Clinical trial NCT03644186
Conditions: Breast Cancer Estrogen Receptor Positive Tumor HER2-positive Breast Cancer
Keywords: hormone receptor positive early breast cancer HER2 receptor positive early breast cancer
Sponsor: ETOP IBCSG Partners Foundation
Start date: 2019-04-16; Completion date: 2023-04-14
Enrollment: 147 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a phase II open-label, multicentre, randomized trial. The study assesses the treatment of postmenopausal patients with hormone receptor positive/HER2 positive early breast cancer with neoadjuvant palbociclib in combination with hormonal therapy and HER2 blockade, versus the treatment with paclitaxel in combination with HER2 blockade.

Detailed description:
TOUCH is an open label, international, phase II neoadjuvant trial which will assess the treatment of elderly patients with hormone receptor positive / human epidermal growth factor receptor-2 (HER2) positive early breast cancer with neoadjuvant palbociclib in combination with hormonal therapy and HER2 blockade, versus the treatment with paclitaxel in combination with HER2 blockade.

The neo-adjuvant setting was chosen to evaluate these therapy combinations in a short time-frame and to provide access to biomaterial both at baseline and after the end of the treatment, at surgery. Biopsy specimens will be analyzed at the end of the trial by gene-expression profiling to assess RBsig status. This marker may represent a tool to identify the participants who are more likely to benefit from a chemotherapy-free regimen in this population.

Palbociclib is a potent, highly selective, reversible, orally active, inhibitor of cyclin-dependent kinases 4 and 6 (CDK 4/6), therefore inhibiting cell growth and can be safely and effectively administered to older patients without need for dose adjustment based solely on age. Treatment de-escalation, namely harnessing and taking maximum advantage of targeted therapies vs conventional treatment (chemotherapy) in order to limit side effects, is particularly appealing in the older population.

Clinical data from the HR positive /HER2 negative setting show that combinations of palbociclib and letrozole are safe and effective. These combinations have not yet been tested in the HR positive /HER2 positive population that the investigators include in this trial. However, combinations of trastuzumab and endocrine treatment (ET), including letrozole have shown to be safe and to have some additional activity compared to ET alone in the HR positive /HER2 positive population. Therefore, the role of palbociclib in addition to letrozole and trastuzumab plus pertuzumab needs to be further studied.

Current standard of care for treatment of HER2 positive BC incorporates chemotherapy and anti-HER2 agents, with chemotherapy regimens of sequential anthracyclines and taxanes, used as single agents or in combination with other chemotherapy drugs. Trastuzumab is often administered concurrently with a single agent taxane to avoid the possible additive cardiac toxicity of combinations of anthracycline containing regimens and trastuzumab.

A regimen of weekly paclitaxel and trastuzumab plus pertuzumab was chosen as the comparator arm in this trial. More aggressive chemotherapy may not be justified in this population and trial participants may receive additional treatment after surgery, at the discretion of the treating doctor.

Preclinical and clinical rationale exists to support the proposal that palbociclib may represent a valuable option for increasing the activity of ET and anti-HER2 agents, such that a triple combination with these agents could prove superior to a standard treatment with chemotherapy and anti-HER2 agents.

The investigators hypothesize that the combination of palbociclib, letrozole and trastuzumab plus pertuzumab proposed in this trial will be more efficacious compared to the combinations of anti-HER2 agents and ET reported in other trials.

In 2019, it is estimated that of 260,600 newly diagnosed cases of invasive breast cancer in the United States, 82% occurred in women aged 50 or over. Furthermore, of the 41,760 breast cancer-related deaths in the same year, 90% occurred in this predominantly post-menopausal age group. Around 40% of BCs occur in women aged 65 and older. Of these, 10-15% have tumors that overexpress HER2. Elderly patients are generally underrepresented in clinical trials and may benefit from anti-HER2 agents as much as the younger population. Post-menopausal patients with HR positive /HER2 positive BC represent a unique group of patients with an unmet clinical need. This population is the focus of the TOUCH trial.

Arms: arm 1: Receiving paclitaxel 80mg/m2 i.v. on day 1, 8, 15 every 28 days for 4 cycles, trastuzumab 600mg s.c. every 3 weeks for a total of 5 doses and pertuzumab 840 mg i.v. loading dose followed by 420 mg i.v. every 3 weeks for a total of 5 doses. arm 2: Receiving palbociclib 125 mg/day orally for 21 days followed by 7 day's rest, for four 28 day cycles, letrozole 2.5 mg/day orally for 16 weeks and trastuzumab 600 mg s.c. every 3 weeks for a total of 5 doses and pertuzumab 840 mg i.v. loading dose followed by 420 mg i.v. every 3 weeks for 5 doses.
Interventions: intervention 1: Paclitaxel intervention 2: Trastuzumab intervention 3: Pertuzumab intervention 4: Palbociclib intervention 5: Letrozole intervention 6: Trastuzumab intervention 7: Pertuzumab
Intervention descriptions: intervention 1: Chemotherapy plus HER2 Blockade intervention 2: Chemotherapy plus HER2 Blockade intervention 3: Chemotherapy plus HER2 Blockade intervention 4: CDK Inhibition plus Hormonal Therapy plus HER2 Blockade intervention 5: CDK Inhibition plus Hormonal Therapy plus HER2 Blockade intervention 6: CDK Inhibition plus Hormonal Therapy plus HER2 Blockade intervention 7: CDK Inhibition plus Hormonal Therapy plus HER2 Blockade

Protocol documents:
Prot_SAP_001.pdf: 
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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Amendment 2, Protocol V2.1 - 12 June 2020 
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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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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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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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19. Buzdar AU, Suman VJ, Meric-Bernstam F et al. Fluorouracil, epirubicin, and 
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26. Schneeweiss A, Chia S, Hickish T et al. Pertuzumab plus trastuzumab in combination with 
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27. von Minckwitz G, Procter M, de Azambuja E et al. Adjuvant Pertuzumab and Trastuzumab 
in Early HER2-Positive Breast Cancer. N Engl J Med 2017; 377: 122-131. 
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41. Finn RS, Martin M, Rugo HS et al. Palbociclib and Letrozole in Advanced Breast Cancer. 
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48. Turner NC, Huang Bartlett C, Cristofanilli M. Palbociclib in Hormone-Receptor-Positive 
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treatment of ER+/HER2– advanced breast cancer (PALOMA-1; TRIO-18). Journal of 
Clinical Oncology 2017; 35: 1001-1001. 
50. Turner NC, Slamon DJ, Ro J et al. Overall Survival with Palbociclib and Fulvestrant in 
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51. Hu W, Sung T, Jessen B et al. Mechanistic investigation of bone marrow suppression 
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57. Romond EH, Perez EA, Bryant J et al. Trastuzumab plus adjuvant chemotherapy for 
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58. Biganzoli L, Wildiers H, Oakman C et al. Management of elderly patients with breast 
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65. Sonke GS, Hart LL, Campone M et al. Efficacy and safety of ribociclib (LEE011) + 
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70. Malorni L, Piazza S, Ciani Y et al. A gene expression signature of Retinoblastoma loss-of-
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71. Risi E, Biagioni C, Benelli M et al. An RB-1 loss of function gene signature as a tool to 
predict response to neoadjuvant chemotherapy plus anti-HER2 agents: a substudy of the 
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72. Gianni L, Bisagni G, Colleoni M et al. Abstract P4-21-39: Neo-adjuvant treatment with 
trastuzumab and pertuzumab associated with palbociclib and fulvestrant in HER2-positive 
and ER-positive breast cancer: Effect on Ki67 during and after treatment. A phase II 
Michelangelo study. Cancer Research 2017; 77: P4-21-39-P24-21-39. 
73. Krop IE, Lin NU, Blackwell K et al. Trastuzumab emtansine (T-DM1) versus lapatinib 
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nervous system metastases: a retrospective, exploratory analysis in EMILIA. Ann Oncol 
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better defined their role in older patients? A position paper from a SIOG Task Force. 
Cancer Treat Rev 2016; 43: 19-26. 
75. Gianni L, Bisagni G, Colleoni M et al. Neoadjuvant treatment with trastuzumab and 
pertuzumab plus palbociclib and fulvestrant in HER2-positive, ER-positive breast cancer 
(NA-PHER2): an exploratory, open-label, phase 2 study. Lancet Oncol 2018; 19: 249-256. 
76. Demidenko E. Sample size and optimal design for logistic regression with binary 
interaction. Stat Med 2008; 27: 36-46. 
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to assessing treatment-covariate interactions in survival data. Stat Med 2009; 28: 1255-
1268. 
78. Yip WK, Bonetti M, Cole BF et al. Subpopulation Treatment Effect Pattern Plot (STEPP) 
analysis for continuous, binary, and count outcomes. Clin Trials 2016; 13: 382-390. 
 
