Clinical trial NCT02907918
Conditions: Breast Cancer Cancer of Breast Breast Carcinoma
Sponsor: Washington University School of Medicine
Start date: 2017-06-30; Completion date: 2020-09-23
Enrollment: 26 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The investigators propose to influence estrogen receptor (ER) signaling by combining endocrine therapy with CDK4/6 inhibition along with trastuzumab in ER+/ human epidermal growth factor receptor 2 (HER2)+ early stage breast cancer.

Detailed description:

Arms: arm 1: * Neoadjuvant palbociclib + letrozole (plus goserelin if premenopausal) + trastuzumab for a total of 16 weeks, consisting of (4) 28-day cycles
* Definitive surgery will be performed preferably within 6 weeks after the end of Cycle 4. Letrozole and trastuzumab will continue until the day of surgery. Letrozole will continue to be taken daily and trastuzumab will be given every 3 weeks per standard of care guidelines. Adjuvant therapy following definitive surgery will be at the discretion of the treating physician
Interventions: intervention 1: Palbociclib intervention 2: Letrozole intervention 3: Trastuzumab intervention 4: Goserelin intervention 5: Breast surgery intervention 6: Research tumor biopsy intervention 7: Research bone marrow (OPTIONAL) intervention 8: Research blood sample intervention 9: Research blood for germline DNA intervention 10: Blood for detection of circulating tumor cells
Intervention descriptions: intervention 1: Palbociclib is an oral drug given at a dose of 125 mg daily on Days 1-21 of each 28-day cycle for a total of 4 cycles. intervention 2: Letrozole is an oral drug given at a dose of 2.5 mg orally once a day. It will be taken continuously (Days 1-28 of each cycle) until the day of definitive surgery. intervention 3: * Or FDA approved biosimilar
* Trastuzumab will be administered on a weekly basis for 16 weeks (on Days 1, 8, 15, and 22 of each 28-day cycle for a total of 4 cycles). The first dose of trastuzumab on Cycle 1 Day 1 will be a loading dose of 4 mg/kg IVPB over 90 minutes. Subsequent doses of trastuzumab will be 2 mg/kg IVPB over 30 minutes. Weekly trastuzumab will continue after the completion of Cycle 4 of palbociclib until surgery. intervention 4: Goserelin is given subcutaneously at a dose of 3.6 mg on Day 1 of each cycle. Goserelin will be continued (once every 28-days) after the completion of Cycle 4 of palbociclib if required. intervention 5: Standard of care intervention 6: Baseline, cycle 1 day 15, and surgery intervention 7: Baseline and surgery intervention 8: Baseline, cycle 1 day 15, surgery, and yearly post-surgery for 5 years intervention 9: Baseline intervention 10: Baseline

Protocol documents:
Prot_SAP_000.pdf: 
 
 
Protocol Version: 11/13/2020, Amendment 6 
 
Page 1 of 75 
 
 
A Phase II Neoadjuvant Study of Palbociclib in Combination with Letrozole and Trastuzumab as 
Neoadjuvant Treatment of Stage II-III ER+ HER2+ Breast Cancer (PALTAN) 
 
Washington University School of Medicine, Division of Oncology 
660 South Euclid Avenue, Campus Box 8056, St. Louis, MO  63110 
 
Protocol #: 201610019 
Version Date:  11/13/2020 
 
Coordinating Center:  
Washington University School of Medicine 
 
Principal Investigator:  
Foluso O. Ademuyiwa, M.D., MPH 
Phone:  (314) 454-8313 // E-mail:  bisiademuyiwa@wustl.edu  
 
Correlative Science: 
 
Cynthia X. Ma, M.D., Ph.D., Washington University 
 
 
 
 
Rebecca L. Aft, M.D., Ph.D., Washington University 
 
Sub-Investigators 
 
Institution 
 
 
Modality 
Ron Bose, M.D., Ph.D. 
 
Washington University 
 
Medical Oncology 
Katherine Clifton, M.D. 
 
Washington University 
 
Medical Oncology 
Amy Cyr, M.D.  
 
Washington University 
 
Surgery 
Andrew Davis, M.D. 
 
Washington University 
 
Medical Oncology 
Timothy Eberlein, M.D. 
 
Washington University 
 
Surgery 
Ashley Frith, M.D. 
 
Washington University 
 
Medical Oncology 
Will Gillanders, M.D. 
 
Washington University 
 
Surgery 
Ian Hagemann, M.D., Ph.D. 
Washington University 
 
Pathology 
Leonel Hernandez Aya, M.D. 
Washington University 
 
Medical Oncology 
Jingqin (Rosy) Luo, Ph.D.  
Washington University 
 
Biostatistics 
Peter Oppelt, M.D. 
 
Washington University 
 
Medical Oncology 
Mateusz Opyrchal, M.D., Ph.D. 
Washington University 
 
Medical Oncology 
Haeseong Park, M.D. 
 
Washington University 
 
Medical Oncology 
Lindsey Peterson, M.D. 
 
Washington University 
 
Medical Oncology 
Caron Rigden, M.D. 
 
Washington University 
 
Medical Oncology 
Souzan Sanati, M.D. 
 
Washington University 
 
Pathology 
Rama Suresh, M.D. 
 
Washington University 
 
Medical Oncology 
R. Reid Townsend, M.D., Ph.D. 
Washington University 
 
Proteomics 
Nusayba Bagegni, M.D. 
 
Washington University 
 
Medical Oncology 
Ellis Levine, M.D. 
 
Roswell Park 
 
 
Medical Oncology 
Donald Northfelt, M.D. 
 
Mayo Clinic – Arizona 
 
Medical Oncology 
 
Study Drug(s):  
 
Palbociclib (Ibrance) 
Letrozole (Femara) 
Trastuzumab (Herceptin) 
 
IND #:  
 
132365 EXEMPT  
ClinicalTrials.gov #: 
NCT02907918 
 
 
 


 
 
Protocol Version: 11/13/2020, Amendment 6 
 
Page 2 of 75 
CONFIDENTIAL 
The information contained in this document is regarded as confidential and, except to the extent necessary to obtain 
informed consent, may not be disclosed to another party unless law or regulations require such disclosure.  Persons to 
whom the information is disclosed must be informed that the information is confidential and may not be further disclosed 
by them 


 
 
Protocol Version: 11/13/2020, Amendment 6 
 
Page 3 of 75 
A Phase II Neoadjuvant Study of Palbociclib in Combination with Letrozole and 
Trastuzumab as Neoadjuvant Treatment of Stage II-III ER+ HER2+ Breast Cancer 
(PALTAN) 
 
 
Protocol Revision History 
 
Initial Approval Version 
 
 
 
 
 
 
12/23/16 
Amendment #1 Version 
 
 
 
 
 
 
03/10/17 
Amendment #2 Version 
 
 
 
 
 
 
09/20/17 
Amendment #3 Version 
 
 
 
 
 
 
11/07/17 
Amendment #4 Version 
 
 
 
 
 
 
08/09/18 
Amendment #5 Version 
 
 
 
 
 
 
10/25/19 
Amendment #6 Version 
 
 
 
 
 
 
11/13/2020 
 
 
 
 


 
 
Protocol Version: 11/13/2020, Amendment 6 
 
Page 4 of 75 
A Phase II Neoadjuvant Study of Palbociclib in Combination with Letrozole and 
Trastuzumab as Neoadjuvant Treatment of Stage II-III ER+ HER2+ Breast Cancer 
(PALTAN) 
 
Principal Investigator Signature Page 
 
 
Principal Investigator 
(printed): 
      
Name of Institution:       
  
 PI Signature 
 
 
 
 
 
Date 
 
By my signature, I agree to personally supervise the conduct of this study 
and to ensure its conduct in compliance with the protocol, informed 
consent, IRB/HRPO procedures, the Declaration of Helsinki, ICH Good 
Clinical Practices guidelines, and the applicable parts of the United 
States Code of Federal Regulations or local regulations governing the 
conduct of clinical studies. 
 
 
 
 


 
 
Protocol Version: 11/13/2020, Amendment 6 
 
Page 5 of 75 
A Phase II Neoadjuvant Study of Palbociclib in Combination with Letrozole and 
Trastuzumab as Neoadjuvant Treatment of Stage II-III ER+ HER2+ Breast Cancer 
(PALTAN) 
 
 
SCHEMA 
 
 
Surgery  
(6 weeks post-Cycle 4 Day 21) 
 
Evaluation for pathologic response 
Research tumor for molecular analysis 
OPTIONAL bone marrow biopsy 
Adjuvant treatment per MD discretion 
 
Eligible Patients: 
 Clinical Stage II or III ER+/HER2+ Breast Cancer, staging criteria is 
to be based on AJCC 7  
Treatment Plan: 
Neoadjuvant Palbociclib PO daily (days 1-21 of a 4 week cycle), Letrozole PO daily,  
Trastuzumab (or FDA approved biosimilar) every week x 16 weeks 
(Letrozole dosing will continue until surgery, Trastuzumab will be given every 3 
weeks after 16 week completion)   
If premenopausal: add LHRH Agonist SC every 4 weeks (Day 1 of each cycle) 
 
Research tumor biopsy for molecular analysis (Cycle 1 Day 15) 
Research tumor biopsy for molecular analysis 
OPTIONAL bone marrow biopsy 


 
 
Protocol Version: 11/13/2020, Amendment 6 
 
Page 6 of 75 
Glossary of Abbreviations 
 
AE 
Adverse event 
ALT (SGPT) 
Alanine transaminase (serum glutamate pyruvic transaminase) 
ANC 
Absolute neutrophil count 
AST (SGOT) 
Aspartate transaminase (serum glutamic oxaloacetic transaminase) 
AUC 
Area under the curve 
B-HCG 
Beta human chorionic gonadotropin  
BC 
Breast cancer 
BM 
Bone marrow 
BWFI 
Bacteriostatic water for injection 
CBC 
Complete blood count 
CFR 
Code of Federal Regulations 
CHF 
Congestive heart failure 
CR 
Complete response 
CRF 
Case report form 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTEP 
Cancer Therapy Evaluation Program 
DNA 
deoxyribonucleic acid 
DSM 
Data and Safety Monitoring  
DSMC 
Data Safety Monitoring Committee 
DTC 
Disseminated tumor cell 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EDTA 
ethylenediaminetetraacetic acid 
ER 
Estrogen receptor 
FDA 
Food and Drug Administration 
FFPE 
Formalin-fixed paraffin-embedded 
FSH 
Follicle stimulating hormone 
FWA 
Federal wide assurance 
GCP 
Good Clinical Practice 
GnRH 
Gonadotropin releasing hormone 
HHS 
Department of Health and Human Services 
HIV 
Human Immunodeficiency Virus 
HR 
Hormone receptor 
HRPO 
Human Research Protection Office (IRB) 
IB 
Investigator brochure 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
IULN 
Institutional upper limit of normal 
IV 
Intravenous 
IVPB 
IV piggyback 


 
 
Protocol Version: 11/13/2020, Amendment 6 
 
Page 7 of 75 
LH 
Luteinizing hormone 
LVEF 
Left ventricular ejection fraction 
NC 
No change 
NCI 
National Cancer Institute 
NIH 
National Institutes of Health 
OCT 
Optimum cutting temperature 
OHRP 
Office of Human Research Protections  
pCR 
Pathologic complete response 
PD 
Progressive disease 
PFS 
Progression-free survival 
PI 
Principal investigator 
PO 
Per os (by mouth) 
PR 
Partial response 
QASMC 
Quality Assurance and Safety Monitoring Committee 
QD 
Quaque die (one a day) 
RNA 
Ribonucleic acid 
SAE 
Serious adverse event 
SC 
Subcutaneous 
SCC 
Siteman Cancer Center 
SWFI 
Sterile water for injection 
TTP 
Time to progression 
UPN 
Unique patient number 
WHO 
World Health Organization 
WUSM 
Washington University School of Medicine 
 
 


 
 
Protocol Version: 11/13/2020, Amendment 6 
 
Page 8 of 75 
Table of Contents 
SCHEMA ...................................................................................................................................... 5 
1.0 
BACKGROUND AND RATIONALE .......................................................................... 10 
1.1 
HER2 Positive Breast Cancer ............................................................................... 10 
1.2 
Palbociclib ................................................................................................................... 11 
1.3 
Letrozole ...................................................................................................................... 15 
1.4 
Trastuzumab .............................................................................................................. 15 
1.5 
Safety Data ................................................................................................................. 16 
1.6 
Correlative Studies Background .......................................................................... 16 
2.0 
OBJECTIVES ................................................................................................................. 17 
2.1 
Primary Objective ..................................................................................................... 17 
2.2 
Secondary Objective ................................................................................................ 17 
2.3 
Exploratory Objectives ............................................................................................ 17 
3.0 
PATIENT SELECTION ................................................................................................. 17 
3.1 
Inclusion Criteria ...................................................................................................... 17 
3.2 
Exclusion Criteria .................................................................................................... 18 
3.3 
Inclusion of Women and Minorities ................................................................... 19 
4.0 
REGISTRATION PROCEDURES .............................................................................. 19 
4.1 
Confirmation of Patient Eligibility ....................................................................... 19 
4.2 
Patient Registration in the Siteman Cancer Center OnCore Database .. 20 
4.3 
Assignment of UPN .................................................................................................. 20 
5.0 
TREATMENT PLAN ...................................................................................................... 20 
5.1 
Premedications .......................................................................................................... 21 
5.2 
Agent Administration .............................................................................................. 21 
5.3 
Post Surgery Therapy .............................................................................................. 22 
5.4 
Toxicity and Response Evaluations .................................................................... 22 
5.5 
Patient Reported Outcomes .................................................................................. 22 
5.6 
General Concomitant Medication and Supportive Care Guidelines ........ 22 
5.7 
Women of Childbearing Potential ........................................................................ 22 
5.8 
Duration of Therapy ................................................................................................ 23 
5.9 
Duration of Follow-up ............................................................................................. 24 
6.0 
DOSE DELAYS/DOSE MODIFICATIONS ............................................................. 24 
6.1 
Re-Treatment Criteria ............................................................................................. 24 
6.2 
Dose Modifications for Palbociclib ...................................................................... 24 
6.3 
Dose Modifications for Trastuzumab (or FDA Approved Biosimilar) ....... 26 
6.4 
Dose Modifications for Letrozole .......................................................................... 28 
7.0 
REGULATORY AND REPORTING REQUIREMENTS ........................................ 28 
7.1 
WU PI Reporting Requirements ........................................................................... 28 
7.2 
Secondary Sites Reporting Requirements ........................................................ 31 
7.3 
Exceptions to Expedited Reporting ............................................................... 31 
8.0 
PHARMACEUTICAL INFORMATION ...................................................................... 32 
8.1 
Palbociclib (Ibrance) ................................................................................................ 32 
8.2 
Trastuzumab (Herceptin) ....................................................................................... 39 
8.3 
Letrozole (Femara) .................................................................................................... 41 
8.4 
Goserelin (Zoladex) ................................................................................................... 42 
8.5 
Lupron (Leuprolide) ................................................................................................. 43 


 
 
Protocol Version: 11/13/2020, Amendment 6 
 
Page 9 of 75 
9.0 
CORRELATIVE STUDIES .......................................................................................... 44 
9.1 
Archival Tumor Sample Submission .................................................................. 44 
9.2 
Tumor Biopsy and Peripheral Blood Collection ............................................. 44 
9.3 
OPTIONAL Bone Marrow Biopsy ......................................................................... 47 
10.0 STUDY CALENDAR...................................................................................................... 49 
11.0 DATA SUBMISSION SCHEDULE ............................................................................ 51 
11.1 Adverse Event Collection in the Case Report Forms .................................... 51 
12.0 MEASUREMENT OF EFFECT .................................................................................. 51 
12.1 Neoadjuvant Treatment .......................................................................................... 51 
12.2 Treatment Resistance ............................................................................................. 52 
12.3 Surgery ......................................................................................................................... 52 
12.4 Post-surgery ............................................................................................................... 52 
13.0 DATA AND SAFETY MONITORING ......................................................................... 53 
14.0 AUDITING ....................................................................................................................... 54 
15.0 STATISTICAL CONSIDERATIONS ........................................................................... 55 
15.1 Sample Size Calculation ......................................................................................... 55 
15.2 Data Analysis Plan ................................................................................................... 55 
15.3 Early Stopping Rule ................................................................................................. 56 
15.4 Accrual Strategy ........................................................................................................ 57 
16.0 MULTICENTER REGULATORY REQUIREMENTS ............................................. 57 
17.0 REFERENCES ............................................................................................................... 59 
APPENDIX A: ECOG Performance Status Scale ........................................................... 61 
APPENDIX B: Strong CYP3A4 Inhibitors or Inducers ................................................. 62 
APPENDIX C: Pfizer Reportable Event Cover Sheet ..................................................... 63 
APPENDIX D: PALBOCICLIB MEDICATION DIARY ..................................................... 64 
APPENDIX E: LETROZOLE MEDICATION DIARY ........................................................ 65 
APPENDIX F: NCI PRO-CTCAE QUESTIONNAIRE....................................................... 66 
APPENDIX G: ARCHIVAL TUMOR SPECIMEN SUBMISSION FORM .................... 68 
APPENDIX H: Definitions for Adverse Event Reporting ............................................. 69 
APPENDIX I: Reporting Timelines ..................................................................................... 71 
APPENDIX J: Washington University SAE Reporting Cover Sheet......................... 75 
  
 


 
 
Protocol Version: 11/13/2020, Amendment 6 
 
Page 10 of 75 
1.0 
BACKGROUND AND RATIONALE 
 
1.1 
HER2 Positive Breast Cancer 
 
Breast cancer (BC) is the most common invasive cancer in women, with more than one 
million cases and over 411,000 deaths annually worldwide. Breast cancer is genetically 
heterogeneous and biologically diverse and is no longer considered a single disease. The 
long recognized clinical and phenotypic differences have been shown to correlate with 
differences at the gene expression level.1,2 Five distinct molecular subtypes of BC are 
defined by hierarchical cluster analyses of array gene expression data and include luminal 
A, luminal B, HER2 amplified, basal-like and normal-like.3 20-25% of BC diagnoses are 
characterized by HER2 gene amplification or overexpression.4-6 HER2 signaling drives 
cell proliferation and inhibits apoptosis in HER2+ BC.4,6,7 Incorporating HER2-directed 
therapies is essential for the treatment of patients with HER2+ BC. However, despite 
available treatment options, over 10-20% of patients with HER2+ BC relapse with distant 
metastasis.   
 
