Conditions: HR+ HER2- Metastatic Breast Cancer, Ovarian Cancer, Fallopian Tube Cancer, Primary Peritoneal Cancer, Triple Negative Breast Cancer, Male Breast Cancer
Keywords: Hormone Receptor (HR) Positive Breast Cancer Estrogen receptor (ER) positive Progesterone receptor (PR) positive Cyclin-dependent kinase (CDK) Human epidermal growth factor receptor 2 (HER2) negative Advanced breast cancer Metastatic breast cancer (MBC) Triple negative breast cancer (TNBC) Epithelial ovarian cancer (EOC) Fallopian tube cancer Primary peritoneal cancer (PPC) CDK4/6 inhibitor Endocrine Therapy (ET) Measurable disease Luteinizing Hormone Releasing Hormone (LHRH) Agonist Goserelin Leuprolide acetate
Allocation: NON_RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 155
Healthy volunteers: no

Brief summary:
The purpose of this clinical trial is to learn about the safety and effects of study medicine (PF-06873600) when taken alone or with hormone therapy by people with cancer.

People may be able to participate in this study if they have the following types of cancer: Hormone Receptor positive (HR+) breast cancer; Human Epidermal Growth Factor Receptor 2 (HER2)-negative breast cancer that is advanced or metastatic (spread to other parts of the body); triple negative breast cancer; epithelial ovarian cancer; fallopian tube cancer; or primary peritoneal cancer.

All participants in this study will receive the study medicine by mouth, 1 to 2 times a day at home. The dose of the study medicine may be changed during the study.

Some participants will also receive hormone therapy. The hormone therapy will be either letrozole by mouth once a day at home, or fulvestrant as a shot into the muscle. Fulvestrant will be given every two weeks at the study clinic for the first month, and then once a month after that.

Participants will take part in this study for at least 7 to 8 months, depending on how they respond to the therapy. During this time participants will visit the study clinic once a week for the first 2 cycles and every cycle thereafter.

Detailed description:
This is a Phase 1/2a, open-label, multi-center, non-randomized, multiple dose, safety, tolerability, pharmacokinetic, and pharmacodynamic study of PF-06873600 administered as a single agent in sequential dose levels and then in combination with endocrine therapy. In Part 1A and Part 1C, successive cohorts of patients will receive escalating doses of PF-06873600 and then in dose finding (Part 1B) with PF-06873600 in combination with endocrine therapy (ET). This study contains 2 parts, dose escalation with single agent (Part 1A and 1C) and then dose finding with PF-06873600 in combination with endocrine therapy (Part 1B) followed by dose expansion arms of PF-06873600 in combination with endocrine therapy (Part 2).

Arms:
arm 1: Single Agent Dose Escalation arm 2: Part 1B PF-06873600 plus Endocrine Therapy 1 arm 3: Part 1B PF-06873600 plus Endocrine Therapy 2 arm 4: PF-06873600 as a Single Agent arm 5: PF-06873600 as a Single Agent in Various Tumor Types arm 6: PF-06873600 in Combination with Endocrine Therapy 1 arm 7: PF-06873600 in Combination with Endocrine Therapy 1 arm 8: PF-06873600 in Combination with Endocrine Therapy 2

Interventions: intervention 1: PF-06873600 intervention 2: Endocrine Therapy 1 intervention 3: Endocrine Therapy 2
Intervention descriptions: intervention 1: PF-06873600 tablet for oral dosing intervention 2: Endocrine Therapy 1 intervention 3: Endocrine Therapy 2

Protocol document:
Prot_000.pdf: 
PF-06873600 
C3661001 
Final Protocol Amendment 9, 03 March 2023 
PFIZER CONFIDENTIAL 
Page 1 
 
 
This document and accompanying materials contain confidential information belonging to Pfizer. Except as 
otherwise agreed to in writing, by accepting or reviewing these documents, you agree to hold this 
information in confidence and not copy or disclose it to others (except where required by applicable law) or 
use it for unauthorized purposes. In the event of any actual or suspected breach of this obligation, Pfizer 
must be promptly notified. 
 
 
PHASE 1/2a DOSE ESCALATION AND EXPANSION STUDY EVALUATING 
SAFETY, TOLERABILITY, PHARMACOKINETIC, PHARMACODYNAMICS AND 
ANTI-TUMOR ACTIVITY OF PF-06873600 AS A SINGLE AGENT AND IN 
COMBINATION WITH ENDOCRINE THERAPY 
 
Investigational Product Number: 
PF-06873600 
Investigational Product Name: 
N/A (Not applicable) 
United States (US) Investigational New 
Drug (IND) Number: 
European Clinical Trials Database 
(EudraCT) Number: 
134457 
 
2020-001757-40 
Protocol Number: 
C3661001 
Phase: 
1/2a 
NCT# 
NCT03519178 
 
 


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Document History 
 
Document 
Version Date 
Summary of Changes and Rationale 
Amendment 9 
03 March 2023 
The primary purpose of this amendment is to define the 
primary completion date (PCD), end of study date, and 
clarify continued access to study intervention for eligible 
patients who continue to derive a clinical benefit from 
study treatment. 
• 
Section 13.2 added to define primary completion 
date, clarify end of trial and access to the 
investigational product for the patients who 
continue to derive clinical benefit. Section 13.1 
revised to define end of trial for all countries. 
• 
Appendix 8 added to detail study procedures after 
PCD and until end of study. 
• 
An additional SoA table SCHEDULE OF 
ACTIVITIES Following Amendment 09: Treatment 
and Follow-up added to detail study activities after 
PCD and to replace ALL other SoA tables. 
• 
Text added in Section 7 to clarify the SoA after 
PCD. 
Updates from Protocol Administrative Change Letter 
(PACL) dated 21 February 2022 pertaining to safety 
include the following: 
• 
Added text to clarify that hematology labs for C1 
and C2D8, D15 and D21 for Part 2 are required in 
footnote 11 of SCHEDULE OF ACTIVITIES 
(Part 1, Part 2 and J-LIC). 
• 
Clarification of the dose modification guidelines for 
PF-06873600 related hematologic toxicity in 
Section 5.4.3.4 Table 3. 
Additional updates to incorporate changes per PACLs 
dated 03 October 2022 and 21 February 2022: 
Per PACL 03 October 2022: 
• 
Removal of scheduled PK and select biomarker 
sampling for participants in Part 2 in Section 7.3.5 
and footnotes b and e in Schedule of 
Pharmacokinetic, Biopsy and Biomarker 
Assessments – Immediate release formulation in 
Part 2 (Arms A ,B and C) and footnote f in 
Schedule of Pharmacokinetic, Biopsy and 
Biomarker Assessments - Modified Release 
Formulation in Part 2. 
• 
Remove long term follow-up for Part 2 in 
Section 7.7 and footnote 14 in SCHEDULE OF 
ACTIVITIES (Part 1, Part 2 and J-LIC). 


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Document 
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Per PACL 21 February 2022: 
• 
Remove mandatory skin biopsy requirement for 
patients in the mandatory paired biopsy subset in 
Part 2 in footnote d in Schedule of Pharmacokinetic, 
Biopsy and Biomarker Assessments – Immediate 
release formulation in Part 2 (Arms A, B and C) and 
footnote e in Schedule of Pharmacokinetic, Biopsy 
and Biomarker Assessments - Modified Release 
Formulation in Part 2, and in Section 1.5.1. 
In addition, clarifications, administrative and 
typographical modifications were made. 
Amendment 8 
08 July 2021 
The primary purpose of this amendment is to incorporate 
feedback received from PMDA which is applicable to 
Japan only. 
Appendix 7 Country-Specific Requirement, 
Appendix 7.1 Japan Specific Requirements: 
The following sections were updated or added. 
• 
Japan Participation: Japan Lead-in Cohort. 
• 
Figure 10 and Japan Lead-in Cohort statement were 
updated. 
• 
Exclusion Criterion was added: 
Current or history of idiopathic interstitial 
pneumonias (IIPs), drug-induced pneumonitis or 
radiation pneumonitis. In some cases, imaging with 
scarring may be observed in asymptomatic patients 
resulting from prior treatments. These cases (eg, if 
the scarring is identified at baseline and not 
considered clinically significant and/or active 
disease) may be eligible at the discretion of the PI, 
following a discussion and agreement with the 
Sponsor. 
Hepatitis B Viral monitoring: 
• 
Corrected typo. 
Added text for Granulocyte-colony stimulating factors: 
• 
Clarified the definition of use of G-CSF. 
Interstitial lung disease (ILD) and pneumonitis: 
• 
Added the screening for ILD. 
• 
Dose interruption and discontinuation related ILD. 


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Version Date 
Summary of Changes and Rationale 
Pregnancy Testing: 
• 
Clarified the pregnancy testing requirements. 
In addition, clarifications, administrative and 
typographical modifications were made: 
• 
3.1.5 Criteria for Dose Escalation 
• 
Language around a DLT period of 28 days for 
Part 2 was removed from the text, as this is not 
applicable. 
• 
Language around 28-count blister packs for 
Letrozole has been added SOA and 
Section 5.3.1.2. 
Amendment 7 
07 June 2021 
The primary purpose of this amendment is to add Arm C 
in Part 2 of the study (ie, PF-06873600 in combination 
with fulvestrant in HR-positive HER2-negative locally 
advanced or mBC (naïve to CDK4/6 inhibitors). 
In addition, a Japan lead-in cohort (J-LIC) has been 
added to confirm the safety of PF-06873600 
monotherapy in Japanese participants (Appendix 7 was 
added to provide all the J-LIC details). 
The following clarifications were added to the 
SCHEDULE OF ACTIVITIES (PART 1 AND PART 2) 
• 
Addition of ‘and J-LIC' in the title. 
• 
Footnote 11: addition of ‘and Cycle 2’. 
• 
Footnote 12: addition of ‘For Japan only, 
participants with HBsAb and HBcAb should be 
monitored with HBV viral load (refer to 
Appendix 7). 
SCHEDULE OF PHARMACOKINETIC, BIOPSY 
AND BIOMARKER ASSESSMENTS (PART 1– 
EXCEPT MODIFIED RELEASE SELECTION 
COHORT WITHIN PART 1C*– QD AND BID 
DOSING REGIMEN 
• 
Addition of ‘AND J-LIC**’ and removal of ‘QD’in 
the title; 
• 
Addition in the footnote of: 
• 
The necessity of hospitalization and its duration of 
DLT assessment period for Japanese participants in 
J-LIC are based on the investigator’s decision 
• 
Addition in footnote j of the sentence ‘Exceptions 
may be granted after consultation with the Sponsor’. 


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SCHEDULE OF PHARMACOKINETIC, BIOPSY 
AND BIOMARKER ASSESSMENTS - IMMEDIATE 
RELEASE FORMULATION IN PART 2 (ARMS A 
ANDB) 
• 
Addition of' ARM C' in the title and removal of the 
row 'PF-06873600 PK Urine collectionb' in the 
table. 
• 
The row 'PF-06873600 PK Urine collection', the 
row 'Semm Biomarkers' and the footnote h were 
removed this was an en-or and should have be.en 
removed in the previous protocol amendment. 
• 
Footnote c and d: the wording 'Arms A and B' was 
replaced by 'each aim'. 
• 
Footnote g: addition of the sentence 'A sample is 
also to be collected when patient develops 
progressive disease'. 
SCHEDULE OF PHARMACOKINETIC, BIOPSY 
AND BIOMARKER ASSESSMENTS - MODIFIED 
RELEASE FORMULATION IN PART 2 
• 
The row' Se11llllBiomarkers' and the footnote i 
were removed. 
• 
Footnotes d and e: the wording 'Anus A and B' was 
replaced by 'each rum'. 
• 
Footnote h: addition of the sentence: 'A sample is 
also to be collected when patient develops 
progressive disease'. 
 
I 
I 
Section 2. Study Objectives and Endpoints 
• 
The additional group of patients (ie, Alm C) was 
described in Pait 2 of the primary objective: 
HR-positive HER2-negative locally advanced or 
mBC (PF-06873600+fulvestrant) (nai've to CDK4/6 
inhibitors). 


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Document 
Version Date 
Summary of Changes and Rationale 
Section 3.1. Study Overview 
• 
A brief explanation for the addition sub-cohort (the 
Japan lead-in cohort) was provided. 
• 
The number of patients in the last sentence of this 
section has been changed from ‘70’ to ‘100’. 
Section 3.1. Study Overview 
• 
Figure 8 has been modified to reflect the addition of 
the extra groups of patients. 
Section 3.2. Part 2 PF-06873600 Combination Dose 
Expansion 
• 
In Section 3.2.2, the wording ‘Arm A prior to 
initiating this dose expansion arm’ was removed. 
The wording ‘who have not previously received’ 
was replaced by ‘who have not received any prior 
treatment with a’. The word available was added in 
front of ‘preliminary’. The information ‘(prior 
adjuvant therapy with AI is permitted)’ was added 
after metastatic setting. 
• 
Addition of ‘Section 3.2.3 Part 2/Arm C- 
PF-06873600 in Combination with Fulvestrant in 
HR-Positive HER2-Negative Locally Advanced or 
mBC (naïve to CDK4/6 inhibitors)’ describing the 
evaluation PF-06873600 in this Arm C. 
Section 3.3.1. Tumor Biopsy 
• 
The number of patients was changed from 
12 patients to 10 patients and the wording ‘Arms A 
and B’ was replaced by ‘the dose expansion arm’. 
3.3.2. Skin Biopsy 
• 
Deletion of the wording ‘Arms A and B’. 
Section 4.1. Inclusion Criteria 
• 
In Part 2, Arm A: Addition of the sentence 
‘Participants with only non-measurable disease may 
be enrolled if a compelling clinical rationale is 
provided by the investigator and approved by the 
sponsor’ to allow for increased patient access. In 
addition, more than one line of chemotherapy may 
be allowed following a discussion with SPONSOR. 
• 
In Part 2, Arm B: Addition of the wording ‘as 
treatment’ in the 2nd bullet point and addition of the 
sentence ‘Have not received an aromatase inhibitor 


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Summary of Changes and Rationale 
in the advanced or metastatic setting (prior adjuvant 
therapy with AI is pennitted). Addition of the 
sentence 'Participants with only non-measurable 
disease may be enrolled if a compelling clinical 
rationale is provided by the investigator and 
approved by the sponsor' to allow for increased 
patient access in the 5th bullet point 
• 
Addition of the inclusion criteria of the Alm C. 
• 
Addition of the wording 'c:::20 years in Japan in the 
3rd bullet. 
• 
Addition of the sentence 'When there is a high FSH 
level, it should be confinned that there is no other 
medical cause'. 
Section 4.3. Lifestyle Requirements 
• 
A clarification in the first paragraph was added: 'as 
approved by local regulatory authority'. 
• 
Section 5.7.3. Hematopoietic Grov.rth Factors 
• 
A clarification and a note were added; 
• 
For Japan only: since the indication and dosage 
of G-CSF compounds approved in Japan may differ 
from ASCO guidelines, refer to Japanese package 
insert and local clinical guideline. 
• 
Note: erythropoietin is not approved for anemia 
caused by chemotherapy in all local regions, nor is 
it cwTently approved in Japan. 
Section 7.1.3. Laboratory Safety Assessments 
• 
Table 4: Addition of 'or aPTT' in the 
platelet-coagulation row and addition of 'or 
Bicarbonate' next to carbon dioxide in the 
Chemistry colwnn. 
I 


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Document 
Version Date 
Summary of Changes and Rationale 
I 
Section 7.3.3. Skin Biopsy 
• 
The wording 'AmlSA and B' was removed. 
Section 9.3.2. Pait 2 
• 
The number of patients has been changed from 70 
to 100. 
• 
The sample size determination for the Ann C was 
added. 
Section 9.7. Data Monitoring Committee 
• 
Addition of the sentence 'These data would also 
include all treated paiticipants'. 
Appendix 7 was added to provide the infoimation for the 
Japanese cohoit: Appendix 7 Japan Country-Specific. 
Amendment6 
15 December 2020 
The primaiy purpose of this amendment is to delete 
Pait 1 Alm D and Pait 2 Alms A, B, and C, which will 
no longer be studied as a result of focused development 
of PF-06873600 in combination with fulvestrant in 
patients who have received a prior CDK4/6 inhibitor and 
a nonsteroidal aromatase inhibitor (ie, Pait 2 Alm E) and 
PF-06873600 in combination with letrozole in patients 
who have not been previously treated for their advanced 
or metastatic HR+/HER2- breast cancer (ie, Pait 2 
Alm D). These changes were made to align with a 
change in development strategy by the SPONSOR. 
In addition, clarifications, administrative and 
typographical modifications were made. 
SCHEDULE OF ACTIVITIES (PART 1 AND PART 2) 
and SCHEDULE OF ACTMTIES (MODIFIED 
RELEASE SELECTION COHORT WITHIN PART 
lC) 
• 
Deleted reference to Pait lD (Dose Titration Alm). 
• 
Added COVID-19 to Viral disease screening tests 
footnote. 
SCHEDULE OF PHARMACOKINETIC, BIOPSY 
AND BIOMARKER ASSESSMENTS (PART 1- 
EXCEPT MODIFIED RELEASE SELECTION 


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COHORT WITHIN PART lC)-QD AND BID 
DOSING REGIMEN: 
• 
Footnoted: Clarified that C2Dl biopsy should be 
taken at 4hr post the moming dose in the C2D1±3 
days window. 
• 
Footnote e: Allowed a ±2 days window for the 
ClD15 skin biopsy, and clarified that biopsies 
should be taken at the specified hours post the 
moming dose. 
• 
 Footnote j: Clarified that tumor tissue from 
cytologic sampling and bone biopsy specimens are 
not adequate and should not be submitted. 
SCHEDULE OF PHARMACOKINETIC, BIOPSY 
AND BIOMARKER ASSESSMENTS - IMMEDIATE 
RELEASE FORMULATION IN ARM A AND ARM B 
IN PART 2: 
• 
• 
 Footnoted: Clarified that the C2Dl biopsy can be 
collected within ±3 days from C2D1 at 4 hr post the 
moming dose. 
• 
• 
 Urine PK assessments have been removed from the 
SOA table. 
SCHEDULE OF PHARMACOKINETIC, BIOPSY 
ANDBIOMARKERASSESSMENTS: PART 1D 
and 
SCHEDULE OF PHARMACOKINETIC, BIOPSY 
AND BIOMARKER ASSESSMENTS - ARM A 
(STUDY PARTICIPANTS ASSIGNED TO THE 
FOOD EFFECT ASSESSMENT ONLY) IN PART 2 


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Document 
Version Date 
Summary of Changes and Rationale 
• 
Deleted Prut lD and coITesponding Schedule of 
Activities Table. 
• 
 Deleted food effect substudy in Pait 2 and 
coITesponding Schedule of Activities Table. 
Section 1.5.1 Rationale for Pre-, On- and End of 
Treatment Biopsies 
r 
 
• 
 Clarified the patient population in Prut 2 of the 
study, which will enroll 2 different dose expansion 
anns. 
Section 2. Study Objectives and Endpoints: 
Paits lA and lC: Single agent dose escalation and 
Pait lB: Combination dose finding: 
 
I 
 
I 
 
Pait 2: PF-06873600 Combination Dose Expansion: 
• 
Changed secondary endpoint of PD modulation 
from following treatment with PF-06873600 to 
PF-06873600 in combination with fulvestrant or 
letrozole. 
 
I 
 
I 
 
Section 3.1 Study Design 
• 
Updated overall study schema and deleted the 
Pait lD PF-06873600 dose titration cohoit. 
• 
The term recommended dose for expansion (RDE) 
replaces recommended Phase 2 dose (RP2D). 


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Document 
Version Date 
Summary of Changes and Rationale 
• 
Clarified that both available formulations of 
PF-06873600 at the respective RDE will be studied 
in combination with endocrine therapy in Part 1B 
(approximately 12 patients to be dosed in the 
respective endocrine therapy combinations, with 
approximately 6 patients receiving PF-06873600 IR 
+ endocrine therapy and approximately 6 patients 
receiving PF-06873600 MR + endocrine therapy in 
both the fulvestrant and letrozole arms). 
• 
Updated the approximate number of patients 
expected to be enrolled in the dose 
escalation/finding safety cohorts is 75 patients and 
approximately 70 patients are expected to be 
enrolled in Part 2. 
Section 3.1.4 Part 1D PF-06873600 Dose Titration 
Cohort 
• 
Deleted Part 1D dose titration cohort, as well as 
information pertaining to dose-escalation, minimum 
safety criteria, and dose de-escalation. 
Section 3.2 changed to Part 2 PF-06873600 
Combination Dose Expansion 
• 
Deleted Arms A, B, and C in Part 2, and renamed 
Part 2/Arm E to Arm A, and added Part 2/Arm B 
(PF-06873600 in Combination with Letrozole in 
HR-positive HER2-negative Locally Advanced or 
mBC (first-or second-line setting). 
Section 3.2.1 changed to Part 2/Arm A 
– PF-06873600 in Combination with Fulvestrant in HR 
positive HER2 negative Locally Advanced or mBC 
(second or third line setting). 
• 
The sample size for Part 2A has been increased 
from 30 patients (formally Part 2E) to 
approximately ~40 patients to allow for additional 
flexibility to test either formulation being studied. 
Section 3.3.1 Tumor Biopsy 
• 
Editorial changes/clarifications. 
Section 3.4 Food Effect Substudy in Part 2 Arm A 
• 
Deleted single agent dose expansion cohort in Part 2 
to examine the effect of food on the PK of 
PF-0687360) which was previously planned as part 
of the monotherapy arm in Part 2, which is no 
longer being studied. 


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Document 
Version Date 
Summary of Changes and Rationale 
Section 4.1 Inclusion Criteria 
• 
Clarified that in Pait lB, measurable disease per 
RECIST 1.1 is required. 
• 
Deleted inclusion criteria peitaining to deleted 
Arms A, B, and C in Pait 2. 
• 
Changed Arm E to Alm A (Patients with 
HR-positive HER2-negative locally advanced or 
mBC (second- or third-line setting [histologically or 
cytologically proven]). 
• 
 Added criteria for added Arm B in Pait 2 (Patients 
with HR-positive HER2-negative locally advanced 
or mBC who are nai've to CDK4/6 inhibitors 
[histologically or cytologically proven]). 
Section 5.4.3.4 Dose Reductions 
• 
Deleted instmctions for dose reduction guidelines 
for pruticipating in the Pait lD. 
Section 5.4 Administration 
• 
Deleted TID dosing regimen information. 
• 
Deleted requirements for the food effect cohort 
(Pait 2 Arm A). 
Section 7.2.2 
Deleted urine for analysis of PF-06873600 
concentration from the protocol due to the absence of 
monotherapy anus. 
Section 7.3 Biomarker and Phannacodynrunic 
Assessments 
• 
Deleted duplicate and unnecessru-yparagraphs. 
I 
I 
 


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Document 
Version Date 
Summary of Changes and Rationale 
• 
Removed unnecessary sentences. 
• 
Other editorial changes/clarifications. 
Section 9.3 Sample Size Detennination 
• 
Updated samples sizes for Part 1 and Pait 2 Ann A 
PF-06873600 + fulvestrant (second or third line 
setting) and Prut 2 Arm B PF-06873600 + letrozole 
ann (first line setting). 
Section 7.6.1 Additional Research 
• 
Editorial changes. 
Section 9.5.1.1 Single-Dose and Steady-State 
PF-06873600 Phaimacokinetic Analysis 
• 
Deleted analysis of urine drng concentrations. 
Section 9.5.1.2 Effect of Food on PF-06873600 
Phannacokinetics 
• 
Deleted assessment of PK pru·ameters from food 
effect substudy. 
Amendments 
25 August 2020 
The primary purpose of this amendment is to add 
Pait lD, which will use a dose titration design to allow 
patients the opportunity to titrate up to a higher dose of 
PF-06873600 on C2Dl to maximize efficacy following 
a thorough review of safety parameters. 
In addition, clarifications, administrative, and 
typographical modifications were made. 
Updated reference and abbreviation lists as applicable. 
SCHEDULE OF ACTIVITIES (PART 1 AND PART 
2): 
• 
 12-Lead ECG row: Added "and C2 Pait lD only" 
on Day 8 of Cycles 1 and 2 for clarity. 
• 
 Added timing of CT/MRI scans for Pait lD in table 
during active treatment phase. 
• 
Footnote# 9: Added bullet for tirning of ECG for 
Pait lD only. 


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Summary of Changes and Rationale 
• 
 Footnote #16: Added clarifying language for 
patients in Part lD (Dose Titration Ann) only, 
patients may titrate up their dose to three times a 
day (TID) starting in Cycle 2. Added specifics for 
tablet counts for PF-06873600 for sites to consider 
when scheduling drug dispensing visits. 
• 
 Footnote #17: Added specifics for tablet counts for 
letrozole for sites to consider when scheduling chug 
dispensing visits. 
SCHEDULE OF ACTIVITIES (MODIFIED RELEASE 
SELECTION COHORT WITHIN PART lC) 
• 
 Footnote 14: Added specifics for tablet counts for 
PF-06873600 for sites to consider when scheduling 
chug dispensing visits. 
SCHEDULE OF PHARMACOKINETIC, BIOPSY 
AND BIOMARKER ASSESSMENTS (PART 1- 
EXCEPT MODIFIED RELEASE SELECTION 
COHORTWITHINPARTlC*ANDPARTlD)-QD   
AND BID DOSING REGIMEN: 
• 
Added Prut lD to the title. 
• 
Made ClD15 6 hour post-dose skin biopsy optional 
for all patients. 
• 
 Added a 4-hour post-dose assessment column 
(including allowable window) for C2Dl. Moved 
PF-06873600 PK blood sampling and skin biopsy 
biospecimen collections from C2D1 0 hours post­ 
dose to 4 hours post-dose. 
• 
Footnote c: Added instructional text for PK samples 
for Cl5Dl and C2Dl. 
• 
• 
 Footnote e, Skin Biopsy Biospecimen: Indicated 
that screening and C2D1 skin punch biopsies are 
mandatory for patients enrolled in the biomarker 
cohorts of Prut 1 and optional for other patients, and 
that ClD15 biopsy is optional for all patients. 
Added reference to Laboratory Manual for details. 


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• 
 
SCHEDULE OF PHARMACOKINETIC, BIOPSY 
AND BIOMARKER ASSESSMENTS- PART 1D 
• 
Added new table with footnotes for Patt lD. 
SCHEDULE OF PHARMACOKINETIC, BIOPSY 
AND BIOMARKER ASSESSMENTS (PART 1*) - 
TID DOSING REGIMEN 
• 
Title: Added (NOT PART 1 D- DOSE 
TITRATION ARM) for clarification. 
• 
 Made ClD15 6 hour post-dose biopsy optional for 
all patients. 
• 
 Added a 4 hour post-dose assessment column 
(including allowable window) for C2Dl. Moved 
PF-06873600 PK blood sampling and skin biopsy 
biospecimen collections from C2D1 0 hours post­ 
dose to 4 hours post-dose. 
• 
• 
 Footnote e, Skin Biopsy Biospecimen: Indicated 
that screening and C2D1 skin punch biopsies are 
mandatory for patients enrolled in the biomarker 
cohorts of Patt 1 and optional for other patients, and 
that ClD15 biopsy is optional for all patients. 
Added reference to Laboratory Manual for details. 
• 
SCHEDULE OF PHARMACOKINETIC, BIOPSY 
AND BIOMARKER ASSESSMENTS - ARM A, ARM 
B (STUDY PARTICIPANTS NOT ASSIGNED TO 
THE FOOD EFFECT ASSESSMENT), ARM C, ARM 
D AND ARM E IN PART 2 
• 
Added a 4 hour post-dose assessment column 
(including allowable window) for Cycles :?:2. 
Moved PF 06873600 PK blood sam lino and skin 


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biopsy biospecimen collections from C2Dl O hours 
post-dose to 4 hours post-dose. 
• 
Added an assessment ofthymidine kinase on ClD8. 
• 
Updated footnotes c, d. and i with biopsy 
requirements. 
• 
Footnote k: Removed Cycle 3. 
SCHEDULE OF PHARMACOKINETIC, BIOPSY 
AND BIOMARKER ASSESSMENTS - ARM B 
(STUDY PARTICIPANTS ASSIGNED TO THE 
FOOD EFFECT ASSESSMENT ONLY) IN PART 2 
• 
Deleted (Ann) B from title and table row, replaced 
with A. 
• 
Added column for ClD8, 0 hours post-dose for 
thymidine kinase assessment. 
• 
• 
Updated footnotes d, f, and k with biopsy 
requirements. 
• 
Footnote h: Removed Cycle 3. 
Section 1 Introduction: 
• 
Section 1.5.1 Rationale for Pre, On, and End of 
Treatment Biopsies: 
• 
 Indicated that serial and skin biopsy samples will be 
collected and indicated the number of patients in 
each coho1t of Pait 1. Added "and skin punch 
biopsy" to the mandato1y tumor collections for a 
subset of patients in Anns A and B. 
• 


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• 
• 
• 
Section 1.6 Overview ofLetrozole (Femara®) 
updated USPI to most cwTent version (2020). 
Section 1.7 Overview ofFulvestrant (Faslodex®) 
updated USPI to most cwTent version (2020). 
Section 2. Study Objectives and Endpoints: 
• 
 Added Pait lD as applicable to objectives and 
endpoints. 
Section 3 Study Design: 
• 
Section 3.1: Added description of Pait lD as 
applicable, updated Figw-e 8 to include Pait lD, 
added Figure 10: Part lD Dose Titration Study 
Schema. Added descriptive text for dosing 
frequency for patients in Prut lD. 
• 
 Updated patient numbers for the dose 
escalation/finding safety cohorts and biomarker 
cohorts in Paits lA and lB. 
• 
Added Section 3.1.4: Pait lD PF-06873600 dose 
titration cohoit. 
• 
Section 3.1.6 Criteria for Dose Escalation: Updated 
paragraph under Table 2 for clarity; replaced 
"unless related to treatment emergent toxicity" with 
"unless the patient has experienced a DLT prior to 
receiving 75% of the planned dose", and added In 
Pait lD, a patient is considered evaluable for the up­ 
titration if he/she receives at least 75% of the 
planned doses of the study intervention dw-ing 
cycle 1 and cycle 2. 
• 
Section 3.3.1 Tumor Biopsy: Specified the number 
of patients. Deleted "and skin" from last paragraph 
as it is not applicable. 
• 
Section 3.3.2 Skin Biopsy: Added details for skin 
biopsy requirements. 


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• 
Section 3.4 Food Effect Substudy in Part 2 Arm A: 
Changed Arm B to Arm A. 
• 
Section 4.2 Exclusion Criteria: Criterion #10, added 
text for SARs-CoV2 testing and infections and 
added a reference/hyperlink to Appendix 6 for 
SARs-CoV2 infection eligibility. 
Section 5 Study Treatments: Listed letrozole and 
fulvestrant as investigational products rather than 
standard of care. 
• 
Section 5.2 Patient Compliance: Indicated that 
fulvestrant will be administered at the 
investigational site and PF-06873600 and letrozole 
will be distributed to the patient. 
• 
Section 5.3 Investigational Product Supplies: 
Indicated that letrozole and fulvestrant will be 
supplied by Pfizer, 
• 
Section 5.3.1.1 PF-06873600: Updated strengths for 
the immediate and modified-release (MR) tablets 
and added details regarding table counts. 
• 
Section 5.3.1.2 Letrozole: 
• 
Removed “and Fulvestrant” from section title. 
• 
Added new section: Section 5.3.1.3 Fulvestrant 
• 
Section 5.4.1, PF-06873600: Added bullet for Part 
1D only. Added instructions for the administration 
of letrozole and fulvestrant. 
• 
Section 5.4.2. 5.4.2.2. Requirements for the Food 
Effect Cohort (Part 2 Arm A): Replaced Arm B 
with Arm A. 
• 
Added new section: 5.4.3.2 Dose Interruption of 
Patients with Presumed or Active 
COVID-19/SARs-CoV2 Infection. 
• 
Section 5.4.3.4 Dose Reductions: Added 
instructions for patients in Part 1D and added that at 
the discretion of the investigator or Sponsor based 
on emerging safety data patients may be asked to 
reduce their dose within the DLT window. 
• 
Table 3 Dose Modifications for PF-06873600- 
Related Toxicity. Added instructions for patients in 


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Pait lD with Grade 3 nonhematologic and 
hematologic toxicities. 
Section 6.4: Updated text regarding permanent 
discontinuation of study intervention and the study with 
text to comply with updated protocol template language 
effective December 2019/May 2020. 
I 
I 
I 
Section 8 Adverse Event Repoiting 
• 
Section 8.1.4 Time Period for Collecting AE/SAE 
Infonnation: Added details for long-term follow-up 
collection period for Prut 2 only. 
Sections 9.2.2/9.3.1/9.3.2 Prut 1 and Pait 2: Updated 
number of patients to be enrolled. 
Section 9.5.1.1 Single Dose and Steady State PF 
06873600 Phannacokinetic Analysis: Added PK 
sampling for patients in Part lD added specifics for 
samples on C2D8. 
Appendix 4. RECIST (Response Evaluation Criteria In 
Solid Tumors) version 1.1 Guidelines: Best Overall 
Response section, Stable disease bullet: changed timing 
after randomization from 8 weeks to 6 weeks. 
Added Altemative Measures During Public Emergencies 
appendix (Appendix 6), with hyperlinks to appendix in 


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the schedule of activities section as well as Sections 4.2 
(exclusion criterion # 10) and 7 as appropriate. 
Amendment4 
08 April 2020 
The purpose of this amendment is to add the Schedule of 
Phannacokinetic, Biopsy and Biomarker Assessments 
for Pait 2 of this study. 
Pait 2 dose expansion is an open-label, multi-center, 
non-randomized study to assess the preliminaiy 
anti-tumor activity and the safety and tolerability of 
PF-06873600. PF-06873600 will be administered at the 
RP2D in 28 day cycles as a single agent in 2 separate 
dose expansion arms and in combination with endocrine 
therapy in 3 separate dose expansion arms. 
In addition, clarifications, administrative and 
typographical modifications were made. 
• 
I 
 
• 
Schedule of Phaimacokinetic, Biopsy and 
Biomarker Assessments - Ann A, Alm B (Study 
Paiticipants Not Assigned to the Food Effect 
Assessment), Alm C, Alm D and Alm E in Pait 2 
has been added. 
• 
Schedule Of Phannacokinetic, Biopsy Alld 
Biomarker Assessments - Ann B (Study 
Paiticipants Assigned To The Food Effect 
Assessment Only) In Part 2 Has Been Added. 
Section 1.5.1 Rationale for Pre-, On- and End of 
Treatment Biopsies - Clarification around Part 2,I 
-- 
biopsies has been added: 
• 


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Section 2 Study Objectives and Endpoints - Part 2 
Seconda1y Endpoint (Phannacokinetic parameters have 
been clarified): 
Phannacokinetic parameters of PF-06873600, including 
but not limited to: 
• 
SD - Cmax, T max, 
• 
 MD (asswning steady state is achieved) - Css,max, 
T ss,max, Css,minand Rae, 
I 
I 
Section 5.5 Investigational Product Storage: 
Modified text to clarify storage for immediate release 
and modified release. PF-06873600 should be stored at 
15-25°C for the immediate release fonnulation and at 2- 
8°C for the modified release formulation, which has 
been coITected in the protocol. 
Section 7.2.2 Urine for Analysis of PF-06873600 
Concentrations: 
More detailed info1mation around the collection, storage 
and processing of Urine PK samples has been added to 
the protocol. 
Section 7.3 Biomarker and Phannacodynamic 
Assessments: 
All patients in Pait 2 will have the option to provide 
pre-, on-, end of treatment tumor biopsies, but 
mandato1y pre- and on-treatment biopsies will be 
collected for up to 12 paired biopsies to yield a 
minimwn of 6 evaluable pairs in each of the dose 
expansion Arms A and B. 


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Section 9.5.1.1 Single-Dose and Steady-State 
PF-06873600 Pharmacokinetic Analysis: 
Urine concentration data will be analyzed to estimate the 
fraction of drug excreted unchanged in urine (Ae%) and 
renal clearance (CLr) for PF-06873600. 
Section 9.5.2 Population Pharmacokinetic Analysis or 
Pharmacokinetic/Pharmacodynamic (PK/PD) Modeling: 
Section has been updated to reflect the analysis that will 
be conducted. 
Amendment 3 
29 April 2019 
The purpose of this amendment is to add additional 
cohorts of patients to evaluate a modified release 
formulation of PF-06873600, as indicated, based on 
emerging and available preliminary clinical data, 
including safety/tolerability, laboratory, PK and 
PD findings. 
In addition, clarifications, administrative and 
typographical modifications were made. 
SCHEDULE OF ACTIVITIES: 
• 
Added Modified Release Dose Selection Cohort 
Within Part 1C SOA table. 
• 
Added Schedule of Pharmacokinetic, Biopsy and 
Biomarker Assessments (Modified Release 
Selection Cohort in Part 1C) SOA table. 
• 
Modified the title and PK footnote for SOA table 
“Schedule of Pharmacokinetic, Biopsy and 
Biomarker Assessments (Part 1 – Except Modified 
Release Selection Cohort within Part 1C) – QD and 
BID Dosing Regimen. 
Section 1.5.1. Rationale for Pre-, On- and End of 
Treatment Biopsies: 
Qualitative language added. 
Section 2. Study Objectives and Endpoints: 
Study Objectives and Endpoints were updated to reflect 
the addition of Part 1C. 
Section 3.1 Study Design: 


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• 
Addition of Part lC description. 
• 
Overall Study Schema updated to include Part 1C. 
• 
 Addition of Figure 9: MR Selection Cohoit Study 
Schema (within Part lC through Cycle 1). 
Section 3.1.3. Pait lC PF 06873600 MR F01mulation: 
Addition of MR Foimulation lead-in and MR escalation 
rationale including starting doses. 
Section 3.1.5. Criteria for Dose Escalation: 
• 
Addition of Part lC included. 
Section 3.1.6. DLT Definition (added): 
• 
Significant adverse events considered to be related 
to the investigational product for treatment under 
investigation that occur during the DLT observation 
period in the MR Selection Cohoit will be reviewed 
in context of all safety data available. That review 
may involve re-evaluation of the dosing level or 
regimen. 
Administrative clarifications made. 
Section 4 Patient Eligibility Criteria: 
• 
Clarifications made to include Pait 1C. 
• 
Clarification made to include "cytotoxic" in the 
inclusion criteria, "Received 1 or 2 prior lines of 
cytotoxic chemotherapy in the advanced or 
metastatic setting." 
Section 5.3.1 Dosage Foims and Packaging: 
• 
The description of the modified release fonnulations 
were added. 
Section 7.3. Biomarker and Phannacodynamic 
Assessments: 
• 
Clarifications made to include Pait 1C. 


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Table 5: Administrative clarifications made. 
 
Administrative clarifications made. 
Section 9.5.1.1 Single Dose and Steady State PF 
06873600 Phrumacokinetic Analysis: 
• 
Clarifications made to include Patt 1C. 
Amendment2 
26 October 2018 
The primaty purposes of the amendment are to adjust 
the approach to selection of the dose level increases 
during dose escalation and to incotporate the option to 
evaluate an alternative dosing regimen (eg, QD or TID) 
which may be considered during the course of dose 
escalation or after determination of the MTD for the 
BID regimen based on emerging and available 
preliminary clinical data, including safety/tolerability, 
laboratory, PK and PD findings. 
In addition, clarifications, administrative and 
typographical modifications were made. 
Protocol Cover Page: 
NCT number added per Pfizer template update. 
SCHEDULE OF ACTMTIES (Patt 1 and Prut 2) 
PF-06873600 administration: 
• 
 Removed the words "twice daily (BID)" from the 
description of dosing in the table as well as 
footnote. 
• 
Added reference to Section 5 to the dosing footnote 
(Footnote: 16). 
SCHEDULE OF ACTMTIES (Patt 1 and Prut 2); 
Footnote 19: 


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• 
The words “with HR-positive HER2-negative 
advanced or mBC” was added to the requirement 
for treatment with an LHRH agonist in women who 
are pre or peri menopausal at study entry. 
Schedule of Pharmacokinetic, Biopsy and Biomarker 
Assessments (Part 1A and 1B*) – “QD and BID Dosing 
Regimen” was added to the table to differentiate it from 
a new table developed for the potential three times a day 
(TID) dosing regimen. 
Schedule of Pharmacokinetic, Biopsy and Biomarker 
Assessments (Part 1A and 1B*) – QD and BID Dosing 
Regimen; FOOTNOTE f: 
• 
Added the words “such as” to description of 
pharmacodynamic markers to be analyzed for added 
flexibility. 
Schedule of Pharmacokinetic, Biopsy and Biomarker 
Assessments (Part 1A and 1B) – QD and BID Dosing 
Regimen; FOOTNOTE j: 
• 
Minor modification, in the description of the 
assessments to be conducted on tumor tissue, was 
made for additional clarity and flexibility. 
Schedule of Pharmacokinetic, Biopsy and Biomarker 
Assessments (Part 1A and 1B) – TID Dosing Regimen: 
• 
New table and accompanying footnotes added for 
potential TID dosing regimen. 
Section 1.3.2. Nonclinical Pharmacokinetics (PK): 
• 
A PF-06873600 oral dosing regimen of TID may be 
evaluated during dose escalation based on the 
continued evaluation of preliminary PK from the 
BID dose escalation. In addition, an accelerated 
dose escalation (as utilized for the initial dose 
levels) may be adopted until the observation of 
clinically relevant adverse events or the dose levels 
approaching the projected pharmacologically active 
dose (PAD). 
• 
Rationale: If a suboptimal half-life is observed at 10 
mg BID and higher, a PF 06873600 oral dosing 
regimen of three times daily (TID) may be 
evaluated during dose escalation. In addition, a 
higher than predicted clearance could result in a 
higher PAD than the originally predicted 10-15 mg 
BID and therefore require an accelerated dose 


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escalation in order to minimize the number of 
patients exposed to sub-therapeutic dose levels. 
Section 1.5.1. Rationale for Pre, On and End of 
Treatment Biopsies: 
• 
• 
Rationale: The modification better reflects the 
biomarker analysis plan. 
I 
I 
 
I 
Section 3.1. Study Overview: 
• 
 A description of how and when the potential of a 
PF-06873600 oral dosing regimen ofTID may be 
evaluated during dose escalation based on the 
continued evaluation of preliminary PK from the 
BID dose escalation. 
• 
 Added language to provide an example of how the 
MTD would be detennined if the TID regimen is 
evaluated. 
Section 3.1 Study Overview: 
Study Scheme was modified to clarify that the initiation 
of the biomarker cohorts will not strut at Dose Level 3 as 
previously depicted but potentially occwring at a 
subsequent dose level to be detennined. 


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Section 3.1.4. Criteria for Dose Escalation: 
• 
The description for dose escalation increments was 
modified to approximate 100%-150% increases, 
beyond dose level 4, based on emerging available 
clinical data, including safety/tolerability, 
laboratory, PK and PD findings. 
• 
Additionally, the total daily dose will be 
administered in divided doses of either two (BID) or 
three times a day (TID). 
Section 3.1.4. Criteria for Dose Escalation; Table 2: 
PF-06873600 Dose Levels: 
• 
Table was updated to add a column for “Total Daily 
Dose” to reflect the dose escalation increment 
modifications made earlier in the section. 
Section 3.1.4. Criteria for Dose Escalation and Section 
9.1 Analysis Sets: 
• 
Modified the percentage requirement for planned 
doses from 70 to 75% based in order to be evaluable 
for DLT assessment. This modification is based on 
Institutional Review Board (IRB) feedback. 
Section 3.1.4. Criteria for Dose Escalation: 
• 
Repetitive text removed from list of bullets 
describing criteria for stopping the study. 
Section 4.1. Inclusion Criteria: 
• 
#8: The words “or liver” was added to the criteria 
for defining adequate alkaline phosphatase levels 
based on investigator feedback. 
Section 4.1. Inclusion Criteria: 
• 
#11: The words “with HR-positive HER2-negative 
advanced or mBC” was added to the requirement 
for treatment with an LHRH agonist in women who 
are pre or peri menopausal at study entry. This 
requirement doesn’t apply to patients with ovarian 
cancer or TNBC. 
• 
#3 and #4 for gender requirements were combined. 
Section 4.2. Exclusion Criteria: 


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• 
#3: The addition of “that has an external component 
such as those used for… or central venous catheter 
that is externally exposed (eg, perphierally inserted 
central catheter (PICC line)” was added to the 
description of indwelling catheters. This change 
also clarified that indwelling catheters that are fully 
internalized (eg, PORT-A-CATH®) are permitted. 
Section 4.2. Exclusion Criteria: 
• 
#7: The addition of washout criteria for antibody 
based agent(s) (approved or investigational) was 
added based on protocol template updates. 
Section 4.2. Exclusion Criteria: 
• 
#8: The addition of “or 5 half-lives, whichever is 
shorter” was added to the washout for prior 
investigational drug(s) based on protocol template 
updates. 
Section 5.4.1. PF-06873600 Administration: 
• 
TID was added to the potential dosing regimens. 
• 
Dosing intervals for QD, BID and TID were 
delineated. 
• 
Administrative updates were made. 
Section 5.4.2. Food Requirements: 
• 
TID was added to the potential dosing regimens for 
food effect requirement studies. 
Section 5.8. Luteinizing Hormone Releasing Hormone 
(LHRH) Agonist: 
• 
The words “with HR-positive HER2-negative 
advanced or mBC” was added to the requirement 
for treatment with an LHRH agonist in women who 
are pre or peri menopausal at study entry. 
Section 7.2.2. Urine for Analysis of PF 06873600 
Concentrations: 
• 
Given the potential for TID dosing, modifications to 
the section were made in the event the urine PK 
evaluations are necessary in the TID dosing 
regimen. 


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Section 7.3. Biomarker and Pharmacodynamic 
Assessments: Table 5. Biomarker and Phannacod 
Updates in the above sections were required after 
modifications were made to: 
• 
 The footnote description of the evaluations in the 
"Schedule of Pharmacokinetic, Biopsy and 
Biomarker Assessments (Pait lA and lB)-QD and 
BID Dosing Regimen and TID Dosing Regimen"; 
and 
• 
Section 9.2.2. Statistical Method for Estimating the 
MTD: 
Text was added to clarify that if the TID dosing regimen 
is evaluated, the MTD will be determined independently 
based on dose escalation following the mTPI method. 
Appendix 1. Abbreviations: 
• 
New abbreviations added. 
Amendment 1 
22 January 2018 
The primaiy purpose of the amendment is to incoiporate 
feedback received from the United States (US) Food and 
Drug Administration (FDA). 
In addition, clarifications, administrative and 
typographical modifications were made. 
Protocol Title and Section 3.1: 
• 
 The "a" was added for consistency with Phase of 
study described on the cover page of the protocol. 
SCHEDULE OF ACTMTIES (Pait 1 and Pait 2); 
Footnote 9: 
• 
For patients enrolled in dose level 1 and 2 that 
undergo intra patient dose escalation, as described 
in Section 3.1.4, triplicate ECGs should be 
perfonned on Day 8 and Day 15 in the first cycle at 
the escalated dose of PF-06873600. 


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SCHEDULE OF ACTIVITIES (Part 1 and Part 2); 
Footnote 12: 
• 
Typographical error. 
Schedule of Pharmacokinetic, Biopsy and Biomarker 
Assessments (Part 1A and 1B*): 
• 
The window period for the 12-hour PK sample on 
Cycle 1 Day 1 and 15 was extended to 120 minutes 
to allow flexibility for clinical site and patient 
convenience. 
Schedule of Pharmacokinetic, Biopsy and Biomarker 
Assessments (Part 1A and 1B*): 
• 
The additional clarification that the 24-hour PK 
sample on Cycle 1, Day 1 and Day 15, if indicated, 
would correspond to Day 2 and Day 16. 
Schedule of Pharmacokinetic, Biopsy and Biomarker 
Assessments (Part 1A and 1B*); FOOTNOTE d and e: 
• 
Part 1 of the study includes a dose escalation 
(Part 1A) and dose finding (de-escalation, Part 1B) 
component. The addition of “dose finding” was 
added for clarity. 
Section 1.1. Mechanism of Action/Indication: 
• 
The section was modified to include female and 
male patients. 
Section 1.2.2 Hormone Receptor (HR) Positive Breast 
Cancer: 
• 
Statistics for male breast cancer were added. 
Section 1.3.3. Nonclinical Safety: 
• 
Nonclinical safety findings for compounds with 
CDK 4/6 inhibition was added to the nonclinical 
safety summary due to the addition of male patients 
with breast cancer in Part 1A of the study. 
Section 1.5.1 Rationale for Pre-, On- and End of 
Treatment Biopsies: 
• 
Clarification that Part 1 contains a dose escalation 
(Part 1A) and a dose finding (Part 1B) component. 


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• 
Part 1A description modified to include female and 
male patients. 
Section 2 Study Objectives and Endpoints, Primary 
Objective, Part 1B: 
• 
Table header updated to “1B: Combination Dose 
Finding”. 
• 
The last sentence of the 3rd bullet under primary 
Objective for Part 1A was moved out for clarity. 
• 
Part 1B of the study is designed to assess the safety 
and tolerability of PF-06873600 at the single agent 
MTD in combination with letrozole and in 
combination with fulvestrant, in a de-escalation 
manner, if indicated. The reference to “increasing 
doses” was removed. 
Section 3.1 Study Overview: 
• 
Clarification that Part 1A only will evaluate 
successive cohorts of escalating doses of 
PF-06873600) and that Part 1 contains a dose 
escalation (Part 1A) and a dose finding (Part 1B) 
component. 
Section 3.1 Study Overview, Figure 8 Overall Study 
Schema: 
• 
The study figure section header for Part 1 was 
modified from “Part 1B PF-06873600 + ET 
Combination Dose Escalation” to “Part 1B 
PF-06873600 + ET Combination Dose Finding”. 
• 
The figure and legend were updated to differentiate 
the dose escalation safety cohorts (Part 1A) from 
the dose finding safety cohort (Part 1B). 
Section 3.1 Study Overview: 
• 
Part 1A description modified to include both female 
and male patients. 
• 
Part 1B and Part 2 will only evaluate women 
patients in an effort to evaluate a more homogenous 
study population and minimize variability in 
response rates. 


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• 
Language to describe the patient population for 
Part 1B was added to the study overview for 
consistency and clarity. 
Section 3.1.1 Part 1A PF-06873600 Single Agent Dose 
Escalation: 
• 
Part 1A description modified to include female and 
male patients. 
Section 3.1.2 Part 1B PF-06873600 Dose Finding in 
Combination with Endocrine Therapy: 
• 
Language to describe the patient population for 
Part 1B was added for consistency and clarity. 
Section 3.1.4 Criteria for Dose Escalation: 
• 
Part 1 of the study includes a dose escalation 
(Part 1A) and dose finding (de-escalation, Part 1B) 
component. The addition of “dose finding” was 
added for clarity. 
• 
Table 1: the title was modified to include 
“de-escalation” since the actions described in the 
table apply to both escalation and de-escalation. 
Section 3.1.5 DLT Definition: 
• 
The addition of “dose finding” was added for 
clarity. 
• 
Grade 3 thrombocytopenia will include clinically 
significant bleeding as indicated by ≥ Grade 2 
bleeding. 
• 
Grade 3 nausea, vomiting, or diarrhea will only be 
considered a DLT if it persists for ≥72 hours despite 
optimal supportive care. 
• 
Grade 5 event will be considered a DLT unless 
attributed to a cause clearly not related to study 
treatment. 
Section 3.1.6 MTD Definition: 
• 
The addition of “dose finding” was added for 
clarity. 


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Section 3.3.1 Tumor Biopsy: 
• 
Text was added to differentiate the Part-1A 
single-agent dose escalation safety cohorts from the 
Part 1B combination dose de-escalation safety 
cohorts. 
• 
The reference to women was removed since Part 1A 
will now include female and male patients. 
Section 3.3.2. Skin Biopsy: 
• 
Part 1 of the study includes a dose escalation 
(Part 1A) and dose finding (de-escalation, Part 1B) 
component. Text was removed for clarity. 
• 
The reference to women was removed since Part 1A 
will now include female and male patients. 
Section 4.1 Inclusion Criteria: 
• 
Part 1A and Part 2, Arm B: Ovarian Patients: To 
clarify platinum resistance, language was added that 
each line of therapy that includes platinum, as a 
single agent or in combination, will be considered a 
unique treatment line. 
• 
Part 2, Arm A: Bullet point for measurable disease 
per RECIST 1.1 requirement was removed since it 
is already stated in Inclusion #10 (previously 
inclusion #8). 
• 
New criterion #2 was added: All patients in Part 1 
must be refractory to or intolerant of existing 
therapies known to provide clinical benefit for their 
condition. 
• 
New criterion #4 was added: Male patients age 
≥18 years old will be included in Part 1A only. 
• 
Inclusion #7 (previously inclusion #5): Adequate 
renal function will be defined as Estimated 
creatinine clearance ≥60 mL/min for Part 1 and 
≥50 mL/min for Part 2 as calculated using the 
method standard for the institution. 
• 
Inclusion #11 (previously inclusion #9): If female 
patients of nonchildbearing potential meet one of 
the criteria listed, a screening serum pregnancy test 
will not be required. 