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IBCSG 55-17 TOUCH 
 
1-47 
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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2 
Amendment 2, Protocol V2.1 - 12 June 2020 
 Coordinating Center Effingerstrasse 40 CH-3008 Bern Switzerland www.ibcsg.org 
Trial Specific Contacts 
Trial Co-Chairs 
Laura Biganzoli, MD 
USL Toscana Centro, Hospital of 
Prato, Italy 
Email: laura.biganzoli@uslcentro.toscana.it 
Tel: +39 (0574) 802523 
Fax: +39 (0574) 802903 
Etienne Brain, MD, PhD  
Institut Curie, Paris, France 
Email: etienne.brain@curie.fr 
Tel: +33 1 47 11 18 75 
Fax: +33 1 47 11 16 64 
Trial Chair for translational 
research 
Luca Malorni, MD, PhD 
USL Toscana Centro, Hospital of 
Prato, Italy 
Email: lmalorni@uslcentro.toscana.it 
Tel: +39 (0574) 802520 
Trial Statisticians 
Meredith Regan, ScD 
Svitlana Tyekucheva, PhD 
IBCSG Statistical Center 
Email: mregan@jimmy.harvard.edu 
Email: svitlana@jimmy.harvard.edu 
Tel: +1 617-632-3012 
Fax: +1 617-632-5444 
Trial Data Manager Trial 
Coordinator 
Susan Fischer 
Meredith Kissel 
IBCSG Data Management Center 
Email: ibcsg55_touch@frontierscience.org 
Tel: +1 716-834-0900 (general) 
Fax: +1 716-833-3990 
Trial Monitoring 
 
TOUCH-Monitoring@ibcsg.org 
Translational Research Coordinator Rosita Kammler 
 
Email: rosita.kammler@ibcsg.org 
 
IBCSG Contacts 
Coordinating Center 
Anita Hiltbrunner 
Barbara Ruepp, PharmD 
Manuela Rabaglio, MD 
Heidi Roschitzki, PhD 
Linda Fritzsche 
IBCSG Coordinating Center 
Effingerstrasse 40 
CH-3008 Bern, Switzerland 
Email: anita.hiltbrunner@ibcsg.org  
Email: barbara.ruepp@ibcsg.org 
Email: manuela.rabaglio@ibcsg.org 
Email: heidi.roschitzki@ibcsg.org 
Email: drugsupply@ibcsg.org 
Tel: +41 31 511 94 00 
Fax: +41 31 511 94 01 
Data Management Center 
Lynette Blacher 
Karolyn Scott 
Holly Shaw 
Frontier Science 4033 Maple Rd. 
Amherst, NY 14226 USA 
Email: blacher@frontierscience.org 
Email: scott@frontierscience.org 
Email: hshaw@frontierscience.org 
Tel: +1 716 834-0900 
Fax: +1 716 833-3990 
Data Quality Control Office 
IBCSG Data Management Center 
Email: ib.dqc@frontierscience.org 
Center Training Office 
IBCSG Data Management Center 
Email: ibcsg.training@frontierscience.org 
Statistical Center 
Meredith M. Regan, ScD 
Div. of Biostatistics, CLSB 11007 
Dana-Farber Cancer Institute 
450 Brookline Ave. 
Boston, MA 02215 USA 
Email: mregan@jimmy.harvard.edu 
Tel: +1 617-632-3012 
Fax: +1 617-632-5444 
Scientific Committee Co-Chairs 
Dr. Marco Colleoni  
European Institute of Oncology 
Milan, Italy 
Email: marco.colleoni@ieo.it 
 
Dr. Angelo Di Leo 
USL Toscana Centro, Hospital of 
Prato, Italy 
 
Email: angelo.dileo@uslcentro.toscana.it 
In collaboration with Pfizer Italy (supply of palbociclib and trial support) and Roche (supply 
of trastuzumab and pertuzumab). 
 
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IBCSG 55-17 TOUCH 
 
3 
Amendment 2, Protocol V2.1 - 12 June 2020 
 Coordinating Center Effingerstrasse 40 CH-3008 Bern Switzerland www.ibcsg.org 
Protocol Signature Page Amendment 2 
 
IBCSG 55-17 TOUCH 
Approved by: 
Group Statistician, International Breast Cancer Study Group 
Dr. M.M. Regan 
 
______________________________________________________________________________________________________________________ 
 
_______________________________________________ 
 
Date 
 
 
Approved by: 
Director, International Breast Cancer Study Group 
Anita Hiltbrunner 
 
______________________________________________________________________________________________________________________ 
 
_______________________________________________ 
 
Date 
 
 
Approved by: 
Trial Co-Chair;  
Dr. Laura Biganzoli, "Sandro Pitigliani" Medical Oncology Department, Hospital of Prato, Prato, 
Italy 
 
 
______________________________________________________________________________________________________________________ 
 
_______________________________________________ 
 
Date 
 
 
Approved by: 
Trial Co-Chair;  
Dr. Etienne Brain, Institut Curie, Paris, France 
 
______________________________________________________________________________________________________________________ 
 
_______________________________________________ 
 
Date 
 
 
Approved by: 
Trial Chair Translational Research;  
Dr. Luca Malorni, "Sandro Pitigliani" Medical Oncology Department, Hospital of Prato, Prato, Italy 
 
 
______________________________________________________________________________________________________________________ 
 
_______________________________________________ 
 
Date 
DocuSign Envelope ID: 19E1CCAE-970A-4D1B-87A3-481172E12D24
16.06.2020
18.06.2020
16.06.2020
16.06.2020
16.06.2020


IBCSG 55-17 TOUCH 
 
4 
Amendment 2, Protocol V2.1 - 12 June 2020 
 Coordinating Center Effingerstrasse 40 CH-3008 Bern Switzerland www.ibcsg.org 
Principal Investigator Protocol Signature Page Amendment 2 
 