Approximately 50% of HER2+ BC is hormone receptor (HR) positive, a population that 
comprises about 10% of all BC patients.8 Unlike the HR-/HER2+ tumors, which are HER2-
E by molecular subtyping, HR+/HER2+ breast cancer has a high proportion in the luminal 
A and luminal B category.9,10 Although the significance of these molecular features is to 
be further investigated, it is clear from previous neoadjuvant trials that these tumors are 
less likely to achieve a pathologic complete response (pCR) following neoadjuvant 
chemotherapy in combination with HER2 targeted agents, or to dual HER2 blockade.10-12 
In NeoSphere, therapy with neoadjuvant pertuzumab and trastuzumab with docetaxel 
resulted in improved pCR in patients with locally advanced BC.11 However, fewer pCR 
rates were noted in HR+ versus HR- tumors (26.0% versus 63.2%, respectively). Similarly, 
the TRYPHAENA study, assessing both cardiac toxicity and pCR rate in patients with 
HER2+ BC undergoing neoadjuvant pertuzumab and trastuzumab with combinations of 
anthracycline- and non-anthracycline-based chemotherapy, found that the pCR rates were 
higher in patients with HR- tumors compared with HR+ tumors treated with combination 
of pertuzumab and trastuzumab.12 The phase II CALGB 40601 study randomized nearly 
300 patients to receive both trastuzumab and lapatinib, along with paclitaxel (THL), versus 
paclitaxel and trastuzumab (TH), versus paclitaxel and lapatinib (TL).10 The pCR rate was 
similar between the THL and TH groups, 56% versus 46%, respectively (p = 0.13). Once 
again, there was no effect of dual therapy in the HR+ subset but a significant increase in 
pCR with dual therapy in HR- subset (p = 0.01). Furthermore, there was significant 
molecular heterogeneity using mRNA sequencing, with pCR rates significantly differing 
by intrinsic subtype (HER2 enriched, 70%; luminal A, 34%; luminal B, 36%; p< 0.001). 
These findings suggest that HR+/HER2+ tumors may be heavily influenced by ER 
signaling. Given this, it is of utmost importance to optimize selection of HER2 targeted 
treatment by identifying groups of patients not likely to benefit from dual HER2 blockade, 
both to minimize potential toxicities and improve cost-effectiveness. 
 
‘Cross-talk’ between HER2 and ER pathways contributes to resistance to hormonal therapy 
in HR+/HER2+ BC. BC cell lines that are once sensitive to anti-estrogen therapy become 


 
 
Protocol Version: 11/13/2020, Amendment 6 
 
Page 11 of 75 
resistant once transfected with the HER-2/neu gene, suggesting an association between 
HER-2/neu overexpression and estrogen independence.13 Trastuzumab restores tumor 
sensitivity to endocrine therapy also signifying a role for combination therapy compared 
to endocrine therapy alone. TAnDEM, a phase III trial in patients with HER2+/HR+ 
metastatic BC, demonstrated that the addition of trastuzumab to anastrozole improved time 
to disease progression (TTP) and progression free survival (PFS).14 In the eLEcTRA trial, 
median TTP was 3.3 months in the letrozole alone group compared to 14.1 months in the 
letrozole plus trastuzumab group in HR+/HER2+ BC.8 The phase II WSG-ADAPT trial 
assessed efficacy of 12 weeks of neoadjuvant TDM-1 or trastuzumab with endocrine 
therapy in HER2+/HR+ early BC in an attempt to determine responders of dual targeted 
therapy.15 However the pCR rate was only 15.1% following neoadjuvant trastuzumab with 
endocrine therapy. Novel strategies are needed to improve the treatment efficacy for this 
patient population.  
 
Dysregulation of cell cycle checkpoints is common in cancer, including BC. Preclinical 
data suggests that cyclin dependent kinases (CDK4/6) inhibition may play a key role in the 
treatment of subsets of BC. CDK4/6 in complex with cyclin D plays a critical role in G1 
to S phase cell cycle progression through the regulation of the phosphorylation state of 
pRb.16-18 Goel et al. recently reported that BC cells surviving HER2 withdrawal expressed 
high levels of cyclin D1 and CDK4 at time of recurrence in their transgenic mouse model16. 
Knockdown of cyclin D1 increased sensitivity of HER2-resistant cells to HER2 inhibition 
and a combined inhibition of CDK4/6 and HER2 resulted in synergistic reduction in cell 
proliferation in HER2 inhibitor–sensitive cells, thus restoring sensitivity to HER2 
inhibition in previously resistant cells.  
 
We propose to influence ER signaling by combining endocrine therapy with CDK4/6 
inhibition along with trastuzumab in ER+/HER2+ early stage BC. 
 
1.2 
Palbociclib 
 
1.2.1 Mechanism of Action 
 
Palbociclib (PD 0332991) is a highly selective inhibitor of CDK4/cyclin D1 kinase 
activity. PD 0332991 has selectivity for CDK4/6, with little or no activity against 
a large panel of 34 other protein kinases including other CDKs and a wide variety 
of tyrosine and serine/threonine kinases. CDK6, another enzyme that also 
complexes with cyclin-D subunits, is also commonly expressed in mammalian cells 
and tumors. CDK6 is highly homologous to CDK4 and can perform the same 
function by phosphorylating Rb, thus potentially creating a redundant mechanism 
to promote cell cycle progression. Consequently, inhibition of both enzymes is 
necessary to ensure complete suppression of Rb phosphorylation and the greatest 
possible spectrum of antitumor activity. Results indicate that PD 0332991 inhibits 
CDK6 with equivalent potency to CDK4. 
 
 


 
 
Protocol Version: 11/13/2020, Amendment 6 
 
Page 12 of 75 
1.2.2 Non Clinical Studies 
 
In vitro single-agent activity of PD 0332991  
The only known natural substrate for CDK4/cyclinD1 is the retinoblastoma gene 
product (Rb). Specific CDK4 phosphorylation sites on Rb include serine-780 and 
serine-795. Therefore, the phosphorylation status of Rb at these specific sites in 
treated tumors can serve as an appropriate biomarker for target modulation by PD 
0332991. The IC50 for reduction of Rb phosphorylation at serine-780 in the MDA-
MB-435 breast carcinoma cell line was 0.066 μM. PD 0332991 was equally 
effective at reducing Rb phosphorylation at serine-795 in this tumor cell line with 
an IC50 of 0.063 μM. Similar effects on serine-780 and serine-795 Phosphorylation 
were obtained in the Colo-205 colon carcinoma cell line. 
 
PD 0332991 inhibits cellular proliferation and prevents cellular DNA synthesis by 
preventing cells from entering S phase of the cell cycle. PD 0332991 inhibited 
thymidine incorporation into the DNA of a panel of Rb-positive human breast, 
colon, and lung carcinomas, with IC50 values ranging from 0.040 to 0.17 μM. PD 
0332991 was also effective in preventing cell cycle progression in human 
leukemias and in non-transformed human epithelial cells and fibroblasts and was 
equally effective in suppressing cell division in human tumor cell lines. A selective 
CDK4/cyclin D inhibitor should cause a specific accumulation of cells in G1, but 
have no effect on other phases of the cell cycle, in which cells should continue to 
progress and eventually decline in number. MDA-MB-453 breast carcinoma cells 
that were exposed to various concentrations of PD 0332991 for 24 hours show a 
significant increase in the percentage of cells in G1 in the presence of as little as 
0.04 μM PD 0332991 with a concomitant decline in other phases of the cell cycle. 
 
Finally, to provide further evidence of the selectivity of PD 0332991, the compound 
was tested against Rb-negative tumor cells, which should not be sensitive to a 
specific Cdk4 inhibitor. PD 0332991 was tested against the MDA-MB-468 human 
breast carcinoma and the H2009 human non-small cell lung carcinoma, both of 
which have deleted Rb. The compound had no anti-proliferative activity on these 
cells when assayed at 3 μM (highest concentration tested), which is 1 to 2 orders of 
magnitude higher than the concentration necessary to inhibit Rb-positive tumor 
cells. 
 
In Vivo Activity Studies  
PD 0332991-0002 (hydrochloride salt) was used in all in vivo tumor models. 
Additionally, PD 0332991-0054 (isethionate salt) was used in the MDA-MB-435 
breast carcinoma model, and had comparable efficacy to the hydrochloride salt. 
 
The MTD in SCID mice was 150 mg/kg/day when administered orally, once a day, 
for 14 days. The MTD was defined as the highest dose that was nonlethal (<LD10). 
At the MTD on this regimen, PD 0332991 has significant antitumor efficacy against 
multiple human tumor xenograft models. The Colo-205 model is exquisitely 
sensitive to PD 0332991. At doses as low as 12.5 mg/kg, a 13-day growth delay 


 
 
Protocol Version: 11/13/2020, Amendment 6 
 
Page 13 of 75 
was obtained, indicating a 90% inhibition of tumor growth rate. PD 0332991 was 
inactive against the H23 lung and the SW-620 colon carcinomas. The lack of 
response may be associated with the presence of oncogenic K-ras mutations in SW-
620 and H23; none of the xenografts sensitive to PD 0332991 had such mutations. 
 
Further evidence that the anti-tumor activity observed in Rb-positive tumors is due 
to inhibition of CDK4/6 protein kinase activity was obtained by testing PD 0332991 
in the MDA-MB-468 breast carcinoma and the DU-145 prostate tumor models. 
These are Rb negative tumors; neither of which responded to this compound. The 
lack of efficacy in Rb-negative tumors is consistent with the lack of anti-
proliferative activity observed in vitro. Taken together, these results support the 
proposed mechanism of PD 0332991 (inhibition of CDK4/6-mediated Rb 
phosphorylation) and the specificity of the compound demonstrated in enzyme 
activity tests. 
 
Further studies investigated whether continuous daily dosing of PD 0332991 was 
needed for optimal efficacy. Four dosing schedules were employed against the 
MDA-MB-435 breast carcinoma model over 14 days of treatment, including 
continuous daily, every other day, every third day, and 3 courses of 3 days dosing 
followed by 4-day drug holidays. The design of this experiment was such that the 
total compound administered over the 2-week period was identical for each 
treatment schedule. The results show that a similar degree of efficacy was attained 
with all schedules, implying that an intermittent regimen is feasible without 
compromising activity. Similar experiments were conducted against the Colo-205 
colon carcinoma model. Again, intermittent schedules were as efficacious as daily 
dosing, with tumor regressions occurring during all dosing regimens. 
 
During the 14-day treatment period employed for most of the efficacy experiments, 
no cures were documented, and the tumors grew back after therapy. It is possible 
that a tumor variant had selectively grown back and acquired resistance to the 
compound. To address this possibility, Colo-205 colon tumors that had initially 
significantly regressed in response to treatment with PD 0332991 were harvested 
and reimplanted into naive mice. After the tumors grew to 100 to 150 mg, these 
tumor-bearing mice were treated with PD 0332991 with a dose and dosing schedule 
identical to the original experiment. The tumors responded with equal sensitivity to 
the drug and fully regressed, indicating that no resistance had developed during the 
initial treatment. A similar result was observed with retreated MDAMB-435 
tumors. 
 
Pharmacokinetics  
The single-dose pharmacokinetics of PD 0332991 following IV or PO routes of 
administration were investigated in Sprague-Dawley rats and Beagle dogs 
(toxicology species), and in cynomolgus monkeys. PD 0332991 was administered 
intravenously to determine elimination kinetics and absolute bioavailability from 
the PO route. Following IV administration, mean plasma clearance values of PD 
0332991 in all species were low to moderate and were all lower than the 
corresponding hepatic blood flow. The mean apparent volumes of distribution at 


 
 
Protocol Version: 11/13/2020, Amendment 6 
 
Page 14 of 75 
steady state were approximately 10-fold greater than total body water. Mean 
absolute oral bioavailability of PD 0332991 was moderate in all species tested. In 
rats on Day 1 of repeat dose studies, mean PD 0332991 Cmax and AUC values 
increased in a dose-related manner up to 300 mg/kg. In dogs, mean PD 0332991 
Cmax and AUC values increased in a dose-related manner up to 20 mg/kg on Day 
1, and did not increase between 20 and 40 mg/kg. Mean PD 0332991 Cmax and 
AUC values in female rats were less than in male rats (up to one ninth and up to 
one sixteenth the values for male rats, respectively). There was no observed sex 
difference in systemic exposure in dogs. Mean PD 0332991 Cmax and AUC values 
following 3 weeks of dosing indicate up to 3-fold accumulation upon multiple 
dosing in both rats and dogs. 
 
1.2.3 Clinical Development 
 
As of 01 September 2015, 6 clinical studies in patients with palbociclib are ongoing 
and 3 clinical studies have completed. Additionally, as of 01 September 2015 
palbociclib has been investigated in 16 completed and 4 ongoing Phase 1 clinical 
pharmacology studies in healthy volunteers. Four hundred seventy-three (473) 
healthy volunteers have received single doses of palbociclib ranging from 50 mg to 
150 mg, and twenty-six healthy volunteers have received multiple doses of 
palbociclib on a 125 mg QD regimen. 
 
1.2.4 Clinical Pharmacokinetics 
 
To date pharmacokinetic data is available from four studies (see Section 8.1.3). The 
exposure (AUC(0-10) and Cmax) increased in a dose-proportional manner over the 
dose range of 25-225 mg QD following PD 0332991 administration on Days 1 and 
8 of Cycle 1. At a steady state (Day 14 or Day 21), PD 0332991 was absorbed with 
a median Tmax of ~4 hours. PD 0332991 extensively penetrates into peripheral 
tissues, and was eliminated slowly; the mean elimination half-life (t1/2) was 26.5 
hours.  
 
The preliminary results from the recently performed food-effect study (“A5481021, 
a Phase 1, open-label 4 sequence 4 period crossover study of palbociclib (PD-
0332991) in healthy volunteers to estimate the effect of food on the bioavailability 
of palbociclib”) has provided evidence that when a single 125 mg dose of 
palbociclib was administered under fed conditions (including high fat or low fat 
meal given together with palbociclib, or moderate fat meal given 1 hour before and 
2 hours after palbociclib) as a freebase formulation the palbociclib exposure levels 
were more uniform across the population than when taken in the fasting condition. 
 
 
 


 
 
Protocol Version: 11/13/2020, Amendment 6 
 
Page 15 of 75 
1.2.5 Clinical Toxicology 
 
The most frequently reported AEs were predominantly considered treatment-
related. These treatment-related events included fatigue, neutropenia, diarrhea, 
nausea, anemia, and thrombocytopenia. The most common Grade 4 adverse events 
were neutropenia and thrombocytopenia 
 
QT Interval Effects  
Data from non-clinical (in vitro and in vivo) studies indicated that PD 0332991 has 
the potential to delay cardiac repolarization as measured by prolongation of the QT 
interval on the ECG. Prolongation of QTcF (maximum increase of < 30 msec from 
baseline) was observed in a majority of patients in two Phase I trials with PD 
0332991 as a single agent. No patient had a maximum QTcF value of > 500 msec 
during treatment. Notably, one female patient receiving PD 0332991 at 75 mg QD 
on Schedule 3/1 had a maximum QTcF increase of 67 msec from baseline to Cycle 
1. Additionally, QTcF increases ranging from 39 to 51 msec compared to baseline 
persisted throughout her ECG collection period of 5 subsequent cycles. No 
significant changes in blood pressure, pulse rate and body weight have been 
observed in the two completed Phase 1 clinical studies in advanced cancers. 
 
The patients enrolled in clinical studies should be closely monitored for potential 
cardiovascular symptoms. Appropriate monitoring should include clinical 
examinations, vital signs, routine ECGs, and AEs monitoring. 
 
1.2.6 Developmental/Reproductive Toxicity 
 
Fertility and teratology studies with PD 0332991 have not been conducted. Women 
of childbearing potential must have a negative pregnancy test prior to treatment 
with PD 0332991. Female patients must be surgically sterile or be postmenopausal, 
or must agree to use effective contraceptive during the period of the trial and for at 
least 90 days after completion of treatment. 
 
1.3 
Letrozole 
 
Letrozole is indicated and approved for treating patients with HR+ breast cancers. Please 
refer to local prescribing information for key safety information. 
 
1.4 
Trastuzumab 
 
Trastuzumab is indicated and approved for treating patients with HER2+ breast cancers. Signs 
and symptoms of cardiotoxicity and cardiac dysfunction have been observed in patients treated 
with trastuzumab, especially when used concurrently with anthracyclines. Please refer to local 
prescribing information for key safety information. Trastuzumab has available biosimilar 
products FDA approved for use. Trastuzumab or any of the FDA approved commercially 
available biosimilar products for trastuzumab may be administered to patients based on their 
insurance requirements or institutional practice. 


 
 
Protocol Version: 11/13/2020, Amendment 6 
 
Page 16 of 75 
1.5 
Safety Data 
 
Although there is an ongoing Spanish phase 2 study (NCT02448420) with this combination 
of palbociclib, letrozole and trastuzumab in the metastatic setting, no published data is 
available at this time, but per communication with Pfizer, the safety DMC review shows 
no concerning safety signal. 
 
1.6 
Correlative Studies Background 
 
We plan to perform tumor biopsies to assess markers of tumor cell proliferation (Ki67), 
apoptosis (Cleaved PARP), and senescence (beta gal assay) following 2 weeks of 
combination therapy as early predictors of clinical and pathologic response.  In addition, 
pharmacodynamic effect of palbociclib in combination with letrozole and trastuzumab on 
HER2 signaling (pHER2, pAKT, pMEK), ER (pER, PgR), CDK4/6-Rb (phosphor Rb 
Ser801/811 and Ser780) and cyclin D levels, and other relevant targets will be assessed by 
proteomics such as reverse phase protein array and immunohistochemistry analysis of 
tumors collected following 2 weeks of neoadjuvant therapy and at the time of surgery to 
compare with baseline.  
 
Since PIK3CA mutation and PTEN status have been implicated in resistance mechanisms 
for HER2 targeted agents, tumor DNA at baseline and surgery time points will be subjected 
to next generation sequencing for whole exome (if funding permits) or targeted sequencing 
analysis.18-23  
 
We plan to perform cDNA microarray analysis to assign intrinsic subtype using the PAM50 
gene expression signature and to correlate with treatment response.24 Previous studies 
indicated that ER+/HER2+ breast cancers are comprised of a mixture of luminal A, B and 
HER2-E tumors, which potentially affect their response to HER2-targeted agents.25 There 
is no data in the literature indicating whether response to trastuzumab/letrozole/palbociclib 
combination differs according to molecular subtypes of breast cancer.   
 
We will enrich for disseminated tumor cells (DTCs) and perform analysis for HER2 
expression as well as expression of other genes associated with the metastatic potential of 
DTCs in pretreatment and post-treatment bone marrow; this is an optional collection and 
will be performed only in consenting patients. This analysis will lead to the identification 
of new predictive therapeutic markers which are associated with resistance to the 
combination of ER/HER2 targeted therapy. These genes will be compared with the 
expression profile of residual tumor to begin to assess the optimal predictors of recurrent 
disease development in this population of patients. We also examine the relationship 
between tumor subtype and DTC profile with the goal of understanding whether a specific 
tumor subtype is associated with HER2 positive DTCs.  
 
 
 
 


 
 
Protocol Version: 11/13/2020, Amendment 6 
 
Page 17 of 75 
2.0 
OBJECTIVES 
 
2.1 
Primary Objective 
 
To determine the pCR rate in patients with clinical stages II/III ER+ HER2+ breast cancer 
treated with neoadjuvant letrozole, trastuzumab (or FDA approved biosimilar), and 
palbociclib.  
 
2.2 
Secondary Objective 
 
1. To assess safety and tolerability of palbociclib in combination with neoadjuvant 
letrozole and trastuzumab (or FDA approved biosimilar). 
2. To assess the patient reported outcomes associated with palbociclib in combination 
with neoadjuvant letrozole and trastuzumab (or FDA approved biosimilar). 
 
2.3 
Exploratory Objectives 
 
1. To determine if bone marrow disseminated tumor cells (DTC) status is a good indicator 
of clinical response and if subpopulations of DTCs emerge with neoadjuvant treatment. 
2. To assess intrinsic breast cancer subtype utilizing cDNA microarray and to correlate 
with treatment response 
3. To examine the pharmacodynamic effect of the study drug treatment by proteomic and 
immunohistochemistry analysis of baseline, 2-week and surgical tumor sample, and to 
correlate with treatment response 
4. To examine the mutational profiles by whole exome or targeted gene sequencing at 
baseline and at time of definitive surgery to correlate with treatment response 
5. To assess tumor cell apoptosis index post 2 weeks of palbociclib in combination with 
letrozole and trastuzumab (or FDA approved biosimilar). 
6. To examine markers of cell proliferation, apoptosis and senescence on 2-week biopsies 
as predictors of surgical outcome. 
7. To assess serum, plasma and ctDNA sequencing of selected genes, including ESR1, 
TP53, PIK3CA and RB, at baseline and surgery to correlate with response. 
 
