Clinical trial NCT03530696
Conditions: HER2-positive Breast Cancer Breast Cancer Breast Cancer Stage Recurrent Breast Cancer Metastatic Breast Cancer HER2 Positive Breast Carcinoma
Keywords: Breast Cancer HER2-positive T-DM1 HER2-positive Breast Cancer Recurrent Breast Cancer Metastatic Breast Cancer
Sponsor: University of Arizona
Start date: 2018-12-06; Completion date: 2022-12-22
Enrollment: 55 participants; Allocation: RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
This is a single arm, phase II study to evaluate if the combination of T-DM1 with palbociclib improves progression-free survival in patients with metastatic HER2 positive breast cancer. All patients will be treated with T-DM1 with palbociclib.

Detailed description:
This is a multi-center, single arm, phase II study of T-DM1 with palbociclib in the treatment of patients with metastatic HER2-positive breast cancer.

Hypotheses: Combination of T-DM1 with palbociclib improves progression free survival

Primary objective: Progression free survival of the combination of T-DM1 with palbociclib

Secondary objectives i) Response rates ii) Overall survival

Correlative objectives i) Investigate predictive biomarkers of response in blood and archived tumor tissue ii) Investigate mechanisms of resistance for palbociclib in blood and tumor tissue

Arms: arm 1: T-DM1 is given intravenously every 21 days (day 1 of each cycle) Palbociclib is administered orally on days 5-18 of each cycle arm 2: T-DM1 is given intravenously every 21 days (day 1 of each cycle)
Interventions: intervention 1: Palbociclib intervention 2: T-DM1
Intervention descriptions: intervention 1: Palbociclib is to be taken orally on days 5-18 (14 days) of each cycle (each cycle length is 21 days). The starting dose will be 125mg. intervention 2: The recommended dose of T-DM1 is 3.6 mg/kg and is given as an intravenous infusion on Day 1 of every cycle (every 21 days).

Protocol documents:
Prot_SAP_000.pdf: 
 
 
Official Title: 
A single arm phase II study to evaluate efficacy of T-DM1 
with Palbociclib in the treatment of patients with 
metastatic HER2 positive breast cancer 
NCT number: 
NCT03530696 
Document Type:  
Study Protocol and Statistical Analysis Plan 
Date of the 
Document: 
01/25/2021 
 
 


1 
Palbo T-DM1 - Protocol Version 5 & Date 01/25/2021  
Study Title: A single arm phase II study to evaluate efficacy of T-DM1 with Palbociclib in the 
treatment of patients with metastatic HER2 positive breast cancer  
 
 
Principal Protocol Investigator 
 
Pavani Chalasani, MD  
1515 N Campbell Ave 
Tucson, AZ  85724 
(520) 626-7725 
Pchalasani@uacc.arizona.edu 
 
Coordinating Center (multi-site) 
The University of Arizona Cancer Center 
3838 N Campbell Ave 
Tucson, AZ  85719 
 
Sponsor 
Pavani Chalasani MD, MPH                                    
The University of Arizona Cancer Center 
3838 N Campbell Ave 
Tucson, AZ  85719 
 
CRO 
ABRCC-Criterium, Inc       
Phone: 518-583-0095       
358 Broadway, Suite 201       
Saratoga Springs, NY 12866 
 
 
 
Investigational Product  
 
 
 
Palbociclib 
Intervention or Device supplier 
 
 
Pfizer 
 
 
 
 
 
 
 
235 E 42nd Street 
 
 
 
 
 
 
 
New York, NY 10017 
 
 
 
 
 
 
 
  
 
 
Commercial Agent(s) Supplier 
 
 
T-DM1 
 
 
Protocol Version(s) and Date(s) 
 
 
Version 5 – 01/25/2021 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


2 
Palbo T-DM1 - Protocol Version 5 & Date 01/25/2021  
 
Protocol Signature Page  
 
Study Title: A single arm phase II study to evaluate efficacy of T-DM1 with Palbociclib in the 
treatment of patients with metastatic HER2 positive breast cancer  
 
Protocol Identification : Palbo T-DM1 
 
Sponsor Signature: The signature below constitutes approval of this protocol by the sponsor  
   
Lead Principal Investigator:    Pavani Chalasani MD, MPH                                                                                     
                                                                    
Date:                                                                   Signature:         
 
 
 
Investigator Agreement: 
 
I have read, understand and will adhere to the protocol as written, that any changes to the 
protocol will be approved by the sponsor or sponsor-investigator and the IRB, except changes 
to eliminate an immediate hazard to study subjects.  
 
I agree to conduct this study in accordance with the current International Conference on 
Harmonization (ICH) guidance, the Good Clinical Practice (GCP) guidance, the Declaration of 
Helsinki, FDA regulations, local IRB and legal requirements.  
 
 
 
 
 
 
__________________________  
 
 
 
_______________________ 
Signature 
 
 
 
 
 
 
Date (MM/DD/YYYY) 
 
 
 
 
__________________________ 
Name of Principal Investigator 
 
 
 
 
 
 
 
 
 
 


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Palbo T-DM1 - Protocol Version 5 & Date 01/25/2021  
Protocol Version History Page  
Version 
Main Changes 
Version 1 – 4/9/18 
First version 
Version 2 – 6/11/18 
• 
Inclusion criteria – age ≥ 18 years was added 
• 
Inclusion criteria - Measurable disease by RECIST 1.1 
was added 
• 
Exclusion criteria #8 was updated to include: Women of 
childbearing potential and men should use effective 
methods of contraception during the entire duration on 
study and for 6 months after completion 
• 
Study schema has been updated (optional research 
biopsy was removed) 
• 
Schedule of events was updated: T-DM1 administration 
was added to group A, metabolic panel will not be 
collected at D21, concomitant medication information 
will not be collected at long term follow-up, tumor 
measurement in group B will be done every 4th cycles, 
for women of childbearing potential, pregnancy tests 
should be done every 2nd cycle.  
• 
Clarifications were added to section 13 – data and 
safety monitoring plan 
Version 3- 10/1/18 
• 
Page 7- expanded on T-DM1 abbreviation to 
Trastuzumab Emtansine (T-DM1) 
• 
Clarification of startaification factors- enrolling site was 
added to that  
• 
Inclusion criteria No 7- EF was changed to Left 
ventricular ejection fraction 
• 
Inclusion criteria No 13 was further expanded to define 
postmenopausal status and about contraception. It was 
changed to “Female subjects must be surgically sterile 
or be postmenopausal (defined as surgical removal of 
ovaries or no menses for 12 consecutive months or 
monthly gonadotrophin releasing hormone agonist use 
for ovarian suppresion), or must agree to use effective 
contraception during the period of therapy. All female 
subjects with reproductive potential must have a 
negative pregnancy test (serum or urine) prior to 
enrollment 
and 
must 
agree 
to 
use 
effective 
contraception during the period of therapy. Women of 
childbearing potential and men should use effective 
methods of contraception during the entire duration on 
study and for 7 months after completion” 
• 
Exclusion criteria no 9- Calrified about supportive meds. 
Added “Other supportive care medications can be used 
if clinically indicated (like growth factor support)” 


4 
Palbo T-DM1 - Protocol Version 5 & Date 01/25/2021  
• 
Background section was expanded to add supporting 
pre-clinical data and the rationale to study the 
combination therapy  
• 
In SOE calendar, Day 21 has been removed  
• 
Section 7.1- CTCAE version- has been updated to 4.03 
• 
Section 7.6 for Overdose-has been simplified to “An 
overdose is defined as the accidental or intentional 
ingestion or infusing of any dose of study treatment that 
exceeds the dose described in the protocol. Overdoses 
should be reported as a SAE using the SAE forms. 
Version 4-6/5/19 
• 
Page 7- expanded number to sites from 10 to 10-20 
• 
Page 7/8- Inclusion crtieria No 6 was changed from 
measurable disease only to measurable and evaluable 
disease 
• 
Page 8- Inclusion criteria No 8 clarified that serum or 
plasma creatinine can be use, added IULN for bilirubin 
• 
Page 8- Inclusion criteria No 11 , clarified about 
adjuvant use of pertuzumab, deleted upon discussion 
with PI 
• 
Page 18- exclusion crtieria No 8 and 9 - updated the 
previously approved exclusion criteria (to make it 
consistent with synopsis)  
• 
Page 19- under palbociclib administration, clarified that 
it can be given with food , updated side effects based 
on new IB 
• 
Page 20- Drug-related Toxicities for palbociclib was 
updated.  
• 
Page 23 and 24 – updated the SOE to make it easier 
and deleted a row and column to clarify what 
procedures are needed, clarified that imaging has to be 
done every 12wks (or after every 4 cycles), changed 
need for physical exam from every cycle to every 6wks 
after cycle 8, clarified about T-DM1 administration days, 
clarified about long terms survival follow up, deletd 
tumor measurement for visible or palpable only, clarified 
about bone imaging (deleted preferred) and clarified 
that is done per instutional guidelines 
• 
Page 33- under tumor evaluation per RECIST 1.1, 
added about evaluable disease only and discussed 
about non-measurable disease 
• 
Page 37- described about disease progression in non-
measurable disease only 
• 
Page 38- Table 6 of protocol- clarified about overall 
response per RECIST 1.1 
• 
Page 41-Defined end points for the objectives 
Version 5 
• 
All pages-Header and footer change- protocol version 5 & 
Date 01/25/2021 


5 
Palbo T-DM1 - Protocol Version 5 & Date 01/25/2021  
• 
Page 1, 2, 10- updated Study Title: change in study title 
from randomized to single arm, Protocol version and date: 
change to version 5 and 9/28/20 
• 
Page 8, 9- Table of Contents: Page numbers updated 
• 
Page 9-Table of Contents: Deleted randomization from 
registration. 
• 
Page 10- Hypotheses:  Changed to “compared to historical 
controls” instead of single agent T-DM1, Primary objective: 
changed to estimate progression free survival of T-
DM1+Palbociclib, Secondary Objectives: Changed to  
 
Estimate 
response 
rates 
of 
T-
DM1+Palbociclib treatment regimen 
 
Estimate 
overall 
survival 
of 
T-
DM1+Palbociclib treatment regimen 
o 
Study design: changed to single arm study of T-
DM1 with Palbociclib. Clarified that all patients 
going forward will be treated with T-DM1 with 
Palbociclib, Stratification factors removed to reflect 
change in study design, Number of study centers: 
Changed from 10-20 to 15, Number of patients: 
Changed from 132 to 46 evaluable patients, Main 
criteria for inclusion/exclusion:  Inclusion Criteria 
No 6: Clarified that patients must have measurable 
or evaluable disease by RECISIT 1.1,  
• 
Page 11, 19 -Exclusion Criteria No 2: Changed to-Prior 
treatment with T-DM1 in the metastatic setting, if treated 
with prior T-DM1 in the neoadjuvant of adjuvant setting, a 
treatment free interval of at least 12 months, Exclusion 
Criteria No 4: Clarified known active CNS metastases to 
known active symptomatic CNS metastases.Exclusion 
Criteria No 9: Added-If a patient is already on 
Gonadotrophin releasing hormone agonist, it can be 
continued during this study. 
• 
Page 12- Study Schema: Updated to reflect change in study 
design, Sample size calculation: Updated to reflect change 
in study design and sample size. 
• 
Page 10 -Primary Objectives: Updated to reflect Change in 
study design Kaplan-Meier estimate will be used to 
estimate progression free survival of combination arm. No 
longer comparing to single arm using a stratified log rank 
test, Secondary Objectives: Updated to reflect Change in 
study design overall response of Combination arm will be 
estimated using exact binomial confidence interval. No 
longer comparing single arm using chi square test.  
• 
Page 13- Interim monitoring and interim analysis: Futility 
analysis clarified based on combination arm only. 


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Palbo T-DM1 - Protocol Version 5 & Date 01/25/2021  
• 
Page 13- Feasibility issues: Randomized changed to single 
arm. Number of sites changed from 10 to 15, added date of 
first patient accrued (12/2018),  
Q3 2018 changed to Q4 2018 
Accrual estimates changed from 6 to 2-3/month 
Added: Q4 2020-enrolled subjects into combination arm 
are 11, timeline below is for additional 35 subjects and 
anticipated total of 46 
Q3 2020-complete accrual changed to Q42021 
• 
Q4 2020-Q2022  monitor for study completion changed to 
Q4 2021-Q42022  
• 
Page 13-Study Duration: 4 years changed to 5 years. (24 
months changed to 36 months’ accrual) 
• 
Page 10, 18- Study design: updated as above. 
• 
Page 20-Formulation:  Pfizer changed the formulation of 
palbociclib from capsules to tablets. Added: smooth-coated 
tablet formulation. Monthly supply will contain 3 weekly 
blister packs of 7 tablets each along with USPI for the tablet 
formulation. Tablets should not be removed from the blister 
pack and placed in a pill caddy. Each strength of tablet has 
a different shape or color as well as different color carton 
similar to the way the current bottles have differently 
colored labels.  Reconstitution: Capsules changed to 
tablets.  Storage and Stability: Capsules changed to Tablets  
Administration: Clarified patients can take palbociclib with 
or without food.  Procurement: Clarified due to change in 
study design.  Removed-For randomization, Randomization 
will be done centrally and study site will be notified about 
that treatment arm  
• 
Page 21-Drug –related Toxicities: Added #6: Rare 
pneumonitis, Drug interactions: Clarified drug-drug 
interactions when taken concomitantly with CYP3A4 
substrates and P-glycoprotein substrates. Removed- “These 
should be avoided during the course of the study”   
• 
Page 22/23-Administration: Added-If necessary, the 
administration time can be modified to meet institutional 
guidelines. The dose of KADCYLA is 3.6mg/kg and can be 
calculated per cycle or change when weight has changed by 
10% (from the weight used to calculate the dose of 
KADCYLA) 
• 
Page 24-Schedule of events (Table): Updated to reflect 
change in study design. Group A removed Imaging 
assessments window(column ): Clarified and Changed to 
after every 4th cycle ±7 days.  Bottom of table: Spelling 
correction 


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Palbo T-DM1 - Protocol Version 5 & Date 01/25/2021  
• 
Page 25-Schedule of events Group B: Updated to reflect 
change in study design. Added (only applicable for patients 
currently on single T-DM1) 
• 
Page 29-Small print bottom of table: Added-T-DM1 can be 
given -3days to +7 days of a 21 day cycle to give flexibility 
for investigator and patients. 
• 
Page 32- clarified about imaging schedule “ however if 
there are any delays in treatment, the imaging should 
follow 12 week from last imaging schedule” 
• 
Page 37-Registration-Removed- randomization 
• 
Page 37-Analysis population: Clarified primary analysis 
sample for efficacy added- evaluable patients who have 
completed at least 1 cycle of treatment. If a patient was not 
able to complete at least 1 cycle of therapy, they will be 
replaced for the study analysis. Changed to reflect 
combination arm study of T-DM1 with Palbociclib. Safety 
Analysis: Changed number of patients for first safety 
analysis to 16 from 20. Removed “As this is not an efficacy 
analysis we will not adjust the overall alpha level.”  Sample 
Size Calculation: Updated as above 
• 
Page 38-Statistical analysis: Updated as above 
• 
Page 42-Data and Safety Monitoring Plan: Updated change 
from Criterium suppling all reports to monthly reports. 
Added designee to PI. Clarified that Study PI and Criterium 
will provide a monthly DSMB summary report to all study 
sites on a 6 month basis every January and July. The DSMB 
summary report will include summary of University of 
Arizona monthly DSMB reports. Added: if the University of 
Arizona 
DSMB 
identifies 
any 
safety 
concerns, 
all 
participating sites and study investigators will be notified by 
a memo and teleconference. 
 