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Version Date 
Summary of Changes and Rationale 
• 
Inclusion #11 (previously inclusion #9): Clarified 
that patients are to be without chemotherapy, 
endocrine therapy, or other cause for amenorrhea in 
order to determine that 12 months of amenorrhea is 
consistent with determination of menopausal status. 
Section 4.2 Exclusion Criteria: 
• 
New criterion #3 was added to exclude patients with 
an indwelling catheter used for drainage of 
effusion(s) due to the possibility of increased 
infection risk. 
• 
Exclusion #17 (previously #16): Modified to 
exclude fertile male patients in Part 1A that are 
unwilling or unable to use 2 highly effective 
methods of contraception as outlined in this 
protocol for the duration of the study and for at least 
28 days after the last dose of investigational 
product. 
Section 4.3 Lifestyle Requirements: 
• 
The addition of fertile male patients in Part 1A was 
added to the requirement for use of 2 highly 
effective methods of contraception as outlined in 
this protocol for the duration of the study and for at 
least 28 days after the last dose of investigational 
product. 
• 
Text was deleted from the bullet point describing 
male or female condoms to avoid confusion. 
Section 5.7.2 Supportive Care: 
• 
Text was added to clarify that the description of the 
use of a gonadotropin-releasing hormone agonist 
(GnRH agonist) in this section is relevant for female 
patients currently being treated with a GnRH prior 
to study enrollment. 
Section 5.8 Luteinizing Hormone Releasing Hormone 
(LHRH) Agonist: 
• 
To avoid confusion with Section 5.7.2., text was 
added to clarify that this section refers to patients 
not currently receiving an LHRH agonist prior to 
study entry. 
Section 7.1.3 Laboratory Safety Assessment: 


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Document 
Version Date 
Summary of Changes and Rationale 
• 
The table for Other: Pregnancy test was modified to 
indicate that a negative "sernm" assessment is 
required at screening only. On study assessments 
can include a semm or mine pregnancy assessment. 
Section 7.3 Biomarker and Phannacodynamic 
Assessments: 
• 
 Pait 1 of the study includes dose escalation safety 
cohorts (Pait lA) and dose finding safety cohorts 
(de-escalation, Pait lB). Text was removed for 
clarity. 
I 
Section 9.2.1 Statistical Methods for Dose 
Escalation/De-Escalation: 
• 
Pait 1 of the study includes a dose escalation 
(Pait lA) and dose finding (de-escalation, Part lB) 
component. The addition of"dose finding" and 
de-escalation was added for clarity. 
• 
A clarification was made that the mTPI is a 
rnle-based system. 
• 
The abbreviation for the decision to remain at a 
given dose level was modified from "R" to"S" for 
consistency with other areas of the protocol and the 
decision mies were moved from Section 9.2.2. to 
9.2.1. 
Section 9.2.2 Statistical Methods for Estimating the 
MTD: 
• 
Pait 1 of the study includes a dose escalation 
(Pait lA) and dose finding (de-escalation, Part lB) 
component. The addition of"dose finding" and 
de-escalation was added for clarity. 
• 
Duplicate text was removed. 
Section 9.3.1 Pait 1: 
• 
The addition of"dose finding" and de-escalation 
was added for clarity. 


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Document 
Version Date 
Summary of Changes and Rationale 
REFERENCES: 
Several new references were included. 
Original protocol 
30 October 2017 
N/A 
 
This amendment incorporates all revisions to date, including amendments made at the 
request of country health authorities and institutional review boards (IRBs)/ethics committees 
(ECs). 


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TABLE OF CONTENTS 
LIST OF TABLES .................................................................................................................. 43 
LIST OF FIGURES ................................................................................................................. 43 
APPENDICES ......................................................................................................................... 44 
SCHEDULE OF ACTIVITIES (PART 1, PART 2 AND J-LIC) ........................................... 45 
SCHEDULE OF ACTIVITIES (MODIFIED RELEASE SELECTION COHORT 
WITHIN PART 1C) ........................................................................................................... 50 
SCHEDULE OF PHARMACOKINETIC, BIOPSY AND BIOMARKER 
ASSESSMENTS (PART 1– EXCEPT MODIFIED RELEASE SELECTION 
COHORT WITHIN PART 1C*, AND J-LIC**) – BID DOSING REGIMEN ................. 55 
SCHEDULE OF PHARMACOKINETIC, BIOPSY AND BIOMARKER 
ASSESSMENTS (MODIFIED RELEASE SELECTION COHORT IN PART 1C) ........ 57 
SCHEDULE OF PHARMACOKINETIC, BIOPSY AND BIOMARKER 
ASSESSMENTS – IMMEDIATE RELEASE FORMULATION IN PART 2 
(ARMS A, B AND C) ........................................................................................................ 60 
SCHEDULE OF PHARMACOKINETIC, BIOPSY AND BIOMARKER 
ASSESSMENTS - MODIFIED RELEASE FORMULATION IN PART 2. .................... 62 
SCHEDULE OF ACTIVITIES FOLLOWING AMENDMENT 09: TREATMENT 
AND FOLLOW-UP ........................................................................................................... 64 
1. INTRODUCTION ............................................................................................................... 65 
1.1. Mechanism of Action/Indication ............................................................................ 65 
1.2. Background and Rationale ...................................................................................... 65 
1.2.1. CDK 2/4/6 .................................................................................................. 65 
1.2.2. Hormone Receptor (HR) Positive Breast Cancer ....................................... 66 
1.2.3. Other Cancers ............................................................................................. 67 
1.3. Overview of PF-06873600 ...................................................................................... 67 
1.3.1. Nonclinical Efficacy .................................................................................. 68 
1.3.1.1. In Vivo Tumor Growth Inhibition (MCF7 Tumor Model) ....... 68 
1.3.1.2. Tumor Growth Inhibition (HCC1806 Tumor Model) .............. 69 
1.3.1.3. PF-06873600 Inhibits the Proliferation of Drug Naïve and 
Resistant ER-positive Human Breast Cancer Cells .......................... 71 
1.3.1.4. PF-06873600 Inhibits the Proliferation of CCNE1 High 
Cancer Cells Inherently Resistant to Palbociclib .............................. 72 
1.3.2. Nonclinical Pharmacokinetics (PK) ........................................................... 73 
1.3.3. Nonclinical Safety ...................................................................................... 74 


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1.4. Starting Dose Rationale .......................................................................................... 75 
1.5. Study Rationale ....................................................................................................... 76 
1.5.2. Banked Biospecimens ................................................................................ 77 
1.6. Overview of Letrozole (Femara®) .......................................................................... 77 
1.7. Overview of Fulvestrant (Faslodex®) ..................................................................... 78 
2. STUDY OBJECTIVES AND ENDPOINTS ...................................................................... 79 
3. STUDY DESIGN ................................................................................................................ 81 
3.1. Study Overview ...................................................................................................... 81 
3.1.1. Part 1A PF-06873600 Single Agent Dose Escalation ................................ 84 
3.1.2. Part 1B PF-06873600 Dose Finding in Combination with Endocrine 
Therapy ........................................................................................................... 85 
3.1.3. Part 1C PF06873600 MR Formulation ...................................................... 86 
3.1.4. Starting Dose for Part 1A ........................................................................... 86 
3.1.5. Criteria for Dose Escalation ....................................................................... 87 
3.1.6. DLT Definition........................................................................................... 89 
3.1.7. MTD Definition ......................................................................................... 90 
3.1.8. Recommended Dose for Expansion (RDE) and Recommended Phase 
2 Dose (RP2D) Definition ............................................................................... 90 
3.2. Part 2 PF-06873600 Combination Dose Expansion ............................................... 90 
3.2.1. Part 2/Arm A – PF-06873600 in Combination with Fulvestrant in 
HR-Positive HER2-Negative Locally Advanced or mBC (Second- or 
Third-Line Setting) .......................................................................................... 91 
3.2.2. Part 2/Arm B – PF-06873600 in Combination with Letrozole in 
HR-Positive HER2-Negative Locally Advanced or mBC (naïve to 
CDK4/6 inhibitors). ......................................................................................... 91 
3.2.3. Part 2/Arm C – PF-06873600 in Combination with Fulvestrant in 
HR-Positive HER2-Negative Locally Advanced or mBC (naïve to 
CDK4/6 inhibitors) .......................................................................................... 91 
CCI 
 
4. PATIENT ELIGIBILITY CRITERIA ................................................................................. 92 
4.1. Inclusion Criteria ..................................................................................................... 92 
CCI 


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4.2. Exclusion Criteria .................................................................................................... 97 
4.3. Lifestyle Requirements ............................................................................................ 99 
4.3.1. Potential for Photosensitivity .................................................................... 100 
4.4. Sponsor’s Qualified Medical Personnel ................................................................. 100 
5. STUDY TREATMENTS ................................................................................................... 101 
5.1. Allocation to Treatment ......................................................................................... 101 
5.2. Patient Compliance ................................................................................................ 101 
5.3. Investigational Product Supplies ........................................................................... 102 
5.3.1. Dosage Form(s) and Packaging ................................................................ 102 
5.3.1.1. PF-06873600............................................................................ 102 
5.3.1.2. Letrozole .................................................................................. 102 
5.3.1.3. Fulvestrant ............................................................................... 102 
5.3.2. Preparation and Dispensing ....................................................................... 102 
5.4. Administration ....................................................................................................... 103 
5.4.1. PF-06873600 ............................................................................................. 103 
5.4.2. Food Requirements ................................................................................... 104 
5.4.2.1. Food Requirements .................................................................. 104 
5.4.3. Recommended Dose Modifications .......................................................... 104 
5.4.3.1. Dosing Interruptions ................................................................ 105 
5.4.3.2. Dose Interruption of Patients with Presumed or Active 
COVID-19/SARs-CoV2 Infection ................................................... 105 
5.4.3.3. Dose Delays ............................................................................. 106 
5.4.3.4. Dose Reductions ...................................................................... 106 
5.5. Investigational Product Storage ............................................................................. 107 
5.6. Investigational Product Accountability.................................................................. 109 
5.6.1. Destruction of Investigational Product Supplies ....................................... 109 
5.7. Concomitant Treatment(s) ..................................................................................... 109 
5.7.1. Other Anti-tumor or Experimental Drugs ................................................. 110 
5.7.2. Supportive Care ......................................................................................... 110 
5.7.3. Hematopoietic Growth Factors ................................................................. 111 
5.7.4. Diarrhea Management ............................................................................... 111 
5.7.5. Anti-Diarrheal, Anti-Emetic Therapy ....................................................... 111 


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5.7.6. Anti-Inflammatory Therapy ...................................................................... 111 
5.7.7. Corticosteroids .......................................................................................... 111 
5.7.8. Surgery ...................................................................................................... 111 
5.7.9. Permitted Medications .............................................................................. 112 
5.8. Luteinizing Hormone Releasing Hormone (LHRH) Agonist ................................ 112 
6. STUDY PROCEDURES .................................................................................................... 112 
6.1. Screening ............................................................................................................... 112 
6.2. Study Period .......................................................................................................... 112 
6.3. Follow-up ............................................................................................................... 112 
6.4. Patient Withdrawal ................................................................................................ 113 
7. ASSESSMENTS ................................................................................................................ 115 
7.1. Safety Assessment ................................................................................................. 115 
7.1.1. Pregnancy Testing ..................................................................................... 115 
7.1.2. Adverse Events ......................................................................................... 116 
7.1.3. Laboratory Safety Assessment .................................................................. 116 
7.1.4. Vital Signs and Physical Examination ...................................................... 117 
7.1.5. (12-Lead) Electrocardiogram .................................................................... 117 
7.2. Pharmacokinetics Assessments .............................................................................. 118 
7.2.1. Plasma for PK analysis of PF-06873600 .................................................. 118 
CCI 
 
 
 
 
 
 
7.4. Tumor Response Assessments .............................................................................. 121 
7.5. Tumor Markers ...................................................................................................... 122 
CCI 
 
8. ADVERSE EVENT REPORTING .................................................................................... 123 
8.1. Requirements ......................................................................................................... 123 
8.1.1. Additional Details On Recording Adverse Events on the CRF ................ 124 


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8.1.2. Eliciting Adverse Event Information ....................................................... 125 
8.1.3. Withdrawal from the Study Due to Adverse Events (see also the 
Patient Withdrawal section) .......................................................................... 125 
8.1.4. Time Period for Collecting AE/SAE Information ................................... 125 
8.1.4.1. Reporting SAEs to Pfizer Safety ............................................ 125 
8.1.4.2. Recording Non-serious AEs and SAEs on the CRF ............... 126 
8.1.5. Causality Assessment ............................................................................... 126 
8.1.6. Sponsor’s Reporting Requirements to Regulatory Authorities ................ 126 
8.2. Definitions ............................................................................................................ 126 
8.2.1. Adverse Events ........................................................................................ 126 
8.2.2. Abnormal Test Findings ........................................................................... 127 
8.2.3. Serious Adverse Events............................................................................ 128 
8.2.4. Hospitalization ......................................................................................... 128 
8.3. Severity Assessment ............................................................................................. 130 
8.4. Special Situations ................................................................................................. 130 
8.4.1. Potential Cases of Drug-Induced Liver Injury ......................................... 130 
8.4.2. Exposure to the Investigational Product During Pregnancy or 
Breastfeeding, and Occupational Exposure .................................................. 132 
8.4.2.1. Exposure During Pregnancy (EDP) ........................................ 132 
8.4.2.2. Exposure During Breastfeeding .............................................. 133 
8.4.2.3. Occupational Exposure ........................................................... 134 
8.4.3. Medication Errors ..................................................................................... 134 
8.4.3.1. Medication Errors ................................................................... 134 
9. DATA ANALYSIS/STATISTICAL METHODS ............................................................ 135 
9.1. Analysis Sets ......................................................................................................... 135 
9.2. Statistical Methods and Properties ........................................................................ 136 
9.2.1. Statistical Methods for Dose Escalation/De-Escalation ........................... 136 
9.2.2. Statistical Method for Estimating the MTD ............................................. 137 
9.3. Sample Size Determination .................................................................................. 139 
9.3.1. Part 1 ........................................................................................................ 139 
9.3.2. Part 2 ........................................................................................................ 139 
9.4. Efficacy Analysis .................................................................................................. 140 
9.5. Analysis of Pharmacokinetics and Pharmacodynamics ........................................ 140 


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9.5.1. Analysis of Pharmacokinetics .................................................................. 140 
9.5.1.1. Single-Dose and Steady-State PF-06873600 
Pharmacokinetic Analysis ............................................................... 140 
9.5.2. Population Pharmacokinetic Analysis or 
Pharmacokinetic/Pharmacodynamic (PK/PD) Modeling ............................. 141 
9.5.2.1. Pharmacokinetic/Pharmacodynamic Correlation .................... 141 
9.5.3. Biomarkers ............................................................................................... 142 
9.5.3.1. Analysis of Biomarker Endpoints ........................................... 142 
9.6. Safety Analysis ..................................................................................................... 142 
9.6.1. Analysis of the Primary Endpoint for Part 1 ............................................ 142 
9.6.2. Analysis of Primary Endpoints for Safety for Part 1 and 2 ...................... 142 
9.6.3. Electrocardiogram .................................................................................... 143 
9.7. Data Monitoring Committee ................................................................................. 144 
10. QUALITY CONTROL AND QUALITY ASSURANCE .............................................. 144 
11. DATA HANDLING AND RECORD KEEPING ........................................................... 144 
11.1. Case Report Forms/Electronic Data Record ....................................................... 144 
11.2. Record Retention ................................................................................................ 145 
12. ETHICS ........................................................................................................................... 146 
12.1. Institutional Review Board/Ethics Committee ................................................... 146 
12.2. Ethical Conduct of the Study .............................................................................. 146 
12.3. Patient Information and Consent ........................................................................ 146 
12.4. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH 
GCP ......................................................................................................................... 147 
13. DEFINITION OF END OF TRIAL ................................................................................ 147 
13.1. End of Trial in All Participating Countries ......................................................... 147 
13.2. Primary Completion Date ................................................................................... 147 
14. SPONSOR DISCONTINUATION CRITERIA.............................................................. 147 
15. PUBLICATION OF STUDY RESULTS ....................................................................... 148 
15.1. Communication of Results by Pfizer .................................................................. 148 
15.2. Publications by Investigators .............................................................................. 148 
16. REFERENCES ................................................................................................................ 150 


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LIST OF TABLES 
Table 1. 
Dose Escalation/De-Escalation Decision Rules ....................................... 87 
Table 2. 
PF-06873600 Dose Levels (Immediate Release Formulation) ................ 88 
Table 3. 
Dose Modifications for PF-06873600-Related Toxicity ........................ 107 
Table 4. 
Safety Laboratory Tests ......................................................................... 116 
Table 5. 
Objective Response Status at each Evaluation ....................................... 166 
Table 6. 
Objective Response Status at each Evaluation for Patients with 
Non-Target Disease Only ....................................................................... 167 
 
 
LIST OF FIGURES 
Figure 1. 
Schematic Representation of the CDK 2/4/6 Rb pathway ....................... 65 
Figure 2. 
Tumor Growth Inhibition in MCF7 Tumor Xenograft Model ................. 68 
Figure 3. 
PF-06873600 Inhibits pRb in MCF7 Cells .............................................. 69 
Figure 4. 
Tumor Growth Inhibition in HCC1806 Tumor Xenograft Model 
including Palbociclib ................................................................................ 70 
Figure 5. 
Tumor Growth Inhibition in HCC1806 Tumor Xenograft Model ........... 71 
Figure 6. 
PF-06873600 and Palbociclib Inhibit the Proliferation of MCF7 
ER-positive Breast Cancer Cells .............................................................. 72 
Figure 7. 
PF-06873600 is an Inhibitor of CCNE1 High HCC1806 Cell 
Proliferation Where Palbociclib is Ineffective ......................................... 73 
Figure 8. 
Overall Study Schema .............................................................................. 82 
Figure 9. 
Modified Release Selection Cohort Study Schema (within Part 1C 
through Cycle 1): ..................................................................................... 83 
Figure 10. 
Japanese Lead-in Cohort Schema .......................................................... 175 


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APPENDICES 
Appendix 1. Abbreviations .................................................................................................... 153 
Appendix 2. Detailed Dose Escalation/De-Escalation Scheme for mTPI Design ................. 159 
Appendix 3. ECOG Performance Status* ............................................................................. 162 
Appendix 4. RECIST (Response Evaluation Criteria In Solid Tumors) version 1.1 
Guidelines .............................................................................................. 163 
Appendix 5. List of High Risk Medications for QTc Prolongation ...................................... 169 
Appendix 6. Alternative Measures During Public Emergencies ........................................... 170 
Appendix 7. Country-Specific Requirements ........................................................................ 175 
Appendix 7.1. Japan Specific Requirements ......................................................................... 175 
Appendix 8. Study Procedures After Primary Completion Date (PCD) Until End of 
Trial ........................................................................................................ 182 


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SCHEDULE OF ACTIVITIES (PART 1, PART 2 AND J-LIC) 
The schedule of activities table provides an overview of the protocol visits and procedures. Refer to the ASSESSMENTS section of 
the protocol for detailed information on each assessment required for compliance with the protocol. 
The investigator may schedule visits (unplanned visits) in addition to those listed in the schedule of activities in order to conduct 
evaluations or assessments required to protect the well-being of the patient. 
See Appendix 6 for alternative measures during public emergencies including the COVID-19 pandemic. 
 
Protocol Activity 
Screening 
Active Treatment Phase†- One Cycle = 28 days 
End of Treatment/ 
Withdrawal§ 
Post-Treatment 
Follow-Up* 
Cycles 1 and 2 
Cycles ≥3 
Study Day 
Within 28 days prior 
to registration unless 
specified otherwise 
Day 1‡ 
Day 8 
Day 15 
Day 21 
Day 1 
Visit Window 
±3 days 
±3 days 
±3 days 
±5 days 
±7 days 
Informed Consent1 
X 
Medical/Oncological History2 
X 
Baseline Signs/Symptoms3 
X 
Physical Examination4 
X 
X 
Abbreviated Physical Examination5 
X 
X 
X 
X 
X 
X 
Vital Signs6 
X 
X 
X 
X 
X 
X 
X 
X 
Contraception Check7 
X 
X 
X 
X 
ECOG Performance Status8 
X 
X 
X 
X 
X 
12-Lead ECG9 
X 
X 
X 
C19 
and C29 
X 
C1 only 
X 
X 
Laboratory Studies10 
Hematology 
X 
X 
X 
X 
X 
X 
X 
(X) 
Blood Chemistry 
X 
X 
X11 
X11 
X11 
X 
X 
(X) 
Coagulation 
X 
X 
(X) 
Urinalysis 
X 
X 
(X) 
Pregnancy test 
X 
X 
X 
X 
Viral disease screening12 
X 
Disease Assessment 
Tumor markers (for breast cancer: CA 
15-3 and CEA; Part 1 only 
for ovarian cancer: CA 125) 
X 
X 
X 
X 
CT/MRI Scans of Chest, Abdomen, 
Pelvis, any clinically indicated sites of 
X 
Performed every 8 weeks from C1D1 (±7 days) for the 
first 6 months, and then every 12 weeks (±7 days) 
X13 


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Protocol Activity 
Screening 
Active Treatment Phase†- One Cycle = 28 days 
End of Treatment/ 
Withdrawal§ 
Post-Treatment 
Follow-Up* 
Cycles 1 and 2 
Cycles ≥3 
Study Day 
Within 28 days prior 
to registration unless 
specified otherwise 
Day 1‡ 
Day 8 
Day 15 
Day 21 
Day 1 
Visit Window 
±3 days 
±3 days 
±3 days 
±5 days 
±7 days 
disease, and of bone lesions; Clinical 
evaluation of superficial disease13 
thereafter for up to 2 years. After 2 years, performed 
every 4 months thereafter. 
Follow up for Overall Survival (OS) 
Study Treatment 
Registration14 
X 
PF-0687360015 
◄--► 
Orally on Days 1 to 28 of each Cycle 
Letrozole16 
◄--► 
Orally 2.5 mg once daily as continuous 
daily dosing 
Fulvestrant17 
X 
X 
C1 only 
X 
For pre-/peri-menopausal patients with 
HR-positive HER2-negative advanced or 
mBC only: LHRH agonist18 
Administration according to package insert 
Other Clinical Assessments 
Adverse Event Reporting19 
◄--► 
Concomitant Medications/Treatments20 
◄--► 


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Protocol Activity 
Screening 
Active Treatment Phase†- One Cycle = 28 days 
End of Treatment/ 
Withdrawal§ 
Post-Treatment 
Follow-Up* 
Cycles 1 and 2 
Cycles ≥3 
Study Day 
Within 28 days prior 
to registration unless 
specified otherwise 
Day 1‡ 
Day 8 
Day 15 
Day 21 
Day 1 
Visit Window 
±3 days 
±3 days 
±3 days 
±5 days 
±7 days 
Abbreviations: ◄--►= ongoing/continuous event; C = cycle; CA 125 = cancer antigen 125; CA 15-3 = cancer antigen 15-3; carcinoembryonic antigen = CEA; Day = D; 
ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; EOT = end of treatment; CT = computed tomography; LHRH = luteinizing hormone releasing 
hormone; MRI = magnetic resonance imaging; OS = overall survival; (X) = optional assessment. 
After Cycle 1, Day 1, tests and procedures should be done on schedule, but occasional changes by ±3 days (unless otherwise stated differently) are allowed for holidays, vacations 
and other administrative reasons. 
For Pharmacokinetics and additional sampling requirements, please see Schedule of Pharmacokinetic, Biopsy and Biomarker Assessments (Part 1– Except Modified 
Release Selection Cohort within Part 1C*, AND J-LIC**) – BID Dosing Regimen Table. 
† Active Treatment Phase: Assessments should be performed prior to dosing on the visit day unless otherwise indicated. Acceptable time windows for performing each 
assessment are described in the column headers. One cycle consists of 28 days. Day 1 of any cycle visit should coincide with the day the PF-06873600 treatment begins. If 
there are delays due to toxicity, then the start of the next cycle visit may be delayed until the patient has recovered and can begin study treatment again. The active treatment phase 
is ongoing as long as the patient is receiving PF-06873600. 
‡ Cycle 1/Day 1: Blood chemistry, hematology, coagulation tests, and physical examination are not required if acceptable screening assessment is performed within 7 days prior to 
registration. 
§ End of Treatment/Withdrawal: Visit to be performed as soon as possible but no later than 4 weeks from the last dose of investigational products and prior to initiation of any 
new anti-tumor therapy. Obtain assessments if not completed during the previous 4 weeks on study (or within the previous 8 weeks or 12 weeks [as applicable] for disease 
assessments). 
□ Post Treatment Follow-up: At least 28 days, and no more than 35 days after discontinuation of treatment patients will return to undergo review of concomitant medications, 
vital signs, ECOG, abbreviated physical exam, and assessment for resolution of any treatment related toxicity. Patients continuing to experience toxicity at this point following 
discontinuation of treatment will continue to be followed at least every 4 weeks until resolution or determination, in the clinical judgment of the investigator, that no further 
improvement is expected. 
1. 
Informed Consent: Informed consent must be obtained prior to any protocol required assessments. 
2. 
Medical/Oncological History: To include information on oncology disease including details of diagnosis and prior anticancer treatments (systemic treatment, prior surgery 
and radiotherapy, etc). When available primary diagnosis history should also include known molecular characteristics of the patient’s tumor including mutations, 
amplifications, etc. 
3. 
Baseline Signs/Symptoms: Baseline tumor related signs and symptoms will be recorded at the Cycle 1, Day 1 (C1D1) visit prior to initiating treatment and then reported as 
adverse events during the trial if they worsen in severity or increase in frequency. 
4. 
Physical Examination (PE): A full physical examination including an examination of all major body systems and breasts, height (at screening only), weight, blood pressure 
and pulse rate, which may be performed by a physician, registered nurse or other qualified health care provider, as acceptable according to local regulation. Physical 
examinations will be carried out at Screening and the End of Treatment. 
5. 
Abbreviated PE: A symptom directed exam and an assessment for emergent toxicities or changes from prior visits conducted by a physician, trained physician’s assistant or 
nurse practitioner, as acceptable according to local regulation. 
6. 
Vital Signs: blood pressure and heart rate should be recorded after approximately 5 minutes of rest. 


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Protocol Activity 
Screening 
Active Treatment Phase†- One Cycle = 28 days 
End of Treatment/ 
Withdrawal§ 
Post-Treatment 
Follow-Up* 
Cycles 1 and 2 
Cycles ≥3 
Study Day 
Within 28 days prior 
to registration unless 
specified otherwise 
Day 1‡ 
Day 8 
Day 15 
Day 21 
Day 1 
Visit Window 
±3 days 
±3 days 
±3 days 
±5 days 
±7 days 
7. 
Contraception Check: The investigator/designee, in consultation with the patient, will confirm that the patient has selected 2 appropriate methods of contraception for the 
individual patient (and her partner(s)) from the permitted list of contraception methods and will confirm the patient has been instructed in their consistent and correct use. 
Assessment should be performed within 7 days of C1D1, and Day 1 of every other cycle and at the EOT visit. 
8. 
Performance Status: ECOG scale to be assessed within 14 days prior to the first dose of PF-06873600, and as indicated in the table above. 
9. 
Triplicate 12-lead Electrocardiography (ECG): 
Triplicate 12-lead ECG measurements will be performed at the following time points (single ECG is acceptable, as indicated below): 
• 
Screening (single ECG); 
• 
Cycle 1, Day 1: pre-dose (within 6 hours prior to the morning dose of PF-06873600), and 1 hour after the morning dose of PF-06873600; 
• 
Cycle 1, Day 8: within 30 min prior to the morning dose of PF-06873600; 
• 
Cycle 1, Day 15: pre-dose (within 30 min prior to the morning dose of PF-06873600), and 1 hour after the morning dose of PF-06873600; 
• 
Cycle 2 and subsequent cycles, Day 1: within 30 min prior to the morning dose of PF-06873600; 
• 
Cycle 2, Day 8: pre-dose (within 30 mins prior to the morning dose of PF-06873600); 
• 
EOT (single ECG). 
At each time point, (except those with single ECGs) 3 consecutive 12-lead ECGs will be performed approximately 2 minutes apart to determine mean QTcF interval. When 
coinciding with blood sample draws for PK, ECG assessment should be performed prior to blood sample collection, such that the blood sample is collected at the nominal 
time. If the mean QTcF is prolonged (≥501 msec), the ECGs should be re-evaluated by a qualified person at the institution for confirmation. Additional triplicate ECGs may 
be performed as clinically indicated. 
For patients enrolled in dose level 1 and 2 that undergo intra patient dose escalation (Section 3.1.5), triplicate ECGs should be performed on Day 8 (within 30 min prior to the 
morning dose of PF-06873600) and Day 15 (within 30 min prior to the morning dose of PF-06873600 and 1 hour after the morning dose of PF-06873600) in the first cycle at 
the escalated dose of PF-06873600 and then on Day 1 (within 30 min prior to the morning dose of PF-06873600) of each subsequent cycle. 
10. Laboratory Studies: Screening labs to be performed within 7 days of C1D1. Laboratory assessments can be performed earlier but will have to be repeated to be done within 
7 days of C1D1. For subsequent cycles, pre-dose labs may also be drawn up to 3 days (-3 days/72 hours) in advance of scheduled dosing in order to obtain results prior to 
visit. 
• 
See Table 4 in Section 7.1.3 for a full list of safety laboratory assessments. 
• 
For Urinalysis, dipstick is acceptable but microscopic analyses is required if dipstick abnormal. Additional tests may be performed as clinically indicated. 
• 
Pregnancy test at screening and Day 1 of every other cycle only for women of childbearing potential. Test may be repeated as per request of institutional review 
board/independent ethics committee (IRB/IECs) or if required by local regulations. See Section 7.1.1. 
11. Cycle 1 and Cycle 2, Day 8, 15 and 21: Not required for patients in Part 2. 
12. Viral disease screening tests: Hepatitis B virus surface antigen (HBsAg), hepatitis B core antibody (anti-HBc), (HbcAb), hepatitis B surface antibody (anti-HBs), hepatitis C 
virus antibodies (HCVAb), human immunodeficiency virus testing (HIV), and COVID-19 to be conducted by local laboratory where required by local regulations or if 
warranted by patient history. For Japan only, participants with HBsAb and HBcAb should be monitored with HBV viral load (refer to Appendix 7). 


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Protocol Activity 
Screening 
Active Treatment Phase†- One Cycle = 28 days 
End of Treatment/ 
Withdrawal§ 
Post-Treatment 
Follow-Up* 
Cycles 1 and 2 
Cycles ≥3 
Study Day 
Within 28 days prior 
to registration unless 
specified otherwise 
Day 1‡ 
Day 8 
Day 15 
Day 21 
Day 1 
Visit Window 
±3 days 
±3 days 
±3 days 
±5 days 
±7 days 
13. CT/MRI Scans of Chest, Abdomen, and Pelvis: Tumor assessments will include all known or suspected disease sites. Imaging may include chest, abdomen, and pelvis CT 
or MRI scans. Patients with a history of CNS metastases or cord compression are eligible if there is no evidence of progression at time of study enrollment (baseline MRI 
required). Tumor assessment should be repeated at the end of study visit if more than 8 weeks have passed since the last evaluation. 
14. Registration (enrollment): Patient enrollment, dose level allocation (if applicable) and arm (if applicable) will be assigned by Pfizer or designee. 
15. PF-06873600: To be administered orally twice per day as continuous dosing schedule from Day 1 through Day 28. Study drug will initially be administered orally on a 
continuous basis. If indicated by emerging data, an alternative intermittent dosing regimen may be considered eg, 5 days of continuous dosing and 2 days without dose 
administration. Patients will be required to return all bottles of PF-06873600 as well as the completed patient diary for drug accountability. PF-06873600 immediate release 
tablets are supplied in 68-count bottles, modified release tablets are supplied in 62-count bottles; sites should take this into consideration when scheduling drug dispensing 
visits. See Section 5.4.1 for further information. 
16. Letrozole: To be administered according to the prescribing information. Commercial letrozole comes in a 30-count bottle or 28-count blister pack; sites should take this into 
consideration when scheduling drug dispensing visits. 
17. Fulvestrant: Fulvestrant is given on Day 1, Day 15 of Cycle 1, Cycle 2, Day 1 and monthly thereafter (±3 days) to accommodate dosing on Day 1 of each cycle. Refer to the 
prescribing information for more information. 
18. Luteinizing hormone-releasing hormone (LHRH) agonist: Treatment with a LHRH agonist (eg, goserelin and leuprolide acetate) should be used according to the 
prescribing information for all women with HR-positive HER2-negative advanced or mBC who are pre- or peri-menopausal at study entry. Patients must have commenced 
treatment with LHRH agonist at least 1 week prior to C1D1 for the monthly administration form and at least 3 weeks prior to C1D1 for an LHRH that is administered on an 
every 3 month schedule. 
19. Adverse Events (AEs): AEs should be documented and recorded at each visit using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI 
CTCAE) version 4.03. The time period for actively eliciting and collecting AEs and SAEs (“active collection period”) for each patient begins from the time the patient 
provides informed consent through and including a minimum of 28 calendar days after the last investigational product administration. If the patient begins a new anticancer 
therapy, the period for recording non-serious AEs on the CRF ends at the time the new treatment is started. However, any SAEs occurring during the active collection period 
must still be reported to Pfizer Safety and recorded on the CRF, irrespective of any intervening treatment. 
20. Concomitant Treatments: All concomitant medications and treatments, blood products, as well as nondrug interventions received by patients swill be recorded in the CRF. 


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SCHEDULE OF ACTIVITIES (MODIFIED RELEASE SELECTION COHORT WITHIN PART 1C) 
The schedule of activities table provides an overview of the protocol visits and procedures. Refer to the ASSESSMENTS section of 
the protocol for detailed information on each assessment required for compliance with the protocol. 
The investigator may schedule visits (unplanned visits) in addition to those listed in the schedule of activities below in order to 
conduct evaluations or assessments required to protect the well-being of the patient. 
See Appendix 6 for alternative measures during public emergencies including the COVID-19 pandemic. 
 
Protocol Activity 
Screening 
Lead-in 
Active Treatment Phase†- One Cycle = 28 days 
End of 
Treatment/ 
Withdrawal§ 
Post-Treatment 
Follow-Up∗ 
Cycles 1 and 2 
Cycles ≥3 
Study Day 
Within 28 days 
prior to 
registration 
unless specified 
otherwise 
Day 
-7 
Day 
- 6 
Day 
-4 
Day 
-3 
Day 1‡ 
Day 8 
Day 15 Day 21 
Day 1 
Visit Window 
±3 days ±3 days ±3 days 
±5 days 
±7 days 
Informed Consent1 
X 
Medical/Oncological History2 
X 
Baseline Signs/Symptoms3 
X 
X 
X 
Physical Examination4 
X 
X 
Abbreviated Physical Examination5 
X 
X 
X 
X 
X 
X 
X 
X 
Vital Signs6 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Contraception Check7 
X 
X 
X 
X 
X 
ECOG Performance Status8 
X 
X 
X 
C1 only 
X 
X 
X 
12-Lead ECG9 
X 
X 
X 
X 
X 
C1 only 
X 
C1 only 
X 
X 
Laboratory Studies10 
Hematology 
X 
X 
X 
X 
X 
X 
X 
X 
(X) 
Blood Chemistry 
X 
X 
X 
X 
X 
X 
X 
X 
(X) 
Coagulation 
X 
X 
X 
(X) 
Urinalysis 
X 
X 
X 
X 
(X) 
Pregnancy test 
X 
X 
X 
X 
Viral disease screening11 
X 


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Protocol Activity 
Screening 
Lead-in 
Active Treatment Phase†- One Cycle = 28 days 
End of 
Treatment/ 
Withdrawal§ 
Post-Treatment 
Follow-Up∗ 
Cycles 1 and 2 
Cycles ≥3 
Study Day 
Within 28 days 
prior to 
registration 
unless specified 
otherwise 
Day 
-7 
Day 
- 6 
Day 
-4 
Day 
-3 
Day 1‡ 
Day 8 
Day 15 Day 21 
Day 1 
Visit Window 
±3 days ±3 days ±3 days 
±5 days 
±7 days 
Disease Assessments 
Tumor markers (for breast cancer: CA 
15-3 and CEA 
for ovarian cancer: CA 125 
X 
X 
X 
C2 only 
X 
X 
CT/MRI Scans of Chest, Abdomen, 
Pelvis, any clinically indicated sites of 
disease, and of bone lesions; Clinical 
evaluation of superficial disease12 
X 
Performed every 8 weeks from C1D1 (±7 days) for 
the first 6 months, and then every 12 weeks 
(±7 days) thereafter for up to 2 years. After 2 years, 
performed every 4 months thereafter. 
X 
Study Treatment 
Registration13 
X 
PF-0687360014 
X 
X 
◄--► 
Orally on Days 1 to 28 of each Cycle 
For pre-/peri-menopausal patients with 
HR-positive HER2-negative advanced or 
mBC only: LHRH agonist15 
Administration according to package insert 
Other Clinical Assessments 
Adverse Event Reporting16 
◄--► 
Concomitant Medications/Treatments17 
◄--► 
Abbreviations: ◄--►= ongoing/continuous event; C = cycle; CA 125 = cancer antigen 125; CA 15-3 = cancer antigen 15-3; carcinoembryonic antigen = CEA; Day = D; 
ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; EOT = end of treatment; CT = computed tomography; LHRH = luteinizing hormone releasing 
hormone; MR = Modified Release; MRI = magnetic resonance imaging; OS = overall survival; (X) = optional assessment. 
After Cycle 1, Day 1, tests and procedures should be done on schedule, but occasional changes by ±3 days (unless otherwise stated differently) are allowed for holidays, 
vacations and other administrative reasons. 
For Pharmacokinetics and additional sampling requirements, please see Schedule of Pharmacokinetic, Biopsy and Biomarker Assessments (Modified Release Selection Cohort 
in Part 1C) Table below. 
† Active Treatment Phase: Assessments should be performed prior to dosing on the visit day unless otherwise indicated. Acceptable time windows for performing each 
assessment are described in the column headers. One cycle consists of 28 days. Day 1 of any cycle visit should coincide with the day the PF-06873600 treatment begins. If 
there are delays due to toxicity, then the start of the next cycle visit may be delayed until the patient has recovered and can begin study treatment again. The active treatment 
phase is ongoing as long as the patient is receiving PF-06873600. Prior to Cycle 1 only, a single QD dose of PF-06873600 will be administered on Day -7 and Day -4 in the 
AM in the MR lead in cohort. 
‡ Cycle 1/Day 1: Blood chemistry, hematology, coagulation tests, and physical examination are not required if acceptable screening assessment is performed within 7 days 
prior to registration. 


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Protocol Activity 
Screening 
Lead-in 
Active Treatment Phase†- One Cycle = 28 days 
End of 
Treatment/ 
Withdrawal§ 
Post-Treatment 
Follow-Up∗ 
Cycles 1 and 2 
Cycles ≥3 
Study Day 
Within 28 days 
prior to 
registration 
unless specified 
otherwise 
Day 
-7 
Day 
- 6 
Day 
-4 
Day 
-3 
Day 1‡ 
Day 8 
Day 15 Day 21 
Day 1 
Visit Window 
±3 days ±3 days ±3 days 
±5 days 
±7 days 
§ End of Treatment/Withdrawal: Visit to be performed as soon as possible but no later than 4 weeks from the last dose of investigational products and prior to initiation of any 
new anti-tumor therapy. Obtain assessments if not completed during the previous 4 weeks on study (or within the previous 8 weeks or 12 weeks [as applicable] for disease 
assessments). 
∗Post Treatment Follow-up: At least 28 days, and no more than 35 days after discontinuation of treatment patients will return to undergo review of concomitant medications, 
vital signs, ECOG, abbreviated physical exam, and assessment for resolution of any treatment related toxicity. Patients continuing to experience toxicity at this point following 
discontinuation of treatment will continue to be followed at least every 4 weeks until resolution or determination, in the clinical judgment of the investigator, that no further 
improvement is expected. 
1. 
Informed Consent: Informed consent must be obtained prior to any protocol required assessments. 
2. 
Medical/Oncological History: To include information on oncology disease including details of diagnosis and prior anticancer treatments (systemic treatment, prior 
surgery and radiotherapy, etc). When available primary diagnosis history should also include known molecular characteristics of the patient’s tumor including mutations, 
amplifications, etc. 
3. 
Baseline Signs/Symptoms: Baseline tumor related signs and symptoms will be recorded in the Lead-in period for Cycle 1 (Day -7 and Day -4) and on Day 1 (C1D1) visit 
prior to initiating treatment and then reported as adverse events during the trial if they worsen in severity or increase in frequency. 
4. 
Physical Examination (PE): A full physical examination including an examination of all major body systems and breasts, height (at screening only), weight, blood 
pressure and pulse rate, which may be performed by a physician, registered nurse or other qualified health care provider, as acceptable according to local regulation. 
Physical examinations will be carried out at Screening and the End of Treatment. 
5. 
Abbreviated PE: A symptom directed exam and an assessment for emergent toxicities or changes from prior visits conducted by a physician, trained physician’s assistant 
or nurse practitioner, as acceptable according to local regulation. 
6. 
Vital Signs: blood pressure and heart rate should be recorded after approximately 5 minutes of rest. 
7. 
Contraception Check: The investigator/designee, in consultation with the patient, will confirm that the patient has selected 2 appropriate methods of contraception for 
the individual patient (and her partner(s)) from the permitted list of contraception methods and will confirm the patient has been instructed in their consistent and correct 
use. Assessment should be performed within 7 days of C1D-7, and Day 1 of every other cycle and at the EOT visit. 
8. 
Performance Status: ECOG scale to be assessed within 14 days prior to the first dose of PF-06873600, and as indicated in the table above. 
9. 
Triplicate 12-lead Electrocardiography (ECG): 
Triplicate 12-lead ECG measurements will be performed at the following time points (single ECG is acceptable, as indicated below): 
• 
Screening (single ECG); 
• 
Lead-in, Day -7: pre-dose (within 6 hours prior to the morning dose of PF-06873600), and 6 hour after the morning dose of PF-06873600; 
• 
Lead-in, Day -4: pre-dose (within 6 hours prior to the morning dose of PF-06873600), and 6 hour after the morning dose of PF-06873600; Cycle 1, Day 1: pre-dose 
(within 6 hours prior to the morning dose of PF-06873600), and 1 hour after the morning dose of PF-06873600; 
• 
Cycle 1, Day 8: within 30 min prior to the morning dose of PF-06873600; 


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Protocol Activity 
Screening 
Lead-in 
Active Treatment Phase†- One Cycle = 28 days 
End of 
Treatment/ 
Withdrawal§ 
Post-Treatment 
Follow-Up∗ 
Cycles 1 and 2 
Cycles ≥3 
Study Day 
Within 28 days 
prior to 
registration 
unless specified 
otherwise 
Day 
-7 
Day 
- 6 
Day 
-4 
Day 
-3 
Day 1‡ 
Day 8 
Day 15 Day 21 
Day 1 
Visit Window 
±3 days ±3 days ±3 days 
±5 days 
±7 days 
• 
Cycle 1, Day 15: pre-dose (within 30 min prior to the morning dose of PF-06873600), and 1 hour after the morning dose of PF-06873600; 
• 
Cycle 2 and subsequent cycles, Day 1: within 30 min prior to the morning dose of PF-06873600; 
• 
EOT (single ECG). 
At each time point, (except those with single ECGs) 3 consecutive 12-lead ECGs will be performed approximately 2 minutes apart to determine mean QTcF interval. 
When coinciding with blood sample draws for PK, ECG assessment should be performed prior to blood sample collection, such that the blood sample is collected at the 
nominal time. If the mean QTcF is prolonged (≥501 msec), the ECGs should be re-evaluated by a qualified person at the institution for confirmation. Additional triplicate 
ECGs may be performed as clinically indicated. 
10. Laboratory Studies: Screening labs to be performed within 7 days of C1D-.7, assessments can be performed earlier but will have to be repeated to be done within 7 days 
of C1D1. For subsequent cycles, pre-dose labs may also be drawn up to 3 days (-3 days/72 hours) in advance of scheduled dosing in order to obtain results prior to visit. 
• 
See Table 4 in Section 7.1.3 for a full list of safety laboratory assessments. 
• 
For Urinalysis, dipstick is acceptable but microscopic analyses is required if dipstick abnormal. Additional tests may be performed as clinically indicated. 
• 
Pregnancy test at screening and Day 1 of every other cycle only for women of childbearing potential. Test may be repeated as per request of institutional review 
board/independent ethics committee (IRB/IECs) or if required by local regulations. See Section 7.1.1. 
11. Viral disease screening tests: Hepatitis B virus surface antigen (HBsAg), hepatitis B core antibody (anti-HBc), (HbcAb), hepatitis B surface antibody (anti-HBs), 
hepatitis C virus antibodies (HCVAb), human immunodeficiency virus testing (HIV) and COVID-19 to be conducted by local laboratory where required by local 
regulations or if warranted by patient history. 
12. CT/MRI Scans of Chest, Abdomen, and Pelvis: Tumor assessments will include all known or suspected disease sites. Imaging may include chest, abdomen, and pelvis 
CT or MRI scans. Patients with a history of CNS metastases or cord compression are eligible if there is no evidence of progression at time of study enrollment (baseline 
MRI required). Tumor assessment should be repeated at the end of study visit if more than 8 weeks have passed since the last evaluation. 
13. Registration (enrollment): Patient enrollment, dose level allocation (if applicable) and arm (if applicable) will be assigned by Pfizer or designee. 
14. PF-06873600: To be administered orally twice per day as continuous dosing schedule from Day 1 through Day 28. Patients will be required to return all bottles of 
PF-06873600 as well as the completed patient diary for drug accountability. See Section 5 for further information. PF-06873600 doses of the modified release 
formulations (with two different release rates) will be administered during the lead-in period. During the Lead-in period, a single dose of PF-06873600 with the modified 
release formulation will be administered on Day -7 and Day -4 in the AM. Starting from Cycle 1 Day 1, PF-06873600 tablets of the immediate-release formulation will 
be administered orally on a continuous basis. If indicated by emerging data, an alternative intermittent dosing regimen may be considered eg, 5 days of continuous dosing 
and 2 days without dose administration. PF-06873600 immediate release tablets are supplied in 68-count bottles, modified release tablets are supplied in 62-count bottles; 
sites should take this into consideration when scheduling drug dispensing visits. 
15. Luteinizing hormone-releasing hormone (LHRH) agonist: Treatment with a LHRH agonist (eg, goserelin and leuprolide acetate) should be used according to the 
prescribing information for all women with HR-positive HER2-negative advanced or mBC who are pre- or peri-menopausal at study entry. Patients must have 
commenced treatment with LHRH agonist at least 1 week prior to C1D-7 for the monthly administration form and at least 3 weeks prior to C1D1 for an LHRH that is 
administered on an every 3 month schedule. 


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Protocol Activity 
Screening 
Lead-in 
Active Treatment Phase†- One Cycle = 28 days 
End of 
Treatment/ 
Withdrawal§ 
Post-Treatment 
Follow-Up∗ 
Cycles 1 and 2 
Cycles ≥3 
Study Day 
Within 28 days 
prior to 
registration 
unless specified 
otherwise 
Day 
-7 
Day 
- 6 
Day 
-4 
Day 
-3 
Day 1‡ 
Day 8 
Day 15 Day 21 
Day 1 
Visit Window 
±3 days ±3 days ±3 days 
±5 days 
±7 days 
16. Adverse Events (AEs): AEs should be documented and recorded at each visit using the National Cancer Institute Common Terminology Criteria for Adverse Events 
(NCI CTCAE) version 4.03. The time period for actively eliciting and collecting AEs and SAEs (“active collection period”) for each patient begins from the time the 
patient provides informed consent through and including a minimum of 28 calendar days after the last investigational product administration. If the patient begins a new 
anticancer therapy, the period for recording non-serious AEs on the CRF ends at the time the new treatment is started. However, any SAEs occurring during the active 
collection period must still be reported to Pfizer Safety and recorded on the CRF, irrespective of any intervening treatment. 
17. Concomitant Treatments: All concomitant medications and treatments, blood products, as well as nondrug interventions received by patients will be recorded in the 
CRF. 


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SCHEDULE OF PHARMACOKINETIC, BIOPSY AND BIOMARKER ASSESSMENTS (PART 1-EXCEPT MODIFIED 
RELEASE SELECTION COHORT WITHIN PART 1C*, AND J-LIC**)-BID DOSING REGIMEN 
 
Cyclel 
Cycle 2 
Cycle EOT 
3 
Day 1 
Day8 
Day15 
Dayl 
Day 1 
ours Post-Dose*** 
creening o• 0.251 0.51 
1 
2 
3 
4 
6 12b o• o• 0.251 0.51 
1 
2 
3 
4 
6 
12b o• 
4 
o• 
±3 ±3 
min min 
±6 
min 
±15 
min 
±20 
min 
±25 
min 
±40±120 
min min 
±3  ±3 
min min 
±6 
min 
±15 ±20±25±40 
min min min min 
±120 
min 
±60 
min 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
xc 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Abbreviation: CNA = circulating nucleic acid; PK= pha1macokinetic; EOT = End of Treatment; (X) = optional. 
*Table for Pait 2 will be created prior to initiation of enrolhnent in any Anu of Pait 2. Table for Part lC MR Fo1mulation lead in is below. 
**The necessity of hospitalization and its duration ofDLT assessment period for Japanese participants in J-LIC are based on the investigator's decision (See Appendix 7). 
***Collection Time: Sampling times are related to the morning dose. 
tSample collection windows: All other sampling should be within the protocol specified window in the table above. 
12 hour sampling: 12 hour assessments will shift to 24 hours (ie, Day 2 and Day 16-not shown in table above) in patients treated on PF-06873600 QD regimen; sample should 
be collected within 30 min prior to the moming dose of PF-06873600 (See Section 3). 
Details for handling of all specimens including processing, storage, and shipment, will be provided in the Laboratory Manual. 
a. 
Pre-dose sample collection: 
• 
Cycle 1, Day 1: within 6 hotu·s prior to the moming dose of PF-06873600); 
• 
Cycle 1, Day 8, Day 15 and Day 1 of subsequent cycles: within 30 min prior to the moming dose of PF-06873600. 
b. 
Prior to the evening dose for BID regimen. 
c. 
 Pharmacokinetics (PK): Blood samples of 3 mL each (to obtain at least 1 mL of plasma) for detemtination of plasma PF-06873600 drug concentrations will be collected at 
the time points above (NOTE: PK sampling time points may change, pending PK data from early dose levels). Additional PK blood samples may be collected at time of 
occtu1·ence of nnexpected or serious adverse events. On days when patients require pre-dose PK sampling assessments, the moming dose of PF-06873600 should be held 
(NOT taken) prior to the study visit. On those days, the PF-06873600 moming dose can then be taken after the pre-dose PK sampling is obtained. After C15Dl, no 
additional PK samples will be collected with the exception of the EOT sample. On C2D1, the 4-hotu· PK sample will be collected in patients who have consented to C2D1 on­ 
treatment biopsies only. 


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I 
 
Cyclel 
Cycle 2 
Cycle 
3 
EOT 
Day 1 
Day8
Day 15 
Dayl 
Day 1 
o• 0.251 o.51 
1 
2 
3 
4 
6 
12h 
o• 
o• 0.251 o.51 
1 
2 
3 
4 
o• 
4 
o• 
±3 
±3 
±6 ±15 ±20 ±25 ±40 ±120 
±3  ±3 
±6 ±15 ±20 ±25 ±40 ±120 
±60 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
£ 
 ernm 1ospec1men or ym1 me 
nase assay: ne 
ooo specimen optimized for semm preparation will be collected and analyzed for phanuacodynamic 
markers, such as thym.idine kinase (TK) activity. If the PK assessments are postponed, this associated blood sample should also be postponed as well, and resume with the 
PK collection. 
g. 
Cycle 3 only: (pre-dose, aligned with the first tumor assessment on treatment). 
h. 
 Blood Sample for Circulating Nucleic Acid (CNA) Profiling: A IO mL-blood specimen optimized for plasma preparation for circulating nucleic acid analysis will be 
collected. 
1. 
Serum Biomarkers: In addition one 3 mL-blood s ecimen o ti.mi.zed for semm  re aration will be collected and anal  ed for levels of semm biomarkers. 
J· 
 
 
 
 
 
I 
I. 
 
odified Release (MR) dose escalation coho11s only, there will be no 0.25 and 0.5 hotu·s post-dose PK samples taken in 
Cycle I on Day I and Day I5, this includes MR dosing in Pait IB. 