 
3.0 
PATIENT SELECTION 
 
3.1 
Inclusion Criteria 
 
1. Newly diagnosed clinical stage II or III ER+/HER2+ breast cancer with complete 
surgical excision of the breast cancer after neoadjuvant therapy as the treatment goal, 
staging criteria is to be based on AJCC 7. 
  
2. Tumor size at least 2 cm in one dimension by clinical or radiographic exam (WHO 
criteria).  Patients with histologically confirmed palpable lymph nodes may be enrolled 
regardless of breast tumor size. A palpable mass is not required as long as the mass is 
as least 2 cm in one dimension by radiographic exam. 


 
 
Protocol Version: 11/13/2020, Amendment 6 
 
Page 18 of 75 
 
3. At least 18 years of age. 
 
4. ECOG performance status ≤ 1 (see Appendix A). 
 
5. Normal bone marrow and organ function as defined below: 
a. Leukocytes ≥ 3,000/mcL 
b. Absolute neutrophil count ≥ 1,500/mcl 
c. Platelets ≥ 100,000/mcl 
d. Total bilirubin ≤ IULN  
e. AST(SGOT)/ALT(SGPT) ≤ 2.5 x IULN 
f. Creatinine ≤ IULN OR creatinine clearance ≥ 60 mL/min/1.73 m2 for patients with 
creatinine levels above institutional normal 
 
6. LVEF ≥ 50% by transthoracic echocardiogram or MUGA 
 
7. Baseline corrected QT interval (QTcF) < 480 ms. 
 
8. Women of childbearing potential must agree to undergo pregnancy testing within 14 
days of study entry and agree to use adequate contraception (barrier method of birth 
control, abstinence, not hormonal) prior to study entry and for the duration of study 
participation as well as chemical LHRH Agonist with goserelin.  Should a woman 
become pregnant or suspect she is pregnant while participating in this study, she must 
inform her treating physician immediately. 
 
9. Ability to understand and willingness to sign an IRB approved written informed 
consent document (or that of legally authorized representative, if applicable). 
 
3.2 
Exclusion Criteria 
 
1. Prior systemic therapy for indexed breast cancer. 
 
2. Indeterminate or negative HER2 status. 
 
3. Inflammatory breast cancer. 
 
4. A history of other malignancy ≤ 5 years from diagnosis of indexed BC with the 
exception of basal cell or squamous cell carcinoma of the skin treated with local 
resection only or carcinoma in situ of the cervix. 
 
5. Currently receiving any other investigational agents or received any within the past 28 
days. 
 
6. Know to be HIV positive. 
 
7. Known hepatitis B or C infection. 


 
 
Protocol Version: 11/13/2020, Amendment 6 
 
Page 19 of 75 
 
8. A history of allergic reactions attributed to compounds of similar chemical or biologic 
composition to palbociclib, letrozole, trastuzumab, any other aromatase inhibitor, any 
other monoclonal antibody, or other agents used in the study. 
 
9. Uncontrolled intercurrent illness including, but not limited to, ongoing or active 
infection, symptomatic congestive heart failure, unstable angina pectoris, or cardiac 
arrhythmia. 
 
10. Current use or anticipated need for food or drugs that are known strong CYP3A4 
inhibitors (i.e., grapefruit juice, verapamil, ketoconazole, miconazole, itraconazole, 
posaconazole, erythromycin, clarithromycin, telithromycin, indinavir, saquinavir, 
ritonavir, nelfinavir, lopinavir, atazanavir, amprenavir, fosamprenavir, nefazodone, 
diltiazem, and delavirdine) or inducers (i.e. dexamethasone, glucocorticoids, 
progesterone, rifampin, phenobarbital, St. John’s wort). 
 
11. Any condition that impairs the ability to swallow or absorb oral medication (e.g., 
gastrointestinal tract disease resulting in an inability to take oral medication or a 
requirement for IV alimentation, prior surgical procedures affective absorption). 
 
12. Pregnant and/or breastfeeding.  Women of childbearing potential must have a negative 
pregnancy test within 14 days of study entry. 
 
3.3 
Inclusion of Women and Minorities 
 
Women and members of all races and ethnic groups are eligible for this trial. 
 
 
4.0 
REGISTRATION PROCEDURES 
 
Patients must not start any protocol intervention prior to registration through the Siteman 
Cancer Center. 
 
The following steps must be taken before registering patients to this study: 
 
1. Confirmation of patient eligibility by Washington University 
2. Registration of patient in the Siteman Cancer Center database 
3. Assignment of unique patient number (UPN) 
 
Once the patient has been entered in the Siteman Cancer Center OnCore database, the WUSM 
coordinator will forward verification of enrollment and the UPN via email. 
 
4.1 
Confirmation of Patient Eligibility 
 
Confirm patient eligibility by collecting the information listed below and scanning and 
emailing it to the research coordinator listed in the Siteman Cancer Center Clinical Trials 


 
 
Protocol Version: 11/13/2020, Amendment 6 
 
Page 20 of 75 
Core Protocol Procedures for Secondary Sites packet at least one business day prior to 
registering patient: 
 
1. Your name and contact information (telephone number, fax number, and email 
address) 
2. Your site PI’s name, the registering MD’s name, and your institution name 
3. Patient’s race, sex, and DOB 
4. Three letters (or two letters and a dash) for the patient’s initials 
5. Currently approved protocol version date 
6. Copy of signed consent form (patient name may be blacked out) 
7. Planned date of enrollment 
8. Completed eligibility checklist, signed and dated by a member of the study team 
9. Copy of appropriate source documentation confirming patient eligibility 
 
4.2 
Patient Registration in the Siteman Cancer Center OnCore Database 
 
Registrations may be submitted Monday through Friday between 8am and 5pm CT. Urgent 
late afternoon or early morning enrollments should be planned in advance and coordinated 
with the Washington University research coordinator.  Registration will be confirmed by 
the research coordinator or his/her delegate by email within one business day. Verification 
of eligibility and registration should be kept in the patient chart. 
 
All patients at all sites must be registered through the Siteman Cancer Center OnCore 
database at Washington University. 
 
4.3 
Assignment of UPN 
 
Each patient will be identified with a unique patient number (UPN) for this study.  Patients 
will also be identified by first, middle, and last initials.  If the patient has no middle initial, 
a dash will be used on the case report forms (CRFs).  All data will be recorded with this 
identification number on the appropriate CRFs. 
 
 
5.0 
TREATMENT PLAN 
 
Participants will be treated with neoadjuvant palbociclib in addition to letrozole (plus goserelin if 
premenopausal) and trastuzumab (or FDA approved biosimilar) for a total of 16 weeks, consisting 
of four 28-day cycles.   
 
Definitive surgery will be performed preferably within 6 weeks after the end of Cycle 4 but may 
be delayed depending upon the availability of the surgeon. Letrozole and trastuzumab (or FDA 
approved biosimilar) will continue until the day of surgery. Letrozole will continue to be taken 
daily and trastuzumab (or FDA approved biosimilar) will be given every 3 weeks, per standard of 
care guidelines beginning the day after Cycle 4 Day 28. Adjuvant therapy following definitive 
surgery will be at the discretion of the treating physician. 
 


 
 
Protocol Version: 11/13/2020, Amendment 6 
 
Page 21 of 75 
5.1 
Premedications 
 
Patients will receive oral diphenhydramine at a dose of 50 mg and oral acetaminophen at a 
dose of 650 mg 60 minutes prior to the loading dose of trastuzumab (or FDA approved 
biosimilar), and on an as needed basis prior to any subsequent doses of trastuzumab (or 
FDA approved biosimilar). 
 
5.2 
Agent Administration 
 
Palbociclib is an oral drug given at a dose of 125 mg daily on Days 1-21 of each 28-day 
cycle for a total of 4 cycles.  Palbociclib should be taken with food.  If a patient misses a 
day’s dose entirely, she should not make the dose up the next day but just continue with 
the next day’s regular dose.  If a patient vomits any time after taking a dose, she should not 
re-take the dose but just continue to take subsequent doses as prescribed.  If a patient 
inadvertently takes an extra dose during a day, she must be instructed to not take the next 
day’s dose.  Patients will be instructed to complete a drug diary (Appendix D) for 
compliance purposes. 
 
Trastuzumab will be administered on a weekly basis for 16 weeks (on Days 1, 8, 15, and 
22 of each 28-day cycle for a total of 4 cycles).  Baseline weight is to be used for cycles 1-
4. The first dose of trastuzumab on Cycle 1 Day 1 will be a loading dose of 4 mg/kg IVPB 
over 90 minutes.  Subsequent doses of trastuzumab will be 2 mg/kg IVPB over 30 minutes. 
Trastuzumab will continue every 3 weeks after the completion of Cycle 4 of palbociclib 
until surgery beginning the day after Cycle 4 Day 28. Trastuzumab has available biosimilar 
products FDA approved for use. Trastuzumab or any of the FDA approved commercially 
available biosimilar products for trastuzumab may be administered to patients based on 
their insurance requirements or institutional practice. If a biosimilar product is required, 
dosing, schedule of administration, and premedications are identical to the guidance 
described throughout the protocol for trastuzumab. Preparation of the drug product will be 
dependent on the biosimilar selected for use. 
 
Letrozole is an oral drug given at a dose of 2.5 mg orally once a day.  It will be taken 
continuously (Days 1-28 of each cycle) until the day of definitive surgery.  Letrozole may 
be taken with or without food.  If a patient misses a day’s dose entirely, she should not 
make the dose up the next day but just continue with the next day’s regular dose.  If a 
patient vomits any time after taking a dose, she should not re-take the dose but just continue 
to take subsequent doses as prescribed.  If a patient inadvertently takes an extra dose during 
a day, she must be instructed to not take the next day’s dose.  Patients will be instructed to 
complete a drug diary (Appendix E) for compliance purposes. Letrozole will continue after 
the completion of Cycle 4 of palbociclib until the day of surgery. 
 
Patients who are premenopausal will also be treated with goserelin as a means of LHRH 
Agonist. Goserelin is given subcutaneously at a dose of 3.6 mg on Day 1 of each cycle.  
Goserelin will be continued (once every 28-days) after the completion of Cycle 4 of 
palbociclib if required. Lupron (Leuprolide) may be substituted for Goserelin.  
 


 
 
Protocol Version: 11/13/2020, Amendment 6 
 
Page 22 of 75 
5.3 
Post Surgery Therapy  
 
Standard adjuvant treatment, including chemotherapy, antiHER2 therapy, hormonal 
therapy, and radiation (if needed), are recommended after surgery at the discretion of the 
treating physician. 
 
5.4 
Toxicity and Response Evaluations 
 
All patients who receive any study treatment are evaluable for toxicity.  Patients are 
evaluated from first receiving study treatment until a 30-day follow up after the conclusion 
of treatment or death. Patients who do not receive any study treatment will be replaced. 
 
All patients are evaluable for disease response unless they discontinue treatment due to 
treatment related adverse events(s) prior to completion of Cycle 1. 
 
Any patient that receives one dose on study is considered evaluable for toxicity. Patients 
are evaluated from first receiving study treatment until a 30-day follow up after the 
conclusion of treatment or death. Patients who do not receive any study treatment will be 
replaced. 
 
Any patient that completes the first cycle of study treatment is considered evaluable for 
efficacy unless they discontinue treatment due to treatment related adverse events(s) prior 
to completion of Cycle 1. 
 
5.5 
Patient Reported Outcomes 
 
Patient-reported outcomes will be evaluated using a modified PRO-CTCAE at baseline, 
after Cycle 1, and after completion of neoadjuvant therapy (Appendix F).  
 
5.6 
General Concomitant Medication and Supportive Care Guidelines 
 
When taking palbociclib, patients should be instructed to avoid food or drugs that are 
known strong CYP3A4 inhibitors or inducers.  Please refer to Appendix B for a list of 
prohibited medications. 
 
No specific antidotes exist for the treatment of palbociclib overdose. Since renal excretion 
of palbociclib is minimal, the benefit of hemodialysis in the treatment of a palbociclib 
overdose is probably negligible. The treatment of overdose of palbociclib should consist 
of general supportive measures. If indicated, elimination of unabsorbed drug should be 
achieved by emesis or gastric lavage. 
 
Guidelines for trastuzumab and letrozole will be as per standard of care.  Use of estrogen 
containing oral contraceptives is prohibited as it will negate any benefit from letrozole. 
 
5.7 
Women of Childbearing Potential 
 


 
 
Protocol Version: 11/13/2020, Amendment 6 
 
Page 23 of 75 
Women of childbearing potential (defined as women with regular menses, women with 
amenorrhea, women with irregular cycles, women using a contraceptive method that 
precludes withdrawal bleeding, and women who have had a tubal ligation) are required to 
have a negative pregnancy test within 14 days prior to Cycle 1 Day 1.   
 
Patients are required to use two forms of acceptable contraception, including one barrier 
method, during participation in the study and for 90 days following the last dose of 
palbociclib.  Use of estrogen containing oral contraceptives is prohibited as it will negate 
any benefit from letrozole.  Goserelin is not considered an acceptable form of 
contraception. 
 
If a patient is suspected to be pregnant, study treatment should be immediately 
discontinued.  In addition, a positive urine test must be confirmed by a serum pregnancy 
test.  If it is confirmed that the patient is not pregnant, the patient may resume dosing. 
 
If a patient becomes pregnant during therapy or within 28 days after the last dose of study 
treatment, the investigator must be notified in order to facilitate outcome follow-up. 
 
5.8 
Duration of Therapy 
 
If at any time the constraints of this protocol are considered to be detrimental to the 
patient’s health and/or the patient no longer wishes to continue protocol therapy, the 
protocol therapy should be discontinued and the reason(s) for discontinuation documented 
in the case report forms. 
 
In the absence of treatment delays due to adverse events, treatment may continue for a 
maximum of 4 cycles or until one of the following criteria applies: 
 
• Documented and confirmed disease progression 
• Death 
• Adverse event(s) that, in the judgment of the investigator, may cause severe or 
permanent harm or which rule out continuation of study drug 
• General or specific changes in the patient’s condition render the patient unable to 
receive further treatment in the judgment of the investigator 
• Suspected pregnancy 
• Serious non-compliance with the study protocol 
• Lost to follow-up 
• Patient withdraws consent 
• Investigator removes the patient from study 
• The Siteman Cancer Center decides to close the study 
 
Patients who prematurely discontinue treatment for any reason will be followed as 
indicated in the study calendar. Exception: Patients who progress on study, who do not go 
to surgery and initiate a new therapy, will be taken off study, but will continued to be 
followed according to section 5.9.  
 


 
 
Protocol Version: 11/13/2020, Amendment 6 
 
Page 24 of 75 
5.9 
Duration of Follow-up 
 
Patients will be observed post-surgery for 30-60 days or resolution of treatment-related 
adverse events, whichever comes later, then yearly for recurrence and survival status for 5 
years. Patients removed from study for unacceptable adverse events will be followed until 
resolution or stabilization of the adverse event. 
 
6.0 
DOSE DELAYS/DOSE MODIFICATIONS 
 
6.1 
Re-Treatment Criteria 
 
A new cycle of treatment with palbociclib may begin only if: 
• ANC ≥ 1,000/mcL. 
• Platelet count ≥ 50,000/mcL. 
• Non-hematologic 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). 
 
Criteria for dose interruption within cycle: 
• ANC < 500/mcL. 
• Platelet count < 50,000/mcL. 
 
Re-treatment within the cycle may only be started when ANC ≥ 500/mcL and platelet count 
≥ 50,000/mcL. 
 
Doses omitted for toxicity within a cycle are not replaced or restored within the same cycle 
(meaning that the cycle remains 28 days regardless of the number of doses of taken). 
 
If these conditions are not met, treatment with letrozole and trastuzumab may be continued 
but treatment with palbociclib must be delayed by one week. If, after a one-week delay, all 
toxicities have recovered within the limits described above, treatment with palbociclib can 
be resumed. 
 
If the patient has not recovered after 2 weeks (excluding the scheduled one-week off 
treatment period within a cycle) despite dose reduction to the lowest dose level, treatment 
with palbociclib will be permanently discontinued.  
 
6.2 
Dose Modifications for Palbociclib 
 
Dose Modification Table 
Dose Level 
Palbociclib Dose 
(Days 1-21 of each 
28-day cycle) 
1 (starting dose) 
125 mg/day 
-1 
100 mg/day 
-2 
75 mg/day 


 
 
Protocol Version: 11/13/2020, Amendment 6 
 
Page 25 of 75 
 
Dose reduction below 75 mg/day is not allowed. 
 
Patients will be monitored for toxicity and the dose of palbociclib may be adjusted as 
indicated in the table above.  Dose reduction by 1, and if needed, 2 dose levels will be 
allowed depending on the type and severity of toxicity encountered (see table below).  
Patients requiring more than 2 dose reductions will be discontinued from the study. 
 
Recommended dose reductions for palbociclib are detailed in the table below. Doses may 
be held as needed for toxicity resolution during a cycle. Doses omitted for toxicity are not 
replaced or restored within the same cycle (meaning that the cycle remains 28 days 
regardless of the number of doses of taken). 
 
 
Palbociclib Dose Modifications Based on Worst Treatment-Related Toxicity in the 
Previous Cycle 
Worst Toxicity During Previous Cycle 
New Dose Level 
Grade 4 neutropenia 
Decrease by one dose level 
Grade 4 thrombocytopenia 
Decrease by one dose level 
Grade 3 neutropenia associated with a documented 
infection or fever ≥ 38.5 ºC 
Decrease by one dose level 
Grade ≥ 3 non-hematologic toxicity (includes 
nausea, vomiting, diarrhea, and hypertension only if 
persisting despite maximal medical treatment) 
Decrease by one dose level 
Delay by > 1 week in receiving the next scheduled 
dose due to persisting treatment-related toxicities 
If recovery occurs within 2 weeks, 
continue and decrease by one dose 
level 
Inability to deliver at least 80% of the planned dose 
of palbociclib or letrozole due to adverse events 
possibly related to study treatment 
Decrease by one dose level 
 
6.2.1 Dose Adjustments Due to QTc Prolongation 
 
Due to CYP3A inhibition mediated by palbociclib, the pharmacokinetics of drugs 
metabolized by CYP3A may be increased which, depending on the drug, may lead 
to QTc prolongation.  In such situations, palbociclib should be discontinued at the 
physician’s discretion, as should the drug responsible for QTc prolongation. 
 
6.2.2 Dose Adjustments Due to Interstitial Lung Disease (ILD)/Pneumonitis 
 
Monitor patients for pulmonary symptoms indicative of ILD/pneumonitis (e.g. 
hypoxia, cough, and dyspnea). In patients who have new or worsening respiratory 
symptoms and are suspected to have developed ILD/pneumonitis, interrupt 
palbociclib immediately and evaluate the patient. Permanently discontinue 
palbociclib in patients with severe ILD or pneumonitis. 
 
