption in the accrual will be done 
during the interim analysis to maintain the dynamic of accrual in the trial. 
After confirmation of all eligibility criteria, eligible patients will receive pembrolizumab 200 mg every 3 weeks (on D1 
of each 21-day cycle, beginning in Cycle 1) in combination with paclitaxel 80 mg/m2 administered at days 1, 8, 15 of 
each 21-day cycle beginning at cycle 2. Treatment will continue until disease progression, the development of 
unacceptable toxicity, withdrawal of consent, 24 months from the date of the first dose of pembrolizumab or end of 
study, whichever occurs first. 
All patients will be followed for survival from screening until the last patient recruited has been followed for 12 months, 
has progressed, or has died, whichever occurs first. The patient will be followed for survival approximately every 3 
months (± 21 days) until death, withdrawal of consent, loss to follow-up, or study termination by SOLTI. In addition, 
information regarding use of subsequent anti-cancer agents for metastatic HR+/HER2- during the survival follow-up 
period will be collected. 


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1.5 Study Schedule 
 
a) Written informed consent is required before performing any study-specific tests or procedures. Signing of the Informed Consent Form cannot occur outside the 
28-day screening period. All screening evaluations must be completed and reviewed to confirm that patients meet all eligibility criteria before randomization. Results 
of standard-of-care tests or examinations performed prior to obtaining informed consent and within 28 days prior to study entry (except where otherwise specified) 
may be used for screening assessments rather than repeating such tests. The investigator will maintain a screening log to record details of all patients screened 
and to confirm eligibility or record reasons for screening failure, as applicable. 
b) Assessment window of + 3 days for Cycles ≥2, Day 1. If scheduled dosing is precluded because of a holiday, then dosing may be postponed to the soonest 
following date, with subsequent dosing continuing the specified schedule. If treatment was postponed for fewer than 2 days, the patient can resume the original 
schedule. If scheduled study assessments cannot be obtained because of a holiday, these assessments should then be obtained at the soonest following date, 
provided that the soonest following date is not within 2 days of other regularly scheduled study assessments. Assessments scheduled on the day of study treatment 
administration (Day 1) of each cycle should be performed prior to study treatment infusion unless otherwise noted. 
c) Patients will be asked to return to the clinic not more than 30 days after the decision to discontinue treatment for a treatment discontinuation visit. The visit at 
which the decision is made to discontinue treatment (e.g., disease progression is determined or confirmed) may be used as the treatment discontinuation visit. If a 
participant initiates a new anti-cancer therapy within 30 days after the last dose of trial treatment, the 30-day Safety Follow-up visit must occur before the first dose 
of the new therapy. 
d) Cancer history includes stage, date of diagnosis, and prior anti-tumor treatment. Demographic information includes age and self-reported race/ethnicity. 
Reproductive status and smoking history should also be captured. 
e) Concomitant medications include any prescription medications or over-the-counter medications. At screening, any medications the patient has used within the 