IBCSG 55-17 
 
TOUCH 
 
I have read the protocol and agree that it contains all necessary details for conducting this trial. I will 
conduct the trial as outlined in the following protocol and in compliance with GCP, and will apply 
due diligence to avoid protocol deviations. I will provide copies of the protocol and all drug 
information relating to preclinical and prior clinical experience furnished to me by IBCSG, to all 
physicians responsible to me who participate in this trial. I will discuss this material with them 
to assure that they are fully informed regarding the drugs and the conduct of the trial. I agree to 
keep records on all patient information (Case Report Forms and patient's Informed Consent 
statement), drug-shipment and return forms, and all other information collected during the trial for a 
minimum period of 15 years. 
Name of Principal Investigator: ___________________________________________ 
___________________________________________________ 
______________ 
Signature 
Date 
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Amendment 2, Protocol V2.1 - 12 June 2020 
 Coordinating Center Effingerstrasse 40 CH-3008 Bern Switzerland www.ibcsg.org 
TABLE OF CONTENTS  
Section 
Page 
1. 
Protocol Summary ................................................................................................. 8 
2. 
Trial schedule ...................................................................................................... 16 
2.1. 
Arm A (paclitaxel, trastuzumab, pertuzumab) .................................................... 16 
2.2. 
Arm B (palbociclib, letrozole, trastuzumab, pertuzumab) .................................. 18 
3. 
List of abbreviations ............................................................................................ 20 
4. 
Background and scientific rationale .................................................................... 22 
4.1. 
Introduction .......................................................................................................... 22 
4.2. 
Neoadjuvant treatment in HR+ and HER2+ BC ................................................. 22 
4.3. 
Endocrine treatment ............................................................................................. 23 
4.4. 
Chemotherapy ...................................................................................................... 24 
4.5. 
Anti-HER2 treatment ........................................................................................... 25 
4.6. 
CDK inhibition .................................................................................................... 27 
4.7. 
Palbociclib ........................................................................................................... 28 
4.8. 
Elderly patients .................................................................................................... 31 
4.9. 
Biomarkers for CDK4/6 inhibitor activity ........................................................... 32 
4.10. 
Trial hypothesis ................................................................................................... 34 
4.11. 
Overall risk-benefit assessment ........................................................................... 34 
4.12. 
Rationale for the trial design ................................................................................ 34 
5. 
Trial objectives and endpoints ............................................................................ 36 
5.1. 
Primary objective ................................................................................................. 36 
5.2. 
Primary endpoint ................................................................................................. 36 
5.3. 
Secondary objectives ........................................................................................... 37 
5.4. 
Correlative objectives .......................................................................................... 37 
6. 
Trial design, duration and termination ................................................................ 37 
6.1. 
Trial design .......................................................................................................... 37 
6.2. 
Trial schema ......................................................................................................... 38 
6.3. 
Treatment ............................................................................................................. 38 
6.4. 
Clinical evaluations ............................................................................................. 38 
6.5. 
Biological evaluations ......................................................................................... 39 
6.6. 
Sample size and trial duration .............................................................................. 39 
7. 
Patient selection .................................................................................................. 39 
7.1. 
Inclusion criteria .................................................................................................. 39 
7.2. 
Exclusion criteria ................................................................................................. 40 
8. 
Randomization and stratification ........................................................................ 42 
8.1. 
Randomization ..................................................................................................... 42 
8.2. 
Randomization Help Desk ................................................................................... 43 
8.3. 
Stratification ........................................................................................................ 43 
9. 
Trial drugs formulation and handling ................................................................. 43 
9.1. 
Palbociclib ........................................................................................................... 44 
9.2. 
Trastuzumab ........................................................................................................ 44 
9.3. 
Pertuzumab .......................................................................................................... 44 
9.4. 
Paclitaxel .............................................................................................................. 45 
9.5. 
Letrozole .............................................................................................................. 45 
10. 
Treatment ............................................................................................................ 45 
10.1. 
Trial treatments .................................................................................................... 45 
10.2. 
Treatment Administration .................................................................................... 45 
10.3. 
Dose delays and modifications for palbociclib .................................................... 46 
10.4. 
Dose modifications and delays for trastuzumab and pertuzumab ....................... 51 
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Amendment 2, Protocol V2.1 - 12 June 2020 
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10.5. 
Dose modifications and delays for paclitaxel ...................................................... 52 
10.6. 
Dose modifications and delays for letrozole ....................................................... 53 
10.7. 
Concomitant therapy ............................................................................................ 54 
10.8. 
Stop of trial treatment .......................................................................................... 55 
10.9. 
Removal from the trial ......................................................................................... 55 
11. 
Safety ................................................................................................................... 56 
11.1. 
Adverse reactions to palbociclib .......................................................................... 56 
11.2. 
Adverse reactions to trastuzumab ........................................................................ 58 
11.3. 
Adverse reactions to pertuzumab ......................................................................... 59 
11.4. 
Adverse reactions to paclitaxel ............................................................................ 61 
11.5. 
Adverse reactions to letrozole ............................................................................. 63 
11.6. 
Potential drug induced liver injury ...................................................................... 64 
11.7. 
Drug-drug interactions ......................................................................................... 65 
12. 
Adverse event and serious adverse event reporting ............................................ 65 
12.1. 
Adverse event reporting ....................................................................................... 65 
12.2. 
Targeted adverse events ....................................................................................... 66 
12.3. 
Adverse events of special interest (AESIs) ......................................................... 67 
12.4. 
Otherwise reportable events ................................................................................ 67 
12.5. 
Serious adverse event (SAE) ............................................................................... 67 
12.6. 
Reporting SAEs ................................................................................................... 69 
12.7. 
Occupational exposure ......................................................................................... 70 
13. 
Disease assessment, response and progression ................................................... 70 
13.1. 
Tumor measurements ........................................................................................... 70 
13.2. 
Response criteria .................................................................................................. 70 
13.3. 
Best overall response ........................................................................................... 71 
13.4. 
Treatment in case of progression ......................................................................... 71 
13.5. 
Pathological complete response ........................................................................... 71 
14. 
Clinical and laboratory evaluations and follow-up ............................................. 71 
14.1. 
Screening ............................................................................................................. 71 
14.2. 
During treatment .................................................................................................. 73 
14.3. 
Tumor assessments .............................................................................................. 73 
14.4. 
Before surgery ..................................................................................................... 74 
14.5. 
After surgery ........................................................................................................ 74 
15. 
Biological evaluations ......................................................................................... 75 
15.1. 
Tumor tissue ........................................................................................................ 75 
15.2. 
Submitting pathology material to IBCSG............................................................ 75 
15.3. 
Translational research .......................................................................................... 75 
16. 
Data submission .................................................................................................. 76 
16.1. 
Case report forms schedule .................................................................................. 77 
16.2. 
Signing and submitting forms .............................................................................. 78 
16.3. 
Data management ................................................................................................ 78 
16.4. 
Investigator Site File ............................................................................................ 79 
16.5. 
Authorization log ................................................................................................. 80 
16.6. 
Patient identification log ...................................................................................... 80 
17. 
Statistical considerations ..................................................................................... 81 
17.1. 
Design .................................................................................................................. 81 
17.2. 
Sample size determination ................................................................................... 81 
17.3. 
Definitions of Trial Populations .......................................................................... 82 
17.4. 
Primary Objective ................................................................................................ 82 
17.5. 
Secondary Objectives .......................................................................................... 83 
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17.6. 
Interim Analyses .................................................................................................. 83 
17.7. 
Accrual ................................................................................................................. 83 
17.8. 
Data and Safety Monitoring ................................................................................. 84 
17.9. 
Correlative Objectives ......................................................................................... 84 
18. 
Criteria for termination of the trial ...................................................................... 84 
18.1. 
General criteria for termination of the trial .......................................................... 84 
18.2. 
Patient-specific criteria for termination and withdrawal ..................................... 84 
19. 
Ethical aspects, regulatory approval, and patient informed consent ................... 85 
19.1. 
Ethical Review Board/Ethics Committee ............................................................ 85 
19.2. 
Regulatory approval procedures .......................................................................... 85 
19.3. 
Protection of human patients ............................................................................... 86 
19.4. 
Informed Consent ................................................................................................ 86 
20. 
Governance and Administrative Considerations ................................................. 87 
20.1. 
Final report ........................................................................................................... 87 
20.2. 
Clinical trial insurance ......................................................................................... 87 
20.3. 
Steering Committee ............................................................................................. 87 
20.4. 
Data and Safety Monitoring Committee (DSMC) ............................................... 87 
20.5. 
Publication of trial results .................................................................................... 87 
20.6. 
Premature discontinuation of the trial.................................................................. 87 
20.7. 
Quality Assurance ................................................................................................ 88 
20.8. 
Protocol adherence ............................................................................................... 88 
20.9. 
Data protection ..................................................................................................... 88 
20.10. Record Retention ................................................................................................. 89 
21. 
Confidentiality..................................................................................................... 89 
22. 
References ........................................................................................................... 89 
Appendices  
1. 
Patient Information Sheet and Informed Consent Form 
Index of Tables 
Table 1. 
ECOG Performance Status .................................................................................. 41 
Table 2. 
NYHA functional classification .......................................................................... 42 
Table 3. 
Available dose levels for palbociclib .................................................................. 49 
Table 4. 
Palbociclib dose modification and management ................................................. 49 
Table 5. 
Actions to be taken in case of trastuzumab and/or pertuzumab (anti-HER2 therapy) 
related adverse events ......................................................................................... 51 
Table 6. 
Actions to be taken in case of paclitaxel related adverse events ......................... 53 
Table 7. 
Adverse reactions to palbociclib based on pooled dataset from 3 randomized studies 
(N=872) ............................................................................................................... 56 
Table 8. 
Undesirable effects reported with intravenous trastuzumab monotherapy or in 
combination with chemotherapy in pivotal clinical trials (N = 8386) and in post-
marketing ............................................................................................................. 58 
Table 9. 
Summary of ADRs in patients treated with pertuzumab in the metastatic and 
neoadjuvant setting .............................................................................................. 60 
Table 10. Summary of ADRs in patients treated with paclitaxel in the metastatic and post 
marketing surveillance setting ............................................................................. 61 
Table 11. Adverse reactions to letrozole by system organ class and frequency ................. 63 
Table 12. Hypothesized pCR rates in subgroups defined by treatment and RBsig status for sample 
size determination. .............................................................................................. 82 
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. ...................................... 82 
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1. 
Protocol Summary  
 