 


 
 
Protocol Version: 11/13/2020, Amendment 6 
 
Page 26 of 75 
6.3 
Dose Modifications for Trastuzumab (or FDA Approved Biosimilar) 
 
6.3.1 Infusion-associated Symptoms with Trastuzumab (or FDA Approved 
Biosimilar) 
 
Infusion reactions consist of a symptom complex characterized by fever and chills, 
and on occasion nausea, vomiting, pain (in some cases at tumor sites), headache, 
dizziness, hypotension, rash, and asthenia.  In post marketing reports, serious and 
fatal infusion reactions have been reported.  Severe reactions which include 
bronchospasm, anaphylaxis, angioedema, hypoxia, and severe hypotension were 
usually reported during or immediately following the initial infusion.  However, the 
onset and clinical course were variable including progressive worsening, initial 
improvement followed by clinical deterioration, or delayed post-infusion events 
with rapid clinical deterioration.  For fatal events, death occurred within hours to 
days following a serious infusion reaction. 
 
Interrupt trastuzumab (or FDA approved biosimilar) infusion in all patients 
experiencing dyspnea, clinically significant hypotension, and intervention of 
medical therapy administered, which may include: epinephrine, corticosteroids, 
antihistamines, including diphenhydramine, bronchodilators, and oxygen.  Patients 
should be evaluated and carefully monitored until complete resolution of signs and 
symptoms.  The rate of infusion should be decreased for mild or moderate (CTCAE 
4.0 grade 1 or 2) infusion reactions.  Permanent discontinuation should be strongly 
considered in all patients with severe (grade 3 or 4) infusion reactions. 
 
6.3.2 Cardiac Dysfunction 
 
Signs and symptoms of cardiac dysfunction were observed in a number of women 
who received trastuzumab alone or in combination with chemotherapy, most often 
anthracycline-based treatment.  Cardiac dysfunction was observed most frequently 
among patients who received trastuzumab plus AC chemotherapy (28%), compared 
with those who received AC alone (7%), trastuzumab plus paclitaxel (11%), 
paclitaxel alone (1%), or trastuzumab alone (7%).  Severe disability or fatal 
outcome due to cardiac dysfunction was observed in ~1% of all patients. 
 
The nature of the observed cardiac dysfunction was similar to the syndrome of 
anthracycline-induced cardiomyopathy.  The signs and symptoms of cardiac 
dysfunction usually responded to treatment.  Complete and partial responses were 
observed among patients with cardiac dysfunction.  The risk appears to be 
independent of tumor response to therapy.  Analysis of the clinical database for 
predictors of cardiac dysfunction revealed only advanced age and exposure to an 
anthracycline as possible risk factors.  In the clinical trials, most patients with 
cardiac dysfunction responded to appropriate medical therapy, often including 
discontinuation of trastuzumab.  In many cases, patients were able to resume 
treatment with trastuzumab.  In a subsequent study using weekly paclitaxel and 
trastuzumab as first-line treatment for metastatic breast cancer, the observed 


 
 
Protocol Version: 11/13/2020, Amendment 6 
 
Page 27 of 75 
incidence of serious cardiac dysfunction was 3% (N=95).26 Since the occurrence of 
cardiac dysfunction in the trastuzumab plus chemotherapy trial was an unexpected 
observation, no information is available regarding the most appropriate method for 
monitoring cardiac function in patients receiving trastuzumab.  Significant 
advances in the understanding and treatment of CHF have been made in the past 
several years, with many of the new drugs demonstrating the ability to normalize 
cardiac function. Patients who develop symptoms of congestive heart failure while 
on trastuzumab should be treated according to the HFSA guidelines.  
 
All patients must have an evaluation of LVEF at baseline. After baseline, LVEF 
monitoring will be performed as per standard of care.   
Recommended Cardiac Monitoring 
Conduct thorough cardiac assessment, including history, physical examination, and 
determination of LVEF. The following schedule is recommended: 
• Baseline LVEF measurement immediately prior to initiation of 
trastuzumab.  Only patients with LVEF ≥ 50% by transthoracic 
echocardiogram or MUGA will be eligible. 
• LVEF measurements every 3 months during and upon completion of 
trastuzumab using the same modality and same facility as used for baseline 
• Repeat LVEF measurement at 4 week intervals if trastuzumab is withheld 
for significant left ventricular cardiac dysfunction 
 
Asymptomatic Patients 
If a patient does not have significant symptoms related to LV dysfunction, 
administration of trastuzumab will depend on the absolute change in LVEF between 
baseline and follow-up assessments. 
 
Trastuzumab (or FDA approved biosimilar) should be initiated in an asymptomatic 
patient if: 
• The LVEF increased or stayed the same; 
• The LVEF decreased by ≤ 15 percentage points but is still at or above the 
lower limit of normal for the radiology facility. 
 
Trastuzumab (or FDA approved biosimilar) is PROHIBITED in an asymptomatic 
patient if: 
• The LVEF decreased ≤ 15 percentage points and is below the limit of 
normal for the radiology facility: 
• The LVEF decreased by 16 percentage points or more (regardless of lower 
limits of normal for the radiology facility)  
• The LVEF ≤ 50% 
 
Withhold trastuzumab (or FDA approved biosimilar) dosing for at least 4 weeks for 
either of the following: 
• The LVEF ≤ 50% 
• > 16% absolute decrease in LVEF from pre-treatment values 


 
 
Protocol Version: 11/13/2020, Amendment 6 
 
Page 28 of 75 
• LVEF below institutional limits of normal and > 10% absolute decrease in 
LVEF from pretreatment values. 
• Trastuzumab may be resumed if, within 4-8 weeks, the LVEF returns to 
normal limits and the absolute decrease from baseline is < 15%. 
• Permanently discontinue trastuzumab for a persistent (> 8 weeks) LVEF 
decline or for suspension of trastuzumab dosing on more than 3 occasions 
for cardiomyopathy. 
 
If a patient has significant symptoms related to left ventricular (LV) dysfunction, 
cardiac ischemia, or arrhythmia, initiation of trastuzumab (or FDA approved 
biosimilar) is prohibited. 
 
6.4 
Dose Modifications for Letrozole 
 
No dose adjustment is permitted for letrozole, but interruptions no longer than 2 weeks will 
be allowed at the discretion of the treating physician. 
 
 
7.0 
REGULATORY AND REPORTING REQUIREMENTS 
 
The entities providing oversight of safety and compliance with the protocol require reporting as 
outline below. 
 
Patients will be observed post-surgery for 30-60 days or resolution of treatment-related adverse 
events, whichever comes later, then yearly for recurrence and survival status for 5 years.  All 
adverse events must be recorded on the toxicity tracking case report from the (CRF) with the 
exception of: 
• Baseline adverse events, which shall be recorded on the medical history CRF 
•  
 
Refer to the data submission schedule in Section 11.0 for instructions on the collection of AEs in 
the EDC. 
 
Reporting requirements for Washington University study team may be found in Section 7.1.  
Reporting requirements for secondary site study teams participating in Washington University-
coordinated research may be found in Section 7.2.  
 
7.1 
WU PI Reporting Requirements 
 
7.1.1 Reporting to the Human Research Protection Office (HRPO) at 
Washington University 
 
Reporting will be conducted in accordance with Washington University IRB Policies. 
 
Pre-approval of all protocol exceptions must be obtained prior to implementing the change. 
 


 
 
Protocol Version: 11/13/2020, Amendment 6 
 
Page 29 of 75 
7.1.2 Reporting to the Quality Assurance and Safety Monitoring 
Committee (QASMC) at Washington University 
 
The Washington University PI (or designee) is required to notify the QASMC of any 
unanticipated problem occurring at WU or any BJH or SLCH institution that has been 
reported to and acknowledged by HRPO.  (Unanticipated problems reported to HRPO and 
withdrawn during the review process need not be reported to QASMC.) 
 
QASMC must be notified within 10 days of receipt of IRB acknowledgment via email to 
qasmc@wustl.edu.  Submission to QASMC must include the myIRB forms and any 
supporting documentation sent with the form. 
 
For events that occur at secondary sites, the Washington University PI (or designee) is 
required to notify the QASMC within 10 days of Washington University notification via 
email to qasmc@wustl.edu.  Submission to QASMC must include either the myIRB form 
and supporting documentation or (if not submitted to myIRB) the date of occurrence, 
description of the event, whether the event is described in the currently IRB approved 
materials, the event outcome, determination of relatedness, whether currently enrolled 
participants will be notified, and whether the informed consent document and/or any study 
procedures will be modified as a result of this event. 
 
7.1.3 Reporting to Secondary Sites 
 
The Washington University PI (or designee) will notify the research team at each secondary 
site of all unanticipated problems involving risks to participants or  others that have 
occurred at other sites within 10 working days of the occurrence of the event or 
notification of the PI (or designee) of the event.  This includes events that take place both 
at Washington University and at other secondary sites, if applicable. Refer to Section 16.0 
(Multicenter Managament) for more information. 
 
7.1.4 Reporting to Pfizer 
 
Report any unexpected fatal or life-threatening adverse experiences (Appendix H, Section 
C.) associated with use of the drug or any serious, unexpected adverse experiences 
(Appendix H, Section D.), as well as results from animal studies that suggest significant 
clinical risk. 
  
Within 24 hours of first awareness of the event (immediately if the event is fatal or life-
threatening), the PI or designee will report to Pfizer by facsimile any serious adverse drug 
experience (as defined in Appendix H) that occurs during the SAE reporting period (as 
defined in Section 7.0) in a study subject assigned to receive palbociclib.  Such SAEs will 
be reported using MedWatch form and the Pfizer Reportable Event Fax Cover Sheet 
(Appendix C) should also be included.  SAEs should be reported as soon as they are 
determined to meet the definition, even if complete information is not yet available. 
 
Even though there may not be an associated SAE, exposure to palbociclib during 


 
 
Protocol Version: 11/13/2020, Amendment 6 
 
Page 30 of 75 
pregnancy or lactation is reportable. In addition, occupational exposure to palbociclib is 
reportable, and a lack of effect of palbociclib may also be reportable. 
 
Hy’s Law Cases: Cases of potential drug-induced liver injury as assessed by laboratory test 
values (“Hy’s Law Cases”) are also reportable to Pfizer.  If a study subject develops 
abnormal values in aspartate transaminase (AST) or alanine transaminase (ALT) or both, 
concurrent with abnormal elevations in total bilirubin and no other known cause of liver 
injury, that event would be classified as a Hy’s Law Case.  
 
Secondary sites must submit a completed MedWatch form to the Washington University 
PI and research coordinator within the specified time frame.  The Washington University 
PI will be responsible for submitting all MedWatch forms from secondary sites to Pfizer. 
 
7.1.5 Reporting to the FDA 
 
The conduct of the study will comply with all FDA safety reporting requirements.  
PLEASE NOTE THAT REPORTING REQUIREMENTS FOR THE FDA 
DIFFER FROM REPORTING REQUIREMENTS FOR HRPO/QASMC.  It is the 
responsibility of the Washington University principal investigator to report to the 
FDA as follows: 
 
• Report any unexpected fatal or life-threatening suspected adverse reaction 
(refer to Appendix A for definitions) no later than 7 calendar days after 
initial receipt of the information.   
• Report a suspected adverse reaction that is both serious and unexpected 
(SUSAR, refer to Appendix A) no later than 15 calendar days after it is 
determined that the information qualifies for reporting.  Report an adverse 
event (refer to Appendix A) as a suspected adverse reaction only if there is 
evidence to suggest a causal relationship between the drug and the adverse 
event, such as: 
o A single occurrence of an event that is uncommon and known to be 
strongly associated with drug exposure 
o One or more occurrences of an event that is not commonly associated 
with drug exposure but is otherwise uncommon in the population 
exposed to the drug 
o An aggregate analysis of specific events observed in a clinical trial that 
indicates those events occur more frequently in the drug treatment 
group than in a concurrent or historical control group 
• Report any findings from epidemiological studies, pooled analysis of 
multiple studies, or clinical studies that suggest a significant risk in humans 
exposed to the drug no later than 15 calendar days after it is determined that 
the information qualifies for reporting. 
• Report any findings from animal or in vitro testing that suggest significant 
risk in humans exposed to the drug no later than 15 calendar days after it is 
determined that the information qualifies for reporting.  


 
 
Protocol Version: 11/13/2020, Amendment 6 
 
Page 31 of 75 
• Report any clinically important increase in the rate of a serious suspected 
adverse reaction of that listed in the protocol or IB within 15 calendar days 
after it is determined that the information qualifies for reporting. 
 
Submit each report as an IND safety report in a narrative format or on FDA Form 
3500A or in an electronic format that FDA can process, review, and archive.  Study 
teams must notify the Siteman Cancer Center Protocol Development team of each 
potentially reportable event within 1 business day after initial receipt of the 
information, and must bring the signed 1571 and FDA Form 3500A to the Siteman 
Cancer Center Protocol Development team no later than 1 business day prior to the 
due date for reporting to the FDA. 
 
Each notification to FDA must bear prominent identification of its contents (“IND 
Safety Report”) and must be transmitted to the review division in the Center for 
Drug Evaluation and Research (CDER) or in the Center for Biologics Evaluation 
and Research (CBER) that has responsibility for review of the IND.  Relevant 
follow-up information to an IND safety report must be submitted as soon as the 
information is available and must be identified as such (“Follow-up IND Safety 
Report”). 
 
7.2 
Secondary Sites Reporting Requirements 
 
The research team at each secondary site is required to promptly notify the Washington 
University PI and designee of all serious adverse events (refer to Appendix A, Section D) 
within 1 working day of the occurrence of the event or notification of the secondary site’s 
PI of the event.  This notification may take place via email if there is not yet enough 
information for a formal written report using an FDA Form 3500a (MedWatch)and 
Washington University’c cover sheet (Appendix C).  A formal written report must be sent 
to the Washington University PI and designee within 4 calendar days (for fatal or life-
threatening suspected adverse reactions) or 11 calendar days (for serious unexpected 
suspected adverse reactions) of the occurrence of the event or notification of the secondary 
site’s PI of the event.   
 
The research team at a secondary site is responsible for following its site’s guidelines for 
reporting applicable events to its site’s IRB according to its own institutional guidelines.   
 
The research team at Washington University is responsible for reporting all applicable 
events to the FDA, and Pfizer as needed. 
 
Washington University pre-approval of all protocol exceptions must be obtained prior to 
implementing the change.  Local IRB approval must be obtained as per local guidelines.  
Washington University IRB approval is not required for protocol exceptions occurring at 
secondary sites. 
 
7.3 
Exceptions to Expedited Reporting 
 


 
 
Protocol Version: 11/13/2020, Amendment 6 
 
Page 32 of 75 
Events that do not require expedited reporting as described in Section 1.1 include: 
• planned hospitalizations 
• hospitalizations < 24 hours 
• respite care 
• events related to disease progression 
• [study-specific events] 
 
Events that do not require expedited reporting must still be captured in the EDC. 
 
 
8.0 
PHARMACEUTICAL INFORMATION 
 
8.1 
Palbociclib (Ibrance) 
 
8.1.1 Palbociclib Description 
 
Laboratory Code: PD 0332991-00 
Molecular Weight: 447.54 Daltons 
Molecular Formula: C24H29N7O2 
 
Formulation: Capsules will be provided as the active ingredient with precedented 
excipients filled in hard gelatin capsules composed of gelatin and precedented 
colorants.  
 
8.1.2 Clinical Pharmacology 
 
Palbociclib is a highly selective inhibitor of CDK4/cyclinD1 kinase activity (IC50 = 
11 nM; Ki = 2 nM). PD 0332991 has selectivity for CDK4/6, with little or no activity 
against a large panel of 34 other protein kinases including other CDKs and a wide 
variety of tyrosine and serine/threonine kinases. CDK6, another enzyme that also 
complexes with cyclin-D subunits, is also commonly expressed in mammalian cells 
and tumors. CDK6 is highly homologous to CDK4 and can perform the same 
function by phosphorylating Rb, thus potentially creating a redundant mechanism 
to promote cell cycle progression. Consequently, inhibition of both enzymes is 
necessary to ensure complete suppression of Rb phosphorylation and the greatest 
possible spectrum of antitumor activity. Results indicate that palbociclib inhibits 
CDK6 with equivalent potency to CDK4. 
 
8.1.3 Pharmacokinetics and Drug Metabolism 
 
As of 01 September 2015, twenty-seven clinical studies have evaluated the PK of 
palbociclib.  Eight of these trials were conducted in patients with advanced 
malignant disease.  Seventeen Phase 1 clinical pharmacology and biopharmaceutic 
studies of palbociclib were conducted in healthy subjects.  Twelve of these 19 
clinical trials were clinical pharmacology studies conducted to investigate the 
absorption, distribution, metabolism, and excretion of palbociclib as well as 


 
 
Protocol Version: 11/13/2020, Amendment 6 
 
Page 33 of 75 
examine the potential for DDI with palbociclib.  The remaining 7 of the 17 clinical 
trials were biopharmaceutic studies conducted to examine the bioavailability, 
bioequivalence, and food effect of the palbociclib formulations.   
 
Pharmacokinetic (PK) data from patients with advanced cancer from Study 
A5481001 indicate that the plasma pharmacokinetics of palbociclib are low to 
moderately variable with generally dose proportional exposures over the dose range 
evaluated (25 mg to 225 mg) following single and multiple doses.  PK data from 
Studies A5481001, A5481003, and A5481010 indicate that palbociclib is slowly 
absorbed with a median time of maximum concentration (Tmax) between 4 and 8 
hours post-dose, and is slowly eliminated with an elimination half-life (t1/2) ranging 
from 23.2 hours to 28.8 hours.  Palbociclib accumulates after repeated daily dosing 
(median Rac ranged from 1.9 to 2.4), which was consistent with its terminal t1/2. In 
Study A5481010, the median Rss (the predicted accumulation to estimate linearity) 
was 1.1, indicating that palbociclib clearance does not change over time.  In Study 
A5481003, palbociclib was shown to achieve steady-state concentrations following 
8 days of QD dosing.  The palbociclib geometric mean volume of distribution 
(Vz/F) was 2583 L in women with advanced breast cancer (Study A5481003), 
which is significantly greater than total body water (42 L), indicating that 
palbociclib extensively distributes to peripheral tissues. 
 
In humans, metabolism is the major route of elimination of palbociclib. Following 
a 
single 
oral 
administration 
of 
[14C]palbociclib 
to 
healthy 
subjects 
(Study A5481011), the overall median recovery of the administered radioactivity 
in the excreta was 91.6% with a median of 17.5% recovered in urine and a median 
of 74.1% recovered in feces.  Excretion of unchanged palbociclib in the feces and 
urine was 2.3% and 6.9% of dose, respectively, indicating that excretion plays a 
minor role in elimination of palbociclib.  A study in healthy volunteers (A5481015) 
indicated that the absolute oral bioavailability of palbociclib was approximately 
46%.   
 
In vitro data indicate that CYP3A and SULT enzyme SULT2A1 are mainly 
involved in the metabolism of palbociclib.  Palbociclib is a weak time-dependent 
inhibitor of CYP3A following daily 125 mg dosing to steady state in humans.  In 
vitro, palbociclib is not an inhibitor of CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, and 
2D6, and is not an inducer of CYP1A2, 2B6, 2C8, and 3A4 at clinically relevant 
concentrations. 
 
In vitro evaluations indicated that palbociclib has a low potential to inhibit the 
activities of drug transporters P-glycoprotein (P-gp), breast cancer resistance 
protein (BCRP), organic anion transporter (OAT)1, OAT3, organic cation 
transporter (OCT)2, organic anion transporting polypeptide (OATP)1B1, 
OATP1B3, and bile salt export pump (BSEP) at clinically relevant concentrations. 
 