Study Code: 2018-003367-58 (TATEN) 
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28 days prior to Cycle 1, Day 1. At subsequent visits, changes to current medications or medications used since the last documentation of medications will be 
recorded. Concomitant medications administered after 30 days after the last dose of trial treatment should be recorded. 
f) Weekly paclitaxel beginning in Cycle 2. 
g) A complete physical examination should include an evaluation of the head, eyes, ears, nose, and throat, and the cardiovascular, dermatological, musculoskeletal, 
respiratory, gastrointestinal, genitourinary, and neurological systems as well as weight (in kilograms) and height (in centimeters; height is measured at the screening 
visit only). Symptom-directed physical exam after baseline assessment. 
h) Directed physical examination should include symptom-directed examination or as clinically indicated. Limited physical examination will be performed monthly 
every treatment cycle, with additional examinations as clinically indicated at baseline. 
i) Vital signs include heart rate, blood pressure, and temperature. 
j) Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, as assessed within 10 days prior to the start of study treatment 
k) Serum/urine pregnancy test within 72 hours before Cycle 1, Day 1. Afterward, perform every cycle. A positive urine test must be confirmed with a serum test 
l) Hematology consists of CBC, including RBC count, hemoglobin, hematocrit, WBC count with differential (neutrophils, eosinophils, lymphocytes, monocytes, 
basophils, and other cells), and platelet count. A manual differential can be done if clinically indicated. Local laboratory assessments from each cycle must be 
reviewed prior to study treatment administration for each cycle. Laboratory tests for screening should be performed within 10 days prior to the first dose of 
treatment. After Cycle 1, pre-dose laboratory procedures can be conducted up to 72 hours prior to dosing. 
m) Serum chemistry includes creatinine, sodium, potassium, magnesium, calcium, glucose, total bilirubin, ALT, AST, alkaline phosphatase, Lactate dehydrogenase 
(LDH). Local laboratory assessments from each cycle must be reviewed prior to study treatment administration for each cycle. Screening results may be valid for 
Cycle 1, Day 1 if performed within 10 days prior to Week 1, Day 1. 
n) Urinalysis (specific gravity, pH, glucose, protein, ketones, and blood). Screening results may be valid for Week 1, Day 1 if performed within 10 days prior to Week 
1, Day 1. 
o) Tumor assessments performed as standard of care prior to obtaining informed consent and within 28 days prior to Cycle 1, Day 1 may be used rather than 
repeating tests. All measurable and evaluable lesions should be assessed and documented at the screening visit. Radiologic imaging performed during the screening 
period should consist of 1) CT and/or MRI of the chest/abdomen/pelvis 2) Bone scan or PET scan should be performed to evaluate for bone metastases and 3) any 
other imaging studies (CT neck, plain films, bone scan etc.) as clinically indicated by the treating physician. The same radiographic procedures and technique must 
be used throughout the study for each patient (e.g., if the patient had CT chest/abdomen/pelvis performed during screening, then she should subsequently undergo 
CT performed using the same radiologic protocol throughout the remainder of the study). Results must be reviewed by the investigator before dosing at the next 
cycle. Tumor assessments will be performed at baseline, every 9 weeks (63 days ± 5 days). All known sites of disease documented at screening should be re- 
assessed at each subsequent tumor evaluation. Tumor assessments performed after the screening period should consist of 1) CT and/or MRI of the 
chest/abdomen/pelvis, 2) bone scan or PET scan if there were osseous sites of disease identified or if these studies are felt to be clinically indicated by the treating 
physician, and 3) any other imaging studies felt to be clinically indicated by the treating physician. Tumor response will be evaluated using both RECIST v1.1 and 
immune-modified RECIST criteria. In the absence of disease progression, tumor assessments should continue regardless of whether patients discontinue study 
treatment, unless they withdraw consent or the study is terminated by SOLTI, whichever occurs first. 
p) If previous imaging was obtained within 4 weeks prior to the date of discontinuation, then imaging at treatment discontinuation is not mandatory. In participants 
who discontinue study treatment due to documented disease progression and the Investigator elects not to implement iRECIST, this is the final required tumor 
imaging. 
q) In subject who discontinue trial treatment without documented disease progression, every effort should be made to continue monitoring their disease status by 
radiologic imaging every 9 weeks (+ 5 days) until (1) the star of new anti-cancer treatment, (2) disease progression, (3) death, or (4) the end of the study, 
whichever occurs the first. 
r) Tumor tissue should be of good quality based on total and viable tumor. An FFPE block should be provided. Fine-needle aspiration, brushing, cell pellets from 
pleural effusion, and lavage samples are not acceptable. Retrieval of archival tumor sample can occur outside the 28-day screening period (centrally perform PAM50 
test). Tumor sample from metastatic disease period is mandatory. 
s) Plasma from 30 ml of blood will be collected and banked at C1D1 (samples may be extracted within the ten previous days to week 1 day 1), C2D1 and at 
progression. 
t) Survival follow-up information will be collected via telephone calls, patient medical records, and/or clinic visits approximately every 3 months (± 21 days) until 
death, loss to follow-up, withdrawal of consent or until study termination by SOLTI. All patients will be followed for survival and new anti-cancer therapy (including 
targeted therapy and immunotherapy) information unless the patient requests to be withdrawn from follow-up; this request must be documented in the source 
documents and signed by the investigator. If the patient withdraws from study, the study staff may use a public information source (e.g., county records) to obtain 
information about survival status only. 
 
1.6 Trial Diagram 
Figure 1. Trial diagram 
 


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1.7 Sample Size 
This study will utilize the optimal two-stage Simon’s design (1989). The null hypothesis that the true response rate is 
not more than 30% (p  0.3) versus the alternative hypothesis that the true response rate is at least 50% (p ≥ 0.50) 
will be tested. The first stage will be conducted with 15 evaluable patients. If there are 5 or fewer responses in these 
15 patients, the study will be stopped. Otherwise, 31 additional patients will be accrued for a total of 46. The null 
hypothesis will be rejected if 19 or more responses are observed in 46 patients of EP. This design yields a one-sided 
type I error rate of 0.05 (alpha) and power of 80%. 
Up to 46 evaluable patients of EP may therefore be enrolled to this clinical trial. It is expected that approximately 403 
patients will be screened to identify 55 patients who meet all the inclusion and exclusion criteria and who are evaluable 
for response. Assuming a dropout rate of 10%, the study will aim to recruit 55 patients in total to have at least 46 
evaluable patients of EP to attain 80% power at nominal level of one-sided alpha of 0.05. 
2 
STUDY OBJECTIVES 
2.1 Primary objective 
The primary objective of the study is to assess the proportion of patients with best overall response of CR or PR, as 
per local investigator’s assessment and according to RECIST v1.1. 
2.2 Secondary Objectives 
The secondary objectives in this study are to evaluate the progression free survival (PFS), clinical benefit rate (CBR) 
and duration of response (DOR), Time to response (TtR), Pre-PFS, overall survival (OS) and safety. 
3 
DEFINITION OF ENDPOINTS 
3.1 Primary Endpoint 
• 
Overall Response rate (ORR) defined as the proportion of patients with best overall response of complete response 
(CR) or partial response (PR), as per local investigator´s assessment and according to Response Evaluation Criteria 
in Solid Tumors (RECIST) version 1.1 criteria. 
3.2 Secondary Endpoints 
• 
Clinical Benefit Rate (CBR) defined as the proportion of patients with a best overall response of CR, PR or an overall 
lesion response of Stable Disease (SD) or Non-PR/Non-progression disease (PD) lasting ≥ 24 weeks, based on 
local investigator´s assessment according to RECIST v1.1. 
• 
Progression free survival (PFS) defined as the time from allocation to the first occurrence of disease progression, 
as determined locally by the investigator according to RECIST v.1.1, or death from any cause, whichever occurs 
first. 
• 
Duration of response (DoR) defined as the time from the first occurrence of a documented objective response to 
disease progression, as determined locally by the investigator through use of RECIST v.1.1, or death from any 
cause, whichever occurs first 
• 
Time to response (TtR) defined as the time from allocation to the first objective tumor response (tumor shrinkage 
of ≥30%) observed for patients who achieved a CR or PR. 
• 
Overall survival (OS) defined as the time from allocation to death from any cause (OS will be determined at the 
end of the study). 
• 
PFS on study treatment compared to PFS on prior line of therapy (pre-PFS). 
• 
ORR according to PD1 mRNA expression. 


