Phase II Open-label, Multicentre, Randomized Trial of Neoadjuvant Palbociclib in Combination With Hormonal Therapy and HER2 Blockade Versus Paclitaxel in Combination With HER2 Blockade for Postmenopausal Patients With Hormone Receptor Positive/HER2 Positive Early Breast Cancer
Phase: PHASE2
Conditions: Breast Cancer, Estrogen Receptor Positive Tumor, HER2-positive Breast Cancer
Sponsor: ETOP IBCSG Partners Foundation

IBCSG 55-17 TOUCH 
 
48-94 
Amendment 2, Protocol V2.1 - 12 June 2020 
 Coordinating Center Effingerstrasse 40 CH-3008 Bern Switzerland www.ibcsg.org 
Phase II open-label, multicenter, randomized trial of neoadjuvant 
palbociclib in combination with hormonal therapy and HER2 
blockade versus paclitaxel in combination with HER2 blockade for 
postmenopausal patients with hormone receptor positive/HER2 
positive early breast cancer 
To reduce the use of Chemotherapy in postmenopausal patients with 
ER-positive and HER2-positive breast cancer: the TOUCH trial 
EudraCT number: 
2017-005067-40 
Pfizer number: 
WI223904 
Roche number: 
MO40405 
Sponsor: 
International Breast Cancer Study Group 
(IBCSG) 
IBCSG Coordinating Center, Effingerstrasse 40, CH- 3008 Bern 
Phone: +41 31 511 94 00 
Fax: +41 31 511 94 01 
Amendment 2 
Protocol Version 2.1, 12 June 2020 
 
 
 
INTERNATIONAL BREAST CANCER 
STUDY GROUP 
IBCSG 55-17 
TOUCH 
 
 
 
 
 
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If the retreatment parameters are met within 3 weeks of treatment interruption or cycle delay, 
palbociclib may be resumed. Please refer to Dose Reductions Section 10.3.2 for adverse events 
requiring dose reduction at the time of treatment resumption.  
Within 1 treatment cycle, if these parameters have not been met after 3 weeks of dose interruption 
(including the scheduled 1 week off treatment and/or up to 14 days of cycle delay), the patient 
should permanently discontinue palbociclib treatment. Treatment resumption for patients 
recovering from treatment-related toxicity after >3 weeks of treatment interruption 
(corresponding to 1 week rest plus 2 weeks delay), or cycle delay but deemed to be suitable for 
lower dosing, may be considered and needs to be discussed with IBCSG beforehand by contacting 
ibcsg55_touch@frontierscience.org. 
10.3.2. Dose reductions 
Palbociclib dose modifications may occur in three ways: 
 Within a cycle: dosing interruption until adequate recovery and dose reduction, if 
required, during a given treatment cycle; 
 Between cycles: next cycle administration may be delayed due to persisting toxicity 
when a new cycle is due to start; 
 In the next cycle: dose reduction may be required in a subsequent cycle based on 
toxicity experienced in the previous cycle. 
No specific dose adjustments are recommended for Grade 1 or short lasting grade 2 (<3 weeks) 
treatment-related toxicity. However, Investigators should always manage their patients according 
to their medical judgment based on the particular clinical circumstances. 
In case of a grade 2 toxicity lasting for >3 weeks or a grade 3 toxicity (both assessed in the 
presence of maximum supportive care as judged by the Investigator), dose reduction is 
recommended for the subsequent cycles (exception: alopecia grade 2 does not require dose 
reduction). Dose reduction of palbociclib by one, and, if needed, by two dose levels (Table 3 
below) is recommended depending on type and severity of the toxicity. Patients requiring more 
than two dose reductions will be allowed to receive 75 mg/day for 2 weeks after 2 weeks off trial 
treatment (if, per the Investigator’s judgment, such a schedule is manageable and preferred; this 
must be discussed with IBCSG beforehand by contacting ibcsg55_touch@frontierscience.org). 
Taking palbociclib according to recommendation (i.e., with food) should be reinforced and 
confirmed. The Investigator should discuss with IBCSG (see email address above) if the patient 
appears to be unable or unwilling to comply with this recommendation. All dose 
modifications/adjustments must be clearly documented in the patient's source notes and the Form 
55-PALBO.  
Once a dose has been reduced for a given patient, all subsequent cycles should be administered 
at that dose level, unless further dose reduction is required. Dose re-escalation is not allowed. 
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Patients discontinuing palbociclib treatment due to treatment-related toxicity may continue on 
the active treatment phase of the trial receiving letrozole and anti-HER2 therapy at the 
Investigator’s discretion.  
Table 3. 
Available dose levels for palbociclib 
Dose Level 
Palbociclib for 3 out of 4 weeks 
Starting dose 
125 mg/d 
-1 
100 mg/d 
-2 
75 mg/d* 
-3 (for selected 
cases only) 
Discontinue palbociclib treatment or consider schedule of 75mg/d 2 
weeks on / 2 weeks off. This must be discussed with IBCSG beforehand 
by contacting ibcsg55_touch@frontierscience.org. 
If 2 weeks on/2 weeks off is not tolerated, then discontinue palbociclib. 
* Palbociclib dose de-escalation below 75 mg/d is not allowed but if considered appropriate the schedule may move 
to 75 mg/day two weeks on followed by two weeks off. 
Palbociclib recommended dose modifications for treatment related toxicities requiring treatment 
interruption/delay despite optimal medical treatment are described in Table 4 taken from tables 
2 and 3 of the SPC. 
Table 4. 
Palbociclib dose modification and management 
CTCAE grade 
Dose modifications 
Hematological toxicities 
Applies to all hematological adverse reactions except lymphopenia (unless associated with clinical events, 
e.g., opportunistic infections). 
Complete blood count should be monitored prior to the start of palbociclib therapy, and at the beginning of 
each cycle, as well as on day 14 of the first 2 cycles, and as clinically indicated. 
Grade 1 or 2 
No dose adjustment 
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CTCAE grade 
Dose modifications 
Grade 3 
Day 1 of cycle: 
Withhold palbociclib, repeat complete blood count monitoring 
within 1 week. When recovered to grade ≤2, start next cycle at 
same dose 
Day 14 of first 2 cycles: 
Continue palbociclib at current dose to complete cycle, repeat 
complete blood count on day 21. 
Consider dose reduction in cases of prolonged (>1 week) 
recovery from grade 3 neutropenia or recurrent grade 3 
neutropenia in subsequent cycles 
Grade 3 ANC (absolute neutrophil count) 
<1000 to 500/mm3 + fever ≥38°C and/or 
infection 
Withhold palbociclib until recovery to grade ≤2. 
Resume at next lower dose. 
Grade 4 
Withhold palbociclib until recovery to grade ≤2. 
Resume at next lower dose. 
 
Non-hematological toxicities 
Grade 1 or 2 
No dose adjustment is required 
Grade ≥3 non-hematological toxicity (if 
persisting despite medical treatment) 
Withhold until symptoms resolve to: 
- Grade ≤1; 
- Grade ≤2 (if not considered a safety risk for the patient) 
Resume at the next lower dose. 
Permanently discontinue palbociclib in patients with severe interstitial lung disease 
(ILD)/pneumonitis 
 
 
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10.4. Dose modifications and delays for trastuzumab and pertuzumab 
Refer to standard of care guidance or current clinical practice or currently approved trastuzumab 
and pertuzumab European SPCs, as well as the following table. There are no dose modifications 
for trastuzumab or pertuzumab. Administration may be delayed to assess or treat adverse events, 
such as cardiac adverse events or other non-hematological adverse events as shown in Table 5: 
In the case of overlapping toxicities, doses of anti-HER2-therapy should be delayed only if 
toxicity persists after paclitaxel (Arm A) or palbociclib (Arm B) dose has been modified or 
delayed, according to Section 10.3 and Section 10.5, respectively. 
 
Table 5. 
Actions to be taken in case of trastuzumab and/or pertuzumab (anti-HER2 
therapy) related adverse events 
Adverse event (AE) 
Action 
Non-hematological 
grade 
1 
or 
2 
(excluding cardiac) 
Continue anti-HER2 therapy 
Non-hematological 
grade 
3 
or 
4 
(excluding cardiac), and AE resolves to 
grade ≤2 within a maximum of 5 weeks 
from last dose 
Hold anti-HER2 therapy until recovery to 
grade ≤2 
Non-hematological 
grade 
3 
or 
4 
(excluding cardiac), and ARE NOT 
resolved to grade ≤2 within a maximum of 
5 weeks from last dose 
Please contact 
ibcsg55_touch@frontierscience.org for 
advice 
Non-hematological 
grade 
3 
or 
4 
(excluding cardiac), upon rechallenge 
with anti-HER2 therapy 
Discontinue anti-HER2 therapy permanently 
Cardiac: asymptomatic drop in LVEF or 
symptomatic congestive heart failure 
Use algorithm in figure 1 
discontinue anti-HER2 therapy permanently 
in case of symptomatic CHF 
Other cardiac toxicities not covered in  
figure 1 
Follow rules for non-hematological toxicities 
above 
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Amendment 2, Protocol V2.1 - 12 June 2020 
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Adverse event (AE) 
Action 
Hematological (neutropenia grade 3) 
If toxicity persists after paclitaxel (Arm A) or 
palbociclib (Arm B) dose has been modified 
or delayed according to Section 10.3 and 
Section 10.5, hold anti-HER2-therapy until 
recovery to grade ≤2. 
 
Figure 1: Algorithm for continuation and discontinuation of anti-HER2 treatment based on 
interval LVEF assessments, for patients with NYHA class I or II congestive heart failure. LVEF 
drop >10 points: Temporarily discontinue anti-HER2 treatment and repeat LVEF in 3 weeks. If 
LVEF drop >10 points not confirmed, then resume treatment. 
 
Note: If pertuzumab has to be stopped, continue with trastuzumab alone; if trastuzumab has to be 
stopped, stop pertuzumab as well. 
10.5. Dose modifications and delays for paclitaxel 
Refer to standard of care guidance or current clinical practice or currently approved paclitaxel 
European SPC for patients receiving paclitaxel treatment, and to Table 6. 
In case of paclitaxel related adverse effects, doses should be reduced rather than delayed. The 
total cumulative delay across all 4 cycles should not exceed 4 weeks. If the delay is >4 weeks, 
paclitaxel should be stopped and treatment should continue with anti-HER2 drugs. 
 