 


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Palbo T-DM1 - Protocol Version 5 & Date 01/25/2021  
Table of contents   
 
 
Page No 
1. 
STUDY SYNOPIS 
10 
2. 
BACKGROUND AND RATIONALE 
              2.1 
HER2-positive metastatic breast cancer 
              2.2 
Pre-Clinical/clinical experience 
 
 
14 
14 
3.            STUDY DESIGN 
3.1 
Inclusion Criteria 
3.2 
Exclusion Criteria 
 
18 
18 
4. 
STUDY DRUGS 
4.1 
Palbociclib 
4.1.1 
Availability 
4.1.2 
Pharmaceutical data 
a. 
Formulation 
b. 
Reconstitution 
c. 
Storage and Stability 
d. 
Administration 
e. 
Procurement 
f. 
Drug-related Toxicities 
g. 
Drug Interactions 
 
4.2 
T-DM1 
4.2.1      Availability 
4.2.2      Pharmaceutical Data 
 
a.      Formulation 
b. 
Reconstitution 
c. 
Storage and Stability 
d. 
Administration 
e. 
Procurement 
f. 
Drug-related Toxicities 
 
20 
20 
20 
20 
20 
20 
20 
20 
21 
21 
 
 
21 
21 
21 
21 
21 
21 
22 
22 
5. 
TREATMENT PLAN 
5.1 
Schedule of Events Group A : T-DM1 + Palbociclib 
5.2 
Schedule of Events Group B : T-DM1 
 
24 
25 
6. 
DOSE MODIFICATIONS 
6.1 
Palbociclib 
6.2 
T-DM1 
 
26 
26 
7. 
ADVERSE EVENTS 
7.1 
Adverse Events Definition 
7.2 
Serious Adverse Events 
7.3 
Documentation of AE’s 
7.4…. Documentation of SAE’s 
7.5 … Pregnancy 
7.6.    Overdose 
7.7 … FDA expedited reporting 
 
28 
28 
29 
29 
30 
30 
30 
8. 
STUDY PROCEEDURE 
8.1 
Enrollment 
8.2 
Screening 
8.3 
Registration 
 
31 
32 
32 


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Palbo T-DM1 - Protocol Version 5 & Date 01/25/2021  
8.4 
Follow Up 
8.5 
Early Treatment Termination 
8.6 
Off Study 
32 
32 
32 
9. 
TUMOR RESPONSE EVALUATION PER RECIST 
9.1 
Measurable Disease 
9.2 
Non-Measurable Disease 
9.3 
Specifications by Methods of Measurements 
9.4 
Baseline Documentation of “Target and Non-Target” lesions: 
9.5 
Evaluation of Target Lesions 
9.6 
Evaluation of Non-Target Lesions 
9.7 
Evaluation of best overall response per RECIST 
 
33 
33 
33 
34 
35 
35 
36 
10. 
STATISTICAL CONSIDERATIONS 
10.1 Analysis Population 
10.2 Safety Analysis 
10.3 Sample Size Calculations 
10.4 Statistical Analysis 
 
 
37 
37 
37 
38 
 
11. 
ADMINISTRATIVE PROCEEDURES 
11.1 Investigator Responsibilities 
11.2 Subject Confidentiality 
11.3 Study Documentation and Archive 
11.4 Data 
11.5 Protocol Deviations 
11.6..  Record retention 
11.7..  Amendments to protocol 
11.8.   Termination rules 
 
38 
38 
39 
39 
39 
40 
40 
40 
 
12. 
REGULATORY OBLIGATIONS 
12.1 Informed Consent 
12.2 Institutional Review Board 
 
41 
41 
13. 
DATA AND SAFETY MONITORING PLAN 
13.1 Identification of the DSMB obligated for oversight responsibilities 
13.2 Identification of the entity obligated for routine monitoring duties 
13.3 Monitoring progress and data review process 
13.4 Continuous Monitoring 
13.5 Routine safety monitoring 
13.6…Removal of subjects 
 
42 
42 
42 
43 
43 
43 
14.        REFERENCES 
45 
15.        APPENDIX 
             1. ECOG PERFORMANCE STATUS 
            
 
46 
 
 
 


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Palbo T-DM1 - Protocol Version 5 & Date 01/25/2021  
1. STUDY SYNOPSIS 
 
Title of the study: A single arm phase II study of T-DM1 with palbociclib in the treatment of 
patients with metastatic HER2-positive breast cancer 
 
Hypotheses: Combination of Trastuzumab Emtansine (T-DM1) with palbociclib improves 
progression free survival compared to historical controls  
 
Primary objective: Estimate progression free survival of T-DM1 + palbociclib 
 
Secondary objectives 
i) Estimate response rates of T-DM1+Palbociclib treatment regimen 
ii) Estimate overall survival of T-DM1+Palbociclib treatment regimen 
 
Correlative objectives 
i) 
Investigate predictive biomarkers of response in blood and archived tumor tissue 
ii) 
Investigate mechanisms of resistance for palbociclib in blood and tumor tissue  
 
Study design 
This is a multi-center, single arm study of T-DM1 with palbociclib in the treatment of 
patients with metastatic HER2-positive breast cancer. All patients will be treated with T-
DM1 with palbociclib 
 
 
Number of study center: 15 
 
Number of patients: 46 evaluable patients  
 
Main criteria for inclusion/exclusion 
 
To be eligible all patient must/have  
 
1. Be informed of the investigational nature of the study and all pertinent aspects of the trial 
2. Sign and provide written consent in accordance with institutional and federal guidelines. 
3. Age ≥18 years 
4. ECOG Performance status of 0-2 
5. Recurrent or metastatic HER2-positive breast cancer (HER2 positive is defined per 
ASCO-CAP guidelines) 
6. Must have measurable or evaluable disease by RECIST 1.1  
7. Adequate cardiac reserve (Left ventricular ejection fraction ≥50%) 
8. Serum or plasma creatinine ≤ 1.5 x institutional upper limit of normal (IULN), bilirubin ≤ 2.0 
x IULN, and an SGOT/SGPT/alkaline phosphatase ≤ 2.0 x IULN  
9. Adequate bone marrow function (ANC ≥1000, Platelets ≥100,000/ml, Hemoglobin 
≥10gm/dL) 
10. Be willing and able to comply with scheduled visits, treatment plan, laboratory tests and 
other trial procedures 


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Palbo T-DM1 - Protocol Version 5 & Date 01/25/2021  
11. Been treated with pertuzumab previously (neoadjuvant or adjuvant or metastatic setting). 
Patients who weren’t able to tolerate pertuzumab due to side effects can be eligible for 
study  
12. No more than 2 lines of therapy in the metastatic disease setting 
13. Female subjects must be surgically sterile or be postmenopausal (defined as surgical 
removal of ovaries or no menses for 12 consecutive months or monthly gonadotrophin 
releasing hormone agonist use for ovarian suppresion), or must agree to use effective 
contraception during the period of therapy. All female subjects with reproductive potential 
must have a negative pregnancy test (serum or urine) prior to enrollment and must agree 
to use effective contraception during the period of therapy. Women of childbearing 
potential and men should use effective methods of contraception during the entire duration 
on study and for 7 months after completion.  
 
Patients who fulfill any of the following criteria will be excluded 
 
1. HER2 negative tumors 
2. Prior treatment with T-DM1 in the metastatic setting. If treated with prior T-DM1 in the 
neoadjuvant or adjuvant setting, a treatment free interval of at least 12 months 
3. Prior treatment with CDK 4/6 inhibitors 
4. Known active symptomatic CNS metastases or carcinomatous meningitis.  Patients with 
stable CNS metastases including brain metastases who have completed a course of 
radiotherapy are eligible for the study provided they are clinically stable.  However, oral 
corticosteroids for control of CNS symptoms are not allowed on study 
5. Known documented or suspected hypersensitivity to the components of the study drug(s) 
or analogs. 
6. Uncontrolled systemic illness, including but not limited to ongoing or active infection 
7. Symptomatic congestive heart failure, unstable angina pectoris, stroke or myocardial 
infarction within 3 months 
8. Be pregnant or breast feeding.  
9. Concurrent hormonal or other anti-neoplastic therapy is not allowed. Patients can receive 
supportive therapy like bone-directed therapy including bisphosphonates or denosumab. 
Other supportive care medications can be used if clinically indicated (like growth factor 
support). If a patient is already on a Gonadotrophin releasing hormone agonists, it can be 
continued during this study. 
 
 


12 
Palbo T-DM1 - Protocol Version 5 & Date 01/25/2021  
Intervention 
 
T-DM1 is administered IV q21days at 3.6mg/Kg. This is available commercially. 
 
Palbociclib is given orally at 125mg on days 5-18 of 21 day cycle (supplied by Pfizer).  
 
 
 
 
 
Study Schema 
 
  
 
 
Statistical analysis 
 
Sample size calculation  
 
This is a prospective single arm phase II study to estimate progression free survival of 
combination T-DM1 + palbociclib. Expected PFS for T-DM1 based on the EMILIA trial is 9.6 
months. The goal of the study is to detect a  PFS of 16.3 months (HR = 0.56) in the combination 
arm compared to the standard historical control arm, with 80% statistical power and a 0.05 one 
sided alpha level. We propose enrolling a total of 46 subjects into this trial. Enrollment will 
continue and will be briefly held after the first 16 subjects complete 12 months of treatment or 
come off study (whichever comes first) to conduct a futility analysis. If at least 8/16 have PFS 
beyond 12 months, we will restart accrual for a total of 46 evaluable patients.  If at least 24 
evaluable subjects have PFS beyond 12 months then we declare the combination as promising 
for future studies. Our null hypothesis is 40% have PFS at 12mths (median survival of 9.1 
months) Alternative hypothesis is 60% survive 12 months. 


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Palbo T-DM1 - Protocol Version 5 & Date 01/25/2021  
 
Primary Objectives 
 
1. Progression free survival of the combination of T-DM1 with palbociclib will be estimated 
using the Kaplan-Meier  
 
Statistical considerations for secondary aims 
Secondary Objectives  
1. The overall response (CR + PR + stable disease) will be estimated using an exact binomial 
confidence interval  
2. Overall survival will be analyzed similarly as progression free survival. 
 
Interim monitoring and interim analysis 
 
We propose a futility analysis after the first 16 patients complete either 12 months of treatment or 
come off study (which ever comes first). If 8 have PFS beyond 12 months, we will continue accrual 
for a total of 46 evaluable patients (30 additional patients).  Enrollment will be held briefly only 
after the first 16 patients complete either 12 months of treatment or come off study (which ever 
comes first).  
 
Feasibility issues: This is a multi-site single arm phase II trial (expected number of sites is 15)  
01/2018-08/2018-protocol finalizing, contracting with CRO, study sites startups, IND preparation, 
study protocol to be reviewed by IRB and study site activation 
Q4 2018- accrual of first patient (happened 12/2018)  
Accrual estimates – approximately 2-3/month (anticipate accrual of total 46 patients) 
Q42020- enrolled subjects into combination arm are 11, timeline below is for additional 35 
subjects and anticipated total of 46 
Q4 2021- complete accrual 
Q4 2021- Q4 2022- monitor for study completion 
Q1 2023- complete final analysis 
Q1 2023- Q2 2023- ASCO presentation, complete manuscript and prepare for submission 
(JCO/CCR) 
 
Study duration: 5 years (36 months’ accrual and 24 months of follow up) from startup and close 
out would be an additional 10 months. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Palbo T-DM1 - Protocol Version 5 & Date 01/25/2021  
 
2. Background and rationale  
 
HER2-positive metastatic breast cancer 
Overexpression of the human epidermal growth factor 2 (HER2) oncogene is estimated to occur in 25-30% 
of all human breast cancers.  This subset of breast cancer is classified as HER2-positive cancer, a subtype 
that is particularly aggressive and associated with greater risk for disease progression and death (Callahan 
and Hurvitz, 2011).  First line therapy for patients with metastatic HER2-positive breast tumors is combination 
of Taxane with dual HER2 targeted therapy -pertuzumab (perjeta) and trastuzumab (Herceptin), humanized 
monoclonal antibodies targeting the HER2 extracellular domain (Baselga, 2012).  However, despite its 
dramatic impact on the progression free survival and overall survival treatment of HER2-positive breast 
cancer, still many patients develop disease progression Subsequent therapy for such patients includes T-
DMI. The pivotal EMILIA trial demonstrated superiority of T-DM1 over the lapatinib-capecitabine regimen, and 
T-DM1 has attained FDA approval for the treatment of HER2-positive breast cancer as a second line treatment 
(Verma, 2012). However, even with T-DM1, the progression-free survival is only 9.6 mos. It is prudent to know 
that in EMILIA trial patients had prior exposure to trastuzumab only. The true PFS on T-DM1 after disease 
progression on combination treatment with pertuzumab  and trastuzumab is not well defined. After progression 
on T-DM1, lapatinib, a small molecule tyrosine kinase inhibitor that targets both HER2 and the epidermal 
growth factor receptor-EGFR, is typically used in combination with capecitabine (Callahan and Hurvitz, 2011; 
Moreira and Kaklamani, 2010).  This therapy gained FDA approval based on increasing progression-free 
survival in a phase 3 study of approximately six months.  Thus, despite recent advances in the treatment of 
HER2-positive breast cancer, there is still significant need for novel targeted therapies and combination 
regimens to address the continuing problem of therapy resistance and recurrence of this aggressive disease. 
 
2.2 Pre-clinical/clinical experience 
 
Mechanism of action, pre-clinical and clinical data for T-DM1 
T-DM1 is an antibody conjugate with the therapeutic antibody trastuzumab with derivatized lysine linked via 
maleimido bonds to the microtubule poison emtansine.  Preclinical studies demonstrated that T-DM1 is 
effective against HER2+ breast cancer models including cell lines and xenografts that are resistant to 
trastuzumab (Barok, 2011; Junttila, 2011).  These studies indicated that T-DM1 kills HER2-positive breast 
cancer cells both through the cytotoxic effects of emtansine including apoptosis and mitotic catastrophe, while 
also eliciting antibody mediated cellular toxicity. 
T-DM1 has been utilized in the treatment of greater than 500 patients with HER2-positive disease.  The 
phase 1 studies led to the current dosing schedule of 3.6mg/kg by intravenous delivery on a 3-week 
schedule (Krop, 2010).  The main dose limiting toxicity (DLT) was thrombocytopenia.  The phase 2 and 3 
studies demonstrated efficacy relative to the FDA-approved regimens (Verma, 2012) for recurrent disease 
previously treated with HER2 antagonists (trastuzumab or lapatinib) with progression-free survival of 4.6-9.6 
months reported (Krop, 2012; Verma, 2012; Burris, 2011). 
 
Mechanism of action, pre-clinical and clinical data for Palbociclib 
Palbociclib (or PD-0332991) is an orally available, pyridopyridimidine-derived, selective inhibitor of cyclin 
dependent kinase 4/6-CDK4/6 (Fry, 2004; Toogood, 2005).  Functionally, palbociclib is a potent and highly 
selective inhibitor of CDK4/6-cyclin D1 kinase activity, which ultimately results in the inhibition of 
retinoblastoma-Rb protein phosphorylation and cell cycle arrest.  
In vitro and in xenograft model, palbociclib was observed to inhibit a panel of RB-positive, solid tumor cell 
lines (Fry, 2004; Finn, 2009; Dean, 2010; Thangavel, 2011).  In a genetically engineered syngeneic animal 
model, palbociclib was effective at inhibiting the proliferation of mammary tumors in MMTV-HER2/Neu 
transgenic mice (Choi, 2012).  Combined, these data suggest that palbociclib will likely be active in 
advanced breast cancer.  
A phase 1 clinical trial with palbociclib in patients with Rb-positive advanced solid tumors demonstrated a 
therapeutic dose of 125 mg/d for 21d of a 28 d cycle, or 200mg/d for 14d of a 21 d cycle. The principal 


15 
Palbo T-DM1 - Protocol Version 5 & Date 01/25/2021  
dose-limiting toxicity-DLT was myelosuppression (Flaherty, 2011). A phase 2 study (PALOMA-1) of 
palbociclib with letrozole demonstrated a marked delay in disease progression in patients with advanced 
ER-positive breast cancer (Finn, 2012). Subsequently a randomized double-blind phase 3 trial (PALOMA-
2) conducted in postmenopausal women with ER+/HER2 negative metastatic breast cancer demonstrated 
significant improvement in PFS (Finn et al, 2016). Based on the data from PALOMA-1, US FDA granted 
accelerated approval for palbociclib. Results of PALOMA-3 which was a randomized double-blind phase 3 
trial for women with HR+/HER2 negative who progressed on or after endocrine therapy in the adjuvant or 
metastatic setting demonstrated improved PFS for the combination arm (fulvestrant + palbociclib) versus 
single agent fulvestrant (Turner et al 2015). Based on these results currently palbociclib is indicated for the 
treatment of HR+/HER2 negative metastatic breast cancer with an aromatase inhibitor as initial endocrine 
therapy in postmenopausal women or fulvestrant in women with disease progression following endocrine 
therapy.    
 