Title 
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 
Sponsor  
International Breast Cancer Study Group IBCSG 
Pharma 
Partner 
Pfizer and Roche 
Clinical Phase 
Randomized Phase II 
Patient 
population 
Postmenopausal patients with histologically confirmed estrogen receptor positive, HER2 
positive primary breast cancer 
Treatment 
Patients will be randomized in a 1:1 fashion to: 
 Arm A  
Paclitaxel 80 mg/m2 i.v. on day 1, 8, 15 every 28 days for 4 cycles 
Trastuzumab 600 mg s.c. every 3 weeks for a total of 5 doses 
Pertuzumab 840 mg i.v. loading dose followed by 420 mg i.v. every 
3 weeks for a total of 5 doses 
 Arm B  
Palbociclib 125 mg/day orally for 21 days followed by 7 days’ rest, for 
four 28-day cycles 
Letrozole 2.5 mg/day orally for 16 weeks 
Trastuzumab 600 mg s.c. every 3 weeks for a total of 5 doses 
Pertuzumab 840 mg i.v. loading dose followed by 420 mg i.v. every 
3 weeks for a total of 5 doses 
Patients will then proceed to surgery 
Background 
and rationale 
Human epidermal growth factor receptor-2 (HER2) is overexpressed and/or amplified in about 
10-20% of breast tumors. HER2+ breast cancer (BC) is usually treated with regimens containing 
anti-HER2 agents and chemotherapy. Clinically approved anti-HER2 agents include 
monoclonal antibodies (trastuzumab and pertuzumab), tyrosine kinase inhibitors (lapatinib) or 
antibody–drug conjugates (T-DM1).  
Early BC, 
ER+, HER2+,
postmenopausal,
Neo-adj. 
treatment 
planned
R
A:
paclitaxel
trastuzumab
pertuzumab
B:
palbociclib
letrozole
trastuzumab
pertuzumab
surgery
surgery
Week   
1     2     3     4     5     6     7     8     9    10    11   12   13   14   15   16  
+
+
staging
FFPE sample
FFPE sample
Pertuzumab: 
loading dose
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Around 50% of HER2+ tumors co-express estrogen receptors (ERs), dividing HER2+ patients 
into hormone receptor (HR) negative and positive subgroups (HRneg/HER2+ and 
HR+/HER2+). Clinical data have increasingly demonstrated that these two subgroups of HER2+ 
patients show different prognosis when treated with anti-HER2 targeted agents and 
chemotherapy [Prat et al., 2014]. However, patients with HR+/HER2+ BC receive 
chemotherapy in combination with anti-HER2 agents as first choice treatment and only secondly 
endocrine treatment (ET). 
Extensive preclinical evidence indicates that ER and HER2 pathways are strictly interdependent 
and that targeting both pathways in ER- and HER2- co-expressing tumors might be an effective 
therapeutic strategy [Osborne et al., 2011]. Few trials investigated the addition of ET to anti-
HER2 in patients with HR+/HER2+ advanced disease indicating that a proportion of patients 
with HR+/HER2+ advanced BC benefit from the combination of hormonal and anti-HER2 
therapy with manageable side effects [Johnston et al., 2009; Kaufman et al., 2009]. However, 
whether the combination of anti-HER2 and ET would be superior to the approved combination 
of anti-HER2 and chemotherapy in patients with advanced HR+/HER2+ BC remains an open 
question since there is no direct comparison between these two strategies. Additionally, a recent 
phase II pre-operative trial of trastuzumab + lapatinib + the endocrine agent letrozole showed 
that the combination yielded a pCR rate of only 21% in a cohort of 39 ER+/HER2+ patients 
[Rimawi et al, 2013]. These considerations highlight that the current paradigm for the treatment 
of HER2+ patients (chemotherapy + anti-HER2 agents) does not necessarily fit the subgroup of 
patients co-expressing ER, and that current endocrine treatments alone might not be a sufficient 
partner for anti-HER2 agents in HR+/HER2+ disease.  
Cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitors are bringing great improvements in the 
management of patients with HR+/HER2neg advanced BC. Three different CDK4/6 inhibitors 
(palbociclib, abemaciclib and ribociclib) are in clinical development in this patient subgroup, 
mostly in combination with endocrine therapy. Palbociclib has been granted FDA approval in 
the U.S. for the treatment of HR+/HER2neg advanced BC in combination with the hormonal 
treatments letrozole and fulvestrant given the unprecedented results in terms of efficacy of two 
pivotal clinical trials (PALOMA-2 and PALOMA-3) [Finn et al. 2016; Cristofanilli et al., 2016]. 
Palbociclib and other CDK4/6 inhibitors have also shown a good toxicity profile and therefore 
are ideal candidates for combination with hormonal therapy.  
CDK4 and 6 control the transition from the G1 to the S phase in the cell cycle by binding to D-
type cyclins. A primary target of CDK action is the retinoblastoma susceptibility gene product 
(RB), which mediates G1 arrest through sequestration of transcriptional factors of the E2F 
family. Phosphorylation of RR (pRB) by active cyclin-CDK complexes leads to release of E2F 
transcription factors and the transcription of genes required for S-phase entry. CDK4/6 
inhibitors, by inhibiting RB phosphorylation, induce a cell cycle arrest in RB proficient cancer 
cells. CyclinD1-CDK4/6-Rb pathway is critical for the development and maintenance not only 
of ER+ but also of HER2+ tumors [Migliaccio et al., 2014] and molecular alterations involving 
the RB pathway frequently occur both in ER+ and in HER2+ BC [Cancer Genome Atlas, 2012]. 
Indeed, preclinical studies demonstrated that ER+ or HER2+ cell lines are the most sensitive to 
inhibition by CDK4/6 inhibitors and that combination of CDK4/6 inhibitors and ET or CDK4/6 
inhibitors and anti-HER2 agents are synergistic in ER+ or HER2+ BC models, respectively [Finn 
et al., 2009]. CDK4/6 pathway activation is a well-known mechanism of resistance to endocrine 
therapy [Migliaccio et al., 2014], indeed CDK4/6 inhibitors have shown activity in cellular 
models of acquired resistance to endocrine therapies [Wardell et al., 2015]. Also, palbociclib 
showed activity in cellular models of acquired resistance to lapatinib indicating that activation 
of the pathway might be implicated in resistance to such agents [Witkiewicz et al., 2014].  
These data collectively indicate that CDK4/6 are therapeutic targets that function downstream 
of both ER and HER2 pathways. Therefore tumors co-expressing ER and HER2 might be the 
most sensitive to CDK4/6 inhibition.  
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Genetic loss of RB1 is a marker of primary resistance to CDK4/6 inhibitors but it is uncommon 
in HR+ or HER2+ subtypes. Recent studies have shown that functional loss of the 
CyclinD1/CDK4-6/RB pathway can be measured by gene-expression studies. Several gene-
signatures of RB-loss have been developed which have shown to be prognostic in breast cancer 
subtypes as well as predictive of response to neoadjuvant chemotherapy [Witkiewicz et al., 
2012; Herschkowitz et al., 2008]. 
A recently developed gene-signature of functional loss of RB (RBsig) that is prognostic in 
luminal breast cancer subtypes can predict response to the CDK4/6 inhibitor palbociclib in cell 
line models of breast cancer [Malorni et al., 2016]. In particular, cell lines with increased levels 
of RBsig (RBsig HIGH) are among the most resistant to palbociclib treatment. 
Additionally, preliminary data suggest that the RBsig might be also predictive of response to 
chemotherapy + trastuzumab in ER+/HER2+ breast cancer patients. Indeed, we performed a 
retrospective in-silico study using publicly available datasets of gene-expression data (10 
studies) obtained from a total of 514 HER2+ BC patients treated with neoadjuvant chemotherapy 
+/- anti-HER2 therapy. For these patients, we computed the RBsig and correlated the RBsig 
expression with clinical outcome. The pCR rate to neoadjuvant CT + anti-HER2 for patients 
with RBsig LOW expression was significantly lower than the pCR rate for patients with RBsig 
HIGH expression. Results were similar for patients receiving neoadjuvant CT alone. Of note, 
the relationship between RBsig and pCR was observed only in HER2+/ER+, and not in 
HER2+/ER-negative tumors, suggesting that, as expected, RBsig seems to be relevant only in 
tumors with a luminal phenotype. These data suggest that RBsig identifies a subset of 
HR+/HER2+ patients (RBsig LOW) who derive little benefit from chemotherapy. 
Taken together, our data suggest that, among patients with ER+/HER2+ BC, those with RBsig 
HIGH derive benefit from chemotherapy and might be resistant to CDK4/6 inhibitors. 
Conversely, patients with RBsig LOW BC who derive little benefit from chemotherapy may 
benefit from CDK4/6 inhibitors.  
Based on this rationale, we hypothesize that the CDK4/6 inhibitor palbociclib in combination 
with the anti-HER2 trastuzumab + pertuzumab and the endocrine therapy letrozole may be 
effective neoadjuvant therapy in patients with ER+/HER2+ BC, especially in the subset of RBsig 
LOW patients. 
We also hypothesize that patients with RBsig HIGH ER+/HER2+ BC might be particularly 
sensitive to neoadjuvant chemotherapy with paclitaxel and trastuzumab + pertuzumab. 
In 2019, it is estimated that of 260,600 newly diagnosed cases of invasive breast cancer in the 
United States, 82% occurred in women aged 50 or over. Furthermore, of the 41,760 breast 
cancer-related deaths in the same year, 90% occurred in this predominantly post-menopausal 
age group [American Cancer Society, 2019]. Around 40% of breast cancers occur in women 
aged 65 and older. Of these, 10-15% have tumors that overexpress HER2 [Musgrove et al., 2011; 
Turner et al., 2015]. Jenkins et al. recently showed that among patients with HR+/HER2+ 
tumors, BC subtypes vary with age with luminal B tumors ranging from 20% in patients aged 
<60 years to 50% in patients over 60 [Jenkins et al., 2014]. Elderly patients are generally 
underrepresented in clinical trials; subgroup analyses have shown that they benefit from anti-
HER2 agents as much as the younger population [Biganzoli et al., 2012; Miles et al., 2013; Syed 
et al., 2014]. Overall a higher incidence of adverse events has been observed in the elderly, 
mainly related to the chemotherapy backbone of the treatment [Miles et al., 2013]. For this trial, 
we have therefore chosen 4 cycles of weekly paclitaxel with a 3 out of 4 weeks schedule 
[Biganzoli et al., 2016]. Palbociclib can be safely and effectively administered to older patients 
without requiring dose adjustment based solely on age [Rugo et al., 2017]. De-escalation of 
chemotherapy is of particular appeal in the older population. Recruitment of older women and 
prospective use of geriatric assessment instruments in those aged 65 will produce valuable 
safety and efficacy data within this under-represented subgroup. 
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Primary 
Objective and 
Endpoint 
 