 
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Table 6. 
Actions to be taken in case of paclitaxel related adverse events 
Adverse event 
Action 
Non-hematological grade 1 or 2 
Continue paclitaxel 
Non-hematological grade 3 or 4 
Hold paclitaxel until recovery to grade ≤1 
then decrease paclitaxel dose by 20% 
Non-hematological, grade 3 or 4, and 
adverse events NOT resolved to grade ≤2 
within a maximum of 3 weeks from last 
planned administration 
Discontinue paclitaxel 
Hematological adverse events: 
- 
ANC <1.0 × 109/L 
- 
Platelets <75 × 109/L 
- 
Hemoglobin <9.0 g/dL (after 
transfusion if needed) 
Hold paclitaxel therapy until recovery to 
ANC ≥1.0 × 109/L and/or platelets ≥100 × 
109/L. 
If ANC recovers to 1.0 × 109/L within 7 
days, then continue at the same dose. If 
recovery to 1.0 × 109/L requires >7 days, 
then decrease paclitaxel dose by 20% 
Dose modifications for thrombocytopenia: 
same as for neutropenia above. Next cycle 
should not begin until platelet count has 
recovered to ≥ 100 × 109/L. 
Biochemistry: 
- 
unresolved grade 3 or 4 (except 
bilirubin)  
- 
bilirubin ≥2 × ULN  
Hold paclitaxel therapy until recovery to 
grade ≤1 
Serum creatinine ≥2 × ULN or calculated 
clearance ≤40mL/min 
Hold paclitaxel therapy until recovery to 
grade ≤1 
10.6. Dose modifications and delays for letrozole 
Refer to standard of care guidance or current clinical practice or currently approved letrozole 
European SPC for patients receiving letrozole treatment. No dose modifications are allowed. 
Compliance with the protocol endocrine treatment should be strictly observed.  
Interruptions in the administration of letrozole should not exceed 2 days. 
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In the case of adverse event(s) grade ≥3, judged by the Investigator to be at least possibly related 
to letrozole, letrozole treatment will be stopped and patient will continue with the other trial drugs 
or undergo surgical intervention. 
10.7. Concomitant therapy 
The following rules should be followed for both treatment arms: 
 Anti-cancer (cytotoxic or endocrine therapy, other than letrozole and paclitaxel 
provided within the trial protocol) or any other investigational therapy is not 
permitted while patients are on trial therapy.  
 Radiotherapy is not permitted while patients are on trial therapy. 
The use of other concomitant medication/therapy judged by the Investigator to be necessary for 
the care of the patient is permitted. The Investigator should instruct the patient to notify the trial 
site about any new medications she takes after the start of the trial drug. 
Concomitant medications need to be recorded as follows: 
 At baseline, prior to start of treatment, medications or treatments for comorbidities 
should be recorded on the History form 55-H.  
 In case of an SAE, all concomitant medication used to treat the SAE must be reported 
on the SAE form (55-SAE-B). 
10.7.1. CYP3A inhibitors/inducers 
Palbociclib is a weak, time-dependent inhibitor of CYP3A. Strong inhibitors of CYP3A4 
administered concomitantly to palbociclib may lead to increased toxicity. Concomitant use of 
strong CYP3A inhibitors during treatment with palbociclib should be avoided. Co-administration 
should only be considered after careful evaluation of the potential benefits and risks. If co-
administration with a strong CYP3A inhibitor is unavoidable, reduce the palbociclib dose to 75 
mg once daily. When the strong inhibitor is discontinued, increase the palbociclib dose (after 3-
5 half-lives of the inhibitor) to the dose used prior to the initiation of the strong CYP3A inhibitor.  
Co-administration of CYP3A inducers with palbociclib may lead to decreased palbociclib 
exposure and consequently a risk for lack of efficacy. Therefore, concomitant use of palbociclib 
with strong CYP3A4 inducers should be avoided. No dose adjustments are required for co-
administration of palbociclib with moderate CYP3A inducers. 
10.7.2. Medications not recommended 
The following treatments are not recommended throughout the duration of the active treatment 
phase. Alternative therapies should be considered whenever possible. 
 Chronic immunosuppressive therapies should be avoided, including systemic 
corticosteroids. Steroids given for physiological replacement, as anti-emetics or as 
premedication of paclitaxel treatment, or inhaled as well as short course of oral/topical 
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steroids given for allergic reactions or asthma flares are allowed. Steroids given for 
the pre-medication of patients treated with paclitaxel in the chemotherapy arm are 
allowed. 
 The use of herbal medicine is not recommended during the active treatment phase. 
10.8. Stop of trial treatment 
Duration of protocol neoadjuvant therapy is planned as 16 weeks, and will depend on tolerance.  
In case one or more trial medications have to be stopped early, treatment with the other trial drugs 
of the respective arm should be continued if deemed appropriate by the local Investigator. Stop 
of trial treatment is defined as stop of all trial medications assigned by the randomization. Patients 
are not allowed to cross over from the randomly assigned arm to the other arm.  
If pertuzumab has to be stopped, continue with trastuzumab alone; if trastuzumab has to be 
stopped, stop pertuzumab as well. 
All trial medication of the individual patient has to stop in case of: 
 Disease progression as defined in Section 13. 
 Unacceptable adverse event(s). 
 Intercurrent illness that prevents further administration of trial treatment. 
 Patient demonstrates an inability or unwillingness to comply with the treatment regimen 
and/or trial requirements. 
 General or specific changes in the patient’s condition which render her unacceptable for 
further trial treatment in the opinion of the treating Investigator. 
 Patient withdraws consent to continue trial treatment. 
Patients who discontinue all trial medications early for any reason should proceed to surgery.  
After the discontinuation of all trial medications, future therapeutic decisions are at the discretion 
of the Investigator, with no restrictions.  
The End of Treatment (EoT) is defined as the breast cancer surgery. If the patient does not 
undergo surgery, the EoT occurs when all trial medication is stopped. The EoT visit is to be done 
within 30 days after EoT.  
10.9. Removal from the trial 
After a patient has been randomized, she becomes part of the clinical trial population and cannot 
be removed from the trial for any reason other than a decision by the patient to decline any further 
participation with the trial requirements and/or to decline further collection of data and tissue (see 
Section 18.2.2). If the patient discontinues treatment for any of the reasons listed in the prior 
subsection, she should continue to be followed according to the protocol and eCRFs should be 
completed as described in Section 16.1. 
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Patients who have been randomized but never received any trial treatment for whatever reason 
(refusal, medical condition etc.) will be followed until surgery and will have to be documented 
with an End of Treatment visit (see Section 14.5). 
11. 
Safety 
Adverse reactions are ranked under headings of frequency, the most frequent first, using the 
following convention: very common ≥10%, common ≥1% to <10%, uncommon ≥0.1% to <1%, 
rare ≥0.01% to <0.1%, very rare <0.01%, not known (cannot be estimated from the available 
data). 
11.1. Adverse reactions to palbociclib  
Table 7, taken from the SPC, reports the adverse reactions from the pooled dataset of 3 
randomized studies. The median duration of palbociclib treatment across the pooled dataset was 
12.7 months. The adverse reactions are listed by system organ class and frequency category.  
The effect of palbociclib on the QT interval corrected for heart rate (QTc) interval was evaluated 
using time matched electrocardiogram (ECG) change from baseline and pharmacokinetic data in 
77 patients with breast cancer. At the recommended dose, no palbociclib relevant effects on QT 
have been observed. 
Table 7. 
Adverse reactions to palbociclib based on pooled dataset from 3 randomized 
studies (N=872) 
System Organ Class 
 
Frequency 
 
 
Preferred Terma 
All Grades 
n (%) 
Grade 3 
n (%) 
Grade 4 
n (%) 
Infections and infestations 
 
Very common 
 
 
 
Infectionsb 
516 (59.2) 
49 (5.6) 
8 (0.9) 
Blood and lymphatic system disorders 
Very common 
 
 
 
Neutropeniac 
716 (82.1) 
500 (57.3) 
97 (11.1) 
Leukopeniad 
424 (48.6) 
254 (29.1) 
7 (0.8) 
Anaemiae 
258 (29.6) 
45 (5.2) 
2 (0.2) 
Thrombocytopeniaf 
194 (22.2) 
16 (1.8) 
4 (0.5) 
Common 
 
 
 
Febrile neutropenia 
12 (1.4) 
10 (1.1) 
2 (0.2) 
Metabolism and nutrition disorders 
Very common 
 
 
 
Decreased appetite 
152 (17.4) 
8 (0.9) 
0 (0.0) 
Nervous system disorders 
 
 
 
Common 
 
 
 
Dysgeusia 
79 (9.1) 
0 (0.0) 
0 (0.0) 
Eye disorders 
 
 
 
Common 
 
 
 
Vision blurred 
48 (5.5) 
1 (0.1)  
0 (0.0) 
Lacrimation increased 
59 (6.8) 
0 (0.0) 
0 (0.0) 
Dry eye 
36 (4.1) 
0 (0.0) 
0 (0.0) 
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System Organ Class 
 
Frequency 
 
 
Preferred Terma 
All Grades 
n (%) 
Grade 3 
n (%) 
Grade 4 
n (%) 
Respiratory, thoracic and mediastinal disorders 
Common 
 
 
 
Epistaxis 
ILD/pneumonitis*,i 
77 (8.8) 
12(1.4) 
0 (0.0) 
1 (0.1) 
0 (0.0) 
0 (0.0) 
Gastrointestinal disorders 
Very common 
 
 
 
Stomatitisg 
264 (30.3) 
8 (0.9) 
0 (0.0) 
Nausea 
314 (36.0) 
5 (0.6) 
0 (0.0) 
Diarrhoea 
238 (27.3) 
9 (1.0) 
0 (0.0) 
Vomiting 
165 (18.9) 
6 (0.7) 
0 (0.0) 
Skin and subcutaneous tissue disorders 
Very common 
 
 
 
Rashh 
158 (18.1) 
7 (0.8) 
0 (0.0) 
Alopecia 
234 (26.8) 
N/A 
N/A 
Dry skin 
93 (10.7) 
0 (0.0) 
0 (0.0) 
General disorders and administration site conditions 
 
Very common 
 
 
 
Fatigue 
362 (41.5) 
23 (2.6) 
2 (0.2) 
Asthenia 
118 (13.5) 
14 (1.6) 
1 (0.1) 
Pyrexia 
115 (13.2) 
1 (0.1) 
0 (0.0) 
Investigations 
Very common 
 
 
 
ALT increased 
92 (10.6) 
18 (2.1) 
1 (0.1) 
AST Increased 
99 (11.4) 
25 (2.9) 
0 (0.0) 
ALT=alanine aminotransferase; AST=aspartate aminotransferase; ILD=interstitial lung disease; 
N/n=number of patients; N/A=not applicable.   
* Adverse Drug Reaction (ADR) identified post-marketing. 
a 
Preferred Terms (PTs) are listed according to MedDRA 17.1. 
b 
Infections includes all PTs that are part of the System Organ Class Infections and infestations. 
c 
Neutropenia includes the following PTs: Neutropenia, Neutrophil count decreased. 
d 
Leukopenia includes the following PTs: Leukopenia, White blood cell count decreased. 
e 
Anaemia includes the following PTs: Anaemia, Haemoglobin decreased, Haematocrit decreased. 
f 
Thrombocytopenia includes the following PTs: Thrombocytopenia, Platelet count decreased. 
g 
Stomatitis includes the following PTs: Aphthous stomatitis, Cheilitis, Glossitis, Glossodynia, Mouth 
ulceration, Mucosal inflammation, Oral pain, Oropharyngeal discomfort, Oropharyngeal pain, 
Stomatitis. 
h 
Rash includes the following PTs: Rash, Rash maculo-papular, Rash pruritic, Rash erythematous, Rash 
papular, Dermatitis, Dermatitis acneiform, Toxic skin eruption. 
i 
ILD/pneumonitis includes any reported PTs that are part of the Standardised MedDRA Query 
Interstitial Lung Disease (narrow). 
 