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3.3 Safety Endpoints 
Analysis of safety-related data will be: 
• 
The degree of exposure (dose, duration, number of patients) will be assessed to determine the degree to which 
study safety can be assessed. 
• 
Incidence, duration, and severity of Adverse Events (AEs) assessed by the NCI Common Terminology for 
Classification of Adverse Events (CTCAE) version 5, including dose reductions, delays, and treatment 
discontinuations. 
 
3.4 Exploratory Endpoints 
• 
According to iRECIST 1.1: 
o 
ORR 
o 
PFS 
o 
DoR 
o 
TtR 
• 
To determine ORR according to PD-L1 protein expression by IHC. 
• 
To evaluate ORR according to stromal TILs. 
• 
To identify a new gene signature predictive of pembrolizumab and paclitaxel therapy benefit. 
• 
To identify new biomarkers of response to the combination treatment, we aim to further evaluate the expression 
of 752 genes that encompass important genomic signatures and individual genes. The nCounter® Breast Cancer 
360 Panel includes 752 genes that cover established breast cancer diagnostic and research signatures as well as 
key pathways at the interface of the tumor, tumor microenvironment and immune response. Special attention will 
be given to innate immune response genes as well as markers of antigen presentation, which are expected to be 
determinant for this combination treatment. The following genes/signatures will be evaluated among others: 
PAM50 genes and signatures, risk of recurrence (ROR) score, ER signaling biology, immune cell marker (e.g., 
BCL2; CD163; CD68; CD84; CD8A; CD8B; CHIT1), chemo-endocrine score (CES), immune infiltration (e.g. CCL5; 
CD27; CD274; CD276; CD8A; CMKLR1; CXCL9) or proliferation. 
4 
ANALYSIS POPULATIONS 
The following populations will be analyzed: 
• 
Screening Population: All patients who were present at the screening visit will be included in the screening 
population. 
• 
Intent-to-treat (ITT) population: All patients that are enrolled in the study. This population will be used for 
the efficacy analysis, except for overall response rate and clinical benefit rate, which used the evaluable population 
• 
Evaluable population (EP): includes all patients who have received at least one combination dose of 
pembrolizumab and paclitaxel who had measurable disease according to the Investigator site assessment at 
baseline and who had at least one postbaseline tumor assessment . This population will be used for overall 
response rate and cinical benefit rate analysis. 
• 
Safety population (SP): All patients who received at least one (even incomplete) part of the study treatments. 
The SP population will be analyzed for the safety endpoints. 
• 
Exploratory Analysis Set: Exploratory analyses will be performed on those patients who were evaluable for 
exploratory endpoints including enough quality of the sample. 