Rationale for treatment of HER2 positive metastatic breast cancer with palbociclib  
 
Despite the positive impact of trastuzumab on the treatment of HER2-positive breast cancer, immediate 
and acquired resistance to this targeted agent remains a significant clinical issue.  Furthermore, while drugs 
such as T-DM1 and lapatinib have demonstrated efficacy in trastuzumab-resistant patients, disease 
progression remains a challenge (Geyer, 2006; Blackwell, 2009; Blackwell, 2010).  Thus, there is still 
significant need for novel targeted therapies and combination regimens for the treatment of HER2-positive 
breast cancer. Preclinical studies have demonstrated palbociclib combined with microtubule poison 
prevented outgrowth of cell clones (McClendon et al., 2012). In addition, other preclinical studies with 
palbociclib have demonstrated efficacy in HER2-overexpressing cell lines and xenografts as well as mouse 
tumors in vivo (Witkiewicz et al, 2014).  These pre-clinical findings suggest that palbociclib can be 
particularly effective in delaying progression in HER2 positive breast cancer by suppressing ability of tumors 
with acquired resistance to expand.  These data are further supported by ongoing studies in the field 
showing cooperation of palbociclib with trastuzumab (NCT02448420).  
While such preclinical data are suggestive of cooperation between the various components that constitute 
T-DM1, none of these studies can accurately model the complexity of human and tumor physiology or 
predict response.   
Rationale for combination of T-DM1 and palbociclib : T-DM1 elicits cytotoxicity via emtansine and can 
induce ADCC. The CDK4/6 inhibition will be delivered to limit outgrowth of resistant clones and limit 
progression between the bolus delivery of T-DM1. Pre-clinical studies show that T-DM1 and CDK4/6 
inhibition have highly distinct mechanisms of action, and could yield cooperative effects in terms of 
disease control. CDK 4/6 inhibition provides a potent adjunct to HER2 targeted therapies in preclinical 
breast cancer models. (Witkiewicz et al, 2014) 
 
It may be a concern that palbociclib could interfere with the immunological effect of T-DM1.This concern 
is noted however there were several papers published recently that CDK4/6 inhibition (palbociclib) 
increases anti-tumor immune response eg of one such citation is below. Given this combination would be 
appropriate and deems further investigation. (Goel et al.2017) 
 
A phase I trial is currently ongoing to evaluate the safety of combination of T-DM1 with palbociclib.  In an 
effort to mitigate any potential toxicity and utilize each drug to its maximal effect, T-DM1 is being given on 
day 1 (of a 21 day cycle) to target rapidly proliferating tumor tissue. The serum half-life of T-DM1 is about 
3.5 days (Krop, 2010).  Palbociclib is given on day 5 – day 18 while levels of T-DM1 are diminishing and 
thereby any cells that have survived T-DM1 will be prevented from proliferation.  As palbociclib serum half-
life is 24 hours (Schwartz, 2011) the drug is being discontinued four days before the next T-DM1 dose (see 
section 2.2.4 for detailed study design). 
Clinical experience with combination for T-DM1 and palbociclib  
 
There is an ongoing phase I data evaluating the combination of T-DM1 with palbociclib in patients with 
metastatic HER2-positive breast cancer that have failed prior HER2-targeted therapy (including T-DM1 in 


16 
Palbo T-DM1 - Protocol Version 5 & Date 01/25/2021  
the second line) (NCT01976169) The study is based on the preclinical data with T-DM1 and palbociclib.   
T-DM1 is delivered at the standard of care dose (IV q21days at 3.6mg/Kg).    Palbociclib is administered 
orally at increasing dose levels (100mg, 150mg and 200 mg) on days 5-18 (of a 21 day cycle) (Figure 1).  
The rationale of the study was to translate preclinical data investigating if using palbociclib can prevent 
proliferation of resistant disease when the levels of T-DM1 are diminishing based on the pharmacokinetics 
of both agents.   Standard 3+ 3 phase 1 study design was used to guide dose escalation of palbociclib at 
100mg, 150mg and 200mg. The trial accrued 9 patients with three at each dose level. Table 1 lists patient 
characteristics on the trial. Neutropenia was dose related and grade 3 neutropenia was observed in 1/3 
patients at 100mg dose level, 2/3 patients at 150mg and 3/3 patients at 200mg dose. The hematological 
toxicities were resolved with dose interruption. Table 2 lists all the adverse events observed in the trial. No 
grade 4 toxicities were observed. 4/9 patients had stable disease and 3/9 patients had partial response with 
an average of 193 days on study (figure 2).   
 


17 
Palbo T-DM1 - Protocol Version 5 & Date 01/25/2021  
 
 
 


18 
Palbo T-DM1 - Protocol Version 5 & Date 01/25/2021  
 
 
 
The pre-clinical, clinical and toxicity data support  the need for a larger phase II trial with a 
modifiable dose of 125 mg of palbociclib (which is the approved dose currently, to limit the need 
for dose delay and allowing for the evaluation of efficacy). 
 
3. Study design 
 
This is a multi-center, single arm, phase II study of T-DM1 with palbociclib in the treatment of patients with 
metastatic HER2-positive breast cancer. All patients will be treated with combination of T-DM1 and 
palbociclib. 
 
Selection of study population  
 
3.1 Inclusion criteria  
 
1. Be informed of the investigational nature of the study and all pertinent aspects of the trial 
2. Sign and provide written consent in accordance with institutional and federal guidelines. 
3. Age ≥18 years 
4. ECOG Performance status of 0-2 
5. Recurrent or metastatic HER2-positive breast cancer (HER2 positivity is defined per ASCO-CAP 
guidelines) 
6. Must have one of the following by RECIST 1.1  
a. Measurable disease or 
b. Evaluable disease  
7. Adequate cardiac reserve (Left ventricular ejection fraction ≥50%) 


19 
Palbo T-DM1 - Protocol Version 5 & Date 01/25/2021  
8. Serum creatinine ≤ 1.5 x institutional upper limit of normal (IULN), bilirubin ≤ 2.0 x IULN, and an 
SGOT/SGPT/alkaline phosphatase ≤ 2.0 x IULN  
9. Adequate bone marrow function (ANC ≥1000, Platelets ≥100,000/ml, Hemoglobin ≥10gm/dL) 
10. Be willing and able to comply with scheduled visits, treatment plan, laboratory tests and other trial 
procedures 
11. Been treated with pertuzumab previously (neoadjuvant or adjuvant or metastatic setting). Patients 
who weren’t able to tolerate pertuzumab due to side effects can be eligible for study  
12. No more than 2 lines of therapy in the metastatic disease setting 
13. Female subjects must be surgically sterile or be postmenopausal, or must agree to use effective 
contraception during the period of therapy. All female subjects with reproductive potential must 
have a negative pregnancy test (serum or urine) prior to enrollment and must agree to use effective 
contraception during the period of therapy. Women of childbearing potential and men should use 
effective methods of contraception during the entire duration on study and for 7 months after 
completion.  
 
3.2 Exclusion Criteria  
 
Patients who fulfill any of the following criteria will be excluded 
1. HER2 negative tumors 
2. Prior treatment with T-DM1 in the metastatic setting. If treated with prior T-DM1 in the neoadjuvant 
or adjuvant setting, a treatment free interval of at least 12 months 
3. Prior treatment with CDK 4/6 inhibitors 
4. Known active symptomatic CNS metastases or carcinomatous meningitis.  Patients with stable 
CNS metastases including brain metastases who have completed a course of radiotherapy are 
eligible for the study provided they are clinically stable.  However, oral corticosteroids for control of 
CNS symptoms are not allowed on study 
5. Known documented or suspected hypersensitivity to the components of the study drug(s) or 
analogs. 
6. Uncontrolled systemic illness, including but not limited to ongoing or active infection 
7. Symptomatic congestive heart failure, unstable angina pectoris, stroke or myocardial infarction 
within 3 months 
8. Be pregnant or breast feeding.  
9. Concurrent endocrine therapy or other anti-neoplastic therapy is not allowed. Patients can receive 
supportive therapy like bone-directed therapy including bisphosphonates or denosumab. Other 
supportive care medications can be used if clinically indicated (like growth factor support). If a 
patient is already on a Gonadotrophin releasing hormone agonists, it can be continued during this 
study. 
 
 
 
 
 
 
 
 
 


20 
Palbo T-DM1 - Protocol Version 5 & Date 01/25/2021  
 
4. Study drugs  
 
4.1 Palbociclib  
 
4.1.1 Availability  
Palbociclib is currently approved in combination with hormonal therapy (aromatase 
inhibitors or fulvestrant) to treat ER+/HER2 negative metastatic breast cancer. It is 
experimental for the combination proposed in this trial. Palbociclib is produced by 
Pfizer with approval of the FDA for investigational purposes (IND BB#69324).  
Palbociclib  will be provided by Pfizer Pharmaceuticals as commercially available 
preparation, Ibrance and will be shipped directly to participating sites. Individual 
sites will be responsible for the drug accountability and dispensing. 
 
4.1.2 Pharmaceutical data 
 
a.  Formulation 
In 02/2020 Pfizer changed the formulation of palbocilcib from capsule to tablet. 
Palbociclib is supplied as smooth-coated tablet formulation. Monthly supply will 
contain 3 weekly blister packs of 7 tablets each along with USPI for the tablet 
formulation. Tablets should not be removed from the blister pack and placed 
in a pill caddy. Each strength of tablet has a different shape or color as well as 
a different color carton similar to the way the current bottles have different 
colored labels. 
 
b. Reconstitution 
75, 100 and 125 mg tablets will be used.  Patients will use the appropriate 
number of tablets per day with amount dependent on prescribed dose.  Each 
patient will receive a 14-day supply at the beginning of each cycle (cycle is 21 
days).  
 
c. Storage and Stability 
Tablets are stored in line at room temperature (15-25 degrees Celsius).   
 
d. Administration 
The drug is to be taken orally on days 5-18 (14 days) of each cycle (cycle length 
21 days). Starting dose will be 125mg. Patients can take palbociclib with or 
without food.  Patients will be given a drug log to maintain to document 
compliance with administration. 
 
e. Procurement 
Patients are consented at their institution and all required enrollment 
documents must be emailed to Criterium for confirmation of enrollment prior to 
treating a patient. Once eligibility is confirmed, study site is notified to register 
patient. Following patient registration, the study coordinator will notify their IDS 
Pharmacy for dispensing of drug.  Maintenance of a drug accountability record 
is required for palbociclib.  The investigator, or a responsible party designated 
by the investigator, will maintain a careful record of the receipt, disposition, and 
return of all drugs supplied for this study.  


21 
Palbo T-DM1 - Protocol Version 5 & Date 01/25/2021  
 
f.  Drug-related Toxicities 
Toxicities associated with palbociclib include:  
1. 30% or more: decreases in neutrophil blood cells (may increase the 
risk of infection), decreases in while blood cells (infection fighting 
cells), infections, fatigue  
2. 10 to less than 30%: decreases in hemoglobin (may cause 
weakness), decreases in platelets (may cause bleeding and/or 
bruising), inflammation of the mouth, diarrhea, constipation, nausea, 
vomiting, joint pain, back pain, pain in hands and feet, hair loss, rash, 
cough, shortness of breath, headache, dizziness, decreased 
appetite, hot flush, insomnia (inability to sleep), fever, common cold  
3. 5 to less than 10%: abdominal pain, indigestion, dry mouth, asthenia 
(general weakness), swelling of hands and feet, irritation or sores in 
the lining of hollow organs like mouth, throat, stomach, bowels; pain, 
influenza (flu) like illness, muscle pain, pain in the muscles and bone 
including around the chest, muscle cramps, increases in blood liver 
markers that may indicate liver damage, dry skin, itching, 
mouth/throat pain, nosebleed, impaired sense of taste,depression, 
fall, anxiety, high blood pressure, acid reflux (heart burn), increased 
creatinine level (may indicate abnormal kidney function) 
4. The following side effects have been reported in <5% of patients, but 
still deemed important: Fever associated with dangerously low levels 
of a type of white blood cells (neutrophils), blurred vision, increased 
tearing, dry eye. In addition, interstitial lung disease (an inflammation 
of the lungs which can cause cough and shortness of breath) can 
occur  
5. Serious and life-threatening infections have been observed in some 
patients treated with palbociclib  
6. Severe, life-threatening, or fatal ILD and/or pneumonitis can occur in 
patients treated with cyclin-dependent kinase 4/6 (CDK 4/6) 
inhibitors, including palbociclib when taken in combination with 
endocrine therapy. Across clinical trials, 1.4% of palbociclib -treated 
patients had ILD/pneumonitis of any grade, 0.1% had Grade 3, and 
no Grade 4 or fatal cases were reported. Additional cases of 
ILD/pneumonitis have been observed in the post-marketing setting, 
with fatalities reported 
 
g.  Drug interactions 
There is the potential for a drug-drug interaction when taken concomitantly with 
CYP3A4 substrates and P-glycoprotein substrates.   
 
CYP3A Inhibitors: Avoid concurrent use of palbociclib with strong CYP3A 
inhibitors. If the strong inhibitor cannot be avoided, reduce the starting dose of 
palbociclib is indicated. Study PI needs to be contacted to review about patient 
and decide on the starting dose. Trying alternative medications is encouraged 
to start all patients on the recommended starting dose 
CYP3A Inducers: Avoid concurrent use of palbociclib with strong CYP3A 
inducers 
CYP3A Substrates: The dose of sensitive CYP3A4 substrates with narrow 
therapeutic indices may need to be reduced when given concurrently with 


22 
Palbo T-DM1 - Protocol Version 5 & Date 01/25/2021  
palbociclib. A complete list of concomitant medications should be completed at 
time of patient screening and should be submitted as a part of their screening 
package.  
 
4.2 T-DM1 
4.2.1 Availability 
T-DM1 is a licensed drug produced by Genentech with approval of the FDA for 
treatment of patients with HER2-positive, metastatic breast cancer who previously 
received trastuzumab and a taxane, separately or in combination and had received 
prior therapy for metastatic disease or developed disease recurrence during or 
within six months of completing adjuvant therapy (IND BB#69324 and US approval 
for sales in 2013).  T-DM1 is commercially available, therefore the subject’s 
insurance company will be responsible for the prescription. 
4.2.2 Pharmaceutical Data 
a.  Formulation 
Lyophilized powder in single-use vials containing 100 mg per vial or 160 
mg per vial. 
 
b. Reconstitution 
Using aseptic technique for reconstitution and preparation of dosing 
solution, appropriate procedures for the preparation of chemotherapeutic 
drugs should be used.  Using a sterile syringe, slowly inject 5 mL of Sterile 
Water for Injection into the 100 mg KADCYLA vial or 8 mL of Sterile Water 
for Injection into the 160 mg KADCYLA vial to yield a solution containing 
20 mg/mL.  Swirl the vial gently until completely dissolved.  Do not shake.  
Inspect the reconstituted solution for particulates and discoloration.  The 
reconstituted solution should be clear to slightly opalescent and free of 
visible particulates.  The color of the reconstituted solution should be 
colorless to pale brown.  Do not use if the reconstituted solution contains 
visible particles or is cloudy or discolored.  The reconstituted lyophilized 
vials should be used immediately following reconstitution with Sterile Water 
for Injection. Determine the correct dose (mg) and calculate the volume of 
20 mg/mL KADCYLA solution needed.  Withdraw this amount from the vial 
and add to an infusion bag containing 250 mL of 0.9% Sodium Chloride 
Injection.  Gently invert the bag to mix the solution in order to avoid foaming. 
The diluted KADCYLA infusion solution should be used immediately.  If not 
used immediately, the solution may be stored in a refrigerator at 2oC to 8oC 
for up to 4 hrs prior to use.  Do not freeze or shake.  
 
c. Storage and Stability 
Lyophilized powder containing vials may be stored at room temperature.  
Once reconstituted, the shelf life is 4 hrs at 2oC to 8oC. 
 
d.  Administration 
The recommended dose of T-DM1 also called KADCYLA is 3.6 mg/kg 
given as an intravenous infusion Day 1 of every cycle (every 21 days).  
Administer first infusion over 90 min (C1D1).  Subsequent infusions may 
be administered over 30 min if prior infusions were well tolerated (starting 
C2 and going forward). If necessary, the administration time and can be 


23 
Palbo T-DM1 - Protocol Version 5 & Date 01/25/2021  
modified to meet institutional guidelines. The dose of KADCYLA is 
3.6mg/kg and can be calculated per cycle or change when weight has 
changed by 10% (from the weight used to calculate the dose of KADCYLA) 
 
e.  Procurement 
Drug is commercially available and will be procured as standard of care. 
 
f. Drug-related Toxicities 
Toxicities associated with T-DM1 include:  
Frequent 
(>10%): 
fatigue, 
nausea, 
musculoskeletal 
pain, 
thrombocytopenia, headache, increased transaminases, constipation. 
Less Frequent (>5% and ≤10%): infusion-related reactions, hepatotoxicity, 
pulmonary toxicity, peripheral neuropathy. 
Rare (≤5%): liver failure, heart failure, embryo-fetal toxicity, respiratory 
failure, hypersensitivity, insomnia, rash, hypertension. 
 