Interstitial lung disease/pneumonitis 
Severe, life-threatening, or fatal ILD and/or pneumonitis can occur in patients treated with 
palbociclib when taken in combination with endocrine therapy.  
Across clinical trials (PALOMA-1, PALOMA-2, PALOMA-3), 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. For dose modifications in case of signs or symptoms, see section 10.3. 
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Amendment 2, Protocol V2.1 - 12 June 2020 
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11.2. Adverse reactions to trastuzumab 
Patients treated with trastuzumab are at increased risk for developing CHF (New York Heart 
Association [NYHA] Class II-IV) or asymptomatic cardiac dysfunction. These events have been 
observed in patients receiving trastuzumab therapy alone or in combination with paclitaxel, 
particularly following anthracycline (doxorubicin or epirubicin) containing chemotherapy. These 
may be moderate to severe and have been associated with death. In addition, caution should be 
exercised in treating patients with increased cardiac risk, e.g. hypertension, documented coronary 
artery disease, CHF, LVEF of <55%, older age. The following table has been taken from the 
European SPC: 
Table 8. 
Undesirable effects reported with intravenous trastuzumab monotherapy or in 
combination with chemotherapy in pivotal clinical trials (N = 8386) and in 
post-marketing 
System organ class 
Frequency 
Adverse reaction 
Infections and infestations 
Very common 
Infection, nasopharyngitis 
 
Common 
Neutropenic sepsis, cystitis, herpes zoster, influenza, 
sinusitis, skin infection, rhinitis, upper respiratory tract 
infection, urinary tract infection, erysipelas, cellulitis, 
pharyngitis 
 
Uncommon 
Sepsis  
 
Not known 
 
Neoplasms benign, 
malignant and unspecified 
(incl. cysts and polyps) 
Not known 
Malignant neoplasm progression, neoplasm progression 
Blood and lymphatic system 
disorders 
Very common 
Febrile neutropenia, anemia, neutropenia, white blood cell 
count decreased/leukopenia, thrombocytopenia 
 
Not known 
Hypoprothrombinemia, immune thrombocytopenia 
Immune system disorders 
Common 
Hypersensitivity 
 
Not known 
+Anaphylactic reaction, +anaphylactic shock 
Metabolism and nutrition 
disorders 
Very common 
Weight decreased/weight loss, anorexia 
 
Not known 
Hyperkalemia 
Psychiatric disorders 
Very common 
Insomnia 
 
Common 
Anxiety, depression, thinking abnormal 
Nervous system disorders 
Very common 
1Tremor, dizziness, headache, paresthesia, dysgeusia 
 
Common 
Peripheral neuropathy, hypertonia, somnolence, ataxia 
 
Rare 
Paresis 
 
Not known 
Brain edema 
Eye disorders 
Very common 
Conjunctivitis, lacrimation increased 
 
Common 
Dry eye 
 
Not known 
Papilledema, retinal hemorrhage 
Ear and labyrinth disorders 
Uncommon 
Deafness 
Cardiac disorders 
Very common 
1Blood pressure decreased, 1blood pressure increased, 
1heart beat irregular, 1palpitation, 1cardiac flutter, ejection 
fraction decreased* 
 
Common 
+Cardiac failure (congestive), +1supraventricular 
tachyarrhythmia, cardiomyopathy 
 
Uncommon 
Pericardial effusion 
 
Not known 
Cardiogenic shock, pericarditis, bradycardia, gallop 
rhythm present 
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System organ class 
Frequency 
Adverse reaction 
Vascular disorders 
Very common 
Hot flush 
 
Common 
+1Hypotension, vasodilatation  
Respiratory, thoracic and 
mediastinal disorders 
Very common 
+1Wheezing, +dyspnea, cough, epistaxis, rhinorrhea 
 
Common 
+Pneumonia, asthma, lung disorder, +pleural effusion 
 
Rare 
Pneumonitis 
 
Not known 
+Pulmonary fibrosis, +respiratory distress, +respiratory 
failure, +lung infiltration, +acute pulmonary edema, +acute 
respiratory distress syndrome, +bronchospasm, +hypoxia, 
+oxygen saturation decreased, laryngeal edema, orthopnea, 
pulmonary edema, interstitial lung disease 
Gastrointestinal disorders 
Very common 
Diarrhea, vomiting, nausea, 1lip swelling, abdominal pain, 
dyspepsia, constipation, stomatitis 
 
Common 
Pancreatitis, hemorrhoids, dry mouth 
Hepatobiliary disorders 
Common 
Hepatocellular injury, hepatitis, liver tenderness 
 
Rare 
Jaundice 
 
Not known 
Hepatic failure 
Skin and subcutaneous 
tissue disorders 
Very common 
Erythema, rash, 1swelling face, alopecia, nail disorder, 
palmar-plantar erythrodysesthesia syndrome 
 
Common 
Acne, dry skin, ecchymosis, hyperhydrosis, maculopapular 
rash, pruritus, onychoclasis, dermatitis 
 
Uncommon 
Urticaria 
 
Not known 
Angioedema 
Musculoskeletal and 
connective tissue disorders 
Very common 
Arthralgia, 1muscle tightness, myalgia 
 
Common 
Arthritis, back pain, bone pain, muscle spasms, neck pain, 
pain in extremity 
Renal and urinary disorders 
Common 
Renal disorder 
 
Not known 
Glomerulonephritis membranous, glomerulonephropathy, 
renal failure 
Pregnancy, puerperium and 
perinatal conditions 
Not known 
Oligohydramnios, renal hypoplasia, pulmonary hypoplasia 
Reproductive system and 
breast disorders 
Common 
Breast inflammation/mastitis 
General disorders and 
administration site 
conditions 
Very common 
Asthenia, chest pain, chills, fatigue, influenza-like 
symptoms, infusion related reaction, pain, pyrexia, 
mucosal inflammation, peripheral edema 
 
Common 
Malaise, edema 
Injury, poisoning and 
procedural complications 
Common 
Contusion 
+Denotes adverse reactions that have been reported in association with a fatal outcome. 
1Denotes adverse reactions that are reported largely in association with infusion-related reactions. Specific 
percentages for these are not available.  
*Observed with combination therapy following anthracyclines and combined with taxanes. 
11.3. Adverse reactions to pertuzumab 
Pertuzumab has been administered in the adjuvant and neoadjuvant setting in combination with 
trastuzumab, anthracyclines and taxanes. The most common adverse reactions were neutropenia, 
febrile neutropenia, leukopenia, diarrhea, nausea and alopecia.  
Table 9 has been taken from the European SPC (Table 1) 
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Table 9. 
Summary of ADRs in patients treated with pertuzumab in the metastatic and 
neoadjuvant setting 
System organ class 
Very common 
Common 
Uncommon  
Infections and 
infestations  
 
Upper respiratory tract 
infection  
Nasopharyngitis  
Paronychia  
 
 
Blood and lymphatic 
system  
disorders  
Febrile neutropenia*  
Neutropenia  
Leucopenia  
Anemia  
 
 
Immune system 
disorders  
 
Hypersensitivity/  
anaphylactic reaction°  
Infusion 
reaction/cytokine release 
syndrome°°  
 
 
Metabolism and 
nutrition disorders  
Decreased appetite †  
 
 
 
Psychiatric disorders  
 
Insomnia  
 
 
 
Nervous system 
disorders  
 
Neuropathy peripheral  
Headache †  
Dysgeusia  
Peripheral sensory 
neuropathy  
Dizziness  
 
Eye disorders  
 
 
Lacrimation increased  
 
 
Cardiac disorders  
 
 
Left ventricular 
dysfunction †  
(including congestive 
heart failure)**  
 
Respiratory, thoracic 
and mediastinal 
disorders  
Cough †  
 
Pleural effusion  
Dyspnea †  
Interstitial lung disease  
 
Gastrointestinal 
disorders  
 
Diarrhea †  
Vomiting †  
Stomatitis  
Nausea †  
Constipation †  
Dyspepsia  
 
 
Skin and subcutaneous 
tissue disorders  
 
Alopecia  
Rash †  
Nail disorder  
Pruritus  
Dry skin  
 
Musculoskeletal and 
connective tissue 
disorders  
Myalgia  
Arthralgia  
 
 
General disorders and 
administration site 
conditions  
 
Mucositis/mucosal 
inflammation  
Pain †  
Edema †  
Pyrexia  
Fatigue †  
Asthenia †  
Chills  
 
* Including adverse reactions with a fatal outcome.  
** For the overall treatment period across the 3 studies.  
† Except for febrile neutropenia, neutropenia, leukopenia, lacrimation increased, interstitial lung disease, 
paronychia, and alopecia, all events in this table were also reported in at least 1% of patients participating in 
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pertuzumab monotherapy trials, although not necessarily considered causally related to pertuzumab by the 
Investigator. Very common events (reported in ≥ 10% of pertuzumab monotherapy-treated patients) are marked in 
the Table with a †.  
° Hypersensitivity/anaphylactic reaction is based on a group of terms.  
°° Infusion reaction/cytokine release syndrome includes a range of different terms within a time window 
11.4. Adverse reactions to paclitaxel 
Table 10 
has 
been taken from 
the 
electronic Medicines 
Compendium 
(eMC) 
(www.medicines.org.uk). Within each frequency grouping, undesirable effects are presented in 
order of decreasing seriousness.  
Table 10. Summary of ADRs in patients treated with paclitaxel in the metastatic and 
post marketing surveillance setting 
System organ class  
Frequency and adverse reactions 
Infections and infestations:  
Very common: infection (mainly urinary tract and upper respiratory tract 
infections), with reported cases of fatal outcome  
Uncommon: septic shock  
Rare*: sepsis, peritonitis, pneumonia  
Blood and the lymphatic system 
disorders:  
Very common: myelosuppression, neutropenia, anemia, thrombocytopenia, 
leucopenia, bleeding  
Rare*: febrile neutropenia  
Very rare*: acute myeloid leukemia, myelodysplastic syndrome  
Immune system disorders:  
Very common: minor hypersensitivity reactions (mainly excessive flushing 
and rash)  
Uncommon: significant hypersensitivity reactions requiring therapy (e.g., 
hypotension, angioneurotic oedema, respiratory distress, generalised 
urticaria, chills, back pain, chest pain, tachycardia, abdominal pain, pain in 
limbs, pain in extremities, diaphoresis and hypertension)  
Rare*: anaphylactic reactions  
Very rare*: anaphylactic shock  
Metabolism and nutrition 
disorders:  
Very rare*: anorexia  
Not known*: tumor lysis syndrome  
Psychiatric disorders:  
Very rare*: confusional state  
Nervous system disorders:  
Very common: neurotoxicity (mainly: peripheral neuropathy)  
Rare*: motor neuropathy (with resultant minor distal weakness)  
Very rare*: grand mal seizures, autonomic neuropathy (resulting in paralytic 
ileus and orthostatic hypotension), encephalopathy, convulsions, dizziness, 
ataxia, headache  
Eye disorders:  
Very rare*: optic nerve and/or visual disturbances (scintillating scotomata), 
particularly in patients who have received higher doses than recommended  
Not known*: macular oedema, photopsia, vitreous floaters  
Ear and labyrinth disorders:  
Very rare*: hearing loss, ototoxicity, tinnitus, vertigo  
Cardiac disorders:  
Common: bradycardia  
Uncommon: myocardial infarction, AV block and syncope, cardiomyopathy, 
asymptomatic ventricular tachycardia, tachycardia with bigeminy  
Rare: heart failure  
Very rare*: atrial fibrillation, supraventricular tachycardia  
Vascular disorders:  
Very common: hypotension  
Uncommon: thrombosis, hypertension, thrombophlebitis  
Very rare*: shock  
Not known*: phlebitis  
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System organ class  
Frequency and adverse reactions 
Respiratory, thoracic and 
mediastinal disorders:  
Rare*: respiratory failure, pulmonary embolism, lung fibrosis, interstitial 
pneumonia, dyspnoea, pleural effusion  
Very rare*: cough  
Gastrointestinal disorders:  
Very common: diarrhoea, vomiting, nausea, mucosal inflammation  
Rare*: bowel obstruction, bowel perforation, ischaemic colitis, pancreatitis  
Very rare*: mesenteric thrombosis, pseudomembranous colitis, neutropenic 
colitis, ascites, oesophagitis, constipation  
Hepatobiliary disorders:  
Very rare*: hepatic necrosis, hepatic encephalopathy (both with reported 
cases of fatal outcome)  
Skin and subcutaneous tissue 
disorders:  
Very common: alopecia  
Common: transient and mild nail and skin changes  
Rare*: pruritus, rash, erythema  
Very rare*: Stevens-Johnson syndrome, epidermal necrolysis, erythema 
multiforme, exfoliative dermatitis, urticaria, onycholysis (patients on 
therapy should wear sun protection on hands and feet)  
Not known*: scleroderma  
Musculoskeletal and connective 
tissue disorders:  
Very common: arthralgia, myalgia  
Not known*: systemic lupus erythematosus  
General disorders and 
administration site conditions:  
Common: injection site reactions (including localised oedema, pain, 
erythema, induration, on occasion extravasation can result in cellulitis, skin 
fibrosis and skin necrosis)  
Rare*: pyrexia, dehydration, asthenia, oedema, malaise  
Investigations:  
Common: severe elevation in AST (SGOT), severe elevation in alkaline 
phosphatase  
Uncommon: severe elevation in bilirubin  
Rare*: increase in blood creatinine  
* Reported in post marketing surveillance setting 
 