An itraconazole DDI study in healthy volunteers (Study A5481016) and a rifampin 
DDI study in healthy volunteers (Study A5481017) were conducted to evaluate the 


 
 
Protocol Version: 11/13/2020, Amendment 6 
 
Page 34 of 75 
potential for strong CYP3A inhibitors and inducers, respectively, to alter the PK of 
palbociclib. Coadministration of itraconazole and palbociclib increased palbociclib 
AUCinf and Cmax by approximately 87% and 34%, respectively, relative to those 
when palbociclib dose was given alone.  Coadministration of rifampin and 
palbociclib decreased palbociclib AUCinf and Cmax by approximately 85% and 
70%, respectively, relative to palbociclib given alone.  Based on this data, the 
concurrent administration of strong CYP3A inhibitors and inducers with 
palbociclib should be avoided. 
 
A midazolam DDI study in healthy volunteers (Study A5481012) was conducted 
to evaluate the potential for palbociclib to act as a time-dependent inhibitor of 
CYP3A4/5 at steady-state.  Plasma midazolam Cmax and AUCinf values increased 
37% and 61%, respectively, when single oral doses of midazolam were co-
administered with multiple doses of palbociclib as compared to its administration 
alone. This is consistent with weak time-dependent CYP3A4/5 inhibition mediated 
by palbociclib at steady-state following daily 125 mg dosing. 
 
PK data from the Phase 1 portion of Study A5481003 was analyzed to evaluate the 
potential for a drug-drug interaction (DDI) between palbociclib and letrozole at 
steady-state.  These data indicate a lack of a potential for DDIs between palbociclib 
and letrozole when administered in combination.  
 
Data from a DDI study in healthy male subjects indicated that palbociclib exposures 
were comparable when a single dose of palbociclib was coadministered with 
multiple doses of tamoxifen and when palbociclib was given alone. 
 
The effect of food on the exposure of palbociclib when administered as the 
commercial free base capsule was evaluated in healthy subjects (A5481021).  
Compared to palbociclib given under overnight fasted conditions, the AUCinf and 
Cmax of palbociclib increased by 21% and 38% when given with high-fat food, by 
12% and 27% when given with low-fat food, and by 13% and 24% when moderate-
fat food was given 1 hour before and 2 hours after palbociclib dosing.  In addition, 
food intake significantly reduced the intersubject and intrasubject variability of 
palbociclib exposure.  Based on these results, palbociclib commercial free base 
capsules should be taken with food. 
 
The solubility of the palbociclib free base is pH dependent—palbociclib is water 
soluble at low pH (2.1-4.5), while the solubility dramatically decreases as pH rises 
above 4.5.  Concomitant administration of agents which increase gastric pH can 
alter the solubility and absorption of palbociclib free base formulations.  
 
In a drug interaction trial in healthy subjects (A5481038), coadministration of a 
single 125 mg dose of commercial free base capsule with multiple doses of the 
proton pump inhibitors (PPI) rabeprazole under fed conditions decreased 
palbociclib Cmax by 41%, but had limited impact on AUCinf (13% decrease), when 
compared to a single dose of palbociclib administered alone.  Given the reduced 


 
 
Protocol Version: 11/13/2020, Amendment 6 
 
Page 35 of 75 
effect on gastric pH of H2-receptor antagonists and local antacids compared to 
PPIs, the effect of these classes of acid-reducing agents on palbociclib exposure 
under fed conditions is expected to be minimal.  Under fed conditions there is no 
clinically relevant effect of PPIs, H2-receptor antagonists, or local antacids on 
palbociclib exposure.  In another healthy subject study, coadministration of a single 
dose of commercial free base capsule with multiple doses of the PPI rabeprazole 
under fasted conditions decreased palbociclib AUCinf and Cmax by 62% and 80%, 
respectively, when compared to a single dose of palbociclib administered alone.  
Collectively, these antacid DDI data further support the requirement that the free 
base capsule of palbociclib should be taken with food. 
 
Based on a population pharmacokinetic analysis in 183 patients with cancer 
(50 male and 133 female patients, age range from 22 to 89 years, and body weight 
range from 37.9 to 123 kg), gender had no effect on the exposure of palbociclib, 
and age and body weight had no clinically important effect on the exposure of 
palbociclib. 
 
Based on a population pharmacokinetic analysis that included 183 patients, where 
40 patients had mild hepatic impairment (total bilirubin ≤ ULN and AST > ULN, 
or total bilirubin >1.0 to 1.5 × ULN and any AST), mild hepatic impairment had no 
effect on the exposure of palbociclib.  The pharmacokinetics of palbociclib have 
not been studied in patients with moderate or severe hepatic impairment (total 
bilirubin >1.5 × ULN and any AST). 
 
Based on a population pharmacokinetic analysis that included 183 patients, where 
73 patients had mild renal impairment (60 mL/min ≤ CrCl <90 mL/min) and 
29 patients had moderate renal impairment (30 mL/min ≤ CrCl <60 mL/min), mild 
and moderate renal impairment had no effect on the exposure of palbociclib.  The 
pharmacokinetics of palbociclib have not been studied in patients with severe renal 
impairment. 
 
A pharmacokinetic/pharmacodynamic analysis to evaluate the relationship between 
palbociclib exposure and ECG endpoints (RR and QTc intervals) were developed 
using pooled data from 3 clinical trials in patients with advanced malignant disease 
(Studies A5481001, A5481002, and A5481003).  The study population consisted 
of 48 men and 136 women with a median (range) body weight of 73.0 (37.9-123) 
kg and age of 61.5 (22-89) years old.  Palbociclib doses ranged from 25 mg to 225 
mg QD.  The data collected from 184 patients consisted of 569 ECG-palbociclib 
concentration-matched pairs; the observed plasma concentrations had a median 
(range) of 55.2 (2.51-329) ng/mL.  The average heart rate, RR, QT, QT corrected 
for heart rate according to Bazett (QTcB), QT corrected for heart rate according to 
Fridericia (QTcF), and QTcS (QT interval corrected for heart rate according to a 
study-specific correction factor) at baseline for ECG-palbociclib concentration 
matched data were 76.8 beats per minute, 808 msec, 380 msec, 425 msec, 
409 msec, and 412 msec, respectively. 
 


 
 
Protocol Version: 11/13/2020, Amendment 6 
 
Page 36 of 75 
The results of the analysis indicate that palbociclib does not appear to have a 
concentration-dependent effect on heart rate.  A slight positive linear relationship 
between palbociclib concentration and QTcS was observed; however, at the mean 
or median steady-state palbociclib Cmax following administration of the 
recommended clinical dose of palbociclib (125 mg QD) in patients with cancer, the 
upper bound of the one-sided 95% CI for the increase in QTcS fell below the 
threshold of 10 msec, suggesting that QT prolongation is not a safety concern for 
palbociclib at the recommended clinical dose according to the criteria described in 
the ICH guidance for Industry E14.  Similar results were obtained when QTcF and 
QTcB were used. 
 
8.1.4 Supplier(s) 
 
Pfizer will supply the study agent.  The study agent will be free of charge to the 
patient. 
 
8.1.5 Dosage Form and Preparation 
 
Medication will be provided in non-patient specific bottles containing either 75 mg, 
100 mg, or 125 mg capsules. The patient number and the protocol number should 
be recorded on the bottle label in the spaces provided. Site personnel must ensure 
that patients clearly understand the directions for self-medication. Patients should 
be given a sufficient supply to last until their next study visit. Unused drug and/or 
empty bottles should be returned to the site at the next study visit. Palbociclib is an 
agent that must be handled and administered with care. Patients should be instructed 
to keep their medication in the bottles provided and not transfer it to any other 
container. Due to possible unknown hazards associated with topical and 
environmental exposure to experimental agents, capsules must not be opened 
and/or emptied into any vehicle for oral ingestion; capsules must be swallowed 
intact. 
 
8.1.6 Storage and Stability 
 
Palbociclib capsules should be stored at controlled room temperature (20-25°C, 68-
77°F) in their original container. Medication should be kept in a secured locked 
area at the study site in accordance with applicable regulatory requirements. 
Returned medication should be stored separately from medication that needs to be 
dispensed.  
 
All containers of palbociclib that were sent to the investigator throughout the study 
must be returned to the sponsor or designee, whether they are used or unused, and 
whether they are empty or contain capsules. 
 
8.1.7 Administration 
 
Patients should be instructed to swallow palbociclib capsules whole and not to chew 


 
 
Protocol Version: 11/13/2020, Amendment 6 
 
Page 37 of 75 
them prior to swallowing. No capsule should be ingested if it is broken, cracked, or 
otherwise not intact. Patients should take palbociclib with food and should be 
encouraged to take their dose at approximately the same time each day. 
 
8.1.8 Special Handling Instructions 
 
No special handling instructions. 
 
8.1.9 Pregnancy 
 
The nonclinical safety profile of palbociclib has been well characterized through 
the conduct of single- and repeat-dose toxicity studies up to 39 weeks in duration, 
and safety pharmacology, genetic toxicity, reproductive and developmental 
toxicity, and phototoxicity studies.  Consistent with the pharmacologic activity of 
palbociclib (cell cycle inhibition, CDK4/6 inhibition), the primary target organ 
findings included hematolymphopoietic (decreased cellularity of bone marrow and 
lymphoid organs) and male reproductive organ (seminiferous tubule degeneration, 
and secondary effects on the epididymis, prostate, and seminal vesicle) effects in 
rats and dogs, and altered glucose metabolism that was accompanied by effects on 
the pancreas and secondary changes in the eye, teeth, kidney, and adipose tissue in 
rats only, and effects on bone in rats only that were observed following single 
and/or repeat dosing at clinically relevant exposures.  Altered glucose metabolism 
(hyperglycemia/glucosuria) correlated with pancreatic islet cell vacuolation that 
was determined to reflect a loss of beta cells with corresponding decreases in insulin 
and C-peptide.  The reversibility of the effects on glucose homeostasis, pancreas, 
eye, kidney, and bone was not established following a 12-week non-dosing period; 
whereas partial to full reversal of effects on the hematolymphopoietic and male 
reproductive systems, teeth, and adipose tissue were observed.  Additionally, a 
potential for QTc prolongation and hemodynamic effects were identified from 
safety pharmacology studies, and developmental toxicity was identified from 
embryo-fetal development studies in the rat and rabbit.  Though gastrointestinal 
effects would be anticipated from a cell cycle inhibitor and while effects were 
observed in rats and dogs following single- and repeat-dose studies up to 3 weeks 
in duration (emesis, fecal changes, and microscopic changes in stomach and 
intestines), the effects were of limited severity at clinically relevant doses.  
Gastrointestinal effects were not prominent in longer duration studies, limited to 
effects on the glandular stomach and rodent-specific effects on the non-glandular 
stomach in rats following 27 weeks of intermittent dosing that did not reverse 
during a 12-week non-dosing period.  Additional palbociclib-related findings 
considered non-adverse at tolerated doses based on limited severity and/or absence 
of degenerative changes included cellular vacuolation in multiple tissues that was 
morphologically consistent with phospholipidosis; hepatic (increases in liver 
enzymes, hepatocellular hypertrophy/increased vacuolation), renal (increased 
CPN), adrenal (cortical cell hypertrophy), and respiratory (clinical signs, tracheal 
epithelial cell atrophy) effects; and prolonged coagulation times.  Reversibility 


 
 
Protocol Version: 11/13/2020, Amendment 6 
 
Page 38 of 75 
(partial or full) was established for these additional toxicities.  Finally, palbociclib 
was determined to be an aneugen, for which a no effect exposure was identified 
 
 
 


 
 
Protocol Version: 11/13/2020, Amendment 6 
 
Page 39 of 75 
8.1.10 QT Interval 
 
Palbociclib does not appear to have a concentration-dependent effect on heart rate.  
A slight positive linear relationship between palbociclib concentration and QTcS 
was observed; however, at the mean or median steady-state palbociclib Cmax 
following administration of the recommended clinical dose of palbociclib (125 mg 
QD) in patients with cancer, the upper bound of the one-sided 95% CI for the 
increase in QTcS fell below the threshold of 10 msec, suggesting that QT 
prolongation is not a safety concern for palbociclib at the recommended clinical 
dose according to the criteria described in the ICH guidance for Industry E14. 
 
8.2 
Trastuzumab (Herceptin) 
 
8.2.1 Description  
 
Trastuzumab (Herceptin) is a recombinant DNA-derived humanized monoclonal 
antibody that selectively binds with high affinity to the extracellular domain of 
HER2 (Kd = 5 nM).27,28 The antibody is an IgG1 kappa that contains human 
framework regions with the complementarity-determining regions of a murine 
antibody (4D5) that binds to HER2.  
 
8.2.2 Use of FDA Approved Biosimilars 
 
Trastuzumab has available biosimilar products FDA approved for use. 
Trastuzumab or any of the FDA approved commercially available biosimilar 
products for trastuzumab may be administered to patients based on their insurance 
requirements or institutional practice. If a biosimilar product is required, dosing, 
schedule of administration, and premedications are identical to the guidance 
described throughout the protocol for trastuzumab. Preparation of the drug product 
will be dependent on the biosimilar selected for use. 
 
8.2.3 Pharmacokinetics and Drug Metabolism 
 
Trastuzumab 
administered 
once 
weekly 
demonstrated 
dose-dependent 
pharmacokinetics. Mean half-life increased and clearance decreased with 
increasing dose level. The half-life averaged 1.7 and 12 days at the 10 and 500 mg 
dose levels, respectively. Trastuzumab’s volume of distribution was approximately 
that of serum volume (44 mL/kg). At the highest weekly dose studied (500 mg), 
mean peak serum concentrations were 377 mcg/mL.  
 
In studies using a loading dose of 4 mg/kg followed by a weekly maintenance dose 
of 2 mg/kg, a mean half-life of 5.8 days (range = 1 to 32 days) was observed. 
Between Weeks 16 and 32, trastuzumab serum concentrations reached a steady 
state with a mean trough and peak concentrations of approximately 79 
microgram/mL and 123 microgram/mL, respectively.  
 


 
 
Protocol Version: 11/13/2020, Amendment 6 
 
Page 40 of 75 
Data suggest that the disposition of trastuzumab is not altered based on age or serum 
creatinine (up to 2.0 mg/dL). No formal interaction studies have been performed.  
 
8.2.4 Supplier(s) 
 
Trastuzumab is commercially available. 
 
8.2.5 Dosage Form and Preparation 
 
Trastuzumab is a sterile, white to pale yellow, preservative-free lyophilized powder 
for intravenous (IV) administration.  Each 150mg trastuzumab vial for injection is 
supplied in a single-dose vial as a lyophilized sterile powder under vacuum.  
 
Use appropriate aseptic technique.  Each 150 mg vial of trastuzumab should be 
reconstituted with 7.4 ml of SWFI (not supplied) to yield a solution for single-dose 
use, containing 21mg/ml of trastuzumab.  
 
Determine the dose of trastuzumab needed. Calculate the correct dose using 21 
mg/mL trastuzumab solution.  Withdraw this amount from the vial and add it to an 
infusion bag containing 250 mL of 0.9% sodium chloride, USP.  DEXTROSE 
(5%) SOLUTION SHOULD NOT BE USED.  Gently invert the bag to mix the 
solution.  The reconstituted preparation results in a colorless to pale yellow 
transparent solution.  Parenteral drug products should be inspected visually for 
particulates and discoloration prior to administration. 
 
No incompatibilities between trastuzumab and polyvinylchloride or polyethylene 
bags have been observed. 
 
8.2.6 Storage and Stability 
 
Vials of trastuzumab are stable at 2-8°C (36-46°F) prior to reconstitution. Do not 
use beyond the expiration date stamped on the vial. A vial of 150mg trastuzumab 
reconstituted with SWFI contains no preservative and is intended for single-use 
only. The reconstituted trastuzumab solution should be used immediately and any 
unused portion must be discarded. DO NOT FREEZE TRASTUZUMAB THAT 
HAS BEEN RECONSTITUTED. 
  
The solution of trastuzumab for infusion diluted in polyvinylchloride or 
polyethylene bags containing 0.9% Sodium Chloride Injection, USP, may be stored 
at 2-8°C (36-46°F) for up to 24 hours prior to use. Discard after 24 hours.  
 
8.2.7 Administration 
 
Please refer to Section 5.1. 
 
 


 
 
Protocol Version: 11/13/2020, Amendment 6 
 
Page 41 of 75 
8.2.8 Special Handling Instructions 
 
None. 
8.3 
Letrozole (Femara) 
 
8.3.1 Letrozole Description 
 
Letrozole is indicated for: 
• the adjuvant treatment of postmenopausal women with hormone receptor 
positive early breast cancer; 
• the extended adjuvant treatment of early breast cancer in postmenopausal 
women who have received 5 years of adjuvant tamoxifen therapy; 
• first-line treatment of post-menopausal women with hormone receptor 
positive or unknown, locally advanced or metastatic breast cancer; 
• the treatment of advanced breast cancer in postmenopausal women with 
disease progression following antiestrogen therapy. 
 
Letrozole is a nonsteroidal aromatase inhibitor (inhibitor of estrogen synthesis).  It 
is chemically described as 4,4’-(1H-1,2,4-Triazol-1-ylmethylene)dibenzonitrile.  It 
has a molecular weight of 285.31 and an empirical formula of C17H11N5. 
 
8.3.2 Clinical Pharmacology 
 
The growth of some cancers of the breast is stimulated or maintained by estrogens. 
Treatment of breast cancer thought to be hormonally responsive (i.e., estrogen 
and/or progesterone receptor positive or receptor unknown) has included a variety 
of 
efforts 
to 
decrease 
estrogen 
levels 
(ovariectomy, 
adrenalectomy, 
hypophysectomy) or inhibit estrogen effects (antiestrogens and progestational 
agents). These interventions lead to decreased tumor mass or delayed progression 
of tumor growth in some women.  
 
In postmenopausal women, estrogens are mainly derived from the action of the 
aromatase enzyme, which converts adrenal androgens (primarily androstenedione 
and testosterone) to estrone and estradiol. The suppression of estrogen 
biosynthesis in peripheral tissues and in the cancer tissue itself can therefore be 
achieved by specifically inhibiting the aromatase enzyme.  
 
Letrozole is a nonsteroidal competitive inhibitor of the aromatase enzyme system; 
it inhibits the conversion of androgens to estrogens. In adult nontumor- and tumor-
bearing female animals, letrozole is as effective as ovariectomy in reducing uterine 
weight, elevating serum LH, and causing the regression of estrogen-dependent 
tumors. In contrast to ovariectomy, treatment with letrozole does not lead to an 
increase in serum FSH. Letrozole selectively inhibits gonadal steroidogenesis but 
has no significant effect on adrenal mineralocorticoid or glucocorticoid synthesis.  
 


 
 
Protocol Version: 11/13/2020, Amendment 6 
 
Page 42 of 75 
Letrozole inhibits the aromatase enzyme by competitively binding to the heme of 
the cytochrome P450 subunit of the enzyme, resulting in a reduction of estrogen 
biosynthesis in all tissues. Treatment of women with letrozole significantly lowers 
serum estrone, estradiol and estrone sulfate and has not been shown to significantly 
affect adrenal corticosteroid synthesis, aldosterone synthesis, or synthesis of 
thyroid hormones. 
 
8.3.3 Pharmacokinetics and Drug Metabolism 
 
Letrozole is rapidly and complete absorbed from the gastrointestinal tract and 
absorption is not affected by food.  About 90% of letrozole is recovered in urine.  
Its terminal elimination half-life is about 2 days and steady-state plasma 
concentration after daily 2.5 mg dosing is reached in 2-6 weeks. 
 
8.3.4 Supplier(s) 
 
Letrozole is commercially available. 
 
8.3.5 Dosage Form and Preparation 
 
Letrozole is available as 2.5 mg tablets. 
 
8.3.6 Storage and Stability 
 
Store at 25°C (77°F); excursions permitted to 15 to 30°C (59 to 86°F). 
 