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SCHEDULE OF PHARMACOKINETIC, BIOPSY AND BIOMARKER ASSESSMENTS (MODIFIED RELEASE 
SELECTION COHORT IN PART lC) 
 
Lead-in (Part lC) 
Day-7 
Day-6 
Day-4 
Day-3 
1 
2 
3 
4 
6 
12b 
18 
24 
o• 
2 
3 
4 
6 
12 
18 
24 
±6 ±15 ±20 ±25 ±40 ±120 
±120 
±40min 
±6 ±15 ±20 ±25 ±40 ±120 
±120min 
±40min 
min min min min min 
min 
min 
n min min min
min min 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Abbreviation: CNA = circulating nucleic acid; PK= phannacokinetic; EOT = End of Treatment; (X) = optional. 
**Collection Time: Sampling times are related to the morning dose. 
tSample collection windows: All other sampling should be within the protocol specified window in the table above. 
12 hour sampling: 12 hour assessments will shift to 24 hours (ie, Day 2 and Day 16 -not shown in table above) in patients treated on PF-06873600 QD regimen; sample should 
be collected within 30 min prior to the morning dose of PF-06873600 (See Section 3). 
Details for handling of all specimens including processing, storage, and shipment, will be provided in the Laboratory Manual. 
a. 
Pre-dose sample collection: 
• 
Lead-in, Day -7 and Day -4: within 6 hours prior to the morning dose of PF-06873600; 
• 
Cycle I, Day I: within 6 hours prior to the morning dose of PF-06873600; 
• 
Cycle I, Day 8, Day 15 and Day I of subsequent cycles: within 30 min prior to the morning dose of PF-06873600. 
b. 
Prior to the evening dose for BID regimen. 
c. 
 Pharmacokinetics (PK): Blood samples of 3 mL each (to obtain at least I mL of plasma) for detennination of plasma PF06873600 dmg concentrations will be collected at 
the time points above (NOTE: PK sampling time points may change, pending PK data from earlydose levels). Additional PK blood samples may be collected at time of 
occtm·ence of unexpected or serious adverse events. On days when patients require predose PK sampling assessments, the morning dose of PF-06873600 should be held 
(NOT taken) prior to thestudy visit. On those days, the PF-06873600 morning dose can then be taken after the predose PK sampling is obtained. 
I 


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Lead-in (Part 1C) 
Day-3 
Day-7 
Day-6 
Day-4 
 
ours Post-Dose** 
o• 
1 
2 
3 
4 
6 
12b 
18 
24 
o• 
2 
3 
4 
6 
12 
isit Windowt 
±6 ±15 ±20 ±25 ±40 ±120 ±120 
±40 min 
±6 ±15 ±20 ±25 ±40 ±120 
min min min min min 
min 
min 
min min 
min 
min min 


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Abbreviation: CNA = circulating nucleic acid; PK= phannacokinetic; EOT = End of Treatment; (X) = optional. 
**Collection Time: Sampling times are related to the morning dose. 
tSample collection windows: All other sampling should be within the protocol specified window in the table above. 
12 hour sampling: 12 hour assessments will shift to 24 hours (ie, Day 2 and Day 16 -not shown in table above) in patients treated on PF-06873600 QD regimen; sample should 
be collected within 30 min prior to the morning dose of PF-06873600 (See Section 3). 
Details for handling of all specimens including processing, storage, and shipment, will be provided in the Laboratory Manual. 
a. 
Pre-dose sample collection: 
• Lead-in, Day-7 and Day-4: within 6 hours prior to the morning dose of PF-06873600; 
• Cycle 1, Day 1: within 6 hours prior to the morning dose of PF-06873600; 
• Cycle 1, Day 8, Day 15 and Day 1 of subsequent cycles: within 30 min prior to the morning dose of PF-06873600. 
b. 
Prior to the evening dose for BID regimen. 
c. 
 Pharmacokinetics (PK): Blood samples of3 mL each (to obtain at least 1 mL of plasma) for detennination of plasma PF-06873600 dmg concentrations will be collected at 
the time points above (NOTE: PK sampling time points may change, pending PK data from earlydose levels). Additional PK blood samples may be collected at time of 
occtm·ence of unexpected or serious adverse events. On days when patients require predose PK sampling assessments, the morning dose of PF-06873600 should be held 
(NOT taken) prior to thestudy visit. On those days, the PF-06873600 morning dose can then be taken after the predose PK sampling is obtained. 
d. 
 
I 
Cycle 1 (Part lC) 
0.25 
±3 
 
 
 
 
Day 15 
o• 
Cycle 2 
Day 1 
o• 
 
 
 
o• 
 
Day 1 
 
 
 
 
o• 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
creening 


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SCHEDULE OF PHARMACOKINETIC, BIOPSY AND BIOMARKER ASSESSMENTS - IMMEDIATE RELEASE 
FORMULATION IN PART 2 (ARMS A, BAND C) 
 
Cyclel 
Cycle 
EOT 
Dayl 
Day8 
Day15 
Dayl 
Hours Post-Dose** 
Screening o• 
1 
2 
4 
6 
o• 
o• 
1 
2 
4 
6 
o• 
4 
Visit Windowt 
±6min 
±15 min 
±25 min 
±40 min 
±6min 
±15 min ±25 min ±40 min
±60 
min 
PF-06873600 PK blood 
samplingb 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
FoodDia1y 
X 
X 
X 
X 
I 
I 
■- 
■- 
Blood Sample for Circulating 
X 
X 
■ 
I 
Abbreviation: CNA = circulating nucleic acid; PK= pharmacokinetic; EOT = End of Treatment; (X) = optional. 
**Collection Time: Sampling tintes are related to the morning dose. 
tSample collection windows: All other sampling should be within the protocol specified window in the table above. 
Details for handling of all specimens including processing, storage, and shipment, will be provided in the Laboratory Manual. 
a. 
Pre-dose sample collection: 
• 
Cycle I, Day 1: within 6 hours prior to the moming dose of PF-06873600); 
• 
Cycle I, Day 8, Day I5 and Day 1 of subsequent cycles: within 30 min prior to the moming dose of PF-06873600. 
b. 
Pharmacokinetics (PK): Blood samples of3 mL each (to obtain at least 1 mL of plasma) for detenuination of plasma PF-06873600 dmg concentrations may be collected at 
tinte of occtm·ence of unexpected or serious adverse events. 


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e. 
 Blood Sample for Circulating Nucleic Acid (CNA) Profiling: A 10 mL blood specimen optimized for plasma preparation for circulating nucleic acid analysis will be 
collected. 
f. 
 
 
 
 
I 
 
 
o• 
1 
4 
 
 
6 
o• 
o• 
1 
4 
6 
 
 
o• 
 
 
2 
 
2 
 
 
 
 
4 
 
min 
 


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Scl'eening o•
1 
2 
 
 
 
 
 
 
 
 
 
 
Cycle 2:2 
Day 1 
 
 
 
 
 
 
 
X 
X 
 
min 
X 
 
X 
X 
 
min 
X 
±15 min  ±25 min 
±180 min 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
SCHEDULE OF PHARMACOKINETIC, BIOPSY AND BIOMARKER ASSESSMENTS - MODIFIED RELEASE 
FORMULATION IN PART 2. 
 
Abbreviation: CNA = circulating nucleic acid; PK= phannacokinetic; EOT = End of Treatment; (X) = optional. 
**Collection Time: Sampling times are related to the morning dose. 
tSample collection windows: All other sampling should be within the protocol specified window in the table above. 
Details for handling of all specimens including processing, storage, and shipment, will be provided in the Laboratory Manual. 
a. 
Pre-dose sample collection: 
• 
Cycle I, Day I: within 6 hours prior to the moming dose of PF-06873600; 
• 
Cycle I, Day 8, Day I5 and Day I of subsequent cycles: within 30 min prior to the moming dose of PF-06873600. 
b. 
Prior to the evening dose for BID regimen. 
c. 
 Pharmacokinetics (PK): Blood samples of3 mL each (to obtain at least I mL of plasma) for detenuination of plasma PF-06873600 dmg 
concentrations will be collected at the time points above (NOTE: PK sampling time points may change, pending PK data from earlydose levels). 
Additional PK blood samples may be collected at time of occurrence of unexpected or serious adverse events. On days when patients require predose 
PK sampling assessments, the moming dose of PF-06873600 should be held (NOT taken) prior to the study visit. On those days, the PF-06873600 
moming dose can then be taken after the predose PK sampling is obtained. After CI SDI no additional PK samples will be collected. On C2Dl, the 
4-hour PK sample will be collected in patients who have consented to C2Dl on-treatment biopsies only. 
I 


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Cycle! 
Cycle 2:2 
EOT 
Dayl 
Day8 
DaylS 
Day 1 
ours Post-Dose** 
Scl'eening o•
1 
2 
4 
6 
1 
2 
±15 min 
4 
6 
±180 min 
4 
±60 min 
isit Windowt 
±6 
±15 
±25 min ±40 min 
±6 
 
 
 
 
 
 
 
 
 
 
f. 
Cycle 2 only. 
g. 
 Blood Sample for Circulating Nucleic Acid (CNA) Profiling: A 10 mL blood specimen optimized for plasma preparation for circulating nucleic 
acid analysis will be collected. 
I 
 
 
I 


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SCHEDULE OF ACTIVITIES FOLLOWING AMENDMENT 09: TREATMENT AND FOLLOW-UP 
 
Protocol Activity 
Active Treatment Phase 
One Cycle = 28 days 
End of Treatment§ 
Post-Treatment Follow-Up* 
Study Day 
Cycle X Day 1 
Visit Window 
±7 days 
±7 days 
PF-068736001 
Orally on Days 1 to 28 of each Cycle 
Fulvestrant2 
X 
Adverse Event Reporting3 
X 
X 
X 
§ End of Treatment: Visit to be performed as soon as possible from the last dose of investigational products 
* Post-Treatment Follow-up: At least 28 days, and no more than 35 days after discontinuation of treatment. Patients continuing to experience toxicity at this point following 
discontinuation of treatment will continue to be followed at least every 4 weeks until resolution or determination, in the clinical judgment of the investigator, that no further improvement is 
expected. 
1. 
PF-06873600: To be administered orally twice per day as continuous dosing schedule from Day 1 through Day 28. Patients will be required to return all bottles of PF-06873600 as well 
as the completed patient diary for drug accountability. 
2. 
Fulvestrant is given monthly to accommodate dosing on Day 1 of each cycle. Refer to the prescribing information for more information 
3. 
Adverse Events (AEs): AEs should be documented and recorded at each visit using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) 
version 4.03. The time period for actively eliciting and collecting AEs and SAEs (“active collection period”) for each patient begins from the time the patient provides informed 
consent through and including a minimum of 28 calendar days after the last investigational product administration. If the patient begins a new anticancer therapy, the period for 
recording non-serious AEs on the CRF ends at the time the new treatment is started. However, any SAEs occurring during the active collection period must still be reported to Pfizer 
Safety and recorded on the CRF, irrespective of any intervening treatment. 


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1. INTRODUCTION 
1.1. Mechanism of Action/Indication 
PF-06873600 is an inhibitor of cyclin-dependent kinases (CDK) 2, 4 and 6 that is being 
investigated in women of any menopausal status and men with hormone receptor (HR) 
positive human epidermal growth factor receptor 2 (HER2) negative advanced or metastatic 
breast cancer (mBC) and patients with other tumor types that have potential to have increased 
Cyclin E expression/CDK 2 activity, including locally recurrent/advanced or metastatic triple 
negative breast cancer (women and men) and women with advanced platinum resistant 
ovarian cancer. 
1.2. Background and Rationale 
1.2.1. CDK 2/4/6 
Cell division is a highly regulated, conserved process by which normal cells only divide 
when appropriate and checkpoint requirements have been met (Kastan & Bartek, 2004).1 
The cell cycle involves distinctive phases for mitosis and deoxyribonucleic acid (DNA) 
synthesis with growth phases interspersed (Figure 1, M. L. Coleman, et al, 2004).2 During 
the Gap 1 phase (G1), cells normally require CDK4/6-cyclin D1 (CCND1), then 
CDK2-cyclin E1 (CCNE1) to phosphorylate the retinoblastoma (Rb) tumor suppressor 
releasing E2F transcription factors to regulate gene expression leading to S-phase and 
subsequent entry into Gap 2 phase (G2) and subsequent cell cycle progression (Choi & 
Anders, 2014).3 Cancer cells have circumvented these checkpoints with mutations in many 
of these proteins resulting in amplification of CCND1 or CCNE1, Rb deletion, etc 
(Herrera-Abrue et al, 2016).4 Thus, selectively-targeted cell cycle CDKs have been 
considered logical targets as cancer therapies (Malumbres & Barbacid, 2009).5 
Figure 1. Schematic Representation of the CDK 2/4/6 Rb pathway 
 


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1.2.2. Hormone Receptor (HR) Positive Breast Cancer 
It is estimated that by the year 2015, there were more than 3.5 million women living in the 
United States with a history of invasive breast cancer. Seventy-five percent of breast cancer 
survivors (more than 2.6 million women) are ages 60 years or older, while 7% are younger 
than 50 years. The median age of women at diagnosis is 61 years and approximately 19% of 
breast cancers are diagnosed in women ages 30 to 49 years, and 44% occur among women 
who are age 65 years or older (Miller, 2016).6 Male breast cancer is rare, with fewer than 
1% of all breast carcinomas reported in men with an estimated 2470 new cases reported in 
the United States in 2017. The disease can occur in men of any age; however, the median 
age at diagnosis is between 60-70 years old. The risk increases with age and those with high 
estrogen levels or diseases associated with hyperestrogenism, radiation exposure to the 
breast/chest or a family history of breast cancer.34 Overall mortality associated with 
metastatic breast cancer remains high (Shah & Cristofanilli, 2017).7 
Approximately 70-80% of new breast cancers express the estrogen (ER) and/or progesterone 
receptor (Yee and Potter, 2009; Turner, NC et al, 2015).8,9 It was reported that 92% of male 
breast cancers were estrogen-receptor-positive.35 Up to 60% of patients with ER-positive 
tumors may benefit from hormonal therapy (Pietras, 2006).10 Unfortunately, the majority of 
these women will develop resistance to endocrine therapy at some point during treatment 
(Dawood and Cristofanilli, 2007).11 Cancer develops through unchecked progression of the 
cell cycle where checkpoint controls are lost subsequently permitting uncontrolled cellular 
proliferation. Multiple genetic lesions have been identified that augment this process in 
various tumor types. For instance, CCND1 and CCNE1 amplification are common, as are 
deletions of Rb and the endogenous CDK4-CCND1 inhibitor p16 (INK4a, encoded by the 
CDKN2A gene). The prediction that specific pharmacological targeting of the CDK4/6-Rb 
axis would be efficacious in cancer was borne out by the clinical success of the first CDK4/6 
inhibitor palbociclib in combination with anti-estrogens in ER-positive breast cancer 
(Cristofanilli et al, 2016).12 
A more contemporary approach to treat HR-positive advanced or metastatic breast cancer 
involves combining novel agents with existing endocrine therapy to block pathways enabling 
partial or complete endocrine resistance. Palbociclib was the first selective CDK4/6 inhibitor 
proven clinically efficacious in HR-positive breast cancer in combination with anti-hormonal 
therapy in both the first and second line settings (DeMichele et al, 2015; Finn et al, 2016; 
Cristofanilli et al, 2016).13,33,12 More recently additional CDK4/6 inhibitors have been 
approved including ribociclib in combination with anti-hormonal therapy in the first line 
setting along with abemaciclib in combination with anti-hormonal therapy in a second line 
setting and as monotherapy in a third line setting. 
(https://www.pharma.us.novartis.com/sites/www.pharma.us.novartis.com/files/kisqali.pdf. 
Accessed October 04, 2017);14 (https://www.verzenio.com/hcp/. Accessed October 04, 
2017).15 


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While presenting valuable treatment options, these targeted therapies may experience initial 
clinical benefit followed by acquired resistance through mutation or activation of orthologous 
pathways (Chong & Janne, 2013).16 Resistance to CDK4/6 inhibition in preclinical cellular 
models can be overcome by adding CDK2 inhibition (Herrera-Abrue et al, 2016).4 
Therefore, a CDK2/4/6 inhibitor with the ability to treat both intrinsic and acquired resistance 
to CDK4/6, such as treatment with PF-06873600, may have the potential to fill a very high 
unmet medical need for breast cancer patients requiring therapy. 
1.2.3. Other Cancers 
Activation of CDK2 is observed where Cyclin E (encoded by CCNE1 or CCNE2 genes) is 
amplified, representing a common event in triple negative breast cancer (TNBC) and ovarian 
cancer (90-100% of triple negative breast cancer (TNBC) and ~30% of serous ovarian 
carcinoma based on current TCGA data) (The Cancer Genome Atlas Network, 2012, 
Nakayama et al, 2010).17,18 In addition, the genetic predisposition of pancreatic 
adenocarcinoma, head and neck squamous cell carcinoma, and non-small cell lung cancer to 
lose the tumor suppressor CDKN2A (p16) through mutation or deletion (>90%, 22% and 
80% respectively) also implies a CDK2 driven mechanism of growth (Makohon-Moore and 
Iacobuzio-Donahue 2016, Kalu and Johnson 2016, Cooper et al 2013).19,20,21 Further Cyclin 
D1 amplifications are also common in head and neck squamous carcinoma (31%) implicating 
the CDK 2/4/6 axis as a credible target across multiple tumor types. 
While currently no CDK4/6 inhibitors are approved for treatment of the malignancies 
mentioned above, specific targeting of CDK2 in addition to CDK4 and CDK6 represents a 
novel approach to address additional high unmet medical need indications. Importantly, 
preclinical models testing PF-06873600 in pancreatic, non-small cell, head and neck, triple 
negative breast, and ovarian cancer have all shown evidence of anti-tumor activity. Further, 
translation of these in vitro findings to in vivo models has been successful in triple negative 
breast, ovarian and head and neck cancer. In these models, significant tumor growth 
inhibition has been observed at doses predicted to be achievable and tolerable in humans. 
1.3. Overview of PF-06873600 
PF-06873600 is a potent, small molecule inhibitor of CDK2/4/6 that attenuates 
phosphorylation of the tumor suppressor retinoblastoma (Rb) resulting in prevention of cell 
cycling and tumor growth. During cell cycle progression, growth signals allow cyclin D to 
form a complex with CDK 4 or 6 and Cyclin E with CDK2. Subsequently, Rb becomes 
hyperphosphylated, and bound E2F is released. By inhibiting CDK2 in addition to CDK4/6, 
PF-06873600 may potentially provide additional benefit by further regulating and attenuating 
cell cycle progression to S-phase and disrupting malignant proliferation. 


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700  
Grp2. Fulvestranl 10"'9'}<gSC 
G<p3.Palt>ociclib 50 f1V'k9 + Fulveslranl 10 f1V'k9 
G<p4. Palbocidit>50 mg/kgPO OD 
Gr . PF-06873600 50mg/l<gPO 81D 
Grp6. PF-06873600 25 mg,lqjPO 81D 
Grp7. PF-06873600 50 mg/l<g• Fulvestranl 10 lll(1kg 
G<p8, PF-06873600 25 mg/kg• Fulvewant 
 
 
 
 
 
 
' 
' 
' 
 
 
1.3.1. Nonclinical Efficacy 
1.3.1.1. In Vivo Tumor Growth Inhibition (MCF7 Tumor Model) 
The MCF7 cell line derived from ER positive HER2 negative breast adenocarcinoma is 
commonly used as a model of response and resistance to ER-targeted therapy 
(Adrian V. Lee et al 2015).22 Oral administrntion of PF-06873600 was efficacious in the 
ER-positive breast cancer mouse xenograft model MCF7 as shown in Figure 2. Significant 
tumor growth inhibition (TGI) compared to vehicle was observed at a minimlllll dose of 
10 mg/kg PF-06873600 administered twice daily (BID) in combination with 10 mg/kg 
fulvestrant, administered subcutaneous (SC) (Day 46, 57% TGI; p=0.0001, Pfizer internal 
data). Further, a dose-dependent relationship was observed where TGI was observed at the 
lowest dose (10 mg/kg PF-06873600 administered twice daily (BID) in combination with 
10 mg/kg fulvestrant, administered SC) and the greatest TGI was observed in the highest 
dose (50 mg/kg PF-06873600 administered BID in combination with 10 mg/kg fulvestrant, 
administered SC). Palbociclib was efficacious in this model as both a single agent and in 
combination with fulvesti·ant albeit with better anti-tumor activity in the combination than as 
a single agent. 
Figure 2. Tumor Growth Inhibition in MCF7 Tumor Xenograft Model 
 
 
• 
Grpl, Vehicle 
MCF7 Tumor Growth Inhibition 
 
 
 
 
20 
30 
40 
50 
Days Post Implant 
 
Mice propagating MCF7 ER-positive breast cancer cell tumor xenografts were dosed orally BID with the CDK2/4/6 
inhibitor PF-06873600 staiting on Day 25 post cell implant at 50 mg/kg (100 mg/kg total daily dose) and 25 mg/kg 
(50 mg/kg total daily dose) or in combination with 10 mg/kg fulvestrant delivered SC at 50 mg/kg (100 mg/kg total daily 
dose), 25 mg/kg (50 mg/kg total daily dose) and 10 mg/kg (20 mg/kg total daily dose). Dosing regimens ai·e illustrated with 
a1wws for fulvestrant, solid black line for PF-06873600 and dashed line for 50 mg/kg dose of PF-06873600 (in single agent 
[Gip5) and combination [Gip7]). Control coho1ts of mice were dosed with palbocicl.ib 50 mg/kg QD, Fulvestrant 10 mg/kg 
SC, palbociclib (50 mg/kg QD)/Fulvestrant (10 mg/kg SC) in combination or vehicle sta1ting 25 days post cell implant. 
Tumor growth was measured on 28, 32, 35, 39, 42 and 46 days as indicated. Error bars represent standard error of the mean 
tumor volume. 


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1.3.1.1.1. In Vivo PF-06873600 Inhibits pRb in MCF7 ER-positive Breast Cancer Cells 
The cellular activity of PF-06873600 was initially evaluated in ER positive MCF7 cells in 
multiple independent in vitro experiments and compared to palbociclib. Activity was 
determined by phospho1ylation of Rb protein following 24 hour inhibitor treatment. 
PF-06873600 demonstrated inhibition of cellular activity in the phospho-Rb enzyme-linked 
immunosorbent assay (ELISA) assay, shown relative to palbociclib (Figure 3). PF-06873600 
had a mean half maximal inhibito1y concentration (ICso) of 64 nM while palbociclib had a 
mean ICsoof 17 nM. 
Figure 3. PF-06873600 Inhibits pRb in MCF7 Cells 
 
 
 
 
 
 
J:l 
0:: 
"c"o" 
..... 
0co 
Cl) 
C. 
0 
MCF7 pRb 
100 ............................................................ PF-06873600 
--- 
PF-00080665 
 
50 
 
 
0.1 
1 
10 
100 
1000 
10000 
compound (nM) 
 
Representative IC50ctuves for pRb biomarker modulation in MCF7 ER-positive breast cancer cells. MCF7 cells were 
treated for 24 hour with PF-06873600 or palbociclib (PF-00080665, PD-0332991). Cell lysates were subjected to pRb 
ELISA and data nonualized as percent pS807/811 Rb. Data points are the mean of duplicates and en-or bars are standard 
deviation. pRb = Phospho1ylated retinoblastoma. 
 
1.3.1.2. Tumor Growth Inhibition (HCC1806 Tumor Model) 
Oral administration of PF-06873600 was efficacious in the Cyclin E-amplified triple negative 
breast cancer tumor model HCC1806, as shown in Figure 4 and Figure 5. Significant tumor 
growth inhibition compared to vehicle control (Day 21, 41% TGI; p <0.01) was observed in 
at the Inid-level dose of20 mg/kg PF-06873600 adininistered BID as well as at the highest 
dose of 50 mg/kg PF-06873600 adininistered BID (Day 21, 58% TGI; p <0.001) (Figure 4). 
Fmther, a dose-dependent relationship was observed where minimal TGI was observed at the 
lowest dose (5 mg/kg PF-06873600 administered BID) and the greatest TGI was observed in 
the highest dose (50 mg/kg PF-06873600 adininistered BID). Significant tumor growth 
inhibition compared to vehicle control (51% TGI; p <0.001) was also observed in a second 
study with a dose of 30 mg/kg BID (Figure 5) with maximal tumor growth inhibition 
occuning at a dose of 50 mg/kg BID. 


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0
A lack of distinction between the 50 mg/kg BID and 75 mg/kg BID dosing coho1is suggests 
that saturation of the mechanism driving anti-proliferation is achieved at the 50 mg/kg dose. 
The HCC1806 model is intrinsically resistant to the CDK4/6 inhibitor palbociclib as 
illustrated by the minimal tumor growth inhibition observed when administered at a clinically 
relevant dose (Figure 4). This is likely due to the CCNEl amplification in this model which 
results in elevated CDK2 activity. 
Figure 4. Tumor Growth Inhibition in HCC1806 Tumor Xenograft Model including 
Palbociclib 
 
 
 
 
 
 
 
;:;;- 
gE 
Q) E 
HCC1806 Tumor Growth Inhibition 
1000 ♦ 
G1. Vohiclo 
♦ 
G2. PF-06873600 50 mg/kg PO BIO 
♦ 
♦ 
♦  
:I  500 
:> 
E 
:I 
I- 
 
 
 
0+ 
10 
15 
20 
Days Post Implant 
 
Mice propagating HCC1806 triple negative breast cancer cell tumor xenografts were dosed orally BID with the CDK2/4/6 
inhibitor PF-06873600 at 5 mg/kg (10 mg/kg total dailydose), 20 mg/kg (40 mg/kg tot.al dailydose) or 50 mg/kg 
(100 mg/kg total daily dose), palbociclib 50 mg/kg QD or vehicle starting 11 days post cell implant. Tumor growih was 
measured on 14, 18 and 21 days as indicated. EiTor bars represent standard en-or of the mean tumor volume. 
 
G5. Palbociclib 50 mg/l<g PO QO 


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Figure 5. 
Tumor Growth Inhibition in HCC1806 Tumor Xenograft Model 
 
 
900 
 
 
 
• 
Grp1. Vehicle 
HCC1806 Tumor Growth Inhibition 
 
 
 
;:, 
E 600 
§, 
g
: 0  
• 
G<p2. PF.e873MO 75 mg/kgPO 810 
♦ 
G<p3, PF.e873MO 50 mg/kg PO 810 
♦ 
Grp4. PF.e873MO 30 mg/kg PO 810 
 
300 
 
 
 
 
0+------- ----- ------ 
5 
10 
15 
20 
Days Post Implant 
 
 
Mice propagating HCC1806 triple negative breast cancer cell tumor xenografts were dosed orally BID with the CDK2/4/6 
inhibitor PF-06873600 at 30 mg/kg (60 mg/kg total dailydose), 50 mg/kg (100 mg/kg total dailydose) or 75 mg/kg 
(150 mg/kg total daily dose), palbociclib 50 mg/kg QD or vehicle starting 11 days post cell implant. Tumor growih was 
measured on 14, 18 and 21 days as indicated. EiTor bars represent standard e!l'or of the mean tumor volume. 
 
1.3.1.3. PF-06873600 Inhibits the Proliferation of Drug Nai've and Resistant ER-
positive Human Breast Cancer Cells 
To examine the effect of PF-06873600 on the cell proliferation, different types of breast 
cancer cell lines were tested. Figure 6 illustrates representative data of the dose response 
relationship of PF-06873600 to proliferation in the ER-positive breast cancer, palbociclib 
sensitive MCF7 model. The dose-response relationship of palbociclib (PF-00080665, 
PD-0332991) is included as a CDK4/6 inhibitor benchmark. 


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a.
 
Figure 6. PF-06873600 and Palbociclib Inhibit the Proliferation of MCF7 ER-positive 
Breast Cancer Cells 
 
MCF7 7 Day Proliferation assay 
 
100 
C 
0 
.., 
PF-06873600 IC50: 37 nM 
... 
PF-00080665 IC50: 79 nM 
e so 
g! 
i 
 
 
0.1 
1 
10 
100 
1000 
10000 
compound (nM) 
 
Proliferation ofMCF-7 cells relative to vehicle control were assayed across a concentration gradient of the compounds 
indicated (PF-00080665, PD-0332991 =palbociclib). 
 
ICsodata from other ER positive breast cancer cell models including parental T47D, 
CAMAl, and HCC1428, as well as PF-06873600, palbociclib, tamoxifen, and fulvestrant 
drng resistant variants were generated. PF-06873600 had ICsovalues ranging from 53 to 
277 nM in parental breast cancer cell lines. PF-06873600 ICsoranged from 40 to 146 nM in 
cell lines resistant to ER inhibitors fulvestrant and tamoxifen as well as the CDK4/6 inhibitor 
palbociclib. These data illustrate the anti-proliferative effect of PF-06873600 in both 
parental and dmg resistant models of ER-positive breast cancer. 
1.3.1.4. PF-06873600 Inhibits the Proliferation of CCNE1 High Cancer Cells 
Inherently Resistant to Palbociclib 
Oncogenic CCNEl amplification is predicted to activate CDK2 thereby rendering cells 
insensitive to CDK4/6 inhibitors (ie, palbociclib). To address this hypothesis we assessed the 
proliferation ICsoof PF-06873600 and palbociclib in four CCNEl amplified cell lines; 
HCC1806, OvCar3, COV362 and CAOV3. In each case, PF-06873600 was effective at 
inhibiting proliferation with ICsobetween 18.7 to 63.5 nM, while palbociclib had no 
significant anti-proliferative effect at doses relevant to free drng exposure achieved in patient 
(ie, below 100 nM). Representative results from the ti·iple negative breast cancer cell line 
HCC1806 are shown in Figure 7 as a dose response relationship of PF-06873600 to cell 
proliferation, in conti·ast to palbociclib. 


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-= 
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Figure 7. PF-06873600 is an Inhibitor of CCNE1 High HCC1806 Cell Proliferation 
Where Palbociclib is Ineffective 
HCC1806 7 Day Proliferation assay 
 
 
C 100 
0 
t! 
e so 
G> 
> 
i 
..., PF-06873600 IC50: 71 nM 
■ PF-00080665 IC50: >8 µM 
 
I I I • 
 
 
0.1 
1 
10 
100 
1000 
10000 
compound (nM) 
 
 
Proliferation ofHCC1806 cells relative to vehicle control were assayed across a concentration gradient of the compounds 
indicated (PF-00080665, PD-0332991 =palbociclib). 
 
ICso data from the HCC1806 and 3 ovarian cancer cell lines, OvCar3, COV362 and CAOV3 
were generated. In each case, PF-06873600 was effective at inhibiting cell proliferation 
between 18.7 to 63.5 nM, while palbociclib had no anti-proliferative effect. 
1.3.2. Nonclinical Pharmacokinetics (PK) 
Following intrnvenous (IV) administration, the non-clinical PK of PF-06873600 was 
characterized by low plasma clearance (CLp) in rat, dog and monkey (8 to 13 mL/min/kg) 
and high in mouse (63 mL/min/kg). PF-06873600 exhibits a volume of distribution at steady 
state (Vss) of between 0.6 to 1.3 L/kg across species. PF-06873600 exhibits moderate to 
rapid abso1ption (time to maximum concentration (Tmax) = 0.5 to 4 hours) after oral 
administration in preclinical species. The oral bioavailability of PF-06873600 was moderate 
and observed to range between 29% to 59% in the relevant preclinical species. Following 
repeat oral dosing in Inice and dogs, systeinic exposure increased with an increase in dose 
with no evidence of sex-related differences in exposure in either species. There was no 
accumulation of exposure after multiple doses on Day last when compared to the exposure on 
Day 1 in either species. 
In vitro studies suggest PF-06873600 is a substrate for the efflux transporters human 
pe1meability glycoprotein, (P-gp) and human breast cancer resistance protein (BCRP). As a 
result of the high passive pe1meability exhibited by PF-06873600 and moderate 
% F observed in relevant preclinical species (rat, dog, and monkey), the oral abso1ption of 
PF-06873600 in humans is predicted to be moderate. 
Renal and/or bilia1y excretion of PF-06873600 in rats and dogs was minimal. In vitro studies 
using Sandwich Cultured Human Hepatocytes (SCHH) demonstrate that PF-06873600 does 
not exhibit bilia1y excretion and therefore biliaiy excretion is predicted to be minimal in 
humans. 


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Following in vitro evaluation, the primary mechanisms of clearance for PF-06873600 in 
preclinical species and humans appears to be oxidation mediated primarily by cytochrome 
P450 (CYP) enzymes, predominantly CYP3A4. No unique human metabolites were 
identified. Mean IC50 values for inhibition of CYPs 1A2, 2B6, 2C8, 2C9, 2D6, and 3A4/5 
were >100 µM, while the IC50 value for CYP2C19 was 92.8 µM. PF-06873600 
demonstrated time-dependent inhibition (TDI) of CYP3A4 enzymes but did not exhibit 
induction of CYP1A2, CYP3A4, or CYP2B6. PF- 06873600 is not likely to demonstrate 
drug-drug interaction (DDI) with MDR1, OATP1B1, OATP1B3, OAT1, OAT3, OCT1, or 
OCT2; however, PF-06873600 may exhibit DDI mediated by inhibition of BCRP, MATE1, 
or MATE2K. 
In humans, PF-06873600 is predicted to have a low CLp (1.0 mL/min/kg) and a low Vss, 
(0.8 L/kg) resulting in a half-life of approximately 9 hours. In addition, PF-06873600 is 
expected to be moderately absorbed in humans with a projected oral bioavailability of 
approximately 40%. The oral plasma clearance (CLp/F) and the apparent volume of 
distribution (Vd/F) are predicted to be 2.5 mL/min/kg and 2 L/kg for PF-06873600 
respectively. A dose response relationship was established between plasma exposure of 
PF-06873600 and the proximal biomarker of phosphorylated Rb serines 807/811/total Rb in 
the tumor. A pharmacologically active dose (PAD) for PF-06873600 is estimated at 
10 mg BID with a predicted unbound efficacious concentration (Ceff) (equal to minimal 
concentration (Cmin)) of approximately 33 nM (15.6 ng/mL) in HCC1806 tumors (triple 
negative breast cancer) and a PAD of 15 mg BID is estimated with a predicted unbound 
Ceff (equal to Cmin) of approximately 50 nM (23.6 ng/mL) in MCF 7 tumors (metastatic 
ER-positive breast cancer). 
If a suboptimal half-life is observed at 10 mg BID and higher, a PF-06873600 oral dosing 
regimen of three times daily (TID) may be evaluated during dose escalation. In addition, a 
higher than predicted clearance could result in a higher pharmacologically active dose (PAD) 
than the originally predicted 10-15 mg BID. To minimize the number of patients exposed to 
sub-therapeutic dose levels, an accelerated dose escalation with potential for larger dose 
increments (as utilized for the initial dose levels) may be adopted until the observation of 
clinically relevant adverse events or the dose levels approaching the projected PAD. 
1.3.3. Nonclinical Safety 
Consistent with the intended pharmacologic activity of PF-06873600 (ie, cell cycle 
inhibition), the primary target organ systems identified included the hematopoietic and 
gastrointestinal systems. In addition, pancreas and liver findings were identified in 
exploratory toxicity studies, and cardiovascular effects were observed in ex vivo and in vivo 
assessments in dogs. In the pivotal 1-month Good Laboratory Practice (GLP) dog and mouse 
toxicity studies, PF-06873600 was not tolerated at the highest dose tested and was associated 
with clinical signs of body weight loss, dehydration, inappetence, liquid feces, emesis (dog) 
and hypoactivity leading to unscheduled euthanasia. Intolerance to PF-06873600 in the 
mouse and dog was primarily ascribed to adverse gastrointestinal effects. Hematology 
changes in mice correlated with non-adverse microscopic changes of decreased cellularity in 
bone marrow, spleen, thymus and lymph node. Conversely, in the dog, the observed changes 
in hematology, and microscopic pathology of bone marrow and lymphoid organs were 


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considered adverse. The hematolymphopoietic changes observed with PF-06873600 are 
consistent with those observed with other cell cycle inhibitors, palbociclib and ribociclib, and 
are considered a consequence of the primary pharmacology of CDK 4/6 inhibition. Changes 
in the pancreas and liver were observed only in a single species in the 14-Day exploratory 
toxicity studies, were not observed in the 1-month GLP studies, and lack any specific 
mechanistic link; therefore, the relevance of these findings to patients is uncertain. In 
addition, a non-dose limiting decrease in blood pressure, increase in heart rate, and decrease 
in PR interval, were observed in dogs at expected clinically relevant exposures. The 
observed in vivo hypotensive effect was consistent with the decrease in vascular tone 
observed in ex vivo studies. Reversibility was established for all PF-06873600-related target 
organ toxicities identified in the 1-month GLP studies with recovery arms (gastrointestinal 
tract, hematopoietic, lymphoid). 
In exploratory in vitro genetic toxicity assays, PF-06873600 was not mutagenic or 
clastogenic, but was observed to be aneugenic. PF-06873600 absorbs light in the 280 nm to 
500 nM range with the greatest molar extinction coefficient of 20,643 L/mol•cm at 351 nM, 
and therefore has the potential to cause phototoxicity. Developmental and reproductive 
toxicity studies specific for fertility and teratology have not been conducted with 
PF-06873600 but toxicity to reproductive organs was not observed in the 1-month mouse and 
dog GLP general toxicity studies. However, based on the mechanism of action, male 
reproductive and embryo fetal toxicity are potential risks. Adverse effects of other 
CDK 4/6 inhibitors, including ribociclib, abemaciclib, and palbociclib,14,15,34 on male 
reproductive organs, function and fertility in animal studies were observed and partially 
reversible in some instances. In addition, effects on fetal growth, survival and morphology 
were also observed with CDK 4/6 inhibitors in animal studies. 
The nonclinical safety findings related to oral administration of PF-06873600 represent 
toxicities that can be monitored and/or are considered clinically manageable or acceptable 
risks in the intended advanced cancer patient population. 
1.4. Starting Dose Rationale 
The selection of the starting dose and regimen for this first-in-patient (FIP) study was based 
on the nonclinical toxicology and PK results in accordance with the International Conference 
on Harmonization (ICH) S9 Guidance.23 Results from nonclinical toxicity studies indicate 
that the dog is the most sensitive species, and the highest non-severely toxic dose (HNSTD) 
of PF-06873600 in dog was 0.6 mg/kg after daily oral administration. The human equivalent 
dose for the HNSTD of 0.6 mg/kg/day in dog is approximately 20 mg daily (assuming a body 
weight of 60 kg). Per Guidance S9, one-sixth of the HNSTD can be considered as the 
appropriate starting dose. Given the predicted human disposition of half-life of 
approximately 9 hours, the starting dose has been selected to be 1 mg administered orally 
BID. The human area under the curve (AUC) of PF-06873600 at the proposed starting oral 
dose of 1 mg BID (by mouth 2 mg/day) is predicted to be ~26% of the observed AUC0-24 at 
HNSTD in dog (PO 0.6 mg/kg/day), and ~1% of the observed AUC0-24 at the (severely toxic 
dose in 10% of animals) STD10 (severely toxic dose in 10% of animals) of 50 mg/kg/day in 
mouse. 


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Additional infonnation for PF-06873600 may be found in the single reference safety 
document (SRSD), which for this study is the Investigator's Brochure (IB). 
1.5. Study Rationale 
Modulating the cell cycle by inhibiting CDK4/6 in combination with endocrine therapy has 
been shown to provide significant clinical benefit in patients with HR-positive 
HER2-negative advanced or mBC (Finn et al, 2016; Cristofanilli et al, 2016).33•12 Despite the 
proven clinical response observed with this class of diugs, some patients may have intrinsic 
or adaptive resistance to ti·eatment with combined CDK4/6 and endocrine therapy. 
Preclinical studies have shown that resistance to CDK4/6 inhibition in preclinical cellular 
models can be overcome with the addition of CDK2 inhibition to the inhibition of CDK4 and 
6 (Henera-Abme et al, 2016).4 As such, the inhibition ofCDK2/4/6 may provide an 
impo1tant new therapeutic sti·ategy to overcome resistance to combined CDK4/6 and 
endocrine therapy. This study will evaluate the effect of PF-06873600, as a single agent and 
in combination with endocrine therapy, in patients with HR-positive HER2-negative 
advanced metastatic breast cancer, who have failed prior combination CDK4/6 inhibitor and 
endocrine therapy. 
In addition, the effects of PF-06873600 will be explored in tumor types that have potential 
for increased Cyclin E expression and/or CDK2 or 4/6 activity including locally 
recunent/advanced or metastatic TNBC and advanced platinum resistant ovarian cancer. 
Utilizing biomarker coho1ts, the mechanism of action of PF-06873600 as well as putative 
di·ivers for resistance (eg, amplified CCNEl) will also be studied. 
 


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1.5.2. Banked Biospecimens 
Banked biospecimens will be collected for the pm-pose of conductin 
are described in the Banked Bios ecimens section. 
and metabolite variation patterns of patients who 
respond well and those who respond poorly to treatment may help to better define the most 
a 
ro riate ·ou of atients in which to tar et a  iven treatment. 
 
 
 
 
 
 
Banked biospecimens retained in the BBS also can be used in research in advanced or mBC 
and ovarian cancer. Providing these biospecimens is a required study activity for study sites 
and patients, unless prohibited by local regulations or institution review board (IRB)/ethics 
committee (EC) decision. 
1.6. Overview of Letrozole (Femara®) 
Letrnzole (Femara®)is an oral nonsteroidal aromatase inhibitor and it is approved worldwide 
for the first and second line treatment of postmenopausal women with ho1mone receptor 
positive advanced breast cancer. Common side effects include hypercholesterolemia, hot 
flashes/flushing, aiihralgia/arthritis, night sweats, bone fractures, weight increase, nausea, 
fatigue, myalgia, edema, weight decrease, vaginal bleeding, back pain, osteoporosis not 
othe1wise specified (NOS), and bone pain (Nova1iis Phannaceuticals Corporation, United 
States package inse1i (USPI), 2020).14 
Complete info1mation for this compound may be found in the SRSD, which for this study is 
the Novaitis USPI, Femai·a®(letrozole), East Hanover, New Jersey. 


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1.7. Overview of Fulvestrant (Faslodex®) 
Fulvestrant (Faslodex®) is a competitive ER antagonist with an affinity comparable to 
estradiol. It blocks the trophic actions of estrogens without any partial agonist (estrogen-like) 
activity, and is currently indicated for the treatment of hormone receptor positive metastatic 
breast cancer in postmenopausal women with disease progression following antiestrogen 
therapy. The mechanism of action is associated with down-regulation of ER protein levels. 
Clinical trials in postmenopausal women with primary breast cancer have shown that 
fulvestrant significantly down-regulates ER protein in ER-positive tumors compared with 
placebo. There was also a significant decrease in progesterone receptor expression consistent 
with a lack of intrinsic estrogen agonist effects. It has also been shown that fulvestrant 
500 mg/month downregulates ER and the proliferation marker Ki67 to a greater degree than 
fulvestrant 250 mg/month in breast tumors in the postmenopausal neoadjuvant setting. 
Fulvestrant is comparable to aromatase inhibitors (AIs) in terms of efficacy and tolerability 
for women who have progressed on prior tamoxifen therapy (AstraZeneca Pharmaceuticals 
USPI, 2020).25 
Complete information for fulvestrant may be found in the SRSD, which for this study is the 
AstraZeneca Pharma USPI, Faslodex® (fulvestrant) injection, Wilmington, DE.25 


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2. STUDY OBJECTIVES AND ENDPOINTS 
 
Parts 1A and 1C: Single Agent Dose Escalation and Part 1B: Combination Dose Finding 
Primary Objective(s): 
Primary Endpoint(s): 
Parts 1A and 1C: 
To assess the safety and tolerability of increasing doses 
of PF-06873600 in patients with: 
• 
HR-positive HER2-negative advanced or mBC 
patients (third or fourth line setting). 
• 
Locally recurrent/advanced or metastatic TNBC. 
• 
Advanced platinum resistant epithelial ovarian 
cancer/fallopian tube cancer/primary peritoneal 
cancer 
• 
In order to estimate the Maximum Tolerated Dose 
(MTD) and select the Recommended Dose for 
Expansion (RDE) for PF-06873600 as a single 
agent (Part 1A and Part 1C only). 
Part 1B: 
To assess the safety and tolerability of PF-06873600 at 
the single agent RDE in combination with letrozole 
and in combination with fulvestrant (in a de-escalation 
manner, if indicated) in patients with: 
• 
HR-positive HER2-negative advanced or mBC 
(third or fourth line setting) in order to establish 
the RDE for PF-06873600 in combination with 
letrozole and in combination with fulvestrant, 
respectively. 
Parts 1A, Part 1B, and Part 1C: 
• 
Dose-Limiting Toxicities (DLTs). 
• 
Adverse Events as characterized by type, frequency, 
severity (as graded by National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI CTCAE 
version 4.03), timing, seriousness, and relationship to 
study therapy. 
• 
Laboratory abnormalities as characterized by type, 
frequency, severity (as graded by NCI CTCAE 
version 4.03), and timing. 
• 
Vital sign abnormalities. 
• 
Heart rate corrected QT interval (eg, QTcF). 
Secondary Objective(s): 
Secondary Endpoint(s): 
• 
To evaluate the single- and multiple- dose PK of 
PF-06873600 when given as a single agent 
(Part 1A, and Part 1C), in combination with 
letrozole, and in combination with fulvestrant 
(Part 1B). 
Pharmacokinetic parameters of PF-06873600: 
• 
Single Dose (SD) - Cmax, Tmax, AUClast, and as data 
permit, AUCinf, CL/F, Vz/F, and t1/2. 
• 
Multiple Dose (MD) (assuming steady state is achieved) 
- Css,max, Tss,max, AUCss,τ, Css,min, CLss/F, and as data 
permit, Vss/F, t1/2, and Rac (AUCss,τ/AUCsd,τ). 
• 
To document any preliminary evidence of 
anti-tumor activity of PF-06873600. 
• 
Objective Response (OR), as assessed using the Response 
Evaluation Criteria in Solid Tumors (RECIST) 
version 1.1. 
• 
Time-to-event endpoints: eg, Duration of Response 
(DoR), Progression-Free Survival (PFS), Time to 
Progression (TTP). 
• 
To evaluate the pharmacodynamic (PD) 
biomarkers of CDK pathway modulation 
following treatment with PF-06873600 in tumor. 
• 
Modulation of PD biomarkers (eg, pRb, Ki67) of CDK in 
tumor. 


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I 
 
 
Parts lA and lC: Single Agent Dose Escalation and Part 1B: Combination Dose Finding 
 
 
 
Part 2: PF-06873600 Combination Dose Expansion 
Primary Objective(s): 
Primary Endpoint(s): 
• 
To evaluate the preliminary antitumor activity and 
confinu the safety and tolerability of 
PF-06873600: 
In combination (at the RDE from Pait lB) in patients 
with: 
• 
HR-positive/HER2-negative advanced or mBC 
(PF-06873600 + fulvestrant) - (second or third 
line setting). 
• 
HR-positive/HER2-negative advanced or mBC 
(PF-06873600 + a nousteroidal aromatase 
inhibitor) (CDK4/6i naive). 
• 
HR-positive HER2-negative advanced or mBC 
(PF-06873600+fulvestrant) (CDK4/6i nai:ve). 
•  Preliminary antitumor activity meastu·e for efficacy 
includes ORR, as assessed using RECIST 1.1. 
• 
Safety and tolerability: 
• Adverse Events as characterized by type, frequency, 
severity (as graded by National Cancer Institute 
Common Tenuinology. Criteria for Adverse 
Events (NCI CTCAE v 4.03) timing, seriousness 
and relationship to study therapy. 
• Lab abnonualities as characterized by type, 
frequency, severity (as graded by NCI CTCAE 
v 4.03) and timing. 
• Vital sign abno1malities. 
• Heart rate con-ected QT interval (eg, QTcF). 
Secondary Objective(s): 
Secondary Endpoint(s): 
• 
To further explore preliminary antittuuor activity 
of PF-06873600. 
•  Time-to-event endpoints: eg, DOR, PFS, overall smvival 
(OS) and TIP. 
• 
To further evaluate the PK of PF-06873600 in 
combination with letrozole, and in combination 
with fulvestrant at the respective RDE. 
Phrumacokinetic parameters of PF-06873600, including but 
not limited to: 
• 
SD - Cmax, Tmax. 


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I 
 
Part 2: PF-06873600 Combination Dose Expansion 
• 
 MD (assuming steady state is achieved) - Css,max, Tss,max, 
Css,minand Rac,Cmax. 
• 
To evaluate phanuacodynam.ic (PD) biomarkers 
of CDK pathway modulation following treatment 
with PF-06873600 in combination with 
fulvestrant or letrozole in ttuuor. 
• 
Modulation of PD biomarkers (eg, pRb, Ki67) ofCDK in 
tumor. 
 
 
 
 
 
 
 
I 
 
 
 
3. STUDY DESIGN 
3.1. Study Overview 
This is a Phase 1/2a, open-label, multi-center, non-randomized, multiple dose, safety, 
tolerability, phaimacokinetic, and phannacodynamic study of PF-06873600 administered as 
a single agent in sequential dose levels and then in combination with endocrine therapy. In 
Pait IA, successive coho1ts of patients will receive escalating doses of PF-06873600 staiting 
at I mg BID dosed on a continuous basis and then in dose finding (Pait IB) with immediate 
release fo1mulations of PF-06873600 in combination with endocrine therapy (ET) in an 
outpatient setting. In Pait IC, successive coho1ts of patients will receive escalating doses of 
PF-06873600 testing a modified release (MR) fo1mulation in a MR coho1t evaluation and 
then in dose finding (Pali IB) with modified release fo1mulations of PF-06873600 in 
combination with endocrine therapy (ET) in an outpatient setting. 
This study contains 2 pa1ts, dose escalation with single agent (Pait IA and IC) and then dose 
finding with PF-06873600 in combination with endocrine therapy (letrozole and fulvestrant, 
independently with both immediate and modified release fonnulations) (Pait IB) followed by 
dose expansion aims in combination with endocrine therapy (Pait 2). The decision to initiate 
Pait 2 with either the immediate release fonnulation or the modified release fo1mulation will 


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be made following a careful review of all available data from Part 1 (1A, 1B, and 1C) and in 
consultation with the C3661001 Safety Team. 
The Japan lead-in cohort (J-LIC) will be added separately as a sub-cohort in order to assess 
the safety of monotherapy of PF-06873600 in Japanese population. Detailed information is 
provided in the Appendix 7. Japanese participants will be able to enroll into Part 2 after 
safety and tolerability of monotherapy of PF-06873600 in Japanese participants is confirmed. 
The overall study design is depicted in Figure 8 below. 
Figure 8. Overall Study Schema 
 


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Figure 9. Modified Release Selection Cohort Study Schema (within Part 1C through 
Cycle 1): 
 
 
Part 1A will estimate the maximum tolerated dose/recommended Phase 2 dose/recommended 
dose for expansion (MTD/RDE) in sequential dose escalation safety cohorts for 
PF-06873600 as a single agent in women of any menopausal status and men with 
HR-positive HER2-negative advanced or mBC (third or fourth line setting) and in 
women/men with locally recurrent/advanced or metastatic TNBC and women with advanced 
platinum resistant ovarian cancer. 
Any given PF-06873600 dose in Part 1A (or Part 1C) may be escalated or de-escalated at full 
or intermediate dose levels, depending on emerging clinical data. Parallel biomarker cohorts 
may be initiated for HR-positive HER2-negative advanced or mBC patients only, once the 
respective preceding dose escalation safety cohort has cleared (see Section 3.1.1). 
After the MTD/RDE for PF-06873600 as a single agent has been identified in Part 1A (or 
Part 1C) based on safety and clinical observations, initiation of combination dose 
de-escalation with PF-06873600 in combination with letrozole and PF-06873600 in 
combination with fulvestrant independently (Part 1B) will be initiated at the single agent 
MTD or RDE in women of any menopausal status with HR-positive HER2-negative 
advanced or mBC. In Part 1B, the PF-06873600 dose can be de-escalated at full or 
intermediate dose levels. In addition both available formulations of PF-06873600 at the 
respective RDE will be studied in combination with endocrine therapy in Part 1B. 
Approximately 12 patients will be dosed in the respective endocrine therapy combinations, 
with approximately 6 patients receiving PF-06873600 IR + endocrine therapy and 
approximately 6 patients receiving PF-06873600 MR + endocrine therapy in both the 
fulvestrant and letrozole arms. 


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Part 2 will evaluate the dose selected (RDE) in combination with endocrine therapy 
(letrozole and fulvestrant in independent dose expansion arms) depending on clinical 
observations from Part 1B (See Section 3.2). 
PF-06873600 will initially be administered orally BID on a continuous basis. If emerging 
PK data from initial dose levels in Part 1A (or Part 1C), demonstrate the feasibility of once 
daily (QD) dosing, the dose escalation may continue with QD dosing, following the dose 
escalation schema with the same total daily dose as planned for BID dosing. The evaluation 
of an alternative dosing regimen (eg, QD) may be considered during the course of dose 
escalation or after determination of the MTD for the BID regimen based on emerging and 
available preliminary clinical data, including safety/tolerability, laboratory, PK and PD 
findings. If an alternative dosing regimen (eg, QD) assessment occurs after determining the 
MTD of the BID regimen, it will be initiated with a dose level at a comparable total daily 
dose determined from the MTD of the BID regimen. 
Intermittently administered PF-06873600 dosing schedules may also be evaluated if 
indicated based on emerging clinical data. As an option, PF-06873600 may be administered 
continuously for three weeks followed by one week off if indicated by emerging clinical 
safety and PK data. 
All cycles are 28 days in length and treatment will continue until progression of disease, 
uncontrollable toxicity, a decision by the patient or investigator to discontinue treatment or 
the study is terminated. Patients experiencing toxicity including a dose limiting toxicity 
(DLT) may be managed with dose modification or discontinuation from treatment. The 
proposed doses, schedule(s) and PK time points may be reconsidered and amended during 
the study based on the emerging safety and PK data. 
The time on study can vary depending on the observed toxicity and potential benefit an 
individual patient derives. It is estimated that each patient may remain on treatment for 
approximately 6-8 cycles, making total study duration approximately 32-36 weeks. Actual 
duration can be longer, if a patient derives benefit from study treatment. 
Approximately 75 patients are expected to be enrolled in the dose escalation/finding safety 
cohorts and an additional 6-12 patients are expected in the biomarker cohorts in Parts 1A and 
1C. The actual number of patients enrolled will depend on the tolerability of PF-06873600 
and the number of dose levels required to identify the MTD/RDE. Approximately 
100 patients are expected to be enrolled in Part 2. 
3.1.1. Part 1A PF-06873600 Single Agent Dose Escalation 
Part 1A consists of single agent dose escalation in dose escalation safety cohorts as well as 
biomarker cohorts. The dose escalation safety cohorts will be initiated in 1-2 patients for the 
first 2 planned dose levels starting at 1 mg BID orally on a continuous basis and dose 
escalation will proceed according to the modified toxicity probability interval (mTPI) 
method. When a dose level is deemed safe following a DLT observation period of 28 days 
and based on the discussion by the safety review team (comprised of the Investigators and 
the Sponsor), dose escalation will occur to the next dose level (Table 2). 