 
 
 


24 
Palbo T-DM1 - Protocol Version 5 & Date 01/25/2021  
5. Treatment plan 
5.1 Schedule of events: T-DM1 + palbociclib  
 
Day 1 of Each cycle (q21 days)* 
End of Treatment 
(within 30 days of last 
dose) 
Long term Survival Follow up 
Visit Schedule of Procedures 
Screeninga 
D1  
  
Every 6 months$ 
Informed Consent 
X 
  
  
Urine or Serum Pregnancyh 
X 
Xh 
  
  
Medical History 
X 
  
  
Demographics 
X 
  
  
Physical Exam 
X 
Xc,j 
X 
  
Height 
X 
  
  
Weight  
X 
Xc 
  
  
Vital Signs 
X 
Xc 
X 
  
ECOG performance 
X 
Xc,j 
X 
  
Concomitant Medication / Procedure 
X 
Xc 
X 
Adverse Events 
X 
Xc 
Xf 
  
CBC w Diff and Platelets 
X 
Xc,k 
  
  
Comprehensive Metabolic Panelb 
X 
Xc,k 
  
  
LVEF assessment (ECHO or MUGA) 
X 
12 weeks (+/- 7 
days) 
  
  
Imaging (CT or MRI Chest ,Abd / Pelvis w contrast) 
X 
12 weeks (+/- 7 
days) 
 
X 
  
Bone Scan or PET scan or PET component of 
PET/CT scang 
X 
12 weeks (+/- 7 
days) 
X 
  
12-Lead ECG 
X 
X 
  
QOL Questionnaires 
  
Xe 
Xe 
  
T-DM1 Administration 
 
X* 
 
 
 
Palbociclib compliance Monitoring 
  
X 
  
  
Investigational Pharmacy study drug dispensing 
  
X 
  
  
Survival information 
  
  
X 
Biomarker plasma 
  
Xe 
Xe 
  
Archived tumor tissue collection 
X 
  
  
Collection of post - study treatment anti Cancer 
therapy information 
  
  
X 
a-all screening procedures to be done within 28 days of randomization, b- should include creatinine, alkaline phosphatase, ALT, AST and total bilirubin , c- for C1D1 only- does not have to be repeated if done 
within 14 days prior to start of C1D1, e-C1D1 and end of treatment, f- adverse events should be done 30 days after last treatment, it can be done by phone call if no visit is scheduled, g- for patients with bone 
metastasis only,if this is done as a part of standard institutional guidelines h- every 6wks for women of childbearing potential only, i-only when applicable, j- can be done q6wks after cycle 8 , k- starting cycle 2 
labs can be done on day of treatment (Day 1) or upto 2 days prior * T-DM1 cannot be given before 21 days but can be given up to 7 days later and D1 of every cycle is the day T-DM1 is administered, $-every 6 
months upto 5 yrs or until last patient comes off study 
 
 
 
 


25 
Palbo T-DM1 - Protocol Version 5 & Date 01/25/2021  
 
5.2 Schedule of events Group B : T-DM1 (only applicable for patients currently on single T-DM1) 
 
 
Day 1 of Each cycle (q21 days)* 
End of Treatment 
(within 30 days of last 
dose) 
Long term Survival Follow up 
Visit Schedule of Procedures 
Screeninga 
D1 (+/- 3/7 days) 
  
Every 6 months$ 
Informed Consent 
X 
  
  
  
  
Urine or Serum Pregnancyh 
X 
Xh 
  
  
  
Medical History 
X 
  
  
  
  
Demographics 
X 
  
  
  
  
Physical Exam 
X 
Xc,j 
  
X 
  
Height 
X 
  
  
  
  
Weight  
X 
Xc 
  
  
  
Vital Signs 
X 
Xc 
  
X 
  
ECOG performance 
X 
Xc,j 
  
X 
  
Concomitant Medication / Procedure 
X 
Xc 
X 
Adverse Events 
X 
Xc 
Xf 
  
CBC w Diff and Platelets 
X 
Xc,d 
  
  
  
CMPb 
X 
 Xc 
  
  
  
LVEF assessment (ECHO or MUGA) 
X 
 12 weeks (+/- 7 
days) 
  
  
Imaging (CT/MRI Chest , Abd / Pelvis w contrast)  
X 
 12 weeks (+/- 7 
days) 
X 
  
Bone Scan or PET scan or PET component of 
PET/CT scang 
X 
 12 weeks (+/- 7 
days) 
X 
  
12-Lead ECG 
X 
  
  
X 
  
QOL Questionnaires 
  
Xe 
  
X 
  
T-DM1 Administration 
  
X* 
  
  
  
Survival information 
  
  
  
  
X 
Biomarker plasma 
  
Xe 
  
Xe  
  
Archived tumor tissue collection 
X 
  
  
  
  
Collection of post - study treatment anti-Cancer 
therapy information 
  
  
  
  
X 
 
a-all screening procedures to be done within 28 days of randomization, b- should include creatinine, alkaline phosphatase, ALT, AST and total bilirubin , c- for C1D1 only- does not have to be repeated if done 
within 14 days prior to start of C1D1e-C1D1 and end of treatment, f- adverse events should be done 30 days after last treatment, it can be done by phone call if no visit is scheduled, g- for patients with bone 
metastasis only, if this is done as a part of standard institutional guidelines, h- every 6wks for women of childbearing potential only, i-only when applicable, j- can be done q6wks after cycle 8 , * T-DM1 can be 
given -3 days to + 7 days of a 21 day cycle (to give flexibility for investigator and patients) and D1 of every cycle is the day T-DM1 is administered, $-every 6 months up to 5 yrs or until last patient comes off 
study 


26 
Palbo T-DM1 - Protocol Version 5 & Date 01/25/2021  
6. Dose modifications  
 
6.1 Palbociclib  
 
Management of some adverse events may require temporary dose interruptions/delays and/or 
dose reductions, or permanent discontinuation as per dose reduction schedules listed in tables 
1, 2 and 3 below  
 
Table 1: recommended dose modification for adverse reactions 
 
Dose level  
Dose 
Recommended starting dose 
125mg/day 
First dose reduction 
100mg/day 
Second dose reduction 
75mg/day 
• 
If further dose reduction below 75mg/day is required, discontinue the treatment and 
come off study 
 
6.2 T-DM1 
 
If a planned dose is delayed or missed, administer as soon as possible; do not wait until the next 
planned cycle. Adjust the schedule of administration to maintain a 3-week interval between doses. 
Administer the infusion at the dose and rate the patient tolerated in the most recent infusion 
 
Table 2 : Recommended Dose Reduction Schedule for Adverse Events 
 
Dose reduction schedule 
Dose level 
Starting dose 
3.6mg/kg 
First dose reduction 
3mg/kg 
Second dose reduction 
2.4mg/kg 
Requirement for further dose reduction 
Discontinue treatment and come off study 
 
 
Table 3: Recommended dose modifications for T-DM1 and Palbociclib  
 
Adverse Events£ 
Grade 
Palbociclib  
T-DM1# 
Infusion reaction 
2 or 3 
 
4 
Not Applicable 
 
Not Applicable 
Slow or interrupt 
 
Permanently 
discontinue 
Transaminases 
3 
 
 
4 
No change 
 
 
Permanently discontinue  
Hold until <Grade 2, 
then one dose level 
reduced 
 
Permanently 
discontinue 
Bilirubinemia in 
absence of elevated 
transaminases 
2 
 
3 
 
 
No change 
 
Hold until <Grade 1, then 
one dose level reduced  
 
Hold until <Grade 1, 
then same dose 
Hold until <Grade 1, 
then one dose level 
reduced 


27 
Palbo T-DM1 - Protocol Version 5 & Date 01/25/2021  
4 
 
Permanently discontinue 
Permanently 
discontinue 
Transaminases + 
Bilirubinemia 
Transaminases>3xULN 
+ Bilirubin >2xULN  
Permanently discontinue 
Permanently 
discontinue 
QTc 
2 
 
3 
 
 
 
 
 
 
4 
No change 
 
Reversible cause, wait till 
QTc 
<480msec, 
resume 
same dose; No reversible 
cause, 
wait 
till 
QTc 
<480msec, then one dose 
level reduced. 
 
Permanently discontinue 
No change 
 
No change 
 
 
 
 
 
 
No change 
Nodular generative 
hyperplasia of liver 
Any grade 
Permanently discontinue 
Permanently 
discontinue 
LVEF 
>45% 
 
40-45%, decrease 
<10% from baseline 
 
40-45%, decrease 
>10% from baseline 
 
<40% 
 
 
 
No change  
 
No change 
 
 
No change 
 
 
No change 
 
 
 
Continue 
 
Continue, repeat 
imaging in 3wks 
 
Hold, repeat imaging 
3wks, if not recovered, 
discontinue 
Hold, repeat imaging 
3wks, if <40% 
discontinue 
 
 
 
Symptomatic CHF 
Any grade 
Permanently discontinue 
Permanently 
discontinue 
Interstitial lung 
disease/pneumonitis€ 
Any grade 
Permanently discontinue 
Permanently 
discontinue 
Other non-
hematologic 
2 
 
3-4 
No change 
 
If related, when Grade <1, 
restart next lower dose level 
No change 
 
If related, when Grade 
<1, restart next lower 
dose level 
Neuropathy 
Grade 3-4 
No change 
Hold until <Grade 2 
ANC 
<1000/mcL 
Hold until >1000/mcL 
If Grade 4 neutropenia >1wk 
or Grade 3 neutropenia 
>2wks 
or 
Grade 
3-4 
neutropenia complicated by 
T>38.5oC, then reduce by 1 
dose level 
 
Hold until >1000/mcL 
and resume at the same 
dose level  
Platelets Day 1 of 
each cycle 
<LLN->75,000/mcL, 
grade 1 
No change  
 
No change 
 


28 
Palbo T-DM1 - Protocol Version 5 & Date 01/25/2021  
 
50-75,000/mcL,grade 2 
 
 
 
25-50,000/mcLGrade 3 
 
 
 
<25,000/mcL, grade 4  
 
 
 
Hold until >75,000/mcLand 
resume at the same dose 
level 
 
Hold until >75,000/mc, then 
resume at reduced dose by 
one level 
 
Hold until >75,000/mc, then 
resume at reduced dose by 
one level  
 
 
Hold until >75,000/mcL 
and resume at the same 
dose  
 
Hold until >75,000/mcL 
and resume at the same 
dose  
 
Hold until >75,000/mcL 
and resume at reduced 
dose by one level 
 
 
£ If adverse events take more than 14 days to resolve, dose for palbociclib and T-DM1 have to be reduced 
one dose level  
*Dose levels for T-DM1 are 3.6mg/kg starting dose level and 3.0mg/kg one dose level reduced and 
2.4mg/kg two dose levels reduced 
Palbociclib dose levels are 125mg, 100mg and 75mg  
#Based on T-DM1 package insert 
€ Based on clinical symptoms and confirmed by CT or imaging findings 
 
7. Adverse Events (AEs)  
 
7.1 
Adverse Events Definition 
 
AEs will be determined using the revised NCI Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.03 for Toxicity and Adverse Event reporting.  A copy of the CTCAE version 
4.03 can be downloaded from CTEP home page (http://ctep.info.nih.gov). 
 
An adverse event (AE) is any untoward medical occurrence (e.g., an abnormal laboratory finding, 
symptom, or disease temporally associated with the use of a drug) in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not necessarily have 
a causal relationship with this treatment.  An AE can therefore be any unfavorable and unintended 
sign (including an abnormal laboratory finding), symptom, or disease temporally associated with 
the use of a medicinal product, whether or not related to the medicinal product.   
 
Hospitalization for elective surgery or routine clinical procedures that are not the result of an AE 
(e.g., surgical insertion of central line) need not be considered AEs and should not be recorded 
as an AE.  Disease progression should not be recorded as an AE, unless it is attributable by the 
investigator to the study therapy. 
 
 
7.2 
Serious Adverse Events (SAEs) Definition 
 
An AE is considered serious if, in the view of either the investigator or sponsor, it results in any of 
the following outcomes: 
• 
Death; 
• 
Is life-threatening (places the subject at immediate risk of death from the event as 
it occurred); 


29 
Palbo T-DM1 - Protocol Version 5 & Date 01/25/2021  
• 
Requires inpatient hospitalization (>24 hours) or prolongation of existing 
hospitalization;* 
• 
Results in congenital anomaly/birth defect; 
• 
Results in a persistent or significant incapacity or substantial disruption of the 
ability to conduct normal life functions; 
• 
Important medical events that may not result in death, be life-threatening, or 
require hospitalization may be considered a serious adverse drug experience 
when, based upon appropriate medical judgment, they may jeopardize the patient 
or subject and may require medical or surgical intervention to prevent one of the 
outcomes listed in the definition.  For reporting purposes, also consider the 
occurrences of pregnancy as an event which must be reported as an important 
medical event. 
 
*Hospitalization for anticipated or protocol specified procedures such as administration of 
chemotherapy, central line insertion, metastasis interventional therapy, resection of primary 
tumor, or elective surgery, will not be considered serious adverse events. 
 
Pregnancy that occurs during the study must also be reported as an SAE. 
 
7.3   Documentation of AEs 
 
For AEs, documentation must begin from day 1 of study treatment and continue through the 30 
day follow-up period after treatment is discontinued.   
 
Collected information should be recorded in the Case Report Forms (CRF) for that patient. 
Documentation will include, but is not limited to: 
 
• 
Grade 
• 
Relationship to study drug (not related, unlikely, possible, probable, definitely)  
• 
Causality other than study drug (disease related, concomitant medication related, 
intercurrent illness, other)   
• 
Date of onset, date of resolution 
• 
Frequency of event (single, intermittent, continuous) 
• 
Event outcome (resolved, ongoing, death) 
• 
Action taken (none, held, dose reduced, discontinued, medication given) 
 
7.4  Documentation of SAEs  
AEs that meets the definition of an SAE, recording of the event must begin from day 1 of study 
treatment and continue through the 30 day follow-up period after treatment is discontinued.  
 
All SAEs must be recorded as an SAE within the study electronic data capture system and the 
report must be reported to Protocol PI and Criterium PM via email within 24 hours of learning of 
its occurrence.  Specifics will be noted in the SAE Reporting Guidelines.  A paper SAE report form 
might also be required. 
 
SAEs are to be reported to your IRB in accordance with IRB reporting policies. 
 


30 
Palbo T-DM1 - Protocol Version 5 & Date 01/25/2021  
All serious adverse events and any deaths will be reported to the DSMB and to the University of 
Arizona Human Subjects Protection Program per the guidelines set forth in University of Arizona 
Cancer Center Data and Safety Monitoring Board Charter. 
 
All submitted serious adverse events will be processed by the DSMB Coordinator monthly for 
initial trend analysis and then reviewed by the DSMB Chair. The assigned QA/QC Monitor will 
review the SAE reporting process to confirm reporting requirements are met. 
 
7.5  Pregnancy 
 
Pregnancies and suspected pregnancies (including a positive pregnancy test regardless of age 
or disease state) of a female subject occurring while the subject is on study, or within 30 days of 
the subject’s last dose of study should be recorded as SAEs.  The patient is to be discontinued 
immediately (within 24 hours) from the study and the female subject should be referred to an 
obstetrician-gynecologist, preferably one experienced in reproductive toxicity for further 
evaluation and counseling. 
 
Pregnancy, suspected pregnancy, or positive pregnancy test must be reported to the Criterium 
Project Manager & Protocol PI immediately by submitting a completed Pregnancy Report Form 
via email.  Specifics will be outlined in the SAE reporting guidelines. 
 
The Investigator will follow the female subject until completion of the pregnancy, and must 
document the outcome of the pregnancy (either normal or abnormal outcome) and report the 
condition of the fetus or newborn to the Criterium Project Manager and Protocol PI on an updated 
Pregnancy Report Form and submit.  If the pregnancy results in the birth of a child, additional 
follow-up information may be requested.  If the pregnancy results in spontaneous abortion or 
stillbirth, the event should be reported as an SAE.  If there are any abnormal outcomes that meet 
the serious criteria, it must be reported as an SAE.   
 
Pregnancy outcomes must be collected for the female partners of any males who took study drug 
in this study. Consent to report information regarding these pregnancy outcomes should be 
obtained from the female partner. 
 
7.6  Overdose 
 
An overdose is defined as the accidental or intentional ingestion or infusing of any dose of study 
treatment that exceeds the dose described in the protocol. Overdoses should be reported as a 
SAE using the SAE forms. 
 
7.7  FDA Expedited Reporting requirements for studies conducted under an IND: 
 
If an investigator deems that an event is a Suspected Unexpected Serious Adverse Reaction 
(SUSAR),  de-identified supporting documentation defining the event and causality within 24 hrs of 
knowledge of the event should be emailed to the Criterium Project Manager and Protocol PI. 
 
The UACC study manager or designee will report all local and nonlocal events to the UACC IRB 
and DSMC.  It is the responsibility of UACC or designee to ensure that all participating sites are 
notified of the events and resulting action for events which may modify the risk of the protocol or 
which otherwise meet FDA requirements for expedited reporting.  
 


31 
Palbo T-DM1 - Protocol Version 5 & Date 01/25/2021  
If the toxicity is reportable, the study PI at UACC will be responsible for notifying the FDA as per 
Federal Register §312.32 IND safety reports.  
 
Once the Protocol PI determines an event is a SUSAR, the MedWatch 3500A form will be created 
by Protocol PI or designee and submitted to the FDA.   Protocol PI or designee will also report 
information to Pfizer per their requirements.   
 
In particular, (1) Written reports.  The Protocol PI or designee shall notify FDA in a written IND 
safety report of any adverse experiences associated with use of the drug that is serious and 
unexpected.  Such notification shall be submitted to the FDA no later than 7 working days after the 
initial receipt of the information for fatal or life-threatening and 15 calendar days for non-fatal or non-
life-threatening . The written notification to the FDA will be transmitted or mailed to the FDA Division 
of the Center for Drugs and Biologics. (2) Telephone reports.  The Protocol PI or designee shall 
also notify FDA by telephone of any unexpected, fatal or life-threatening experience associated with 
use of the drug in the clinical study conducted under the IND no later than 3 working days after 
receipt of the information. 
The 
MedWatch 
3500a 
form 
can 
be 
accessed 
at: 
http://www.fda.gov/Safety/MedWatch/HowToReport/DownloadForms/default.htm. (Please be sure 
and access form 3500a, and not form 3500).   UNC, as the Sponsor of the study, will make the final 
determination regarding FDA submission.   
 