The primary objective is to explore the interaction between the RBsig status (HIGH or LOW) 
and treatment activity, assessed by pathological complete response (pCR), of palbociclib + 
letrozole versus paclitaxel when given with trastuzumab + pertuzumab) for ER+/HER2+ 
primary BC. 
 
The study hypothesis is that,  
- 
in patients with RBsig LOW, trastuzumab + pertuzumab + palbociclib + letrozole will 
be more active than trastuzumab + pertuzumab + paclitaxel,  
- 
while in patients with RBsig HIGH, trastuzumab + pertuzumab + paclitaxel will be more 
active than trastuzumab + pertuzumab + palbociclib + letrozole. 
Primary endpoint:  
Pathological complete response pCR, defined as absence of invasive tumor cells in the breast 
and in the axillary lymph nodes at the time of surgery (ypT0/ypTis ypN0). 
Secondary 
Endpoints 
 
pCR in breast only 
 
Objective response prior to surgery, defined as partial or complete response assessed 
clinically and by ultrasound and/or mammography 
 
Tolerability, as defined by adverse events according to CTCAE version 5  
 
Rate of breast-conserving surgery 
Number of 
patients 
Randomization of 144 patients during approximately 24 months, after a start-up period of 6 
months as the trial is being activated by participating Centers. Patients will be followed and 
documented until End of Treatment visit to be done within 30 days after surgery. 
Trial duration 
With a start-up period of 6 months during which the sites will be activated, 24 months of 
recruitment, approximately 5 months after the inclusion of the last patient until End of Treatment 
visit, and 6 months for completion of the documentation and writing the trial report, the total 
duration of the trial is estimated to be 41 months after the randomization of the first patient. 
Inclusion 
criteria 
 