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5 
STATISTICAL METHODS 
5.1 General Methodology 
The statistical analysis will be conducted following the principles as specified in International Conference on 
Harmonization (ICH) Topic E9 (CPMP/ICH/363/96). The significance level will be α=0.05 for all tests. As an exploratory 
study, multiple testing without adjustment of the significance level is considered acceptable. 
Definition of baseline: For each safety or efficacy parameter, the last valid assessment made before first study drug 
administration will be used as the baseline for all analyses of that safety or efficacy parameter unless otherwise 
specified. 
Continuous data will be summarized in terms of the number of observations, mean, standard deviation (SD), median, 
minimum, maximum, and first and third quartiles, unless otherwise stated. Where data are collected over time, both 
the observed data and change from baseline will be summarized at each time point. 
The minimum and maximum will be reported to the same number of decimal places as the raw data recorded in the 
database. The mean, median, and first and third quartiles will be reported to one more decimal place than the raw 
data recorded in the database. The SD will be reported to two more decimal places than the raw data recorded in the 
database. In general, the maximum number of decimal places reported shall be four for any summary statistic. 
Categorical data will be summarized in terms of the number of subjects providing data at the relevant time point (n), 
frequency counts and percentages. Changes from baseline in categorical data will be summarized using shift tables 
where appropriate. 
The Kaplan-Meier method will be used to estimate the time to event function the median of time to event and the 95% 
confidence interval of the same will be calculated. These confidence intervals will be calculated based on the 
Greenwood method. Number and proportion of events, median survival time and survival rates, with corresponding 
95%Cl will be calculated. 
Percentages will be presented to one decimal place. A percentage of 100% will be reported as 100%. Percentages will 
not be presented for zero counts. Unless otherwise stated, percentages will be calculated using n as the denominator, 
for frequency tables not assessed by time point the set will be used as denominator. If sample sizes are small, the 
data displays will show the percentages, but any textual report (e.g., clinical study report) will describe frequencies 
only. 
P-values greater than or equal to 0.001, in general, will be presented to three decimal places. However, if a p-value is 
only presented to four decimal places (by SAS) it will not be rounded again but will be presented to four decimal places. 
P-values less than 0.0001 will be presented as “<0.0001”. 
Confidence intervals will be presented to one more decimal place than the raw data. A two-sided significance level of 
5% will be used for confidence intervals. 
For binary endpoints, the 95% confidence intervals (CIs) will be constructed based on an exact binary distribution. 
All scores and change from baseline will be summarized in terms of the number of observations, mean, standard 
deviation, 95%CI of mean, median, range and interquartile range. We will examine the residuals to assess model 
assumptions. 
All report outputs will be produced using SAS® version 9.4 version in a secure and validated environment. All report 
outputs will be provided to the Sponsor in a single Microsoft Word document. 
 
5.2 Subject Disposition 
Descriptive statistics will be provided for the following: 
- 
Overall number of subjects in the screening population, the number of patients eligible to participate in the study, 
and number of screening failures. 
- 
Number and percent of subjects in each of the analysis populations. 


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- 
Number and percent of subjects excluded from each of the analysis populations along with reason for exclusion. 
- 
Listing of subjects excluded from each of the analysis populations along with reason for exclusion. 
- 
Listing of protocol deviations. 
- 
Study termination: 
o 
Number and percent of subjects who completed the study. 
o 
Frequency of premature termination reasons. 
o 
Listing of all dropouts along with reason for termination, treatment group and time of termination. 
No statistical tests are planned for these data. 
 
5.3 Baseline Characteristics 
Baseline characteristics will be provided overall for the Safety, Efficacy and EP populations. 
Descriptive statistics, including number of subjects, mean, standard deviation (SD), median and range for continuous 
variables and frequency and percent for categorical variables will be provided. 
Baseline Characteristics: 
o 
Demographics 
o 
Toxic background 
o 
Oncological history 
o 
Prior significant diseases 
o 
Prior concomitant medication 
o 
History of Breast Cancer 
o 
Oncological history 
o 
Previous treatments for breast cancer 
o 
Previous surgeries for breast cancer 
o 
Physical examination 
o 
Tumor clinical evaluation 
o 
ECOG 
o 
TNM classification 
o 
Histologic grade 
o 
Estrogen receptor (ER) 
o 
Progesterone receptor (PgR) 
o 
HR status 
o 
Ki67 value (%) 
o 
HER2 status 
 
No statistical tests are planned for these data. 
A by-subject listing of all demographic and other baseline characteristics will be provided. 


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5.4 Efficacy 
All efficacy analysis will be based on the ITT and Evaluable population. 
 
5.4.1 Response Efficacy Definitions 
- 
Best Overall Response, defined as the best overall response recorded from the start of the study treatment. 
o 
When CR or PR is the best response across all time points, then best overall response will be CR or PR 
respectively. 
o 
When SD is the best response for ≥ 24 weeks the best overall response will be SD ≥ 24 w. 
o 
When SD is the best response for < 24 weeks the best overall response will be SD < 24 w. 
o 
When non-target disease only and Non-CR/Non-PD is the best response for ≥ 24 weeks the best overall 
response will be SD ≥ 24 w. 
o 
When non-target disease only and Non-CR/Non-PD is the best response for < 24 weeks the best overall 
response will be SD < 24 w. 
o 
When PD is the best response across all time points, best overall response will be PD. 
o 
When there is no evaluable tumor assessments best overall response will be NE. 
- 
Objective Response Rate (ORR) is defined as the proportion of patients with best overall response of CR or PR. 
- 
Clinical Benefit Rate (CBR) is defined as the proportion of patients with best overall response of CR or PR or SD ≥ 
24 w. 
- 
PFS is defined as the time from start dose until death by any cause or objective tumor progression or clinical 
disease progression. Patients with no progression or death will be censored at the date of their last evaluable 
imaging. Censoring rules are specified below: 
 
Situation 
Date of progression or censoring 
Outcome 
Progression documented 
between scheduled visits 
Earliest of: 
• Date of assessment by investigator (if progression is based 
on clinical criteria); 
or 
• Date of assessment showing new lesion (if progression is 
based on new lesion); 
or 
• Date of last radiological assessment of 
measured lesions (if progression is based on 
increase in sum of measured lesions). 
Progressed 
Death before first progression 
disease (PD) assessment 
Date of death. 
Progressed 
Death between adequate 
assessment visits 
Date of death. 
Progressed 
No progression 
Date of last radiological assessment of measured lesions. 
Censored 
Treatment discontinuation for 
undocumented progression 
Date of last radiological assessment of measured lesions. 
Censored 
Treatment discontinuation for 
toxicity or other reason 
Date of last radiological assessment of measured lesions. 
Censored 
Death or progression after more 
than one missed visit 
Date of last radiological assessment of measured lesions. 
Censored 
 
- 
The Overall Survival (OS) is defined as the time from start dose until death from any cause. Patients with no death 
will be censored on the last available follow-up date. 