The Criterium PM or designee is responsible for emailing expedited reports to each site on study of 
all SUSARs reported to the FDA via email as soon as possible.  
 
Questions 
 
Any questions regarding this protocol should be directed to the PI  or study team. 
 
Principal Protocol Investigator 
Pavani Chalasani MD, MPH 
University of Arizona Cancer Center 
Telephone : 520-626-0191 
Fax: 520-626-2225 
 
 
Criterium Project Manager or Designee  
 
Contact information will be provided in the 
Safety Reporting Guidelines. 
 
 
8 Study procedures 
 
8.1 Enrollment 
 
Before a subject participates in the trial, the investigator or delegate (as allowed by the IRB of 
record) is responsible for obtaining written informed consent after adequate explanation of the 
aims, methods, anticipated benefits, subject responsibilities including the use of adequate 
methods to prevent pregnancy, and potential hazards of the study and before any 
protocol-specific screening procedures or any study medications are administered.  
 
Enrollment packets must be approved prior to enrollment.    To enroll a patient, all the necessary 
documents must be submitted to Criterium and will be reviewed and approved by the medical 
monitor.  Materials required to complete the enrollment packet are to be emailed and include, but 
not limited to the following: 
 


32 
Palbo T-DM1 - Protocol Version 5 & Date 01/25/2021  
• 
Consent Form (first page and blinded signature pages) 
• 
HIPAA Authorization (first page and blinded signature pages) 
• 
Eligibility Checklist and all supporting documentation 
 
 
8.2 Screening  
 
Potential subjects will enter the screening period of the study after a completely executed 
informed consent has been obtained.  
 
8.3 Registration  
 
After eligibility has been confirmed, a patient identification number will be assigned. The patient 
will be considered registered, and study treatment may then begin. 
 
For multi-center study registrations, subject identification numbers will begin with the site number 
and end with a sequential number.  Format is to be determined but an example is XX-YYY.  XX 
being the assigned site number (01, 02, 03, etc) and YYY being the sequential patient number for 
that site (001, 002, 003, etc).   
 
8.4 Follow up 
 
Follow-up visits/procedures will be conducted per schema in section 5.   Data regarding further 
treatments and survival information will be captured for this study every 6 months until the final 
patient is off treatment or otherwise determined by the sponsor. 
 
8.5 Early treatment termination  
 
Subjects that terminate treatment early (for reasons other than disease progression or side 
effects) will have an end of treatment (time period i.e. within 30 days of receiving the last 
treatment). Subjects will then follow up with their treating physician per their standard of care.  
 
 
8.6 Off study  
 
Subjects will be considered off study when all end of study and follow-up visits have been 
completed, unless death or withdrawal of consent to continue participation occurs.  
 
9.0 Tumor response evaluation per RECIST 1.1 
 
The revised RECIST 1.1 guidelines (Eisenhauer, 2009) will be used to determine response and 
progression. 
 
Patients with measurable or non-measurable (evaluable) disease (according to RECIST 1.1) will 
be evaluated for response or progression. For the purposes of this study, patients will be 
evaluated by tumor imaging 12 weeks ± 7 days. Whenever possible imaging is done after every 
4 cycles prior to their next cycle of treatment (12 weeks ± 7 days) however if there are any delays 
in treatment, the imaging should follow 12 week from last imaging schedule.  At baseline, tumor 
lesions/lymph nodes/bone lesions will be categorized as measurable or non-measurable based 
on the definitions provided below. 
 


33 
Palbo T-DM1 - Protocol Version 5 & Date 01/25/2021  
9.1 Measurable Disease  
 
Measurable disease is defined by the presence of at least one measurable lesion that can be 
accurately measured in at least 1 dimension (longest diameter in the plane of measurement is to 
be recorded) with a minimum size of 10 mm by CT scan (CT scan slice thickness no greater than 
5 mm); when CT scans have slice thickness > 5 mm, the minimum size for a measurable lesion 
must be twice the slice thickness.  
 
To be considered pathologically enlarged and measurable, a lymph node must be ≥ 15 mm in 
short axis when assessed by CT scan (CT scan slice thickness recommended to be ≤ 5 mm).Only 
the short axis will be measured and followed at baseline and in follow-up (Schwartz, 2009).  
 
9.2 Non-Measurable Disease  
 
All other lesions, including small lesions (longest diameter < 10 mm, or pathological lymph nodes 
≥ 10 mm and < 15 mm on the short axis) as well as truly non-measurable lesions, are considered 
non-measurable disease. Lesions considered truly non-measurable include ascites, pleural or 
pericardial effusion, lymphangitic involvement of skin or lung, or abdominal masses/ abdominal 
organomegaly identified by physical exam (PE) that is not measurable by reproducible imaging 
techniques. 
 
Bone lesions: Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue 
components, that can be evaluated by cross-sectional imaging techniques such as CT scan or 
MRI can be considered as measurable lesions if the soft tissue component meets the definition 
of measurable disease. Blastic bone lesions are considered nonmeasurable disease.  
 
Cystic lesions: Lesions that meet the criteria to be radiographically defined as simple cysts should 
not be considered as malignant lesions (neither measurable nor non-measurable) because they 
are, by definition, simple cysts. Cystic lesions thought to represent cystic metastases can be 
considered as measurable lesions, if they meet the definition of measurable disease. However, if 
non-cystic lesions are present in the same subject, these are preferred for selection as target 
lesions. 
 
Lesions with prior local treatment: Tumor lesions situated in a previously irradiated area, or in an 
area subjected to other loco-regional therapy, are usually not considered measurable unless there 
has been demonstrated progression in the lesion. 
 
9.3 Specifications by Methods of Measurements 
 
The same method of assessment and the same technique should be used to characterize each 
lesion at baseline and throughout the study. Imaging-based evaluation must always be done 
rather than clinical examination unless the lesion(s) being followed cannot be imaged but is/are 
assessable by clinical exam. 
 
Clinical lesions: Clinical lesions will only be considered measurable when they are superficial and 
are ≥ 10 mm diameter as assessed using calipers (e.g., skin nodules). When lesions can be 
evaluated by both clinical exam and imaging, imaging evaluation must be undertaken, because it 
is more objective and may also be reviewed at the end of the study. 
 


34 
Palbo T-DM1 - Protocol Version 5 & Date 01/25/2021  
CT, MRI: CT is the best currently-available and reproducible method for measuring lesions 
selected for response assessment. If a slice thickness > 5 mm is used for CT scanning, then the 
minimum longest diameter for a target lesion will be twice the slice thickness.  
 
Tumor markers: Tumor markers may be obtained per institutional guidelines; however, tumor 
markers cannot be used to assess objective tumor response or PD. Details on tumor markers will 
be captured in the database. 
 
Cytology and histology: These techniques can be used to differentiate between PR and CR in 
rare cases when the nature of a residual lesion is in question. The cytological confirmation of the 
neoplastic origin of any effusion that appears or worsens during treatment can be considered if 
the measurable tumor has met the criteria for response or stable disease (SD) in order to 
differentiate between response (or SD) and PD. 
 
9.4 Baseline Documentation of “Target” and Non-Target” lesions  
 
To assess objective response or future progression, it is necessary to estimate the overall tumor 
burden at baseline and use this estimate as a comparator for subsequent measurements. 
 
Any single lesion that meets the definition of measureable disease (Section 9.1) may be identified 
as a “Target Lesion” and will be recorded and measured at baseline. When > 1 measurable lesion 
is present at baseline, all lesions up to a maximum of 5 total (and a maximum of 2 lesions per 
organ) that are representative of all involved organs will be identified as target lesions and will be 
recorded and measured at baseline. This means that in instances where patients have only 1 or 
2 organ sites involved, a maximum of 2 and 4 lesions, respectively, will be recorded. Target 
lesions will be selected by size (based on their longest diameter) and whether they lend 
themselves to reproducible repeated measurements. Occasionally, the largest lesion does not 
lend itself to reproducible measurement; in this circumstance, the next-largest lesion that can be 
measured reproducibly will be selected. Tumor lesions situated in a previously irradiated area, or 
in an area subjected to other loco-regional therapy, are usually not considered measureable 
unless there has been demonstrated progression in the lesion. 
 
Pathological nodes that are defined as measurable may be identified as target lesions; however, 
only the short axis of these nodes will contribute to the baseline sum. This means that when lymph 
nodes are included as target lesions, the sum of lesions may not be zero even if complete 
response criteria are met, because a normal lymph node is defined as having a short axis of < 10 
mm. For PR, SD, and PD, the actual short axis measurement of the nodes is to be included in the 
sum of target lesions. All other pathological nodes will be considered non-target lesions. 
 
While on study, all lesions (nodal and non-nodal) recorded at baseline will have their actual 
measurements recorded at each subsequent evaluation, even when very small (e.g., 2 mm). 
However, if the lesion is believed to be present and is faintly seen but is too small to measure with 
any accuracy, a default value of 5 mm will be assigned. 
 
A sum of the diameters (longest diameter for non-nodal lesions, short axis for nodal lesions) for 
all target lesions will be calculated and will be reported as the baseline sum of diameters. The 
baseline sum of diameters will be used as reference to further characterize any objective tumor 
regression in the measurable dimension of the disease. 
 


35 
Palbo T-DM1 - Protocol Version 5 & Date 01/25/2021  
All other lesions (or sites of disease) including pathological lymph nodes will be identified as “non-
target lesions” and will also be recorded at baseline. Measurements are not required and these 
lesions will be followed as present, absent, unequivocal progression, or new lesions. 
 
 
9.5 Evaluation of target lesions  
 
Definitions of the criteria used to determine objective tumor response for target lesions are seen 
in table 4:  
 
Table 4: Criteria Definitions for Objective Tumor Response for Target Lesions 
 
Tumor response 
Criteria definition 
Complete Response 
Disappearance of all target lesions. Any 
pathological lymph nodes (whether 
target or non-target) must have reduction in 
short axis to < 10 mm. 
Partial Response 
At least a 30% decrease in the sum of 
diameters of target lesions, taking as 
reference the baseline sum diameters. 
Progressive Disease 
At least a 20% increase in the sum of 
diameters of target lesions, taking as 
reference the smallest sum on study (this 
includes the baseline sum if that is the 
smallest on study). In addition to the relative 
increase of 20%, the sum must 
also demonstrate an absolute increase of at 
least 5 mm. Note: The appearance 
of 1 or more new lesions is considered 
progression. 
Stable Disease 
Neither sufficient shrinkage to qualify for PR 
nor sufficient increase to qualify 
for PD, taking as reference the smallest sum 
of diameters while on study. 
 
9.6 Evaluation of non-target lesions 
Definitions of the criteria used to determine the tumor response for the group of non-target lesions 
are in Table 5. While some non-target lesions may actually be measurable, they need not be 
measured and instead will be assessed only qualitatively at the time points of radiographic 
assessments. 
 
Table 5: Criteria Definitions for Objective Tumor Response for Non-Target 
Lesions (RECIST 1.1) 
 
 
Tumor response 
Criteria definition 
Complete Response 
Disappearance of all non-target lesions and 
normalization of tumor marker 


36 
Palbo T-DM1 - Protocol Version 5 & Date 01/25/2021  
level. All lymph nodes must be non-
pathological in size (< 10 mm short axis). 
Non-CR/Non-PD 
Persistence of 1 or more non-target lesion(s) 
and/or maintenance of tumor 
marker level above the normal limits. 
Progressive Disease 
Unequivocal progression of existing non-
target lesions. (Note: The appearance 
of 1 or more new lesions is also considered 
progression). 
 
Disease progression in subjects with only non-measurable disease 
 
For subjects with only non-measurable disease, disease progression is defined as development 
of new lesions or “unequivocal progression” of existing lesions. Because worsening in non-target 
disease cannot be easily quantified (by definition: if all lesions are truly non-measurable), a useful 
test that can be applied when assessing subjects for unequivocal progression is to consider if the 
increase in overall disease burden, based on the change in non-measurable disease, is 
comparable in magnitude to the increase that would be required to declare PD for measurable 
disease, i.e., an increase in tumor burden representing an additional 73% increase in ‘volume’ 
(which is equivalent to a 20% increase diameter in a measurable lesion). If ‘unequivocal 
progression’ is seen, the subject should be considered to have had overall PD at that point.  
 
New lesions 
The appearance of new malignant lesions denotes disease progression; however, the finding of 
a new lesion should be unequivocal, i.e., not attributable to differences in scanning technique, 
change in imaging modality or findings thought to represent something other than tumor (eg, some 
‘new’ bone lesions may be simply healing or flare of pre-existing lesions). A lesion identified on a 
follow-up study in an anatomical location that was not scanned at baseline is considered a new 
lesion and will indicate disease progression. 
If a new lesion is equivocal (eg, because of small size), continued therapy and follow-up 
evaluation will clarify if it represents truly new disease. If repeat scans confirm there is definitely 
a new lesion, then progression should be declared using the date of the initial scan. 
 
9.7 Evaluation of best overall response per RECIST 1.1 
 
The best overall response is the best response recorded from the start of the randomization until 
disease progression/recurrence per RECIST, taking as reference for PD the smallest 
measurements recorded since the treatment started. The patient’s best response assignment will 
depend on the achievement of both measurement and RECIST criteria. 
 
Table 6 provides overall responses for all possible combinations of tumor responses in target and 
non-target lesions with and without the appearance of new lesions. 
 
Table 6: Overall Responses for Combinations of Tumor Responses per RECIST 1.1 
 
Target 
lesions 
Nontarget 
lesions 
New 
lesions 
Overall response  
CR 
CR 
No 
CR 
CR 
Non-CR/Non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 


37 
Palbo T-DM1 - Protocol Version 5 & Date 01/25/2021  
PR 
Non-CR/not 
evaluated 
No 
PR 
SD 
Non-PD or not all 
evaluated 
No 
SD 
PD 
Any 
Yes or no 
PD 
Any 
PD 
Yes or no 
PD 
Any 
Any 
Yes 
PD 
Not all 
evaluated 
Non-PD 
No 
Unevaluable 
CR=complete response; PD=progressive disease; PR=partial response; SD=stable disease 
Subjects with global deterioration of health status requiring discontinuation of treatment without 
objective 
evidence of disease progression at that time should be reported as “symptomatic deterioration”. 
Every effort should be made to document the objective progression even after discontinuation of 
treatment. 
10. STATISTICAL CONSIDERATIONS 
10.1 Analysis population 
 
Patients with recurrent or metastatic HER2 positive breast cancer who are eligible to start 
treatment with T-DM1 will be enrolled on to this trial.  The primary analysis sample for efficacy will 
be evaluable patients who have completed at least 1 cycle of treatment. If a patient was not able 
to complete at least 1 cycle of therapy, they will be replaced for the study analysis.    
 
Patients will be treated with T-DM1 and Palbociclib. T-DM1 will be administered 3.6mg/kg IV q21 
days. Palbociclib is given orally at 125mg on days 5-18 of every 21 day cycle. 
10.2 Safety Analysis  
The first safety analysis will be conducted when 16 patients have completed 12 months or come 
off study (which ever is first) on T-DM1+ Palbociclib arm. Safety data with regards to number of 
grade 3 or 4 events and unresolved grade 3 or 4 events will be taken into account and if more 
than 20% of subjects have unresolved grade 3 or 4 events, the study advisory board will meet to 
discuss dose and schedule modification. After the first 16 patients, additional safety oversight will 
be provided by the study data monitoring committee (DMC) 
 
10.3 Sample Size Calculation 
 
This is a prospective single arm phase II study to estimate progression free survival of 
combination T-DM1 + palbociclib. Expected PFS for T-DM1 based on the EMILIA trial is 9.6 
months. The goal of the study is to detect an improvement of PFS to 16.3 months (HR = 0.56) in 
the combination arm compared to the standard historical control arm, with 80% statistical power 
and a 0.05 one sided alpha level. We propose enrolling a total of 46 subjects into this trial. We 
will conduct a futility analysis after the first 16 evaluable patients have completed 12 months of 
treatment or come off study (whichever comes. First).  If at least  8 have PFS beyond 12 months, 
we will continue accrual for additional 30 evaluable patients (for a total of 46 evaluable patients). 
If at least 24 evaluable subjects have PFS beyond 12 months then we declare the combination 


38 
Palbo T-DM1 - Protocol Version 5 & Date 01/25/2021  
as promising for future studies. Our null hypothesis is 40% have PFS at 12mths (median survival 
of 9.1 months) Alternative hypothesis is 60% survive 12 months. 
 
Definition of end points 
 
PFS is defined as the time from date of first treatment to the date of investigator-determined 
objective disease progression as defined by RECIST 1.1 or death from any cause. Patients who 
have neither progressed nor died will be censored at the day of their last radiographic tumor 
assessment (if available) or date of randomization if no post initiation (that is post baseline) 
radiographic assessment is available  
 
Response rate 
Overall response rate (ORR): the proportion of patients with CR or PR per RECIST 1.1 
Disease control rate (DCR): the proportion of patients with CR, PR or SD according to RECIST 
1.1 
Clinical benefit rate (CBR): the proportion of patients with CR, PR or SD ≥6mths according to 
RECIST 1:1 
Duration of Response(DOR): The time from the date of first evidence of a CR or PR to the date 
of objective progression or death from any cause,whoever is earlier  (this is only defined in 
responders in both arms)  
 
Overall survival is defined as the time from date of first treatment to date of death due to any 
cause. Patients last known to be alive are censored at their last contact date  
 
10.4 Statistical analysis 
 
Progression free survival of the combination of T-DM1 with palbociclib will be estimated using the 
Kaplan-Meier estimate.  A Cox proportional hazards model will be used to estimate the hazard 
rate with 95% confidence interval.   Overall survival will be analyzed similarly. The overall 
response (CR + PR + stable disease) will be estimated using an exact binomial confidence 
interval. 
 