Histologically confirmed invasive breast cancer, with the following characteristics: 
- 
Early breast cancer with tumor size >1 cm (as measured by at least one of the 
required examination methods of clinical examination, mammography and 
ultrasonography) 
- 
No clinical evidence of regional lymph node metastasis (via physical and/or 
radiological exam) (cN0), OR clinical evidence of cN1 status, defined by nodal 
involvement limited to clinically detectable metastasis to movable ipsilateral level 
I, II axillary lymph node(s) ) 
- 
No evidence of metastasis (M0) 
 
Postmenopausal, defined as women with: 
- 
Prior bilateral surgical oophorectomy; OR 
- 
Amenorrhea and age 60 years; OR 
- 
Age <60 years and amenorrhea for 12 or more consecutive months in the absence 
of alternative pathological or physiological cause (including chemotherapy, 
tamoxifen, toremifene, ovarian suppression, or hormonally-based contraception) 
plus FSH and serum estradiol levels within the laboratory’s reference ranges for 
post-menopausal women 
 
Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 
 
Primary tumor must have positive estrogen receptor (ER) ≥10% 
 
Primary tumor must be HER2-positive (by IHC and/or ISH) 
 
Baseline LVEF ≥55% measured by Echocardiography (preferred) or MUGA scan 
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 
Normal hematologic status,  
- 
Absolute neutrophil count ≥1500/mm3 (1.5 × 109/L) 
- 
Platelets ≥100 × 109/L 
- 
Hemoglobin ≥9 g/dL (≥90 g/L) 
 
Normal renal function: serum creatinine ≤1.5 ULN 
 
Normal liver function:  
- 
Serum total bilirubin ≤1.5 × upper limit of normal (ULN). In the case of known 
Gilbert’s syndrome, a higher serum total bilirubin (<2 × ULN) is allowed 
- 
AST or ALT ≤2.5 × ULN 
- 
Alkaline phosphatase ≤2.5 × ULN 
 
Written Informed Consent (IC) must be signed and dated by the patient and the Investigator 
prior to randomization. 
 
The patient has been informed of and agrees to data transfer and handling, in accordance 
with national data protection guidelines. 
 
The patient agrees in writing to make tumor (mandatory diagnostic core biopsy and surgical 
specimen) available for submission for central pathology review and to conduct translational 
studies as part of this protocol. 
NOTE: Central Pathology Review on the primary tumor is mandatory for this trial, but 
patients will be evaluated for eligibility according to tumor characteristics as determined by 
the local pathologist. Both the diagnostic breast core biopsy specimen and the final breast 
surgical specimen (unless no residual invasive tumor is found at surgery) must be submitted 
for Central Pathology Review which will be done by the IBCSG Central Pathology Office 
in Milan, Italy. 
Exclusion 
criteria 
 
Tumor of any size with direct extension to the chest wall and/or to the skin (ulceration or 
skin nodules) (T4 according to AJCC 8th edition cancer staging TNM) 
 
Inflammatory breast cancer 
 
Bilateral invasive breast cancer 
 
Received any prior treatment for primary invasive breast cancer 
 
Any active tumor of non-breast-cancer histology 
 
Any of the following in the previous 6 months: myocardial infarction, severe/unstable 
angina pectoris, ongoing cardiac dysrhythmias of NCI CTCAE grade ≥2, atrial fibrillation 
of any grade, coronary/peripheral artery bypass graft, symptomatic congestive heart failure 
(NYHA functional classification ≥II), cerebrovascular accident including transient ischemic 
attack, or symptomatic pulmonary embolism 
 
Concurrent disease or condition that would make the subject inappropriate for study 
participation or any serious medical disorder that would interfere with the subject’s safety 
 
Contraindications or known hypersensitivity to any of the trial medications or excipients 
 
Treatment with any investigational agents within 30 days prior to expected start of trial 
treatment 
 
Any GI disorder that may affect absorption of oral medications, such as malabsorption 
syndrome or status post major bowel resection 
 
Evidence via physical and/or radiological exam of cN2 or cN3 nodal involvement defined 
by: metastasis to ipsilateral level I, II axillary lymph nodes that are clinically fixed or matted, 
OR involvement of ipsilateral infraclavicular, internal mammary and/or supraclavicular 
lymph node(s) 
 
History of extensive disseminated/bilateral or known presence of interstitial fibrosis or 
interstitial lung disease, including a history of pneumonitis, hypersensitivity pneumonitis, 
interstitial pneumonia, obliterative bronchiolitis, and pulmonary fibrosis. History of prior 
radiation pneumonitis is not an exclusion criterion. 
Assessments 
Efficacy: 
 
Breast disease assessment with clinical examination by caliper and bilateral breast 
ultrasound and mammography will be performed at baseline and before surgery. 
 
A physical tumor examination by caliper should be done after 2 treatment cycles 
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 
Evaluation of tumor response will be the task of the Investigator. Scans will not be centrally 
reviewed. 
Safety:  
 
Complete blood count will be performed as required by treatment schedule 
 
Blood chemistry will be checked every 4 weeks, prior to the next treatment cycle 
 
Adverse events will be graded according to CTCAE version 5; worst grade of adverse events 
will be recorded at beginning of next cycle 
 
All Serious Adverse Events must be notified to IBCSG within 24h 
 
End of treatment visit within 30 days after surgery 
For patients aged 65 years: geriatric assessment at baseline: 
 
G8  
 
Instrumental Activity of Daily Living (IADL)  
 
Charlson Comorbidity Index  
Documentation Electronic Case Report Forms (eCRFs) must be completed in DFexplore 
Integral 
translational 
research 
Pre-treatment biopsy will be analyzed by gene-expression profiling to assess RBsig status. 
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. 
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 be assessed 
in the context of this trial. 
Randomization 
and 
Stratification 
Stratification will be performed according to: 
 
Age and G8 score (<65 years vs. ≥65y and G8 score >14 vs ≥65y and G8 score ≤14) 
 
No clinical evidence of regional lymph nodes metastasis (cN0) vs nodal involvement limited 
to clinically detectable metastasis to movable ipsilateral level I, II axillary lymph node(s) 
(cN1)  
Randomization will be in a 1:1 ratio to: 
Arm A: paclitaxel + trastuzumab + pertuzumab  
Arm B: palbociclib + letrozole + trastuzumab + pertuzumab 
Statistical 
considerations 
For the primary objective, pCR rates are assumed to be: 
 
 
A: Paclitaxel + trastuzumab 
+ pertuzumab 
B: Palbociclib + letrozole + 
trastuzumab + pertuzumab 
Odds Ratio 
(B:A) 
RBsig LOW 
15% 
30% 
2.429 
RBsig HIGH 
50% 
10% 
0.111 
 