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- 
The duration of response (DoR) is defined as the time from start dose of first tumor response (either CR or PR) to 
disease progression or death due to any cause. The DoR will be calculated for the patients with CR or PR. 
- 
The duration of Clinical Benefit (DoCB) is defined as the time from documentation of first clinical benefit (either 
CR or PR or SD ≥ 24 w) to disease progression or death due to any cause. The DoCB will be only calculated for 
the participants with clinical benefit. 
- 
The Time to Progression (TTP) is defined as the time from start dose to objective tumor progression or clinical 
disease progression (TTP does not include deaths). Patients with no progression will be censored at the date of 
their last evaluable imaging. 
- 
The Time to Response (TTR) is defined as the time from start dose to ORR date. Patients without ORR will be 
censored at the date of their last evaluable imaging. 
- 
Maximum Tumor Shrinkage (best percentage of change from baseline in the size of target tumor lesions) is defined 
as the biggest percentage of tumor shrinkage from baseline (obtained from the sum of the largest diameters of 
the target lesions). 
- 
PFS on study treatment compared to PFS on prior line of therapy (pre-PFS). Pre-PFS is defined as the time from 
the date of first dose of the previous medication to the date of the first documented progression in the previously 
metastatic line. Pre-PFS only applies to patients whose received have previous treatment for metastatic disease 
- 
ORR according to PD1 mRNA expression. The PD1 mRNA will be pre-established cutoff with median or tertiles. 
Median: Cutoff points will be calculated according to the median value for the mRNA expression. Samples with 
mRNA expression above or equal to the median were considered as samples with high expression, while those 
with value below the median as samples with low expression. Tertiles: Cutoff points will be calculated according 
to the tertiles value for the mRNA expression. Samples with mRNA expression above or equal to the tertile-1 (PD1- 
high) were considered as samples with high expression, samples with mRNA expression above or equal to the 
tertile-2 (PD1-high) were considered as samples with intermediate expression, while those with value below the 
tertile-2 as samples with low expression. 
5.4.2 Primary Efficacy Analysis 
The primary analysis is the ORR as per local investigator’s assessment and according RECIST v1.1 in the Evaluable 
Population. 
• 
ORR, as per local investigator’s assessment and according RECIST v1.1, is defined as the proportion of patients 
with best overall response of CR or PR . 
To be consistent with the sample size calculation, the primary hypothesis will be tested at 0.05 level of significance 
(one-sided) and 90% confidence intervals will be reported. Additionally, the ORR will be reported along with associated 
95% confidence interval. 
The ORR with its 95% Wilson Score confidence interval, will be calculated at stage II. One-sided p-value will be 
obtained with exact binomial test at a nominal alpha level of 0.05. The stage II will be declared positive if the number 
of responding patients is ≥19. In this case the null hypothesis (H0: ORR<=30%) will be rejected. 
5.4.3 Secondary Efficacy Analysis 
For binary endpoints, the number and proportion of patients with response with the 95% Pearson-Clopper CI will be 
calculated. 
The Kaplan-Meier estimate of the PFS survival function will be estimated and displayed. The resulting median PFS time 
will be given for each cohort with 95% confidence intervals, as well as 25th and 75th percentiles will be reported. 
The OS curve will be estimated by the Kaplan-Meier methodology, and the 95% CI will be estimated by the Cox 
proportional-hazards models. 
Maximum tumor shrinkage will be described with the median, range, mean, standard deviation, and interquartile range. 
Waterfall plots describing the percentage of change in target tumor lesions will be provided. 


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ORR according to PD1 mRNA expression analysis will be performed by SOLTI. To compare distribution of variables 
between two groups, we used Fisher's exact test. Proportions and 95% CI were also provided. Univariate and 
multivariable logistic regression analyses are done to investigate the association of each variable with ORR. Odds ratios 
(ORs) and 95% CIs are calculated for each variable. All the laboratory analyses are performed blinding to the clinical 
data. 
For analyses of PFS, Kaplan–Meier curves will be plotted, and groups compared using the log-rank test. Hazard ratios 
and associated 95% CIs will be obtained from Cox proportional hazards regression models. In order to determine the 
optimal cut-point for CDR21 in relation to PFS, separate models were fitted with data cut at each observed value of 
CDR21 with the cut-point giving the highest Harrell’s c-index considered optimal. 
For all tests, we will use two-sided p-values with alpha ≤ 0.05 level of significance. P-values emerging from these 
analyses will not be interpreted in a confirmative sense; they will be considered of descriptive nature only. 
 