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While patients enrolled in the dose escalation safety cohorts are being evaluated, patients 
may enroll into additional biomarker cohorts (approximately 6 patients in each cohort) 
requiring mandatory pre- and -on treatment tumor and skin biopsies. An end of treatment 
tumor biopsy is optional but encouraged. Initiation of enrollment into the first biomarker 
cohort will be based on observations of key pharmacodynamic (PD) findings 
(eg, neutropenia, gastrointestinal toxicities, and/or other PK/PD markers) and/or reaching a 
predicted active dose (noted in Figure 8 as §Biomarker Cohort). Enrollment into a biomarker 
cohort can occur after the dose level is deemed safe for escalation to a higher dose level or at 
the MTD. Biomarker cohorts will enroll women and men with HR-positive HER2-negative 
advanced or mBC. Because these additional patients will receive a dose lower than the 
concurrent dose escalation safety cohort or will be enrolled at a dose following the DLT 
evaluation period in the first 2-4 dose escalation safety cohort patients enrolled, their 
potential DLT observations may not be strictly used in the mTPI method for the ongoing 
dose finding. However, the safety profile from these additional patients will be used to 
establish the MTD or RDE. 
3.1.2. Part 1B PF-06873600 Dose Finding in Combination with Endocrine Therapy 
After the single-agent PF-06873600 MTD/RDE has been determined for both the IR and MR 
formulations, enrollment will be initiated into Part 1B which will evaluate the PF-06873600 
in combination with letrozole and in combination with fulvestrant in independent cohorts in 
women with HR-positive HER2-negative advanced or mBC. PF-06873600 will be 
administered orally on a continuous basis (unless the dose schedule has changed during 
Part 1A or Part 1C), while letrozole and fulvestrant will be administered per standard of care. 
Available safety and clinical data will be reviewed by the safety review team. The 
PF-06873600 dose in combination with letrozole may be decreased if determined to not be 
tolerable. The PF-06873600 dose de-escalation in combination with letrozole will follow the 
mTPI method. Similarly, the PF-06873600 dose in combination with fulvestrant may be 
decreased if determined to not be tolerable. The PF-06873600 dose de-escalated in 
combination with fulvestrant will follow the mTPI method. The MTD/RDE of each of the 
PF-06873600 formulations (IR and MR) in combination with the respective endocrine 
therapy (letrozole and fulvestrant) will be declared when at least 6 patients have been 
enrolled at a dose level that is predicted to be the MTD/RDE for each of the respective 
combination per the mTPI. Once the MTD/RDE of PF-06873600 in combination with 
letrozole and the MTD/RDE of PF-06873600 in combination with fulvestrant have been 
confirmed, a recommended dose for expansion for each combination will be declared and 
enrollment into Part 2 may be initiated. The decision to dose either the MR or IR or MR and 
IR formulation in Part 2 will be made following a careful review of all available clinical data 
and in alignment with C3661001 Safety Team. 
Similar to Part 1A and/or Part 1C, dose escalation, all safety, PK and PD information from 
safety cohorts in Part 1B available will be used to determine the PF-06873600 MTD/RDE for 
the respective combination treatments. 


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3.1.3. Part 1C PF06873600 MR Formulation 
“A MR formulation with two designed release rates shorter duration (eg, 6 -hour) and longer 
duration (eg, 12-hour) release, respectively, has been developed for PF-06873600 and were 
studied in the Part 1C MR Selection Cohort only.” Compared to the Immediate Release (IR) 
formulation, the MR formulation has the potential to achieve more prolonged effective target 
inhibition during a dose interval. Emerging pharmacokinetics and safety data for the IR 
formulation suggest there is a large peak-to-trough fluctuation in steady-state concentrations 
and that a lower maximal concentration (Cmax) could potentially improve tolerability. 
Therefore, the MR formulation with the two release rates were evaluated in an MR selection 
cohort in this study. 
The MR selection cohort enrolled 3 to 5 evaluable patients. These patients received two 
single doses of the MR formulation during a 7-day lead-in period (Day -7 to Day -1), prior to 
receiving the IR formulation of PF-06873600 twice daily in 28-day cycles. During the 7-day 
lead-in period, patients first received a single dose of the shorter release tablets on Day -7, 
and then another single dose of the longer release tablets on Day -4. The dose for the shorter 
and longer release MR tablets were administered during the lead-in period, as well as the IR 
dose administered starting from Cycle 1 Day 1, were no higher than the highest nominal dose 
tested found to be safe from the IR dose escalation. Serial PK sampling was performed for 
24 hours following each of the MR formulation doses on Day -7 and Day -4, and for 
12 hours following the IR formulation morning dose on Cycle 1 Day 1. PK was compared 
between the shorter and longer release MR tablets, and also between each of the two release 
rate MR tablets and IR. Based on the PK data from the MR selection cohort, 12-hour release 
rate provides a slower release compared to the 6-hour release rate, thus achieves more 
prolonged drug coverage during a dosing interval. Therefore, 12-hour release rate was 
selected to be further investigated during MR dose escalation. 
The MR dose escalation, proceeded with one of the selected MR formulation release rates 
according to the mTPI method until a MTD/RDE is determined. The starting dose for the 
MR dose escalation was selected to achieve similar steady-state AUC during one dose 
interval (AUCss,τ) as the highest safe IR dose based on prediction. The dose increment will 
be no more than a 50% increase. After MTD/RDE is determined, a biomarker cohort may be 
open to enroll patients with HR-positive HER2-negative advanced or mBC requiring 
mandatory pre- and on-treatment tumor and skin biopsies. 
During the Part 1C dose escalation, all available safety, PK and PD information from dose 
escalation safety and biomarker cohorts in will be used to determine the PF-06873600 
MTD/RDE as a single agent. 
3.1.4. Starting Dose for Part 1A 
The starting dose of PF-06873600 will be 1 mg administered orally BID on a continuous 
basis in 28 day cycles. 


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3.1.5. Criteria for Dose Escalation 
Compared to the traditional mTPI method, the proposed mTPI method for this protocol 
includes stopping rules and dose escalation/finding criteria, which prevents the target DLT 
rate to reach ≥33% for determining the MTD. This proposed mTPI method, targeting a DLT 
rate of 27.5% and an acceptable DLT interval (22.5% to 32.5%), will be utilized in Part 1 
dose escalation/finding phase, and will also be used to monitor the DLTs so as not to cross 
toxicity boundaries in the expansion of a cohort. In this process, the upper limit of the DLT 
rate to determine a MTD will be <33%. This proposed mTPI method is more conservative 
than the traditional toxicity probability interval (TPI) method. 
The mTPI method relies upon a statistical probability algorithm, calculated using all patients 
treated in the current dose level to determine one of the following dose-finding decisions: the 
subsequent dose should be escalated, maintained at the current dose, or de-escalated in the 
next cohort of 1-4 patients, or the trial should be terminated (Table 1). 
 
Table 1. 
Dose Escalation/De-Escalation Decision Rules 
 
DLT 
n=2 
n=3 
n=4 
n=5 
n=6 
n=7 
n=8 
n=9 
n=10 n=11 n=12 
0 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
1 
S 
S 
S 
S 
E 
E 
E 
E 
E 
E 
E 
2 
D 
D 
D 
S 
S 
S 
S 
S 
S 
S 
E 
3 
U 
U 
D 
D 
S 
S 
S 
S 
S 
S 
4 
U 
U 
U 
U 
D 
S 
S 
S 
S 
5 
U 
U 
U 
U 
U 
D 
S 
S 
6 
U 
U 
U 
U 
U 
U 
U 
7 
U 
U 
U 
U 
U 
U 
8 
U 
U 
U 
U 
U 
9 
U 
U 
U 
U 
10 
U 
U 
U 
11 
U 
U 
12 
U 
Actions to be taken: D = De-escalate the dose; E = Escalate the dose; S = Stay at the dose. U = Unacceptable 
toxicity. 


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Initially, dose cohorts may consist of 1-2 patients in the single agent dose escalation in 
Part 1A. When a DLT is observed, additional patients will be enrolled and dose escalation 
decision will follow the mTPI criteria. Table 2 showing escalating doses with a 100% to 
150% increase from the previous dose in dose levels (DLs). In later cohorts it is anticipated 
that total daily dose level increases may approximate 100% or less depending on emerging 
available clinical data, including safety/tolerability, laboratory, PK and PD findings. 
The total daily dose will be administered once a day (QD) or in divided doses of either two 
(BID) or three times a day (TID). 
Initial dose levels are provided in Table 2 and intermediate dose levels may be considered as 
indicated. Intra-patient dose escalation for patients enrolled in dose level 1 and 2 may be 
considered in consultation with the sponsor. Once the respective dose level has been 
declared safe, patients who have completed at least 2 Cycles of treatment at the original 
enrolled dose level may escalate to the next higher dose level that has cleared the DLT 
observation period of 28 days. 
 
Table 2. 
PF-06873600 Dose Levels (Immediate Release Formulation) 
 
DOSE LEVEL (DL)* 
DOSE 
TOTAL DAILY DOSE*** 
DL 1** 
1 mg BID 
2 mg 
DL 2 
2 mg BID 
4 mg 
DL 3 
5 mg BID 
10 mg 
DL 4 
10 mg BID 
20 mg 
DL 5 and Beyond 
Escalation to continue to the MTD or 
desired pharmacological activity 
*The proposed doses, schedule(s), and PK time points may be reconsidered or amended during the study 
based on the emerging safety and PK data. Intermediate doses may be considered when deemed 
necessary based on on-going evaluation of safety and toxicity data. 
**  Starting dose DL1. 
*** Total daily dose may be administered in up to 3 divided doses. 
 
In principle, all patients must be evaluated for a minimum DLT observation period of 
28 days in Part 1. However, in order to be evaluable for DLT assessment patients need to 
have received at least 75% of planned doses unless the patient has experienced a DLT prior 
to receiving 75% of the planned dose. 
The dose escalation in Part 1A, and 1C, dose finding in Part 1B, and each arm of the dose 
expansion in Part 2 of the study will stop as the applicable following criteria are met: 
• The maximum sample size has been achieved (approximately 75 patients in Part 1, 
excluding patients enrolled in biomarker cohorts, and approximately 70 patients in 
Part 2); 


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• 6 to 12 evaluable patients (for Parts 1A, Part 1B, and Part 1C) that have been enrolled 
at a PF-06873600 dose level (as a single agent, in combination with letrozole, and in 
combination with fulvestrant, each)) that is predicted to be the MTD per the mTPI 
method; 
• All dose levels explored appear to be overly toxic, and the MTD cannot be 
determined. 
3.1.6. DLT Definition 
Severity of adverse events (AEs) will be graded according to Common Terminology Criteria 
for Adverse Events (CTCAE) version 4.03. For the purpose of dose escalation/finding, any 
of the following AEs occurring in the first cycle of treatment (28 days) which are attributable 
to one, the other, or both agents in the combination will be classified as DLTs: 
Hematologic 
• Grade 4 neutropenia lasting >7 days; 
• Febrile neutropenia defined as an absolute neutrophil count (ANC) <1.0 x 109/L with 
a single temperature of >38.3°C, or 101°F, or a sustained temperature of ≥38°C, or 
100.4°F, for more than one hour; 
• Grade ≥3 neutropenia with associated infection; 
• Grade 3 thrombocytopenia with clinically significant bleeding as indicated by 
≥ Grade 2 bleeding; 
• Grade 4 thrombocytopenia. 
Nonhematologic: 
• Confirmed case of DILI (Hy’s Law) as per Section 8.4.1. 
• Grade ≥3 AEs that are clinically significant with the following exceptions: 
• Grade 3 nausea, vomiting, or diarrhea for ≥72 hours despite optimal supportive 
care will be considered a DLT; 
• Grade 3 fatigue for ≥5 days will be considered a DLT; 
• Grade 5 event unless attributed to a cause clearly not related to study treatment. 
All DLTs need to represent a clinically significant shift from baseline. 


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Isolated Grade 3 laboratory abnormalities that are not associated with clinical sequelae or are 
corrected with supplementation/appropriate management, if indicated, within 72 hours of 
onset will not be adjudicated as DLTs. However, isolated Grade 4 laboratory abnormalities 
that are clinically significant will be considered as DLTs. Abnormal objective test findings 
should be reported as AEs as per Section 8.2.2. 
Significant adverse events considered to be related to the investigational product for 
treatment under investigation that occur during the DLT observation period in the MR 
Selection Cohort will be reviewed in context of all safety data available. That review may 
involve re-evaluation of the dosing level or regimen. 
3.1.7. MTD Definition 
The MTD is defined as the highest dose associated with a DLT rate of 27.5% with an 
equivalence interval of (22.5%, 32.5%) following the mTPI method. During dose 
escalation/finding, patients will be enrolled in dose cohorts of 1-4 patients in Part 1A and 
2-4 patients in Part 1B and Part 1C in dose cohorts other than the MTD/RDE. Each 
MTD/RDE including single-agent and combination treatments will enroll 6-12 patients. 
Each patient will receive continuous doses of PF-06873600 every 28 days. The dose finding 
decision will be based on 1-cycle (28 days) DLT observation period. DLTs observed after 
the Cycle 1 (28-day) may also be considered in the final determination of the MTD as a 
single agent, in combination with letrozole, and in combination with fulvestrant. 
3.1.8. Recommended Dose for Expansion (RDE) and Recommended Phase 2 Dose 
(RP2D) Definition 
The RDE is the dose chosen for further investigation based on Part 1 study results. If the 
RDE proves to be clinically feasible for long-term administration in a reasonable number of 
patients, then this dose usually becomes the RP2D. Further experience with the RDE may 
result in a RP2D dose lower than the RDE. A RP2D for PF-06873600 as a single agent, in 
combination with letrozole, and in combination with fulvestrant are planned to be 
individually determined based on the respective RDE/MTD and other considerations 
including available pharmacokinetic, pharmacodynamic, and clinical benefit data. 
3.2. Part 2 PF-06873600 Combination Dose Expansion 
Part 2 dose expansion is an open-label, multi-center, non-randomized study to assess the 
preliminary anti-tumor activity and the safety and tolerability of PF-06873600. PF-06873600 
will be administered at the RDE in 28 days cycles in combination with endocrine therapy in 
two separate dose expansion arms. Patients may be treated with IR or MR formulations 
depending on emerging data from Part 1 and availability. 
The single agent PF-06873600 RDE from Part 1A will be used to initiate the Part 2 dose 
expansion arm studies, which may be de-escalated, depending on emerging data if indicated. 
Additionally, the PF-06873600 RDE in combination with letrozole and PF-06873600 RDE in 
combination with fulvestrant from Part 1B will be used to initiate the Part 2 respective 
combination dose expansion arm studies, which may be de-escalated, depending on emerging 
data if indicated. 


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3.2.1. Part 2/Arm A- PF-06873600 in Combination with Fulvestrant in HR-Positive 
HER2-Negative Locally Advanced or mBC (Second- or Third-Line Setting) 
PF-06873600 will be evaluated in combination with fulvestrnnt at the RDE in HR-positive 
HER2-negative advanced or mBC in patients who have received prior combined CDK4/6 
inhibitor and a nonsteroidal aromatase inhibitor, and up to 1 prior line of chemotherapy. This 
expansion coho1t will emoll approximately 40 patients. 
3.2.2. Part 2/Arm B - PF-06873600 in Combination with Letrozole in HR-Positive 
HER2-Negative Locally Advanced or mBC (nai've to CDK4/6 inhibitors). 
PF-06873600 will be evaluated in combination with letrozole at the RDE in HR-positive 
HER2-negative advanced or mBC in patients, with suppo1tive available preliminaiy 
PF-06873600 clinical data. Patients who have not received any prior treatment with a 
CDK4/6 inhibitor in the advanced or metastatic setting (prior adjuvant therapy with AI is 
permitted) will be emolled. This expansion coho1t will emoll approximately 30 patients. 
3.2.3. Part 2/Arm C- PF-06873600 in Combination with Fulvestrant in HR-Positive 
HER2-Negative Locally Advanced or mBC (nai've to CDK4/6 inhibitors) 
PF-06873600 will be evaluated in combination with fulvestrant at the RDE in HR-positive 
HER2-negative advanced or mBC in patients who have not previously received treatment 
with a CDK4/6 inhibitor in the advanced or metastatic setting. Paiticipants who have prior 
treatment with CDK4/6 inhibitors, fulvestrant, everolimus, and any agents with MOA that 
inhibits PI3k-mTOR pathway ai·e excluded. This expansion coho1t will emoll approximately 
30 patients. 
 
 
 
 


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4. PATIENT ELIGIBILITY CRITERIA 
This study can fulfill its objectives only if appropriate patients are emolled. The following 
eligibility criteria are designed to select patients for whom pa1ticipation in the study is 
considered appropriate. All relevant medical and nonmedical conditions should be taken into 
consideration when deciding whether a paiticular patient is suitable for this protocol. 
4.1. Inclusion Criteria 
Patients must meet all of the following inclusion criteria to be eligible for emollment in the 
study: 
1. 
Pait 1: 
 
• 
Patients with HR-positive HER2-negative advanced or metastatic breast cancer 
(third or fomth line setting) (histologically or cytologically proven). 


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• Documentation of ER-positive and/or progesterone receptor-positive tumor 
(≥1% positive stained cells) based on most recent tumor biopsy (unless 
non-measurable disease where most recent documentation will be provided) 
utilizing an assay consistent with local standards. 
• Documentation of HER2-negative tumor: HER2-negative tumor is determined 
as immunohistochemistry score 0/1+ or negative by in situ hybridization 
(FISH/CISH/SISH/DISH) defined as a HER2/CEP17 ratio <2 or for single 
probe assessment a HER2 copy number <4. 
• Received one prior line of combined CDK4/6 inhibitor and endocrine therapy. 
• Received 1 or 2 prior lines of cytotoxic chemotherapy in the advanced or 
metastatic setting. 
• Measurable disease or non-measurable disease per RECIST 1.1 (with the 
exception of Part 1B where measurable disease per RECIST 1.1 is required). 
• Patients in the biomarker cohort must have a lesion amenable to biopsy. 
Part 1A and 1C only: 
• TNBC: Patients with locally recurrent/advanced or metastatic TNBC who 
have received up to 2 prior lines of chemotherapy in the advanced or metastatic 
setting. 
• Documentation of ER-negative and/or progesterone receptor-negative tumor 
(<1% positive stained cells) based on local testing on most recent tumor 
biopsy (described above). 
• Documentation of HER2-negative tumor based: HER2-negative tumor is 
determined as immunohistochemistry score 0/1+ or negative by in situ 
hybridization (FISH/CISH/SISH/DISH) defined as a HER2/CEP17 ratio <2 or 
for single probe assessment a HER2 copy number <4. 
• Ovarian cancer: Patients with advanced platinum resistant epithelial ovarian 
cancer (EOC)/fallopian tube cancer/primary peritoneal cancer (PPC) 
(histologically or cytologically proven) who have received up to 3 prior lines of 
therapy (NOTE: each line of therapy that includes platinum [as a single agent or 
in combination] will be considered a unique treatment line). 


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Part 2: 
Arm A: 
Patients with HR-positive HER2-negative locally advanced or ≥mBC (second or 
third line setting) (histologically or cytologically proven). 
• Documentation of ER-positive and/or progesterone receptor-positive tumor 
(≥1% positive stained cells) and HER2-negative tumor (described above). 
• Received one prior line of combined CDK4/6 inhibitor and a nonsteroidal 
aromatase inhibitor with disease progression either on or after treatment. 
• More than one prior line of cytotoxic chemotherapy in the advanced or metastatic 
setting is allowed after discussion with sponsor. 
•  More than one line of prior endocrine therapy in the advanced setting may be 
permitted after discussion with the sponsor. 
• Have measurable disease per RECIST 1.1. Participants with only non-measurable 
disease may be enrolled if a compelling clinical rationale is provided by the 
investigator and approved by the sponsor. 
Arm B: 
Patients with HR-positive HER2-negative locally advanced or mBC who are 
naïve to CDK4/6 inhibitors (histologically or cytologically proven). 
• Documentation of ER-positive and/or progesterone receptor-positive tumor 
(≥1% positive stained cells) and HER2-negative tumor (described above). 
• Have not received a CDK4/6 inhibitor as treatment as adjuvant therapy or as 
treatment in the advanced or metastatic setting. 
• Have not received an aromatase inhibitor in the advanced or metastatic setting 
(prior adjuvant therapy with AI is permitted). 
• One prior line of cytotoxic chemotherapy in the advanced or metastatic setting is 
allowed if the patient is CDK 4/6 inhibitor naïve. 
• Have measurable disease per RECIST 1.1. Participants with only non-measurable 
disease may be enrolled if a compelling clinical rationale is provided by the 
investigator and approved by the sponsor. 


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Arm C: 
Patients with HR-positive HER2-negative locally advanced or mBC who are 
naïve to CDK4/6 inhibitors (histologically or cytologically proven). 
• Documentation of ER-positive and/or progesterone receptor-positive tumor 
(≥1% positive stained cells) and HER2-negative tumor (described above). 
• Have not received a CDK4/6 inhibitor as treatment as adjuvant therapy or as 
treatment in the advanced or metastatic setting. One prior line of cytotoxic 
chemotherapy in the advanced or metastatic setting is allowed if the patient is 
CDK 4/6 inhibitor naïve. 
• Have measurable disease per RECIST 1.1. Participants with only non-measurable 
disease may be enrolled if a compelling clinical rationale is provided by the 
investigator and approved by the sponsor. 
• Progressed during treatment or within 12 months of completion of adjuvant 
therapy with an aromatase inhibitor if postmenopausal, or tamoxifen if pre- or 
peri-menopausal, or 
• Progressed while on or within 1 month after the end of prior aromatase inhibitor 
therapy for advanced/metastatic breast cancer if postmenopausal, or prior 
endocrine treatment for advanced/metastatic breast cancer if pre- or 
peri-menopausal. 
2. All patients must be refractory to or intolerant of existing therapies known to 
provide clinical benefit for their condition (Part 1 only). 
3. 
Female patients age ≥18 years (all Parts) or male patients ≥18 years (Part 1A and 
Part 1C) and/or ≥20 years in Japan. 
4. 
Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0 or 1. 
5. 
Adequate Bone Marrow Function, including: 
a. Absolute Neutrophil Count (ANC) ≥1,500/mm3 or ≥1.5 x 109/L; 
b. Platelets ≥100,000/mm3 or ≥100 x 109/L; 
6. Hemoglobin ≥9 g/dL. 
7. Adequate Renal Function, defined as: 
a. Estimated creatinine clearance ≥60 mL/min for Part 1 and ≥50 mL/min for 
Part 2 as calculated using the method standard for the institution. In equivocal 


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cases, a 24-hour urine collection test can be used to estimate the creatinine 
clearance more accurately. 
8. Adequate Liver Function, including: 
a. Total serum bilirubin ≤1.5 x ULN unless the patient has documented Gilbert 
syndrome; 
b. Aspartate and alanine aminotransferase (AST and ALT) ≤2.5 x ULN; 
≤5.0 x ULN if there is liver involvement by the tumor; 
c. Alkaline phosphatase ≤2.5 x ULN (≤5 x ULN in case of bone or liver 
metastasis). 
9. 
Resolved acute effects of any prior therapy to baseline severity or CTCAE 
Grade ≤1 except for adverse events (AEs) not constituting a safety risk by 
investigator judgment. 
10. For Part 2 only, measurable disease as defined by RECIST 1.1 is required. 
11. Serum pregnancy test (for females of childbearing potential) negative at screening. 
Female patients of nonchildbearing potential must meet at least 1 of the following 
criteria and will not require a serum pregnancy test at screening: 
• Achieved postmenopausal status, defined as follows: cessation of regular 
menses for at least 12 consecutive months not due to prior chemotherapy, 
endocrine therapy or other pharmacologic cause and with no alternative 
pathological or physiological cause; postmenopausal status may be confirmed 
with a serum follicle-stimulating hormone (FSH) level. When there is a high 
FSH level, it should be confirmed that there is no other medical cause. 
• Have undergone a documented hysterectomy and/or bilateral oophorectomy. 
• Have medically confirmed ovarian failure. 
• Female patients who do not meet the above criteria (including female patients 
with tubal ligations) are considered to be of childbearing potential. Female 
patients with HR-positive HER2-negative advanced or mBC considered to be 
of child bearing potential must then undergo medically-induced menopause by 
treatment with luteinizing hormone-releasing hormone (LHRH) agonist 
goserelin, the gonadotropin releasing hormone (GnRH) agonist leuprolide 
(Lupron Depot®), or equivalent agents to induce chemical menopause 
(See Section 4.3). 
12. Evidence of a personally signed and dated informed consent document indicating 
that the patient has been informed of all pertinent aspects of the study. 


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13. Willing and able to comply with scheduled visits, treatment plan, laboratory tests, 
and other procedures. 
4.2. Exclusion Criteria 
Patients with any of the following characteristics/conditions will not be included in the study: 
1. Known active uncontrolled or symptomatic Central Nervous System (CNS) 
metastases, carcinomatous meningitis, or leptomeningeal disease as indicated by 
clinical symptoms, Cerebral edema, and/or progressive growth. Patients with a 
history of CNS metastases or cord compression are eligible if they have been 
definitively treated (eg, radiotherapy, stereotactic surgery) and are clinically stable 
off anticonvulsants and steroids for at least 4 weeks before randomization and have 
no evidence of progression at time of study enrollment. 
2. Patients with advanced/metastatic, symptomatic, visceral spread, that are at risk of 
life-threatening complications in the short term (including patients with massive 
uncontrolled effusions [pleural, pericardial, peritoneal], pulmonary lymphangitis, 
and over 50% liver involvement). 
3. Patients with an indwelling catheter that has an external component such as those 
used for drainage of effusion(s) or central venous catheter that is externally exposed 
(eg, peripherally inserted central catheter (PICC) line). Indwelling catheters that 
are fully internalized (eg, PORT-A-CATH®) are permitted. 
4. Any other active malignancy within 3 years prior to randomization, except for 
adequately treated basal cell or squamous cell skin cancer, or carcinoma in situ. 
5. Major surgery within 4 weeks prior to study entry. 
6. Radiation therapy within 4 weeks prior to study entry. 
7. Last anti-cancer treatment within 2 weeks (or 5 half-lives, whichever is shorter, 
unless the last immediate anti-cancer treatment contained an antibody based 
agent(s) (approved or investigational), then the interval of 4 weeks or 5 half-lives 
(whichever is shorter)) is required prior to receiving the investigational product. 
8. Participation in other studies involving investigational drug(s) within 4 weeks (or 
5 half-lives, whichever is shorter) prior to study entry. 
9. Previous high-dose chemotherapy requiring stem cell rescue. 
10. Active and clinically significant bacterial, fungal, or viral infection, including 
hepatitis B virus (HBV), hepatitis C virus (HCV), known human immunodeficiency 
virus (HIV) or acquired immunodeficiency syndrome (AIDS) - related illness. In 
equivocal cases, with positive serology, those patients with a negative viral load are 
potentially eligible provided the other entry criteria are met. This protocol excludes 
patients with active infections, as noted above. While SARS-CoV2 testing is not 


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mandated for entry into this protocol, testing should follow local clinical practice 
standards. If a patient has a positive test result for SARS-CoV2 infection, is known 
to have asymptomatic infection or is suspected of having SARS-CoV2, he/she is 
excluded. See Appendix 6 for more information around SARS-CoV2. 
11. Any of the following in the previous 6 months: myocardial infarction, congenital 
long QT syndrome, Torsades de pointes, arrhythmias (including sustained 
ventricular tachyarrhythmia and ventricular fibrillation), right bundle branch block 
and left anterior hemiblock (bifascicular block), unstable angina, 
coronary/peripheral artery bypass graft, symptomatic congestive heart failure (New 
York Heart Association class III or IV), cerebrovascular accident, transient 
ischemic attack, or symptomatic pulmonary embolism; deep venous thrombosis 
(DVT); arterial occlusive disease; ongoing cardiac dysrhythmias of National 
Cancer Institute (NCI) CTCAE Grade ≥2, atrial fibrillation of any grade that is 
uncontrolled, or QTcF interval >470 msec at screening. 
12. Hypertension that cannot be controlled by medications (>150/100 mmHg despite 
optimal medical therapy). 
13. Known abnormalities in coagulation such as bleeding diathesis, or treatment with 
anticoagulants precluding intramuscular injections of fulvestrant or goserelin 
(if applicable). 
14. Known or suspected hypersensitivity to active ingredient/excipients of 
PF-06873600, letrozole, fulvestrant and goserelin (or equivalent agent to induce 
chemical menopause). 
15. Other acute or chronic medical or psychiatric condition, including recent (within 
the past year) or active suicidal ideation or behavior or laboratory abnormality that 
may increase the risk associated with study participation or investigational product 
administration or may interfere with the interpretation of study results and, in the 
judgment of the investigator, would make the patient inappropriate for entry into 
this study. 
16. Investigator site staff members directly involved in the conduct of the study and 
their family members, site staff members otherwise supervised by the investigator, 
or patients who are Pfizer employees, including their family members, directly 
involved in the conduct of the study. 
17. Pregnant female patients; breastfeeding female patients, female patients of 
childbearing potential and fertile male patients (Part 1A and Part 1C only) who are 
unwilling or unable to use 2 highly effective methods of contraception as outlined 
in this protocol for the duration of the study and for at least 28 days after the last 
dose of investigational product. 
18. Active inflammatory gastrointestinal (GI) disease, known diverticular disease or 
previous gastric resection or lap-band surgery. Impairment of gastro-intestinal 


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function or GI disease that may significantly alter the absorption of PF-06873600, 
such as history of GI surgery with may result in intestinal blind loops and patients 
with clinically significant gastroparesis, short bowel syndrome, unresolved nausea, 
vomiting, active inflammatory bowel disease or diarrhea of CTCAE Grade >1. 
Gastroesophageal reflux disease under treatment with proton-pump inhibitors is 
allowed. 
19. Current use of drugs as shown in Appendix 5, which have a risk for QTc 
prolongation. 
20. Current use or anticipated need for food or drugs that are known strong 
CYP3A4/5 inhibitors, including their administration within 5 half-lives of the 
CYP3A4/5 inhibitor, prior to first dose of investigational product. Current or 
anticipated use of moderate CYP3A4/5 inhibitors (including their administration 
within 5 half-lives of the CYP3A4/5 inhibitor, prior to first dose of investigational 
product) should be avoided if possible, and any use will need to be reviewed and 
approved by the Sponsor (See Section 5.7). 
21. Current use or anticipated need for drugs that are known strong CYP3A4/5 
inducers, including their administration within 5 half-lives of the CYP3A4/5 
inducer, prior to the first dose of investigational product (See Section 5.7). 
4.3. Lifestyle Requirements 
In this study, female patients who are of childbearing potential, and fertile male patients as 
applicable to the study will receive PF-06873600 as a single agent or in combination with 
endocrine therapy, which currently has unknown teratogenicity/fetotoxicity so must be 
considered as suspected. Patients who are, in the opinion of the investigator, sexually active 
and at risk for pregnancy with their partner(s) must agree to use 2 methods of highly effective 
contraception throughout the study and for at least 28 days after the last dose of 
PF-06873600. The investigator or his or her designee, in consultation with the patient, will 
confirm that the patient has selected 2 appropriate methods of contraception for the 
individual patient (and her partner(s)) from the list of permitted contraception methods (see 
below) and will confirm that the patient has been instructed in their consistent and correct 
use. At time points indicated in the Schedule of Activities, the investigator or designee will 
inform the patient of the need to use 2 highly effective methods of contraception consistently 
and correctly and document the conversation, and the patient’s affirmation, in the patient’s 
chart. In addition, the investigator or designee will instruct the patient to call immediately if 
1 or both of the selected contraception methods is discontinued or if pregnancy is known or 
suspected in the patient or partner. 
Highly effective methods of contraception are those that, alone or in combination, result in a 
failure rate of less than 1% per year when used consistently and correctly (ie, perfect use) and 
include the following: 
1. 
Established use of hormonal methods of contraception associated with inhibition of 
ovulation (eg, oral, inserted, injected, implanted, transdermal as approved by local 


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regulatory authority), provided the patient or male patient’s female partner plans to 
remain on the same treatment throughout the entire study and has been using that 
hormonal contraceptive for an adequate period of time to ensure effectiveness. 
2. 
Correctly placed copper-containing intrauterine device (IUD). 
3. 
Male condom or female condom used WITH a separate spermicide product (ie, 
foam, gel, film, cream, or suppository). For countries where spermicide is not 
available or condom plus spermicide is not accepted as highly effective 
contraception, this option is not appropriate. 
4. 
Male sterilization with absence of sperm in the post vasectomy ejaculate. 
5. 
Bilateral tubal ligation/bilateral salpingectomy or bilateral tubal occlusive 
procedure (provided that occlusion has been confirmed in accordance with the 
device’s label). All sexually active male patients must agree to prevent potential 
transfer to and exposure of partner(s) to drug through ejaculate by using a condom 
consistently and correctly, beginning with the first dose of investigational product 
and continuing for at least 28 days after the last dose of PF-06873600. 
4.3.1. Potential for Photosensitivity 
Patients will be advised to report any reaction to sun exposed skin. In addition, special 
precautions will be taken to limit any potential photo irritation effect, by minimizing the 
patients’ exposure to light including high intensity ultraviolet B (UVB) light sources such as 
tanning beds, tanning booths and sunlamps. Patients may wish to limit exposure to the sun 
and should be encouraged to apply sunscreen/sunblock daily. 
4.4. Sponsor’s Qualified Medical Personnel 
The contact information for the sponsor's appropriately qualified medical personnel for the 
study is documented in the study contact list located in the team SharePoint site. 
To facilitate access to appropriately qualified medical personnel on study-related medical 
questions or problems, patients are provided with a contact card. The contact card contains, 
at a minimum, protocol and investigational product identifiers, patient study numbers, 
contact information for the investigator site, and contact details for a contact center in the 
event that the investigator site staff cannot be reached to provide advice on a medical 
question or problem originating from another healthcare professional not involved in the 
patient’s participation in the study. The contact number can also be used by investigator staff 
if they are seeking advice on medical questions or problems; however, it should be used only 
in the event that the established communication pathways between the investigator site and 
the study team are not available. It is therefore intended to augment, but not replace, the 
established communication pathways between the investigator site and the study team for 
advice on medical questions or problems that may arise during the study. The contact 
number is not intended for use by the patient directly, and if a patient calls that number, he or 
she will be directed back to the investigator site. 


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5. STUDY TREATMENTS 
For the purposes of this study, and per International Conference on Harmonisation (ICH) 
guidelines, investigational product is defined as a pharmaceutical form of an active 
ingredient or placebo being tested or used as a reference/comparator in a clinical trial, 
including a product with a marketing authorization when used or assembled (formulated or 
packaged) in a way different from the approved form, or when used for an unapproved 
indication, or when used to gain further information about an approved use (ICH E6 1.33). 
For this study, the investigational products are PF-06873600, letrozole, and fulvestrant. 
5.1. Allocation to Treatment 
Dose level allocation will be performed by the sponsor after patients have given their written 
informed consent and have completed the necessary baseline assessments. The site staff will 
fax or e-mail a complete Registration Form to the designated sponsor study team member or 
designee. The sponsor will assign a patient identification number and supply this number to 
the site. The patient identification number will be used on all study-related documentation at 
the site. 
No patient shall receive investigational product until the investigator or designee has received 
the following information in writing from the sponsor: 
• Confirmation of the patient’s enrollment; 
• Specification of the dose level for that patient (and Arm in Part 2) and; 
• Permission to proceed with dosing the patient. 
The sponsor or designee will notify the other sites of the inclusion of a new patient, and will 
inform study sites about the next possible enrollment date. 
5.2. Patient Compliance 
Fulvestrant will be administered by the appropriately designated study staff at the 
investigational site. PF-06873600 tablets and letrozole will be distributed to the patient by 
the appropriately designated study staff at the investigational site. 
Patients will be required to return all unused study treatment at the beginning of each cycle. 
The number of tablets returned by the patient will be counted, documented, and recorded. 
A patient diary will be provided to the patients to aid in patient compliance with the dosing 
instructions. The diary will be maintained by the patient to include missed or changed 
PF-06873600 doses. Patients will be required to return all bottles of PF-06873600 every 
cycle. The number of PF-06873600 tablets remaining will be documented and recorded at 
each clinic visit or Day 1 of each cycle. The patient diary may also be used to support this 
part of the accountability process. The information above, regarding diary completion, 


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requirement to return all bottles and accountability documentation will also be performed on 
patients receiving letrozole (where applicable). 
Letrozole and fulvestrant will be administered in accordance with the package insert (or 
equivalent). All PF-06873600, letrozole, and fulvestrant administration will be documented 
on the corresponding investigational product administration CRF. 
5.3. Investigational Product Supplies 
PF-06873600, letrozole, and fulvestrant will be supplied by Pfizer. Study centers will 
receive PF-06873600 as well as letrozole and fulvestrant if needed, prior to enrollment of the 
first patient. 
5.3.1. Dosage Form(s) and Packaging 
5.3.1.1. PF-06873600 
PF-06873600 will be provided as tablets for oral administration. The 5 mg, and 25 mg 
immediate release tablets and the 10 mg and 40 mg MR tablets will be supplied in separate 
bottles and labeled according to local regulatory requirements. PF-06873600 immediate 
release tablets are supplied in 68-count bottles, modified release tablets are supplied in 
62-count bottles. 
5.3.1.2. Letrozole 
Letrozole will be supplied by Pfizer. Letrozole is available as 2.5 mg tablets in a 30-count 
bottle or a 28 count blister pack. Detailed information about letrozole can be found in the 
approved package insert. 
5.3.1.3. Fulvestrant 
Fulvestrant (Faslodex®) will be supplied by Pfizer. Fulvestrant is available as two 5-mL clear 
neutral glass (Type 1) barrels, each containing 250 mg/5 mL of fulvestrant solution for 
intramuscular injection and fitted with a tamper evident closure. The syringes are presented 
in a tray with polystyrene plunger rod and safety needles (SafetyGlideTM) for connection to 
the barrel. 
Refer to the local package insert fulvestrant (Faslodex®) for instructions and steps necessary 
for drug preparation and administration. Drug preparation and administration will be 
performed at the site by a physician, registered nurse, or other qualified health care provider. 
5.3.2. Preparation and Dispensing 
Only qualified personnel who are familiar with procedures that minimize undue exposure to 
them and to the environment should undertake the preparation, handling, and safe disposal of 
chemotherapeutic agents. Refer to package inserts for commercial product preparation and 
storage. 
The study treatment should be dispensed at each visit per the schedule of treatment. A 
qualified staff member will dispense the investigational product in the bottles provided, in 


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quantities appropriate for the study visit schedule. The patient/caregiver should be instructed 
to maintain the product in the bottle provided throughout the course of dosing, keep the 
investigational product away from children, and return the bottle to the site at the next study 
visit. 
Dose adjustments or discontinuations should be managed according to the Section 5.4.3 
below. However, per the investigator’s discretion, other dose adjustments may be discussed 
with the Sponsor. 
Any unused product or waste material should be disposed of in accordance with local 
requirements. 
5.4. Administration 
5.4.1. PF-06873600 
Patients will swallow the investigational product whole, and will not manipulate or chew the 
investigational product prior to swallowing. 
PF-06873600 will initially be administered orally BID on a continuous basis. If supported by 
emerging data, the QD continuous regimen or alternative intermittent dosing regimen may be 
considered. A cycle is defined as 28 days, regardless of missed doses or dose delays. 
The dosing intervals are as follows: 
• 
For the QD dosing regimen, the single dose should be administered in 24 ±4 hour 
intervals (ie, no less than 20 hours and no more than 28 hours apart); 
• 
For the BID dosing regimen, the doses should be administered in 12 ±4 hour 
intervals (ie, no less than 8 hours and no more than 16 hours apart); 
PF-06873600 will be administered orally on an empty stomach without adjustment for body 
size at every cycle. Patients should be instructed to take their medication at approximately 
the same time each day and to not take more than the prescribed dose at any time. If a 
patient misses a dose or day of treatment, she or he must be instructed not to “make it up” 
(unless it was less than 4 hours since their planned dosing time) and to resume subsequent 
doses the next scheduled time as prescribed. In addition, if a patient vomits any time after 
taking a dose; she or he must be instructed not to “make it up” but to resume subsequent 
doses the next day as prescribed. Lastly, if a patient inadvertently takes 1 extra dose during a 
day, the patient should not take the next dose of PF-06873600. 
Letrozole 
Letrozole will be administered orally once daily continuously together with PF-06873600. 
Refer to the package insert for additional administration instructions. 


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No dose adjustment for letrozole is permitted but dosing interruptions are allowed. 
Treatment interruption for letrozole-related toxicities will be performed as per the 
investigator’s best medical judgment. 
Fulvestrant 
Fulvestrant 500 mg will be administered intramuscularly into the buttocks slowly 
(1-2 minutes per injection) as two 5 mL injections, one in each buttock. Drug preparation 
and administration will be performed at the site by a physician, registered nurse or other 
qualified health care provider. Refer to the local product label for Faslodex® for detailed 
administration instructions. 
No dose adjustment for fulvestrant is permitted. A single fulvestrant injection can be skipped 
in case of a fulvestrant-related toxicity or dosing can be delayed. Treatment delay for 
fulvestrant-related toxicities will be performed as per the investigator’s best medical 
judgment, but by no more than 7 days. If a delay of longer than 7 days is required then the 
dose should be skipped. In the event of a toxicity requiring dosing delay of PF-06873600, 
fulvestrant can also be delayed by a maximum of 7 days. Fulvestrant should not be 
administered if the platelet count is <50,000/mm3. 
5.4.2. Food Requirements 
5.4.2.1. Food Requirements 
Oral PF-06873600 will be administered with at least 8 ounces (240 mL) of water on an 
empty stomach. No food or liquids other than water will be consumed for 2 hours before and 
1 hour following each dose throughout the study for BID dosing. No food or liquids other 
than water will be consumed for 2 hours before and 2 hours following each dose throughout 
the study for QD dosing. These fasting requirements may be removed (via a letter to the 
investigators) if the data from the food-effect study indicate that there is no meaningful effect 
of food on the bioavailability of PF-06873600. 
5.4.3. Recommended Dose Modifications 
Every effort should be made to administer investigational product on the planned dose and 
schedule. 
In the event of significant toxicity, dosing may be delayed and/or reduced as described 
below. In the event of multiple toxicities, dose modification should be based on the worst 
toxicity observed. Patients are to be instructed to notify investigators at the first occurrence 
of any adverse symptom. 
Dose modifications may occur in one of three ways: 
• 
Within a cycle: dosing interruption until adequate recovery and dose reduction, if 
required, during a given treatment cycle; 


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• 
Between cycles: next cycle administration may be delayed due to persisting 
toxicity when a new cycle is due to start; 
• 
In the next cycle: dose reduction may be required in a subsequent cycle based on 
toxicity experienced in the previous cycle. 
5.4.3.1. Dosing Interruptions 
Patients experiencing the following adverse events should have their treatment interrupted: 
• 
DLT in Cycle 1 (DLT observation period of 28 days [see Section 3.1.6]); 
• 
AEs meeting DLT criteria after the DLT observation period. 
Appropriate follow-up assessments should be done until adequate recovery occurs as 
assessed by the investigator. Criteria required before treatment can resume are described in 
the Dose Delays section. 
Doses may be held as needed until toxicity resolution. Depending on when the adverse event 
resolved, a treatment interruption may lead to the patient missing all subsequent planned 
doses within that same cycle or even to delay the initiation of the subsequent cycle. 
If the adverse event that led to the treatment interruption recovers within the same cycle, then 
re-dosing in that cycle is allowed. Doses omitted for toxicity are not replaced within the 
same cycle. The need for a dose reduction at the time of treatment resumption should be 
based on the criteria defined in the Dose Reductions section, unless expressly agreed 
otherwise following discussion between the investigator and the sponsor. If a dose reduction 
is applied in the same cycle, the patient may need to return to the clinic to receive new drug 
supply. 
In the event of a treatment interruption for reasons other than treatment-related toxicity 
(eg, elective surgery) lasting 4 weeks treatment resumption will be decided in consultation 
with the sponsor. 
5.4.3.2. Dose Interruption of Patients with Presumed or Active COVID-19/SARs-CoV2 
Infection 
Ongoing patients who have active (confirmed [positive by regulatory authority-approved 
test] or presumed [test pending/clinical suspicion]) SARS-CoV2 infection, should follow the 
treatment guidelines: 
• 
For symptomatic patients with active SARS-CoV2 infection, investigational 
treatment should be delayed for at least 14 days from start of symptoms. This 
delay is intended to allow resolution of symptoms of SARS-CoV2 infection. 
• 
Prior to restarting treatment, the patient should be afebrile for 72 hours and 
SARS-CoV2-related symptoms should have recovered to Grade ≤1 for a minimum 
of 72 hours. The sponsor should be informed when restarting treatment. 


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• 
Continue to consider potential drug-drug interactions for any concomitant 
medication administered for treatment of SARS-CoV2 infection. 
5.4.3.3. Dose Delays 
Re-treatment following treatment interruption for treatment -related toxicity or at the start of 
any new cycle may not occur until all of the following parameters have been met: 
• 
ANC ≥1,000/mm3; 
• 
Platelets count ≥50,000/mm3; 
• 
Hemoglobin ≥8.0 g/DL; 
• 
Nonhematologic toxicities have returned to baseline or Grade ≤1 severity (or, at the 
investigator’s discretion, Grade ≤2 if not considered a safety risk for the patient). 
If a treatment delay results from worsening of hematologic or biochemical parameters, the 
frequency of relevant blood tests should be increased as clinically indicated. 
If these conditions are met within 2 weeks of treatment interruption or cycle delay, 
PF-06873600 may be resumed. Refer to the Dose Reductions section for adverse events 
requiring dose reduction at the time of treatment resumption. 
If these conditions are not met, treatment resumption must be delayed up to a maximum of 
4 weeks. If patients require discontinuation of PF-06873600 for more than 4 weeks at any 
time during the study, then study treatment should be permanently discontinued, unless it is 
for reasons other than treatment -related toxicity or the investigator’s benefit/risk assessment 
suggests otherwise after discussion with the sponsor’s medical monitor. 
If a treatment interruption continues beyond Day 28 of the current cycle, then the day when 
PF-06873600 is restarted will be counted as Day 1 of the next cycle but tumor assessment 
will be maintained relative to Cycle 1 Day 1. 
5.4.3.4. Dose Reductions 
Following dosing interruption or cycle delay due to toxicity, the PF-06873600 dose may need 
to be reduced when treatment is resumed. 
No specific dose adjustments are recommended for Grade 1/2 treatment -related toxicity. 
However, investigators should always manage their patients according to their medical 
judgment based on the particular clinical circumstances. 
Dose reduction of PF-06873600 by 1 and, if needed, 2 dose levels, or intermediate dose 
levels, will be allowed depending on the type and severity of toxicity encountered. Patients 
requiring more than 2 dose reductions will be discontinued from the treatment and entered 
into the follow-up phase, unless otherwise agreed between the investigator and the sponsor. 


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All dose modifications/adjustments must be clearly documented in the patient's source notes 
and CRF. 
Patients experiencing a DLT may resume dosing at the next lower dose level (if applicable) 
once adequate recovery is achieved at the discretion of the investigator. No dose reductions 
are planned for patients experiencing toxicities other than those listed as DLTs. However, 
patients experiencing recurrent and intolerable toxicity that does not meet the criteria for 
DLT (ie, recurrent transient high grade neutropenia or diarrhea) or are Grade 2 may resume 
dosing at the next lower dose level once recovery to Grade ≤1 or baseline is achieved. 
Dose reductions during the DLT observation period are not permitted unless the patient 
experiences a DLT. However, at the discretion of the investigator or sponsor based on 
emerging safety data, patients may be asked to reduce their dose within the DLT window. 
Recommended dose reductions for Part 1 and Part 2 are described in Table 3. 
 
Table 3. 
Dose Modifications for PF-06873600-Related Toxicity 
 
Toxicity 
Grade 1 
Grade 2* 
Grade 3** 
Grade 4 
Nonhematologic 
Continue at the 
Continue at the 
Withhold dose until 
Withhold dose until 
same dose level. 
same dose level. 
toxicity is Grade ≤1, or 
toxicity is Grade ≤1, 
has returned to baseline, 
or has returned to 
then resume treatment at 
baseline, then 
the same dose level or 
reduce the dose by 
reduce the dose by 
1 level and resume 
1 level at the discretion 
treatment, or 
of the investigator. 
discontinue at the 
discretion of the 
investigator.*** 
Hematologic 
Continue at the 
same dose level. 
Continue at the 
same dose level. 
Withhold dose until 
toxicity is Grade ≤2, or 
has returned to baseline, 
then resume treatment at 
the same dose level. 
Reduce the dose by 
1 level if recurrent or 
prolonged Grade 3 
hematologic toxicity *** 
Withhold dose until 
toxicity is Grade ≤2, 
or has returned to 
baseline, then 
reduce the dose by 
1 level and resume 
treatment. 
Reduce the dose to 
15 mg BID if Grade 
4 neutropenia*** 
*For recurrent and intolerable toxicity that does not meet DLT criteria or Grade 2, see language above. 
**Nausea, vomiting, or diarrhea must persist at Grade 3 despite optimal supportive care to require dose modification. 
Thrombocytopenia must be Grade 3 with Grade ≥2 bleeding to require dose modification. 
For QTcF ≥501 msec, refer to Section 7.1.5. 
***Cycle will not be extended to cover for the missing doses. 
Note: Patients with confirmed Hy's Law, must be discontinued. 
5.5. Investigational Product Storage 
The investigator, or an approved representative, eg, pharmacist, will ensure that all 
investigational products, including marketed products, are stored in a secured area with 


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controlled access under required storage conditions and in accordance with applicable 
regulatory requirements. 
Investigational products should be stored in their original containers and in accordance with 
the labels. PF-06873600 should be stored as described on the label and as outlined in the IP 
manual and patient dosing diaries. 
Any storage conditions stated in the SRSD will be superseded by the storage conditions 
stated on the product label (for each combination drug letrozole/fulvestrant). 
Site systems must be capable of measuring and documenting (for example, via a log), at a 
minimum, daily minimum and maximum temperatures for all site storage locations (as 
applicable, including frozen, refrigerated, and/or room-temperature products). This should 
be captured from the time of investigational product receipt throughout the study. Even for 
continuous-monitoring systems, a log or site procedure that ensures active evaluation for 
excursions should be available. The intent is to ensure that the minimum and maximum 
temperature is checked each business day to confirm that no excursion occurred since the last 
evaluation and to provide the site with the capability to store or view the minimum/maximum 
temperature for all nonworking days upon return to normal operations. The operation of the 
temperature monitoring device and storage unit (for example, refrigerator), as applicable, 
should be regularly inspected to ensure they are maintained in working order. 
Any excursions from the product label storage conditions should be reported to Pfizer upon 
discovery. The site should actively pursue options for returning the product to the storage 
conditions described in the labeling, as soon as possible. Deviations from the storage 
requirements, including any actions taken, must be documented and reported to Pfizer. 
Once an excursion is identified, the investigational product must be quarantined and not used 
until Pfizer provides permission to use the investigational product. It will not be considered a 
protocol deviation if Pfizer approves the use of the investigational product after the 
temperature excursion. Use of the investigational product prior to Pfizer approval will be 
considered a protocol deviation. 
Specific details regarding information the site should report for each excursion will be 
provided to the site. 
Receipt of materials, door opening and closing, and other routine handling operations where 
the products are briefly out of the temperature range described in the labeling are not 
considered excursions. 
Site staff will instruct patients on the proper storage requirements for take home 
investigational products. 