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 Coordinating Center Effingerstrasse 40 CH-3008 Bern Switzerland www.ibcsg.org 
Statistical power for RBsig-by-treatment interaction is summarized below for varied sample 
sizes and for two-sided alpha error of 0.05, under two assumptions of RBsig prevalence: 
Prevalence 
N=100 
N=110 
N=120 
RBsig 
low / high 
α=0.05 
α=0.05 
α=0.05 
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 a questionable 
model 
Power was estimated on the basis of simulations of exact logistic regression test for RBsig-by-
treatment interaction, as with the two low expected pCR rates, the appropriateness of an 
asymptotic method such as that of Demidenko et al., 2008 was uncertain. On the basis of 
simulations, taking into consideration the frequency with which 0 pCRs occurred in one of the 
subgroups, we propose an analyzable sample size of 120 patients with successful RBsig results. 
The enrolled sample size is inflated by 20% to 144 to account for non-assessable RBsig status 
(which is determined after randomization).  
The primary analysis will use exact logistic regression to test RBsig-by-treatment interaction 
and estimate the odds ratios for Arm B vs. A according to RBsig (rate ratios and rate differences 
will also be estimated; all with alpha-level confidence intervals).  
References 
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Society, Inc. 2019 
Biganzoli L, Wildiers H, Oakman C, et al. Management of elderly patients with breast cancer: updated 
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within HER2-positive breast cancer. J Natl Cancer Inst 2014; 106. 
Rimawi MF, Mayer IA, Forero A et al. Multicenter phase II study of neoadjuvant lapatinib and 
trastuzumab with hormonal therapy and without chemotherapy in patients with human epidermal growth 
factor receptor 2-overexpression breast cancer: TBCRC 006. J Clin Oncol 2013; 31:1726-1731. 
Rugo HS, Turner NC, Finn RS, et al. Palbociclib in combination with endocrine therapy in treatment-
naive and previously treated elderly women with HR+, HER2– advanced breast cancer: a pooled analysis 
from randomized phase 2 and 3 studies [abstract]. In: Proceedings of the Thirty-Ninth Annual CTRC-
AACR San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): 
AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P4-22-03 
Syed BM, Green AR, Ellis IO, Cheung KL. Human epidermal growth receptor-2 overexpressing early 
operable primary breast cancers in older (≥70 years) women: biology and clinical outcome in comparison 
with younger (<70 years) patients. Ann Oncol 2014; 25: 837-842 
Turner NC, Ro J, Andre F, et al. Palbociclib in Hormone-Receptor-Positive Advanced Breast Cancer. N 
Engl J Med 2015; 373:209-219. 
Wardell SE, Ellis MJ, Alley HM, et al. Efficacy of SERD/SERM Hybrid-CDK476 Inhibitor Combinations 
in Models of Endocrine Therapy-Resistant Breast Cancer. Clin Cancer Res 2015;21:5121-5130 
Witkiewicz AK, Ertel A, McFalls J, et al. RB-pathway disruption is associated with improved response 
to neoadjuvant chemotherapy in breast cancer. Clin Cancer Res 2012; 18: 5110-5122 
Witkiewicz AK, Cox D, Knudsen ES. CDK4/6 inhibition provides a potent adjunct to Her2-targeted 
therapies in preclinical breast cancer models. Genes Cancer 2014; 5:261-272. 
 
 
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Amendment 2, Protocol V2.1 - 12 June 2020 
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2. 
Trial schedule 
2.1. 
Arm A (paclitaxel, trastuzumab, pertuzumab) 
 
≤4 weeks 
prior to 
rando 
week 
Up to 4 
weeks 
prior to 
surgery 
30 days 
after 
surgery 
week 
 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
 
 
Informed consent 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
History 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination, ECOG 
PS 
x 
Day 1 of every paclitaxel cycle 
x 
x 
Baseline comorbidities 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse events 
 
At the end of every cycle: all grades for targeted events, all grade 3/4 non-targeted events;  
record grade 2 non-targeted events only if they require relevant medical intervention 
SAEs 
only 
Geriatric assessment (for 
patients aged 65 years) 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Neoadjuvant Treatment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Paclitaxel 80 mg/m2 1 
 
x  
x 
x 
 
x 
x 
x 
 
x 
x 
x 
 
x 
x 
x 
 
 
 
Trastuzumab 600 mg 
2 
 
x 
 
 
x 
 
 
x 
 
 
x 
 
 
x 
 
 
 
 
 
Pertuzumab 420 mg 
3 
 
x  
 
 
x 
 
 
x 
 
 
x 
 
 
x 
 
 
 
 
 
Laboratory tests 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology
4 
x 
Prior to every dose of paclitaxel 
x 
 
Blood chemistry
5 
x 
Prior to every paclitaxel cycle 
x 
 
Tumor Evaluation 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Caliper/ruler 
x 
 
 
 
 
 
 
 
x* 
 
 
 
 
 
 
 
 
x 
 
Mammography6 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
Breast Ultrasound6
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
Chest x-ray or CT7 
√ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abdominal US or CT 8 
√ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Bone scan9 
√ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Amendment 2, Protocol V2.1 - 12 June 2020 
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≤4 weeks 
prior to 
rando 
week 
Up to 4 
weeks 
prior to 
surgery 
30 days 
after 
surgery 
week 
 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
 
 
Other tests 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Electrocardiogram (ECG) 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
Echocardiography (preferred) 
or MUGA scan 
x 
 
 
 
 
 
 
x* 
 
 
 
 
 
 
 
 
 
x 
 
Pathology eval. (local) 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
FFPE sample10 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
x = mandatory 
√ = if medically indicated 
* = ±1 week 
# only SAEs 
Legend for trial schedule: 
Neoadjuvant treatment: 4 cycles of 28 days each 
1. Paclitaxel 80 mg/m2 i.v. on day 1,8,15 for four cycles of 28 days 
2. Trastuzumab 600 mg s.c. every 3 weeks for a total of 5 doses 
3. Pertuzumab 840 mg i.v. loading dose followed by 420 mg i.v. every 3 weeks for a total of 5 doses. 
Laboratory tests 
4. Hematology (Hemoglobin, platelet count, white blood cell count including differential (absolute neutrophil count) must be done within 14 days prior to 
randomization, on day 1 or within 3 days prior to every paclitaxel dose, and at the visit prior to surgery.  
5. Blood chemistry (creatinine, alkaline phosphatase, AST or ALT, total bilirubin) must be done within 14 days prior to randomization, on day 1 or within 3 days 
prior to every 28 day paclitaxel cycle, and at the visit prior to surgery. 
Tumor evaluation 
6. Bilateral mammography, and tumor assessments by breast/axilla palpation and ultrasound (caliper/ruler measurement) must be done prior to randomization, and 
prior to surgery. A tumor assessment (breast/axilla palpation and caliper measurement) should be done after 2 paclitaxel cycles. 
7. Chest X-ray or CT scan, if medically indicated; not required in patients who have undergone a PET scan.  
8. Abdominal ultrasound or CT scan, if medically indicated not required in patients who have undergone a PET scan. 
9. Bone scan if medically indicated. Requiredif the patient has unexplained bone pain; not required in patients who have undergone a PET scan. 
Biological material 
10. A formalin-fixed, paraffin-embedded (FFPE) tumor block from core biopsy at diagnosis and from surgery (if not pCR) must be submitted for central pathology 
review and for gene-expression profiling to assess RBsig status and future translational research studies.  
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Amendment 2, Protocol V2.1 - 12 June 2020 
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2.2. 
Arm B (palbociclib, letrozole, trastuzumab, pertuzumab) 
 
≤4 weeks 
prior to 
rando 
week 
Up to 4 
weeks 
prior to 
surgery 
30 days 
after 
surgery 
week 
 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
 
 
Informed consent 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
History 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination, ECOG PS 
x 
Day 1 of every palbociclib cycle 
x 
x 
Baseline comorbidities 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse events 
 
At the end of every cycle: all grades for targeted events, all grade 3 and 4 non-targeted events;  
record grade 2 non-targeted events only if they require relevant medical intervention 
SAEs 
only 
Geriatric assessment (for patients 
aged 65 years) 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Neoadjuvant Treatment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Palbociclib 125 mg/day 
1 
 
........daily ♯..... 
 
........daily ♯..... 
 
........daily ♯..... 
 
........daily ♯..... 
 
 
 
Letrozole 2.5 mg/day 
2 
 
 ......................................................…….daily.........................................................……….. 
 