11. ADMINISTRATIVE PROCEDURES 
11.1 Investigator Responsibilities 
The Principal Investigator is responsible for the conduct of the clinical trial at the site in accordance 
with Title 21 of the Code of Federal Regulations and/or the Declaration of Helsinki.  The Principal 
Investigator is responsible for personally overseeing the treatment of all study patients.  The 
Principal Investigator must assure that all study site personnel, including sub-investigators and 
other study staff members, adhere to the study protocol and all FDA/GCP/NCI regulations and 
guidelines regarding clinical trials both during and after study completion. 
 
The Principal Investigator at each institution or site will be responsible for assuring that all the 
required data will be collected and entered into the eCRFs.  Periodically, data monitoring will be 
conducted and the Principal Investigator or designee must provide de-identified source upon 
request to permit remote verification of proper entry of data. At the completion of the study, all 
eCRFs will be reviewed by the Principal Investigator and will require his/her final signature to 
verify the accuracy of the data. 
 
  
11.2 Subject Confidentiality 


39 
Palbo T-DM1 - Protocol Version 5 & Date 01/25/2021  
  
The principal investigator will ensure that the subject’s confidentiality is maintained in compliance 
with Federal regulations, the International Conference on Harmonization (ICH), and Good Clinical 
Practice (GCP) Guidelines.  
 
Oversight entities and/or regulatory authorities will be permitted direct access to review the 
subject’s original medical records, electronic medical records or certified copies for verification of 
study-related procedures and data. Direct access includes examining, analyzing, verifying, and 
reproducing any records and reports that are important to the evaluation of the study.  
 
11.3 Study Documentation and Archive 
 
The investigator will maintain a list of appropriately qualified persons to whom he/she has 
delegated study duties. All persons authorized to make entries and/or corrections on CRFs will 
be included on the Delegation of Responsibilities Form.  
 
Source documents, data, and records from which the subject’s CRF data are obtained include, 
but are not limited to, hospital records, clinical/office/research charts, laboratory and pharmacy 
records, diaries, microfiches, radiographs, and correspondence. Source data will include 
information necessary for the reconstruction and evaluation of the trial.  
 
The principal investigator or sponsor-investigator is responsible for maintaining a comprehensive 
and centralized filing system of all study-related (essential) documentation as required per ICH 
Guidelines. This can be accomplished by the PI, through the site’s standard operating procedures 
and/or the institutions infrastructure. 
 
The investigator will follow ICH Good Clinical Practice Guidelines and the Code of Federal 
Regulations for records and record retention.  
 
11.4 Data 
 
Applicable data as specified as required in the protocol will be reported/submitted in the case 
report form (CRF). Data reported in the case report forms that are derived from source documents 
must be consistent with the source documents or the discrepancies must be explained. All the 
CRF’s data will be entered into a central database determined and managed by Criterium, Inc.  
 
Additional procedures and assessments may be performed as the institution’s standard of care; 
however, these data should remain in the medical records and should not be provided as part of 
the clinical study data unless it pertains to an adverse event or serious adverse event.  
 
The investigator is required to prepare and maintain adequate and accurate case histories that 
record all observations and other data pertinent to the investigation on each individual 
administered the investigational product/intervention/device, or employed as a control in the 
investigation.  
 
11.5 Protocol Deviations   
 
The investigator will conduct the study in conformance with this protocol, generally accepted 
standards of Good Clinical Practice and all applicable federal, state and local laws, rules, and 
regulations.  
 


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Approvals or waivers for protocol deviations will be obtained from the sponsor-investigator prior 
to occurring, except changes to eliminate an immediate hazard to study subjects. If immediate 
verbal approval is obtained, it will be documented by the research staff obtaining the approval 
and followed by a written protocol deviation form per the site standard operating procedures. The 
sponsor or the sponsor-investigator will sign the Protocol Deviation (Waiver) Approval Form or 
other similar document. The original will be filed in the regulatory binder and a copy will be placed 
in the subject’s research file. 
11.6 Record Retention 
Study documentation includes all eCRFs, data correction forms or queries, source documents, 
Sponsor-Investigator correspondence, monitoring logs/letters, and regulatory documents (e.g., 
protocol and amendments, IRB correspondence and approval, signed patient consent forms). 
 
Source documents include all recordings of observations or notations of clinical activities and all 
reports and records necessary for the evaluation and reconstruction of the clinical research study. 
 
Government agency regulations and directives require that all study documentation pertaining to 
the conduct of a clinical trial must be retained by the study investigator.  In the case of a study 
with a drug seeking regulatory approval and marketing, these documents shall be retained for at 
least two years after the last approval of marketing application in an International Conference on 
Harmonization (ICH) region.  In all other cases, study documents should be kept on file until three 
years after the completion and final study report of this investigational study. 
11.7 Amendments to the Protocol 
Should amendments to the protocol be required, the amendments will be originated and 
documented by the Protocol Principal Investigator.  It should also be noted that when an 
amendment to the protocol substantially alters the study design or the potential risk to the patient, 
a revised consent form might be required.   
 
The written amendment, and if required the amended consent form, must be sent to the site IRB 
for approval prior to implementation.   
 
All sites must submit their informed consent revisions to the Criterium Project Manager or 
designee for review and approval prior to submission to their IRB.   
11.8 Termination Rules 
The protocol Principal Investigator and Criterium have the right to terminate this clinical study at 
any time. The protocol principal investigator and Criterium, as appropriate, will be involved in any 
decisions regarding terminating the study, temporarily suspending enrollment, or stopping 
ongoing treatment with study treatment. 
 
 
Reasons for terminating the clinical study or a study site’s participation include, but are not limited 
to, the following: 
•The incidence or severity of an adverse reaction related to treatment in this study or other 
studies indicates a potential health hazard to patients 
 
• Patient enrollment is unsatisfactory 
 
• Data recording is significantly inaccurate or incomplete 
 
• Study site personnel are noncompliant with study procedures 
 
• Pattern of noncompliance is observed 


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12. Regulatory Obligations  
 
12.1 Informed Consent 
 
Before a subject’s participation in the clinical study, the investigator or identified designee is 
responsible for obtaining written informed consent from the subject or legally authorized 
representative after adequate explanation of the aims, methods, anticipated benefits, and 
potential hazards of the study and before any protocol specified procedures, investigational 
product, intervention or device are administered or initiated.  
 
12.2 Institutional Review Board   
 
A copy of the protocol, proposed ICF, and all other applicable subject information will be submitted 
to the individual site’s IRB for written approval. A copy of the written approval of the protocol and 
ICF must be on file at the individual institution before recruitment of subjects into the study.   
 
The principal investigator at each site is responsible for obtaining IRB approval/renewal at least 
annually throughout the duration of the study. Copies of the investigator’s reports and the IRB 
continuance of approval must be on file at the institution.  
 
The investigator must submit study information to the IRB as required by all applicable guidelines 
and requirements. The investigator will obtain IRB approval for subsequent protocol amendments; 
except changes to eliminate an immediate hazard to study subjects, and changes to the informed 
consent document from the IRB prior to implementation.  
 
The investigator will notify the IRB of deviations from the protocol or serious adverse events 
occurring at the site and other serious adverse event reports occurring at or received from 
participating centers as applicable for multi-center trials following the IRB policies and procedures. 
 
All the sites must notify the primary site (UACC) and Criterium of any SAE and notification to their 
IRB. 
 
 
 


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13. DATA AND SAFETY MONITORING PLAN 
 
13.1 Identification of the DSMB obligated for oversight responsibilities 
 
University of Arizona will be responsible for the conduct of this study as the DSMB of record, 
overseeing participant safety, executing the data and safety monitoring (DSM) plan, and ensuring 
compliance with all reporting requirements to state and federal authorities. Criterium,Inc will 
provide the site monitoring function for this trial and provide monthly reports to the University of 
Arizona DSMB. The University of Arizona DSMB is responsible for ensuring data quality and study  
participant safety.  A summary of the DSMC’s activities is as follows: 
  
• 
Conduct internal audits  
• 
Has the authority to close and/or suspend studies for safety or conduct issues 
• 
May submit recommendations for corrective actions to the lead PI 
  
SAEs, SUSARS, and reportable AEs are reported to the DSMC.  All SUSARs will be reported to 
site principal investigators on study.  All SAEs and reportable AEs are to be reported to the DSMC 
monthly for review.  All SUSARs will be reported to the DSMC within 5 business days of 
knowledge.   
  
Criterium is responsible for organizing regularly scheduled teleconferences with all participating 
sites.  Lead PI (or designee) will be responsible for conducting the teleconferences. Criterium will 
also be responsible for including data from all of the participating sites to include the minutes from 
these regularly scheduled teleconferences between the sponsor investigator and the sites within 
the overall trial’s six-month DSM report. 
  
Study PI and Criterium will provide a DSMB summary report to all study sites on a six-month basis 
(every January and July). The DSMB summary report will include summary of University of 
Arizona monthly DAMB reports, a protocol summary, current enrollment numbers, summary of 
toxicity data to include specific SAEs, UAPs and AEs, any dose modifications, all protocol 
deviations and protocol amendments. The DSMB report might also include, if applicable, the 
results of any efficacy or fulity data analysis conducted. Criterium is then responsible for ensuring 
this letter is submitted to the participating sites for submission to their IRBs of record in 
accordance with their IRB policy. If University of Arizona DSMB identifies any safety concerns, all 
participating sites and study investigators will be notified by a memo and teleconferences.  
  
Study audits conducted by the DSMC will consist of a review of the regulatory documents, consent 
forms, and source data verification.  Documentation of the audit conducted by the DSMC will then 
need to be submitted to the IRB of record at the time of the IRB’s continuing review of this trial.    
13.2 Identification of the entity obligated for routine monitoring duties 
Criterium will perform routine monitoring duties remotely as determined in the Monitoring Plan. 
Criterium will ensure that the monitoring plan will incorporate monitoring frequencies that are 
compliant with site requirements. 
13.3 Monitoring progress and data review process 
The assigned data management personnel at Criteirum will be responsible to review all CRF’s for 
missing data, inconsistencies, data outliers and trends. This is done using internal table listings, 
programmed study edits and manual study edits.  A listing of current study edits is included in the 


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Palbo T-DM1 - Protocol Version 5 & Date 01/25/2021  
Data Quality Procedures document. Data management personnel will follow all procedures 
outlined in the Data Management Plan for the study. 
 
13.4 Continuous Monitoring 
 
Continuous monitoring will consist of remotely reviewing portions of the ICF to ensure consenting 
is properly documented and the use of current version, review of re-consenting when applicable, 
review of CRF reports that include AEs, SAEs, and dosing, and reconciliation of drug 
accountability against the CRF entries. 
 
13.5 Routine Safety Monitoring 
 
Plan for assuring data accuracy and protocol compliance: 
Routine study activity and safety information will be reported to the DSMB on a monthly 
basis, or more frequently if requested. These reports will include: 
Study activity, cumulative and for the period under review; 
• 
Safety (narrative description on non-serious and serious adverse events, protocol 
pre-determined early stopping rules for safety or treatment-emergent adverse 
events); 
• 
Predetermined protocol early stopping rules for efficacy/futility;  
• 
Status of study in relationship to stopping rules;   
• 
Current dose level of study agent;  
• 
Routine monitoring and protocol compliance (describe the monitoring process and 
identify the status of the monitoring); 
• 
Comments;  
• 
Attachments (AE data reviewed by the PI to compile the report, SAE letters and 
reports, results of any review(s), applicable correspondence with the IRB or other 
regulatory agencies.  
 
Data, safety and study progress will be reported to: 
• 
Human Subjects Protection Program (IRB) at least annually; 
• 
Sponsor (if applicable) at least quarterly. 
 
Identification of the sponsor or funding agency, as applicable 
The PI will immediately notify, in writing, to Pfizer, if applicable, any action resulting in a temporary 
or permanent suspension of the study. A copy of this correspondence will also be forwarded to 
the DSMB and the IRB.  
 
13.6 Removal of Subjects 
 
Subjects have the right to withdraw from the study at any time and for any reason without prejudice 
to their future medical care by the physician or at the institution. If this occurs, the investigator, or 
designee, is to discuss with the subject the safe and appropriate processes for discontinuation 
from the investigational product, intervention or device. 
 
Subjects that wish to discontinue active IP treatment/intervention/device may elect to continue 
with the other protocol required assessments. The investigator should discuss with the subject 


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Palbo T-DM1 - Protocol Version 5 & Date 01/25/2021  
the options for continuation of the study schedule of assessments (i.e. blood work, scans, physical 
exams, diaries) and collection of data, including endpoints and adverse events. 
 
The investigator or designee must document the change in status of the subject’s participation in 
the study and as applicable, the level of follow up that is agreed to by the subject (i.e. agrees to 
follow up exams, adverse event review, phone contact, but not to further treatment and/or 
procedures).  
 
Subject withdrawal of consent for a study indicates that the subject does not wish to receive further 
protocol required therapies or procedures, and the subject does not wish to, or is unable to 
continue further study participation. Subject data only up to the time when consent is withdrawn 
will be included in the analysis of the study.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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References  
 
1 
Baselga J. Treatment of HER2-overexpressing breast cancer. Ann Oncol 2010;21 Suppl 
7:vii36-40. 
2 
Baselga J, Swain SM. CLEOPATRA: a phase III evaluation of pertuzumab and 
trastuzumab for HER2-positive metastatic breast cancer. Clin Breast Cancer 2010;10:489-91. 
3 
Verma S, Miles D, Gianni L, Krop IE, Welslau M, Baselga J, et al. Trastuzumab emtansine 
for HER2-positive advanced breast cancer. N Engl J Med 2012;367:1783-91. 
4 
Yu Q, Geng Y, Sicinski P. Specific protection against breast cancers by cyclin D1 ablation. 
Nature 2001;411:1017-21. 
5 
Choi YJ, Li X, Hydbring P, Sanda T, Stefano J, Christie AL, et al. The requirement for 
cyclin D function in tumor maintenance. Cancer Cell 2012;22:438-51. 
6 
Witkiewicz AK, Cox D, Knudsen ES. CDK4/6 inhibition provides a potent adjunct to Her2-
targeted therapies in preclinical breast cancer models. Genes & cancer 2014;5:261-72. 
7 
Goel S, Wang Q, Watt AC, Tolaney SM, Dillon DA, Li W, et al. Overcoming Therapeutic 
Resistance in HER2-Positive Breast Cancers with CDK4/6 Inhibitors. Cancer Cell 2016;29:255-
69. 
8 
Finn RS, Dering J, Conklin D, Kalous O, Cohen DJ, Desai AJ, 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 2009;11:R77. 
9. Finn RS, Martin M, Rugo HS, et al. Palbociclib and letrozole in advanced breast cancer. N Engl 
J Med. 2016;375(20):1925-1936 
 
10. Turner NC,  Ro J, Andre F, et al. Palbociclib in Hormone-Receptor-Positive Advanced Breast 
Cancer. N Engl J Med. 2015 Jul 16;373(3):209-19. doi: 10.1056/NEJMoa1505270. Epub 2015 
Jun 1. 
11. Witkiewicz AK, Cox D, Knudsen ES. CDK4/6 inhibition provides a potent adjunct to Her2-
targeted therapies in preclinical breast cancer models. Genes Cancer. 2014 Jul;5(7-8):261-72. 
12. Eisenhauer, E.A., et al., New response evaluation criteria in solid tumours: revised  RECIST 
guideline (version 1.1). Eur J Cancer, 2009. 45(2): p. 228-47   
13: Goel S, DeCristo MJ,Watt AC et  al. CDK4/6 inhibition triggers anti-tumour immunity. 
Nature. 2017 Aug 24;548(7668):471-475. 
 
 


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Palbo T-DM1 - Protocol Version 5 & Date 01/25/2021  
 
 
 
Appendix  1: ECOG performance status 
 
ECOG PERFORMANCE STATUS 
Grade ECOG 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of 
a light or sedentary nature, e.g., light house work, office work 
2 
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 
Capable of only limited self-care, confined to bed or chair more than 50% of waking 
hours 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair 
5 
Dead 
 

ICF_001.pdf: 
 
 
Official Title: 
A single arm phase II study to evaluate efficacy of T-DM1 
with Palbociclib in the treatment of patients with 
metastatic HER2 positive breast cancer 
NCT number: 
NCT03530696 
Document Type:  
Consent Form 
Date of the 
Document: 
Version 02/15/2021, IRB approved 7/15/2021 
 
 


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Consent to Participate in Research 
Study Title: A single arm phase II study to evaluate efficacy of T-DM1 with Palbociclib in the 
treatment of patients with metastatic HER2 positive breast cancer 
Protocol Identification: Palbo T-DM1 
Principal Investigator: Pavani Chalasani MD, MPH 
Sponsor: University of Arizona Cancer Center 
Funding Source:  Pfizer  
This is a consent form for research participation.  It contains important information about this 
study and what to expect if you decide to participate.  Please consider the information 
carefully. Feel free to discuss the study with your friends and family and to ask questions before 
making your decision whether or not to participate. 
The University of Arizona receives compensation from the Pfizer for the conduct of this study.  
If you have any questions, please discuss this with your study doctor. 
 