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5.6. Investigational Product Accountability 
The investigator site must maintain adequate records documenting the receipt, use, loss, or 
other disposition of the investigational product supplies. All investigational products will be 
accounted for using a drug accountability form/record. 
All bottles of study drug, including any unused tablets, must be returned to the investigator 
by the patient at designated study visits and at the end of the trial. 
5.6.1. Destruction of Investigational Product Supplies 
The sponsor or designee will provide guidance on the destruction of unused investigational 
product (eg, at the site). If destruction is authorized to take place at the investigator site, the 
investigator must ensure that the materials are destroyed in compliance with applicable 
environmental regulations, institutional policy, and any special instructions provided by 
Pfizer, and all destruction must be adequately documented. 
For all bottles returned to the investigator by the patient, the investigator will maintain the 
returned supply until destruction is authorized. Pfizer will provide instructions as to the 
disposition of any unused investigational product. 
5.7. Concomitant Treatment(s) 
Concomitant treatment considered necessary for the patient’s well-being may be given at 
discretion of the treating physician. 
All concomitant treatments, blood products, as well as nondrug interventions 
(eg, paracentesis) received by patients from screening until the end of study visit will be 
recorded on the CRF. 
Because inhibition of CYP3A4/5 isoenzymes may increase PF-06873600 exposure leading to 
potential increases in toxicities, the use of known strong CYP3A4/5 inhibitors is not 
permitted within 5 half-lives of the respective CYP3A4/5 inhibitor(s), prior to the first dose 
of PF-06873600. 
Strong CYP3A4/5 inhibitors may include grapefruit juice or grapefruit/grapefruit related 
citrus fruits (eg, Seville oranges, pomelos), ketoconazole, miconazole, itraconazole, 
voriconazole, posaconazole, clarithromycin, telithromycin, indinavir, saquinavir, ritonavir, 
nelfinavir, amprenavir, fosamprenavir, nefazodone, lopinavir, troleandomycin, mibefradil, 
and conivaptan. 
Use of moderate CYP3A4/5 inhibitors should be avoided if possible, and any use needs to be 
reviewed and approved by the sponsor. Moderate CYP3A4 inhibitors may include 
erythromycin, verapamil, atazanavir, fluconazole, darunavir, diltiazem, delavirdine, 
aprepitant, imatinib, tofisopam, ciprofloxacin, and cimetidine. 
Because induction of CYP3A4/5 isoenzymes may decrease PF-06873600 exposure leading to 
potential decrease in efficacy, the use strong CYP3A4/5 inducers is not permitted within 


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5 half-lives of the respective CYP3A4/5 inducer(s), prior to the first dose of PF-06873600. 
Strong CYP3A4/5 inducers may include phenobarbital, rifampin, phenytoin, carbamazepine, 
rifabutin, rifapentin, clevidipine, and St. John’s Wort. In addition, the use of moderate 
CYP3A4/5 inducers warrants caution. Moderate CYP3A4/5 inducers may include bosentan, 
efavirenz, etravirine, modafinil, and nafcillin (www.druginteractioninfo.org).26 
Concomitant use of PF-06873600 and a CYP3A4/5 substrate may increase the exposure of 
the CYP3A4/5 substrate. Therefore, caution is warranted for the coadministration of 
PF-06873600 with CYP3A4/5 substrates with a narrow therapeutic indices. CYP3A4/5 
substrates of a narrow therapeutic indices, may include astemizole, terfenadine, cisapride, 
pimozide, quinidine, tacrolimus, cyclosporine, sirolimus, (alfentanil and fentanyl, excluding 
transdermal patch), or ergot alkaloids (ergotamine, dihydroergotamine) 
(www.druginteractioninfo.org).26 
Concomitant use of PF-06873600 and a substrate of the MATE1 or MATE2K renal 
transporters may increase the exposure of the MATE1 or MATE2K substrate. Therefore, 
caution is warranted for the coadministration of PF-06873600 with MATE1 or MATE2K 
substrates. MATE1 or MATE2K substrates may include metformin, cimetidine, 
procainamide, cephalexin, acyclovir, gancyclovir, fexofenadine 
(www.druginteractioninfo.org).26 
5.7.1. Other Anti-tumor or Experimental Drugs 
No additional anti-tumor treatment will be permitted while patients are receiving study 
treatment. Additionally, the concurrent use of select herbal supplements (including those 
listed in Section 5.7) is not permitted. 
Palliative radiotherapy on study is permitted for the treatment of painful bony lesions 
provided that the lesions were known at the time of study entry and the investigator clearly 
indicates that the need for palliative radiotherapy is not indicative of disease progression. In 
view of the current lack of data about the interaction of PF-06873600 with radiotherapy, 
PF-06873600 treatment should be interrupted during palliative radiotherapy, stopping 3 days 
or 5 half-lives (whichever is longer) before and resuming treatment after recovery to 
baseline. 
5.7.2. Supportive Care 
Palliative and supportive care for disease related symptoms may be administered at the 
investigator’s discretion and according to available American Society of Clinical Oncology 
(ASCO) guidelines. 
Female patients currently being treated with a gonadotropin-releasing hormone agonist 
(GnRH agonist) prior to study enrollment may continue treatment while on study treatment 
as long as the GnRH agonist treatment has been well tolerated for at least 3 months prior to 
study entry. 


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5.7.3. Hematopoietic Growth Factors 
Primary prophylactic use of granulocyte-colony stimulating factors is not permitted prior to 
Cycle 1, Day 1 (C1D1), but they may be used to treat treatment emergent neutropenia as 
indicated by the current ASCO guidelines. For Japan only: since the indication and dosage 
of G-CSF compounds approved in Japan may differ from ASCO guidelines, refer to Japanese 
package insert and local clinical guideline. 
Erythropoietin may be used at the investigator’s discretion for the supportive treatment of 
anemia (Note: erythropoietin is not approved for anemia caused by chemotherapy in all local 
regions, nor is it currently approved in Japan). 
5.7.4. Diarrhea Management 
Diarrhea is a possible adverse event based on the preclinical toxicology data. As there is no 
prior clinical experience with PF-06873600, the exact nature of treatment related diarrhea in 
humans is unknown. In general, management of cancer treatment-induced diarrhea have 
been described (Benson et al, 2004).28 Initial management for mild to moderate diarrhea may 
include dietary modifications (eliminating lactose and other high-osmolar dietary 
supplements), loperamide or diphenoxylate/atropine, along with oral antibiotics if persistent 
with concern for infection. Management of higher severity or more complicated diarrhea 
may also include consideration of intravenous fluids for hydration, electrolyte replacement, 
octreotide, stool workup along with hospitalization for observation and treatment if indicated 
in the investigator’s medical judgment. 
5.7.5. Anti-Diarrheal, Anti-Emetic Therapy 
Primary prophylaxis of diarrhea, nausea and vomiting is not permitted prior to C1D1. 
Anti-diarrheal and anti-emetic therapies may be used to treat treatment emergent diarrhea, 
nausea and vomiting as early as during Cycle 1. The choice of the drug as well as the 
duration of treatment is up to the investigator, assuming there is no known or expected 
drug-drug interaction and assuming the drug is not included in the Concomitant Treatment(s) 
section. 
5.7.6. Anti-Inflammatory Therapy 
Anti-inflammatory or narcotic analgesic may be offered as needed assuming there is no 
known or expected drug-drug interaction and assuming the drug is not included in the 
Concomitant Treatment(s) section. 
5.7.7. Corticosteroids 
Chronic systemic corticosteroid use for palliative or supportive purposes is not permitted. 
Acute emergency administration, topical applications, inhaled sprays, eye drops, or local 
injections of corticosteroids are allowed. 
5.7.8. Surgery 
Caution is advised on theoretical grounds for any surgical procedures during the study. The 
appropriate interval of time between surgery and PF-06873600 required to minimize the risk 


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of impaired wound healing and bleeding has not been determined. Stopping PF-06873600 is 
recommended at least stopping 3 days or 5 half-lives (whichever is longer) prior to surgery. 
Postoperatively, the decision to reinitiate PF-06873600 treatment should be based on a 
clinical assessment of satisfactory wound healing and recovery from surgery. 
5.7.9. Permitted Medications 
• 
H2-Receptor Antagonists (H2RAs) for symptomatic treatment of gastrointestinal 
disorder (including, but not limited to famotidine, ranitidine, nizatidine, 
cimetidine). 
• 
Local antacids for symptomatic treatment of gastrointestinal disorder 
(eg, aluminum/calcium hydroxide, aluminum/calcium carbonate, bismuth 
subsalicylate). 
• 
Acid reducing agents (including proton pump inhibitors (PPIs)) can be used for 
symptomatic treatment of gastrointestinal disorder. 
5.8. Luteinizing Hormone Releasing Hormone (LHRH) Agonist 
Pre/peri-menopausal women with HR-positive HER2-negative advanced or mBC can be 
enrolled if amenable to be treated with the LHRH agonist. Treatment with a LHRH agonist 
(eg, goserelin, leuprolide acetate or equivalent agents) should be used according to the 
prescribing information for all women who are pre- or peri-menopausal at study entry to 
induce chemical menopause throughout the study. 
Patients not currently receiving an LHRH agonist prior to study entry must have commenced 
treatment with LHRH agonist at least 1 week prior to C1D1 for the monthly administration 
form and at least 3 weeks prior to C1D1 for patients receiving the LHRH on an every 
3 month schedule. 
6. STUDY PROCEDURES 
6.1. Screening 
For screening procedures see the Schedule of Activities and ASSESSMENTS sections. 
6.2. Study Period 
For the treatment period procedures, see the Schedule of Activities and 
ASSESSMENTS sections. 
6.3. Follow-up 
For follow-up procedures see the Schedule of Activities and ASSESSMENTS sections. 


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6.4. Patient Withdrawal 
Withdrawal of consent: 
Patients who request to discontinue receipt of study treatment will remain in the study and 
must continue to be followed for protocol specified follow-up procedures. The only 
exception to this is when a patient specifically withdraws consent for any further contact with 
him or her or persons previously authorized by the patient to provide this information. 
Patients should notify the investigator in writing of the decision to withdraw consent from 
future follow-up, whenever possible. The withdrawal of consent should be explained in 
detail in the medical records by the investigator, as to whether the withdrawal is only from 
further receipt of investigational product or also from study procedures and/or posttreatment 
study follow-up, and entered on the appropriate CRF page. In the event that vital status 
(whether the patient is alive or dead) is being measured, publicly available information 
should be used to determine vital status only as appropriately directed in accordance with 
local law. 
Lost to follow-up: 
All reasonable efforts must be made to locate patients to determine and report their ongoing 
status. This includes follow-up with persons authorized by the patient as noted above. Lost 
to follow-up is defined by the inability to reach the patient after a minimum of 2 documented 
phone calls, faxes, or e-mails as well as lack of response by the patient to 1 registered mail 
letter. All attempts should be documented in the patient’s medical records. If it is 
determined that the patient has died, the site will use locally permissible methods to obtain 
the date and cause of death. If the investigator’s use of a third-party representative to assist 
in the follow-up portion of the study has been included in the patient’s informed consent, 
then the investigator may use a sponsor-retained third-party representative to assist site staff 
with obtaining the patient’s contact information or other public vital status data necessary to 
complete the follow-up portion of the study. The site staff and representative will consult 
publicly available sources, such as public health registries and databases, in order to obtain 
updated contact information. If, after all attempts, the patient remains lost to follow-up, then 
the last-known-alive date as determined by the investigator should be reported and 
documented in the patient’s medical records. 
Patients may withdraw from treatment at any time at their own request, or they may be 
withdrawn at any time at the discretion of the investigator or sponsor for safety (see also the 
Withdrawal from the Study Due to Adverse Events (see also the Patient Withdrawal section) 
or behavioral reasons, or the inability of the patient to comply with the protocol -required 
schedule of study visits or procedures at a given investigator site. 
In rare instances, it may be necessary for a patient to permanently discontinue study 
intervention (definitive discontinuation). Reasons for definitive discontinuation of study 
intervention may include the following: 
• 
Objective disease progression; 


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• 
Global deterioration of health status requiring discontinuation; 
• 
Unacceptable toxicity; 
• 
Pregnancy; 
• 
Significant protocol violation; 
• 
Lost to follow-up; 
• 
Patient refused further treatment; 
• 
Study terminated by sponsor; 
• 
Death; 
A patient may withdraw from the study at any time at his/her own request. Reasons for 
discontinuation from the study may include: 
• 
Completed study follow-up; 
• 
Study terminated by sponsor; 
• 
Lost to follow-up; 
• 
Refused further follow-up; 
• 
Death. 
If a patient does not return for a scheduled visit, every effort should be made to contact the 
patient. All attempts to contact the patient and information received during contact attempts 
must be documented in the patient’s medical record. In any circumstance, every effort 
should be made to document patient outcome, if possible. The investigator should inquire 
about the reason for withdrawal, request that the patient return all unused investigational 
product(s), request that the patient return for a final visit, if applicable, and follow up with 
the patient regarding any unresolved AEs. 
If the patient refuses further visits, the patient should continue to be followed unless the 
patient withdraws consent for disclosure of future information or for further contact. In this 
case, no further study-specific evaluations should be performed and no additional data should 
be collected. The sponsor may retain and continue to use any data collected before such 
withdrawal of consent. 
If the investigator feels that the patient is still deriving benefit from the therapy, may elect to 
continue therapy at the same dose or 1 dose lower in consultation with the sponsor until the 
benefit no longer exists. 


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7. ASSESSMENTS 
The collection of the efficacy, safety, PK, biopsy and biomarker data per protocol will be 
completed as of the primary completion date (PCD). Participants who continue on study 
beyond PCD will follow local standard of care for safety procedures and the disease 
assessment. SAE reporting to Pfizer Safety will continue per protocol until end of trial. 
AEs reporting in eCRF will continue to be collected per local regulatory requirements. Refer 
to Section 13.2 and Appendix 8 for the details. 
Every effort should be made to ensure that the protocol-required tests and procedures are 
completed as described. However, it is anticipated that from time to time there may be 
circumstances outside of the control of the investigator that may make it unfeasible to 
perform the test. In these cases the investigator will take all steps necessary to ensure the 
safety and well-being of the patient. When a protocol-required test cannot be performed, the 
investigator will document the reason for this and any corrective and preventive actions that 
he or she has taken to ensure that normal processes are adhered to as soon as possible. The 
study team will be informed of these incidents in a timely manner. 
For samples being collected and shipped, detailed collection, processing, storage, shipment 
instructions and contact information will be provided to the investigator site prior to initiation 
of the study. 
See Appendix 6 for alternative measures during public emergencies including the COVID-19 
pandemic. 
7.1. Safety Assessment 
Safety assessments will include collection of AEs, serious adverse events (SAEs), vital signs 
and physical examination, electrocardiogram (ECG [12-lead]), laboratory assessments, 
including pregnancy tests and verification of concomitant treatments. 
7.1.1. Pregnancy Testing 
All pregnancy tests used in this study, either urine or serum, must have a sensitivity of at 
least 25 mIU/mL and must be performed by a certified laboratory. For female patients of 
childbearing potential, 2 negative pregnancy tests are required before receiving PF-06873600 
(1 negative pregnancy test at screening and 1 at the baseline visit immediately before 
PF-06873600 administration). Following a negative pregnancy test result at screening, 
appropriate contraception must be commenced and the second negative pregnancy test result 
will then be required at the baseline visit and within 5 days after the first day of the menstrual 
period (counting the first day of the menstrual period as Day 1) before the patient may 
receive PF-06873600. In the absence of regular menstrual bleeding, the study candidate 
should have used 2 forms of contraception for at least 1 month before the second pregnancy 
test. Pregnancy tests will also be repeated at Day 1 of every other Cycle and at the end of the 
study to confirm that the patient has not become pregnant during the study. Pregnancy tests 
will also be done whenever 1 menstrual cycle is missed during the active treatment period 
and when potential pregnancy is otherwise suspected, and may be repeated if requested by 
institutional review boards (IRBs)/ethics committees (ECs) or if required by local 


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regulations. In the case of a positive confirmed pregnancy, the patient will be withdrawn 
from administration of investigational product and from the study. 
7.1.2. Adverse Events 
Assessment of adverse events will include the type, incidence, severity (graded by the NCI 
CTCAE version 4.03) timing, seriousness, and relatedness. 
7.1.3. Laboratory Safety Assessment 
Safety laboratory assessment to be drawn at the time points described in the Schedule of 
Activities and analyzed at local laboratories. 
 
Table 4. 
Safety Laboratory Tests 
 
Hematology 
Chemistry 
Coagulation 
Urinalysis 
Other: 
Hemoglobin 
ALT* 
PT or INR* 
Urine dipstick for 
urine protein: If 
positive collect 
24-hour and 
microscopic (Reflex 
Testing) 
Pregnancy test: for 
female patients of 
childbearing 
potential, serum 
(screening) or urine 
Platelets 
AST* 
PTT or 
aPTT 
WBC 
Alk Phos* 
Absolute Neutrophils 
Sodium 
Absolute 
Lymphocytes 
Potassium 
Absolute Monocytes 
Magnesium 
Urine dipstick for 
urine blood: If 
positive collect a 
microscopic (Reflex 
Testing) 
Absolute Eosinophils 
Chloride 
Hepatitis B 
testing** 
Absolute Basophils 
Total calcium 
Hepatitis C virus 
Antibodies*** 
Total bilirubin* 
Human 
immunodeficiency 
virus (HIV) 
BUN or Urea 
Creatinine* 
Uric Acid 
Glucose (nonfasted) 
Albumin 
Phosphorus or 
Phosphate 
Amylase 
Lipase 


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Table 4. 
Safety Laboratory Tests 
 
Hematology 
Chemistry 
Coagulation 
Urinalysis 
Other: 
Carbon Dioxide or 
Bicarbonate 
* 
For potential Hy's Law cases, in addition to repeating AST and ALT, laboratory tests should include 
albumin, creatine kinase, total bilirubin, direct and indirect bilirubin, gamma-glutamyl transferase, 
prothrombin time (PT)/INR and alkaline phosphatase. 
** Hepatitis B testing includes: Hepatitis B Surface Ag (HBsAg), Hepatitis B Core Ab (anti-HBc), 
Hepatitis B Surface Ab (anti-HBs) to be conducted by local laboratory where required by local 
regulations or if warranted by patient history. 
*** Hepatitis C virus antibodies (HCVAb) to be conducted by local laboratory where required by local 
regulations or if warranted by patient history. 
 
7.1.4. Vital Signs and Physical Examination 
Patients will have a full physical examination to include an examination of all major body 
systems and breasts, height (at screening only), weight, blood pressure and pulse rate, which 
may be performed by a physician, registered nurse or other qualified health care provider, as 
acceptable according to local regulation. Blood pressure and heart rate should be recorded 
after approximately 5 minutes rest. An abbreviated physical exam is an assessment for 
emergent toxicities or changes from prior visits and a symptom directed exam conducted by a 
physician, trained physician’s assistant or nurse practitioner, as acceptable according to local 
regulation. 
7.1.5. (12-Lead) Electrocardiogram 
Standard electrocardiogram (ECG): 12-lead (with a 10-second rhythm strip) tracing will be 
used for all ECGs. It is preferable that the machine used has a capacity to calculate the 
standard intervals automatically. At each time point (see the Schedule of Activities), 
3 consecutive ECGs (except single ECG at screening and End of Treatment) will be 
performed at approximately 2 minutes apart to determine the mean QTcF interval. If the 
mean QTcF is prolonged ≥501 msec, ie, CTCAE Grade ≥3), then the ECGs should be 
re-evaluated by a qualified person at the site for confirmation as soon as the finding is made, 
including verification that the machine reading is accurate. 
If manual reading verifies a QTcF of ≥501 msec, immediate correction for reversible causes 
(including electrolyte abnormalities, hypoxia and concomitant medications for drugs with the 
potential to prolong the QTcF interval) should be performed. In addition, repeat ECGs 
should be immediately performed hourly for at least 3 hours until the QTcF interval falls 
below 501 msec. If QTcF interval reverts to less than 501 msec, and in the judgment of the 
investigator(s) and sponsor is determined to be due to cause(s) other than investigational 
product, treatment may be continued with regular ECG monitoring. 
If reversible causes are treated and the QTcF intervals remains ≥501 msec, the investigational 
product will be held until the QTcF interval decreases to less than 501 msec. Patients will 
then restart the investigational product at the next lowest dose level. 


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If the QTcF interval has still not decreased to less than 501 msec after 2 weeks, or if at any 
time a patient has a QTcF interval >515 msec or becomes symptomatic, the patient will be 
removed from the study. Additional triplicate ECGs may be performed as clinically 
indicated. 
Prior to concluding that an episode of prolongation of the QTcF interval is due to 
investigational product, thorough consideration should be given to potential precipitating 
factors (eg, change in patient clinical condition, effect of concurrent medication, electrolyte 
disturbance) and possible evaluation by a specialist. 
If a patient experiences a cardiac or neurologic AE (specifically syncope, dizziness, seizures, 
or stroke), an ECG (triplicate) should be obtained at the time of the event. 
When matched with PK sampling, the ECG must be carried out before each PK sample 
drawing such that the PK sample is collected at the nominal time (ie, the timing of the PK 
collections over rides the timing of the ECG collections). 
7.2. Pharmacokinetics Assessments 
Additional details regarding the collection, processing, storage and shipping of the PK 
plasma samples will be offered, prior to study start, in a manual developed by the 
sponsor-identified central laboratory. 
7.2.1. Plasma for PK analysis of PF-06873600 
Blood samples (3 mL) to provide a minimum of 1 mL plasma for PK analysis will be 
collected into appropriately labeled tubes containing dipotassium ethylenediaminetetraacetic 
acid (K2EDTA) as outlined in the Schedule of Activities. The PK sampling schedule may be 
modified based on emerging PK data, but the total number of PK samples will remain the 
same. 
On days when patients have clinical visits where require pre-dose PK sampling assessments 
are to be obtained, the morning dose of PF-06873600 should be held (NOT taken) prior to 
the study visit. On those days, the PF-06873600 morning dose can be taken after the study 
procedures that are required prior to the morning dose have been performed (ie, the pre-dose 
PK sampling is obtained). 
In addition to samples collected at the scheduled times, an additional blood sample should be 
collected from patients experiencing unexpected and/or serious AEs and the date and time of 
blood sample collection and of last dosing prior to PK collection documented on the CRF. 
Where noted in the Schedule of Activities, blood samples for PF-06873600 concentrations 
will be collected at approximately the same time as other assessments such as PD samples, 
ECGs (first ECG then PK collection) and bone marrow aspirate collections etc, wherever 
possible. 
All efforts will be made to obtain the PK samples at the scheduled nominal time relative to 
dosing. However, the exact time of the sample collection will always be noted on the CRF. 


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If a scheduled blood sample collection cannot be completed for any reason, the missed 
sample time may be re-scheduled with agreement of the clinical investigator, patient, and 
sponsor. 
PK samples will be assayed for PF-06873600 using a validated analytical method in 
compliance with Pfizer standard operating procedures (SOPs). 
The PK samples must be processed and shipped as indicated in the instructions provided to 
the investigator site to maintain sample integrity. Any deviations from the PK sample 
handling procedure (eg, sample collection and processing steps, interim storage or shipping 
conditions), including any actions taken, must be documented and reported to the sponsor. 
On a case-by-case basis, the sponsor may make a detennination as to whether sample 
integrity has been compromised. Any deviation from the specified sample handling 
procedure resulting in compromised sample integrity will be considered a protocol deviation. 
As pa1t of understanding the PK of the investigational product, samples may be used for 
metabolite identification and/or evaluation of the bioanalytical method, as well as for other 
internal explorato1y purposes. These data will not be included in the Clinical Study Report 
(CSR). 
 
 
 


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7.4. Tumor Response Assessments 
Tumor assessments will include all known or suspected disease sites. Imaging may include 
chest, abdomen and pelvis computed tomography (CT) or magnetic resonance imaging 
(MRI) scans; brain CT or MRI scan for patients with known or suspected brain metastases; 
bone scan and/or bone x-rays for patients with known or suspected bone metastases. Use of 
contrast in imaging is at the investigator's discretion. In the case of known allergy or 
hypersensitivity to contrnst agent, non-contrast CT of the chest and MRI of the abdomen may 
be considered. 
The same imaging technique used to characterize each identified and reported lesion at 
baseline will be employed in the following tumor assessments. 


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Anti-tumor activity will be assessed through radiological tumor assessments conducted at 
baseline, dming ti·eatment as specified in the Schedule of Activities, whenever disease 
progression is suspected (eg, symptomatic deterioration), and at the time of withdrawal from 
ti·eatment (if not done in the previous 8 weeks). 
Assessment of response will be made using RECIST version 1.1 (see Appendix 4). 
All patients' files and radiologic images must be available for somce verification and for 
potential peer review. 
7.5. Tumor Markers 
Blood tumor markers will be analyzed according to the Schedule of Activities. For patients 
that are emolled with HR-positive HER2-negative and TNBC, CA 15-3 and CEA will be 
assessed. For patients with ovarian cancer, CA 125 will be assessed. 
 
 


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8. ADVERSE EVENT REPORTING 
8.1. Requirements 
The table below summarizes the requirements for recording safety events on the CRF and for 
repo1iing safety events on the Clinical Trial (CT) Serious Adverse Event (SAE) Report Fo1m 
to Pfizer Safety. These requirements are delineated for 3 types of events: (1) SAEs; 
(2) non-serious adverse events (AEs); and (3) exposure to the investigational product under 
study during pregnancy or breastfeeding, and occupational exposure. 
 
Safety Event 
Recorded on the CRF 
Reported on the CT 
SAE Report Form to 
Pfizer Safety Within 
24 Hours of Awareness 
SAE 
All 
All 
Non-serious AE 
All 
None 
Exposure to the 
investigational product under 
study during pregnancy or 
All (regardless of whether 
associated with an AE), 
except occupational 
Exposure during 
pregnancy, exposure via 
breastfeeding, 
breastfeeding, and 
occupational exposure 
exposure 
occupational exposure 
(regardless of whether 
associated with an AE) 


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All observed or volunteered events regardless of treatment group or suspected causal 
relationship to the investigational product(s) will be reported as described in the following 
paragraphs. 
Events listed in the table above that require reporting to Pfizer Safety on the CT SAE Report 
Form within 24 hours of awareness of the event by the investigator are to be reported 
regardless of whether the event is determined by the investigator to be related to an 
investigational product under study. In particular, if the SAE is fatal or life-threatening, 
notification to Pfizer Safety must be made immediately, irrespective of the extent of available 
event information. This time frame also applies to additional new (follow-up) information on 
previously forwarded reports. In the rare situation that the investigator does not become 
immediately aware of the occurrence of an event, the investigator must report the event 
within 24 hours after learning of it and document the time of his/her first awareness of the 
event. 
For each event, the investigator must pursue and obtain adequate information both to 
determine the outcome and to assess whether it meets the criteria for classification as an SAE 
(see the Serious Adverse Events section below). In addition, the investigator may be 
requested by Pfizer Safety to obtain specific follow-up information in an expedited fashion. 
This information is more detailed than that recorded on the CRF. In general, this will include 
a description of the event in sufficient detail to allow for a complete medical assessment of 
the case and independent determination of possible causality. Any information relevant to 
the event, such as concomitant medications and illnesses, must be provided. In the case of a 
patient death, a summary of available autopsy findings must be submitted as soon as possible 
to Pfizer Safety. Any pertinent additional information must be reported on the CT SAE 
Report Form; additional source documents (eg, medical records, CRF, laboratory data) are to 
be sent to Pfizer Safety ONLY upon request. 
As part of ongoing safety reviews conducted by the sponsor, any non-serious AE that is 
determined by the sponsor to be serious will be reported by the sponsor as an SAE. To assist 
in the determination of case seriousness, further information may be requested from the 
investigator to provide clarity and understanding of the event in the context of the clinical 
study. 
8.1.1. Additional Details On Recording Adverse Events on the CRF 
All events detailed in the table above will be recorded on the AE page(s) of the CRF. It 
should be noted that the CT SAE Report Form for reporting of SAE information is not the 
same as the AE page of the CRF. When the same data are collected, the forms must be 
completed in a consistent manner. AEs should be recorded using concise medical 
terminology and the same AE term should be used on both the CRF and the CT SAE Report 
Form for reporting of SAE information. 


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8.1.2. Eliciting Adverse Event Information 
The investigator is to record on the CRF all directly observed AEs and all AEs spontaneously 
reported by the study patient. In addition, each study patient will be questioned about the 
occurrence of AEs in a non-leading manner. 
8.1.3. Withdrawal from the Study Due to Adverse Events (see also the Patient 
Withdrawal section) 
Withdrawal due to AEs should be distinguished from withdrawal due to other causes, 
according to the definition of AE noted below, and recorded on the CRF. 
When a patient withdraws from the study because of an SAE, the SAE must be recorded on 
the CRF and reported, as appropriate, on the CT SAE Report Form, in accordance with the 
Requirements section above. 
8.1.4. Time Period for Collecting AE/SAE Information 
The time period for actively eliciting and collecting AEs and SAEs (“active collection 
period”) for each patient begins from the time the patient provides informed consent, which 
is obtained before the patient’s participation in the study (ie, before undergoing any 
study-related procedure and/or receiving investigational product), through and including a 
minimum of 28 calendar days; except as indicated below after the last administration of the 
investigational product. 
Part 2 Only: During the long-term follow-up period in this study for survival, only SAEs will 
be actively elicited and collected after completion of the active collection period described 
above. The SAEs identified during long-term follow-up will be reported to Pfizer Safety on 
the CT SAE Report Form only if considered reasonably related to the study intervention. 
For patients who are screen failures, the active collection period ends when screen failure 
status is determined. 
8.1.4.1. Reporting SAEs to Pfizer Safety 
All SAEs occurring in a patient during the active collection period are reported to Pfizer 
Safety on the CT SAE Report Form. 
SAEs occurring in a patient after the active collection period has ended are reported to Pfizer 
Safety if the investigator becomes aware of them; at a minimum, all SAEs that the 
investigator believes have at least a reasonable possibility of being related to investigational 
product must be reported to Pfizer Safety. 
Follow up by the investigator continues throughout and after the active collection period and 
until the event or its sequelae resolve or stabilize at a level acceptable to the investigator, and 
Pfizer concurs with that assessment. 


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If a patient begins a new anticancer therapy, SAEs occurring during the above-indicated 
active collection period must still be reported to Pfizer Safety irrespective of any intervening 
treatment. 
8.1.4.2. Recording Non-serious AEs and SAEs on the CRF 
During the active collection period, both non-serious AEs and SAEs are recorded on the 
CRF. 
Follow-up by the investigator may be required until the event or its sequelae resolve or 
stabilize at a level acceptable to the investigator, and Pfizer concurs with that assessment. 
If a patient begins a new anticancer therapy, the recording period for non-serious AEs ends at 
the time the new treatment is started; however, SAEs must continue to be recorded on the 
CRF during the above-indicated active collection period. 
8.1.5. Causality Assessment 
The investigator’s assessment of causality must be provided for all AEs (serious and 
non-serious); the investigator must record the causal relationship on the CRF, and report such 
an assessment in accordance with the SAE reporting requirements, if applicable. An 
investigator’s causality assessment is the determination of whether there exists a reasonable 
possibility that the investigational product caused or contributed to an AE; generally, the 
facts (evidence) or arguments to suggest a causal relationship should be provided. If the 
investigator does not know whether or not the investigational product caused the event, then 
the event will be handled as “related to investigational product” for reporting purposes, as 
defined by the sponsor. If the investigator's causality assessment is “unknown but not 
related” to investigational product, this should be clearly documented on study records. 
In addition, if the investigator determines that an SAE is associated with study procedures, 
the investigator must record this causal relationship in the source documents and CRF, and 
report such an assessment in the dedicated section of the CT SAE Report Form and in 
accordance with the SAE reporting requirements. 
8.1.6. Sponsor’s Reporting Requirements to Regulatory Authorities 
AE reporting, including suspected unexpected serious adverse reactions, will be carried out 
in accordance with applicable local regulations. 
8.2. Definitions 
8.2.1. Adverse Events 
An AE is any untoward medical occurrence in a study patient administered a product or 
medical device; the event need not necessarily have a causal relationship with the treatment 
or usage. Examples of AEs include, but are not limited to: 
• 
Abnormal test findings; 
• 
Clinically significant signs and symptoms; 


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• 
Changes in physical examination findings; 
• 
Hypersensitivity; 
• 
Drug abuse; 
• 
Drug dependency. 
Additionally, AEs may include signs and symptoms resulting from: 
• 
Drug overdose; 
• 
Drug withdrawal; 
• 
Drug misuse; 
• 
Drug interactions; 
• 
Extravasation; 
• 
Exposure during pregnancy (EDP); 
• 
Exposure via breastfeeding; 
• 
Medication error; 
• 
Occupational exposure. 
Worsening of signs and symptoms of the malignancy under study should be recorded as AEs 
in the appropriate section of the CRF. Disease progression assessed by measurement of 
malignant lesions on radiographs or other methods should not be reported as AEs. 
8.2.2. Abnormal Test Findings 
Abnormal objective test findings should be recorded as AEs when any of the following 
conditions are met: 
• 
Test result is associated with accompanying symptoms; and/or 
• 
Test result requires additional diagnostic testing or medical/surgical intervention; 
and/or 
• 
Test result leads to a change in study dosing (outside of any protocol-specified 
dose adjustments) or discontinuation from the study, significant additional 
concomitant drug treatment, or other therapy; and/or 
• 
Test result is considered to be an AE by the investigator or sponsor. 


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Merely repeating an abnormal test, in the absence of any of the above conditions, does not 
constitute an AE. Any abnormal test result that is determined to be an error does not require 
recording as an AE. 
8.2.3. Serious Adverse Events 
A serious adverse event is any untoward medical occurrence at any dose that: 
• 
Results in death; 
• 
Is life-threatening (immediate risk of death); 
• 
Requires inpatient hospitalization or prolongation of existing hospitalization; 
• 
Results in persistent or significant disability/incapacity (substantial disruption of 
the ability to conduct normal life functions); 
• 
Results in congenital anomaly/birth defect. 
Or that is considered to be: 
• 
An important medical event. 
Medical and scientific judgment is exercised in determining whether an event is an important 
medical event. An important medical event may not be immediately life-threatening and/or 
result in death or hospitalization. However, if it is determined that the event may jeopardize 
the patient or may require intervention to prevent one of the other AE outcomes, the 
important medical event should be reported as serious. 
Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization; 
or development of drug dependency or drug abuse. 
Progression of the malignancy under study (including signs and symptoms of progression) 
should not be reported as an SAE unless the outcome is fatal within the active collection 
period. Hospitalization due to signs and symptoms of disease progression should not be 
reported as an SAE. If the malignancy has a fatal outcome during the study or within the 
active collection period, then the event leading to death must be recorded as an AE on the 
CRF, and as an SAE with Common Terminology Criteria for Adverse Events (CTCAE) 
Grade 5 (see the Severity Assessment section). 
8.2.4. Hospitalization 
Hospitalization is defined as any initial admission (even less than 24 hours) in a hospital or 
equivalent healthcare facility, or any prolongation of an existing admission. Admission also 
includes transfer within the hospital to an acute/intensive care unit (eg, from the psychiatric 
wing to a medical floor, medical floor to a coronary care unit, or neurological floor to a 


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tuberculosis unit). An emergency room visit does not necessarily constitute a hospitalization; 
however, the event leading to the emergency room visit is assessed for medical importance. 
Hospitalization does not include the following: 
• 
Rehabilitation facilities; 
• 
Hospice facilities; 
• 
Respite care (eg, caregiver relief); 
• 
Skilled nursing facilities; 
• 
Nursing homes; 
• 
Same-day surgeries (as outpatient/same-day/ambulatory procedures). 
Hospitalization or prolongation of hospitalization in the absence of a precipitating clinical 
AE is not in itself an SAE. Examples include: 
• 
Admission for treatment of a preexisting condition not associated with the 
development of a new AE or with a worsening of the preexisting condition (eg, for 
workup of a persistent pretreatment laboratory abnormality); 
• 
Social admission (eg, patient has no place to sleep); 
• 
Administrative admission (eg, for yearly physical examination); 
• 
Protocol-specified admission during a study (eg, for a procedure required by the 
study protocol); 
• 
Optional admission not associated with a precipitating clinical AE (eg, for elective 
cosmetic surgery); 
• 
Hospitalization for observation without a medical AE; 
• 
Preplanned treatments or surgical procedures. These should be noted in the 
baseline documentation for the entire protocol and/or for the individual patient; 
• 
Admission exclusively for the administration of blood products. 
Diagnostic and therapeutic noninvasive and invasive procedures, such as surgery, should not 
be reported as SAEs. However, the medical condition for which the procedure was 
performed should be reported if it meets the definition of an SAE. For example, an acute 
appendicitis that begins during the reporting period should be reported if the SAE 
requirements are met, and the resulting appendectomy should be recorded as treatment of the 
AE. 


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8.3. Severity Assessment 
 
GRADE 
Clinical Description of Severity 
0 
No change from normal or reference range (This grade is not included in the 
Version 4.03 CTCAE document but may be used in certain circumstances.) 
1 
MILD adverse event 
2 
MODERATE adverse event 
3 
SEVERE adverse event 
4 
LIFE-THREATENING consequences; urgent intervention indicated 
5 
DEATH RELATED TO adverse event 
Note the distinction between the severity and the seriousness of an AE. A severe event is not 
necessarily an SAE. For example, a headache may be severe (interferes significantly with 
the patient’s usual function) but would not be classified as serious unless it met one of the 
criteria for SAEs, listed above. 
8.4. Special Situations 
8.4.1. Potential Cases of Drug-Induced Liver Injury 
Humans exposed to a drug who show no sign of liver injury (as determined by elevations in 
transaminases) are termed “tolerators,” while those who show transient liver injury, but adapt 
are termed “adaptors.” In some patients, transaminase elevations are a harbinger of a more 
serious potential outcome. These patients fail to adapt and therefore are "susceptible" to 
progressive and serious liver injury, commonly referred to as drug-induced liver injury 
(DILI). Patients who experience a transaminase elevation above 3 times the upper limit of 
normal (× ULN) should be monitored more frequently to determine if they are an “adaptor” 
or are “susceptible.” 


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In the majority of DILI cases, elevations in aspartate aminotransferase (AST) and/or alanine 
aminotransferase (ALT) precede total bilirubin (TBili) elevations (>2 × ULN) by several 
days or weeks. The increase in TBili typically occurs while AST/ALT is/are still elevated 
above 3 × ULN (ie, AST/ALT and TBili values will be elevated within the same lab sample). 
In rare instances, by the time TBili elevations are detected, AST/ALT values might have 
decreased. This occurrence is still regarded as a potential DILI. Therefore, abnormal 
elevations in either AST OR ALT in addition to TBili that meet the criteria outlined below 
are considered potential DILI (assessed per Hy’s law criteria) cases and should always be 
considered important medical events, even before all other possible causes of liver injury 
have been excluded. 
The threshold of laboratory abnormalities for a potential DILI case depends on the patient’s 
individual baseline values and underlying conditions. Patients who present with the 
following laboratory abnormalities should be evaluated further as potential DILI (Hy’s law) 
cases to definitively determine the etiology of the abnormal laboratory values: 
• 
Patients with AST/ALT and TBili baseline values within the normal range who 
subsequently present with AST OR ALT values >3 × ULN AND a TBili value 
>2 × ULN with no evidence of hemolysis and an alkaline phosphatase value 
<2 × ULN or not available; 
• 
For patients with baseline AST OR ALT OR TBili values above the ULN, the 
following threshold values are used in the definition mentioned above, as needed, 
depending on which values are above the ULN at baseline: 
• Preexisting AST or ALT baseline values above the normal range: AST or ALT 
values >2 times the baseline values AND >3 × ULN; or >8 × ULN (whichever is 
smaller). 
• Preexisting values of TBili above the normal range: TBili level increased from 
baseline value by an amount of at least 1 × ULN or if the value reaches 
>3 × ULN (whichever is smaller). 
Rises in AST/ALT and TBili separated by more than a few weeks should be assessed 
individually based on clinical judgment; any case where uncertainty remains as to whether it 
represents a potential Hy’s law case should be reviewed with the sponsor. 
The patient should return to the investigator site and be evaluated as soon as possible, 
preferably within 48 hours from awareness of the abnormal results. This evaluation should 
include laboratory tests, detailed history, and physical assessment. 
In addition to repeating measurements of AST and ALT and TBili for suspected Hy’s law 
cases, additional laboratory tests should include albumin, creatine kinase (CK), direct and 
indirect bilirubin, gamma-glutamyl transferase (GGT), prothrombin time (PT)/international 
normalized ratio (INR), and alkaline phosphatase. Consideration should also be given to 
drawing a separate tube of clotted blood and an anticoagulated tube of blood for further 


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testing, as needed, for further contemporaneous analyses at the time of the recognized initial 
abnormalities to determine etiology. A detailed history, including relevant information, such 
as review of ethanol, acetaminophen (either by itself or as a coformulated product in 
prescription or over-the-counter medications), recreational drug, supplement (herbal) use and 
consumption, family history, sexual history, travel history, history of contact with a 
jaundiced person, surgery, blood transfusion, history of liver or allergic disease, and potential 
occupational exposure to chemicals, should be collected. Further testing for acute 
hepatitis A, B, C, D, and E infection and liver imaging (eg, biliary tract), total bile acids, and 
collection of serum samples for acetaminophen/paracetamol drug and/or protein adduct 
levels may be warranted. 
All cases demonstrated on repeat testing as meeting the laboratory criteria of AST/ALT and 
TBili elevation defined above should be considered potential DILI (Hy’s law) cases if no 
other reason for the liver function test (LFT) abnormalities has yet been found. Such 
potential DILI (Hy’s law) cases are to be reported as SAEs, irrespective of availability 
of all the results of the investigations performed to determine etiology of the LFT 
abnormalities. 
A potential DILI (Hy’s law) case becomes a confirmed case only after all results of 
reasonable investigations have been received and have excluded an alternative etiology. 
8.4.2. Exposure to the Investigational Product During Pregnancy or Breastfeeding, and 
Occupational Exposure 
Exposure to the investigational product under study during pregnancy or breastfeeding and 
occupational exposure are reportable to Pfizer Safety within 24 hours of investigator 
awareness. 
8.4.2.1. Exposure During Pregnancy (EDP) 
For both unapproved/unlicensed products and for marketed products, an EDP occurs if: 
• A female becomes, or is found to be, pregnant either while receiving or having been 
exposed (eg, because of treatment or environmental exposure) to the investigational 
product; or the female becomes or is found to be pregnant after discontinuing and/or 
being exposed to the investigational product; 
• An example of environmental exposure would be a case involving direct contact 
with a Pfizer product in a pregnant woman (eg, a nurse reports that she is pregnant 
and has been exposed to chemotherapeutic products). 
• A male has been exposed (eg, because of treatment or environmental exposure) to the 
investigational product prior to or around the time of conception and/or is exposed 
during his partner’s pregnancy. 
If a patient or patient’s partner becomes or is found to be pregnant during the patient’s 
treatment with the investigational product, the investigator must report this information to 
Pfizer Safety on the CT SAE Report Form and an EDP supplemental form, regardless of 


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whether an SAE has occurred. In addition, the investigator must submit information 
regarding environmental exposure to a Pfizer product in a pregnant woman (eg, a patient 
reports that she is pregnant and has been exposed to a cytotoxic product by inhalation or 
spillage) to Pfizer Safety using the EDP supplemental form. This must be done irrespective 
of whether an AE has occurred and within 24 hours of awareness of the exposure. The 
information submitted should include the anticipated date of delivery (see below for 
information related to termination of pregnancy). 
Follow-up is conducted to obtain general information on the pregnancy and its outcome for 
all EDP reports with an unknown outcome. The investigator will follow the pregnancy until 
completion (or until pregnancy termination) and notify Pfizer Safety of the outcome as a 
follow-up to the initial EDP supplemental form. In the case of a live birth, the structural 
integrity of the neonate can be assessed at the time of birth. In the event of a termination, the 
reason(s) for termination should be specified and, if clinically possible, the structural 
integrity of the terminated fetus should be assessed by gross visual inspection (unless 
pre-procedure test findings are conclusive for a congenital anomaly and the findings are 
reported). 
If the outcome of the pregnancy meets the criteria for an SAE (ie, ectopic pregnancy, 
spontaneous abortion, intrauterine fetal demise, neonatal death, or congenital anomaly [in a 
live-born baby, a terminated fetus, an intrauterine fetal demise, or a neonatal death]), the 
investigator should follow the procedures for reporting SAEs. 
Additional information about pregnancy outcomes that are reported to Pfizer Safety as SAEs 
follows: 
• 
Spontaneous abortion includes miscarriage and missed abortion; 
• 
Neonatal deaths that occur within 1 month of birth should be reported, without 
regard to causality, as SAEs. In addition, infant deaths after 1 month should be 
reported as SAEs when the investigator assesses the infant death as related or 
possibly related to exposure to the investigational product. 
Additional information regarding the EDP may be requested by the sponsor. Further 
follow-up of birth outcomes will be handled on a case-by-case basis (eg, follow-up on 
preterm infants to identify developmental delays). In the case of paternal exposure, the 
investigator will provide the patient with the Pregnant Partner Release of Information Form 
to deliver to his partner. The investigator must document in the source documents that the 
patient was given the Pregnant Partner Release of Information Form to provide to his partner. 
8.4.2.2. Exposure During Breastfeeding 
Scenarios of exposure during breastfeeding must be reported, irrespective of the presence of 
an associated SAE, to Pfizer Safety within 24 hours of the investigator’s awareness, using the 
CT SAE Report Form. An exposure during breastfeeding report is not created when a Pfizer 
drug specifically approved for use in breastfeeding women (eg, vitamins) is administered in 


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accord with authorized use. However, if the infant experiences an SAE associated with such 
a drug’s administration, the SAE is reported together with the exposure during breastfeeding. 
8.4.2.3. Occupational Exposure 
An occupational exposure occurs when, during the performance of job duties, a person 
(whether a healthcare professional or otherwise) gets in unplanned direct contact with the 
product, which may or may not lead to the occurrence of an AE. 
An occupational exposure is reported to Pfizer Safety within 24 hours of the investigator’s 
awareness, using the CT SAE Report Form, regardless of whether there is an associated 
SAE. Since the information does not pertain to a patient enrolled in the study, the 
information is not recorded on a CRF; however, a copy of the completed CT SAE Report 
Form is maintained in the investigator site file. 
8.4.3. Medication Errors 
Other exposures to the investigational product under study may occur in clinical trial settings, 
such as medication errors. 
 
Safety Event 
Recorded on the CRF 
Reported on the CT 
SAE Report Form to 
Pfizer Safety Within 
24 Hours of Awareness 
Medication errors 
All (regardless of whether 
associated with an AE) 
Only if associated with 
an SAE 
8.4.3.1. Medication Errors 
Medication errors may result from the administration or consumption of the investigational 
product by the wrong patient, or at the wrong time, or at the wrong dosage strength. 
• 
Medication errors involving patient exposure to the investigational product; 
• 
Potential medication errors or uses outside of what is foreseen in the protocol that 
do or do not involve the participating patient. 
Such medication errors occurring to a study participant are to be captured on the medication 
error page of the CRF, which is a specific version of the AE page. 
In the event of medication dosing error, the sponsor should be notified immediately. 
Whether or not the medication error is accompanied by an AE, as determined by the 
investigator, the medication error is recorded on the medication error page of the CRF and, if 
applicable, any associated AE(s), serious and non-serious, are recorded on an AE page of the 
CRF. 


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Medication errors should be reported to Pfizer Safety within 24 hours on a CT SAE Report 
Form only when associated with an SAE. 
9. DATA ANALYSIS/STATISTICAL METHODS 
Detailed methodology for summary and statistical analyses of the data collected in this study 
is outlined here and further detailed in a statistical analysis plan (SAP), which will be 
maintained by the sponsor. The SAP may modify what is outlined in the protocol where 
appropriate; however, any major modifications of the primary endpoint definitions or their 
analyses will also be reflected in a protocol amendment. 
9.1. Analysis Sets 
1. Safety analysis set. 
The safety analysis set includes all enrolled patients who receive at least one dose of 
study treatment. 
2. Full analysis set. 
The full analysis set includes all enrolled patients. 
3. Per-protocol analysis set (evaluable for MTD). 
The per protocol analysis set includes all enrolled patients who receive at least one 
dose of study treatment and who do not have major treatment deviations during the 
first cycle. Patients with major treatment deviations during the first cycle of 
treatment are not evaluable for the MTD assessment and will be replaced as needed to 
permit the MTD estimation. Major treatment deviations include the failure to satisfy 
major entry criteria (eg, confirmation of the target disease; signed informed consent) 
or use of other anticancer treatments during the active treatment period and disease 
follow-up phases other than as defined/allowed in this protocol. Major treatment 
deviations will also include: 
• Administration of less than 75% of the planned number of doses of PF-06873600 
(provided that the reduction in doses is not due to toxicity attributable to 
PF-06873600). 
• Administration of more than 110% of the planned number of doses of 
PF-06873600. 
4. Modified Intent-to-Treat (mITT) Population. 
• The modified intent-to-treat (mITT) is the analysis population that will follow the 
ITT principle and include patients receiving at least 1 dose of investigational 
product with baseline assessment and at least 1 post baseline assessment, disease 
progression, or death before the first tumor assessment. The mITT population 


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will be used for analyses and to support conference presentations when the study 
is still ongoing. 
5. PK analysis sets. 
The PK parameter analysis population is defined as all enrolled patients treated who 
have sufficient information to estimate at least 1 of the PK parameters of interest. 
The PK concentration population is defined as all enrolled patients who are treated 
and have at least 1 analyte concentration. 
6. Biomarker analysis set(s). 
• The PD/Biomarker analysis population is defined as all enrolled patients with 
PD/Biomarkers evaluated at pre-and/post dose. 
9.2. Statistical Methods and Properties 
9.2.1. Statistical Methods for Dose Escalation/De-Escalation 
Many alternative designs have been proposed to the standard 3+3 design for Phase 1 dose 
escalation studies that improve its accuracy, efficiency and statistical validity. 
The traditional mTPI design (Ji et al., 2010)29 uses a Bayesian statistics framework and a 
beta/binomial hierarchical model to compute the posterior probability of 3 dosing intervals 
that reflect the relative difference between the toxicity rate of each dose level to the target 
rate (pT = 0.275). If the toxicity rate of the currently used dose level is far smaller than pT, 
the mTPI will recommend escalating the dose level; if it is close to target probability (pT), 
the mTPI will recommend continuing at the current dose; if it is far greater than pT, the mTPI 
will recommend de-escalating the dose level. These rules are conceptually similar to those 
used by the 3+3 design, except the decisions of an mTPI design are based on posterior 
probabilities calculated under a coherent probability model. The proposed modified TPI 
method for this protocol includes stopping rules and dose escalation/finding criteria, which 
prevents the target DLT rate to reach ≥33% for determining the MTD. This proposed mTPI 
method is more conservative than the traditional TPI method. Being a rule-based design, 
mTPI automatically and appropriately tailors dose-escalation and de-escalation decisions for 
different studies with different toxicity parameters. More importantly, all the dose-escalation 
and de-escalation decisions for a given study can be pre-calculated under the mTPI design 
and presented in a two-way table (See Section 3.1.5). Thus, compared to other advanced 
model-based designs published in the literature, the mTPI design is logistically less 
complicated and easier to implement. Recently, a Phase 1 study based on the mTPI design 
has been published (Fanale, 2011).30 
Decision rules are based on calculating unit probability mass (UPM) of 3 dosing intervals 
corresponding to under, proper, and over dosing in terms of toxicity. Specifically, the 
underdosing interval is defined as (0; pT-e1), the over-dosing interval (pT+e2, 1), and the 
proper-dosing interval (pT- e1, pT+ e2), where e1 and e2 are small fractions. Based on the 
safety profile of PF-06873600 as a single-agent in study (C3661001), e1 is selected as 


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0.05 and e2 is selected as 0.05. Therefore, the target interval for the DLT rate is 
(0.225, 0.325). 
The 3 dosing intervals are associated with 3 different dose-escalation decisions. The 
underdosing interval corresponds to a dose-escalation (E), overdosing corresponds to a dose 
de-escalation (D), and proper dosing corresponds to remaining at the current dose (S). Given 
a dosing interval and a probability distribution, the unit probability mass (UPM) of that 
dosing interval is defined as the probability of a patient belonging to that dosing interval 
divided by the length of the dosing interval. The mTPI design calculates the UPMs for the 
3 dosing intervals, and the one with the largest UPM informs the corresponding dose-finding 
decision, which is the dose level to be used for future patients. For example, if the 
under-dosing interval has the largest UPM, the decision will be to escalate, and the next 
cohort of patients will be treated at the next higher dose level. Ji et al. (2010)29 have 
demonstrated that the decision based on UPM is optimal in that it minimizes a posterior 
expected loss (ie, minimizes the chance of making a wrong dosing decision). The decision 
rules to “dose escalate” (E), “no change in dose” (S), “dose de escalate” (D) or “dose 
de escalate, unacceptable toxicity” (U) are described in Section 3.1.5 (see Table 1). 
9.2.2. Statistical Method for Estimating the MTD 
This study contains dose escalation and/or de-escalation with single agent in Part 1 followed 
by a single agent and combination dose expansion (Part 2). The MTD determination will be 
assessed independently for each dosing regimen evaluated in Part 1A and 1C and dose 
de-escalation Part 1B based on the mTPI method described in Section 9.2.1. The overall 
study design is depicted in Figure 8. 
Parts 1A and 1C will estimate the MTD/RDE in sequential dose escalation cohorts in: 
• 
HR-positive HER2-negative advanced or mBC patients with prior CDK4/6 
inhibitor and endocrine therapy in the advanced or metastatic setting, or 
• 
Locally recurrent/advanced or metastatic TNBC, or 
• 
Advanced platinum resistant epithelial ovarian cancer/fallopian tube 
cancer/primary peritoneal cancer. 
During Part 1 dose finding, all available safety information from safety and biomarker 
cohorts in Part 1A and 1C will be used to determine the respective MTD/RDE. Because 
these additional patients in biomarker cohorts will receive a dose lower than the concurrent 
dose escalation safety cohort or will be enrolled at a dose following the DLT evaluation 
period in the first 2-4 dose escalation safety cohort patients enrolled, their potential DLT 
observations may not be strictly used in the mTPI method for the ongoing dose finding in 
Part 1A and 1C. However, the safety profile from these additional patients in biomarker 
cohorts will be used to establish the respective MTD or RDE in Part 1A and Part 1C, if 
applicable. 