 
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11.5. Adverse reactions to letrozole 
Table 11 has been taken from the European SPC (Table 1): 
Table 11. Adverse reactions to letrozole by system organ class and frequency 
System organ class  
Frequency 
Adverse reaction 
Infections and infestations 
Uncommon 
Urinary tract infection 
Neoplasms, benign, malignant 
and unspecified (including cysts 
and polyps) 
Uncommon 
Tumor pain 1 
Blood and the lymphatic system 
disorders 
Uncommon 
Leukopenia 
Immune system disorders 
Not known 
Anaphylactic reaction 
Metabolism and nutrition 
disorders 
Very common 
Hypercholesterolemia 
 
Common 
Anorexia, appetite increase 
Psychiatric disorders 
Common 
Depression 
 
Uncommon 
Anxiety (including nervousness), irritability 
Nervous system disorders 
Common 
Headache, dizziness 
 
Uncommon 
Somnolence, insomnia, memory impairment, 
dysesthesia (including paresthesia, hypoesthesia), 
taste disturbance, cerebrovascular accident 
Eye disorders 
Uncommon 
Cataract, eye irritation, blurred vision 
Cardiac disorders 
Uncommon 
Palpitations1, tachycardia, ischemic cardiac 
events(including new or worsening angina, angina 
requiring surgery, myocardial infarction and 
myocardial ischemia) 
Vascular disorders 
Very common 
Hot flushes 
 
Common 
Hypertension 
 
Uncommon 
Thrombophlebitis (including superficial and deep 
vein thrombophlebitis) 
 
Rare 
Pulmonary embolism, arterial thrombosis, 
cerebrovascular infarction 
Respiratory, thoracic and 
mediastinal disorders 
Uncommon 
Dyspnea, cough 
Gastrointestinal disorders 
Common 
Nausea, dyspepsia1, constipation, abdominal pain, 
diarrhea, vomiting 
 
Uncommon 
Dry mouth, stomatitis1 
Hepatobiliary disorders 
Uncommon 
Increased hepatic enzymes 
 
Not known 
Hepatitis 
Skin and subcutaneous tissue 
disorders 
Very common 
Increased sweating 
 
Common 
Alopecia, rash (including erythematous, 
maculopapular, psoriaform, and vesicular rash), dry 
skin 
 
Uncommon 
Pruritus, urticaria 
 
Not known 
Angioedema, toxic epidermal necrolysis, erythema 
multiforme 
Musculoskeletal and connective 
tissue disorders 
Very common 
Arthralgia 
 
Common 
Myalgia, bone pain1, osteoporosis, bone fractures 
 
Uncommon 
Arthritis 
Renal and urinary disorders 
Uncommon 
Increased urinary frequency 
Reproductive system and breast 
disorders 
Common 
Vaginal bleeding 
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System organ class  
Frequency 
Adverse reaction 
 
Uncommon 
Vaginal discharge, vaginal dryness, breast pain 
General disorders and 
administration site conditions 
Very common 
Fatigue (including asthenia, malaise) 
 
Common 
Peripheral edema 
 
Uncommon 
General edema, mucosal dryness, thirst, pyrexia 
Investigations 
Common 
Weight increase 
 
Uncommon 
Weight loss 
1 Adverse drug reactions reported only in the metastatic setting 
11.6. Potential drug induced liver injury 
Abnormal values in aspartate transaminase (AST) and/or alanine transaminase (ALT) concurrent 
with abnormal elevations in total bilirubin that meet the criteria outlined below in the absence of 
other causes of liver injury are considered potential cases of drug-induced liver injury (potential 
Hy’s Law cases) and should always be considered important medical events. 
The threshold for laboratory abnormalities in the case of potential drug-induced liver injury 
depends on the patient’s individual baseline values and underlying conditions. Patients who 
present with the following laboratory abnormalities should be evaluated further to definitively 
determine the etiology of the abnormal laboratory values:  
 Patients with AST or ALT and total bilirubin baseline values within the normal range 
o who subsequently present with AST or ALT ≥3 × ULN 
concurrent with  
o a total bilirubin ≥2 × ULN with no evidence of hemolysis and an alkaline 
phosphatase ≤2 × ULN or not available.  
 Patients with pre-existing AST or ALT baseline values above the normal range: 
o  AST or ALT ≥2 × the baseline values and ≥3 × ULN, or ≥8 × ULN (whichever 
is smaller) 
concurrent with  
o total bilirubin ≥2 × ULN and increased by 1 × ULN over baseline or ≥3 × ULN 
(whichever is smaller) with no evidence of hemolysis and an alkaline phosphatase 
≤2 × ULN or not available 
The patient should return to the investigational site and be evaluated as soon as possible, 
preferably within 48 hours from awareness of the abnormal results. This evaluation should 
include laboratory tests, detailed history and physical assessment. In addition to repeating AST 
and ALT, laboratory tests should include albumin, creatine kinase, total bilirubin, direct and 
indirect bilirubin, gamma-glutamyl transferase, prothrombin time (PT)/INR, and alkaline 
phosphatase. A detailed history, including relevant information, such as review of ethanol, 
acetaminophen, recreational drug and supplement consumption, family history, occupational 
exposure, sexual history, travel history, history of contact with a jaundiced subject, surgery, blood 
transfusion, history of liver or allergic disease, and work exposure, should be collected. Further 
testing for acute hepatitis A, B, or C infection and liver imaging (e.g., biliary tract) may be 
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warranted. All cases confirmed on repeat testing as meeting the laboratory criteria defined above, 
with no other cause for liver function test abnormalities identified at the time should be 
considered potential Hy’s Law cases irrespective of availability of all the results of the 
investigations performed to determine etiology of the abnormal liver function tests. Such 
potential Hy’s Law cases must be reported as SAEs. 
 
11.7. Drug-drug interactions 
Drug interaction studies for palbociclib have not been conducted in humans. Palbociclib is 
metabolized in vitro primarily via CYP3A4. See Sections 10.7.1 and 10.7.2 for medications that 
are not recommended. 
Palbociclib is metabolized to multiple metabolites in a qualitatively similar manner in rat, dog 
and human liver microsomes. In vitro, palbociclib is primarily metabolized by Cytochrome P-
450 (CYP) 3A4 enzymes. 
12. 
Adverse event and serious adverse event reporting 
12.1. Adverse event reporting 
The main criterion for tolerability is the occurrence of toxicities and adverse events. The severity 
and causality will be classified according to the NCI CTCAE Version 5. The CTCAE is available 
for downloading on the internet at http://evs.nci.nih.gov/ftp1/CTCAE/About.html.  
An adverse event is defined as any untoward medical occurrence that occurs from the first dose 
of trial medication until 30 days after all discontinuation of trial medication, regardless of whether 
it is considered related to a medication. 
Adverse events should be reported on the Adverse Event Form (55-AE) in DFexplore. See 
Section 12.1.1 for requirements of reporting. Symptoms of the targeted cancer (if applicable) 
should not be reported as adverse events. 
12.1.1. Severity / intensity 
The adverse event severity grade provides a qualitative assessment of the extent or intensity of 
an adverse event, as determined by the Investigator or as reported by the patient. The severity 
grade does not reflect the clinical seriousness of the event, only the degree or extent of the 
affliction or occurrence (e.g., severe nausea, mild seizure), and does not reflect the relationship 
to trial drug. 
Severity grade for other adverse events not covered in the toxicity grading scale: 
Grade 1 = Mild – transient or mild discomfort; no limitation in activity; no medical 
intervention/therapy required 
Grade 2 = Moderate – mild to moderate limitation in activity, some assistance may be needed; 
no or minimal medical intervention/therapy required 
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Grade 3 = Severe – marked limitation in activity, some assistance usually required; medical 
intervention/therapy required, hospitalization is possible 
Grade 4 = Life threatening – extreme limitation in activity, significant assistance required; 
significant medical intervention/therapy required, hospitalization or hospice care probable 
Grade 5 = Death – the event results in death 
The term “severe” is often used to describe the intensity of a specific event (as in mild, moderate 
or severe myocardial infarction); the event itself, however, may be of relatively minor medical 
significance (such as severe headache). This criterion is not the same as “serious” which is based 
on patient/event outcome or action criteria associated with events that pose a threat to a patient’s 
life or functioning. 
Seriousness, not severity, serves as a guide for defining regulatory obligations. 
Note: 
 
Report the highest grade observed in a cycle.  
 
Targeted AEs of any grade will have to be documented on the 55-AE Form. 
 
Any other AEs grade ≥3 as well as other AEs grade 2 requiring relevant medical 
intervention will have to be documented on the 55-AE Form.  
 
Abnormal laboratory values will have to be documented on the treatment forms 55-
PALBO or 55-PAC, respectively, and not on the 55-AE Form. For non-targeted adverse 
events caused by an abnormal lab value, grades ≥3 should be reported in the 55-AE 
Form. 
 