Why is this study being done? 
The purpose of this study is to see if combination of T-DM1 with palbociclib is safe and assess if 
it has signal of efficacy for metastatic HER2 positive breast cancer.  Palbociclib is considered 
investigational in this combination because this combination has not been approved to be used 
for treatment in the United States by the Food and Drug Administration (FDA), at this time.  
However, Palbociclib is currently approved in combination with hormonal therapy for 
treatment of hormone receptor positive but HER2 negative metastatic breast cancer.   
What will happen if I take part in this study?  
You will be asked to: 
• sign this consent form; 
• give your health history.  The study staff will review your medical history and test 
results to see if you can be part of this study. 
• tell the study staff if you take any over-the-counter or prescription drugs, vitamins, or 
herbs. 
 
 
 
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The study staff will discuss what is required for you to be part of this study.  If you have HER2+ 
metastatic breast cancer and meet all study entry criteria you may be able to participate in this 
study. 
 
Screening Visit 
• Physical examination 
• Measure of your vital signs (blood pressure, heart rate, temperature, respirations) 
including height and weight 
• Electrocardiogram (ECG) and Echocardiogram (ECHO) to evaluate your heart (if not done 
previously in the past 28 days of signing the informed consent form) 
• Blood sample of about 3 tablespoons to assess blood counts and chemistry analysis (if 
not done previously within 14 days of signing the informed consent form) 
• Blood sample of about 1 tablespoon for a pregnancy test if you are a person of 
childbearing potential 
• Complete review of your medical history 
• Review how well you perform daily tasks 
• Review all medications (including any herbal or nutritional supplement you may be 
taking).  Please bring all medications, vitamins, and supplements that you are taking to 
this visit for review. 
• CT Scan or MRI or Bone Scan or X-ray, or PET Scan of your chest, abdomen, and pelvis (if 
not done previously within 14 days of signing the informed consent form) 
• 
Assessing availability of archival tumor tissue sample for research. If available, 5-10 
unstained slides will be used for research purposes. If no archival tissue is available, you 
will still be able to participate in this trial 
 
Study Treatment Groups 
This study will have only 1 group for research subjects like you.  All subjects will be treated with 
T-DM1 in combination with study drug Palbociclib.  
 
T-DM1 is delivered through your vein. This is known as an infusion. You will receive an infusion 
lasting anywhere between 30-90 minutes, depending on tolerability, once every cycle (Day 1 of 
a cycle).  A cycle is 21 days (3 weeks).  Palbociclib is provided in tablets taken orally.  You will be 
taking this for 14 days of the 21-day cycle starting on Day 5 of a cycle (day 5-18 of 21 days).   
Day 1 of every cycle 
If after all screening tests and procedures your study doctor determines that you are eligible for 
participation in the study, you will come to the clinic for your first visit.  This is considered Cycle 
1 Day 1.  It is not expected that you will need to stay in the hospital during this study. 
 
The following procedures will be done on Day 1 of every Cycle, but some might not need to be 
repeated if they have previously been done close enough to Day 1 (within 14 days). 
• Physical examination 
• Vital signs including weight 
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• Blood sample of about 3 tablespoons to assess blood counts and chemistry analysis 
• Blood sample of about 2-3 tablespoons for biomarker study for research (Only for Cycle 
1) 
• Blood sample of about 1 tablespoon for a pregnancy test if you are a person of 
childbearing potential (every 2nd cycle) 
• Review how well you perform daily tasks (Only for Cycle 1) 
• Review all medications (including any herbal or nutritional supplement you may be 
taking) 
• Complete a Quality of Life questionnaire (Only for Cycle 1) 
• Receive infusion of T-DM1 
• Receive a patient diary and Palbociclib for use on Days 5-18 of a cycle  
• Review patient diary from previous cycle to ensure compliance with dosing of 
Palbociclib  
• Review any signs or symptoms you might be experiencing 
 
End of Treatment 
This visit will take place within 14 days of your last dose of T-DM1 or Palbociclib (whichever is 
last) 
• Physical examination 
• Vital signs  
• Blood sample of about 2-3 tablespoons for biomarker study for research 
• Review how well you perform daily tasks  
• Review all medications (including any herbal or nutritional supplement you may be 
taking) 
• Complete a Quality of Life questionnaire  
• Review any signs or symptoms you might be experiencing 
• Review patient diary from previous cycle to ensure compliance with dosing of 
Palbociclib  
 
Routine Follow Up 
• After you have stopped treatment on this study, you will be followed every 6 months 
until final patient is completed or study is terminated, whichever is first.  This may be 
done by review of your medical records or a phone call.  We will be collecting 
information about treatments you are receiving and survival.   
 
Additional Procedures 
Every 3 months (12 weeks) before starting the next cycle you will have a CT Scan (Computed 
Tomography) of your chest, abdomen, and pelvis as well as any other areas of known disease or 
MRI (Magnetic Resonance Imaging) of the same to measure tumor size.  This might also be 
repeated at the End of Treatment Visit if greater than 12 weeks from previous scans. You will 
also get your heart function assessed (by Echocardiogram or MUGA scans) every 3 months. 
 
 
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Your Responsibility 
• You will have to go to the study visits, complete the study assessments, and follow the 
instructions the doctors give you 
• You will need to agree to receive and take the treatment as directed 
• You must not take part in other studies while you are taking part in this study 
• You and your partner must be willing to avoid pregnancy during the study and for 6 
months after the last dose of drug by using adequate contraception. Please reference 
the Reproductive Risks section on page 8 of this consent form for a thorough 
explanation of approved methods of contraception. 
• You agree not to breastfeed while you are taking part in the study 
• You will need to contact the study doctor or nurse if you feel any discomfort while you 
are taking part in the study 
• You will need to inform your study doctor or nurse of any changes in your medication 
• Upon study completion or early withdrawal, it is important for you to speak with your 
study doctor to arrange follow-up care  
 
How long will I be in this study? 
 
If you are interested in this study and would like to participate, you will need to come to clinic 
for a screening visit, which might last 4-8 hours to determine if you are eligible to be in the 
study.  If after screening you are eligible for participation and are enrolled in the study you will 
start treatment and can remain on study until your disease progresses, you decide to withdraw 
consent, your physician removes you from treatment due to intolerable side effects, or the 
study is terminated by the sponsor, whichever comes first.  Follow up visits while you are on 
study are part of your routine clinical care.  
 
Once you are no longer actively being treated on the study, study staff will conduct follow up 
visits with you every 6 months to check on your cancer and to see if you are receiving any new 
treatments.  These follow up visits will continue until the last patient on the study has 
completed treatment.  
 
How many people will take part in this study? 
 
Approximately 46 individuals will be enrolled in this study nationwide in the United States.  We 
expect to enroll about 5-7 subjects at our site. 
 
What risks, side effects or discomforts can I expect from being in the study? 
 
Discomforts and risks may vary from person to person. Everyone in the study will be watched 
carefully for side effects; however, we do not know all the discomforts and risks that may 
happen. You may experience some, none, or many of these discomforts.  Also, there is the risk 
of a rare or previously unknown side effect occurring. These may be mild or severe and can be 
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life-threatening or fatal. If any side effects occur, you must tell your study doctor who may give 
you treatment to ease the undesirable affects you may experience.    
You will be monitored closely for all side effects. Palbociclib has been given to approximately 
1674 patients with breast cancer who received palbociclib together with hormonal treatment in 
Pfizer sponsored clinical trials. The following side effects reported with the hormonal treatment 
and palbociclib: 
• 30% or more: decreases in neutrophil blood cells (may increase the risk of infection), 
decreases in while blood cells (infection fighting cells), infections, fatigue 
• 10 to less than 30%: decreases in hemoglobin (may cause weakness), decreases in 
platelets (may cause bleeding and/or bruising), inflammation of the mouth, diarrhea, 
constipation, nausea, vomiting, joint pain, back pain, pain in hands and feet, hair loss, 
rash, cough, shortness of breath, headache, dizziness, decreased appetite, hot flush, 
insomnia (inability to sleep), fever, common cold 
• 5 to less than 10%: abdominal pain, indigestion, dry mouth, fever, asthenia (general 
weakness), swelling of hands and feet, irritation or sores in the lining of hollow organs 
like mouth, throat, stomach, bowels; pain, influenza (flu) like illness, muscle pain, pain in 
the muscles and bone including around the chest and neck, muscle cramps, increases in 
blood liver markers that may indicate liver damage, dry skin, itching, mouth/throat pain, 
nosebleed, impaired sense of taste, high blood pressure, depression, fall, anxiety, acid 
reflux (heart burn), increased creatinine level (may indicate abnormal kidney function) 
• The following side effects have been reported in less than 5% of patients, but are still 
deemed important: Fever associated with dangerously low levels of a type of white 
blood cells (neutrophils), blurred vision, increased tearing, dry eye. In addition, 
interstitial lung disease (an inflammation of the lungs which can cause cough and 
shortness of breath) can occur. If you were to develop a dry cough or shortness of 
breath while at rest or with low levels of activity please contact your study team 
immediately. 
• Serious and life-threatening infections have been observed in some patients treated 
with Palbociclib. Severe, life-threatening, or fatal ILD and/or pneumonitis can occur in 
patients treated with cyclin-dependent kinase 4/6 (CDK 4/6) inhibitors, including 
palbociclib when taken in combination with endocrine therapy.   
 
Palbociclib is also being evaluated in a number of clinical trials run in a variety of tumor types 
given alone or together with other drugs. The side effects reported in these studies to date are 
similar to those mentioned above.   
 
In a rat study where palbociclib was administered for the lifespan of the rat, microglial cell 
tumors  (this a type of cell located in the central nervous system)  were seen when palbociblib 
in their blood was at a higher level than those used to treat humans.  It is currently unknown 
what these findings observed only in male rats mean for patients treated with palbociclib over 
time. 
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T-DM1 is standard of care treatment for metastatic HER2+ breast tumor. Your study physician 
will review the side effects in detail with you. Briefly, in clinical trials, T-DM1 has been 
evaluated as single-agent in 884 patients with HER2-positive metastatic breast cancer.  Side 
effects from T-DM1 include:  
• More than 25% reported fatigue, nausea, musculoskeletal pain, hemorrhage (bleeding), 
thrombocytopenia (low platelet count which can increase risk of bruising or bleeding), 
headache, increased liver enzymes, constipation and nose bleeds 
• Heart issues: a decrease in heart pumping function (measured by left ventricular 
ejection fraction) to <40% has been observed in 1.8% of patients treated with T-DM1 
• Inflammation of the lungs (pneumonitis) has been reported in 0.8% of patients treated  
• Reactions during infusion or hypersensitivity reactions of T-DM1 have been reported in 
1.4% of patients.  There has been only 1 case of a serious allergic reaction to T-DM1. 
• Peripheral neuropathy (all grades 21.2%), severe neuropathy was reported in 2.2% in T-
DM1 group  
• Hepatotoxicity (severe liver injury and/or failure) has been reported in clinical trials with 
T-DM1 . Rare cases of nodular regenerative hyperplasia (a form of liver side effect) have 
been seen in the trials (0.003% cases were reported in clinical trials, 0.001% were fatal) 
 
The combination of T-DM1 with different doses of palbociclib (200mg, 150mg and 100mg) was 
studied in a small trial of 9 patients. The most frequent side effects noted (more than 30%) 
were anemia, thrombocytopenia, neutropenia and decrease in lymphocyte count. The 
incidence of these side effects was higher at the higher dose levels of palbociclib (200mg and 
150mg than the 100mg dose) 
 
Other risks and effects of the testing of the study 
You may feel discomfort during some of these tests or may experience some inconveniences. 
Some may also have risks, which may include: 
 
Blood Draws: 
The risk of drawing blood from your arm may cause pain, bruising, lightheadedness, and rarely, 
infection.  
 
Routine blood tests to check your overall health require a little more than 1 tablespoon of blood 
(about 15 mL), although efforts will be made to collect smaller amounts of blood where 
possible. Blood tests to check how much study drug is in your system, to check whether your 
body is making antibodies towards the study drug, and for biomarker testing requires 
approximately 2 tablespoons of blood altogether (about 30 mL).  
Generally, blood samples will be drawn by single needle-sticks. However, when multiple 
samples are to be taken in one day a member of the study team may insert a thin, flexible tube 
(called a catheter) into one of the veins (probably in your arm) so you won’t need to be stuck 
with a needle many times on the same day.  
 
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Electrocardiograms (ECGs): 
To perform the test, stickers will be placed on your skin to record your heart’s activity. No pain 
or other side effects are expected to be associated with these tests, but you may feel some 
discomfort, similar to pulling off an adhesive bandage, when the technician removes the 
electrodes after the procedure. The adhesive patches can also cause skin irritation or rash in 
some patients. 
MUGA scan: 
The MUGA heart scan (used as an alternative to echocardiograms) will be done using a 
radioactive tracer.  The radioactive tracer will be injected through a needle placed in the vein of 
your arm.  The amount of radiation is very low and does not cause radiation sickness.  The 
Radiology staff will check you closely for an allergic reaction, which is rare but could be life-
threatening. 
X-Rays: 
The amount of radiation that you receive during an x-ray is very small, so the risk of damage to 
cells in your body from an x-ray is very low. The total radiation exposures you will receive from 
the X-rays in this study are not expected to negatively affect you or the treatment of your 
disease. 
Bone Scintigraphy (also known as a Bone Scan): 
Bone scans are used to determine the presence and/or extent of cancer in your bones and 
require the injection of a small amount of radioactive substance into your vein. The 
radioactivity means there is exposure to radiation. The amount of radiation is very small so your 
radiation exposure is very low and the radioactivity does not affect the normal processes of 
your body. There is a chance that you may experience discomfort, pain or swelling at the 
injection site and, as is the case with any injection, there is an increased risk of infection at the 
site.  Rarely, some people may have a life-threatening allergic response to the radioactive 
material.  If you have any trouble breathing during the test, you should tell the scanner 
operator right away.  A few people may experience a rash or swelling. There is a slight risk of 
bleeding when the needle goes into your vein. 
Computed Tomography (CT) Scans: 
A CT scan is non-invasive, but involves exposure to radiation. There is a potential risk of 
radiation exposure from CT scans; this risk is considered small. Sometimes, an intravenous (in 
the vein) contrast dye is given with a CT scan.  Contrast (or dye) given through an IV may cause 
a slight burning sensation at the IV site. It can also cause a metallic taste in the mouth. Some 
people complain of a warm flushing of the body.  These sensations are all normal and go away 
within a few seconds. This contrast dye is iodine based.  
A person who has allergies is more likely to have an allergic reaction to the dye. This reaction 
may be mild, such as skin rash or hives, to severe, such as breathing difficulties or shock. You 
will be closely monitored and treated should this occur. A severe allergic reaction would require 
immediate medical treatment and could result in permanent disability or death. You should 
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discuss any history of allergies or concerns with your doctor. You may also experience 
discomfort related to lying still in an enclosed space for a prolonged period of time. The study 
staff prior to performing the procedure will provide additional instructions to you.  
Magnetic Resonance Imaging (MRI) Scans: 
Having an MRI (Magnetic Resonance Imaging) scan involves lying still on a table that slides into 
a tunnel slightly wider than your body.  People who feel uncomfortable in confined spaces may 
feel uncomfortable in the narrow cylinder.  If you feel uncomfortable in confined spaces please 
tell your study doctor.  Your study doctor may give you a medication to make you feel more 
comfortable.  MRI uses powerful magnets to make images.  Therefore, people with certain 
metal implants, such as pacemakers, should not have an MRI.  If you have an implant or any 
metal in your body, please check with your study care doctor to know whether you can have an 
MRI or not.  For people without metal implants, there are no known health risks associated 
with exposure to the magnet.  As images are taken, a loud banging noise is produced.  Earplugs 
or headphones will be available if needed.  The MRI can be stopped at any time at your request, 
but the scan may not be complete. 
Positron Emission Tomography (PET) Scans: 
A PET/CT scan with sodium fluoride F 18 injection (18F NaF) is a nuclear imaging test that scans 
the entire skeletal system and produces images of the bones for detecting cancer that has 
spread to the bone from a tumor that started in a different organ, such as the breast. The risks 
to you associated with PET/CT scans that are part of normal cancer care are small. A radiotracer 
chemical is used in a PET or some CT scans; the amount of radiation you are exposed to is low 
and is considered so small that it does not affect the normal processes of the body.  
The PET radiotracer may expose the fetus of patients who are pregnant or infants of women 
who breastfeed to radiation. Women who are pregnant, plan on becoming pregnant, or are 
breastfeeding are not allowed on the study. You and your doctor need to consider this risk 
compared with the need for and potential information to be gained from the PET or CT scan.  
Genetic Test/Research: 
The sponsor cannot absolutely guarantee that your genetic research result could never be 
linked to you, meaning there is risk for loss of privacy or confidentiality. If disclosed to 
unauthorized persons, this could mean a possible risk for discrimination by employers or 
insurance providers. 
Please talk to the study doctor or staff about any questions or concerns that you may have 
about the procedures required for this study. 
Reproductive Risks: 
You should not become pregnant or breastfeed a child while in this study.  Naturally, the best 
way not to become pregnant is not to have vaginal sex (intercourse).  If you are sexually active, 
you should talk with your study doctor about the types of birth control that are best for you 
and your partner.  Tell your study doctor right away if you become pregnant or think you are 
pregnant. 
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Taking part in this study can result in risks to an unborn child or breastfeeding child.  You must 
use birth control for 7 months after the last dose of the study drug if you are sexually active.  
The form of birth control you use must not be hormonal.  Ask your study doctor if you have any 
questions. 
Some methods of birth control which are taken orally, are applied as a patch, or given by 
injection (medication that travels throughout your blood stream), might be less effective due to 
a possible interaction with palbociclib.  Barrier methods of birth control used with a spermicide 
should not be affected by study drugs taken by mouth or injection.  The method of birth control 
that you use must be approved by your study doctor. 
Male reproductive organ effects were seen in some of the rats and dogs that were given 
palbociclib for at least 3 weeks. These effects include degeneration of seminiferous tubule 
structure (tubes in the testes where sperm is produced) and a decrease in semen fluid secretion 
(ability of semen to flow). These effects on male reproductive organs were minimal to severe, 
depending on the dose given. These toxicities were observed at drug levels that are used in 
clinical research studies. Partial to complete reversal of these effects were seen at least 4 weeks 
after palbociclib dosing stopped. It is currently unknown what these findings mean for patients 
treated with palbociclib over time. If you are a male patient and want to have children at a later 
time, it is recommended that you preserve your sperm prior to beginning therapy. 
Exposure to T-DM1 during pregnancy or within 7 months prior to conception can result in fetal 
harm. Women of reproductive potential are recommended to use effective contraception 
during treatment and for 7 months following the last dose of T-DM1 
Other Risks: 
In addition to the side effects already described, palbociclib, T-DM1 and other drug(s) required 
by the protocol and the combination of the study drugs, and the study procedures may have 
other unknown risks.  There may be unknown risks of possible harmful interaction with other 
medication you may be taking.  You should not give the study drug to other people.  Only you 
should take the study drug.  It must be kept out of the reach of children or anyone else who 
may not be able to read or understand the label. 
If new information becomes available that is relevant to your willingness to participate in the 
trial, you will be informed.  
What benefits can I expect from being in this study? 
You may or may not receive any benefit from being in this study.  If you take part in this study, 
other people with metastatic breast cancer may be helped. Information obtained from this 
study may benefit study participants in the future. 
You may receive information from physical examinations, laboratory tests, or other testing that 
is done in this study, but these tests may not have any impact on your health. 
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What happens if I am injured because I took part in this study? 
 