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Part 1B will include PF-06873600 in combination with letrozole and in combination with 
fulvestrant. The starting dose for this combination will start with PF-06873600 at MTD/RDE 
for the single agent (established in Part 1A or Part 1C) and the prescribed dose for letrozole 
and fulvestrant, respectively. The PF-06873600 dose may be decreased if determined to be 
intolerable in a dose de-escalation manner based on mTPI. The MTD/RDE for this 
combination regimen, if selected, will be based on 6 to 12 patients. 
For data analysis purpose, data from all patients receiving the MTD/RDE in Part 1B and 
Part 2 expansion cohort will be combined under the same treatment regimen and same tumor 
type. 
Part 2 will evaluate the PF-06873600 dose selected (MTD/RDE) from Part 1 as a single 
agent (from Part 1A or Part 1C) and in combination with endocrine therapy (from Part 1B). 
The dose finding process in Part 1 using mTPI is designed to establish the MTD defined as 
the highest dose that yields a target of approximately 27.5% probability of DLT and 
considers equivalent doses that yield probability of DLT in the interval (Equivalence 
Interval) of (22.5%, 32.5%). The 27.5% target was chosen based on safety considerations 
and is considered appropriate based on simulations performed on other Pfizer Phase 1 study 
protocols (ie, B7831001, PF-06671008) and expert input. The prior distribution of DLT is 
set as a beta (0.5,0.5) and the threshold probability for early termination and dose exclusion is 
set to 0.95 as suggested in the original mTPI method (Ji et al., 2010).29 A modification of the 
mTPI could be applied for dose levels that are tested in more than 6 patients: a decision to 
increase the dose could be made only if the observed DLT rate is <22.5% (2 DLT out of 
10 Patients) and a decision to test more patients at a dose only if the DLT rate is below 
32.5%. In addition, doses with an incidence of DLT, eg, 4 out of 10, or apparently higher 
than 32.5% cannot be selected as MTD, even though it might be allowed by the mTPI 
method. 
Cohorts of patients could receive doses already tested but a dose that is associated with 
decision to “Dose de-escalate, unacceptable toxicity” cannot be revisited and no more 
patients should be treated at this dose or higher doses for the remainder of the trial. 
The maximum sample size for Part 1 would be approximately N=75 for the dose 
escalation/finding safety cohorts and N=6 to 12 for the biomarker cohorts but actual sample 
size will depend on the underlying dose toxicity profile and variability in actual data 
realization. 
The study will continue accruing until one of the three stopping conditions below is 
triggered. 
The algorithm will stop if any of the following criteria is met: 
1. The maximum sample size has been achieved; 
2. MTD has been identified with sufficient accuracy: 6 to 12 patients have been 
accumulated on a dose that is currently estimated to be the MTD/RDE; or 


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3. All doses explored appear to be overly toxic and the MTD cannot be detennined. 
Due to binomial data variability in small samples, DLTs may be observed in a first cohort(s) 
by chance even when the trne Probability (DLT) is fairly low. This could result in the 
estimated posterior DLT rate to exceed the targeted 27.5% ve1y early in the trial. 
The following table shows the probability of escalating to the next dose level for a range of 
underlying trne DLT rates. For example, for a coho1t size of n=3 and for a DLT that occurs 
in 10% of patients, there is a greater than 90% probability of escalating. Conversely, for a 
DLT that occurs with a rate of 70%, the probability of escalating is 3%. It is assumed that 
dose escalation occurs with either 0/3 or 1/6 patients with DLTs. 
Probability of Escalating Dose 
 
9.3. Sample Size Determination 
9.3.1. Part 1 
In Pait IA, Pait lB, and Part IC patients will paiticipate in a dose escalation/finding phase 
aimed at estimating the MTD. The sample size for this component of the study will vaiy 
depending on the number of DLTs observed. 
Approximately 75 patients ai·e expected to be enrolled in the dose escalation/finding safety 
coho1ts and an additional 6-12 patients are expected in the biomarker cohorts in Paits IA and 
IC. The actual number of patients enrolled will depend on the tolerability of PF-06873600 
and the number of dose levels required to identify the MTD/RDE. Pait IA, Pait 1C and each 
independent combination coho1t in Pait lB (PF-06873600 in combination with letrozole and 
PF-06873600 in combination with fulvestrant) can be stopped and MID declai·ed with 
approximately 6 to 12 patients. As for the number of patients treated at each dose, it is 
expected to be at 1 to 4 patients for the doses actually studied. However, since vai·iable 
coho1t size is allowed, the actual number of patients treated at each dose (including MTD) 
will vaiy from 1 to 12. 
9.3.2. Part 2 
Pait 2, the expansion aims will be conducted to assess efficacy as well as safety and 
tolerability of PF-06873600 in single agent and combination therapy. The sample sizes for 
Pait 2 are dete1mined based on published historical data as benchmai·k data, I-sided type 1 
eITor rate of a, =0.1 with 80% power or higher. Approximately 100 patients ai·e expected to 
be enrolled in Pait 2. Enrolhnent of paiticipants into a iven coho1t ma be discontinued if 
minimal or no anti-tumor activi is obse1ved. 
 
 
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9.4. Efficacy Analysis 
In this First In Patient study anti-tumor activity is a primaiy objective for Pait 2 of the study. 
Tumor response will be presented in the fo1m of patient data listings that include, but are not 
limited to, tumor type, staiting dose, tumor response at each visit, and best overall response. 
In addition, progression date, death date, date of first response and last tumor assessment 
date, and date of last contact will be listed. Objective response rate (ORR), progression-free 
survival (PFS), overall survival (OS), time to progression (TTP), and duration of response 
(DoR) will be sUilllnai·ized and presented if data pe1mits. 
The definition of each response catego1y is provided in Appendix 4 (RECIST 1.1). 
9.5. Analysis of Pharmacokinetics and Pharmacodynamics 
9.5.1. Analysis of Pharmacokinetics 
9.5.1.1. Single-Dose and Steady-State PF-06873600 Pharmacokinetic Analysis 
Plasma concentrations of PF-06873600 will be smnmai·ized descriptively (n, mean, standai·d 
deviation, CV, median, minimum, maximum, geometric mean and its associated CV) by 
dose, cycle, day, and nominal time. 


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Plasma concentration-time data within a dose interval after the morning dose on Cycle 1, 
Day 1 (for patients of Part 1A and 1B), Cycle 1, Day 15 (for all patients, with exception of 
the MR formulation selection cohort) or for patients of the MR formulation selection cohort, 
plasma concentration-time data after Day -7 and Day -4, respectively, will be analysed for 
individual patients using noncompartmental methods. The noncompartmental analysis will 
estimate PK parameters including the following: 
1. Cycle 1 Day 1 (and also Lead-in Day -7 and Day -4 for patients of the MR 
formulation selection cohort within Part 1C): the maximal concentration (Cmax), time 
to maximum plasma concentration (Tmax), and area under the plasma concentration 
versus time curve from time 0 to the last sampling time point within the dose interval 
(AUClast), and if data permit, area under the plasma concentration versus time curve 
from time 0 extrapolated to infinity (AUCinf), terminal elimination half-life (t1/2), 
apparent oral plasma clearance (CL/F), apparent volume of distribution (Vz/F); 
2. Cycle 1 Day 15: steady state Cmax (Cmax,ss), Tmax, AUC within one dose interval 
(AUCτ,ss), minimum plasma concentration (Cmin,ss), oral CL (CLss/F), and if data 
permit, apparent volume of distribution (Vss/F), t1/2, and accumulation ratio (Rac). 
The single-dose and steady-state PK parameters will be summarized descriptively (n, mean, 
standard deviation, coefficient of variation (CV), median, minimum, maximum, geometric 
mean and its associated CV) by dose, cycle and day. 
Dose normalized AUCinf (AUCτ at steady state), AUClast and Cmax will be plotted against 
dose (using a logarithmic scale) by cycle and day. These plots will include individual patient 
values and the geometric means for each dose. These plots will be used to help understand 
the relationship between the PK parameters and dose. 
9.5.2. Population Pharmacokinetic Analysis or Pharmacokinetic/Pharmacodynamic 
(PK/PD) Modeling 
Population PK assessment may be conducted with plasma PF-06873600 concentrations from 
all patients using the nonlinear mixed effect modeling. The population PK model may be 
further combined with data on biomarkers and relevant efficacy and safety endpoints for 
population PK/PD analysis. 
The population PK and PK/PD analysis, if performed, will be reported in a Population 
Modeling and Analysis Report (PMAR), separate from the clinical study report of this study. 
9.5.2.1. Pharmacokinetic/Pharmacodynamic Correlation 
The relationship between PF-06873600 exposure and PD endpoint(s), such as p-Rb, and TK 
activity will be explored if data permit. 


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9.6. Safety Analysis 
Summaries and analyses of safety parameters will include all patients in the Safety Analysis 
Set. 
9.6.1. Analysis of the Primary Endpoint for Part 1 
DLT is the prima1y endpoint of the Pali 1 component of the study. The occmTence ofDLTs 
observed in the dose levels to be evaluated is used to estimate the MTD as described in the 
STUDY DESIGN section. Adverse Events constituting DLTs will be listed per dose level. 
9.6.2. Analysis of Primary Endpoints for Safety for Part 1 and 2 
Adverse Events 
AEs will be graded by the investigator according to the CTCAE version 4.03 and coded 
using the Medical Dictionaiy for Regulato1y Activities (MedDRA). The focus of AE 
summaries will be on Treatment Emergent Adverse Events, those with initial onset or 
increasing in severity after the first dose of study treatment. The number and percentage of 
patients who experienced any AE, SAE, treatment related AE, and treatment related SAE 
will be summarized according to worst toxicity grades. The summaries will present AEs 
both on the entire study period and by cycle (Cycle 1 and Cycles beyond 1). 


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Laboratory Test Abnormalities 
The number and percentage of patients who experienced laboratory test abnormalities will be 
summarized according to worst toxicity grade observed for each laboratory assay. The 
analyses will summarize laboratory tests both on the entire study period and by cycle 
(Cycle 1 and Cycles beyond 1). Shift tables will be provided to examine the distribution of 
laboratory toxicities. 
For laboratory tests without CTCAE grade definitions, results will be categorized as normal, 
abnormal, or not done. 
9.6.3. Electrocardiogram 
The analysis of ECG results will be based on patients in the safety analysis set with baseline 
and on-treatment ECG data. 
ECG measurements (an average of the triplicate measurements) will be used for the 
statistical analysis and all data presentations. Any data obtained from ECGs repeated for 
safety reasons after the nominal time-points will not be averaged along with the preceding 
triplicates. Interval measurements from repeated ECGs will be included in the outlier 
analysis (categorical analysis) as individual values obtained at unscheduled time points. 
QT intervals will be corrected for heart rate (QTc) using standard correction factors 
(ie, Fridericia’s (default correction), Bazett’s, and possibly a study-specific factor, as 
appropriate). Data will be summarized and listed for QT, heart rate, RR and PR interval, 
QRS, QTcF (and other correction factors, eg, QTcB as appropriate). Individual QT (all 
evaluated corrections) intervals will be listed. The most appropriate correction factor will be 
selected and used for the following analyses of central tendency and outliers and used for the 
study conclusions. Descriptive statistics (n, mean, median, standard deviation, minimum, 
and maximum) will be used to summarize the absolute corrected QT interval and changes 
from baseline in corrected QT after treatment, dose and time point. For each patient and by 
treatment, the maximum change from baseline will be calculated as well as the maximum 
post-baseline interval across time-points. Categorical analysis will be conducted for the 
maximum change from baseline in corrected QT and the maximum post-baseline QT 
interval. 
Shift tables will be provided for baseline vs worst on treatment corrected QT (one or more 
correction methods will be used) using maximum CTCAE Grade. Shift tables will also be 
provided for ECG abnormality at baseline vs on treatment (yes, no, not done: (n, %)). 
Patients experiencing clinically relevant morphological ECG changes will be summarized 
(including frequency and percentage). 
The effect of drug concentrations on corrected QT change from baseline will be explored 
graphically. Additional concentration-corrected QT analyses may be performed. Data may 
be pooled with other study results and/or explored further with PK/PD models. 


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9.7. Data Monitoring Committee 
An external Data Safety Monitoring Committee will not be established for the study. For the 
purpose of this protocol, Pfizer procedures for periodic safety review by a safety review 
team, comprised of the investigators and the sponsor, will be applied in order to review 
individual and summary data collected in the safety and clinical databases. These data would 
also include all treated participants. 
Discussions between the investigators and the sponsor regarding safety will occur in an 
on-going manner at regular teleconferences and/or meetings to determine the safety profile 
and risk/benefit ratio and determine if further patient enrollment is appropriate. 
10. QUALITY CONTROL AND QUALITY ASSURANCE 
Pfizer or its agent will conduct periodic monitoring visits during study conduct to ensure that 
the protocol and Good Clinical Practices (GCPs) are being followed. The monitors may 
review source documents to confirm that the data recorded on CRFs are accurate. The 
investigator and institution will allow Pfizer monitors/auditors or its agents and appropriate 
regulatory authorities direct access to source documents to perform this verification. This 
verification may also occur after study completion. 
During study conduct and/or after study completion, the investigator site may be subject to 
review by the IRB/EC, and/or to quality assurance audits performed by Pfizer, or companies 
working with or on behalf of Pfizer, and/or to inspection by appropriate regulatory 
authorities. 
The investigator(s) will notify Pfizer or its agents immediately of any regulatory inspection 
notification in relation to the study. Furthermore, the investigator will cooperate with Pfizer 
or its agents to prepare the investigator site for the inspection and will allow Pfizer or its 
agent, whenever feasible, to be present during the inspection. The investigator site and 
investigator will promptly resolve any discrepancies that are identified between the study 
data and the patient's medical records. The investigator will promptly provide copies of the 
inspection findings to Pfizer or its agent. Before response submission to the regulatory 
authorities, the investigator will provide Pfizer or its agents with an opportunity to review 
and comment on responses to any such findings. 
It is important that the investigator(s) and their relevant personnel are available during the 
monitoring visits and possible audits or inspections and that sufficient time is devoted to the 
process. 
11. DATA HANDLING AND RECORD KEEPING 
11.1. Case Report Forms/Electronic Data Record 
As used in this protocol, the term CRF should be understood to refer to either a paper form or 
an electronic data record or both, depending on the data collection method used in this study. 


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A CRF is required and should be completed for each included patient. The completed 
original CRFs are the sole property of Pfizer and should not be made available in any form to 
third parties, except for authorized representatives of Pfizer or appropriate regulatory 
authorities, without written permission from Pfizer. 
The investigator has ultimate responsibility for the collection and reporting of all clinical, 
safety, and laboratory data entered on the CRFs and any other data collection forms (source 
documents) and ensuring that they are accurate, authentic/original, attributable, complete, 
consistent, legible, timely (contemporaneous), enduring, and available when required. The 
CRFs must be signed by the investigator or by an authorized staff member to attest that the 
data contained on the CRFs are true. Any corrections to entries made in the CRFs or source 
documents must be dated, initialed, and explained (if necessary) and should not obscure the 
original entry. 
In most cases, the source documents are the hospital or the physician's chart. In these cases, 
data collected on the CRFs must match the data in those charts. 
In some cases, the CRF may also serve as the source document. In these cases, a document 
should be available at the investigator site and at Pfizer that clearly identifies those data that 
will be recorded on the CRF, and for which the CRF will stand as the source document. 
11.2. Record Retention 
To enable evaluations and/or inspections/audits from regulatory authorities or Pfizer, the 
investigator agrees to keep records, including the identity of all participating patients 
(sufficient information to link records, eg, CRFs and hospital records), all original signed 
informed consent documents, copies of all CRFs, safety reporting forms, source documents, 
and detailed records of treatment disposition, and adequate documentation of relevant 
correspondence (eg, letters, meeting minutes, and telephone call reports). The records should 
be retained by the investigator according to ICH guidelines, according to local regulations, or 
as specified in the clinical study agreement (CSA), whichever is longer. 
If the investigator becomes unable for any reason to continue to retain study records for the 
required period (eg, retirement, relocation), Pfizer should be prospectively notified. The 
study records must be transferred to a designee acceptable to Pfizer, such as another 
investigator, another institution, or to an independent third party arranged by Pfizer. 
Investigator records must be kept for a minimum of 15 years after completion or 
discontinuation of the study or for longer if required by applicable local regulations. 
The investigator must obtain Pfizer's written permission before disposing of any records, 
even if retention requirements have been met. 


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12. ETHICS 
12.1. Institutional Review Board/Ethics Committee 
It is the responsibility of the investigator to have prospective approval of the study protocol, 
protocol amendments, informed consent documents, and other relevant documents, eg, 
recruitment advertisements, if applicable, from the IRB/EC. All correspondence with the 
IRB/EC should be retained in the investigator file. Copies of IRB/EC approvals should be 
forwarded to Pfizer. 
The only circumstance in which an amendment may be initiated prior to IRB/EC approval is 
where the change is necessary to eliminate apparent immediate hazards to the patients. In 
that event, the investigator must notify the IRB/EC and Pfizer in writing immediately after 
the implementation. 
12.2. Ethical Conduct of the Study 
The study will be conducted in accordance with the protocol, legal and regulatory 
requirements, and the general principles set forth in the International Ethical Guidelines for 
Biomedical Research Involving Human Subjects (Council for International Organizations of 
Medical Sciences 2002), ICH Guideline for Good Clinical Practice, and the Declaration of 
Helsinki. 
12.3. Patient Information and Consent 
All parties will ensure protection of patient personal data and will not include patient names 
or other identifiable data in any reports, publications, or other disclosures, except where 
required by law. 
When study data are compiled for transfer to Pfizer and other authorized parties, patient 
names, addresses, and other identifiable data will be replaced by numerical codes based on a 
numbering system provided by Pfizer in order to de-identify study patients. The investigator 
site will maintain a confidential list of patients who participated in the study, linking each 
patient’s numerical code to his or her actual identity. In case of data transfer, Pfizer will 
maintain high standards of confidentiality and protection of patients’ personal data consistent 
with applicable privacy laws. 
The informed consent documents and any patient recruitment materials must be in 
compliance with ICH GCP, local regulatory requirements, and legal requirements, including 
applicable privacy laws. 
The informed consent documents used during the informed consent process and any patient 
recruitment materials must be reviewed and approved by Pfizer, approved by the IRB/EC 
before use, and available for inspection. 
The investigator must ensure that each study patient is fully informed about the nature and 
objectives of the study and possible risks associated with participation. 


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The investigator, or a person designated by the investigator, will obtain written informed 
consent from each patient before any study-specific activity is performed. The investigator 
will retain the original of each patient's signed consent document. 
12.4. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP 
In the event of any prohibition or restriction imposed (ie, clinical hold) by an applicable 
regulatory authority in any area of the world, or if the investigator is aware of any new 
information that might influence the evaluation of the benefits and risks of the investigational 
product, Pfizer should be informed immediately. 
In addition, the investigator will inform Pfizer immediately of any urgent safety measures 
taken by the investigator to protect the study patients against any immediate hazard, and of 
any serious breaches of this protocol or of ICH GCP that the investigator becomes aware of. 
13. DEFINITION OF END OF TRIAL 
13.1. End of Trial in All Participating Countries 
End of trial in all participating countries is defined as last subject last visit (LSLV). 
13.2. Primary Completion Date 
The Primary Completion Date (PCD) is the date of the last study visit where data is collected 
for the primary analysis of study outcome(s) also as stated in Section 13.1. The PCD will 
take place on or around 5 April 2023. The final CSR will include data collected up to PCD. 
At the time of PCD the applicable participants will either 1) complete the transition to 
PfizerCares (expanded access) program, where such program is available, or 2) continue on 
study under Amendment 9 in the countries where expanded access program is not available. 
The end of trial will take place when last patient discontinues study treatment or on 
October 31 2024, whichever occurs first. The study procedures after PCD are detailed in 
Appendix 8. The supplemental CSR will include safety data collected after PCD until the end 
of study. 
14. SPONSOR DISCONTINUATION CRITERIA 
Premature termination of this study may occur because of a regulatory authority decision, 
change in opinion of the IRB/EC, or investigational product safety problems, or at the 
discretion of Pfizer. In addition, Pfizer retains the right to discontinue development of 
PF-06873600 at any time. 
If a study is prematurely terminated, Pfizer will promptly notify the investigator. After 
notification, the investigator must contact all participating patients and the hospital pharmacy 
(if applicable) within 72 hours. As directed by Pfizer, all study materials must be collected 
and all CRFs completed to the greatest extent possible. 


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15. PUBLICATION OF STUDY RESULTS 
15.1. Communication of Results by Pfizer 
Pfizer fulfills its commitment to publicly disclose clinical trial results through posting the 
results of studies on www.clinicaltrials.gov (ClinicalTrials.gov), the European Clinical Trials 
Database (EudraCT), and or www.pfizer.com, and other public registries in accordance with 
applicable local laws/regulations. 
In all cases, study results are reported by Pfizer in an objective, accurate, balanced, and 
complete manner and are reported regardless of the outcome of the study or the country in 
which the study was conducted. 
www.clinicaltrials.gov 
Pfizer posts clinical trial US Basic Results on www.clinicaltrials.gov for Pfizer-sponsored 
interventional studies (conducted in patients) that evaluate the safety and/or efficacy of a 
Pfizer product, regardless of the geographical location in which the study is conducted. US 
Basic Results are submitted for posting within 1 year of the primary completion date (PCD) 
for studies in adult populations or within 6 months of the PCD for studies in pediatric 
populations. 
PCD is defined as the date that the final patient was examined or received an intervention for 
the purposes of final collection of data for the primary outcome, whether the clinical study 
concluded according to the prespecified protocol or was terminated. 
EudraCT 
Pfizer posts European Union (EU) Basic Results on EudraCT for all Pfizer-sponsored 
interventional studies that are in scope of EU requirements. EU Basic Results are submitted 
for posting within 1 year of the PCD for studies in adult populations or within 6 months of 
the PCD for studies in pediatric populations. 
www.pfizer.com 
Pfizer posts Public Disclosure Synopses (CSR synopses in which any data that could be used 
to identify individual patients has been removed) on www.pfizer.com for Pfizer-sponsored 
interventional studies at the same time the US Basic Results document is posted to 
www.clinicaltrials.gov. 
15.2. Publications by Investigators 
Pfizer supports the exercise of academic freedom and has no objection to publication by the 
principal investigator (PI) of the results of the study based on information collected or 
generated by the PI, whether or not the results are favorable to the Pfizer product. However, 
to ensure against inadvertent disclosure of confidential information or unprotected 
inventions, the investigator will provide Pfizer an opportunity to review any proposed 


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publication or other type of disclosure of the results of the study (collectively, “publication”) 
before it is submitted or otherwise disclosed. 
The investigator will provide any publication to Pfizer at least 30 days before it is submitted 
for publication or otherwise disclosed. If any patent action is required to protect intellectual 
property rights, the investigator agrees to delay the disclosure for a period not to exceed an 
additional 60 days. 
The investigator will, on request, remove any previously undisclosed confidential 
information before disclosure, except for any study- or Pfizer product-related information 
necessary to the appropriate scientific presentation or understanding of the study results. 
If the study is part of a multicenter study, the investigator agrees that the first publication is 
to be a joint publication covering all investigator sites, and that any subsequent publications 
by the PI will reference that primary publication. However, if a joint manuscript has not 
been submitted for publication within 12 months of completion or termination of the study at 
all participating sites, the investigator is free to publish separately, subject to the other 
requirements of this section. 
For all publications relating to the study, the institution will comply with recognized ethical 
standards concerning publications and authorship, including Section II - “Ethical 
Considerations in the Conduct and Reporting of Research” of the Uniform Requirements for 
Manuscripts Submitted to Biomedical Journals, http://www.icmje.org/index.html#authorship, 
established by the International Committee of Medical Journal Editors. 
Publication of study results is also provided for in the CSA between Pfizer and the 
institution. In this section entitled Publications by Investigators, the defined terms shall have 
the meanings given to them in the CSA. 
If there is any conflict between the CSA and any attachments to it, the terms of the CSA 
control. If there is any conflict between this protocol and the CSA, this protocol will control 
as to any issue regarding treatment of study patients, and the CSA will control as to all other 
issues. 


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(https://www.cancer.gov/types/breast/hp/male-breast-treatment-pdq. Accessed 
January 18, 2018 [PMID: 26389234]). 
35. Male Breast Cancer is Different in Terms of Biology and Outcomes. December 17, 
2004. 
(http://www.breastcancer.org/research-news/male-bc-biology-and-outcome-differs. 
Assessed on January 18, 2018). 
36. Pfizer, Inc (March 2017) Highlights of prescribing information. Ibrance® (palbociclib) 
(http://labeling.pfizer.com/ShowLabeling.aspx?id=2191Assessed January 12, 2018). 


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Appendix 1. Abbreviations 
The following is a list of abbreviations that may be used in the protocol. 
 
Abbreviation 
Term 
ACRIN 
American College of Radiology Imaging Network 
ADA 
anti-drug antibodies 
ADR 
adverse drug reaction 
AE 
adverse event 
AI 
aromatase inhibitor 
AIDS 
acquired immunodeficiency syndrome 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
ANOVA 
analysis of variance 
aPTT 
activated partial thromboplastin time 
ASCO 
American Society of Clinical Oncology 
AST 
aspartate aminotransferase 
AUC 
area under the curve 
BBS 
Biospecimen Banking System 
BCRP 
Breast Cancer Resistance Protein 
BID 
twice daily 
BOR 
best overall response 
BP 
blood pressure 
BUN 
blood urea nitrogen 
C 
Cycle 
CCND1 
Cyclin D1 
CCI 
CCNE2 
Cyclin E2 
C1D1 
Cycle 1, Day 1 
C2D1 
Cycle 2, Day 1 
CDK 
Cyclin-dependent kinase 
CEA 
Carcinoembryonic antigen 
CHF 
congestive heart failure 
CI 
confidence interval 
CK 
creatine kinase 
Ceff 
efficacious concentration 
CL 
clearance 
CLp 
plasma clearance 
CLp/F 
oral plasma clearance 
Cmax 
maximal concentration 
Cmin 
minimal concentration 
CNS 
central nervous system 
COVID-19 
coronavirus disease 2019 
CR 
complete response 


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Abbreviation 
Term 
CRF 
case report form 
CRM 
Continual Reassessment Method 
CSA 
clinical study agreement 
CSF 
cerebrospinal fluid 
CSR 
clinical study report 
CT 
computed tomography 
CTA 
clinical trial application 
CTCAE 
Common Terminology Criteria for Adverse Events 
CV 
coefficient of variation 
CYP 
cytochrome P450 
DDI 
drug-drug interaction 
DILI 
drug-induced liver injury 
DLI 
Donor Lymphocyte Infusion 
DLs 
dose levels 
DLT 
dose-limiting toxicity 
DMC 
data monitoring committee 
DNA 
deoxyribonucleic acid 
DoR 
Duration of Response 
DU 
dispensable unit 
DVT 
deep vein thrombosis 
EC 
ethics committee 
ECG 
electrocardiogram 
ECHO 
echocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
E-DMC 
external data monitoring committee 
EDP 
exposure during pregnancy 
eg, 
for example 
EFS 
event-Free Survival 
ELISA 
enzyme-linked immunosorbent assay 
EOC 
epithelial ovarian cancer 
ER 
estrogen receptor 
ER+BC 
estrogen receptor positive breast cancer 
ET 
endocrine therapy 
Etc 
‘and other things’ or ‘and so forth’ 
EU 
European Union 
EudraCT 
European Clinical Trials Database 
FDA 
Food and Drug Administration (United States) 
FFPE 
formalin-fixed paraffin-embedded 
FIP 
first in patient 
FSH 
follicle-stimulating hormone 
Gap 1 
G1 
Gap 2 
G2 
GCS-F 
Granulocyte-colony stimulating factors 


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Abbreviation 
Term 
GCP 
Good Clinical Practice 
GGT 
gamma-glutamyl transferase 
GLP 
Good Laboratory Practice 
GnRH 
gonadotropin-releasing hormone agonist 
GVHD 
graft versus host disease 
H2RAs 
H2 receptor agonists or H2 blockers 
HBsAg 
hepatitis B virus surface antigen 
HBV 
hepatitis B virus 
HbcAb 
hepatitis B core antibody 
HCVAb 
hepatitis C virus antibodies 
HCV 
hepatitis C virus 
HER 
human epidermal growth factor receptor 
Hgb 
hemoglobin 
HIV 
human immunodeficiency virus 
HNSTD 
highest non-severely toxic dose 
HR 
hormone receptor 
HRCT 
High-resolution computed tomography 
IB 
Investigator’s brochure 
IC50 
half maximal inhibitory concentration 
ICH 
International Conference on Harmonisation 
ID 
identification 
ie 
that is 
IHC 
immunohistochemistry 
IIP 
Idiopathic interstitial pneumonitis 
ILD 
interstitial lung disease 
IND 
investigational new drug application 
INR 
international normalized ratio 
IP manual 
Investigational Product manual 
IR 
immediate release 
IRB 
institutional review board 
IRC 
internal review committee 
IRT 
interactive response technology 
ITT 
intent to treat 
IUD 
intrauterine device 
IV 
intravenous 
IWR 
interactive Web-based response 
J-LIC 
Japan Lead-in-Cohort 
JSH 
Japan Society of Hepatology 
K2EDTA 
dipotassium ethylenediaminetetraacetic acid 
KL-6 
clinical biomarker assessment for ILD 
LFT 
liver function test 
LHRH 
luteinizing hormone-releasing hormone 
LSLV 
last subject last visit 


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Abbreviation 
Term 
LVEF 
left ventricular ejection fraction 
mBC 
metastatic breast cancer 
mITT 
modified intent-to-treat 
mTPI 
modified toxicity probability interval 
MD 
multiple dose 
MedDRA 
Medical Dictionary for Regulatory Activities 
MFD 
maximum feasible dose 
MOA 
Mechanism of action 
MR 
modified release 
MRI 
magnetic resonance imaging 
MTD 
maximum tolerated dose 
MUGA 
multigated acquisition scan 
N 
number 
N/A 
not applicable 
NCI 
National Cancer Institute 
NE 
non evaluable 
NGS 
next generation sequencing 
NOS 
not otherwise specified 
OBD 
optimal biological dose 
OR 
Objective Response or Overall Response 
ORR 
overall response rate 
OS 
overall survival 
pT 
target probability 
PACL 
Protocol Administrative Change Letter 
PAD 
pharmacologically active dose 
PCD 
primary completion date 
PD 
pharmacodynamics 
PET 
positron emission tomography 
PFS 
Progression-Free Survival 
PFS 
prefilled syringe 
PI 
principal investigator 
PI3K 
phosphoinositide-3 kinase 
PK 
pharmacokinetic 
P-gp 
p-glycoprotein 1 
PGx 
pharmacogenomics 
PMDA 
Pharmaceuticals and Medical Devices Agency 
PO 
by mouth 
PPC 
primary peritoneal cancer 
PPIs 
proton pump inhibitors 
PR 
partial response 
p-Rb 
phospho-Rb 
PS 
performance status 
PT 
prothrombin time 


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Abbreviation 
Term 
PTT 
partial thromboplastin time 
QD 
every day 
QT 
time between the start of the Q wave and the end of the T 
wave 
RAC 
accumulation ratio 
Rb 
retinoblastoma 
RD 
Response/Remission Duration 
RDE 
recommended dose for expansion 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RFS 
Relapse-Free Survival 
CCI 
RP2D 
recommended Phase 2 dose 
RR 
response rate 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SARS-CoV2 
severe acute respiratory syndrome coronavirus-2 
SC 
subcutaneous 
SCHH 
Sandwich Cultured Human Hepatocytes 
SD 
single dose, stable disease 
SOP 
standard operating procedure 
Sp02 
oxygen saturation 
SRSD 
single reference safety document 
SS 
steady-state 
STD10 
severely toxic dose in 10% of animals 
T1/2 
terminal elimination half-life 
TBili 
total bilirubin 
TBR 
tumor background ratio 
TCGA 
The Cancer Genome Atlas Network 
TDI 
time-dependent inhibition 
TGI 
tumor growth inhibition 
TID 
three times a day 
TK 
thymidine kinase 
Tmax 
time to maximal concentration 
TNBC 
triple negative breast cancer 
TPI 
toxicity probability interval 
TTP 
time to progression 
ULN 
upper limit of normal 
UPM 
unit probability mass 
US 
United States 
USPI 
United States package insert 
UVB 
ultraviolet B 
Vd/F 
apparent volume of distribution 
Vss 
volume of distribution at steady state 


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Abbreviation 
Term 
Vz/F 
apparent volume of distribution 
WBC 
white blood cell 


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Appendix 2. Detailed Dose Escalation/De-Escalation Scheme for mTPI Design 
Escalation/De-escalation algorithms for total number of patients treated at the current 
dose level (current and previous cohorts) 
• With 2 patients treated at current dose level: 
• 
0 DLT -> escalate; 
• 
1 DLT -> remain at the same dose; 
• 
2 DLTs -> de-escalate and consider current dose as intolerable. 
• With 3 patients treated at current dose level: 
• 
0 DLT -> escalate; 
• 
1 DLT -> remain at the same dose; 
• 
2 DLTs -> de-escalate; 
• 
3 DLTs -> de-escalate and consider current dose as intolerable. 
• With 4 patients treated at current dose level: 
• 
0 DLT -> escalate; 
• 
1-2 DLTs -> remain at the same dose; 
• 
3-4 DLTs -> de-escalate and consider current dose as intolerable. 
• With 5 patients treated at current dose level: 
• 
0 DLT -> escalate; 
• 
1-2 DLTs -> remain at the same dose; 
• 
3 DLTs -> de-escalate; 
• 
4-5 DLTs -> de-escalate and consider current dose as intolerable. 
• With 6 patients treated at current dose level: 
• 
0-1 DLT -> escalate; 
• 
2 DLTs -> remain at the same dose; 
• 
3 DLTs -> de-escalate; 


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• 
4-6 DLTs -> de-escalate and consider current dose as intolerable. 
• With 7 patients treated at current dose level: 
• 
0-1 DLT -> escalate; 
• 
2-3 DLTs -> remain at the same dose; 
• 
4 DLTs -> de-escalate; 
• 
5-7 DLTs -> de-escalate and consider current dose as intolerable. 
• With 8 patients treated at current dose level: 
• 
0-1 DLT -> escalate; 
• 
2-3 DLTs -> remain at the same dose; 
• 
4 DLTs -> de-escalate; 
• 
5-8 DLTs -> de-escalate and consider current dose as intolerable. 
• With 9 patients treated at current dose level: 
• 
0-1 DLT -> escalate; 
• 
2-4 DLTs -> remain at the same dose; 
• 
5-9 DLTs -> de-escalate and consider current dose as intolerable. 
• With 10 patients treated at current dose level: 
• 
0-1 DLT -> escalate; 
• 
2-4 DLTs -> remain at the same dose; 
• 
5 DLTs -> de-escalate; 
• 
6-10 DLTs -> de-escalate and consider current dose as intolerable. 
• With 11 patients treated at current dose level: 
• 
0-1 DLT -> escalate; 
• 
2-5 DLTs -> remain at the same dose; 
• 
6-11 DLTs -> de-escalate and consider current dose as intolerable. 


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• With 12 patients treated at current dose level: 
• 
0-2 DLTs -> escalate; 
• 
3-5 DLTs -> remain at the same dose; 
• 
6 DLTs -> de-escalate; 
• 
7-12 DLTs -> de-escalate and consider current dose as intolerable. 


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Appendix 3. ECOG Performance Status* 
 
Grade 
ECOG 
0 
Fully active, able to cany on all pre-disease perfonnance without restriction. 
1 
Resti·icted in physically sti·enuous activity but ambulato1y and able to cany out 
work of a light or sedentaiy nature, eg, light house work, office work. 
2 
Ambulato1y and capable of all self-care but unable to cany out any work 
activities. Up and about more than 50% of waking hours. 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours. 
4 
Completely disabled. Cannot cany on any self-care. Totally confined to bed or 
chair. 
5 
Dead. 
*As published in Am J Clin Oncol 5:649-655, 1982. 


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Appendix 4. RECIST (Response Evaluation Criteria In Solid Tumors) version 1.1 
Guidelines 
Adapted from E.A. Eisenhauer, et al: New response evaluation criteria in solid tumours: 
Revised RECIST guideline (version 1.1). European Journal of Cancer 45 (2009) 228–247 
CATEGORIZING LESIONS AT BASELINE 
Measurable Lesions 
• 
Lesions that can be accurately measured in at least one dimension. 
• 
Lesions with longest diameter twice the slice thickness and at least 10 mm or 
greater when assessed by CT or MRI (slice thickness 5-8 mm). 
• 
Lesions with longest diameter at least 20 mm when assessed by Chest X-ray. 
• 
Superficial lesions with longest diameter 10 mm or greater when assessed by 
caliper. 
• 
Malignant lymph nodes with the short axis 15 mm or greater when assessed by CT. 
NOTE: The shortest axis is used as the diameter for malignant lymph nodes, longest axis for 
all other measurable lesions. 
Non-measurable disease 
Non-measurable disease includes lesions too small to be considered measurable (including 
nodes with short axis between 10 and 14.9 mm) and truly non-measurable disease such as 
pleural or pericardial effusions, ascites, inflammatory breast disease, leptomeningeal disease, 
lymphangitic involvement of skin or lung, clinical lesions that cannot be accurately measured 
with calipers, abdominal masses identified by physical exam that are not measurable by 
reproducible imaging techniques. 
• 
Bone disease: Bone disease is non-measurable with the exception of soft tissue 
components that can be evaluated by CT or MRI and meet the definition of 
measurability at baseline. 
• 
Previous local treatment: A previously irradiated lesion (or lesion subjected to 
other local treatment) is non-measurable unless it has progressed since completion 
of treatment. 


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Normal sites 
• 
Cystic lesions: Simple cysts should not be considered as malignant lesions and 
should not be recorded either as target or non-target disease. Cystic lesions thought 
to represent cystic metastases can be measurable lesions, if they meet the specific 
definition above. If non-cystic lesions are also present, these are preferred as target 
lesions. 
• 
Normal nodes: Nodes with short axis <10 mm are considered normal and should 
not be recorded or followed either as measurable or non-measurable disease. 
Recording Tumor Assessments 
All sites of disease must be assessed at baseline. Baseline assessments should be done as 
close as possible prior to study start. For an adequate baseline assessment, all required scans 
must be done within 28 days prior to randomization and all disease must be documented 
appropriately. If baseline assessment is inadequate, subsequent statuses generally should be 
non-evaluable. 
Target Lesions 
All measurable lesions up to a maximum of 2 lesions per organ, 5 lesions in total, 
representative of all involved organs, should be identified as target lesions at baseline. 
Target lesions should be selected on the basis of size (longest lesions) and suitability for 
accurate repeated measurements. Record the longest diameter for each lesion, except in the 
case of pathological lymph nodes for which the short axis should be recorded. The sum of 
the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target lesions 
at baseline will be the basis for comparison to assessments performed on study. 
• 
If two target lesions coalesce the measurement of the coalesced mass is used. If a 
large target lesion splits, the sum of the parts is used. 
• 
Measurements for target lesions that become small should continue to be recorded. 
If a target lesion becomes too small to measure, 0 mm should be recorded if the 
lesion is considered to have disappeared; otherwise a default value of 5 mm should 
be recorded. 
NOTE: When nodal lesions decrease to <10 mm (normal), the actual measurement should 
still be recorded. 
Non-target Disease 
All non-measurable disease is non-target. All measurable lesions not identified as target 
lesions are also included as non-target disease. Measurements are not required but rather 
assessments will be expressed as CR, Non-CR/Non-PD, PD, Non-evaluable (NE). Multiple 
non-target lesions in one organ may be recorded as a single item on the case report form 
(eg, ‘multiple enlarged pelvic lymph nodes’ or ‘multiple liver metastases’). 


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OBJECTIVE RESPONSE STATUS AT EACH EVALUATION 
Disease sites must be assessed using the same technique as baseline, including consistent 
administration of contrast and timing of scanning. If a change needs to be made the case 
must be discussed with the radiologist to determine if substitution is possible. If not, 
subsequent objective statuses might be non-evaluable. 
Target Disease 
1. Complete Response (CR): Complete disappearance of all target lesions with the 
exception of nodal disease. All target nodes must decrease to normal size (short axis 
<10 mm). All target lesions must be assessed. 
2. Partial Response (PR): Greater than or equal to 30% decrease under baseline of the 
sum of diameters of all target measurable lesions. The short diameter is used in the 
sum for target nodes, while the longest diameter is used in the sum for all other target 
lesions. All target lesions must be assessed. 
3. Stable: Does not qualify for CR, PR or Progression. All target lesions must be 
assessed. Stable can follow PR only in the rare case that the sum increases by less 
than 20% from the nadir, but enough that a previously documented 30% decrease no 
longer holds. 
4. Objective Progression (PD): 20% increase in the sum of diameters of target 
measurable lesions above the smallest sum observed (over baseline if no decrease in 
the sum is observed during therapy), with a minimum absolute increase of 5 mm. 
5. Non-evaluable (NE): Progression has not been documented, and 
• One or more target measurable lesions have not been assessed; or 
• One or more target lesions cannot be measured accurately (eg, poorly visible 
unless due to being too small to measure); or 
• One or more target lesions were excised or irradiated. 
Non-target disease 
1. CR: Disappearance of all non-target lesions and normalization of tumor marker 
levels. All lymph nodes must be ‘normal’ in size (<10 mm short axis). 
2. Non-CR/Non-PD: Persistence of any non-target lesions and/or tumor marker level 
above the normal limits. 


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3. PD: Unequivocal progression of pre-existing lesions. Generally the overall tumor 
burden must increase sufficiently to merit discontinuation of therapy. In the presence 
of SD or PR in target disease, progression due to unequivocal increase in non-target 
disease should be rare. 
4. NE: Progression has not been determined and one or more non-target sites were not 
assessed or assessment methods were inconsistent with those used at baseline. 
New Lesions 
The appearance of any new unequivocal malignant lesion indicates PD. If a new lesion is 
equivocal, for example due to its small size, continued assessment will clarify the etiology. 
If repeat assessments confirm the lesion, then progression should be recorded on the date of 
the initial assessment. A lesion identified in an area not previously scanned will be 
considered a new lesion. 
Supplemental Investigations 
• 
If CR determination depends on a residual lesion that decreased in size but did not 
disappear completely, it is recommended the residual lesion be investigated with 
biopsy or fine needle aspirate. If no disease is identified, objective status is CR. 
• 
If progression determination depends on a lesion with an increase possibly due to 
necrosis, the lesion may be investigated with biopsy or fine needle aspirate to 
clarify status. 
Subjective Progression 
Patients requiring discontinuation of treatment without objective evidence of disease 
progression should not be reported as PD on tumor assessment CRFs. This should be 
indicated on the end of treatment CRF as off treatment due to Global Deterioration of Health 
Status. Every effort should be made to document objective progression even after 
discontinuation of treatment. 
 
Table 5. 
Objective Response Status at each Evaluation 
 
Target Lesions 
Non-target Disease 
New Lesions 
Objective status 
CR 
CR 
No 
CR 
CR 
Non-CR/Non-PD 
No 
PR 
CR 
NE or Missing 
No 
PR 
PR 
Non-CR/Non-PD, NE or 
Missing 
No 
PR 
SD 
Non-CR/Non-PD, NE or 
Missing 
No 
Stable 


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Table 5. 
Objective Response Status at each Evaluation 
 
Target Lesions 
Non-target Disease 
New Lesions 
Objective status 
NE or Missing 
Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
 
If the protocol allows enrollment of patients with only non-target disease, the following table 
will be used: 
 
Table 6. 
Objective Response Status at each Evaluation for Patients with 
Non-Target Disease Only 
 
Non-target Disease 
New Lesions 
Objective status 
CR 
No 
CR 
Non-CR/Non-PD 
No 
Non-CR/Non-PD 
NE 
No 
NE 
Unequivocal progression 
Yes or No 
PD 
Any 
Yes 
PD 
Best Overall Response 
The best overall response (BOR) is the best response recorded from the randomization until 
disease progression or death due to any cause. This is derived from the sequence of objective 
statuses. Objective statuses are not considered after objective progression is documented or 
after start of the first anticancer treatment post discontinuation of protocol treatment. BOR 
for each patient will be derived as one of the following categories. 
• 
Complete response (CR): At least one objective status of CR documented before 
progression. 
• 
Partial response (PR): At least one objective status of PR documented before 
progression. 
• 
Stable disease (SD): At least one objective status of stable documented at least 
6 weeks after randomization date and before progression but not qualifying as CR, 
PR. 
• 
Progressive Disease (PD): Objective status of progression within 16 weeks of 
randomization, not qualifying as CR, PR or SD. 


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• 
Non-evaluable (NE): Progression not documented within 16 weeks after 
randomization and no other response category applies. 


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Appendix 5. List of High Risk Medications for QTc Prolongation 
 
Antiarrhythmics: 
Miscellaneous: 
Amiodarone; 
Arsenic; 
Disopyramide; 
Cisapride; 
Dofetilide; 
Droperidol; 
Ibutilide; 
Thioridazine; 
Procainamide; 
Pentamidine. 
Quinidine; 
Sotalol. 
Adapted from: Regions Guidelines for Managing Medications and QTc prolongation. Source: 
https://cpnp.org/sites/default/files/shared/2013/QTc_Prolongation_Med_Managment_Guideline.doc. 


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Appendix 6. Alternative Measures During Public Emergencies 
The alternative study measures described in this section are to be followed during public 
emergencies, including the COVID-19 pandemic. This appendix applies for the duration of 
the COVID-19 pandemic and will become effective for other public emergencies only upon 
written notification from Pfizer. 
These planned changes are being implemented immediately in response to the COVID-19 
pandemic and are planned for the duration of the COVID-19 pandemic. This applies to 
patients who are quarantined or wish to not attend scheduled visits or perform study 
procedures or tests on site due to safety concerns and/or local government health or health 
institute suggestions and/or guidelines issued in an effort to limit exposure of vulnerable 
populations to the virus. 
Use of these alternative study measures are expected to cease upon the return of business as 
usual circumstances (including the lifting of any quarantines and travel bans/advisories). 
Eligibility 
While SARS-CoV2 testing is not mandated for this study, local clinical practice standards for 
testing should be followed. A patient should be excluded if he/she has a positive test result 
for SARS-CoV2 infection, is known to have asymptomatic infection, or is suspected of 
having SARS-CoV2. Patients with active infections are excluded from study participation as 
per exclusion criterion # 10: “Active and clinically significant bacterial, fungal, or viral 
infection, including hepatitis B virus (HBV), hepatitis C virus (HCV), known human 
immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS) related 
illness. In equivocal cases, with positive serology, those patients with a negative viral load 
are potentially eligible provided the other entry criteria are met. 
Telehealth Visits 
Study patients who can attend scheduled study visits on site and complete all study 
procedures as described in the protocol per the Schedule of the Activities should do so; all 
other participants should make every effort to participate in study visits by telephone via a 
telehealth visit. Video contact can be used if available and permitted by local regulations. 
In the event that in-clinic study visits cannot be conducted, every effort should be made to 
follow up on the safety of study patients at scheduled visits per the Schedule of Activities or 
unscheduled visits. Telehealth visits may be used to continue to assess patient safety and 
collect data points. Telehealth includes the exchange of healthcare information and services 
via telecommunication technologies (eg, audio, video, video-conferencing software) 
remotely, allowing the patient and the investigator to communicate on aspects of clinical 
care, including medical advice, reminders, education, and safety monitoring. The following 
assessments must be performed during a telehealth visit: 
• 
Review and record study intervention(s), including compliance and missed doses 
using the protocol required dosing diary. 


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• 
Review and record any AEs and SAEs since the last contact. Refer to Section 8.1. 
• 
Review and record any new concomitant medications or changes in concomitant 
medications since the last contact. 
• 
Review and record contraceptive method and results of pregnancy testing. 
Confirm that the patient is adhering to the contraception method(s) required in the 
protocol. Refer to Section 4.3 and the Laboratory Testing section of this appendix 
regarding pregnancy tests. 
• 
Review of physical symptoms in place of mandated physical exams. 
Study patient must be reminded to promptly notify site staff about any change in their health 
status. 
Alternative Facilities for Safety Assessments 
If the study participant is unable to visit the study site, protocol specified safety laboratory 
tests and/or tumor assessments may alternatively be performed at an alternative local 
laboratory or facility, where allowable by law or local guidance. 
Laboratory Testing 
If a study patient is unable to visit the site for protocol-specified safety laboratory 
evaluations, testing may be conducted at a local laboratory if permitted by local 
regulations. The local laboratory may be a standalone institution or within a hospital. At the 
discretion of the treating physician home blood draws may be permitted. All safety 
laboratory tests outlined in this protocol can be done at a local laboratory. 
If a local laboratory is used, qualified study site personnel must order, receive, and review 
results. Site staff must collect the local laboratory reference ranges and certifications/ 
accreditations for filing at the site. Laboratory test results are to be provided to the site staff 
as soon as possible. The local laboratory reports should be filed in the patient’s source 
documents/medical records. Relevant data from the local laboratory report should 
be recorded on the CRF. 
If a patient requiring pregnancy testing cannot visit a local laboratory for pregnancy testing, a 
home urine pregnancy testing kit with a sensitivity of at least 25 IU/mL may be used by the 
patient to perform the test at home, if compliant with local regulatory requirements. The 
pregnancy test outcome should be documented in the patient’s source documents/medical 
records and relevant data recorded on the CRF. Confirm that the patient is adhering to the 
contraception method(s) required in the protocol. 
Any results that are considered clinically significant must be reported in a timely manner and 
as directed in the protocol. 


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Imaging and Efficacy Assessments 
If the patient is unable to visit the study site for planned or unplanned imaging assessments 
the patient may visit an alternative facility to have these assessments performed. Qualified 
study site personnel must order, receive, and review results and any abnormalities, including 
progression of disease must be reported to the Pfizer clinical team in a timely manner and as 
directed in the protocol. 
Electrocardiograms 
If the patient is unable to visit the study site for ECGs, the patient may visit an alternative 
facility to have the ECGs performed. Qualified study site personnel must order, receive, and 
review results. 
Study Intervention 
If the safety of a trial patient is at risk because they cannot complete required evaluations or 
adhere to critical mitigation steps, then discontinuing that patient from study intervention 
must be considered. 
PF-06873600 and letrozole may be shipped by courier to study patient if permitted by local 
regulations and in accordance with storage and transportation requirements for the 
PF-06873600 and letrozole. Pfizer does not permit the shipment of PF-06873600 and 
letrozole by mail. The tracking record of shipments and the chain of custody of 
PF-06873600 and letrozole must be kept in the patient’s source documents/medical records. 
Pfizer’s standard clinical stability studies for small molecule clinical drug products support 
the temporary lift for the use of temperature monitors if the total duration of ground 
transportation only from initiation, defined as movement outside of clinical site control, 
ie, picked up by courier to receipt at final destination is <36 hours. Air transport is not 
permitted. 
Your investigational site must document the shipment process followed (including courier 
tracking details) and obtain study patient’s verbal consent to accept delivery of the study drug 
at home. Consent is to be documented in the patient medical record. 
• Study sites should follow up with the patient once the investigational product is 
received by the patient to review when to start using the new bottles, the dosing 
instructions, and completion of the dosing diary/logs. 
• Dosing diary/logs should be shipped with the investigational product. 
• Upon delivery of study drug, the patient (or caregiver) must communicate the below 
information back to the site: 
• Description of the state of the package (any physical damage); 


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• Contents. 
• Number of bottles and lot numbers. 
• Dosing diary/logs. 
• Patients should be instructed not to re-use or dispose of any bottles dispensed at a 
previous visit. 
• All bottles and dosing diary/logs must be returned to the study site at the next on-site 
visit. 
The following is recommended for the administration of PF-06873600 for patient who have 
active [confirmed (positive by regulatory authority-approved test) or presumed (test 
pending/clinical suspicion)] SARS-CoV2 infection: 
• 
For symptomatic patient with active SARS-CoV2 infection, PF-06873600, 
letrozole and fulvestrant should be delayed for at least 14 days from the start of 
symptoms. This delay is intended to allow the resolution of symptoms of SARS- 
CoV2 infection. 
• 
Prior to restarting treatment, the patient should be afebrile for 72 hours, and 
SARS-CoV2-related symptoms should have recovered to ≤ Grade 1 for a minimum 
of 72 hours. Notify the study team when treatment is restarted. 
• 
Continue to consider potential drug-drug interactions as described in this protocol 
for any concomitant medication administered for treatment of SARS-CoV2 
infection. 
Home Health Visits 
A home health care service maybe utilized to facilitate scheduled visits per the Schedule of 
Activities. Home health visits include a healthcare provider conducting an in-person study 
visit at the patient’s location, rather than an in-person study visit at the site. The following 
may be performed during a home health visit (at the discretion of the treating physician and 
in consultation with the SPONSOR): scheduled visits per the Schedule of Activities 
(eg, evaluation of physical symptoms in place of protocol mandated physical examinations, 
review of adverse events or serious adverse events, dosing compliance, contraception check, 
and concomitant medication checks, etc.). 
Adverse Events and Serious Adverse Events 
Study treatment should continue unless the investigator/treating physician is concerned about 
the safety of the patient, in which case temporary or permanent discontinuation may be 
required. 