Non-targeted AEs should not be reported in a narrative description, but rather by using 
the applicable CTCAE v5.0 term. 
12.2. Targeted adverse events 
The presence of any grade of the following AEs must be indicated on the Adverse Event Form 
55-AE: 
 Neutrophil count decreased 
 Febrile neutropenia 
 Anemia 
 Platelet count decreased 
 Nausea  
 Diarrhea  
 Thromboembolic event 
 Infections  
 Skin and cutaneous disorders 
 Left ventricular systolic dysfunction 
 Hypertension 
 Ejection fraction decreased 
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 Hepatobilliary disorder 
 ILD/pneumonitis 
12.3. Adverse events of special interest (AESIs) 
Potential cases of drug-induced liver injury (see Section 11.6) are considered AESIs and need to 
be notified to IBCSG immediately (i.e., within 24h), following the SAE reporting instructions 
described in Section 0, even if not fulfilling a seriousness criterion.  
12.4. Otherwise reportable events 
Certain types of events, as identified below, are reportable to IBCSG under the reporting 
processes and requirements for SAEs, even if there is no associated adverse event. These are 
considered “otherwise reportable events” and generally reflect circumstances that could lead to 
an increased risk of an adverse event. Like an SAE, an otherwise reportable event is to be reported 
to IBCSG within 24 hours of awareness and followed up to determine outcome, including the 
later occurrence of an associated SAE. 
12.4.1. Relevant overdose of IMP  
An overdose (accidental or intentional) with the IMP is an event suspected by the Investigator or 
spontaneously notified by the patient and defined as the intake of  
 more than 23 capsules of palbociclib during a cycle (e.g.. two capsules on more than two 
days of a cycle, or more than two capsules during the week of break), or  
 more than 2 capsules of palbociclib on the same day. 
The overdose has to be reported within 24h on the 55–SAE–A Form. 
12.5. Serious adverse event (SAE)  
12.5.1. Definition 
An SAE is defined in general as any undesirable medical occurrence/adverse drug experience 
that occurs from signature of Informed Consent until 30 days after stopping all trial treatment 
that, at any dose, results in any of the following:  
 fatal (any cause) 
 life-threatening 
 requires or prolongs inpatient hospitalization 
 persistent or significant disability/incapacity 
 secondary (non-breast) malignancy 
 constitutes an important medical event 
Important medical events are defined as those occurrences that may not be immediately life-
threatening or result in death, hospitalization, or disability, but may jeopardize the patient or 
require medical or surgical intervention to prevent one of the other outcomes listed above. 
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Medical and scientific judgment should be exercised in deciding whether such an AE should be 
considered serious. 
Report all SAEs up to 30 days after completion of trial treatments (for EoT definition see Section 
10.8).  
A suspected unexpected serious adverse reaction (SUSAR) is an adverse event that is serious, 
related to the investigational drug and not listed as a known toxicity of the investigational drug 
in the Investigator’s brochure. All suspected unexpected serious adverse reactions judged by 
either the Investigator or IBCSG as the sponsor will be reported in accordance with applicable 
local regulations. 
12.5.2. Exceptions to the definition 
Hospitalizations occurring under the following circumstances are not considered to be serious 
adverse events:  
 elective surgery 
 occur on an outpatient basis and do not result in admission (hospitalization <24h) 
 are part of the normal treatment or monitoring of the studied treatment 
12.5.3. Causality assessment 
The Investigator needs to assess the relationship between protocol treatment and the occurrence 
of each SAE following the definitions in this table: 
 
Relationship to the 
protocol treatment  
Description 
Suspected 
The possibility that the protocol treatment caused the event is 
deemed definite or probable or possible 
Not suspected 
The possibility that the protocol treatment caused the event is 
deemed unlikely or unrelated 
 
The Investigator will use clinical judgment to determine the relationship. Alternative causes, such 
as natural history of the underlying diseases, medical history, concurrent conditions, concomitant 
therapy, other risk factors, and the temporal relationship of the event to the protocol treatment 
will be considered and investigated. 
The decision will be recorded on the SAE Form and if necessary the reason for the decision will 
also be recorded. 
12.5.4. Expectedness assessment 
The expectedness assessment is the responsibility of the sponsor of the trial. The expectedness 
assessment will be performed against the SPCs of the respective drugs. 
 
 
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12.6. Reporting SAEs 
Any SAE and any AESI or other reportable event (Sections 12.3 and 12.4) occurring in a patient 
after providing Informed Consent must be reported, including death due to any cause , which 
occurs within 30 days following cessation of treatment or the initiation of a new anticancer 
therapy, whichever is earlier, whether or not related to the investigational product. Information 
about all such events will be collected and recorded on the IBCSG Serious Adverse Event eCRFs 
(55–SAE–A and 55–SAE–B). 
To ensure patient safety, the IBCSG must be informed of each SAE using the procedures 
described below: 
 The Investigator/MD responsible for the patient must complete a Serious Adverse Event 
(SAE-A) eCRF in English within 24 hours of awareness via DFexplore. A copy is 
automatically forwarded to the IBCSG Safety Office for medical review. 
 Queries may be issued by the IBCSG Safety Office via email; a timely response by the 
Investigator to all SAE-related queries is crucial. 
 Follow-up information should be completed, via DFexplore, on the Serious Adverse 
Event (SAE-B) eCRF as soon as available and not later than 15 days of the initial report, 
even if the event reported in the SAE-A eCRF is not yet resolved. If the event is not 
resolved within 15 days, revise the original Serious Adverse Event (SAE-B) eCRF in 
DFexplore to report the final resolution. 
 All SAEs that have not resolved upon discontinuation of the patient’s participation in the 
trial must be followed until recovered, recovered with sequelae, not recovered (death due 
to another cause) or death (due to the SAE). 
 If a non-serious adverse event becomes serious, this and other relevant follow-up 
information must also be provided within 24 hours. 
 If submitting photocopies of SAE examinations, please send via DFSend (preferred) or 
fax. Care should be taken to ensure that the patient's identity is protected and the Patient 
ID number is properly included on ALL pages of any reports. For laboratory results, 
include the laboratory normal ranges. Please also note on each page that the information 
is “SAE related” so it can be properly categorized in DFexplore. 
 In the event the eCRF system is not working, the SAE Forms can be found in the Trial 
Site File or downloaded from the IBCSG trial webpage and sent via fax or DFSend into 
the DFexplore system. 
If an SAE (SAE-A and SAE-B Forms) was submitted by fax or DFSend, the original forms and 
the fax confirmation sheet(s) must be kept at the Participating Center. 
The IBCSG will inform Pfizer Pharmacovigilance and other appropriate persons about all SAEs 
within 24 hours of receipt at the IBCSG. 
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The IBCSG will record the SAE and prepare a monthly SAE report. Principal Investigators will 
receive the summary report on a monthly basis, and these reports can be found on the IBCSG 
web site (www.ibcsg.org). 
12.7. Occupational exposure 
If any patient-care or other personnel comes into contact with the content of palbociclib capsules 
then this needs to be reported to IBCSG via email to ibcsg55_touch@frontierscience.org.  
13. 
Disease assessment, response and progression 
Objective response prior to surgery will be assessed using the WHO tumor measurement and 
response criteria. 
13.1. Tumor measurements 
Bilateral mammography and breast/axilla ultrasound are required at baseline and prior to surgery. 
A physical tumor evaluation (by palpation, measured by caliper) should be done after 2 cycles. 
The technique(s) used for measurement of the tumor (breast and axilla) should include physical 
and imaging and, for each patient the same technique(s) should be used throughout the study 
treatment period. Whenever possible, measurements should be made by the same clinician for all 
assessments for each patient. 
All measurements (bi-dimensional) should be recorded in metric notations (centimeters and 
tenths of centimeters) using a ruler or calipers. 
Primary tumor diameters as well as nodal status must be reported in the appropriate sections of 
the eCRF. 
In case of multifocal or multicentric disease, only the lesion with the largest dimensions will be 
considered. 
All measurable lesions with diameter(s) that decrease to <0.5 cm will continue to be recorded as 
having a diameter of 0.5 cm until the lesion is completely resolved or until the diameter increases 
to >0.5 cm. When the diameter increases to >0.5 cm, the actual measured diameter will again be 
recorded. When the lesion is completely resolved, record as: 0.0 × 0.0 cm. 
13.2. Response criteria 
To determine response, changes in tumor size from baseline to the assessments after 2 cycles will 
be measured physically by caliper (palpation). Prior to surgery, changes in tumor size from 
baseline will be measured physically by caliper and by breast tumor imaging using a ruler. The 
response will be determined using WHO criteria. 
No confirmatory assessment will be required. 
13.2.1. Complete response (CR) 
The disappearance of all known disease. 
13.2.2. Partial response (PR) 
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A 50% or more decrease in total tumor size, i.e., the sum of the products of the maximal diameter 
(MD) and the corresponding largest perpendicular diameter (LPD) of the lesions which have been 
measured to determine the effect of therapy. In addition, there can be no appearance of new 
lesions or progression of any lesion. 
13.2.3.  Stable disease (SD)  
Neither a 50% decrease in total tumor size (i.e., the sum of the products MD*LPD of lesions), 
nor a 25% increase in the size of one or more measurable lesions has been determined. 
13.2.4. Progressive disease (PD) 
An increase of least 25% in total tumor size relative to the smallest size measured during the trial 
(i.e., the sum of the products MD*LPD of lesions), and/or the appearance of one or more new 
lesions. 
13.3. Best overall response 
Best overall response is defined as best response recorded from the start of treatment across all 
time points until disease progression or surgery. Confirmation of partial or complete response by 
additional imaging is not requested in this trial. Best overall response will be reviewed by the 
Head of Medical Affairs. 
13.4. Treatment in case of progression 
Patients with evidence of complete response, partial response, or no change will remain on 
treatment for the full protocol-defined neoadjuvant treatment. 
Patients with progressive disease confirmed by imaging will stop all trial medication and will 
undergo surgery, if clinically appropriate. 
13.5. Pathological complete response 
pCR (ypT0N0 or ypTisN0, see also Section 5.2) will be determined from the local histopathologic 
evaluation according to the American Joint Committee on Cancer Staging Manual, and is defined 
by the absence of invasive carcinoma in the breast and lymph nodes. The presence of in situ 
cancer after trial treatment in the absence of residual invasive disease constitutes a pCR. 
The presence of tumor within lymphatic and / or vascular spaces in the breast (lymphatic vascular 
invasion – LVI) with or without other residual invasive cancer precludes classification as a 
complete pathological response. 
Patients who do not proceed to surgery will be considered as not having pCR. 
14. 
Clinical and laboratory evaluations and follow-up 
14.1. Screening  
The following examinations should be done within a maximum of 4 weeks before randomization 
(hematology and blood chemistry: within 14 days before randomization). If examinations were 
done prior to 28 days before randomization, they have to be repeated. 
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14.1.1. Obtain informed consent for screening evaluations and trial participation. (Informed 
consent may be obtained earlier than within 28 days before randomization.) 
14.1.2. Confirm that primary tumor is ER-positive (ER ≥ 10%) and HER2-positive by IHC 
and/or ISH. 
14.1.3. Confirm with local pathologist that one FFPE block from the diagnostic biopsy is 
available exclusively for the purposes of this trial. This block will have to be sent to the 
IBCSG Central Pathology Office within 4 weeks after randomization. 
14.1.4. Medical history including details of malignancy: date of diagnosis, primary tumor type 
characteristics. 
14.1.5. Physical (breast and axilla palpation) and radiological (by mammography and 
ultrasound) tumor assessments. 
14.1.6. Chest X-ray or CT scan, if medically indicated; not required in patients who have 
undergone a PET scan. 
14.1.7. Abdominal ultrasound or CT if medically indicated; not required in patients who have 
undergone a PET scan. 
14.1.8. Bone scan if medically indicated. Required if the patient has unexplained bone pain; not 
required in patients who have undergone a PET scan. 
14.1.9. Feasibility of surgery and type of planned breast cancer surgery. 
14.1.10. Cardiac evaluation: Electrocardiogram (ECG) and Echocardiogram. 
14.1.11. Physical examination according to local standards, ECOG Performance Status, height, 
weight. 
14.1.12. Hematology, within 14 days prior to randomization: Hemoglobin, platelet count, white 
blood 
cell 
count 
including 
differential 
(absolute 
neutrophil 
count). 
 