8.3.7 Administration 
 
Please refer to Section 5.1. 
 
8.3.8 Special Handling Instructions 
 
None. 
 
8.4 
Goserelin (Zoladex) 
 
8.4.1 Goserelin Description 
 
Goserelin is a gonadotropin releasing hormone (GnRH) agonist indicated for: 
• Use in combination with flutamide for the management of locally confined 
carcinoma of the prostate 
• Palliative treatment of advanced carcinoma of the prostate 
• The management of endometriosis 
• Use as an endometrial-thinning agent prior to endometrial ablation for 
dysfunctional uterine bleeding 


 
 
Protocol Version: 11/13/2020, Amendment 6 
 
Page 43 of 75 
• Use in the palliative treatment of advanced breast cancer in pre- and peri-
menopausal women 
 
 
Goserelin acetate is chemically described as an acetate salt of [D-
Ser(But)6,Azgly10]. Its chemical structure is pyro-Glu-His-Trp-Ser-Tyr-D-
Ser(But)-Leu-Arg-Pro-Azgly-NH2 acetate [C59H84N18O14·(C2H4O2)x where x = 1 
to 2.4]. 
 
8.4.2 Clinical Pharmacology 
 
Goserelin is a synthetic decapeptide analogue of GnRH. Goserelin acts as an 
inhibitor of pituitary gonadotropin secretion when administered in the 
biodegradable formulation. 
 
8.4.3 Supplier(s) 
 
Goserelin is commercially available. 
 
8.4.4 Dosage Form and Preparation 
 
Goserelin is available in two dosages. At a dose of 10.8 mg, it is administered 
subcutaneously every 12 weeks into the anterior abdominal wall. At a dose of 3.6 
mg, it is administered every 28 days. 
 
8.4.5 Storage and Stability 
 
 
 
Do not store above 25°C. 
 
8.4.6 Administration 
 
Please refer to Section 5.1 
 
8.4.7 Special Handling Instructions 
 
None. 
 
8.5 
Lupron (Leuprolide) 
 
8.5.1 Lupron Description 
 
Lupron may be substituted for Goserelin. It is a synthetic gonadotropin-releasing 
hormone indicated for: 
• Use in combination with flutamide for the management of locally confined 
carcinoma of the prostate 
• Palliative treatment of advanced carcinoma of the prostate 


 
 
Protocol Version: 11/13/2020, Amendment 6 
 
Page 44 of 75 
 
• The management of endometriosis 
• Use as an endometrial-thinning agent prior to endometrial ablation for 
dysfunctional uterine bleeding 
• Use in the palliative treatment of advanced breast cancer in pre- and peri-
menopausal women 
 
 
9.0 
CORRELATIVE STUDIES 
 
9.1 
Archival Tumor Sample Submission  
 
Ten of 5 micron section unstained slides from the pre-treatment archival 
diagnostic core biopsy of the primary breast cancer will be requested for 
correlative studies that investigate predictors of response and mechanisms of 
action of the study treatment. Alternatively, a tumor block could be submitted, 
which will be returned after sectioning.  
 
All samples should be marked with the patients' study number, initials and date of 
the sample using an indelible marker.  Please include the pathology report 
associated with the archival tumor material. 
 
Archival tumor specimens along with the completed Archival Tumor Specimen 
Submission Form (Appendix G) are to be shipped to Dr. Cynthia Ma’s laboratory 
at the address below: 
 
Dr. Cynthia Ma Laboratory 
Attn: Jeremy Hoog 
Washington University School of Medicine 
4515 McKinley Research Building 
Campus Box 8076 
3rd Floor, Room 3111A 
St. Louis, MO 63110 
Phone: (314) 747-9309 
 
9.2 
Tumor Biopsy and Peripheral Blood Collection 
 
9.2.1 Collection of Specimen(s) 
 
The kit is a two-chamber kit in which it is possible to send both frozen and ambient 
specimens. The kit is stocked with all the necessary items needed to draw blood 
and obtain tissue specimens. It also contains the necessary materials used to process 
and prepare specimens for shipment in accordance to IATA regulations. Finally the 
kit contains all required documentation and labels required to return the kit to the 
Washington University Tissue Procurement Core Facility (address listed below).  


 
 
Protocol Version: 11/13/2020, Amendment 6 
 
Page 45 of 75 
 
It is advised that the baseline samples are harvested during port placement to 
optimize tissue acquisition.  
 
Please note, secondary sites will not be submitting PDX samples. 
 
 
Correlative 
study 
Blood/tumor 
Type of tube 
Volume 
Time point 
Process at 
site 
Temperature conditions 
for storage/shipping 
Archival 
Tumor  
Tumor rich 
block/slides 
N/A 
N/A 
Diagnostic, 
Surgery 
Yes 
Blocks/slides can be 
shipped at room temperature 
same day or overnight 
Tumor for 
research 
Core biopsies 
1 core snap 
frozen, 2 
cores 
preserved 
OCT, 1 core 
PDX (no 
C1D15), 1 
core 10% 
formalin 
(C1D15 
only) 
14G core 
needle 
Baseline, 
C1D15, Surgery 
No  
Cores should be 
immediately snap frozen 
and ship on dry ice; cores in 
formalin should be stored / 
shipped at ambient 
temperature same day or 
overnight (Avoid Fridays). 
Plasma for 
research 
Whole blood 
EDTA 
(purple) 
10mL 
Baseline, 
C1D15, Surgery, 
Yearly post-
surgery for 5 
years 
Yes 
-80ºC  
 
Serum for 
research 
Whole blood 
Clot tube 
(red) 
10mL 
Baseline, 
C1D15, Surgery 
Yes 
-80ºC  
 
Germline DNA 
for research 
Whole blood 
EDTA 
(purple) 
10mL 
Baseline 
No 
Ambient 
Whole blood 
for plasma 
circulating 
DNA 
Whole blood 
Cell-free 
DNA BCT 
(Streck) 
10mL x2 
Baseline, 
C1D15, Surgery, 
Yearly post-
surgery for 5 
years 
No 
Room temperature, same 
day or overnight shipment 
(avoid Fridays) 
Blood for 
detection of 
circulating 
tumor cells 
Whole blood 
EDTA 
(purple) 
10 mL 
Baseline 
No 
Dr. Aft’s lab 
 
 
 
 
9.2.2 Handling of Specimen(s) 
 
9.2.2.1 Biopsies 
 
For biopsies at each time point: 4 cores (14 G core needle) will be taken at 
each time point. Care needs to be taken to reduce the ischemic time to as 
much as possible to less than 30 min.  
 
Samples can be obtained at the time of surgery. Care needs to be taken to 
reduce the ischemic time to as much as possible to less than 30 minutes. 


 
 
Protocol Version: 11/13/2020, Amendment 6 
 
Page 46 of 75 
 
An additional 20 of 5 micron section unstained slides from a tumor rich 
block of the resected breast cancer following surgery are requested.  
Alternatively, a tumor block could be submitted, which will be returned 
after sectioning.  These sections or the tumor block with the completed 
Archival Tumor Specimen Submission Form (Appendix G) are to be 
shipped to Dr. Cynthia Ma’s laboratory at the address in Section 9.1. 
 
Additional tumor samples from surgical pathology may be requested if the 
research core does not contain sufficient tumor for correlative studies.  
 
Secondary sites will not be submitting PDX samples. 
 
Tissue will be distributed as follows: 
• Baseline: 1 core fresh for PDX, 1 core snap frozen to the Tissue 
Procurement Core (TPC), and 2 cores preserved in OCT to the TPC 
• C1D15: 1 core snap frozen to TPC, 1 core preserved in 10% 
formalin to TPC, and 2 cores preserved in OCT to TPC 
• Surgery: 1 core fresh for PDX, 1 core snap frozen to TPC, and 2 
cores preserved in OCT to TPC 
 
9.2.2.2 Peripheral Blood 
 
Serum and plasma processing: The blood samples must be processed to 
plasma and placed in the freezer at -80°C within one hour of collection. To 
process the blood samples to plasma, centrifuge the blood samples at 
approximately 4°C at 1700xg for approximately 10 minutes. Using a 
separate pipette for each time point, transfer the plasma samples into pre-
labeled amber polypropylene cryovials and store at approximately -80°C 
until shipment. As much as practical, keep the blood and plasma samples 
away from direct sunlight and unfiltered lab light. Ship the samples on dry 
ice to the analytical labs.  
 
Germ line DNA processing: The EDTA tube should be mixed several times 
and labeled with the patient’s study number, date of birth, and collection 
date and time. Whole blood specimens are shipped in the specimen kit and 
must be received by the Washington University Tissue Procurement 
Facility within 48 hours of the time of collection. Do not freeze whole 
blood.  
 
Whole blood for plasma circulating DNA: The cell free DNA collection 
BCT tube (provided with the kits) should be mixed several times and 
labeled with the patient’s study number, date of birth, and collection date 
and time. Whole blood specimens are shipped in the specimen kit and must 
be received by the Washington University Tissue Procurement Facility 


 
 
Protocol Version: 11/13/2020, Amendment 6 
 
Page 47 of 75 
within 48 hours of the time of collection. Do not freeze whole blood. Do 
not put BCT tubes on ice.  
 
9.2.3 Shipping of Specimen(s) 
 
All samples should be labeled with institutional surgical pathology number (tumor 
samples), study number, patient ID number, patient initials, sample collection date 
and time and be accompanied by the completed specimen submission forms.  
 
All samples should be shipped to the Wash U Tissue Procurement Core Facility.  
 
Specimens may be sent to the Wash U Tissue Procurement Facility on Monday 
through Thursday for next day delivery. The Bank cannot receive specimens on 
Saturdays, Sundays, or holidays. Do not send specimens on Friday, Saturday, or 
the day before a holiday.  
 
The institution is expected to pay the cost of mailing specimens and will be 
reimbursed through capitation fees set for each individual study.  
 
Arrange for Federal Express pick-up through your usual institutional procedure. 
Ship specimens to the address below:  
Wash U Tissue Procurement Core 
425 S. Euclid Ave, Room 5120  
St. Louis, MO 63110-1005  
Phone: (314) 454-7615  
E-mail: tbank@wudosis.wustl.edu  
 
On the day that specimens are sent to the specimen bank, please contact the 
bank by phone, fax, or e-mail to notify what is being sent and when the 
shipment is expected to arrive. 
 
9.3 
OPTIONAL Bone Marrow Biopsy 
 
9.3.1 Collection of Specimen(s) 
 
Bone marrow aspirations for DTCs will be obtained only from patients who consent 
at the following two time points:  
• Baseline  
• At definitive surgery  
 
Bone marrow collection and analysis will be paid for by research funds and will 
not be charged to the patient or patient’s insurance. 
 
The baseline bone marrow aspiration will be performed in the operating room at 
the time of port placement if possible to avoid a second procedure. The 2nd bone 
marrow aspiration will be performed in the operating room at the time of definitive 


 
 
Protocol Version: 11/13/2020, Amendment 6 
 
Page 48 of 75 
surgery. 
 
Sixteen mL of bone marrow aspirate will be collected from the right and/or left iliac 
crest. After the collection of 8 mL the needle will be redirected to minimize the 
collection of peripheral blood. If the patient tolerates the collection of bone marrow 
from one side, then bone marrow will be collected from the contralateral side if 
needed to obtain additional aspirate.  
 
The right or left posterior superior iliac crest region or the anterior iliac crest will 
be identified, and the area will be sterilely prepped with an alcohol based solution.  
 
The region to be entered will be anesthetized with lidocaine and/or 
lidocaine/bupivacaine mixture and, following adequate anesthesia, an Illinois or 
Jamshidi needle will be inserted into the iliac crest region.  
 
The bone marrow cavity will be penetrated and approximately 16 mL of bone 
marrow aspirate will be obtained from the iliac crest. If BM is collected from both 
iliac crests, then 1-4 mL of BM from each side will be combined and placed in a 
tube provided by a commercial vendor for DTC enumeration/Her2+ determination, 
1-4 ml will be taken to a research lab for enrichment by filtration and molecular 
analysis. The remainder of the BM will be divided between 1-3 EDTA tubes. The 
procedure will be repeated on the contralateral side. After aspiration, the needle 
will be removed. The puncture sites will be cleaned and bandaged. Each participant 
will receive printed wound care instructions containing contact information for 
medical assistance if the participant experiences any adverse symptoms or 
problems following the procedure. 
 
9.3.2 Handling of Specimen(s) 
 
All tubes containing bone marrow will be labeled with UPN and the site of 
collection.  
 
One to 2 EDTA tubes will be taken to a research laboratory for DTC enrichment 
and molecular analysis. If analyzed, two of the tubes will be used for RT-PCR 
analysis, and one tube will be stored. The Cee Sure tubes or tubes from other 
commercial vendors will be shipped in the kits provided by the vendor to Biocept 
or other commercial vendor according to the vendor’s instructions. The EDTA 
tubes will be transported to the Siteman Cancer Center Tissue Procurement Core 
for processing and storage.   
 
All tubes from non-WU sites will be shipped at room temperature to the WU Tissue 
Procurement Core (see Section 9.1.3). 
 
 


 
 
Protocol Version: 11/13/2020, Amendment 6 
 
Page 49 of 75 
10.0 
STUDY CALENDAR 
 
Screening/baseline evaluations are to be conducted within 4 weeks prior to start of protocol therapy.  Scans and x-rays must be done no 
more than 12 weeks prior to the start of the protocol therapy. There is a +/- 1 day window for each study visit. 
 
 
Screening Baseline 
Day 1 of 
Each 
Cycle5 
C1D15 
End 
of 
C1 
End 
of 
C4 
Pre-
Surgery 
Surgery 
Post-
Surgery11 
Follow-
Up1 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
H&P 
X 
 
X 
 
 
X 
 
 
X 
 
Vital signs 
X 
 
X 
 
 
X 
 
 
X 
 
CBC w/diff 
X 
 
X 
X10 
 
X 
 
 
X 
 
CMP 
X 
 
X 
 
 
X 
 
 
X 
 
Pregnancy test2 
X 
 
 
 
 
 
 
 
 
 
12-lead ECG 
X 
 
 
 
 
 
 
 
 
 
Echocardiogram or MUGA12 
X 
 
 
 
 
 
 
 
 
 
Mammogram 
X4 
 
 
 
 
 
X 
 
 
 
Ultrasound 
X4 
 
 
 
 
 
X 
 
 
 
Clinical evaluation 
 
 
X 
 
 
 
 
 
 
 
Palbociclib 
 
 
X6 
 
 
 
 
 
 
 
Trastuzumab (or FDA approved biosimilar)13 
 
 
X7 
 
 
 
 
 
 
 
Letrozole 
 
 
X8 
 
 
 
 
 
 
 
Goserelin3 
 
 
X 
 
 
 
 
 
 
 
Research tumor tissue 
 
X 
 
X 
 
 
 
X 
 
 
Research bone marrow9 
 
X 
 
 
 
 
 
X 
 
 
Research blood 
 
X 
 
X 
 
 
 
X 
 
X 
Blood for germline DNA 
 
X 
 
 
 
 
 
 
 
 
NCI PRO-CTCAE 
 
X 
 
 
X 
X 
 
 
 
 
Adverse events assessment 
 
 
Collected from prior to the first treatment to 30 days after 
the last dose of palbociclib 
 
 
1. Yearly post-surgery for 5 years for recurrence and survival 
2. Women of childbearing potential only 
3. Premenopausal women only 


 
 
Protocol Version: 11/13/2020, Amendment 6 
 
Page 50 of 75 
4. Must include bi-dimensional breast measurements, but retrospective measurement is allowed 
5. Each cycle is 28 days; total of 4 cycles 
6. Days 1-21 of each cycle, total of 4 cycles 
7. Weekly (Days 1, 8, 15, and 22) of each cycle; after completion of 16 weeks, Trastuzumab maintenance will continue every 3 weeks  
8. Daily until day of surgery 
9. OPTIONAL 
10. Also D15 of C2 
11. Visit should coincide with Trastuzumab administration 
12. After baseline, perform as per standard of care. 
13. Trastuzumab or any of the FDA approved commercially available biosimilar products for trastuzumab may be administered to patients based on their insurance 
requirements or institutional practice. 
 
 


 
 
Protocol Version: 11/13/2020, Amendment 6 
 
Page 51 of 75 
11.0 
DATA SUBMISSION SCHEDULE 
 
Case report forms with appropriate source documentation will be completed according to the 
schedule listed in this section. 
 
Case Report Form 
Submission Schedule 
On Study Form 
Baseline 
Treatment Form 
Clinical Measurements Form 
End of each cycle 
NCI PRO-CTCAE Form 
Baseline 
End of Cycle 1 
End of Cycle 4 
Correlatives Form 
Baseline 
Cycle 1 Day 15 
Surgery 
Annually after surgery for 5 years 
Imaging Form 
Baseline 
Pre-Surgery 
Surgery Form 
Surgery 
Treatment Summary Form 
Off treatment 
Follow-Up Form 
Annually after surgery for 5 years 
AE Form 
Continuous 
MedWatch 
As described in Section 7.0 
 
Any queries generated by Washington University must be responded to within 28 days of receipt 
by the participating site.  The Washington University research team will conduct a regular review 
of data status at all secondary sites, with appropriate corrective action to be requested as needed. 
 
11.1 
Adverse Event Collection in the Case Report Forms 
 
All adverse events that occur beginning with start of treatment (minus exceptions defined 
in Section 1.0) must be captured in the Toxicity Form.  Baseline AEs should be captured 
on the Medical History Form. 
 
Participant death due to disease progression should be reported on the Toxicity Form as 
grade 5 disease progression.  If death is due to an AE (e.g. cardiac disorders: cardiac arrest), 
report as a grade 5 event under that AE.  Participant death must also be recorded on the 
Death Form. 
 
 
12.0 
MEASUREMENT OF EFFECT 
 
12.1 
Neoadjuvant Treatment 
 
  
Clinical Evaluation: Prior to Cycle 1, and at the beginning of each neoadjuvant treatment 


 
 
Protocol Version: 11/13/2020, Amendment 6 
 
Page 52 of 75 
cycle (that is, at the beginning of Cycles 2-4) the longest axis and the perpendicular axis of 
the measurable lesion should be measured and recorded in metric notation by tape, ruler or 
caliper technique on the case report forms. Clinical assessments will be done with bi-
dimensional measurements using either tape, ruler, or calipers in centimeters. If discrete 
breast masses are not palpable, measurements will be recorded as 0 X 0 cm. The clinical 
measurements will be used to evaluate the best treatment response by clinical evaluation. 
The final response will be documented by a Principal Investigator Note to File and entered 
on the Treatment Summary Case Report Form.    
 
Radiologic evaluation of tumor size:  Mammogram and ultrasound imaging will be 
performed up to 12 weeks prior to Cycle 1 and at the end of Cycle 4 combination therapy 
for bidimensional measurement of the tumor. The baseline imaging is used for baseline 
measurement as study allows radiographic size or physical exam for eligibility. The pre-
surgery imaging will be used to compare with baseline imaging to determine the % change 
from baseline.  
 
WHO criteria will be used to assess clinical and radiologic responses. 
 
Complete Response (CR) is defined as the disappearance of all known disease based on 
a comparison between the pre-treatment measurements and the measurements taken at the 
completion of neo-adjuvant therapy (that is, at the end of cycle 4 neo-adjuvant combination 
therapy).  In addition, there is no appearance of new lesions.  
 