5.4.4 Handling of Missing Data 
Study variables could be missing for patients who withdrawn from the trial or for specific visits. We will report reasons 
for withdrawal. 
Patient with missing in response outcomes (ORR and CBR) will considered as no responders. Patients without any post- 
baseline assessment will be considered as non-responders or without clinical benefit. 
For the analysis of maximum tumor shrinkage only observed cases will be used. 
The analysis of timed endpoints is based on a Kaplan-Meier method (PFS, DoR and OS), therefore, not affected by 
patient withdrawals (as they are censored) provided that dropping out is unrelated to prognosis. 
For PFS, patients without a date of disease progression will be analyzed as censored observations on the date of last 
tumor assessment. If no post-baseline tumor assessment is available, patients will be censored at the date of treatment 
initiation + 1 day. Data for patients with an event who missed two or more scheduled assessments immediately prior 
to the event will be censored at the last tumor assessment prior to the missed visits. 
For OS, patients who are not reported as having died will be analyzed as censored observations on the date they were 
last known to be alive. If no post-baseline data are available, OS will be censored at the date of treatment initiation + 
1 day. 
The other variables will be managed with simple imputations methods (last observation carried forward). The effect 
that any missing data might have on results will be assessed via sensitivity analysis. 
 
5.4.5 Exploratory Analysis 
These statistical analyses will be exploratory. Exploratory analyses will be performed on the exploratory analysis set. 
iRECIST: 
- 
ORR iRECIST is defined as the proportion of patients with best overall response of iRECIST Complete Response 
(iCR) or iRECIST Partial Response (iPR) 
- 
PFS iRECIST is defined as the time from start dose until death by any cause or iRECIST Progressive Disease (iCPD) 
or clinical disease progression. 
- 
DoR iRECIST is defined as the time from start dose of first tumor response (either iCR or iPR) date to iCPD or 
death due to any cause. The DoR will be calculated for the patients with iCR or iPR. 
- 
TTR iRECIST is defined as the time from start dose to first tumor response (either iCR or iPR) date. Patients without 
response will be censored at the date of their last evaluable. 
The MTS will be described (N, mean, median, standard deviation, minimum, and maximum) and analyzed based on 
Wilcoxon test. The use of multiple regression adjust by baseline factors will be deliberated. 


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The statistical analysis plan did not include a provision for correcting for multiplicity in tests for secondary and 
exploratory analyses. For all tests, we will use two-sided P-values with alpha ≤ 0.05 level of significance. The P-values 
emerging from these analyses will not be interpreted in a confirmative sense but will be considered of descriptive 
nature only. Changes in biomarkers will be evaluated on a univariate level regarding their association with treatment. 
Baseline and post-treatment values of quantitative biomarkers will be described with median, standard deviations, 
median and range in quantitative measures (copy numbers, immunoscore…). Baseline and post-treatment values of 
categorical biomarkers (mutations, molecular profiling, and breast cancer subtypes…) will be described with frequency 
and percentage. 
Change from baseline between values of quantitative biomarkers will be analyzed with mean and median differences. 
The corresponding 95% confidence intervals, applicable test statistics and p-values will be presented. P-values and 
95%CI for mean differences will be based on paired T-test. P-values for ranks will be based on Wilcoxon paired test. 
The 95%CI for median difference will be based on bootstrap percentile method. Change from baseline between 
percentage of categorical biomarkers will be analyzed with McNemar’s test. 
Markers will be evaluated on a univariate level regarding their change over potential for prediction of the clinical 
endpoints (ORR, PFS and OS). Biomarker and response correlations with clinical covariates will be investigated. It will 
be checked whether covariates can improve the prediction and whether there is an interaction with the biomarkers. 
Further multivariate techniques (e.g., Multiple Logistic Regression, Cox regression and penalized regressions models) 
will be evaluated to study combinations of markers. Techniques to control false discovery rate and overfitting (cross- 
validation) will be also considered. Analysis will be performed on exploratory analysis set. 
ORR according to PD1 mRNA expression analysis will be performed by SOLTI. Analysis involving gene expression data 
will be performed by SOLTI. 
 
5.5 Safety 
All safety analyses will be performed on the Safety Population. These data will include report of AEs, laboratory analysis, 
vital signs, ECOG PS, changes in ECG, time of trial dosing, and proportion of interruptions. Terms and severity of AE 
will be obtained and reported according to the NCI CTCAE v.5. Statistical summaries of characteristics, frequency, 
grading, duration, and relationship with treatment will be presented. 
All safety tables will list or summarize subjects on the safety population. These safety assessments will be subjected 
to clinical review and summarized by appropriate descriptive statistics. 
 