14.1.13. Biochemistry, within 14 days prior to randomization: creatinine, alkaline phosphatase, 
AST or ALT, total bilirubin. 
14.1.14. Geriatric assessment (for patients aged 65 years): all three questionnaires are available 
in the local language. Complete all three questionnaires by reading the questions to the 
patient and if necessary explain them further. 
 G8: complete and then calculate the score, which is needed for the stratification (see 
Section 8.1.3; patient cannot be randomized without entering the score in the 
randomization system) 
 Instrumental Activity of Daily Living (IADL) 
 Charlson Comorbidity Index (CCI) 
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14.1.15. Baseline comorbidities (record on 55-H Form, and add medication to treat the 
corresponding comorbidity).  
14.2. During treatment 
The following should be done prior to the start of the next treatment cycle. 
Investigations marked with * need to be repeated on day 1 of the cycle prior to start of treatment 
if not done within 3 days prior to this day. 
14.2.1. Physical examination according to local standards, ECOG Performance Status and 
weight. 
14.2.2. * Hematology: Hemoglobin, platelet count, white blood cell count including differential 
(absolute neutrophil count). 
Note: Hematology needs to be done  
 prior to every paclitaxel dose (Arm A only)  
 on day 1 and 14 for the first two palbociclib cycles, and on day 1 of cycles 3 and 4 
(Arm B only). 
Note: Generally, frequency of hematology needs to be adapted to the treatment and the 
condition of the patient throughout the 4 treatment cycles 
14.2.3. * Biochemistry: creatinine, alkaline phosphatase, AST or ALT, total bilirubin. 
14.2.4. Echocardiogram or MUGA must be repeated 3 months into the trial treatment (at week 
7, plus/minus 1 weeks and before surgery). 
14.2.5. For adverse events observed in the previous cycle, record all grades for any targeted 
adverse event (see Section 12.2). Record all grade ≥3 non-targeted events. Record grade 
2 non-targeted events if they require relevant medical intervention. Assign the 
appropriate adverse events grade according to the NCI CTCAE Version 5.0. Record 
medication used to treat the AEs. 
14.2.6. Arm B: Compliance assessment; check patient diary; hand out new patient diary for next 
cycle.  
14.2.7. Monitor patients for pulmonary symptoms indicative of ILD/pneumonitis (e.g. hypoxia, 
cough, dyspnea). In patients who have new or worsening respiratory symptoms and are 
suspected to have developed ILD/pneumonitis, interrupt palbociclib immediately and 
evaluate the patient. 
14.3. Tumor assessments 
Tumor measurements have to be done at baseline, and before surgery:  
14.3.1. Baseline: Physical (breast and axilla palpation and caliper) and radiological 
(mammography and ultrasound, and ruler) tumor assessments.  
Chest X-ray or CT scan, if clinically indicated: not required in patients who have 
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undergone a PET scan. 
14.3.2. A physical tumor evaluation (by caliper) should be done after 2 paclitaxel cycles (Arm 
A) or 2 palbociclib cycles (Arm B).  
14.3.3. Before surgery: tumor assessment by breast and axilla palpation (and caliper) and by 
mammography and ultrasound (and ruler). 
14.3.4. Bone scan, if medically indicated; Required if the patient has unexplained bone pain; 
not required in patients who have undergone a PET scan. 
14.4. Before surgery 
After the end of trial treatment and before surgery:  
14.4.1. Physical examination according to local standards, weight and ECOG Performance 
Status. 
14.4.2. For adverse events observed in the last cycle before surgery, record all grades for any 
targeted adverse event (see Section 12.2). Record all grade ≥3 non-targeted events. 
Record grade 2 non-targeted events if they require relevant medical intervention. Assign 
the appropriate adverse events grade according to the NCI CTCAE Version 5.0. Record 
medication used to treat the AEs. 
14.4.3. Hematology: Hemoglobin, platelet count, white blood cell count including differential 
(absolute neutrophil count). 
14.4.4. Biochemistry: creatinine, alkaline phosphatase, AST or ALT, total bilirubin. 
14.4.5. If not done in the 30 days prior to this visit, determination of response through physical 
and radiological tumor assessments by breast and axilla palpation (caliper) and 
ultrasound and mammography (ruler; see Section 13). 
14.4.6. Electrocardiogram (ECG) and echocardiogram. 
14.5. After surgery 
Immediately after surgery, if there is residual invasive tumor, secure FFPE tumor specimen for 
central review and translational research. 
The end of treatment visit has to be done within 30 days after EoT as defined in Section 10.8. 
(time of breast cancer surgery; if not operated, date of stop of all trial medication). The following 
should be documented:  
14.5.1. Physical examination according to local standards, weight and ECOG Performance 
Status. 
14.5.2. Serious adverse events up to 30 days after EoT (for EoT definition see Section 10.8). 
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15. 
Biological evaluations 
15.1. Tumor tissue 
Tumor tissue from the biopsy taken prior to start of treatment will be sent to the IBCSG Central 
Pathology Office (CPO) in Milan, Italy, and biobanked. 
A tumor tissue specimen from definitive surgery must also be sent to the CPO. If there is no 
residual invasive tumor, please inform IBCSG. 
All biological material will be logged in the IBCSG Pathology Material Tracking System and 
banked in the IBCSG Biobank. 
15.2. Submitting pathology material to IBCSG 
Both FFPE blocks and copies of Pathology Reports must be marked with the IBCSG Patient ID 
number. Please erase or black out any other identifiers like name or date of birth. Refer to the 
IBCSG website for additional FFPE specimen shipping recommendations.  
Both FFPE blocks should be submitted within 4 weeks after being taken: 
 Tumor tissue from the biopsy taken prior to start of treatment 
 Tumor tissue specimen from definitive surgery  
Mailing address for the FFPE blocks and Pathology Reports: 
IBCSG Central Pathology Office 
European Institute of Oncology, EIO 
Division of Pathology 
Via Ripamonti 435 
20141 Milano, Italy 
Email: pathology.ibcsg@ieo.it 
NOTE: Pathology Reports must also be submitted to DFexplore via fax or DFSend. 
15.3. Translational research 
15.3.1. Integral translational research 
Pre-treatment biopsy will be analyzed by gene-expression profiling to assess RBsig status. 
15.3.2. Further translational research 
Pre-treatment biopsy gene-expression profiling may also be utilized to explore potential 
biomarkers in the randomized arms. Surgical tumor tissue samples may be analyzed by gene-
expression profiling to assess changes in RBsig status between baseline and surgery and explore 
potential biomarkers of resistance to treatment. 
Additionally, studies on proteins and genes involved in the ER and RB1 pathway may be 
conducted using immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) on 
both pre-treatment and surgical samples. 
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15.3.3. Not yet specified translational research 
The use of the biological material for future research not outlined in this protocol will be under 
the guardianship of the Steering Committee. As part of the trial Informed Consent process, 
patients are asked to indicate whether they agree to donate their sample for not yet specified 
future research. The patient’s decision is recorded on the trial Consent Form. 
Translational research proposals not outlined in this protocol will be assessed by IBCSG’s 
Biological Protocol Working Party (BPWG) for merit and feasibility.  
Biomarkers that are published in the future and considered to be of relevance may also be assessed 
in the context of this trial. 
16. 
Data submission 
We will conduct the trial according to the ICH Good Clinical Practice (GCP) guidelines. Keeping 
accurate and consistent records is essential to a cooperative trial. The following forms are to be 
submitted at the indicated times by the participating institutions for each patient: 
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16.1. Case report forms schedule 
Forms 
Description/Name 
Forms Submission  
ALL data should be completed in DFexplore 
(unless otherwise specified) 
Informed 
Consent Form 
Consent to participation in clinical 
trial and biologic material 
submission 
Obtain before registration and keep with patient 
records as documentation (hard copy only). 
Registration and Randomization 
Geriatric 
assessment (only 
for patients aged 
65 years) 
Geriatric Assessment G8 
questionnaire (55-G8) 
Lawton Instrumental Activities of 
Daily Living Scale (55-IADL) 
Charlson Comorbidity Index (55-
CCI) 
Complete questionnaires in local language on 
paper with the patient; note that the G8 score is 
needed in order to randomize the patient. 
After randomization, complete eCRF within 1 
week. 
55-A 
Confirmation of Randomization 
Form 
Complete eCRF after you have randomized the 
patient in the IBCSG Registration/ 
Randomization System and to confirm 
eligibility. Patient will be available eCRF within 
24 hours of successful randomization. 
Baseline  
55-H 
History Form 
Complete eCRF within 1 week of 
randomization. 
55-TEV-B 
Tumor Evaluation Baseline Form 
Complete eCRF within 1 week of 
randomization.  
55-Pathology Report 
During 
neoadjuvant 
treatment 
 
 
55-TP 
Arms A and B Trastuzumab / 
Pertuzumab Log 
Complete at Baseline and update every 3 weeks 
with each injection (and at Week 7 with 
Echo/MUGA result) 
55-PAC 
Arm A Paclitaxel Form 
For patients on Arm A, complete eCRF at the 
end of each 28 day cycle until treatment stops. 
55-PALBO 
Arm B Palbociclib Form 
For patients on Arm B, complete eCRF at the 
end of each 28 day cycle until treatment stops. 
55-LET 
Arm B Letrozole Form 
For patients on Arm B, complete eCRF at the 
end of letrozole treatment. 
55-AE 
Adverse Events Form 
Complete eCRF at the end of each 28 day cycle 
(on day 1 of the next cycle). 
 
 
 
55-TEV-Phys 
Tumor Evaluation Physical Exam 
Form 
Complete after 2 cycles of Arm A paclitaxel or 
Arm B palbociclib. 
 
After completion 
of trial 
medication, 
prior to Surgery 
 
 
55-TEV-PRESX 
Tumor Evaluation Pre-Surgery Form 
Complete eCRF within 4 weeks after trial 
treatment stops but prior to surgery. 
55-AE 
Adverse Events Form 
Complete eCRF after all trial medication is 
complete up to 4 weeks prior to surgery. 
55-TMC 
Trial Medication Completion Form 
Complete eCRF after all trial medication is 
complete up to 4 weeks prior to surgery. 
Surgery 
55-C 
Surgery form 
Complete eCRF within 2 weeks after surgery. 
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Forms 
Description/Name 
Forms Submission  
ALL data should be completed in DFexplore 
(unless otherwise specified) 
55-P 
Pathology form 
Complete eCRF within 2 weeks after surgery. 
Pathology report 
Pathology report for definitive surgery. 
Follow Up (after 
discontinuation 
of trial treatment 
and after 
surgery) 
 
 
55-EoT 
End of Treatment Form 
Complete eCRF 30 days after surgery or, if no 
surgery, after ALL protocol treatment stops. 
 