Partial Response (PR) is defined as a 50% or greater decrease in the product of the bi-
dimensional measurements of the lesion (total tumor size) between the pre-treatment 
measurements and the measurements taken at the completion of neo-adjuvant therapy (that 
is, at the end of cycle 4 neo-adjuvant combination therapy).  In addition, there can be no 
appearance of new lesions or progression of any lesion. 
 
No Change (NC): a 50% decrease in total tumor size cannot be established nor has a 25% 
increase in the size of the lesion been demonstrated. 
 
Progressive Disease (PD): A 25% or greater increase in the total tumor size of the lesion 
from its pretreatment measurements or the appearance of new lesions.  
 
12.2 
Treatment Resistance 
 
A patient is said to have resistance disease if clinical with confirmed radiographical 
progressive disease is documented any time during neoadjuvant endocrine therapy. 
 
12.3 
Surgery 
 
A pathologic complete response (pCR) is defined as no histology evidence of invasive 
tumor cells in the surgical breast specimen and sentinel or axillary lymph nodes.  
 
12.4 
Post-surgery 


 
 
Protocol Version: 11/13/2020, Amendment 6 
 
Page 53 of 75 
 
Local recurrence is defined as histologic evidence of ductal carcinoma in situ or invasive 
breast cancer in the ipsilateral breast or chest wall.  
 
Regional recurrence is defined as the cytologic or histologic evidence of disease in the 
ipsilateral internal mammary, ipsilateral supraclavicular, ipsilateral infraclavicular and/or 
ipsilateral axillary nodes or soft tissue of the ipsilateral axilla. 
 
Distant recurrence is defined as the cytologic, histologic, and/or radiographic evidence 
of disease in the skin, subcutaneous tissue, lymph nodes (other than local or regional 
metastasis), lung, bone narrow, central nervous system or histologic and/or radiographic 
evidence of skeletal or liver metastasis.  
 
Second primary breast cancer is defined histologic evidence of ductal carcinoma in situ 
or invasive breast cancer in the contralateral breast or chest wall.  
Second primary cancer (non-breast) is defined as any non-breast second primary cancer 
other than squamous or basal cell carcinoma of the skin, melanoma in situ, or carcinoma 
in situ of the cervix is to be reported and should be confirmed histologically whenever 
possible. 
 
 
13.0 
DATA AND SAFETY MONITORING 
 
In compliance with the Washington University Institutional Data and Safety Monitoring Plan, an 
independent Data and Safety Monitoring Board (DSMB) will be specifically convened for this 
trial to review toxicity data at least every 6 months following the activation of the first secondary 
site.  A DSMB will consist of no fewer than 3 members including 2 clinical investigators and a 
biostatistician.  DSMB members must be employed by Washington University, Barnes-Jewish  
Hospital, or St. Louis Children’s Hospital.  Like investigators, DSMB members are subject to the 
Washington University School of Medicine policies regarding standards of conduct. Individuals 
invited to serve on the DSMB will disclose any potential conflicts of interest to the trial principal 
investigator and/or appropriate university officials, in accordance with institution policies. 
Potential conflicts that develop during a trial or a member’s tenure on a DSMC must also be 
disclosed.  
 
Until such a time as the first secondary site enrolls its first patient, a semi-annual DSM report to 
be prepared by the study team will be submitted to the Quality Assurance and Safety Monitoring 
Committee (QASMC) semi-annually beginning six months after study activation at Washington 
University (if at least one patient has been enrolled) or one year after study activation (if no patients 
have been enrolled at the six-month mark). 
 
The DSM report for the DSMB will be prepared by the study team with assistance from the study 
statistician, will be reviewed by the DSMB, and will be submitted to the Quality Assurance and 
Safety Monitoring Committee (QASMC).  This report will include: 


 
 
Protocol Version: 11/13/2020, Amendment 6 
 
Page 54 of 75 
• HRPO protocol number, protocol title, Principal Investigator name, data coordinator name, 
regulatory coordinator name, and statistician 
• Date of initial HRPO approval, date of most recent consent HRPO approval/revision, date 
of HRPO expiration, date of most recent QA audit, study status, and phase of study 
• History of study including summary of substantive amendments; summary of accrual 
suspensions including start/stop dates and reason; and summary of protocol exceptions, 
error, or breach of confidentiality including start/stop dates and reason 
• Study-wide target accrual and study-wide actual accrual including numbers from 
participating sites 
• Protocol activation date at each participating site 
• Average rate of accrual observed in year 1, year 2, and subsequent years at each 
participating site 
• Expected accrual end date and accrual by site 
• Objectives of protocol with supporting data and list the number of participants who have 
met each objective 
• Measures of efficacy 
• Early stopping rules with supporting data and list the number of participants who have met 
the early stopping rules 
• Summary of toxicities at all participating sites 
• Abstract submissions/publications 
• Summary of any recent literature that may affect the safety or ethics of the study 
 
Further DSMC responsibilities are described in the DSMC charter. 
The study principal investigator and coordinator will monitor for serious toxicities on an ongoing 
basis. Once the principal investigator or coordinator becomes aware of an adverse event, the AE 
will be reported to the HRPO and QASMC according to institutional guidelines (please refer to 
Section 7.0). 
 
Refer to the Washington University Quality Assurance and Data Safety Monitoring Committee 
Policies and Procedures for full details on the responsibilities of the DSMC.   
This is located on the QASMC website at https://siteman.wustl.edu/research/clinical-research-
resources/protocol-office-prmcqasmc/.   
 
 
14.0 
AUDITING 
 
As coordinating center of this trial, Washington University (via the Quality Assurance and Safety 
Monitoring Committee (QASMC)) will monitor each participating site to ensure that all protocol 
requirements are being met; that applicable federal regulations are being followed; and that the 
best practices for patient safety and data collection are being followed per protocol.  Participating 
sites will be asked to send copies of all audit materials, including source documentation.  The audit 
notification will be sent to the Washington University Research Patient Coordinator, who will 
obtain the audit materials from the participating institution. 
 


 
 
Protocol Version: 11/13/2020, Amendment 6 
 
Page 55 of 75 
Notification of an upcoming audit will be sent to the research team one month ahead of the audit. 
Once accrual numbers are confirmed, and approximately 30 days prior to the audit, a list of the 
cases selected for review (up to 10 for each site) will be sent to the research team. However, if 
during the audit the need arises to review cases not initially selected, the research team will be 
asked to provide the additional charts within two working days. 
 
Items to be evaluated include: 
• Subject screening and enrollment 
• Reporting of adverse events 
• Maintenance of HIPAA compliance 
• Completeness of regulatory documentation 
• Acquisition of informed consent 
• IRB documentation 
• Issues of protocol adherence 
 
Additional details regarding the auditing policies and procedures can be found at 
https://siteman.wustl.edu/wp-content/uploads/2015/10/QASMC-Policies-and-Procedures-
03.31.2015.pdf  
 
15.0 
STATISTICAL CONSIDERATIONS 
 
15.1 
Sample Size Calculation 
 
We assume a null hypothesis of 15% pCR rate in this setting. We further hypothesize that 
a pCR rate of 30% or higher warrants further investigation. A one stage single arm phase 
II design was adopted for sample size planning. 48 eligible patients will be enrolled to 
achieve 80% power at a 1-sided 0.05 significance level. If we observe 12 or more pCRs, 
the treatment regimen shows better efficacy and warrants further investigation.  
 
It is estimated based on the accrual rate of 2 patients per month across 3 participating 
centers that the completion of enrollment will take 24 months.  
 
15.2 
Data Analysis Plan 
 
All data will be evaluated as observed, and no imputation method for missing values will 
be used. Descriptive statistics will be used to summarize the trial results, i.e., statistics for 
continuous variables may include means, medians, ranges and appropriate measures of 
variability such as standard deviation and inter-quartile range. Qualitative variables will be 
summarized by counts and percentages. The uncertainty of estimates will be assessed by 
confidence intervals.  
 
The primary endpoint, pCR rate, defined as the proportion of patients with pCR in breast 
and axilla, will be calculated with 95% confidence interval. SAEs will be summarized by 
descriptive statistics. For the markers of interest in the correlative studies, Wilcoxon ranks 
um test or two sample t-test as appropriate will be conducted to compare a quantitative 


 
 
Protocol Version: 11/13/2020, Amendment 6 
 
Page 56 of 75 
marker between responders and non-responders while Fisher’s exact test will be used for 
comparison of qualitative markers such as subtype and mutation.  All analyses and 
estimates will be conducted among all patients overall, as well as by subgroups of interest. 
 
Safety analyses will be done separately for the full intention-to-treat population and also 
for subjects who receive any study treatment.  All patients are evaluable for disease 
response unless they discontinue treatment due to treatment-related adverse events prior to 
completion of Cycle 1. 
 
15.3 
Early Stopping Rule 
 
Early stopping of this trial will be based on unacceptable toxicity or futility. Approximately 
less than 15% of patients are expected to experience grade 3 and up non-hematological 
toxicity and that a non-hematological toxicity rate of 33% or more would definitely be 
unacceptable. Based on the sequential probability ratio test (SPRT) with 80% power and 
0.05 significance level, the study will be halted if 4 of the first 6, or 5 of the first 10, or 6 
of the first 15, or 7 of the first 19, or 8 of the first 23, or 9 of the first 28, or 10 of the first 
32, or if the14th toxicity is observed before the last patient has completed the trial. Accrual 
will be stopped and the event will be reviewed by the Data Safety and Monitoring Board 
if a grade 5 toxicity is observed. 
 
Once the first 20 evaluable patients are available in the study, we will start sequential 
futility monitoring for pCR. A Bayesian sequential monitoring method (Thall et al. 1995, 
1996; Ivanova et al 2005) will be implemented for futility analysis using a free software 
“Multc 
Lean” 
(version 
2.1.0) 
from 
M.D 
Anderson 
Cancer 
Center 
(https://biostatistics.mdanderson.org/softwaredownload/SingleSoftware.aspx?Software_I
d=12). The stopping rule is defined as Pr (θE > θ0 |observed data)<0.10, with θE denoting 
the pCR rate evaluated against a cutoff value θ0 and observed data referring to evaluable 
data in the study at the time of evaluation. Since the literature showed a pCR rate of 15% 
with standard neoadjuvant treatment regimen in this patient population with letrozole and 
trastuzumab, we will set the cutoff θ0=20% in the current monitoring plan. The above 
stopping rule is interpreted as: the study will stop when there is <10% probability that the 
combination treatment with letrozole, palbociclib, and trastuzumab achieves a pCR rate 
above 20%. The stopping boundaries on the number of pCRs where the posterior 
probability of the combination treatment regimen being less responsive (<0.2) is greater 
than 0.9 were calculated using “Multc Lean”. Specifically, we assumed that θE follows a 
beta distribution, θE ~ beta (α + x, β + n – x), where x and n-x represent the observed 
numbers of pCRs and non-pCRs respectively, while α and β is the shape and scale 
parameter for a prior beta distribution. We adopted the prior distribution beta (0.2, 0.48), 
which corresponds to a mean of 0.2 and a relatively large variance of 0.1, serving as a non-
informative prior. The trial will be recommended to stop for futility if we observe at most 
2 subjects with pCR out of the first 20-26 evaluable patients, at most 3 out of the first 28-
32 patients, at most 4 out of the first 34-38 patients, at most 5 out of 40-44 patients and at 
most 6 out of 48 patients. 
 


 
 
Protocol Version: 11/13/2020, Amendment 6 
 
Page 57 of 75 
15.4 
Accrual Strategy 
 
a) Use our weekly breast cancer research meeting to identify potentially eligible 
patients for PALTAN that will be seen by our breast medical oncologists. There are 
currently NO COMPETING trials for this population. 
b) Disseminate availability of the PALTAN trial to local medical and surgical 
community oncologists via letters. 
c) Provide ongoing feedback to referring physicians while their patients are on 
PALTAN. 
d) Involvement of patient advocate in education and in trial promotion. We have 
involved a breast cancer patient advocate, Judy Johnson, who has been involved in 
the design of this clinical protocol and consent form from a patient’s perspective.  
Judy Johnson will also assist with the development of a patient brochure for 
PALTAN. 
e) Identify and address reasons why eligible patients decline PALTAN trial 
participation, via screening logs to be reviewed every month by PI and study 
clinical research associate. 
f) Engagement of minority recruitment specialist. We will maximize recruitment of 
minorities through assistance of Jessica Thein, who works at our cancer center to 
increase minority participation in clinical trials. 
g) Employ the use of social media (FACEBOOK) to enhance recruitment to via 
posting a link to the PALTAN patient brochure on the Siteman Cancer Center 
Facebook page. 
h) Provide access to peer mentors (other patients who have participated in other 
clinical trial) and patient navigators for those patients identified as in need of 
additional support. 
i) Include multilingual staff and medical interpreters as members of the PALTAN 
research team as the need arises. 
 
 
16.0 
MULTICENTER REGULATORY REQUIREMENTS 
 
Washington University requires that each participating site sends its informed consent document 
to be reviewed and approved by the Washington University Regulatory Coordinator (or designee) 
prior to IRB/IEC submission.    
 
Site activation is defined as when the secondary site has received official written documentation 
from the coordinating center that the site has been approved to begin enrollment.  At a minimum, 
each participating institution must have the following documents on file at Washington University 
prior to study activation: 
• Documentation of IRB approval of the study in the form of a letter or other official 
document from the participating institution’s IRB.  This documentation must show which 
version of the protocol was approved by the IRB. 
• Documentation of IRB approval of an informed consent form. The consent must include a 
statement that data will be shared with Washington University, including the Quality 


 
 
Protocol Version: 11/13/2020, Amendment 6 
 
Page 58 of 75 
Assurance and Safety Monitoring Committee (QASMC), the DSMC (if applicable), and 
the Washington University study team. 
• Documentation of FWA, signed FDA Form 1572 (if applicable), and the CVs of all 
participating investigators. 
• Protocol signature page signed and dated by the investigator at each participating site. 
 
The coordinating center Principal Investigator (or designee) is responsible for disseminating to the 
participating sites all study updates, amendments, reportable adverse events, etc.  Protocol/consent 
modifications and IB updates will be forwarded electronically to the secondary sites within 4 
weeks of obtaining Washington University IRB approval.  Activated secondary sites are expected 
to submit protocol/consent/IB modifications to their local IRBs within 4 weeks of receipt unless 
otherwise noted.  Upon the secondary sites obtaining local IRB approval, documentation of such 
shall be sent to the Washington University study team within 2 weeks of receipt of approval. 
 
Documentation of participating sites’ IRB approval of annual continuing reviews, protocol 
amendments or revisions, all SAE reports, and all protocol violations/deviations/exceptions must 
be kept on file at Washington University. 
 
The investigator or a designee from each institution must participate in a regular conference call 
to update and inform regarding the progress of the trial. 
 
 


 
 
Protocol Version: 11/13/2020, Amendment 6 
 
Page 59 of 75 
17.0 
REFERENCES 
 
 
1. 
Sorlie T: Molecular portraits of breast cancer: tumour subtypes as distinct disease 
entities. Eur J Cancer 40:2667-75, 2004 
 
2. 
Perou CM, Sorlie T, Eisen MB, et al: Molecular portraits of human breast tumours. 
Nature 406:747-52, 2000 
 
3. 
Goldhirsch A, Wood WC, Coates AS, et al: Strategies for subtypes--dealing with 
the diversity of breast cancer: highlights of the St. Gallen International Expert Consensus on the 
Primary Therapy of Early Breast Cancer 2011. Ann Oncol 22:1736-47, 2011 
 
4. 
Slamon DJ, Clark GM, Wong SG, et al: Human-Breast Cancer - Correlation of 
Relapse and Survival with Amplification of the Her-2 Neu Oncogene. Science 235:177-182, 1987 
 
5. 
Hudis CA: Trastuzumab--mechanism of action and use in clinical practice. N Engl 
J Med 357:39-51, 2007 
 
6. 
Jones A: Combining trastuzumab (Herceptin) with hormonal therapy in breast 
cancer: what can be expected and why? Ann Oncol 14:1697-704, 2003 
 
7. 
Spector NL, Blackwell KL: Understanding the mechanisms behind trastuzumab 
therapy for human epidermal growth factor receptor 2-positive breast cancer. J Clin Oncol 
27:5838-47, 2009 
 
8. 
Huober J, Fasching PA, Barsoum M, et al: Higher efficacy of letrozole in 
combination with trastuzumab compared to letrozole monotherapy as first-line treatment in 
patients with HER2-positive, hormone-receptor-positive metastatic breast cancer - results of the 
eLEcTRA trial. Breast 21:27-33, 2012 
 
9. 
Prat A, Bianchini G, Thomas M, et al: Research-based PAM50 subtype predictor 
identifies higher responses and improved survival outcomes in HER2-positive breast cancer in the 
NOAH study. Clin Cancer Res 20:511-21, 2014 
 
10. 
Carey LA, Berry DA, Cirrincione CT, et al: Molecular Heterogeneity and Response 
to Neoadjuvant Human Epidermal Growth Factor Receptor 2 Targeting in CALGB 40601, a 
Randomized Phase III Trial of Paclitaxel Plus Trastuzumab With or Without Lapatinib. J Clin 
Oncol 34:542-9, 2016 
 
11. 
Gianni L, Pienkowski T, Im YH, et al: Efficacy and safety of neoadjuvant 
pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-
positive breast cancer (NeoSphere): a randomised multicentre, open-label, phase 2 trial. Lancet 
Oncol 13:25-32, 2012 
 
12. 
Schneeweiss A, Chia S, Hickish T, et al: Pertuzumab plus trastuzumab in 
combination with standard neoadjuvant anthracycline-containing and anthracycline-free 
chemotherapy regimens in patients with HER2-positive early breast cancer: a randomized phase 
II cardiac safety study (TRYPHAENA). Ann Oncol 24:2278-84, 2013 
 
13. 
Witters L, Engle L, Lipton A: Restoration of estrogen responsiveness by blocking 
the HER-2/neu pathway. Oncol Rep 9:1163-6, 2002 
 
14. 
Kaufman B, Mackey JR, Clemens MR, et al: Trastuzumab plus anastrozole versus 
anastrozole alone for the treatment of postmenopausal women with human epidermal growth 
factor receptor 2-positive, hormone receptor-positive metastatic breast cancer: results from the 
randomized phase III TAnDEM study. J Clin Oncol 27:5529-37, 2009 
 
15. 
Harbeck N, Gluz O, Christgen M, et al: Efficacy of 12-weeks of neoadjuvant TDM1 
with or without endocrine therapy in HER2-positive hormone-receptor-positive early breast 


 
 
Protocol Version: 11/13/2020, Amendment 6 
 
Page 60 of 75 
cancer: WSG-ADAPT HER2+/HR+ phase II trial. , American Society of Clinical Oncology. 
Chicago, IL., 2015 
 
16. 
Goel S, Wang Q, Watt AC, et al: Overcoming Therapeutic Resistance in HER2-
Positive Breast Cancers with CDK4/6 Inhibitors. Cancer Cell 29:255-69, 2016 
 
17. 
Eichhorn PJ, Gili M, Scaltriti M, et al: Phosphatidylinositol 3-kinase 
hyperactivation results in lapatinib resistance that is reversed by the mTOR/phosphatidylinositol 
3-kinase inhibitor NVP-BEZ235. Cancer Res 68:9221-30, 2008 
 
18. 
Berns K, Horlings HM, Hennessy BT, et al: A functional genetic approach 
identifies the PI3K pathway as a major determinant of trastuzumab resistance in breast cancer. 
Cancer Cell 12:395-402, 2007 
 
19. 
Ellis MJ, Tao Y, Luo J, et al: Outcome prediction for estrogen receptor-positive 
breast cancer based on postneoadjuvant endocrine therapy tumor characteristics. J Natl Cancer Inst 
100:1380-8, 2008 
 
20. 
Finn RS, Dering J, Conklin D, et al: PD 0332991, a selective cyclin D kinase 4/6 
inhibitor, preferentially inhibits proliferation of luminal estrogen receptor-positive human breast 
cancer cell lines in vitro. Breast Cancer Res 11:R77, 2009 
 
21. 
Dowsett M, Smith IE, Ebbs SR, et al: Short-term changes in Ki-67 during 
neoadjuvant treatment of primary breast cancer with anastrozole or tamoxifen alone or combined 
correlate with recurrence-free survival. Clin Cancer Res 11:951s-8s, 2005 
 
22. 
Ellis MJ, Ding L, Shen D, et al: Whole-genome analysis informs breast cancer 
response to aromatase inhibition. Nature 486:353-60, 2012 
 
23. 
Dowsett M, Smith IE, Ebbs SR, et al: Prognostic value of Ki67 expression after 
short-term presurgical endocrine therapy for primary breast cancer. J Natl Cancer Inst 99:167-70, 
2007 
 
24. 
Parker JS, Mullins M, Cheang MC, et al: Supervised risk predictor of breast cancer 
based on intrinsic subtypes. J Clin Oncol 27:1160-7, 2009 
 
25. 
Prat A, Pineda E, Adamo B, et al: Clinical implications of the intrinsic molecular 
subtypes of breast cancer. Breast 24 Suppl 2:S26-35, 2015 
 
26. 
Seidman AD, Fornier MN, Esteva FJ, et al: Weekly trastuzumab and paclitaxel 
therapy for metastatic breast cancer with analysis of efficacy by HER2 immunophenotype and 
gene amplification. J Clin Oncol 19:2587-95, 2001 
 
27. 
Coussens L, Yang-Feng TL, Liao YC, et al: Tyrosine kinase receptor with extensive 
homology to EGF receptor shares chromosomal location with neu oncogene. Science 230:1132-9, 
1985 
 
28. 
Slamon DJ, Godolphin W, Jones LA, et al: Studies of the HER-2/neu proto-
oncogene in human breast and ovarian cancer. Science 244:707-12, 1989 
 
 
 
 
We would like to thank the Alvin J. Siteman Cancer Center at Washington University School of 
Medicine and Barnes-Jewish Hospital in St. Louis, Missouri, for the use of the Clinical Trials Core 
which provided protocol development services. The Siteman Cancer Center is supported in part 
by an NCI Cancer Center Support Grant #P30 CA91842. 
 