5.5.1 Duration and Extent of Exposure of Study Treatment 
The study treatment period is defined as the time between the study entry and the last dose of study combination 
therapy. 
Duration and extent of exposure will be based on the safety set. 
The following parameters will be calculated: 
• 
b: “Actual Cycle Duration” is the difference between start and stop date dose. 
• 
c: “Actual Cycle Dose Days” is the number of days with dose administration in the cycle, considering the 
interruptions. 
• 
d: “Actual Total Dose” is the total dose a patient took in a cycle, considering interruptions and reductions. 
• 
e: “Intended Daily Dose per Cycle”. 
• 
f: “Intended Cycle Duration”. 
• 
g: “Intended Cycle Dose Days”. 
• 
A: “Total number of cycles” = 1 
• 
B: “Treatment Duration” = Sum over all cycles of (b). 


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• 
C: “Days on drug” = Sum over all cycles of (c). 
• 
D: “Total Actual Total Dose” = Sum over all cycles of (d). 
• 
E: “Mean Intended Daily Dose” = Mean over all cycles of (e). 
• 
F: “Total Intended Duration” = Sum over all cycles of (f). 
• 
G: “Total Intended Dose Days” = Sum over all cycles of (g). 
• 
H: “Intended Total Dose” = G*E 
• 
I: “Actual Average Daily Dose on Dose Days” = D/C 
• 
J: “Ratio for Dose Interruption” = C/G 
• 
K: “Ratio for Cycle Duration” = F/B 
• 
L: “Actual Average Daily Dose Intensity” = I*J*K 
• 
M: “Relative Dose Intensity (RDI)” = L/E*100 
The treatment duration (days), days on Drug and Treatment compliance (%) will be summarized in terms of the 
number of observations, mean, standard deviation (STD), median, minimum and maximum. 
Extent of exposure measured as RDI (dose level) will be described with median, interquartile range (IQR) and range. 
The RDI will be dichotomized in different cutoffs (≥50%, ≥70%, ≥80%, ≥90%, ≥100%) and described with 
frequencies and percentages. 
5.5.2 Concomitant Medications 
The number and percent of unique patients taking concomitant medications will be summarized by therapeutic 
classification, coded term, and dose level. Elective surgeries/procedures performed during the study will be presented 
in a listing. 
The following are conventions that will be used to classify individual medications as prior and/or concomitant: 
- 
Medications with stop dates prior to screening visit date will be considered prior. 
- 
Medications with missing stop dates or stop dates the day of or after screening visit date will be considered 
concomitant, regardless of start date. Additionally, if the start date is prior to screening visit date or missing, the 
medication will also be considered prior. 
Frequencies and by-subject listing of all prior and concomitant medications will be provided, containing variables listed 
on Prior/Concomitant Assessment eCRF, their corresponding categories (Prior or Concomitant), and WHO Anatomical 
Therapeutic Chemical (ATC) level 2 and ATC Name. 
 
5.5.3 Adverse Events 
All AEs will be recorded on the eCRF “Adverse Events” page and will be coded using the current version of MedDRA® 
to give a system organ class (SOC) and preferred term (PT) for each event. All adverse event safety data will be 
updated to the version of MedDRA that is current at the time of the database lock and statistical analyses. Adverse 
events will be coded with grades defined according to CTCAE V5.0 criteria. 
Treatment-emergent AEs (i.e., those events occur after the first study medication administration and were not present 
at baseline or worsened in severity following the start of treatment) will be tabulated. The TEAE will be tabulated 
according to intensity and causality. If intensity of an AE or causality of an AE to the study medication is missing, a 
worst-case scenario will prevail (severe in intensity or probably related will be assumed). In the summary tables the 
number of subjects with events and the number of events will be presented. 
The onset date of an AE will be compared to the date of first dose of study drug to determine whether the AE is 
treatment emergent. Adverse events with an onset date on or after the date of first dose of study drug will be classified 
as treatment emergent. 


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All deaths and SAEs, regardless of cause, from treatment start until 90 days after final dose of treatment or 30 days 
following cessation of study treatment if the participant initiates new anticancer therapy. Non-fatal AEs occurring after 
treatment start regardless of cause, up until 30 days after final dose of treatment or until start of new anti-cancer 
treatment, whichever is first. Disease progression is not considered a treatment emergent adverse event unless the 
patient dies of disease prior to 28 days after discontinuation of treatment. Events that are continuations of baseline 
abnormalities are considered treatment emergent adverse events only if there is an increase in grade over baseline, 
or if there is an increase following a decrease during the study. 
Treatment emergent adverse events with cause possibly, probably, or definitely related to treatment as judged by the 
investigator. Events that are continuation of baseline abnormalities are not considered treatment related unless there 
is an increase in grade, or if there is an increase following a decrease, and the increase is judged by the investigator 
to be due to treatment. 
Descriptive statistics will be used to characterize the profiles of treatment-related AEs, treatment-related deaths, SAEs, 
treatment-related delays, dose reductions, and/or treatment discontinuations. All AEs will be graded according to the 
current version of the NCI-CTCAE v.5 and the Medical Dictionary for Regulatory Activities (MedDRA). 
The following summaries will be provided: 
- 
Summary of Adverse Events 
o 
Subjects with at least one Adverse Event (AE) 
o 
Subjects with at least one Treatment Emergent AE (TEAE) 
o 
Subjects with at least one related study drug TEAE 
o 
Subjects with at least one grade 3 or 4 or 5 TEAE 
o 
Subjects with at least one related grade 3 or 4 or 5 TEAE 
o 
Subjects with at least one serious TEAE 
o 
Subjects with at least one related serious TEAE 
o 
Subjects with at least one non-serious TEAE 
o 
Subjects with at least one Adverse Event of Special Interest (AESI) 
o 
Deaths due to TEAE 
o 
Subjects with TEAE leading to Discontinuation of Study Treatment 
o 
Subjects dropped out due to AE 
- 
Summary by SOC and PT of the number and percentage of subjects reporting each: 
o 
Treatment Emergent Adverse Events 
o 
Treatment Emergent Adverse Events by Treatment and Haematologic 
o 
Treatment Emergent Adverse Event Related to Study Drug 
o 
Related Treatment Emergent Adverse Event by Treatment and Haematologic 
o 
AESI Treatment Emergent Adverse Events 
o 
Treatment Emergent Adverse Events with Grade 3 or 4 or 5 
o 
Related Treatment-Emergent Adverse Event with Grade 3 or 4 or 5 
o 
Serious Treatment Emergent Adverse Event 
o 
Serious and Related Treatment Emergent Adverse Event 
o 
Treatment Emergent Adverse Event by Maximum Severity 
o 
Treatment Emergent Adverse Event Leading to Discontinuation of Study Drug 