 
 
Event Driven  
 
 
55-SAE-A 
Serious Adverse Event/Adverse 
Event of Special Interest Form A - 
Initial report 
Complete eCRF within 24 hours of the SAE 
awareness. If eCRF is not available, submit the 
form within 24 hours to IBCSG DMC. 
55-SAE-B 
Serious Adverse Event/Adverse 
Event of Special Interest Form B - 
Follow-up report 
Complete eCRF as soon as follow-up 
information available, and not later than 15 days 
of the initial report (55-SAE-A). If event is not 
resolved in 15 days, update 55-SAE-B again at 
the time of resolution. 
55-COC 
Change of Consent Form 
Complete eCRF if there is any change in 
patient's consent to participate in the trial, see 
Section 18.2.2. 
55-E-Death 
Death Form 
Complete eCRF if a patient dies, if patient is still 
in active follow-up. 
The DFexplore User Manual and the Data Managers’ Manual for this trial contain instructions 
for completing and submitting forms using the DFexplore system.  
16.2. Signing and submitting forms 
An Authorization Log (see Section 16.5) should be completed at each Participating Center to 
identify the persons who are authorized to complete CRFs. 
CRFs should be completed on-line in DFexplore. Reports (lab, pathology, etc.) and any other 
non-CRF data will need to be sent to the DFexplore system via fax or DFSend. Full instructions 
on submitting forms will be available on the IBCSG website (www.ibcsg.org). Also available on 
the website is a list of fax numbers that are available for faxing CRFs. 
16.3. Data management 
Data collected in this trial will be submitted to the IBCSG Data Management Center in Amherst, 
NY, USA. The Data Management Center will process the data and will generate queries and 
forms requests. The Data Quality Control Office will oversee overall data submission and query 
resolution. The IBCSG Coordinating Center in Bern, Switzerland will provide medical review 
and summary of SAEs. The IBCSG Statistical Center in Boston, MA, USA will perform the data 
analysis. 
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16.4. Investigator Site File 
Each Participating Center should keep documentation about this trial in an Investigator Site File 
(ISF). Please arrange the documentation in the order foreseen in the ISF index which will be 
provided by IBCSG. The following documents should be included (list is not complete): 
 Protocol and appendices  
 Activation letter 
 Accrual reports 
 Amendments 
 Copy of signed Protocol Signature Pages 
 Sample CRFs including blank SAE Forms 
 For patients aged 65 years: geriatric assessment sheets (G8, IADL, Charlson 
Comorbidity Index) in local languages 
 Patient diary for treatment with letrozole and palbociclib (Arm B) 
 Data Managers’ Manual 
 Obvious Corrections Document and Signature Page 
 Randomization Manual 
 DFexplore Manual 
 Drug Supply Manual 
 Patient information and Informed Consent templates approved by Ethics Committee 
 Palbociclib SPC 
 Letrozole SPC 
 Trastuzumab SPC 
 Pertuzumab SPC 
 Paclitaxel SPC 
 Ethics Committee (and Health Authority, if applicable) approval of protocol, Patient 
Information Sheet and Informed Consent, amendments 
 Ethics Committee review of SAE, Investigators' alert, and other documents 
 Correspondence with Ethics Committee and Health Authority (if applicable) 
 Certificate of clinical trial insurance 
 Agreement with IBCSG 
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 Center Activation email(s) from IBCSG Data Management Center (protocol and 
amendments, if any) 
 Correspondence with / Information issued by IBCSG Coordinating Center, Data 
Management Center 
 SAE Reports sent from IBCSG Data Management Center 
 Normal laboratory values/reference ranges 
 Laboratory Certifications 
 CV of Principal Investigator and Co-Investigators, GCP certificates  
 Trial Training Certificates issued by IBCSG Center Training Office 
 Documentation of any training done internally (e.g. by use of IBCSG Training 
Confirmation Log) 
 Authorization Log 
 Center Information Sheet 
 Patient screening log 
 Patient identification log (see Section 16.6) 
 Drug shipment records 
 Drug accountability log (including certificates of destruction if applicable) 
 Temperature logs 
 Weblink to ICH GCP guidelines/Declaration of Helsinki and updates 
 Audit certificates / monitoring follow-up letters 
16.5. Authorization log 
The Principal Investigator (PI) should identify the other members of the Clinical Trial Team who 
are supervised by the PI and approved to provide information in CRFs, queries, etc. Instructions 
for completing the Authorization Log can be found in the Authorization Log Manual, posted on 
the IBCSG website. All changes need to be communicated to IBCSG by updating and emailing 
the authorization log. 
16.6. Patient identification log 
No patients’ names should be used in CRFs or any other documentation transmitted to IBCSG 
central offices. The only item used to identify a patient is the Patient ID (Randomization 
Number). It is therefore imperative that the local data manager keep an identification log for all 
patients entered in this trial including: 
 Patient's name 
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 Patient ID issued by the Registration/Randomization System 
 Date of birth 
 Date of randomization 
17. 
Statistical considerations 
17.1. Design  
This is an international, multi-center, randomized phase II trial that will randomize women with 
ER+/HER2+ primary breast cancer, in a 1:1 ratio, to receive the combination of: (A) paclitaxel + 
trastuzumab + pertuzumab versus (B) palbociclib + letrozole + trastuzumab + pertuzumab. 
Tumor RBsig status (high vs. low) by gene expression profiling will be assessed after the 
recruitment period in a central laboratory from a pre-treatment biopsy FFPE specimen. 
17.2. Sample size determination 
The primary efficacy endpoint is pathological complete remission pCR, as defined in Section 5.2. 
The trial hypothesis is that, in patients with RBsig LOW, palbociclib plus letrozole plus 
trastuzumab + pertuzumab will be more active than paclitaxel plus trastuzumab +pertuzumab, 
while in patients with RBsig HIGH, paclitaxel plus trastuzumab + pertuzumab will be more active 
than palbociclib plus letrozole plus trastuzumab + pertuzumab. 
The overall pCR rate is expected to be 26%, on the basis of patients with HR+ tumors treated 
with docetaxel-trastuzumab-pertuzumab in the NeoSphere trial [25] and those treated with 
palbociclib-fulvestrant-trastuzumab-pertuzumab in the NA-PHER2 [75]. The assumed pCR rates 
in the 4 subgroups defined by randomized treatment assignment and RBsig status are summarized 
in Table 12, on the basis of the retrospective in-silico study of RBsig (see Section 4.9) and 
ongoing analyses of other clinical trial cohorts (Malorni, personal communication). It is assumed 
that 50% of pre-biopsy samples are RBsig-high and 50% RBsig-low, which was the cutpoint in 
the in-silico study and ongoing studies but not yet adequately confirmed as the optimal cutpoint; 
as sensitivity analysis, a distribution of 25%/75% was also assessed, which has been a secondary 
cutpoint evaluated in the in-silico and ongoing studies. Sample size was determined on the basis 
of simulations of exact logistic regression test for treatment-by-RBsig interaction. An asymptotic 
method, such as that of Demidenko [76] was not used because the number of patients per 
subgroup will be relatively small and the pCR rates relatively low, and the appropriateness of an 
asymptotic method was uncertain. On the basis of simulations, an assessable sample size of 120 
patients with successful RBsig results was determined to provide 86% power for the test of 
treatment-by-RBsig interaction (two-sided α=0.05; Table 13). The enrolled sample size is inflated 
by 20% to 144 patients to account for non-assessable RBsig status (which is determined after 
randomization).  
 
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Table 12. Hypothesized pCR rates in subgroups defined by treatment and RBsig status 
for sample size determination. 
 
RBsig 
Prevalence 
A: Paclitaxel 
+ trastuzumab 
+ pertuzumab  
B: Palbociclib 
+ letrozole + 
trastuzumab + 
pertuzumab 
Odds Ratio 
(B:A) 
Rate Ratio 
(B/A) 
 
 
pCR rate 
 
 
RBsig LOW 
50% 
15% 
30% 
2.429 
2.0 
RBsig HIGH 
50% 
50% 
10% 
0.111 
0.2 
 
Table 13. Statistical power for test of treatment-by-RBsig interaction in exact logistic 
regression model (two-sided α=0.05) on the basis of simulations. 
 
N=100 
N=110 
N=120 
RBsig LOW / HIGH 
 
 
 