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It is recommended that the investigator discuss temporary or permanent discontinuation of 
study intervention with the study medical monitor. 
Patient Data Monitoring and Protocol Deviations 
Every effort should be made to ensure that required protocol tests and procedures are 
completed as described with the protocol. However, the circumstances around the ongoing 
COVID-19 pandemic may make it unfeasible to perform some of the tests and procedures. 
In these cases, the investigator must take all of the necessary steps to ensure the safety and 
wellbeing of the study participant. When a required protocol test or procedure cannot be 
performed, the investigator will promptly document the reason for the missed test or 
procedure and any corrective and preventive actions they have taken to ensure that required 
processes will be adhered to as soon as possible. The study team must be informed of these 
incidents in a timely manner. 
Patient data monitoring will continue without interruption. Remote data monitoring will be 
permitted, wherever possible. The CRA will continue monitoring data in an ongoing manner 
via remote access following all institutional processes, if applicable. 
Any other deviations to the protocol, except for these approved modifications, must be 
documented as protocol deviations, and if related to the pandemic, the reason should clearly 
state “COVID-19”. These are not immediately required to be reported to health authorities 
or IRB/ECs unless requested locally. 


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25 mg IR , monotherapy, 
N=3~6 
Collect safety data and 
serial PK samples 
 
Evaluate PK data in 
 
Serial PK data is 
 
Part 2 Combination Dose E 
nsion 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ArmC 
CDK246 +Ful 
Untreated 
ArmB 
CDK246 +Let 
Untreated 
Arm A 
CDK246 +Ful 
Prior CDK4/6 +Let 
 Final Protocol Amendment 9, 03 March 2023 
 
 
Appendix 7. Country-Specific Requirements 
Appendix 7.1. Japan Specific Requirements 
Japan Participation: Japan Lead-in Cohort 
The Japan lead-in coho1i (J-LIC) will be conducted at sites in Japan and added as a 
sub-coho1i to this study. The primaiy and secondai ob·ectives ai·e to assess the safe 
tolerabili 
and PK of PF-06873600. 
See Section 2 for more 
infonnation about the endpoints of this study. For paiiicipants emolled into the J-LIC, 
PF-06873600 will be administered orally BID on a continuous basis as a single agent. At 
least 3 patients, and if necessaiy up to 6 patients, will be emolled in this coho1i overall. 
Figure 10. Japanese Lead-in Cohort Schema 
 
 
*Dose de-escalation or discontinuation of patient enrollment would be considered 
 
 
The dose of J-LIC will be the RDE of monotherapy (ie, 25 mg IR) that was detennined to be 
tolerable based on mTPI in a non-Japanese population in Pa1i IA. At this RDE, no DLTs 
were repo1ied. While dose escalation and de-escalation decision will not be selected for 
J-LIC, DLT evaluation will follow the mTPI using a beta (0.5,0.5) as a prior DLT 
distribution on the RDE for Japanese patients; therefore, evaluation results on the RDE 
co1Tesponding to DLT outcomes in J-LIC ai·e the saine as for non-Japanese patients in Table 
1. The sample size for J-LIC will be 3-6 patients. If no patients in the first 3 patients 
experienced DLT in Cycle 1, this dose level will be declai·ed tolerable for Japanese patients 
(Actions to be taken in Table 1 will be "E"). If one patient experienced DLT in the first 
3 patients (Actions to be taken in Table 1 will be "S"), 2-3 additional patients will be treated 
with the saine dose. If the additional patients do not experience DLTs in Cycle 1, this dose 


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level will be declared tolerable for Japanese patients (Actions to be taken in Table 1 will be 
“S”). If 1 DLT is observed in the additional patient group (ie, 2 of 5 patients), 1 additional 
patient (total 6 patients) will be enrolled. Japan participation in Part 2 will be determined 
based on the safety data review meeting comprised of the investigator and the sponsor, in 
order to ensure the safety of Japanese patients. If DLT is observed in ≥2 of 3 patients or 
≥3 of 6 patients, dose de-escalation, or discontinuation of patient enrollment will be 
considered. 
Patients not evaluable for assessment of DLT (eg, consent withdrawal in Cycle 1) will be 
replaced, and the safety information obtained from all patients who received at least 1 dose 
will be used for tolerability assessment. 
When a dose level of J-LIC is deemed safe following a DLT observation period of 28 days 
and based on discussion by the safety review team (comprised of the Investigators and the 
Sponsor), Japanese participants will be able to join in Part 2 of the main study. 
Japanese participants will be evaluated according to the current eligibility criteria will 
undergo the same study procedures and DLT evaluation period and will be evaluated using 
the same discontinuation criteria as participants in the dose escalation cohort of Part 1 of the 
main study, unless otherwise specified. The followings are only applicable in J-LIC. 
1. DLT Definition: 
In addition to Section 3.1.6 DLT Definition, the following toxicities will be classified as 
DLTs if they occur in patients in the J-LIC. 
• Grade 4 anemia. 
• Grade 3 anemia requiring transfusions or steroids. 
• Grade 3 thrombocytopenia requiring transfusions. 
• Inability to complete at least 75% of the first cycle doses of PF-06873600 due to 
investigational product related toxicity. 
• Clinically important or persistent toxicities (eg, toxicities responsible for >3 weeks 
dose delay) that are not included in the above criteria may also be considered a DLT 
following review by the investigators and the sponsor. All DLTs need to represent a 
clinically significant shift from baseline. 
2. Eligibility criteria: 
In J-LIC, the inclusion criteria #1 and #2 (Section 4.1) will be replaced with “Patients with a 
histological or cytological diagnosis of locally advanced or metastatic solid tumor that is 
resistant to standard therapy or for which no standard therapy is available.” mBC and solid 
tumors with known CCNE amplification will be encouraged to enroll. The specific type of 


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solid tumor with CCNE amplification considered after consultation between the investigator 
and the sponsor as necessary. 
2.1. Rationale for including additional solid tumors in Japan: 
The target participants for J-LIC follow the Guidelines for Clinical Evaluation Methods of 
Anti-Cancer Drugs in Japan.1 Given the potential mechanism of action for the study drug, 
participants with mBC and other solid tumor with known to CCNE amplification will be 
encouraged to enroll. 
CCNE amplification has been observed in several cancers2,3,4 and may be a predictive factor 
for chemotherapy resistance5 and a powerful driver in tumor growth.6 No effective 
anti-tumor treatments exist for participants with these cancers currently. Preclinical models 
testing PF-06873600 in ER+ BC, triple negative breast cancer, and ovarian cancers have all 
shown evidence of anti-tumor activity. Further, translation of these in vitro findings to in 
vivo models has been successful in triple negative breast, ovarian and head and neck cancers 
(See Section 1.2.3). Additionally, preclinical studies testing CDK2 inhibitors showed 
anti-tumor activity in several sarcomas, a tumor with evidence of CCNE1 
amplification/increased expression.6 
These data support the hypothesis that PF-06873600 may provide clinical benefit for patients 
with CCNE amplification (irrespective of the solid tumor type) that is resistant to standard 
therapy or for which no standard therapy is available. 
3. Exclusion Criteria: 
The underlined parts were added into the exclusion criteria for patients considered for the 
J-LIC. 
#14. Known or suspected hypersensitivity or severe allergy to active ingredient/excipients of 
PF 06873600, letrozole, fulvestrant and/or goserelin (or equivalent agent to induce chemical 
menopause). 
#17. Pregnant female patients; breastfeeding female patients (including participants who 
intend to interrupt breastfeeding), female patients of childbearing potential and fertile male 
patients (Part 1A and Part 1C only) who are unwilling or unable to use 2 highly effective 
methods of contraception as outlined in this protocol for the duration of the study and for at 
least 90 days after the last dose of investigational product. 
#22. Current or history of idiopathic interstitial pneumonias (IIPs), drug-induced pneumonitis 
or radiation pneumonitis. In some cases, imaging findings with scarring may be observed in 
asymptomatic patients resulting from prior treatments. These cases (eg, if the scarring is 
identified at baseline and not considered clinically significant and/or active disease) may be 
eligible to enroll at the discretion of the PI, following a discussion and agreement with the 
sponsor. This criteria is only applicable in Japan. 


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4. Lifestyle Requirements: 
Lifestyle Requirements follow Section 4.3, methods of contraception which as indicated with 
an asterisk have not been approved in Japan. 
1. Established use of hormonal methods of contraception associated with inhibition of 
ovulation (eg, oral, inserted*, injected*, implanted*, transdermal* as locally 
approved), provided the patient or male patient’s female partner plans to remain on 
the same treatment throughout the entire study and has been using that hormonal 
contraceptive for an adequate period of time to ensure effectiveness. 
a. Combined (estrogen and progestogen containing) hormonal contraception 
associated with inhibition of ovulation: 
• Oral; 
• Intravaginal*; 
• Transdermal*; 
• Injectable*. 
b. Progestogen only hormone contraception associated with inhibition of ovulation: 
• Oral*; 
• Injectable*. 
2. Correctly placed copper containing intrauterine device (IUD). 
3. Male condom or female* condom used WITH a separate spermicide product* 
(ie, foam, gel, film, cream, or suppository). For countries where spermicide is not 
available or condom plus spermicide is not accepted as highly effective 
contraception, this option is not appropriate. 
4. Male sterilization with absence of sperm in the post vasectomy ejaculate. 
5. Bilateral tubal ligation/bilateral salpingectomy or bilateral tubal occlusive procedure 
(provided that occlusion has been confirmed in accordance with the device’s label). 
All sexually active male patients must agree to prevent potential transfer to and 
exposure of partner(s) to drug through ejaculate by using a condom consistently and 
correctly, beginning with the first dose of investigational product and continuing for 
at least 90 days after the last dose of PF-06873600. 


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5. Hepatitis B Viral monitoring: 
Participants with positive HBsAb or positive HBcAb are allowed to participate in the study if 
they have negative HBV DNA test at screening but HB viral load should be monitored for 
re-activation every 12 weeks. Participants with HBsAb positive who have been vaccinated 
with HBV are exempted from the testing of HB viral load. 
A participant who is tested viral load positive for HBV at any time during the study will 
interrupt administration of PF-06873600, and should consider starting nucleoside antagonist 
immediately in parallel with consultation with hepatologist in accordance with the Japan 
Society of Hepatology (JSH) Guidelines for the management of Hepatitis B Virus infection.7 
6. Hospitalization during the DLT assessment period: 
The study investigator determines the necessity of hospitalization and its duration each 
participants with the circumstance of participants. Although hospitalization is not mandatory 
required, it may necessary to permit evaluation of the safety of participants in the event of 
the need for an emergency response. Hospitalization should be considered if participants’ 
safety is difficult to ensure.1 
7. Condition to be met for discharge (in cases of hospitalization): 
• When a participant is discharged from the hospital during the DLT evaluation period, 
the following conditions (tests, medical examinations, etc.) should be performed on 
the day of the scheduled discharge by the investigators, and the appropriateness of 
discharge should be determined. The tests/medical examinations which are needed to 
confirm the participant’s status will be conducted per clinical practice at the study site 
as appropriate. 
• There are no current clinically significant adverse or side effects or medical reasons 
that require monitoring in a hospital setting. 
• If a clinically significant adverse or side effect has occurred or continues to be 
present, the investigator will determine that the event is manageable by appropriate 
treatment or prophylaxis in an out-of- hospital setting. The investigator will ensure 
the adverse event are followed up according to the protocol requirement. 
• Overall physical condition is stable and acceptable. 
• In case of emergency, the participant may return to the clinical study site or other 
medical institution. If a participant goes to a medical institution other than the 
clinical study site, the clinical study site will ask that the participant contacts the 
study site, study investigator and doctor at the medical institution who will 
communicate to discuss appropriate treatments. A study site keeps the framework for 
emergency situations that is available even during nights and holidays, and the 
sponsor will ensure that the selected study site will thoroughly follow all participants 
according to study procedures. 


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 Final Protocol Amendment 9, 03 March 2023 
 
 
 
 
9. Granulocyte-colony stimulating factors 
Primary prophylactic use of granulocyte-colony stimulating factors are not pennitted during 
the DLT observation period, but they may be used for ti·eatment emergent neuu-openia per 
Japanese package inse1i and local clinical guideline. If GCS-F is used prophylactically in 
Cycle 1 (28 days), the patient will not be DLT evaluable. 
10. Interstitial lung disease (ILD) and pneumonitis 
10.1. Screening for IIPs, drug-induced pneumonitis or radiation pneumonitis, and 
ILD/pneumonitis monitoring for early detection 
1.  SpO2and auscultation of the chest will be monitored at screening and study visits 
following the Schedule of Activities in Japan only. 
2. Clinical biomarker KL-6 will be assessed eve1y cycle Day 1 in Japan only. 
3. Evaluate ILD/pneumonitis by CT/MRI for tumor assessments following the 
SCHEDULE OF ACTIVITIES (Paii 1, Part 2 and J-LIC). In addition, 
high-resolution(HR) CT of the chest will be perfo1med as necessaiy for patients with 
suspected ILD/pneumonitis in Japan only. 
4. Advise patients to immediately repo1i cough, dyspnea, fever, and/or any new or 
worsening respirato1y symptoms. 
5. Conducts a detailed interview and cai·eful examination for signs and symptoms of 
ILD/pneumonitis (eg, cough, dyspnea, fever, hypoxemia). Evaluate patients with 
suspected ILD/pneumonitis with Chest X-ray and Chest HRCT, if deemed necessa1y 
per PI clinical judgement. 
10.2. Dose interruption and discontinuation of PF-06873600 related ILD/pneumonitis 
If::::Grade •1 pneumonitis is observed after PF-06873600 adminisu-ation, dosing must be 
intenupted immediately and initiation of co1iicosteroid ti·eatment should be considered. The 


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dosing of PF-06873600 must be discontinued if the ILD or pneumonitis is related to 
PF-06873600. 
* CTCAE version 4.03. 
11. Pregnancy Testing 
All pregnancy tests used in this study, either urine or serum, must have a sensitivity of at 
least 25 mIU/mL and must be performed by a certified laboratory. For female patients of 
childbearing potential, 2 negative pregnancy tests are required before receiving 
PF-06873600. Following a negative pregnancy test result at screening, appropriate 
contraception must be commenced and the second negative pregnancy test result will then be 
required at the baseline visit and before the patient may receive PF-06873600. Pregnancy 
tests will also be repeated at Day 1 of every other Cycle and at the end of the study to 
confirm that the patient has not become pregnant during the study. Pregnancy tests will also 
be done whenever 1 menstrual cycle is missed during the active treatment period and when 
potential pregnancy is otherwise suspected. In the case of a positive confirmed pregnancy, 
the patient will be withdrawn from administration of investigational product and from the 
study. 
1 
The Guidelines for clinical Evaluation Methods of Anti-Cancer Drugs in Japan, 31 Mar 
2021, available from https://www.mhlw.go.jp/hourei/doc/tsuchi/T210401I0060.pdf. 
Accessed 15 May 2021. 
2 
Gorski JW, Ueland FR, Kolesar JM. CCNE1 amplification as a predictive biomarker of 
chemotherapy resistance in epithelial ovarian cancer. Diagnostics. 2020; 10(5), 279. 
3 
Kim B, Shin, HC, Heo YJ, et al. CCNE1 amplification is associated with liver 
metastasis in gastric carcinoma. Pathology - Research and Practice. 2019; 215(8), 
152434. 
4 
Skalicky DA, Kench JG, Segara D, et al. Cyclin E expression and outcome in pancreatic 
ductal adenocarcinoma. Cancer Epidemiology and Prevention Biomarkers. 2006; 
15(10), 1941-1947. 
5 
Gorski JW, Ueland FR, Kolesar JM. CCNE1 amplification as a predictive biomarker of 
chemotherapy resistance in epithelial ovarian cancer. Diagnostics. 2020; 10(5), 279. 
6 
Kohlmeyer JL, Gordon DJ, Tanas MR, et al. CDKs in sarcoma: Mediators of disease 
and emerging therapeutic targets. International journal of molecular sciences. 2020; 
21(8), 3018. 
7 
JSH Guidelines for the Management of Hepatitis B Virus Infection, May 2021, version 
3.4, https://www.jsh.or.jp/lib/files/medical/guidelines/jsh_guidlines/B_v3.4.pdf., 
Accessed May 15, 2021. 


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Appendix 8. Study Procedures After Primary Completion Date (PCD) Until End of 
Trial 
The Sponsor made a business decision to terminate the Phase 1 clinical study C3661001 on 
07 September 2022. The PCD is defined as the date of the last study visit where data is 
collected for the primary analysis of study outcome(s) and will occur around 5 April 2023. 
The participants who continue to derive clinical benefit and wish to continue study treatment, 
will have access to the investigational product 1) through PfizerCares (expanded access) 
program, where it is available, or 2) under Amendment 9 in the countries where expanded 
access is not available due to regulatory requirements. 
The end of trial will occur when the last patient discontinues study treatment or on 
31 October 2024, whichever occurs first. The participants are allowed to be followed for 
28 days (up to 35 days) after last dose of study treatment or until the consent is withdrawn, 
whichever occurs first. 
Upon approval of Amendment 9, for the patients who continue on study: 
• Study drug (PF-06873600 and fulvestrant) administration will continue per protocol 
as described in Section 5.4 end of trial. 
• Efficacy assessment will continue per local standard of care and institutional 
guidelines. No reporting of efficacy data to the sponsor is required. 
• Safety assessment will continue per the local standard of care, institutional guidelines, 
and PI judgement based on the available safety profile of the study drug. 
SAE reporting will continue per Pfizer guidance as in Section 8. AE reporting after 
PCD and until end of study is required per Japan and EU regulations, therefore AEs 
collected by the investigators will continue to be reported to the Sponsor. 

SAP_001.pdf: 
Protocol C3661001 (PF 06873600) 
Statistical Analysis Plan 
Page 1 of 42 
 
 
 
 
 
Protocol C3661001 
PF-06873600 
 
 
 
 
PHASE 1/2 DOSE ESCALATION AND EXPANSION 
STUDY EVALUATING SAFETY, TOLERABILITY, 
PHARMACOKINETIC, PHARMACODYNAMICS AND 
ANTI TUMOR ACTIVITY OF PF 06873600 AS A 
SINGLE AGENT AND IN COMBINATION WITH 
ENDOCRINE THERAPY 
Statistical Analysis Plan 
(SAP) 
 
Version: 4.0 
Author: PPD 
Date: 
23 March 2023 


Protocol C3661001 (PF 06873600) 
Statistical Analysis Plan 
Page 2 of 42 
 
 
 
 
TABLE OF CONTENTS 
1. AMENDMENTS FROM PREVIOUS VERSION(S) ............................................................ 5 
2. INTRODUCTION .................................................................................................................. 6 
2.1. Study Design ............................................................................................................. 6 
2.1.1. Part IA PF-06873600 Single Agent Dose Escalation .................................. 8 
2.1.2. Part JB PF-06873600 Dose Finding in Combination with Endocrine 
Therapy  ............................................................................................................. 9 
2.1.3. Pait IC PF-06873600 MR Fonnulation ........................................................ 9 
2.1.4. Dose Escalation and MID Detennination in Part IA and IB .................... 10 
2.1.5. Recommended Dose/or Expansion (RDE) and Recommended Phase 
2 Dose (RP2D) Definition ................................................................................ 13 
2.2. Part 2 PF-06873600 Combination Dose Expansion .............................................. 13 
2.2.l. Part 2 Respective Starting Doses for PF 06873600 Combination 
Cohorts ............................................................................................................ 13 
2.2.2. Part 2/Arm A PF 06873600 in Combination with Fulvestrant in HR 
Positive HER2 Negative Local y Advanced or mBC (Second- or Third- 
Line Setting) ..................................................................................................... 13 
2.2.3. Part 2/Arm B -PF 06873600 Part 2/Arm B -PF-06873600 in 
Combination with Letrozole in HR-Positive HER2-Negative Locally 
Advanced or mBC (naive to CDK4/6 inhibitors) ............................................. 13 
2.2.4. Part 2/Arm C-PF-06873600 in Combination with Fulvestrant in 
HR-Positive HER2-Negative Local y Advanced or mBC (naive to 
CDK4/6 inhibitors) ........................................................................................... 14 
2.3. Study Objectives and Endpoints ............................................................................. 14 
3. INTERIM ANALYSES, FINAL ANALYSES AND UNBLINDING ................................ 16 
4. HYPOTHESES AND DECISION RULES ......................................................................... 16 
4.1. Statistical Hypotheses .............................................................................................. 16 
4.2. Statistical Decision Rules ........................................................................................ 17 
4.2.1. Pait l ............................................................................................................ 17 
4.2.2. Pait 2 ........................................................................................................... 17 
5. SAMPLE SIZE DETERMINATION ................................................................................... 18 
6. ANALYSIS SETS ................................................................................................................ 19 
6.1. Safety analysis set .................................................................................................... 19 


Protocol C3661001 (PF 06873600) 
Statistical Analysis Plan 
Page 3 of 42 
 
 
6.2. Full analysis set ........................................................................................................ 19 
6.3. Per-protocol analysis set (evaluable for MTD) ........................................................ 19 
6.4. Modified Intent-to-Treat (mITT) Population ........................................................... 19 
6.5. Response Analysis Set ............................................................................................. 20 
6.6. PK analysis sets ....................................................................................................... 20 
6.7. Biomarker analysis set(s) ......................................................................................... 20 
6.8. Treatment Misallocations ........................................................................................ 20 
6.9. Protocol Deviations ................................................................................................. 20 
7. ENDPOIN'TS AND COVARIATES .................................................................................... 20 
7.1. Efficacy Endpoint(s) ................................................................................................ 20 
7.2. Safety Endpoints ...................................................................................................... 22 
7.2.1. DLT Definitions .......................................................................................... 22 
7.2.2. MTD Definition .......................................................................................... 22 
7.2.3. Recommended Dose for Expansion (RDE) and Recommended Phase 
2 Dose (RP2D) Definition ................................................................................ 22 
7.2.4. Vitals Signs ................................................................................................. 22 
7.2.5. Laboratory Data .......................................................................................... 22 
7.2.6. Adverse Events ........................................................................................... 23 
7.2.7. ECG and QTc Interval ................................................................................ 23 
7.3. Covariates ................................................................................................................ 24 
7.4. Definition of baseline for efficacy and safety analyses ........................................... 24 
8. HANDLIN'G OF MISSING VALUES ................................................................................ 24 
8.1. Missing Dates ........................................................................................................... 24 
8.2. Efficacy Analysis ..................................................................................................... 24 
8.3. Pharmacokinetics ..................................................................................................... 24 
9. STATISTICAL METHODOLOGY AND STATISTICAL ANALYSES ........................... 25 
9.1. Statistical Methods .................................................................................................. 25 
9.2. Statistical Analyses .................................................................................................. 26 
9.2.1. Pri1nary Analysis ......................................................................................... 26 
9.2.2. Seconda1y Analyses .................................................................................... 26 
9.2.2.1. Efficacy Analysis ....................................................................... 26 
9.2.2.2. Pharmacokinetics Analyses ....................................................... 27 


Protocol C3661001 (PF 06873600) 
Statistical Analysis Plan 
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9.2.2.3. Biomarker Analyses .................................................................. 29 
9.2.3. Safety Analyses ........................................................................................... 30 
9.2.3.1. Adverse Events .......................................................................... 30 
9.2.3.2. Laborato1y Tests Abnonnalities ................................................. 30 
9.2.3.3. Vital Signs ................................................................................. 30 
9.2.3.4. Electrocardiogram ..................................................................... 30 
9.2.4. Standard Analyses ....................................................................................... 31 
10. REFERENCES ................................................................................................................... 33 
11. APPENDICES .................................................................................................................. 34 
11.1. APPENDIX 1: CATEGORICAL CLASSES FOR ECG AND VITAL    SIGNS 
 34 
11.2. APPENDIX 2: RECIST (Response Evaluation Criteria In Solid Tumors) 
version 1.1 Guidelines ............................................................................................... 34 
11.3. APPENDIX 3: CENSORING DETAILS .............................................................. 41 
LIST OF FIGURES 
Figure 1 Overall Study Schema.................................................................................................. 7 
LIST OF TABLES 
Table 1 PF-06873600 Dose Levels (Immediate Release Fonnulation) .................................... 11 
Table 2 Dose Escalation Decision Rules.................................................................................. 12 
Table 3 Summaiy of Efficacy Analysis ................................................................................... 27 
Table 4 Objective Response Status at each Evaluation ............................................................ 38 
Table 5 Objective Response Status at each Evaluation for Patients with Non-Tai·get 
Disease Only ......................................................................................................... 38 
Table 6 Progression Free Survival and Duration of Response ................................................ 41 
Table 7 Time to Progression .................................................................................................... 41 


Protocol C3661001 (PF 06873600) 
Statistical Analysis Plan 
Page 5 of 42 
 
 
 
 
1. AMENDMENTS FROM PREVIOUS VERSION(S) 
 
 
Version 
Date 
Author( 
s) 
Summary of Changes/Comments 
4.0 
March 
23,2023 
 
• fuclude updates up through those incorporated in 
Protocol Amendment 9 dated 03 Mar 2023. 
• fuclude detailed infonnation regarding censonng 
efficacy endpoints for analysis based on sponsor 
decision to terminate study. (Section 7.1, Appendix 3) 
3.0 
October 
19,2022 
r1 
The pmpose of this amendment is to add additional 
analysis to include updates until Protocol Amendment 8 
dated 08 July 2021. 
2.0 
Septemb 
er 25, 
2019 
DPD 
The pmpose of this amendment is to add 
additional coho11s of patients to evaluate a 
modified release fonnulation of PF-06873600, 
as indicated, based on emerging and available 
prelimina1y clinical data, including 
safety/tolerability, laborato1y, PK and 
PD findings. 
fu addition, clarifications, administrative and 
typographical modifications were made. 
Section 2.1 Study Design. 
• 
Addition of Paii l C description. 
• 
Overall Study Schema updated to include Part IC. 
• 
Study Schema (within Paii lC through Cycle 1). 
• 
 Addition of Section 2.1.3. Paii lC PF 06873600 MR 
Fonnulation. 
Section 2.3. Study Objectives and Endpoints. 
Study Objectives and Endpoints were updated 
to reflect the addition of Pali 1C 
Modified the percentage requirement for planned doses 
from 70 to 75% based in order to be evaluable for DLT 
assessment. This modification is based on fustitutional 
Review Board (IRB) feedback. 


Protocol C3661001 (PF 06873600) 
Statistical Analysis Plan 
Page 6 of 42 
 
 
 
 
 
New dose levels for the immediate release fonnulation 
updated in Table 1 
TEAE definition in 7.2.6 was updated based on CDSB 
decision (UIMS 141184) 
1.0 
June 29, 
2018 
PD  r1 
First version 
 
 
2. INTRODUCTION 
This document describes the planned statistical analyses for Protocol C3661001 
(Ammendment 9, to be finalized Mar 2023). This analysis plan is meant to supplement the 
study protocol. fu this document, any text taken directly from the protocol is italicized. Any 
deviations from this analysis plan will be described in the Clinical Study Report (CSR). 
2.1. Study Design 
This is a Phase I/2a, open-label, multi-center, non-randomized, multiple dose, safety, 
tolerability, pharmacokinetic, and pharmacodynamic study of PF-06873600 administered as 
a single agent in sequential dose levels and then in combination with endocrine therapy. In 
Part IA, successive cohorts of patients will receive escalating doses of PF-06873600 starting 
at I mg BID dosed on a continuous basis and then in dose finding (Part IB) with immediate 
release formulations of PF-06873600 in combination with endocrine therapy (ET) in an 
outpatient setting. In Part IC, successive cohorts of patients will receive escalating doses of 
PF-06873600 testing a modified release (MR) formulation in a MR cohort evaluation and 
then in dose finding (Part IB) with modified release formulations of PF-06873600 in 
combination with endocrine therapy (ET) in an outpatient setting. 
This study contains 2 parts, dose escalation with single agent (Part IA and IC) and then 
dose finding with PF-06873600 in combination with endocrine therapy (letrozole and 
fulvestrant, independent y with both immediate and modified release formulations) (Part IB) 
followed by dose expansion arm in combination with endocrine therapy (Part 2). The overall 
study design is depicted in Figure 1 and Figure 2 below. 
The Japan lead-in cohort (J-LIC) will be added separately as a sub-cohort in order to assess 
the safety of monotherapy of PF-06873600 in Japanese population. Detailed information is 
provided in the Appendix 7. Japanese participants will be able to enroll into Part 2 after 
safety and tolerability of monotherapy of PF-06873600 in Japanese participants is 
confirmed. 
In Part IA, Part IB, and Part IC patients will partidpate in a dose escalation/finding phase 
aimed at estimating the MTD. The sample size for this component of the study will vary 
depending on the number of DLTs observed. 


Protocol C3661001 (PF 06873600) 
Statistical Analysis Plan 
Page 7 of 42 
 
 
 
.. 
 
Selection 
J 
 
 
 
 
 
Modified ftQlcaH 
 and 
 
 
06873600 
 
 
HR+HER2- advanced or mBC and 
potl'ntiallv increased Cvclin E 
expression/ CDK tumors • TNBC 
HR+ HER2- advanced or mBC 
PF-06873600 +Ful 
PF-06873600 + let 
Part2 
HR+ HER2- advanced or mBC 
 
PF-06873600 + Al 
 
ARM B • PF-06873600 + Al 
HR+HER2·advanced or mBC 
Untreated, up to n:30 
ARM A - PF-06873600 + Ful 
HR+ HER2- advanced or mBC 
Prior CDK 4/6 + let,upton•40 
 
 
Approximate y 75 patients are expected to be enrolled in the dose escalation/finding safety 
cohorts and an additional 6-12 patients are expected in the biomarker cohorts in Parts IA 
and IC. The actual number of patients enrolled will depend on the tolerability of PF­ 
O68736OO and the number of dose levels required to identify the MTDIRDE. Part IA, Part 
JC and each independent combination cohort in Part IB (PF-O68736OOin combination with 
letrozole and PF-O68736OOin combination withfulvestrant) can be stopped and MTD 
declared with approximately 6 to 12 patients. As for the number of patients treated at each 
dose, it is expected to be at I to 4 patients for the doses actually studied. However, since 
variable cohort size is allowed, the actual number of patients treated at each dose (including 
MTD) will va,y from I to 12 .. 
Part 2, the expansion arms will be conducted to assess efficacy as well as safety and 
tolerability of PF-O68736OOin single agent and combination therapy. The sample sizes for 
Part 2 are determined based on published historical data as benchmark data, I-sided type I 
error rate of a= 0.l with 80% power or higher. Approximately JOO patients are expected to 
be enrolled in Part 2. Enrollment of participants into a given cohort may be discontinued if 
minimal or no anti-tumor activity is observed. 
Figure 1 Overall Study Schema 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
UQ Go'-1:s 
1"'""'941at.eJtelHle{IIQ1nlll M kele1H(MRJcomblM11onwfth[T 
J n &...ad-in-Cot-1: C-Appenth 7) 
Figme 2 Modifed Release Selection Coho11 Study Schema (within Paii lC through Cycle 1) 
ARM C- PF-06873600 + Ful 
HR+HER2- advanced or mBC 
Untreated, up to n-30 
■■ 


Protocol C3661001 (PF 06873600) 
Statistical Analysis Plan 
Page 8 of 42 
 
 
 
D-7 0-4 
I 
I 
Day 1: 
 
. 
06873600 
12 -hr PK 
 
I
 
 
 
 
 
 
 
N=3-5 
Lead-in 
Repeat dosing 
_j_ 
 
 
 
C1D15... 
 
 
 
Day-7 
' 
' 
i 
r 
Day 15: 
• Single AM dose of 
MRPF-06873600 
 
Day8: 
• Pre-dosesampleonly 
• 24-hr PK sampling 
 
Day-4: 
• Single AM dose 
of 
MR PF-06873600 
• 24-hr,PK 
- 
sampling 
 
 
• Pre-dose sample only 
2.1.1. Part IA PF-06873600 Single Agent Dose Escalation 
Part IA consists of single agent dose escalation in dose escalation safety cohorts as well as 
biomarker cohorts. The dose escalation safety cohorts will be initiated in 1-2 patients for the 
first 2 planned dose levels starting at I mg BID orally on a continuous basis and dose 
escalation will proceed according to the modified toxicity probability interval (mTPI) 
method. When a dose level is deemed safe following a DLT observation period o/28 days 
and based on the discussion by the safety review team (comprised of the Investigators and 
the Sponsor), dose escalation will occur to the next dose level. 
While patients enrolled in the dose escalation safety cohorts are being evaluated, patients 
may enroll into additional biomarker cohorts (approximately 6 patients in each cohort) 
requiring mandatory pre- and -on treatment tumor and skin biopsies. An end of treatment 
tumor biopsy is optional but encouraged. Initiation of enrollment into the first biomarker 
cohort will be based on observations of key pharmacodynamic (PD) findings (eg, 
neutropenia, gastrointestinal toxicities, and/or other PK/PD markers) and/or reaching a 
predicted active dose (noted in Figure 8 of the protocol as Biomarker Cohort). Enrollment 
into a biomarker cohort can occur after the dose level is deemed safe for escalation to a 
higher dose level or at the MTD. Biomarker cohorts will enroll women and men with HR­ 
positive HER2-negative advanced or mBC. Because these additional patients will receive a 
dose lower than the concurrent dose escalation safety cohort or will be enrolled at a dose 
following the DLT evaluation period in the first 2-4 dose escalation safety cohort patients 
enrolled, their potential DLT observations may not be strict y used in the mTPI method for 
the ongoing dose finding. However, the safety profile from these additional patients will be 
used to establish the MTD or RDE. 


Protocol C3661001 (PF 06873600) 
Statistical Analysis Plan 
Page 9 of 42 
 
 
 
 
2.1.2. Part JB PF-06873600 Dose Finding in Combination with Endocrine Therapy 
After the single-agent PF-06873600 MTDIRDE has been determined for both the IR and MR 
formulations, enrollment will be initiated into Part JB which will evaluate the PF-06873600 
in combination with letrozole and in combination with fulvestrant in independent cohorts in 
women with HR-positive HER2-negative advanced or mBC. PF-06873600 will be 
administered orally on a continuous basis (unless the dose schedule has changed during 
Part JA or Part 1C), while letrozole and fulvestrant will be administered per standard of 
care. 
Available safety and clinical data will be reviewed by the safety review team. The PF- 
06873600 dose in combination with letrozole may be decreased if determined to not be 
tolerable. The PF-06873600 dose de-escalation in combination with letrozole will follow the 
mTPI method. Similarly, the PF-06873600 dose in combination withfulvestrant may be 
decreased if determined to not be tolerable. The PF-06873600 dose de-escalated in 
combination withfulvestrant will follow the mTPI method. The MTDIRDE of each of the 
PF-06873600 formulations (IR and MR) in combination with the respective endocrine 
therapy (letrozole and fulvestrant) will be declared when at least 6 patients have been 
enrolled at a dose level that is predicted to be the MTDIRDE for each of the respective 
combination per the mTPl Once the MTDIRDE of PF-06873600 in combination with 
letrozole and the MTDIRDE of PF-06873600 in combination withfulvestrant have been 
confirmed, a recommended dose for expansion for each combination will be declared and 
enrollment into Part 2 may be initiated. The decision to dose either the MR or IR or MR and 
IRformulation in Part 2 will be made following a careful review of all available clinical data 
and in alignment with C3661001 Safety Team. 
 
Similar to Part JA and/or Part JC, dose escalation, all safety, PK and PD information from 
safety cohorts in Part JB available will be used to determine the PF-06873600 MTDIRDE 
for the respective combination treatments. 
 
2.1.3. Part 1C PF-06873600 MR Formulation 
A modified release (MR) formulation with two designed release rates shorter duration (eg, 6- 
hour) and longer duration (eg,12-hour) release, respectively) has been developed for 
PF-06873600 and were studied in the Part 1C MR Selection Cohort only. Compared to the 
Immediate Release (JR) formulation, the MR formulation has the potential to achieve more 
prolonged effective target inhibition during a dose interval. Emerging pharmacokinetics and 
safety data for the IRformulation suggest there is a large peak-to-trough fluctuation in 
steady-state concentations and a lower maximal concentration (Cmax) could potentially 
improve tolerability.  Therefore, the MR formulation with the two release rates were 
evaluated in an MR selection cohort in this study. 
The MR selection cohort enrolled 3 to 5 evaluable patients. These patients received two 
single doses of the MRformulation during a 7-day lead-in period (Day -7 to Day -1), prior to 
receiving the IR formulation of PF-06873600 twice dai y in 28-day cycles. During the 7-day 
lead-in period, patients will first received a single dose of the shorter release tablets on Day 
-7, and then another single dose of the longer release tablets on Day-4. The dose for the 


Protocol C3661001 (PF 06873600) 
Statistical Analysis Plan 
Page 10 of 42 
 
 
 
 
shorter and longer release MR tablets to be administered during the lead-in period, as well 
as the IR dose to be administered startingfrom Cycle 1 Day 1, were no higher than the 
highest nominal dose tested found to be safe from the IR dose escalation. Serial PK 
sampling was performed for 24 hours following each of the MRformulation doses on Day -7 
and Day -4, and for 12 hours following the IR formulation morning dose on Cycle 1 Day 1. 
PK were compared between the shorter and longer release MR tablets, and also between 
each of the two release rate MR tablets and IR. Based on the PK data from the MR selection 
cohort, 12-hour release rate provides a slower release compared to the 6-hour release rate, 
thus achieves more prolonged drug coverage during a dosing interval. Therefore, 12-hour 
release rate was selected to be further investigated during MR dose escalation. 
The MR dose escalation, if to be performed, proceeded with one of the selected MR 
formulation release rates according to the mTPI method until a MTD is determined. The 
starting dose for the MR dose escalation was selected to achieve similar steady-state AUC 
during one dose interval (AUCss,J as the highest safe IR dose based on prediction. The dose 
increment will be no more than a 50% increase. After MTDIRDE is determined, a biomarker 
cohort may be open to enroll patients with HR-positive HER2-negative advanced or mBC 
requiring mandatory pre- and on-treatment tumor and skin biopsies. 
During the Part 1C dose escalation, all available safety information from dose escalation 
safety and biomarker cohorts in will be used to determine the PF-06873600 MTDIRP2D as a 
single agent. 
2.1.4. Dose Escalation and MTD Determination in Part 1A and 1B 
The starting dose of PF 06873600 will be 1 mg administered orally BID on a continuous 
basis in 28 day cycles. 
The MTD is defined as the highest dose associated with a DLT rate of 2 7.5% with an 
equivalence interval of (22.5%, 32.5%) following the mTPI method. During dose 
escalation/finding, patients will be enrolled in dose cohorts of 1-4 patients in Part JA and 
2-4 patients in Part 1B and Part 1C in dose cohorts other than the MTDIRDE. Each 
MTDIRDE including single-agent and combination treatments will enroll 6-12 patients. 
Each patient will receive continuous doses of PF-06873600 eve1y 28 days. The dose finding 
decision will be based on ]-cycle (28 days) DLT observation period. DLTs observed after 
the Cycle 1 (28-day) may also be considered in the final determination of the MTD as a 
single agent, in combination with letrozole, and in combination with fulvestrant. 
A modified toxicity probability interval (mTPI) method will be utilized in Pait 1 of the study. 
Typically patients will be emolled in coho1ts of 2 to 4 patients. Intra patient dose escalation 
for patients emolled in dose level 1 and 2 may be considered in consultation with the 
sponsor. Once the respective dose level has been declared safe, patients who have completed 
at least 2 Cycles of treatment at the original emolled dose level may escalate to the next 
higher dose level that has cleared the DLT observation period of 28 days. 


Protocol C3661001 (PF 06873600) 
Statistical Analysis Plan 
Pagel l of 42 
 
 
 
 
The potential dose levels planned for Pait 1 of the study are shown in Table 1. Additional 
dose levels, or inte1mediate doses, may be explored, if appropriate based on emerging safety, 
PK or PD data. 
Table 1 PF-06873600 Dose Levels (Immediate Release Formulation) 
 
DOSE LEVEL 
(DL)* 
DOSE 
TOTAL DAILY DOSE*** 
DL l** 
1 mg BID 
2mg 
DL2 
2 mg BID 
4mg 
DL3 
5 mg BID 
10mg 
DL4 
10 mg BID 
20mg 
DL 5 and Beyond 
Escalation to continue to the 
MTD or desired phaimacological 
activity 
* 
The proposed doses, schedule(s), and PK time points may be reconsidered or amended during the study 
based on the emerging safety and PK data. Intennediate doses may be considered when deemed 
necessa1y based on on-going evaluation of safety and toxicity data. 
**  Staiting dose DLI. 
*** Total daily dose may be administered in up to 3 divided doses. 
 
 
The mTPI design uses a Bayesian decision-theoretic :framework and a beta/binomial 
hierai·chical model to tailor dose-escalation and de-escalation decisions. These rnles are 
conceptually similar to those used by the 3+3 design and all the dose-escalation decisions for 
a given trial can be pre-calculated under the mTPI design and presented in a two-way table. 
The decision rnles to "dose escalate" (E), "no change in dose" (S), "dose de-escalate" (D) or 
"dose de-escalate, unacceptable toxicity" (U) are described below: 


Protocol C3661001 (PF 06873600) 
Statistical Analysis Plan 
Page 12 of 42 
 
 
 
 
Table 2 Dose Escalation Decision Rules 
 
DLT 
n=2 
n=3 
n=4 
n=5 
n=6 
n=7 
n=8 
n=9 
n=l0 n=ll 
n=12 
0 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
1 
s 
s 
s 
s 
E 
E 
E 
E 
E 
E 
E 
2 
D 
D 
D 
s 
s 
s 
s 
s 
s 
s 
E 
3 
u 
u 
D 
D 
s 
s 
s 
s 
s 
s 
4 
u 
u 
u 
u 
D 
s 
s 
s 
s 
5 
u 
u 
u 
u 
u 
D 
s 
s 
6 
u 
u 
u 
u 
u 
u 
u 
7 
u 
u 
u 
u 
u 
u 
8 
u 
u 
u 
u 
u 
9 
u 
u 
u 
u 
10 
u 
u 
u 
11 
u 
u 
12 
u 
 
Actions to be tak.en: D = De-escalate the dose; E = Escalate the dose; S = Stay at the dose. U = Unacceptable 
toxicity. 
 
In prindple, all patients must be evaluated for a minimum DLT observation period of 
28 days in both Part 1 and Part 2. However, in order to be evaluable for DLT assessment 
patients need to have received at least 75% of planned doses unless related to treatment 
emergent toxicity. 
The dose escalation in Part IA and JC, dose finding in Part JB, and each arm of the dose 
expansion in Part 2 of the study will stop as the applicable following criteria are met: 
 
• 
The maximum sample size has been achieved (approximately 50 patients in Part 1, 
excluding patients enrolled in biomarker cohorts, and approximately 30 patients in 
each dose arm in Part 2); 
• 
 6 to 12 evaluable patients (for Parts IA, Part 1Band Part 1C) that have been 
enrolled at a PF-06873600 dose level (as a single agent, in combination with 
letrozole, and in combination withfulvestrant, each)) that is predicted to be the MTD 
per the mTPI method; 
• 
All dose levels explored appear to be overly toxic, and the MTD cannot be 
determined. 


Protocol C3661001 (PF 06873600) 
Statistical Analysis Plan 
Page 13 of 42 
 
 
 
 
2.1.5. Recommended Dose for Expansion (RDE) and Recommended Phase 2 Dose 
(RP2D) Definition 
The RDE is the dose chosen for further investigation based on Part 1 study results. If the 
MTD proves to be clinically feasible for long-term administration in a reasonable number of 
patients, then this dose usually becomes the RP2D. Further experience with the RDE may 
result in a RP2D dose lower than the RDE. A RP2D for PF-06873600 as a single agent, in 
combination with letrozole, and in combination with fulvestrant are planned to be 
individually determined based on the respective RDEIMTD and other considerations 
including available pharmacoldnetic, pharmacodynamic, and clinical benefit data. 
2.2. Part 2 PF-06873600 Combination Dose Expansion 
Part 2 dose expansion is an open-label, multi-center, non-randomized study to assess the 
prelimina,y anti-tumor activity and the safety and tolerability of PF-06873600. 
PF-06873600 will be administered at the RDE in 28 days cycles in combination with 
endocrine therapy in two separate dose expansion arms. Patients may be treated with IR or 
MRformulations depending on emerging data from Part 1 and availability. 
2.2.1. Part 2 Respective Starting Doses for PF 06873600 Combination Cohorts 
The single agent PF-06873600 RDEfrom Part IA will be used to initiate the Part 2 dose 
expansion arm studies, which may be de-escalated, depending on emerging data if indicated. 
Additionally, the PF-06873600 RDE in combination with letrozole and PF-06873600 RDE in 
combination withfulvestrantfrom Part JB will be used to initiate the Part 2 respective 
combination dose expansion arm studies, which may be de-escalated, depending on 
emerging data if indicated. 
2.2.2. Part 2/Arm A PF 06873600 in Combination with Fulvestrant in HR Positive HER2 
Negative Locally Advanced or mBC (Second- or Third-Line Setting) 
PF-06873600 will be evaluated in combination withfulvestrant at the RDE in HR-positive 
HER2-negative advanced or mBC in patients who have received prior combined CDK4/6 
inhibitor and a nonsteroidal aromatase inhibitor, and up to 1 prior line of chemotherapy in 
advanced/metastatic setting. This expansion cohort will enroll approximately 40 patients. 
2.2.3. Part 2/Arm B -PF 06873600 Part 2/Arm B -PF-06873600 in Combination with 
Letrozole in HR-Positive HER2-Negative Locally Advanced or mBC (naive to CDK4/6 
inhibitors). 
PF-06873600 will be evaluated in combination with letrozole at the RDE in HR-positive 
HER2-negative advanced or mBC in patients, with supportive available prelimina,y PF- 
06873600 clinical data. Patients who have not received any prior treatment with a CDK4/6 
inhibitor in the advanced or metastatic setting (prior adjuvant therapy with AI is permitted) 
will be enrolled. This expansion cohort will enroll approximately 30 patients. 


Protocol C3661001 (PF 06873600) 
Statistical Analysis Plan 
Page 14 of 42 
 
 
 
 
2.2.4. Part 2/Arm C-PF-06873600 in Combination with Fulvestrant in HR-Positive 
HER2-Negative Locally Advanced or mBC (nai've to CDK4/6 inhibitors) 
PF-06873600 will be evaluated in combination withfulvetsrant at the RDE in HR-positive 
HER2-negative advanced or mBC in patients who progressed on prior endocrine therapy in 
advanced/metastatic setting but have not previously received treatment with a CDK4/6 
inhibitor in the advanced or metastatic setting. Participants who have prior treatment with 
CDK4/6 inhibitors,fulvestrant, everolimus, and any agents with MOA that inhibits PI3k 
mTORpathway are excluded. 
This expansion cohort will enroll up to 30 patients. 
2.3. Study Objectives and Endpoints 
 
Part lA: Single Agent Dose Escalation and Part JB: Combination Dose Finding 
Primary Objective(s): 
Primary Endpoint(s): 
Part JA and 1C: 
To assess the safety and tolerability of increasing 
doses of PF-06873600 in patients with: 
•  HR-positive HER2-negative advanced or mBC 
patients (third or fourth line setting). 
•  Locally recurrent/advanced or metastatic 
TNBC. 
•  Advanced platinum resistant epithelial ovarian 
cancer/fallopian tube cancer/primary peritoneal 
cancer 
• 
In order to estimate the Maximum Tolerated 
Dose (MTD) and select the Recommended Dose 
for Expansion (RDE) for PF-06873600 as a 
single agent (Part JA and Part 1Conly). 
Part JB: 
To assess the safety and tolerability of PF-06873600 
at the single agent MTD in combination with 
letrozole and in combination with fulvestrant (in a 
de-escalation manner, if indicated) in patients with: 
•  HR-positive HER2-negative advanced or mBC 
(third or fourth line setting) in order to establish 
the MTD and select the RP2D for PF-06873600 
in combination with letrozole and in 
combination with falvestrant, respectively. 
Part JA, Part JB and Part JC: 
• 
Dose-Limiting Toxicities (DLTs). 
• 
Adverse Events as characterized by type, frequency, 
severity (as graded by National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI CTCAE 
version 4.03), timing, seriousness, and relationship to 
study therapy. 
•  Laboratory abnonnalities as characterized by type, 
frequency, severity (as graded by NCI CTCAE version 
4.03), and timing. 
• 
Vital sign abnormalities. 
• 
Heart rate corrected QT interval (eg, QTcF). 
Secondary Objective(s): 
Secondary Endpoint(s): 
• 
To evaluate the single- and multiple- dose PK of 
PF-06873600 when given as a single agent 
(Part JA and Part 1C), in combination with 
letrozole, and in combination with falvestrant 
(Part JB). 
Pharmacokinetic parameters of PF-06873600 
• 
Single Dose (SD) - Cmax, Tmax, AUC1asi and as data 
permit, t112, AUC;nJ, CUF, VzlF, and t112. 
• 
Multiple Dose (MD) (assuming steady state is 
achieved) - Css,max,Tss,max, AUCss,r, Css,min, CLsslF, and as 
data pennit, VsslF, t112, and Rae(A UCss,,IAUCs<i,-r}. 


Protocol C3661001 (PF 06873600) 
Statistical Analysis Plan 
Page 15 of 42 
 
 
 
 
Part lA: Single Agent Dose Escalation and Part JB: Combination Dose Finding 
• 
To document any preliminary evidence of 
anti-tumor activity of PF-06873600. 
• 
 Objective Response (OR}, as assessed using the Response 
Evaluation Criteria in Solid Tumors (RECIST) version 
1.1. 
• 
 Time-to-event endpoints: eg, Duration of Response 
(DOR}, Progression-Free Survival (PFS}, Time to 
Progression (ITP). 
• 
To evaluate the pharmacodynamic (PD} 
markers ofCDKpathway modulation following 
treatment with PF-06873600 in tumor. 
• 
Modulation of PD biomarlrers (eg, pRb, Ki67} of CDK in 
tumor. 
 
 
 
 
 
 
I 
 
 
 
 
Part 2: PF-06873600 Single Agent and Combination Dose Expansion 
Primary Objective(s): 
Primary Endpoint(s): 
To evaluate the preliminary antitumor activity and 
confirm the safety and tolerability of PF-06873600: 
In combination (at the RDEfrom Part lB) in patients 
with: 
1. 
HR-positive/HER2-negative advanced or mBC 
{PF-06873600 + falvestrant) (second or third 
line setting}; 
2. HR-positive/HER2-negative advanced or mBC 
{PF-06873600 + a nonsteroidal aromatase 
inhibitor) (CDK4/6i naive); 
3. 
HR-positive/HER2-negative advanced or mBC 
{PF-06873600 + falvestrant)- (CDK4/6i 
naive). 
•  Preliminary antitumor activity measure for efficacy 
includes OR, as assessed using RECIST 1.1. 
• 
Safety and tolerability: 
• 
Adverse Events as characterized by type, frequency, 
severity (as graded by National Cancer Institute 
Common Terminology. Criteria for Adverse Events 
(NCI CTCAE v 4.03) timing, seriousness and 
relationship to study therapy. 
•  Lab abnormalities as characterized by type, 
frequency, severity (as graded by NCI CTCAE 
v 4.03) and timing. 
• 
Vital sign abnonnalities. 
• 
Heart rate corrected QT interval (eg, QTcF). 


Protocol C3661001 (PF 06873600) 
Statistical Analysis Plan 
Page 16 of 42 
 
 
 
 
Part 2: PF-06873600 Single Agent and Combination Dose Expansion 
Secondary Objective(s): 
Secondary Endpoint(s): 
• 
To farther explore preliminary antitumor 
activity of PF-06873600. 
• 
Time-to-event endpoints: eg, DOR, PFS, overall survival 
(OS) and TTP. 
• 
To farther evaluate the PK of PF-06873600, in 
combination with letrozole, and in combination 
with falvestrant at the respective RDE. 
Pharmacokinetic parameters of PF-06873600 
• 
SD - Cmax, Tmax. 
• 
 MD (assuming steady state is achieved) - Css,m,u, Tss,max, 
Css,min, RacCmax, 
• 
To evaluate pharmacodynamic (PD) markers of 
CDK pathway modulation following treatment 
with PF-06873600 in in combination with 
falvestrant or letrozole in tumor. 
• 
Modulation of PD biomarkers (eg, pRb, Ki67) of CDK in 
tumor. 
 