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5.5.4 Clinical Laboratory Parameters 
The following summaries will be produced for all hematology and biochemistry laboratory parameters: 
- 
Shift tables of low, normal, high distribution (n; %) with respect normal ranges of center, at each post-baseline 
cycle by baseline (cycle 1 day 1) distribution. 
- 
Shift tables of low, normal, high distribution (n; %) of clinically significant at each post-baseline cycle comparing 
with baseline (cycle 1 day 1) distribution. 
- 
The value distribution will be displayed using a serial box plot at each cycle, for each treatment arm. 
5.5.5 Vital Signs 
The following summaries will be produced for all vital sign’s parameters: 
- 
Shift tables of low, normal, high distribution (n; %) at each post-baseline cycle by baseline (cycle 1 day 1) 
distribution. 
5.5.6 Physical Examination 
The following summaries will be produced for all physical examination’s parameters: 
- 
Shift tables of low, normal, high distribution (n; %) at each post-baseline cycle by baseline (cycle 1 day 1) 
distribution. 
5.6 Interim Analysis 
The Stage I interim analysis will be conducted when 15 patients are evaluable for ORR as determined locally by the 
investigator using RECIST v.1.1. If 5 or fewer responses are observed in up to 15 patients of evaluable population 
(EP), the trial will be terminated in favor of the null for futility. Otherwise, up to a further 31 patients may be evaluated, 
for a maximum total of 46 evaluable patients. Recruitment will not be halted during the interim analysis period. 
Therefore, no interruption in the accrual will be done during the interim analysis to maintain the dynamic of accrual in 
the trial. 
Stage I interim analysis report will summarize descriptively the following results: 
o 
Baseline Characteristics 
o 
ORR (Overall Response Rate), as per local investigator´s assessment and according RECIST v1.1 
o 
Median PFS (Progression Free Survival), as determined locally by the investigator according RECIST v1.1. 
o 
DOR (Duration of response), as determined locally by the investigator according RECIST v1.1 
o 
CBR (Clinical Benefit Rate), as determined locally by the investigator according RECIST v1.1 
o 
OS (Overall Survival) 
o 
Maximum Tumor shrinkage, according RECIST v1.1 
o 
Extent of Exposure 
o 
Concomitant Medication 
o 
Adverse Events 
 
No statistical tests are planned for these data. 
 
5.7 Deviations from SAP 
Any deviations from the original statistical plan will be described and justified in the final clinical study report. 


Study Code: 2018-003367-58 (TATEN) 
Statistical Analysis Plan 
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6 
APPENDICES 
6.1 SAS Codes for Primary Endpoint 
All report outputs will be produced using SAS® version 9.4 (TS1M5) version in a secure and validated 
environment. 
ORR 
The number and proportion of patients with ORR, with its 95% Wilson confidence intervals will be calculated. 
proc freq data=EP; 
tables ORR / binomial(wilson p=.30) alpha=.05; 
title 'ORR (EP)'; 
run; 
 
 
6.2 List of Tables, Listings, Figures 
A complete list of tables, listings and figures (TLFs) will be given in a separate document which can be updated without 
updating the SAP. The list will serve as a reference for both the Sponsor, the trial statistician and the statistical 
programmer and includes the totality of statistical output to be produced. 
All output will be headed with an appropriate heading specifying the study ID and abbreviated study title. 
All output will be dated and have page numbers in the form 'Page [x / y]' where x denotes the current page within an 
output and y the total number of pages of that output. 
All statistical output will identify the underlying analysis populations and indicate the number of patients/events in this 
population (N) and the number of patient/events actuals contributing to the output (n). All statistical output will be 
presented per treatment (if applicable). 
All patient listings will contain additionally to the patient identification the analysis population and the treatment.