50% / 50% 
75% 
80% 
86% 
Freq. questionable fit* 
(9%) 
(7%) 
(5%) 
25% / 75% 
52% 
60% 
68% 
Freq. questionable fit* 
(17%) 
(13%) 
(11%) 
* Frequency that simulation resulted in a 0% pCR rate in one subgroup and the fit of the model was questionable 
17.3. Definitions of Trial Populations 
Randomized Population: Will include all patients who are randomized, according to treatment 
assignment.  
Assessable Population: Will include the subset of the randomized population with RBsig status 
successfully determined who received at least 1 dose of trial medication. 
Treated Population: Will include the subset of the randomized population who receive at least 1 
dose of trial medication. 
17.4. Primary Objective 
The primary objective will be tested in the assessable population.  
The primary endpoint is pCR, as defined in Section 5.2. pCR rate will be estimated as the number 
of patients with pCR documented, divided by the number of patients in the assessable population. 
Patients whose disease progresses and do not undergo surgery will be considered as not having 
pCR documented; patients who otherwise do not have available surgery results (e.g., stop study 
participation early) will be considered as not having pCR documented. Sensitivity analyses will 
be included in the statistical analysis plan, e.g., excluding the latter patients.  
pCR rates will be summarized as N (%) with two-sided 95% CIs, by treatment and RBsig status. 
The primary objective will be tested using exact logistic regression analysis with pCR as the 
dependent variable, by testing treatment-by-RBsig interaction and estimating the odds ratios 
(95% CIs) for Arm A versus B according to RBsig. Rate ratios and rate differences will also be 
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estimated (with 95% CIs). As noted in Section 17.2, the cutpoint of RBsig as high and low for 
the primary objective is presumed to be the median, and the cutpoint will be confirmed and pre-
specified in the statistical analysis plan. Further, treatment-by-RBsig interaction with RBsig as a 
continuous value will be explored using STEPP methodology [77, 78] on both the relative and 
absolute treatment effects. 
pCR rates and odds ratios may also be estimated by subgroups defined by the stratification factors 
(see Section 8.3). 
The pCR rates will also be summarized according to treatment on the basis of the treated 
population. 
17.5. Secondary Objectives 
Among patients in the assessable population, the rate of pCR in breast only will be estimated as 
the number of patients with absence of invasive tumor cells in the breast at the time of surgery 
(ypT0/ypTis), divided by the number of patients in the assessable population. Rates will be 
summarized as N (%) with two-sided 95% CIs, by treatment and RBsig status. The rates will also 
be summarized according to treatment on the basis of the treated population. 
Among patients in the assessable population, the rate of objective response (as defined in Section 
13) will be estimated as the number of patients with best overall response of complete response 
or partial response, divided by the number of patients in the assessable population. Rates will be 
summarized as N (%) with two-sided 95% CIs, by treatment and RBsig status. The rates will also 
be summarized according to treatment on the basis of the treated population. 
Among patients in the treated population, treatment tolerability will be assessed according to 
treatment on the basis of adverse events (AEs). For each AE, the frequency (N, %) of patients by 
worst grade of the AE will be summarized and tabulated by treatment. Two-sided 95% CI for the 
between-treatment difference in proportion of patients with each type of grade 3 or higher 
targeted AE will be estimated.  
Among patients in the assessable population, the breast-conserving surgery (BCS) rate will be 
estimated as the number of patients undergoing BCS, divided by the number of patients in the 
assessable population. In addition, the rates will be recalculated with the denominator considering 
only those patients reported at baseline not to be candidates for BCS. Rates will be summarized 
as N (%) with two-sided 95% CIs, by treatment and RBsig status. The rates will also be 
summarized according to treatment on the basis of the treated population. 
17.6. Interim Analyses 
Interim analyses are not planned.  
17.7. Accrual 
Enrollment of 144 patients is anticipated over approximately 24 months, after a start-up period 
of 6 months as the trial is being activated by Participating Centers and enrollment will be slow. 
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17.8. Data and Safety Monitoring 
Accrual, treatment and surgery completion, and AEs will be reviewed by the IBCSG Data and 
Safety Monitoring Committee (DSMC) twice per year. Successful assessment of RBsig status 
will be reviewed after the recruitment period. 
17.9. Correlative Objectives 
Among patients in the treated population that do not experience pCR, the tumor Ki67 
proliferation marker changes between pre-treatment biopsy and residual disease of surgery 
sample will be calculated. Absolute and relative changes in Ki67 will be summarized 
descriptively and graphically, by treatment and by RBsig status (including unknown status). 
Exact logistic regression will be used to identify features of pre-treatment tumor samples 
associated with pathologic response to treatment, and to explore the predictive value of such 
features for differential responsiveness to trial treatments.  
Logistic regression will also be used to explore whether features in baseline geriatric assessments 
(for the subgroup of women aged 65 years) are associated with adverse events experienced on 
trial treatments. 
18. 
Criteria for termination of the trial 
18.1. General criteria for termination of the trial 
The trial may be discontinued early in parts or completely if the information on the trial treatments 
leads to doubt as to the benefit/risk ratio, by decision of the IBCSG Foundation Council upon 
recommendation of the IBCSG 55-17 TOUCH Steering Committee and DSMC. 
The trial can be terminated at any time if the authorization and approval to conduct the trial is 
withdrawn by ethics committee or regulatory authority decision, insufficient accrual, emerging 
new data impacting the scientific value of the trial or ethical grounds. 
18.2. Patient-specific criteria for termination and withdrawal 
18.2.1. Cessation of trial treatment 
Patients have the right to refuse further trial treatment at any time during the trial. Patients may 
also be withdrawn from trial treatment at any time at the discretion of the Investigator due to an 
adverse event, or based on any other relevant medical condition. Such patients will remain in the 
trial. The patient will continue to be documented according to protocol. See Section 10.8 for 
details on stop of trial treatment. 
18.2.2. Withdrawal of consent 
Patients have the right to withdraw consent for further trial participation at any time without 
having to specify the reason. The data recorded up to the time point of withdrawal will continue 
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to be evaluated in the trial. The Investigator should ask the patient for consent to continue to 
collect information on her disease up to surgery. 
Withdrawal of consent should be documented in both the medical records and in the eCRF (Form 
55-COC). For the patient’s safety, an end of treatment visit should be performed and documented 
in the eCRF. 
19. 
Ethical aspects, regulatory approval, and patient informed consent 
The Investigator will ensure that this trial is conducted in full conformance with the principles of 
the “Declaration of Helsinki” or with the laws and regulations of the country in which the research 
is conducted, whichever affords the greater protection to the individual. The trial must fully 
adhere to the principles outlined in “Integrated Addendum to ICH E6(R1): Guideline for Good 
Clinical Practice (November 2016)” or with local law if it affords greater protection to the patient. 
For trials conducted in the EU/EEA countries, the Investigator will ensure compliance with the 
current EU legislation.  
19.1. Ethical Review Board/Ethics Committee 
All protocols and the patient Informed Consent forms must have the approval of a properly 
constituted committee or committees responsible for approving clinical trials. The Ethics 
Committee (EC) / Ethics Review Board (ERB) / Institution Review Board (IRB) written, signed 
approval letter/form must contain approval of the designated Investigator, the protocol 
(identifying protocol title and version number), and of the Patient Information Sheet and 
Informed Consent (PIS/IC). Documentation of Ethics Committee approval(s) must be sent to the 
IBCSG Data Management Center prior to enrollment of the first patient. The IBCSG Ethics 
Committee also approves the protocol and reviews it annually. 
Any modifications made to the protocol will be reviewed by the IBCSG Ethics Committee and 
must also be submitted to the appropriate EC/ERB/IRB for information or approval in accordance 
with local procedures and regulatory requirements and to Health Authorities if required.  
Once approved or acknowledged by the appropriate EC/ERB/IRB and by the Health Authorities 
(if required), the Investigator shall implement the protocol modifications. Protocol modifications 
for urgent safety matters may be directly implemented following the instructions of IBCSG. 
19.2. Regulatory approval procedures 
If applicable, in addition to the approval of the Ethics Committee according to national 
legislation, the protocol, other protocol-related documents including patient information and 
Informed Consent and other documents as required locally must be submitted to and be approved 
by the health authority. Documentation of health authority approval must be sent to the IBCSG 
Data Management Center prior to Participating Center activation. 
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19.3. Protection of human patients 
The IBCSG has an Office for Human Research Protection (OHRP) Federal Wide Assurance 
(FWA00009439) and follows all of the policies and procedures that are part of that assurance. 
All potential patients for this trial will receive a Patient Information Sheet with a full explanation 
of the trial, its purpose, treatments, risks, benefits, and all of the other items listed in Section 19.4. 
Additional institution-specific sections should be added to Appendix 1 as needed. 
The medical record must be available for review by the IBCSG monitors and audit team and 
regulatory authorities as described in Section 20.7. 
Serious Adverse Event (SAE) Reports are distributed monthly. In addition they are available on 
the IBCSG website (www.ibcsg.org) for participating Centers. 
19.4. Informed Consent 
Informed Consent for each patient will be obtained prior to initiating any trial procedures in 
accordance with the “IBCSG Patient Information Sheet and Informed Consent" (See Appendix 
1). One signed and dated copy of the Informed Consent must be given to each patient and the 
original copy must be retained in the Investigator's trial records. The Informed Consent form must 
be available in the case of data audits. Verification of signed Informed Consent and the date 
signed are required for randomization to this trial. 
The "Declaration of Helsinki" recommends that consent be obtained from each potential patient 
in biomedical research trials after the aims, methods, anticipated benefits, and potential hazards 
of the trial, and discomfort it may entail, are explained to the individual by the physician 
(http://www.wma.net/en/30publications/10policies/b3/index.html). The potential patient should 
also be informed of her right to not participate or to withdraw from the trial at any time. The 
patient should be told that material from her tumor will be stored and potentially used for 
additional studies not described in this protocol.  
If the patient is in a dependent relationship to the physician or gives consent under duress, the 
Informed Consent should be obtained by an independent physician. By signing this protocol, the 
Investigator agrees to conduct the trial in accordance with GCP and the "Declaration of Helsinki."  
The IBCSG recognizes that each institution has its own local, national, and international 
guidelines to follow with regard to Informed Consent. Therefore, we provide a template 
information sheet and Informed Consent form (Appendix 1), which can be downloaded and 
edited to incorporate information specific to your institution (see www.ibcsg.org). The template 
Patient Information Sheet and Informed Consent (PIS/IC) has been written according to ICH 
guidelines which state the Informed Consent should adhere to GCP and to the ethical principles 
that have origin in the “Declaration of Helsinki”. The final version should receive the Institutional 
Review Board/ Local Ethics Committee approval in advance of its use. Centers should send their 
locally modified PIS/IC to the IBCSG Data Management Center for review and approval before 
submitting to their Ethics Committee.  
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20. 
Governance and Administrative Considerations 
20.1. Final report 
A final clinical trial report will be written and distributed to health authorities as required by 
applicable regulatory requirements 
20.2. Clinical trial insurance 
IBCSG will contract the appropriate liability insurance for this trial. Patients who suffer injuries 
due to the trial should report them immediately to their physician. The local Center should report 
all alleged claims immediately to the IBCSG. 
20.3. Steering Committee 
A Steering Committee will be constituted for this trial. The primary responsibilities of the 
Steering Committee are twofold. First, the Steering Committee is responsible for maintaining the 
scientific integrity of the trial, for example, by recommending changes to the protocol in light of 
emerging clinical or scientific data from other trials. Second, the Steering Committee is 
responsible for the translation of recommendations of the IBCSG Data and Safety Monitoring 
Committee into decisions. Membership will include IBCSG officials, trial chairs and co-chairs, 
trial statisticians, representatives from some Participating Centers. 
General partition of responsibilities: 
The Steering Committee has the authority to make and implement any final decisions, such as 
substudies of the trial or amendments to the trial protocol, and may recommend the 
termination/early termination of the trial. 
The IBCSG Foundation Council decides on the termination/early termination of the trial. 
20.4. Data and Safety Monitoring Committee (DSMC) 
The trial will be presented for review to the IBCSG Data and Safety Monitoring Committee 
(DSMC) at each of their semi-annual meetings. Accrual, safety and accumulation of PFS events 
will be monitored.  
20.5. Publication of trial results 
IBCSG will publish the results of the trial based on the final trial report. 
20.6. Premature discontinuation of the trial 
The trial may be discontinued early in parts or completely if the information on the trial treatment 
leads to doubt as to the benefit/risk ratio. 
The trial can be terminated at any time if the authorization and approval to conduct the Study is 
withdrawn by ethics committee or regulatory authority decision, insufficient accrual, emerging 
new data impacting the scientific value of the trial or ethical grounds. 
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20.7. Quality Assurance 
The IBCSG conducts trials according to the ICH GCP guidelines. The Trial IBCSG Data 
Manager reviews each CRF. In addition, the IBCSG Medical Reviewer reviews each case at 
specific time points. The IBCSG conducts periodic audit visits to ensure proper trial conduct, 
verify compliance with GCP, and perform source data verification. 
The Investigator should ensure that source documents are made available to appropriately 
qualified personnel from IBCSG or its designees, or to health authority inspectors after 
appropriate notification. 
At regular intervals during the clinical trial, the Center will be contacted, through monitoring 
visits, letters or telephone calls, by a representative of the Monitoring Team to review trial 
progress, Investigator and patient compliance with clinical trial protocol requirements and any 
emergent problems. These monitoring visits will include but not be limited to review of the 
following aspects: patient Informed Consent, patient recruitment and follow-up, SAE 
documentation and reporting, AEs with pre-specified monitoring documentation and reporting, 
AE documentation, trial treatment administration, patient compliance with the regimens, drug 
accountability, concomitant therapy use and quality of data. 
20.8. Protocol adherence 
Investigators ascertain they will apply due diligence to avoid protocol deviations. Under no 
circumstances should the Investigator contact IBCSG or personnel monitoring the trial to request 
approval of a protocol deviation, as no deviations are permitted. The Investigator should 
document and explain any deviations from the approved protocol and promptly report them to 
IBCSG and to the EC concerned in accordance with the applicable EC policies and procedures. 
If the Investigator feels a protocol deviation would improve the conduct of the trial this must be 
considered a protocol amendment, and unless such an amendment is developed and activated by 
IBCSG and approved by the EC/ERB/IRB it cannot be implemented. All protocol deviations will 
be documented. 
20.9. Data protection 
The samples and data collected will be coded to protect patient confidentiality. A unique Patient 
Identification (ID)/Randomization Number will be assigned by the IBCSG Registration/ 
Randomization System to each patient registered into the trial. The names of the patients will not 
be disclosed to the IBCSG.  
Only the Patient ID will be used to identify a patient on the eCRF. Identification of patients must 
be guaranteed at the Participating Center. In order to avoid identification errors, Centers should 
keep a Patient Identification Log containing the patients’ name, year of birth, and the Patient ID 
allocated by IBCSG. 
Biological material will be assigned the same unique identifier. No identifiable / personal data 
will be stored in the trial database or the tissue repository in the central lab. 
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Biological material will be transferred outside the treating institution for central review and for 
determination of RRsig and translational research. Results of the assays will be coded only by 
the patient identifier. 
Regulatory authorities and the pertinent Ethics Committee (EC/ERB/IRB) may have access to 
patient data on-site. IBCSG audit or monitoring personnel will also have access to such data on-
site. 
20.10. Record Retention 
The Center must retain all essential documents according to ICH GCP. This includes copies of 
the patient trial records, which are considered as source data, patient Informed Consent statement, 
laboratory printouts, drug inventory and destruction logs, and all other information collected 
during the trial. These documents are to be stored until at least 15 years after the termination of 
the trial. IBCSG guarantees access and availability of the data entered into DFexplore for at least 
15 years after the termination of the trial. 
Longer retention may be required for Participating Centers according to national regulations. 
In the event that the Principal Investigator retires or changes employment, custody of the records 
may be transferred to another competent person who will accept responsibility for those records. 
Written notice of such transfer has to be given to IBCSG and the local Ethics Committee at least 
one month in advance. 
21. 
Confidentiality 
The protocol, CRFs and other protocol-related documents are confidential and are the property 
of the IBCSG. 
22. 
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