Please keep in mind that the treatments and procedures that are part of this study may involve 
risks to you (or to your unborn child should you become pregnant) which are currently 
unforeseeable. 
If you are injured as a result of taking part in this study or for questions about a study-related 
injury, you may contact the Principal Investigator, Dr. Pavani Chalasani. You can tell the doctor 
in person or call her at 520-626-0191. 
 
If you suffer an injury from taking part in this study, you should seek treatment. If such 
problems occur, the researchers will help you get medical care, but any costs for the medical 
care will be billed to you and/or your insurance company.  If you do not have insurance, you will 
be financially responsible for those expenses.  Neither the University of Arizona, Pfizer, nor 
Criterium have funds set aside to pay for a research-related injury, added medical costs, loss of 
a job, or other costs to you or your family. 
 
If you are injured as a result of this study, you do not give up your right to pursue a claim 
through the legal system. 
Can I stop being in this study? 
Your taking part in this study is entirely voluntary.   
You may refuse to take part in the study, or you may stop your participation in the study at any 
time.  Whatever your decision, you may do so without a penalty or loss of benefits to which you 
are otherwise entitled. Your decision will not affect your future relationship with your 
physicians.  If you are a student or employee at the University of Arizona, your decision will not 
affect your grades or employment status. 
What other choices do I have if I do not take part in this study? 
Currently, standard of care treatments for patients with your type of metastatic breast cancer 
include chemotherapy. You doctor will be able to discuss these with you. You have option of 
participating in other clinical trials too. 
If you decide that you don’t want any more active treatment, one of your options is called 
“comfort care.”  Comfort care includes pain medication and other support.  It aims to maintain 
your comfort and dignity rather than cure disease.  Usually, this care can be provided at home.  
If you think you might prefer comfort care, please discuss this with your family, friends, and 
your doctor. 
 
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When may participation in the study be stopped? 
Your participation in this study can be stopped because  
• Your disease progresses while on study 
• You experience a deterioration of your condition 
• Requirement for other anti-tumor therapy 
• Non-compliance to taking the study drug in accordance with instructions provided 
• Pregnancy 
• Death 
• Lost to follow up 
• Any other reason that, in the opinion of your physician, justifies your removal 
• Sponsor terminates the study for any reason 
If you decide to withdraw from the study, please discuss with your study doctor. Withdrawing 
from this study will not interfere in your relationship and care by your physicians.  
If you leave the study before the planned final visit, you may be asked by the study doctor to 
have some tests or procedures done so that you leave the study safely. 
If you stop being part of this study, the study doctor or one of the staff members will talk to you 
about any medical issues regarding the stopping of your participation. 
What are the costs of taking part in this study? 
Pfizer will be supplying the investigational drug, palbociclib, for this study.  Research only 
procedures/services involved in this study will also be paid for, however some of the tests, 
procedures, and treatments that you will receive in this study are the same that will occur 
during a standard of care treatment for your cancer.  T-DM1 is standard chemotherapy and will 
be billed to your insurance 
You and/or your insurance will be financially responsible for any treatment, test, or procedure 
that is considered to be standard of care for your cancer.  Your study doctor will go over the 
costs that are involved in your care during this study.  You will be responsible for copays and 
coinsurance costs.   
 
You may be responsible for payment of any bills that your insurance may refuse to pay due to 
your participation in this research study. 
 
Will I be paid for taking part in this study? 
You will not receive any payment for participating in this study.   
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Will my study-related information be shared, disclosed, and kept confidential? 
It is anticipated that there will be circumstances where your study related information and PHI 
will be released to persons and organizations described in this form. If you sign this form, you 
give permission to the research team to use and/or disclose your PHI for this study. Your 
information may be shared or disclosed with others to conduct the study, for regulatory 
purposes, and to help ensure that the study has been done correctly. These other groups 
include: 
• Office for Human Research Protections or other federal, state, or international 
regulatory agencies 
• Representatives of the U.S. Food and Drug Administration (FDA) 
• Governmental agencies to whom certain diseases (reportable diseases) must be 
reported 
• Banner University Medical Group and Banner Health 
• The University of Arizona (UA) and the UA Institutional Review Board  
• The University of Arizona Cancer Center (UACC), Pfizer 
• The sponsor supporting the study, their agents or study monitors (Criterium) 
• Your health insurance company 
• Your primary care physician or a specialist taking care of your health. 
Your PHI may no longer be protected under the HIPAA privacy rule once it is disclosed by the 
research team.   
 
Your genetic research data may be shared with researchers who are not participating in this 
study or submitted to government or other health research databases for broad sharing with 
other researchers.  You will not be identified by name or any other personally identifying 
information. 
 
A federal law called the Genetic Information Nondiscrimination Act (GINA) generally makes it 
illegal for health insurance companies, group health plans, and most employers to discriminate 
against you based on your genetic information. This law will generally protect you in the 
following ways:  
 
• Health insurance companies and group health plans may not request your genetic 
information from this research.  
• If health insurance companies and group health plans do somehow receive your genetic 
information from this research, they may not use it to make decisions about your 
eligibility or premiums. 
• Employers with 15 or more employees may not use your genetic information from this 
research when making a decision to hire, promote, or fire you or when setting the terms 
of your employment.   
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Be aware that this new law does not protect you against genetic discrimination by companies 
that sell life insurance, disability insurance, or long-term care insurance. 
 
Those persons who receive your health information may not be required by federal privacy 
laws to protect it and may share your information with others without your permission, if 
permitted by laws that apply to them. 
 
If information from this study is presented publicly or published in a medical journal, you will 
not be identified by name. Your blood samples and extracted medical records information will 
be labeled with a coded identification number only. 
 
 
What study-related information and PHI will be obtained, used or disclosed from my 
medical record at Banner? 
 
Information related to this research study that identifies you and your PHI will be collected 
from your past, present, and future hospital and/or other health care provider medical records.  
 
The PHI you are authorizing to be used and/or disclosed in connection with this research study 
is: 
 
• Information in your medical record and research record, for example, results from your 
physical examinations, laboratory tests, procedures, questionnaires and diaries. 
• Name and Demographic Information (age, sex, ethnicity, address, phone number, etc.) 
• Your social security number 
• Portions of your previous and current Medical Records that are relevant to this study, 
including but not limited to Diagnosis(es), History and Physical, laboratory or tissue 
studies, radiology studies, procedure results 
• Research Visit and Research Test records 
• Tissue samples and the data with the samples 
• Billing or financial information 
 
 
Demographic information to be disclosed may include, but is not limited to, your name, 
address, phone number, or social security number. If you receive compensation for 
participating in this research study, information identifying you may be used or disclosed as 
necessary to provide that compensation. 
Your existing health records may include information related to the diagnosis or treatment of 
sexually transmitted disease (STD), acquired immunodeficiency syndrome (AIDS), human 
immunodeficiency virus (HIV), other communicable diseases, genetic information (e.g., genetic 
testing), and/or alcohol and/or drug abuse. The study staff and study sponsor’s monitor may 
see this information while reviewing your regular health records for this study, but they WILL 
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NOT create, collect, or disclose this type of information for the purposes of this research study. 
Study related data is entered into online database and will be shared with collaborating entities 
(Pfizer) through data protected electronic transfers. 
When will my authorization expire? 
There is no expiration date or event for your authorization. Therefore, unless you cancel this 
authorization (as instructed below) this authorization will continue to be effective. Identified 
study related data is stored for 6 years after completion of study. After that, de-identified data 
is stored long term for future research purposes. 
 
Do I have to sign this authorization form? 
You do not have to sign this authorization. However, if you decide not to sign, you will not be 
able to participate in this research study; and it will not affect any non-study Banner Health 
medical treatment or health care, payment, enrollment in any health plans, or benefits. 
 
Also, by signing this form you are authorizing and permitting uses and/or disclosures of your 
PHI for future research purposes (e.g., future studies) as described in this document.  
 
What do I need to know if I decide to cancel my authorization? 
After signing the authorization, you may decide to cancel your previous authorization for the 
research team to use your PHI. If you cancel the authorization, you will no longer be able to 
stay in the research study. Please note that any PHI collected before you cancel the 
authorization may still be used. You may revoke the authorization by contacting the Principal 
Investigator in writing. Contact information is under “Who can answer my questions about the 
study” at the end of this document.  
Will access be limited to your research study record during this study? 
You can ask your study team to provide access to your research data files. You may ask for 
corrections in personal information that you deem incorrect. You will not have access to other 
participant records.  
Will my data or specimens be stored for future research?  
There may be some specimens (blood, tissue, etc) remaining after the study is complete. If you 
are willing to allow the remaining specimens to be used for future research studies, you must 
specify your consent below. Consent for future use of your remaining samples is entirely 
voluntary and may be withdrawn at any time.  
If you decide now that your tissue can be kept for research, you can change your mind at any 
time. Contact your study doctor and let him or her know that you do not want us to use your 
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tissue (or collected blood sample, body fluid, if appropriate), and it will no longer be used for 
research. If your specimen has already been used for research it will not be possible to get it 
back.  
In addition to the treatment study, researchers are also interested in studying tissue, body 
fluids, or other specimens that were, or may be, obtained from you in the normal course of 
your treatment and care. These research tests may be developed during the time you are on 
treatment, or years later.  
We would like to keep any of the tissue that is left over after diagnosis for future research. This 
will be stored in a central facility (called a “tissue bank”) which is located at the University of 
Arizona Cancer Center. Your sample will be stored there permanently and will not be available 
for use in making health care decisions for you. At some time in the future, pieces of this stored 
tissue may be used by other researchers for other tests that are not known at this time. In most 
cases, you will not be told what your sample is being used for.  
When your sample(s) is sent to the researchers, samples will be identified by a unique study 
code only. Researchers to whom the University of Arizona sends your sample and information 
will not know who you are. They must also sign an agreement that they will not try to find out 
who you are. If research results are published, your name and other identifiable information 
will not be used.  
Please read each sentence below and think about your choice. After reading each sentence, 
mark an X in the box for “Yes” or “No.” No matter what you decide to do, it will not affect your 
care. You can participate in the treatment part of the study without participating in all or part 
of the tissue (or collected blood sample, body fluid, if appropriate) research studies. If you have 
any questions, please talk to your doctor.  
1. My tissue (or collected blood sample, body fluid, if appropriate) may be used in future 
research to learn about preventing or treating breast cancer. 
 
_______ Yes  _______ No  
 
2. My doctor may contact me in the future to ask me to take part in more research.  
 
_______ Yes  _______ No 
 
Future Use of PHI 
Future research activity is part of this project. If you choose to participate in the future research 
activity your PHI will be included in this future research activity.  
 
By initialing the line below, you agree to allow your information to be used and/or disclosed for 
the optional future research referenced above. 
 
_______ Initials 
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Who can answer my questions about this study? 
 
Contact your study doctor, Pavani Chalasani, M.D., at 520-694-2873 or 520-694-6000 (pager # 
9940 - 24 hours) or the Oncologist on call at 520-694-6000 (24-hour pager) for any of the 
following reasons: 
• if you have any questions about this study or your part in it; 
• if you feel you have had an injury or bad reaction, or any other unusual health event; 
or 
• if you have questions, concerns, or complaints about the research study. 
 
If you are injured, the study doctor will treat you or refer you for treatment. 
 
You should contact the study doctor first if you have questions, complaints, or concerns about 
the study. 
 
For questions about your rights as a participant in this study or to discuss other study-related 
concerns or complaints with someone who is not part of the research team, you may contact 
the Human Subjects Protection Program Director at 520-626-8630 or online at 
http://rgw.arizona.edu/compliance/human-subjects-protection-program.  Please note that 
your contact with the University of Arizona Human Subjects Protection Program online can be 
anonymous. 
 
If you have any questions or concerns about the authorization for access to your PHI, you 
should contact Sue Colvin, Banner Research Regulatory Affairs Director, at (602) 839-4583 or 
sue.colvin@bannerhealth.com. You may also request and will be provided a copy of the Notice 
of Privacy Practices. 
 
To cancel your authorization for access to PHI you must notify the Principal 
Investigator/Research Team in writing at the following address: 
 
Pavani Chalasani MD, MPH 
1515 N Cambell Ave, PO 245024 
Tucson, AZ 85724 
 
An Institutional Review Board responsible for human subjects research at The University of 
Arizona reviewed this research project and found it to be acceptable, according to applicable 
state and federal regulations and University policies designed to protect the rights and welfare 
of participants in research.     
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by U.S. Law. This Web site will not include information that can identify you. At most, the Web 
site will include a summary of the results. You can search this Web site at any time. 
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Signing the consent form 
I have read (or someone has read to me) this form, and I am aware that I am being asked to 
participate in a research study.  I have had the opportunity to ask questions and have had them 
answered to my satisfaction.  I voluntarily agree to participate in this study and I authorize the 
use and/or disclosure of my PHI. I am not giving up any legal rights by signing this form.  I will be 
given a signed copy of this form. 
 
FOR STUDY PARTICIPANT TO COMPLETE 
_____________________________________________ 
______________________ 
Signature of Study Participant 
Date 
 
 
_____________________________________________ 
Study Participant Name (print or type) 
 
 
FOR INDIVIDUAL CONDUCTING INFORMED 
CONSENT DISCUSSION TO COMPLETE 
 
I have explained the study (such as the purpose, risks, benefits, and the procedures) to the study participant before 
the study participant voluntarily agreed to participate 
 
 
______________________________________________ 
Name of individual conducting informed consent  
discussion (print or type) 
 
 
______________________________________________ 
___________________________ 
Signature of individual conducting informed consent  
Date 
discussion 
 
Signatures for Impartial Witness 
In case the trial study participant is unable to read or write, the signature of an impartial witness to this process is 
required. 
 
I witnessed that the information in the consent and any other written information was accurately explained to, 
and apparently understood by, the study participant, and that informed consent was freely given by the study 
participant. 
 
 
______________________________________________ 
Impartial Witness Name (print or type) 
 
 
______________________________________________ 
___________________________ 
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