 
 


 
 
Protocol Version: 11/13/2020, Amendment 6 
 
Page 61 of 75 
APPENDIX A: ECOG Performance Status Scale 
 
 
Grade 
 
 
Description 
0 
Normal activity.  Fully active, able to carry on all pre-disease 
performance without restriction. 
1 
Symptoms, but ambulatory.  Restricted in physically strenuous 
activity, but ambulatory and able to carry out work of a light or 
sedentary nature (e.g., light housework, office work). 
2 
In bed <50% of the time.  Ambulatory and capable of all self-care, but 
unable to carry out any work activities.  Up and about more than 50% 
of waking hours. 
3 
 
In bed >50% of the time.  Capable of only limited self-care, confined 
to bed or chair more than 50% of waking hours. 
 
4 
100% bedridden.  Completely disabled.  Cannot carry on any self-care.  
Totally confined to bed or chair. 
5 
 
Dead. 
 
 
 
 


 
 
Protocol Version: 11/13/2020, Amendment 6 
 
Page 62 of 75 
APPENDIX B: Strong CYP3A4 Inhibitors or Inducers 
(http://medicine.iupui.edu/clinpharm/ddis/clinical-table/) 
 
Inhibitors 
Indinavir 
Nelfinavir 
Ritonavir 
Clarithromycin 
Itraconazole 
Ketoconazole 
Nefazodone 
 
Inducers 
Carbamazepine 
Efavirenz 
Nevirapine 
Phenobarbital 
Phenytoin 
Pioglitazone 
Rifabutin 
Rifampin 
St. John’s Wort 
Troglitazone 
 
 


 
 
Protocol Version: 11/13/2020, Amendment 6 
 
Page 63 of 75 
APPENDIX C: Pfizer Reportable Event Cover Sheet 
 
 
 


 
 
Protocol Version: 11/13/2020, Amendment 6 
 
Page 64 of 75 
APPENDIX D: PALBOCICLIB MEDICATION DIARY 
 
Today’s Date:    
 
 
 
 
 
 
Agent:  Palbociclib 
 
Cycle:    
 
 
 
 
 
 
 
Study ID#:   
 
 
 
INSTRUCTIONS TO THE PATIENT: 
1. Complete one form for each month.  Take _____mg ( ___capsules) of palbociclib at approximately the same 
time each day with food.  Swallow the capsules whole and do not chew them. 
2. Record the date, the number of capsules taken, and when you took them. 
3. If you forgot to take your dose before 6:00PM, then do not take a dose that day.  Restart taking it the next day. 
4. If you have any questions or notice any side effects, please record them in the comments section.  Record the 
time if you should vomit. 
5. Please return the forms to your physician or your study coordinator when you go to your next appointment.  
Please bring your unused study medications and/or empty bottles with you to each clinic visit so that a pill 
count can be done. 
6. Avoid St. John’s Wort, Seville oranges, grapefruit, grapefruit juice, grapefruit hybrids, pummelos, and exotic 
citrus fruits from 7 days before you start taking palbociclib and throughout the entire study.   
Day 
Date 
What time was 
dose taken? 
# of capsules 
taken 
Comments 
1 
 
 
 
 
2 
 
 
 
 
3 
 
 
 
 
4 
 
 
 
 
5 
 
 
 
 
6 
 
 
 
 
7 
 
 
 
 
8 
 
 
 
 
9 
 
 
 
 
10 
 
 
 
 
11 
 
 
 
 
12 
 
 
 
 
13 
 
 
 
 
14 
 
 
 
 
15 
 
 
 
 
16 
 
 
 
 
17 
 
 
 
 
18 
 
 
 
 
19 
 
 
 
 
20 
 
 
 
 
21 
 
 
 
 
22 
 
 
 
 
23 
 
 
 
 
24 
 
 
 
 
25 
 
 
 
 
26 
 
 
 
 
27 
 
 
 
 
28 
 
 
 
 
 
 
 


 
 
Protocol Version: 11/13/2020, Amendment 6 
 
Page 65 of 75 
APPENDIX E: LETROZOLE MEDICATION DIARY 
 
Today’s Date:    
 
 
 
 
 
 
Agent:  Letrozole 
 
Cycle:    
 
 
 
 
 
 
 
Study ID#:   
 
 
 
 
INSTRUCTIONS TO THE PATIENT: 
1. Complete one form for each month.  Take _____mg ( ___tablets) of letrozole at approximately the same time 
each day with or without food.  Swallow the tablets whole and do not chew them. 
2. Record the date, the number of tablets taken, and when you took them. 
3. If you forgot to take your dose before 6:00PM, then do not take a dose that day.  Restart taking it the next day. 
4. If you have any questions or notice any side effects, please record them in the comments section.  Record the 
time if you should vomit. 
5. Please return the forms to your physician or your study coordinator when you go to your next appointment.  
Please bring your unused study medications and/or empty bottles with you to each clinic visit so that a pill 
count can be done. 
Day 
Date 
What time was 
dose taken? 
# of tablets 
taken 
Comments 
1 
 
 
 
 
2 
 
 
 
 
3 
 
 
 
 
4 
 
 
 
 
5 
 
 
 
 
6 
 
 
 
 
7 
 
 
 
 
8 
 
 
 
 
9 
 
 
 
 
10 
 
 
 
 
11 
 
 
 
 
12 
 
 
 
 
13 
 
 
 
 
14 
 
 
 
 
15 
 
 
 
 
16 
 
 
 
 
17 
 
 
 
 
18 
 
 
 
 
19 
 
 
 
 
20 
 
 
 
 
21 
 
 
 
 
22 
 
 
 
 
23 
 
 
 
 
24 
 
 
 
 
25 
 
 
 
 
26 
 
 
 
 
27 
 
 
 
 
28 
 
 
 
 
 
 
 


 
 
Protocol Version: 11/13/2020, Amendment 6 
 
Page 66 of 75 
APPENDIX F: NCI PRO-CTCAE QUESTIONNAIRE 
 
 


 
 
Protocol Version: 11/13/2020, Amendment 6 
 
Page 67 of 75  


 
 
Protocol Version: 11/13/2020, Amendment 6 
 
Page 68 of 75 
APPENDIX G: ARCHIVAL TUMOR SPECIMEN SUBMISSION FORM 
 
Laboratory of Dr. Cynthia X. Ma 
Archival Tumor Specimen Submission Form 
 
HRPO ID#:   201610019 
 
 
Submitter Last Name:   
 
 
 
 
 
Participant Study #:    
 
 
Submitter First Name:   
 
 
 
 
 
Participant Name (Initials):  Last:       First:      Middle:   
 Submitter’s Phone #:   
 
 
 
 
Collection Site (select one):      ☐Washington University School of Med      ☐Roswell Park     ☐ Mayo 
Arizona 
 
Study Time Point:   
ARCHIVE 
 
 
 
 
 
 
Specimen(s) Submitted:  Clinical Research Coordinator to provide date & time collected and # of 
specimens.  Include completed form with specimen shipment. 
Parent Label 
Parent Type 
Date & Time 
Collected 
Number of 
Specimens 
Site of Tissue 
 
☐Fixed tissue 
block 
☐Fixed tissue slide 
 
 
☐diagnostic core 
biopsy of the 
primary breast 
cancer 
 
 
☐Fixed tissue 
block 
☐Fixed tissue slide 
 
 
☐surgical 
resection of the 
breast cancer post 
neoadjuvant 
therapy 
 
   
Processing Notes: 
10 of 5 micron section unstained slides from the pretreatment archival diagnostic core biopsy of the 
primary breast cancer as well as 20 of 5 micron unstained slides from a tumor rich block of the resected 
breast cancer following neoadjuvant therapy are requested.  Alternatively, a tumor block could be 
submitted, which will be returned after sectioning.  Additional tissue may be requested if the samples are 
insufficient.  Please include pathology report. 
 
Shipment Address: 
 
 
 
 
 
Dr. Cynthia Ma Laboratory 
Attn: Jeremy Hoog 
Washington University School of Medicine 
4515 McKinley Research Building 
Campus Box 8076 
3rd Floor, Room 3111A 
St. Louis, MO 63110 
Phone: (314) 747-9309 
 
 


 
 
Protocol Version: 11/13/2020, Amendment 6 
 
Page 69 of 75 
APPENDIX H: Definitions for Adverse Event Reporting 
 
A. Adverse Events (AEs) 
 
As defined in 21 CFR 312.32: 
 
Definition: any untoward medical occurrence associated with the use of a drug in humans, 
whether or not considered drug-related. 
 
Grading: the descriptions and grading scales found in the revised NCI Common Terminology 
Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for all toxicity reporting.  A 
copy of the CTCAE version 4.0 can be downloaded from the CTEP website. 
 
Attribution (relatedness), Expectedness, and Seriousness: the definitions for the terms 
listed that should be used are those provided by the Department of Health and Human Services’ 
Office for Human Research Protections (OHRP).  A copy of this guidance can be found on 
OHRP’s website: 
http://www.hhs.gov/ohrp/policy/advevntguid.html 
 
B. Suspected Adverse Reaction (SAR) 
 
As defined in 21 CFR 312.32: 
 
Definition: any adverse event for which there is a reasonable possibility that the drug caused 
the adverse event.  “Reasonable possibility” means there is evidence to suggest a causal 
relationship between the drug and the adverse event.  “Suspected adverse reaction” implies a 
lesser degree of certainty about causality than adverse reaction, which means any adverse event 
caused by a drug. 
 
C. Life-Threatening Adverse Event / Life Threatening Suspected Adverse Reaction  
 
As defined in 21 CFR 312.32: 
 
Definition: any adverse drug event or suspected adverse reaction is considered “life-
threatening” if, in the view of the investigator, its occurrence places the patient at immediate 
risk of death. It does not include an adverse event or suspected adverse reaction that, had it 
occurred in a more severe form, might have caused death. 
 
D.  Serious Adverse Event (SAE) or Serious Suspected Adverse Reaction 
 
As defined in 21 CFR 312.32: 
 
Definition:  an adverse event or suspected adverse reaction is considered “serious” if, in the 
view of the investigator, it results in any of the following outcomes: 
o Death 
o A life-threatening adverse event 


 
 
Protocol Version: 11/13/2020, Amendment 6 
 
Page 70 of 75 
o Inpatient hospitalization or prolongation of existing hospitalization 
o A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 
o A congenital anomaly/birth defect 
o Any other important medical event that does not fit the criteria above but, based upon 
appropriate medical judgment, may jeopardize the subject and may require medical or 
surgical intervention to prevent one of the outcomes listed above 
 
E. Protocol Exceptions 
 
Definition: A planned change in the conduct of the research for one participant. 
 
F. Deviation 
 
Definition: Any alteration or modification to the IRB-approved research without prospective 
IRB approval.  The term “research” encompasses all IRB-approved materials and documents 
including the detailed protocol, IRB application, consent form, recruitment materials, 
questionnaires/data collection forms, and any other information relating to the research study. 
 
A minor or administrative deviation is one that does not have the potential to negatively impact 
the rights, safety, or welfare of participants or others or the scientific validity of the study. 
 
A major deviation is one that does have the potential to negatively impact the rights, safety, or 
welfare of participants or others or the scientific validity of the study. 
 
 
 


 
 
Protocol Version: 11/13/2020, Amendment 6 
 
Page 71 of 75 
APPENDIX I: Reporting Timelines 
Expedited Reporting Timelines 
Event 
HRPO 
QASMC 
FDA 
IBC 
Pfizer 
Serious AND 
unexpected suspected 
adverse reaction 
 
 
Report no later than 15 
calendar days after it is 
determined that the 
information qualifies for 
reporting 
N/A 
Within 24 hours of first 
awareness of the event 
Unexpected fatal or 
life-threatening 
suspected adverse 
reaction 
 
 
Report no later than 7 
calendar days after initial 
receipt of the information 
 
Within 24 hours of first 
awareness of the event 
(immediately if the 
event is fatal or life-
threatening) 
 
Unanticipated 
problem involving risk 
to participants or 
others 
Report within 10 working days.  
If the event results in the death 
of a participant enrolled at 
WU/BJH/SLCH, report within 
1 working day. 
Report via email after 
IRB acknowledgment 
 
 
 
Major deviation 
Report within 10 working days.  
If the event results in the death 
of a participant enrolled at 
WU/BJH/SLCH, report within 
1 working day. 
 
 
 
 
A series of minor 
deviations that are 
being reported as a 
continuing 
noncompliance 
Report within 10 working days.    
 
 
 
Protocol exception 
Approval must be obtained 
prior to implementing the 
change 
 
 
 
 
Clinically important 
increase in the rate of 
a serious suspected 
adverse reaction of 
 
 
Report no later than 15 
calendar days after it is 
determined that the 
 
 


 
 
Protocol Version: 11/13/2020, Amendment 6 
 
Page 72 of 75 
Expedited Reporting Timelines 
Event 
HRPO 
QASMC 
FDA 
IBC 
Pfizer 
that list in the protocol 
or IB 
information qualifies for 
reporting 
Complaints 
If the complaint reveals an 
unanticipated problem 
involving risks to participants 
or others OR noncompliance, 
report within 10 working days.  
If the event results in the death 
of a participant enrolled at 
WU/BJH/SLCH, report within 
1 working day.  Otherwise, 
report at the time of continuing 
review. 
 
 
 
 
Breach of 
confidentiality 
Within 10 working days. 
 
 
 
 
Incarceration 
If withdrawing the participant 
poses a safety issue, report 
within 10 working days.   
 
If withdrawing the participant 
does not represent a safety issue 
and the patient will be 
withdrawn, report at continuing 
review. 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
Protocol Version: 11/13/2020, Amendment 6 
 
Page 73 of 75 
 
 
Routine Reporting Timelines 
Event 
HRPO 
QASMC 
FDA 
Pfizer 
Adverse event or SAE 
that does not require 
expedited reporting 
If they do not meet the definition of an 
unanticipated problem involving risks to 
participants or others, report summary 
information at the time of continuing review 
Adverse events will be 
reported in the toxicity 
table in the DSM report 
which is typically due 
every 6 months. 
The most current 
toxicity table from the 
DSM report is provided 
to the FDA with the 
IND’s annual report. 
 
Minor deviation 
Report summary information at the time of 
continuing review. 
 
 
 
Complaints 
If the complaint reveals an unanticipated problem 
involving risks to participants or others OR 
noncompliance, report within 10 working days.  If 
the event results in the death of a participant 
enrolled at WU/BJH/SLCH, report within 1 
working day.  Otherwise, report at the time of 
continuing review. 
 
 
 
Incarceration 
If withdrawing the participant poses a safety 
issue, report within 10 working days.   
 
If withdrawing the participant does not represent a 
safety issue and the patient will be withdrawn, 
report at continuing review. 
 
 
 
Pregnancy and/or 
lactation 
 
 
 
Within 24 hours of first 
awareness of the event 
(immediately if the event is 
fatal or life-threatening) 
Occupation Exposure 
 
 
 
Within 24 hours of first 
awareness of the event 
(immediately if the event is 
fatal or life-threatening) 
Hy’s Law Case (Drug-
Induced Liver Injury) 
 
 
 
Within 24 hours of first 
awareness of the event 


 
 
Protocol Version: 11/13/2020, Amendment 6 
 
Page 74 of 75 
(immediately if the event is 
fatal or life-threatening) 
 
Expedited Reporting Timelines for Secondary Sites 
Event 
WU (Coordinating Center) 
Local IRB 
FDA 
Pfizer 
Serious AND unexpected 
suspected adverse reaction 
Report no later than 11 calendar days 
after it is determined that the information 
qualifies for reporting. 
Report all applicable 
events to local IRB 
according to local 
institutional guidelines. 
The research team at 
Washington University is 
responsible for reporting all 
applicable events to the 
FDA as needed. 
The research team at 
Washington University is 
responsible for reporting all 
applicable events to Pfizer as 
needed. 
Unexpected fatal or life-
threatening suspected 
adverse reaction 
Report no later than 4 calendar days after 
initial receipt of the information. 
Unanticipated problem 
involving risk to participants 
or others 
Report no later than 4 calendar days after 
initial receipt of the information. 
Adverse event or SAE that 
does not require expedited 
reporting 
As per routine data entry expectations 
Protocol exception 
Approval must be obtained prior to 
implementing the change. 
 
 
 


 
 
Protocol Version: 11/13/2020, Amendment 6 
 
Page 75 of 75 
APPENDIX J: Washington University SAE Reporting Cover Sheet 
 
SAE COVER SHEET- Secondary Site Assessment 
 
Washington University HRPO#:  
Sponsor-Investigator:  
Subject Initials:   
Subject ID:  
Treating MD:  
Treating Site:  
EVENT TERM:  
Event Start Date: 
EVENT GRADE: 
Date of site’s first notification: 
 
Treating MD Event Assessment:  
 
 
Is this event possibly, probably, or definitely related study treatment? 
 
 yes  
 
 no 
 
If yes, please list which drug (if more than one)______________________________ 
 
       
Explain ______________________________________________________________________ 
 
______________________________________________________________________________ 
 
 
 
_________________________           ___________________________      _________________  
Physician’s Name 
 
 
Physician’s Signature 
 
Date