 
 
 
 
 
I 
 
 
 
3. INTERIM ANALYSES, FINAL ANALYSES AND UNBLINDING 
No fo1mal interim analysis or blinding is planned for this study. The final analysis will be 
conducted after the last subject last visit (LSLV). 
4. HYPOTHESES AND DECISION RULES 
4.1. Statistical Hypotheses 
There are no statistical hypotheses. The emphasis of the final analyses will be on estimation 
of key sUilllllaiy statistics. 


Protocol C3661001 (PF 06873600) 
Statistical Analysis Plan 
Page 17 of 42 
 
 
 
 
4.2. Statistical Decision Rules 
4.2.1. Part 1 
Decision mles are based on calculating unit probability mass (UPM) of three dosing inte1vals 
conesponding to under, proper, and over dosing in tenns of toxicity. Specifically, the 
underdosing inte1val is defined as (0; J)T-e1), the over-dosing inte1val (pr+e2), and the 
proper-dosing inte1val (pT-el, pr+ e2), where el and e2 are small fractions. For a target DLT 
rate of 0.275, the target equivalence inte1val is (0.225, 0.325). The three dosing inte1vals are 
associated with three different dose-escalation decisions (Table 1). The under-dosing 
inte1val conesponds to a dose escalation (E), over-dosing conesponds to a dose de-escalation 
(D), and proper-dosing conesponds to remaining at the cmTent dose (S). Given a dosing 
inte1val and a probability distribution, the unit probability mass (UPM) is defined as the ratio 
of the probability of the inte1val to the length of the inte1val. Once the safety assessment is 
complete for Cycle 1 (ie, 28 days after the first dose), the focus will be on allocation of new 
subjects to the dose most likely to be an MTD. 
The dose escalation in Part IA and JC, dose finding in Part JB, and each arm of the dose 
expansion in Part 2 of the study will stop as the applicable following criteria are met: 
 
• 
The maximum sample size has been achieved (approximately 75 patients in Part 1, 
excluding patients enrolled in biomarker cohorts, and approximately 70 patients in 
Part 2); 
• 
 6 to 12 evaluable patients (for Parts IA, Part 1Band Part 1C) that have been 
enrolled at a PF-06873600 dose level (as a single agent, in combination with 
letrozole, and in combination withfulvestrant, each)) that is predicted to be the MTD 
per the mTPI method; 
• 
All dose levels explored appear to be overly toxic, and the MTD cannot be 
determined. 
Specifically the mTPI approach fonnalizes stopping mies as follow: 
Rule 1 (early tennination): if the first dose is too toxic 
Pr(p1 > PT I data)> ; 
; = 0.975 
 
Rule 2 (dose exclusion), if dose= i is too toxic 
Pr(Pi > PT I data)>; 
then exclude doses 
i 
4.2.2. Part 2 
; = 0.975 
Part 2 dose expansion is an open-label, multi-center, non-randomized study to assess the 
prelimina,y anti-tumor activity and the safety and tolerability of PF-06873600. PF- 
06873600 will be administered at the RDE in 28 days cycles in combination with endocrine 
therapy in two separate dose expansion arms. Patients may be treated with IR or MR 
formulations depending on emerging data from Part 1 and availability. 


Protocol C3661001 (PF 06873600) 
Statistical Analysis Plan 
Page 18 of 42 
 
 
 
 
Analyses may be perfo1med on data from both Part 1 and Pait 2 to explore the relationships 
between PK parameters, safety endpoints, and efficacy endpoints. 
5. SAMPLE SIZE DETERMINATION 
5.1. Pait 1 
In Part IA, Part IB and Part IC, patients will participate in a dose escalation/finding phase 
aimed at estimating the MTD. The sample size for this component of the study will vary 
depending on the number of DLTs observed. 
Approximate y 75 patients are expected to be enrolled in the dose escalation/finding safety 
cohorts and an additional 6-12 patients are expected in the biomarker cohorts in Parts IA 
and IC. The actual number of patients enrolled will depend on the tolerability of PF­ 
O68736OO and the number of dose levels required to identify the MTDIRDE. Part IA, Part 
JC and each independent combination cohort in Part IB (PF-O68736OOin combination with 
letrozole and PF-O68736OOin combination withfulvestrant) can be stopped and MTD 
declared with approximately 6 to 12 patients. As for the number of patients treated at each 
dose, it is expected to be at I to 4 patients for the doses actually studied. However, since 
variable cohort size is allowed, the actual number of patients treated at each dose (including 
MTD) will va,y from I to 12. 
5.2. Pait 2 
Part 2, the expansion arms will be conducted to assess efficacy as well as safety and 
tolerability of PF-O68736OOin single agent and combination therapy. The sample sizes for 
Part 2 are determined based on published historical data as benchmark data, I-sided type I 
error rate of a= 0.l with 80% power or higher. Approximately JOO patients are expected to 
be enrolled in Part 2. Enrollment of participants into a  ·ven cohort may be discontinued i 
minimal or no anti-tumor activity is observed. 
 
 
I 
 
 
I 


Protocol C3661001 (PF 06873600) 
Statistical Analysis Plan 
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• 
 
 
 
 
 
 
 
6. ANALYSIS SETS 
6.1. Safety analysis set 
The safety ana ysis set includes all enrolled patients who receive at least one dose of 
study treatment. 
6.2. Full analysis set 
The full analysis set includes all enrolled patients. 
6.3. Per-protocol analysis set (evaluable for MTD) 
The per protocol analysis set includes all enrolled patients who receive at least one 
dose of study treatment and who do not have major treatment deviations during the 
first cycle. Patients with major treatment deviations during the first cycle of 
treatment are not evaluable for the MTD assessment and will be replaced as needed 
to permit the MTD estimation. Major treatment deviations include the failure to 
satisfy major entry criteria (eg, confirmation of the target disease,· signed informed 
consent) or use of other anticancer treatments during the active treatment period and 
disease follow-up phases other than as defined/allowed in this protocol. Major 
treatment deviations will also include: 
• 
Administration of less than 75% of the planned number of doses of PF-06873600 
during DLT observation period (provided that the reduction in doses is not due to 
toxicity attributable to PF-06873600). 
• 
Administration of more than 110% of the planned number of doses of 
PF-06873600 during DLT observation period. 
6.4. Modified Intent-to-Treat (mITT) Population 
• 
 The modified intent-to-treat (mITT) is the analysis population that will follow the 
ITT principle and include patients receiving at least 1 dose of investigational 
product with baseline assessment and at least 1 post baseline assessment, disease 
progression, or death before the first tumor assessment. The mITT population 
will be used for analyses and to support conference presentations when the study 
is still ongoing. 


Protocol C3661001 (PF 06873600) 
Statistical Analysis Plan 
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6.5. Response Evaluable Set 
The response evaluable population will include all paiiicipants who received at least 
one dose of study treatment and had baseline disease and at least one post baseline 
disease assessment. 
6.6. PK analysis sets 
The PK parameter analysis population is defined as all enrolled patients treated who 
have sufficient information to estimate at least 1 of the PK parameters of interest. 
The PK concentration population is defined as all enrolled patients who are treated 
and have at least 1 analyte concentration. 
6.7. Biomarker analysis set(s) 
• 
The PD/Biomarker analysis population is defined as all enrolled patients with 
PD/Biomarkers evaluated at pre-and/post dose. 
6.8. Treatment Misallocations 
Patients who receive the wrong initial dose for whatever reason will be analyzed according to 
the initial dose actually received. Patients who receive the wrong dose after the initial dose 
will be analyzed according to the initial dose received. 
6.9. Protocol Deviations 
All deviations will be listed in the clinical study repo1i (CSR). Major treatment deviations 
requiring a patient to be excluded from the MTD evaluaton ai·e in Section 6.3. 
7. ENDPOINTS AND COVARIATES 
7.1. Efficacy Endpoint(s) 
ill this First ill Patient study anti tumor activity is a primaiy objective for Pali 2 of the study. 
Tumor response will be presented in the fo1m of patient data listings that include, but are not 
limited to, tumor type, staiiing dose, tumor response at each visit, and best overall response. 
ill addition, progression date, death date, date of first response and last tumor assessment 
date, and date of last contact will be listed. Objective response rate (ORR), progression free 
survival (PFS), overall survival (OS), time to progression (TTP), and duration of response 
(DOR) will be summai·ized and presented if data pe1mits. 
The above efficacy endpoints ai·e derived based on the disease response per investigator 
evaluation on the CRF pages, which is the primaiy method of documentation of disease. 
 
• 
Overall Response Rate (ORR) -defined as the propo1iion of patients who achieved best 
overall response of complete response (CR) or paiiial response (PR) according to 
Appendix 2 RECIST 1.1. Overall response is the best response recorded from first dose 
until disease progression/recurrence. 


Protocol C3661001 (PF 06873600) 
Statistical Analysis Plan 
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Unconfi1med CR (uCR) is defined as one objective status of CR documented before PD, while 
confi1med CR requires two objective statuses of CR a minimum of four weeks apait documented 
before PD. Sequences of CR - Non-evaluable - CR ai·e considered confamed CR as long as the 
two CR responses are observed at a minimum of 4 weeks apa1t. Similai·ly, unconfamed PR 
(uPR) is defined as one objective status of PR documented before PD but not qualifying as uCR. 
Confi1med PR is defined as two objective statuses of PR or better (PR followed by PR or PR 
followed by CR) a minimum of four weeks apait documented before PD, but not qualifying as 
CR. Sequences of PR - Stable Disease or Non-evaluable - PR are considered PRs as long as the 
two PR responses are observed at a minimum of 4 weeks apait. Based on these definitions, the 
unconfi1med ORR analysis will include both confamed CR or PR and unconfamed CR or PR as 
responders, whereas the confi1med ORR analysis will only include confamed CR or PR as 
responders. 
 
 
• 
 Progression Free Survival (PFS) - is defined as the time from Cycle 1 Day 1 (ClDl) to 
first documentation of disease progression or death due to any cause, whichever occurs 
first. Patients last known to be 1) alive 2) on treatment or within the post-treatment 
follow-up period and 3) progression-free, are censored at the date of the last disease 
assessment that verified lack of disease progression. Patients who strut new anti-cancer 
treatment prior to the end of post-treatment follow-up period and have adequate baseline 
and on-treatment objective disease assessments without evidence of progressive disease 
ai·e censored at the date of the last objective disease assessment. Patients with inadequate 
baseline or no on-study disease assessments ai·e censored at ClDl unless death occuned 
prior to the first planned assessment (in which case the death is an event). Patients with 
at least one on-study disease assessment who discontinue treatment without disease 
progression and without death within 28 days of discontinuation are censored at the date 
of the last objective disease assessment that verified lack of disease progression (if 
progression or death is within 28 days of discontinuation the progression or death is an 
event). Patients with documentation of progression or death after an unacceptably long 
interval (>16 weeks) since the previous disease assessment will be censored at the time of 
the previous assessment. If applicable, patients who ai·e still ongoing at time of study 
te1mination by sponsor ai·e censored at the date of study te1mination. 
PFS (days)= [progression/death date - ClDl + 1]. 
If last adequate tumor assessment is within 6 months of C1D1, any event of death or 
progression occmTing after more than 18 weeks of last tumor assessment, then it qualifies 
for 2 missing and we censor at last adequate tumor assessment. 
If last adequate tumor assessment is after 6 months and before 24 months of ClDl, any 
event of death or progression occmTing after more than 26 weeks of last tumor 
assessment, then it qualifies for 2 missing and we censor at last adequate tumor 
assessment. 
If last adequate tumor assessment is after 24 months of ClDl, any event of death or 
progression occmTing after more than 4 months and 2 weeks of last tumor assessment, 
then it qualifies for 2 missing and we censor at last adequate tumor assessment. 


Protocol C3661001 (PF 06873600) 
Statistical Analysis Plan 
Page 22 of 42 
 
 
 
 
• 
Duration of Response (DOR): Time from the date of first documentation of CR or PR 
to the date of first documentation of objective progression or death due to any cause. 
• 
Time to Progression (TTP): Time from randomization until disease progression. 
More details of censoring are provided in Appendix 3. 
7.2. Safety Endpoints 
7.2.1. DLT Definitions 
Severity of adverse events (AEs) will be graded according to Common Terminology Criteria 
for Adverse Events (CTCAE} version 4.03. The definition is provided in Section 3.1.6. of the 
protocol. 
7.2.2. MTD Definition 
The MTD is defined as the highest dose associated with a DLT rate of 2 7.5% with an 
equivalence interval of (22.5%, 32.5%) following the mTPI method. During dose 
escalation/finding, patients will be enrolled in dose cohorts of 1-4 patients in Part JA and 
2-4 patients in Part 1B and Part 1C in dose cohorts other than the MTDIRDE. Each 
MTDIRDE including single-agent and combination treatments will enroll 6-12 patients. 
Each patient will receive continuous doses of PF-06873600 eve1y 28 days. The dose finding 
decision will be based on ]-cycle (28 days) DLT observation period. DLTs observed after 
the Cycle 1 (28-day) may also be considered in the final determination of the MTD as a 
single agent, in combination with letrozole, and in combination with fulvestrant. 
7.2.3. Recommended Dose for Expansion (RDE) and Recommended Phase 2 Dose 
(RP2D) Definition 
The RDE is the dose chosen for further investigation based on Part 1 study results. If the 
RDE proves to be clinically feasible for long-term administration in a reasonable number of 
patients, then this dose usually becomes the RP2D. Further experience with the RDE may 
result in a RP2D dose lower than the RDE. A RP2D for PF-06873600 as a single agent, in 
combination with letrozole, and in combination with fulvestrant are planned to be 
individually determined based on the respective RDEIMTD and other considerations 
including available pharmacoldnetic, pharmacodynamic, and clinical benefit data. 
7.2.4. Vitals Signs 
Vital signs to be obtained include temperature, blood pressure and pulse rate. See Schedule 
of Activities in the protocol for details. 
7.2.5. Laboratory Data 
Screening labs to be performed within 7 days of CJD1. Laboratory assessments can be 
performed earlier but will have to be repeated to be done within 7 days of CJD]. For 
subsequent cycles, pre-dose labs may also be drawn up to 3 days (-3 days/72 hours) in 
advance of scheduled dosing in order to obtain results prior to visit. 


Protocol C3661001 (PF 06873600) 
Statistical Analysis Plan 
Page 23 of 42 
 
 
 
 
The laborato1y results will be graded according to the NCI CTCAE v4.03 severity grade. For 
labs for which an NCI CTCAE v4.03 scale does not exist, the frequency of patients with 
values below, within, and above the nonnal ranges will be summarized by dose. Baseline 
evaluations for laborato1y data are those collected: 
 
• 
Within 28 days prior to Cycle 1/Day 1. 
 
• 
Closest but prior to Cycle 1/Day 1 if there is more than one baseline evaluation. 
7.2.6. Adverse Events 
Assessment of adverse events will include the type, incidence, severity (graded by the 
National Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE] 
version 4.03) timing, seriousness, and relatedness. 
All AEs will be coded by system organ class (SOC) and prefe1Ted te1m using Medical 
Dictionaiy for Regualto1y Activities (MedDRA). The severity of all AEs will be graded by 
the investigator using NCI CTCAE Version 4.03 whenever possible. For other AEs without 
specific CTC definitions, results are identified according to CTCAE "other" categories. 
Adverse events will be assigned to the appropriate cycle based on Day 1 of each cycle. 
Treatment Emergent Adverse Events 
 
An adverse event is considered a Treatment-Emergent Adverse Event (TEAE) if the event 
staiied during the effective duration of treatment (i.e., from the first dose of study treatment 
until last dose of study treatment+ 28 days or start of new anti-cancer therapy - 1 day, 
whichever occurs first). 
Treatment Related Adverse Events 
 
Treatment Related Adverse Events ai·e treatment emergent adverse events with cause 
categorized by the investigator as related to study treatment. Events that ai·e continuations of 
baseline abno1malities (signs and symptoms) ai·e not considered treatment emergent, and 
hence are not considered treatment related, unless there is an increase in grade over baseline. 
7.2.7. ECG and QTc Interval 
Standard electrocardiogram (ECG): 12-lead (with a JO-second rhythm strip) tracing will be 
used for all ECGs. It is preferable that the machine used has a capacity to calculate the 
standard intervals automatically. At each time point (see the Schedule of Activities in the 
Protocol), 3 consecutive ECGs (except single ECG at screening and End of Treatment) will 
be performed at approximately 2 minutes apart to determine the mean QTcF interval. If the 
mean QTcF is prolonged :?501 msec, ie, CTCAE Grade :?3}, then the ECGs should be 
re-evaluated by a qualified person at the site for confirmation as soon as the finding is made, 
including verification that the machine reading is accurate. 


Protocol C3661001 (PF 06873600) 
Statistical Analysis Plan 
Page 24 of 42 
 
 
 
 
7.3. Covariates 
Not applicable. 
7.4. Definition of baseline for efficacy and safety analyses 
The last available assessment prior to the sta1t of study treatment is defined as 'baseline' 
value or 'baseline' assessment for safety and efficacy analyses. If an assessment is planned to 
be perfo1med prior to the first dose of study treatment in the protocol and the assessment is 
peifonned on the same day as the first dose of study treatment, it will be assumed that it was 
peifonned prior to study ti-eatment administration, if assessment time point is not collected or 
is missing. If assessment time points are collected, the observed time point will be used to 
dete1mine pre-dose on study day 1 for baseline calculation. Unscheduled assessments will be 
used in the dete1mination of baseline. However, if time is missing, an unscheduled 
assessment on study day 1 will be considered to have been obtained after study ti·eatment 
administi·ation. 
8. Handling of Missing Values 
8.1. Missing Dates 
ill compliance with Pfizer standards, if the day of the month is missing for any date used in a 
calculation, the 1st of the month will be used to replace the missing date unless the 
calculation results in a negative time duration (eg, date of onset cannot be prior to day one 
date). ill this case, the date resulting in 0 time duration will be used. Pfizer standards are 
also used if both month and day are missing (Jan 1 unless negative time duration). This 
excludes the phaimacokinetic, ECG, and pha1macodynainic analyses, which will only use the 
actual date collected or if date not available deem the data missing. 
8.2. Efficacy Analysis 
Censoring rnles for time-to-event endpoints are detailed in Section 11.3 Appendix 3. 
 
8.3. Pharmacokinetics 
Concentrations below the limit of quantification 
ill all data presentations (except listings), concentrations below the limit of quantification 
(BLQ) will be set to zero. (ill listings BLQ values will be repo1ted as "<LLQ", where LLQ 
will be replaced with the value for the lower limit of quantification.). 
Deviations, missing concentrations and anomalous values 
Patients who experience events that may affect their PK (eg, incomplete dosing due to 
vomitting) may be excluded from the PK analysis. 
ill mug concentration summaiy tables and plots of median PK profiles (plots of PK profiles 
will only be done for Part IA and lB patients), statistics will be calculated with 
concentrations set to missing if one of the following cases is ti11e: 


Protocol C3661001 (PF 06873600) 
Statistical Analysis Plan 
Page 25 of 42 
 
 
 
 
1. 
A concentration has been repo1ied as ND (ie, not done) or NS (ie, no sample), 
2. 
A deviation in sampling time is of sufficient concern or a concentration has been 
flagged anomalous by the phannacokineticist. 
Note that Sllllllllaiy statistics will not be presented at a paiiiculai· time point if more than 50% 
of the data are missing. 
An anomalous concentration value is one that, after verification of bioanalytical validity, is 
grossly inconsistent with other concentration data from the same individual or from other 
subjects. For example, a BLQ concentration that is between quantifiable values from the 
same 
dose is considered as anomalous. Anomalous concentration values may be excluded from PK 
analysis at the discretion of the PK analyst. 
Pharmacokinetic parameters 
Actual PK sampling times will be used in the derivation of PK parameters. If a PK pai·ameter 
cannot be derived from a patient's concentration data, the pai·ameter will be coded as NC (ie, 
not calculated). (Note that NC values will not be generated beyond the day that a subject 
discontinues). 
fu Slllllllla1y tables, statistics will not be presented for a paiiiculai· treatment group if more 
than 50% of the data ai·e NC. For statistical analyses, PK pai·ameters coded as NC will also 
be set to missing. 
If an individual patient has a known biased estimate of a PK parameter (due for example to 
an unexpected event such as vomiting before all the dose is absorbed in the body), this will 
be footnoted in summaiy tables and will not be included in the calculation of Slllllllla1y 
statistics or statistical analyses. 
OTc 
For the QTc analyses, no values will be imputed for missing data. 
Pharmacodynamic parameters 
Missing data for the phai"Inacodynamic parameters will be treated as such and no imputed 
values will be derived. 
9. STATISTICAL METHODOLOGY AND STATISTICAL ANALYSES 
9.1. Statistical Methods 
No fo1mal hypothesis testing will be perfonned in this explorato1y study. 
Analyses of Time-to-Event Endpoints 


Protocol C3661001 (PF 06873600) 
Statistical Analysis Plan 
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Time-to-event endpoints will be summarized using the Kaplan-Meier method and displayed 
graphically when appropriate. Median event times and 2-sided 95% confidence intervals for 
each time-to-event endpoint (Brookmeyer and Crowley, 1982) will be provided. 
Analyses of Binary Endpoint 
The rates ofbinaiy endpoints will be provided along with the conesponding 2-sided 95% 
confidence intervals using an exact method. 
Analyses of Continuous Data 
Descriptive statistics, such as the mean, standard deviation, coefficient of vai·iation, median, 
minimum, and maximum values, will be provided for continuous endpoints. 
9.2. Statistical Analyses 
9.2.1. Primary Analysis 
Dose Limiting Toxicity (DLT) is the primaiy endpoint of the study, which will be 
smnmai·ized by dose level using the Per Protocol Analysis Set for patients in the dose 
escalation po1iion of the study. A listing of the DLTs will also be provided. 
9.2.2. Secondary Analyses 
9.2.2.1. Efficacy Analysis 
ill this First ill Patient study anti-tumor activity is a primaiy objective for Pait 2 of the study. 
Tumor response will be presented in the fo1m of patient data listings that include, but are not 
limited to, tumor type, staiiing dose, tumor response at each visit, and best overall response. 
ill addition, progression date, death date, date of first response and last tumor assessment 
date, and date of last contact will be listed. Objective response rate (ORR), progression-free 
survival (PFS), time to progression (TTP), and duration of response 
(DOR) will be summai·ized and presented. The definition of each response catego1y is 
provided in Appendix 2 (RECIST 1.1). 
Efficacy analysis will be summai·ized by dose coho1ts for pa.ii 2 of the study (dose 
expansion). For paii l (dose escalation), no fo1mal efficacy analysis will be presented; 
instead, results will be listed. 
For response-based metrics (BOR, ORR and DOR), analyses will be presented based on 
confnmed responses. Analysis of progression free smvival and time to progression ai·e 
defined as time from the date of first dose. Summai·ies of then and% of subjects with PFS, 
and TTP and data listing by tumor type and dose will be generated. If applicable, the PFS 
may also be summai·ized using the Kaplan-Meier method at all or some of the following 
timepoints: PFS, DOR, and TTP at 3, 6, 9, 12, 18, and then eve1y 6 months. 
The 95% confidence inte1vals will be generated. Confidence inte1vals for medians and 
quaitiles will be based on the Brookmeyer-Crowley method. Confidence inte1vals for the 
estimated probability of an event at a pa1ticulai·time point will be generated using the 


Protocol C3661001 (PF 06873600) 
Statistical Analysis Plan 
Page 27 of 42 
 
 
 
 
Greenwood fo1mula. Duration of response will be summarized with number of responders, 
number and percentage of event/censorship, mean, standard deviation, minimum, maximum 
and median of duration in unit of months. ORR will be summarized by number of subjects 
meeting respective criteria, percentage. The 95% confidence intervals will be generated for 
PFS, TTP, and ORR. Definitions of PFS, TTP, DOR, and ORR are outlined in section 7.1 of 
this SAP. Supportive figures depicting the change in tumor size may also be provided. 
 
The following table provides an overview of the efficacy analysis. 
Table 3 Summary of Efficacy Analysis 
 
Endpoint 
Analysis Set 
Statistical 
Method 
Model/ 
Covariates/ 
Strata 
Missing 
Data 
Interpretation 
Overall 
(confnmed) 
response 
Full Analysis 
Set, Response 
Evaluable set. 
Exact CI 
By dose 
range/arms 
Censored 
per Section 
11.3 
Secondruy 
Analysis 
Progression 
Free Smvival 
(PFS) 
Full Analysis 
Set. 
Kaplan- 
Meier1 
By dose 
range/arms. 
Censored 
per Section 
11.3 
Secondruy 
Analysis 
Time to 
Progression 
(TTP) 
Full Analysis 
Set. 
Kaplan- 
Meier 
By dose 
range/arms. 
Censored 
per Section 
11.3 
Secondruy 
Analysis 
Dmation of 
(confnmed) 
Response 
(DOR) 
Full Analysis 
Set. 
Kaplan- 
Meier 
By dose 
range/arms. 
Censored 
per Section 
11.3 
Secondruy 
Analysis 
1 Kaplan EL, Meier P. Nonparametric estimation from incomplete obse1vations. J Am Stat 
Assoc 1958; 53:457-481. 
9.2.2.2. Pharmacokinetics 
Analyses Pharmacokinetic 
Parameters 
Plasma Concentration Summaiy 
Presentations for plasma drng concentrations will include: 
 
- a listing of all concentrations sorted by dose level, subject ID, cycle, day, and nominal time. 
The concentration listing will also include the actual times. Deviations from the nominal 
time will be given in a separate listing. 
- median concentrations versus nominal time plots (on both lineai· and seini-log scales) for a 
dose inte1val after the morning dose on Cycle 1 Day 1 and Cycle 1 Day 15, sepai·ately, by 
dose level (all treatments on the same plot per scale, based on the SllilllilaIY of concentrations 
by dose level and time). 


Protocol C3661001 (PF 06873600) 
Statistical Analysis Plan 
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- mean concentrations versus nominal time plots (on both linear and semi-log scales) for a 
dose interval after the morning dose on Cycle 1 Day 1 and Cycle 1 Day 15, separately, by 
dose level (all ti·eatments on the same plot per scale, based on the summaiy of concentrations 
by dose level and time). 
- median concenti·ations versus nominal time plots (on both linear and semi-log scales) after 
single dose on Cycle 1 Day -7, Cycle 1 Day -4 and Cycle 1 Day 1 (Paii 1C MR Selection 
Coho1i). 
- mean concentrations versus nominal time plots (on both linear and semi-log scales) after 
single dose on Cycle 1 Day -7, Cycle 1 Day -4 and Cycle 1 Day 1 (Paii 1C MR Selection 
Coho1i). 
Plasma dmg concenti·ation time data within a dose interval after the morning dose on Cycle 
1, Day 1 (for all patients), Cycle 1, Day 15 (for all patients except Paii IC MR Selection 
Coho1i) and Cycle 1 Day -7/-4 (Paii IC MR Selection Cohort) will be analysed for individual 
patients using noncompaiimental methods. The noncompa1imental analysis will estimate PK 
parameters including the following: 
1. 
Cycle 1, Day 1: the maximal concentration (Cmax), time to maximum plasma 
concentration (Tmax), and ai·ea under the plasma concenti·ation versus time curve from time 
0 to the last sampling time point within the dose interval (AUClast), and if data pennit, area 
under the plasma concentration versus time curve from time 0 extrapolated to infinity 
(AUCinf), tenninal elimination half life (tl/2), apparent oral plasma clearance (CL/F), 
apparent volume of distribution (Vz/F); 
2. 
Cycle 1, Day 15: steady state Cmax (Cmax,ss), Tmax, AUC within one dose inte1val 
(AUCr,ss), minimum plasma concenti·ation (Cmin,ss), oral CL (CLss/F), and if data permit, 
apparent volume of distribution (Vss/F), tl/2, and accumulation ratio (Rae); 
3. 
Cycle 1, Day -7/-4: the maximal concenti·ation (Cmax), time to maximum plasma 
concentration (Tmax), and ai·ea under the plasma concenti·ation versus time cmve from time 
0 to the last sampling time point within the dose inte1val (AUClast), and if data pennit, area 
under the plasma concentration versus time cmve from time 0 extrapolated to infinity 
(AUCinf), tenninal elimination half life (tl/2), apparent oral plasma clearance (CL/F), 
apparent volume of distribution (Vz/F). 
PK parameters will be calculated from the PK concentration-time data using standard non 
compaiimental methods: 


Protocol C3661001 (PF 06873600) 
Statistical Analysis Plan 
Page 29 of 42 
 
 
 
Parameter 
Method of Determination 
C.,.,.. Cmax ss C ,n ss 
Observed directly from data 
AUC1as1 AUC. ss 
Linear/log trapezoidal method 
AUCint 
AUC1as1+ (C1as1*1ke1), 
where C1as1* is the predicted concentration at the last quantifiable time point 
estimated from the log-linear regression analysis, and ke1 is the terminal phase rate 
constant calculated by a linear regression of the log-linear concentration-time 
curve. For the determination ofke1, only those data values that are consistent with 
the terminal log-linear phase of the log transformed concentration-time curve will 
be included. The tenninal log-linear phase will be determined from a minimum of 
3 concentration-time data points, and will be verified with the r2 value. 
Tmax 
Observed directly from data. 
CLIP 
Dose I AUCinf 
CLsslF 
Dose I AUC"s 
t½" 
ln21ke1 
VJP 
Dose/ (AUCinrkei) 
v.p• 
Dose/(AUC.·k.1) 
Rae 
AUc.lAUC1as1 
• if data pemut 
 
The actual time of sample collection will be used in PK parameter calculation. In the event 
that the actual sampling time is not available, the nominal time may be used if there is no 
evidence that the actual sampling time deviates substantially from the nominal time. 
The single dose and steady state PK parameters will be summarized descriptively (n, mean, 
standard deviation, CV, median, minimum, maximum, geometi·ic mean and its associated 
CV) by dose, cycle and day. 
Pharmacokinetic/Pharmacodynamic (PK/PD) Correlation 
PK and PD data from this study may be analyzed using modeling approaches and may also 
be pooled with data from other studies to investigate any association between PF-06873600 
exposure and biomarkers or significant safety endpoints. The results of these analyses, if 
peifonned, may be reported separately. 
9.2.2.3. Biomarker Analyses 
Level of pha1macodynamic (PD) markers, pRb and Ki67 from each dose will be analyzed at 
two time points, at screening and at cycle 2 day 1 of each patient. Percent changes of 
biomarkers at Cycle 2 Day 1 from Screening (baseline) will be calculated and summarized; 
actual biomarker levels will be listed by visit. 
Summruy statistics for percentage change from baseline of biomru·ker level may include 
geometi-ic mean, 95% confidence interval, median, and minimum/maximum. Other 
explorato1y biomru·kers analyzed with the remaining tumor specimens will be described in 
the biomarker Statistical Analysis Plan (bSAP). 


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9.2.3. Safety Analyses 
9.2.3.1. Adverse Events 
Adverse Events (Aes) will be graded by the investigator according to the CTCAE version 
4.03 and coded using the Med.ORA. The focus of AE summaries will be on Treatment 
Emergent Adverse Events, those with initial onset or increasing in severity after the first dose 
of study treatment. The number and percentage of patients who experienced any AE, serious 
AE (SAE), treatment related AE, treatment related SAE, and any AEs leading to dose 
intenuptions, dose reductions, chug discontinuations, and/or death will be summarized 
according to worst toxicity grades. The summaries will present AEs based on the entire 
study period (all cycles). The Safety Analysis Set will be used. 
9.2.3.2. Laboratory Tests Abnormalities 
The number and percentage of patients who experienced laborato1y test abnonnalities will be 
summarized according to worst toxicity grade observed for each laborato1y test. The 
analyses will summarize laborato1y tests based on the entire study period (all cycles). Shift 
tables will be provided to examine the distribution of laborato1y abnonnalities, and worst on­ 
study abnonnalities will be summarized. The Safety Analysis Set will be used. 
For laborato1y tests without CTC grade definitions, results will be categorized as nonnal, 
abnonnal high/low or not done. 
9.2.3.3. Vital Signs 
Vital signs data will be presented as summaries for change from baseline and as categorical 
summaries for absolute value, decrease and increase from baseline. The Safety Analysis Set 
will be used. 
9.2.3.4. Electrocardiogram 
The analysis of ECG results will be based on patients in the safety analysis set with baseline 
and on-treatment ECG data. 
ECG measurements (an average of the triplicate measurements) will be used for the 
statistical analysis and all data presentations. Any data obtained from ECGs repeated for 
safety reasons after the nominal time-points will not be averaged along with the preceding 
triplicates. Interval measurements from repeated ECGs will be included in the outlier 
analysis (categorical analysis) as individual values obtained at unscheduled time points. 
QT intervals will be corrected for hea1t rate (QTc) using standard correction factors (ie, 
Fridericia's and possibly a study specific factor). Data will be summarized and listed for QT, 
HR, RR, PR, QRS, QTcF and QTcB by treatment and dose. fudividual QTc (QTcF and 
QTcB) intervals will be listed by compound, time and dose. Descriptive statistics (n, mean, 
median, standard deviation, minimum, and maximum) will be used to summarize the 
absolute QTcF value and changes from baseline in QTcF after treatment by compound, dose 
and by time point. For each patient and by treatment, the maximum change from baseline 


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will be calculated as well as the maximum post-baseline value across time-points. 
Categorical outlier analysis of the QTcF data will be conducted and summarized as follows: 
• 
The number of patients with maximum change from baseline in 30ms < QTcF 
60 
ms, QTcF > 60 ms. 
• 
The number of patients with maximum post-dose (post-baseline) 450ms 
QTcF 
480 ms, 481 
QTcF 
500 ms and QTcF 
501 ms. 
fu addition, the number of patients with coITected and uncoITected QT values501 msec will 
be summarized. 
 
Shift tables will be provided for baseline vs worst on treatment corrected QT (one or more 
correction methods will be used) using maximum CTCAE (version 4.03) Grade. Shift tables 
will also be provided for ECG abnormality at baseline vs on treatment (yes, no, not done: 
(n, %)). Patients experiencing clinically relevant morphological ECG changes will be 
summarized (includingfrequency and percentage). 
If more than one ECG is collected at a nominal time post dose (for example, ti·iplicate 
ECGs), the mean of the replicate measurements will be used to represent a single observation 
at that time point. If any of the three individual ECG tracings has a QTcF value501 msec, 
but the mean of the ti·iplicates is no5
t 01 msec, the data from the subject's individual tracing 
will be described in a safety section of the study report in order to place the501 msec value 
in appropriate clinical context. However, values from individual tracings within ti·iplicate 
measurements that are500 msec will not be included in the categorical analysis unless the 
average from those u-iplicate measurements is also500 msec. Changes from baseline will be 
defined as the change between QTcF post dose from Day 0, or the pre-dose values on Day 1. 
 
The effect of chug concenti·ations on QTcF change from baseline will be explored 
graphically. fu addition, an attempt will be made to explore and characterize the relationship 
between plasma concentration and QTcF interval length using a PK/PD modeling approach. 
If a PK/PD relationship is found, the impact of subject factors (covariates) on the relationship 
will be examined. 
Patients experiencing clinically-relevant morphological ECG changes will be summarized 
(including frequency and percentage). 
Changes from baseline for the ECG parameters QT interval, heali rate (HR), QTc interval, 
PR interval and QRS interval will be summarized by coho1t and timepoint. Categorical data 
analysis will follow Appendix 1. 
9.2.4. Standard Analyses 
Study Conduct and Patient Disposition 
An accounting of the study patients will be tabulated. The subject evaluation groups will be 
listed. The Full Analysis Set will be used. 


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Patient discontinuation from ti·eatment and study will be tabulated and listed separately with 
their reason for discontinuation. The Safety Analysis Set will be used. 
Baseline Characteristics 
Baseline characteristics such as demographics, prior medication, medical histo1y, ECOG 
peifonnance status, HER2 status, and prima1y diagnosis will be tabulated and listed. For 
ECOG perfo1mance status a shift table (worst post-baseline vs baseline may be produced). 
The Safety Analysis Set will be used. 
Treatment Administration/Compliance 
Listings and tables by dose level will be provided. Cycle length is 28 days. Day 1 of a cycle 
is the first date of dose within that cycle. The safety analysis set will be used. 
Dose modifications may occur in the following ways: 
 
• 
Cycle delay-Day 1 of cmTent cycle staiis later than 28+3 days from Day 1 of the 
previous cycle (only applies to cycle 2 and above); 
 
• 
Dose reduction-A decrease in the administered total daily dose (non-zero) compai·ed to 
the planned total daily dose upon enrollment. 
fun-a-patient dose escalation is not allowed in this study. The following will be smrunai·ized 
by patient for each dose level: 
 
• 
Number of subjects per dose level 
• 
Median and range of number of cycles staiied per subject 
• 
Number(%) of subjects staiiing a cycle (1, 2, 3... ) 
• 
Number(%) of subjects with cycle delays 
• 
Number (%) of dose inte1n1ptions (include both known and unknown dates) 
• 
Number(%) of subjects with dose reductions 
• 
Number (%) of each reason (AE vs. Other) for cycle delays, dose intenuptions and 
dose reductions 
• 
Time on u-eatinent (median, range) 
 
The following will be smmnai·ized by cycle received for each dose level: 
 
• 
Total number of cycles staiied 
• 
Number of cycles staiied per subject (median, range) 
• 
Number of cycles before 1st delay (median, range) 
• 
Number of cycles before 1st reduction (median, range) 
• 
Number of cycles before 1st inte1n1ption (median, range) 
 
The following will be smmnai·ized for cumulative dose by dose level and cycle: 


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• 
 Summruy statistics (mean, median, standru·d deviation and range) of cumulative dose 
and percent of staiiing dose (compai·ed to Day 1 dose of each cycle) 
 
Listings by patient (ordered by dose level): staii date and stop date of each dosing period 
within each cycle (including records with 0mg), administered total daily dose for each 
period, any missed doses with unknown dates (yes/no), number of missed doses with 
unknown dates, reason for any dosing changes will be provided. 
Listings by subject and each cycle (ordered by dose level): cycle length, total planned dose, 
administered total dose, percentage of planned dose, dose delay (yes/no), dose reduction 
(yes/no), and dose intenuption (yes/no) will be provided. 
 
Prior, Concomitant, and Further Therapies 
Prior, concomitant, and further therapies (diug and non-diug treatments) will be coded by the 
World Health Organization (WHO) medical dictiona1y. Listings of prior, concomitant, and 
fmther therapies will be provided separately. 
10. REFERENCES 
Brookmeyer R, Crowley JJ. A confidence interval for the median smvival time. Biometrics 
1982; 38:29-41. 
E.A. Eisenhauer, P. Therasseb, J. Bogae1is, L.H. Schwaiiz, D. Sargent, R. Ford, J. Dancey, S. 
Arbuck, S. Gwyther, M. Mooney, L. Rubinstein, L. Shankru·, L. Dodd, R. Kaplan, D. 
Lacombe, J. Ve1weij: New response evaluation criteria in solid tumours: Revised RECIST 
guideline (version 1.1). European Jomnal of Cancer 45 (2009) 228-247 
ICH E14 - The clinical evaluation of QT/QTc inte1val prolongation and proaIThythmic 
potential for non-antianhythmic di11gs. CHMP/ICH/2/04. 
Kaplan EL, Meier P. Nonpai·ametric estimation from incomplete obse1vations. J Am Stat 
Assoc 1958; 53:457-481. 
NCI Common Terminology Criteria for Adverse Events v4.03 (CTCAE). 
https://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03/ 


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11. APPENDICES 
11.1. APPENDIX 1: CATEGORICAL CLASSES FOR ECG AND VITAL SIGNS 
Categories for QTcF 
 
QTcF(ms) 
450< max. <480 
481< max. <500 
max. >501 
QTcF(ms) 
change from 
baseline 
30<max. '.S60 
max. >60 
 
 
Categories for PR and QRS 
 
PR(ms) 
max>300 
PR (ms) increase 
from baseline 
Baseline >200 
and max. 
>25% increase 
Baseline '.S200 and 
max. c:::50% 
mcrease 
ORS (ms) 
max>200 
QRS (ms) 
increase from 
baseline 
Baseline >100 
and max. 
>25% increase 
Baseline '.Sl00 and 
max. c:::50% 
mcrease 
 
Categories for Vital Signs 
 
Svstolic BP (mm Hg) 
min. <90 
Systolic BP (mm Hg) 
change from baseline 
max. decrease c:::30 
max. increase c:::30 
Diastolic BP (mm Hg) 
min. <50 
Diastolic BP (mm Hg) 
change from baseline 
max. decrease c:::20 
max. increase c:::20 
Supine pulse rate (born) 
min. <40 
max. >120 
 
Measurements that fulfil these criteria are to be listed in the study repo1t. 
11.2. APPENDIX 2: RECIST (Response Evaluation Criteria In Solid Tumors) version 
1.1 Guidelines 
Adapted from E.A. Eisenhauer, et al: New response evaluation criteria in solid tumours: 
Revised RECIST guideline (version 1.1). European Journal of Cancer 45 (2009) 228-247 
CATEGORIZING LESIONS AT BASELINE 
Measurable Lesions 
• 
Lesions that can be accurately measured in at least one dimension. 
 
• 
Lesions with longest diameter twice the slice thickness and at least 10 Illill or greater 
when assessed by CT or MRI (slice thickness 5-8 mm). 
 
• 
Lesions with longest diameter at least 20 mm when assessed by Chest X-ray. 


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• 
Superficial lesions with longest diameter 10 rmn or greater when assessed by caliper. 
 
• 
Malignant lymph nodes with the short axis 15 rmn or greater when assessed by CT. 
NOTE: The shortest axis is used as the diameter for malignant lymph nodes, longest axis for 
all other measurable lesions. 
Non-measurable disease 
Non-measurable disease includes lesions too small to be considered measurable (including 
nodes with sho1i axis between 10 and 14.9 rmn) and tiuly non-measurable disease such as 
pleural or pericardia! effusions, ascites, inflarmnato1y breast disease, leptomeningeal disease, 
lymphangitic involvement of skin or lung, clinical lesions that cannot be accurately measured 
with calipers, abdominal masses identified by physical exam that are not measurable by 
reproducible imaging techniques. 
• 
 Bone disease: Bone disease is non-measurable with the exception of soft tissue 
components that can be evaluated by CT or MRI and meet the definition of 
measurability at baseline. 
• 
 Previous local tl'eatinent: A previously inadiated lesion (or lesion subjected to other 
local tl'eatinent) is non-measurable unless it has progressed since completion of 
ti·eatment. 
Normal sites 
 
• 
Cystic lesions: Simple cysts should not be considered as malignant lesions and should 
not be recorded either as target or non-target disease. Cystic lesions thought to 
represent cystic metastases can be measurable lesions, if they meet the specific 
definition above. If non-cystic lesions are also present, these are prefened as target 
lesions. 
• 
Nonnal nodes: Nodes with sho1i axis <10 mm are considered nonnal and should not 
be recorded or followed either as measurable or non-measurable disease. 
Recording Tumor Assessments 
All sites of disease must be assessed at baseline. Baseline assessments should be done as 
close as possible prior to study sta1i. For an adequate baseline assessment, all required scans 
must be done within 28 days prior to randoinization and all disease must be documented 
appropriately. If baseline assessment is inadequate, subsequent statuses generally should be 
non-evaluable. 


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Target Lesions 
All measurable lesions up to a maximum of 2 lesions per organ, 5 lesions in total, 
representative of all involved organs, should be identified as target lesions at baseline. 
Target lesions should be selected on the basis of size (longest lesions) and suitability for 
accurate repeated measurements. Record the longest diameter for each lesion, except in the 
case of pathological lymph nodes for which the short axis should be recorded. The sum of 
the diameters (longest for non-nodal lesions, sho1i axis for nodal lesions) for all target lesions 
at baseline will be the basis for comparison to assessments perf01med on study. 
• 
If two target lesions coalesce the measurement of the coalesced mass is used. If a 
large target lesion splits, the sum of the paiis is used. 
 
• 
 Measurements for tai·get lesions that become small should continue to be recorded. If 
a tai·get lesion becomes too small to measure, 0 mm should be recorded if the lesion is 
considered to have disappeared; othe1wise a default value of 5 mm should be 
recorded. 
NOTE: When nodal lesions decrease to <10 nun (no1mal), the actual measurement should 
still be recorded. 
Non-target Disease 
All non-measurable disease is non-target. All measurable lesions not identified as target 
lesions are also included as non-target disease. Measurements ai·e not required but rather 
assessments will be expressed as CR, Non-CR/Non-PD, PD, Non-evaluable (NE). Multiple 
non-tai·get lesions in one organ may be recorded as a single item on the case repo1i fo1m 
(eg, 'multiple enlarged pelvic lymph nodes' or 'multiple liver metastases'). 
OBJECTIVE RESPONSE STATUS AT EACH EVALUATION 
Disease sites must be assessed using the same technique as baseline, including consistent 
administration of contrast and timing of scanning. If a change needs to be made the case 
must be discussed with the radiologist to detennine if substitution is possible. If not, 
subsequent objective statuses might be non-evaluable. 
Target Disease 
1. Complete Response (CR): Complete disappearance of all target lesions with the 
exception of nodal disease. All tai·get nodes must decrease to n01mal size (sho1i axis 
<10 mm). All tai·get lesions must be assessed. 
2.  Paiiial Response (PR): Greater than or equal to 30% decrease under baseline of the sum 
of diameters of all target measurable lesions. The sho1i diameter is used in the sum for 
tai·get nodes, while the longest diameter is used in the sum for all other tai·get lesions. All 
tai·get lesions must be assessed. 


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3. Stable: Does not qualify for CR, PR or Progression. All target lesions must be assessed. 
Stable can follow PR only in the rare case that the sum increases by less than 20% from 
the nadir, but enough that a previously documented 30% decrease no longer holds. 
4. Objective Progression (PD): 20% increase in the sum of diameters of target measurable 
lesions above the smallest sum observed (over baseline if no decrease in the sum is 
observed during therapy), with a minimum absolute increase of 5 mm. 
5. Non-evaluable (NE): Progression has not been documented, and 
 
• 
One or more target measurable lesions have not been assessed; or 
 
• 
One or more target lesions cannot be measured accurately (eg, poorly visible unless 
due to being too small to measure); or 
• 
One or more target lesions were excised or i1rndiated. 
Non-target disease 
6. CR: Disappearance of all non-target lesions and n01malization of tumor marker levels. 
All lymph nodes must be 'nonnal' in size (<10 mm sho1i axis). 
7. Non-CR/Non-PD: Persistence of any non-target lesions and/or tumor marker level above 
the nonnal limits. 
8. PD: Unequivocal progression of pre-existing lesions. Generally the overall tumor burden 
must increase sufficiently to merit discontinuation of therapy. fu the presence of SD or 
PR in target disease, progression due to unequivocal increase in non-target disease should 
be rare. 
9. NE: Progression has not been dete1mined and one or more non-target sites were not 
assessed or assessment methods were inconsistent with those used at baseline. 
New Lesions 
The appearance of any new unequivocal malignant lesion indicates PD. If a new lesion is 
equivocal, for example due to its small size, continued assessment will clarify the etiology. 
If repeat assessments confnm the lesion, then progression should be recorded on the date of 
the initial assessment. A lesion identified in an area not previously scanned will be 
considered a new lesion. 
Supplemental Investigations 
 
• 
 If CR dete1mination depends on a residual lesion that decreased in size but did not 
disappear completely, it is recommended the residual lesion be investigated with 
biopsy or fine needle aspirate. If no disease is identified, objective status is CR. 


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• 
 If progression detennination depends on a lesion with an increase possibly due to 
necrosis, the lesion may be investigated with biopsy or fine needle aspirate to clarify 
status. 
Subjective Progression 
Patients requiring discontinuation of treatment without objective evidence of disease 
progression should not be repo1ied as PD on tumor assessment CRFs. This should be 
indicated on the end of treatment CRF as off treatment due to Global Deterioration of Health 
Status. Eve1y effo1i should be made to document objective progression even after 
discontinuation of treatment. 
Table 4 Objective Response Status at each Evaluation 
 
Tarn:et Lesions 
Non-tarn:et Disease 
New Lesions 
Obiective status 
CR 
CR 
No 
CR 
CR 
Non-CR/Non-PD 
No 
PR 
CR 
NE or Missing 
No 
PR 
PR 
Non-CR/Non-PD, NE or 
Missing 
No 
PR 
SD 
Non-CR/Non-PD, NE or 
Missing 
No 
Stable 
NE or Missing 
Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
If the protocol allows enrollment of patients with only non-target disease, the following table 
will be used: 
Table 5 Objective Response Status at each Evaluation for Patients with Non-Target Disease Only 
 
Non-target Disease 
New Lesions 
Objective status 
CR 
No 
CR 
Non-CR/Non-PD 
No 
Non-CR/Non-PD 
NE 
No 
NE 
Unequivocal progression 
Yes or No 
PD 
Any 
Yes 
PD 
Best Overall Response 
The best overall response (BOR) is the best response recorded from the randomization until 
disease progression or death due to any cause. This is derived from the sequence of objective 


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statuses. Objective statuses are not considered after objective progression is documented or 
after sta1t of the first anticancer treatment post discontinuation of protocol treatment. BOR 
for each patient will be derived as one of the following categories. 
• 
Complete response (CR): At least one objective status of CR documented before 
progress10n. 
 
• 
 Partial response (PR): At least one objective status of PR documented before 
progress10n. 
 
• 
Stable disease (SD): At least one objective status of stable documented at least 
8 weeks after randomization date and before progression but not qualifying as CR, 
PR. 
• 
Progressive Disease (PD): Objective status of progression within 16 weeks of 
randomization, not qualifying as CR, PR or SD. 
• 
Non-evaluable (NE): Progression not documented within 16 weeks after 
randomization and no other response catego1y applies. 


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Appendix 1. List of High Risk Medications for QTc Prolongation 
 
Adapted from: 
https://cpnp.org/sites/default/files/shared/2013/QTc_Prolongation_Med_Managment_Guideli   
ne.doc Regions Guidelines for Managing Medications and QTc prolongation. 


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11.3. APPENDIX 3: CENSORING DETAILS 
Table 6 Progression Free SU1vival and Dmation of Response 
 
Situation 
Date of Progression/Censoring1 
Outcome 
Inadeauate baseline assessment 
Sta1t date (ClDl) 
Censored 
No on-studv assessments 
Sta1t date (ClDl) 
Censored 
Alive, on treatment2 and no 
Progression 
Date oflast objective tumor assessment 
Censored 
Progression Documented on or 
betv.•een scheduled tumor assessments 
prior to treatment discontinuation2 
Date of first objective tumor assessment 
showing objective progression 
Progressed (Event) 
Treatment discontinuation for 
undocumented progression 
Date oflast objective tumor assessment 
prior to discontinuation2 
Censored 
Treatment discontinuation due to 
toxicity or other reason 
Date oflast objective tumor assessment 
prior to discontinuation2 
Censored 
Death prior to first planned tumor 
assessment 
Date of death 
Death (Event) 
Death without objective progression 
prior to treatment discontinuation2 
Date of death 
Death (Event) 
Death or progression after 2 or more 
missed tumor assessments 
Date oflast objective tumor assessment 
prior to the event 
Censored 
Ongoing at time of study tel'lllination 
by sponsor 
Date of study tennination 
Censored 
1: For date of censorship, if a tumor assessment takes place over a number of days (eg, superficial lesions one 
day, scans another), the last date is used as the assessment date. 
2: or within 28 days of discontinuation of treatment. 
 
Table 7 Time to Progression 
 
Situation 
Date of Progression/Censoring1 
Outcome 
Inadeauate baseline assessment 
Sta1t date (ClDl) 
Censored 
No on-study assessments 
Sta1t date (ClDl) 
Censored 
Alive, on treatment2 and no 
Progression 
Date oflast objective tumor assessment 
Censored 
Progression Documented on or 
betv.re.en scheduled tumor assessments 
prior to treatment discontinuation2 
Date of first objective tumor assessment 
showing objective progression 
Progressed (Event) 
Treatment discontinuation for 
undocumented progression 
Date oflast objective tumor assessment 
prior to discontinuation2 
Censored 
Treatment discontinuation due to 
toxicitv or other reason 
Date oflast objective tumor assessment 
prior to discontinuation2 
Censored 
New anticancer treatment <28 days 
after discontinuation of treatment 
without progression 
Date oflast objective tumor assessment 
prior to new anticancer treatment 
Censored 
Death prior to first planned tumor 
assessment 
Sta1t date (ClDl) 
Censored 
Death without objective progression 
prior to treatment discontinuation2 
Date oflast objective tumor assessment 
prior to death 
Censored 
Progression after 2 or more missed 
Date oflast obiective tumor assessment 
Censored 


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tumor assessments 
orior to the event 
Ongoing at time of study termination 
by sponsor 
Date of study tennination 
Censored 
1: For censoring date, if a tumor assessment takes place over a number of days (eg, superficial lesions one day, 
scans another), the last date is used as the assessment date. 
2: or within 28 days of discontinuation of treatment.