 
Trastuzumab 600 mg 
3 
 
x 
 
 
x 
 
 
x 
 
 
x 
 
 
x 
 
 
 
 
 
Pertuzumab 420 mg 
4 
 
x  
 
 
x 
 
 
x 
 
 
x 
 
 
x 
 
 
 
 
 
Laboratory tests 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology
5 
x 
Day 1 and 14 during the first two palbociclib cycles, then on day 1 of cycles 3 and 4 
x 
 
Blood chemistry
6 
x 
Prior to every palbociclib cycle 
x 
 
Tumor Evaluation 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Caliper/ruler 
x 
 
 
 
 
 
 
 
x* 
 
 
 
 
 
 
 
 
x 
 
Mammography7 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
Breast Ultrasound7
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
Chest x-ray or CT8 
√ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abdominal US or CT9 
√ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Bone scan10 
√ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Other tests 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Amendment 2, Protocol V2.1 - 12 June 2020 
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≤4 weeks 
prior to 
rando 
week 
Up to 4 
weeks 
prior to 
surgery 
30 days 
after 
surgery 
week 
 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
 
 
Electrocardiogram (ECG)  
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
Echocardiography (preferred) or 
MUGA scan 
x 
 
 
 
 
 
 
x* 
 
 
 
 
 
 
 
 
 
x 
 
Pathology eval. (local) 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
FFPE sample11 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
x = mandatory 
√ = if medically indicated 
* = ±1 week 
♯ = check patient diary; hand out new patient diary for next cycle 
Legend for trial schedule: 
Neoadjuvant treatment: 4 cycles of 28 days each 
1. Palbociclib 125 mg/day orally for 21 days followed by 7 days rest, for 4 cycles.  
2. Letrozole 2.5 mg/day orally, continuously for 16 weeks 
3. Trastuzumab 600 mg s.c. every 3 weeks for a total of 5 doses 
4. Pertuzumab 840 mg i.v. loading dose followed by 420 mg i.v. every 3 weeks for a total of 5 doses 
Laboratory tests 
5. Hematology (Hemoglobin, platelet count, white blood cell count including differential (absolute neutrophil count)) must be done within 14 days prior to 
randomization, on day 1 (or within 3 days prior) and day 14 during the first two palbociclib cycles, then on day 1 (or within 3 days prior) of cycles 3 and 4, and at 
the visit prior to surgery.  
6. Blood chemistry (creatinine, alkaline phosphatase, AST or ALT, total bilirubin) must be done within 14 days prior to randomization, prior to every palbociclib 
cycle, and at the visit prior to surgery. 
Tumor evaluation 
7. Bilateral mammography, and tumor assessments by breast/axilla palpation and ultrasound (caliper/ruler measurement) must be done prior to randomization and 
prior to surgery. A tumor assessment (breast/axilla palpation and caliper measurement) should be done after 2 palbociclib cycles. 
8. Chest X-ray or CT scan, if medically indicated; not required in patients who have undergone a PET scan.  
9. Abdominal ultrasound or CT scan, if medically indicated; not required in patients who have undergone a PET scan. 
10. Bone scan if medically indicated. Required if the patient has unexplained bone pain; not required in patients who have undergone a PET scan. 
Biological material 
11. A formalin-fixed, paraffin-embedded (FFPE) tumor block from core biopsy at diagnosis and from surgery (if not pCR) must be submitted for central pathology 
review and for gene-expression profiling to assess RBsig status and future translational research studies.  
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3. 
List of abbreviations 
AE 
Adverse event 
AESI 
Adverse event of special interest 
AI 
Aromatase Inhibitor 
AJCC 
American Joint Committee on Cancer 
ALP 
Alkaline phosphatase 
ALT 
Alanine transaminase 
ANC 
Absolute Neutrophil Count 
AST  
Aspartate transaminase 
BC 
Breast Cancer 
BIG 
Breast International Group  
BSC 
Breast-Conserving Surgery 
CBR 
Clinical Benefit Rate 
CDK 
Cyclin Dependent Kinase 
CHF 
Congestive Heart Failure 
CI 
Confidence interval 
CNS 
Central Nervous System 
CPO 
Central Pathology Office 
CR 
Complete Response 
CRF 
Case Report Form 
CT 
Computed tomography 
CTCAE 
Common toxicity criteria for adverse events 
CYP3A 
Cytochrom P450 3A4 
DC 
Disease control  
DMC 
Data Management Center 
DSMC 
Data Safety Monitoring Committee 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic case report form 
EEA 
European Economic Area 
ET 
Endocrine Treatment 
EoT 
End of Treatment 
ER 
Estrogen receptor 
ERB 
Ethical Review Board 
FDG 
Fluoro-D-Glucose 
FFPE 
Formalin-fixed paraffin-embedded 
FISH 
Fluorescence in situ hybridization 
FLT 
Fluorothymidine 
FSTRF 
Frontier Science and Technology Research Foundation 
GCP 
Good clinical practice 
GGT  
Gamma-Glutamyl Transferase 
HER2 
Human Epidermal Growth Factor Receptor 2 
HIV 
Human Immunodeficiency Virus 
HR 
Hormone Receptors 
IADL 
Instrumental Activities of Daily Living 
IB 
Investigator’s Brochure 
IBCSG 
International Breast Cancer Study Group 
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IC 
Informed consent 
IC50 
Half Maximal Inhibitory Concentration 
ICH 
International Conference on Harmonization 
IHC 
Immunohistochemistry 
INR 
International Normalized Ratio 
IMP 
Investigational Medicinal Product 
IRB 
Institutional Review Board 
ISH 
In Situ Hybridization 
LHRH 
Luteinizing Hormone-Releasing Hormone 
LPD 
Largest Perpendicular Diameter 
MBC 
Metastatic breast cancer 
MD 
Maximal Diameter 
MRI 
Magnetic resonance imaging 
MTD 
Maximum tolerated dose 
mTOR 
Mechanistic Target of Rapamycin 
NAT 
Neoadjuvant Treatment 
NCI 
National Cancer Institute 
NE 
Not Evaluable 
NIMP 
Non-Investigational Medicinal Product 
NYHA 
New York Heart Association 
OHRP 
Office for Human Research Protection 
ORR 
Overall response rate 
pCR 
Pathological Complete Response 
PD 
Progressive Disease 
PET 
Positron Emission Tomography 
PFS 
Progression free survival 
PgR 
Progesterone receptor 
PI 
Principal Investigator 
PIS/IC 
Patient information sheet / informed consent 
PR 
Partial response 
pRb 
Phosphorylated Retinoblastoma 
 
PS 
Performance status 
PT 
Prothrombin Time 
QD 
Once daily (Quaque Die) 
QTc 
Corrected QT Interval 
Rb 
Retinoblastoma 
RR 
Response Rate 
SAE 
Serious adverse event 
SD 
Stable disease 
SPC 
Summary of Product Characteristics 
SPIM 
Standard Procedures Imaging Manual 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TEV 
Tumor Evaluation Form 
TNM 
Tumor-Node-Metastasis 
ULN 
Upper limit of normal 
 
 
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4. 
Background and scientific rationale 
4.1. 
Introduction 
About 70% of all invasive breast cancers (BC) express hormone receptors (HR) (Estrogen 
Receptor – ER and Progesterone Receptor – PgR) and are therefore treated with endocrine 
therapy (ET). The human epidermal growth factor receptor-2 (HER2) is overexpressed and/or 
amplified in about 10-20% of BC. Until recently, HER2 positive (HER2+) BC has been 
considered as a single entity, yet studies are increasingly demonstrating that HER2+ BCs are 
clinically and biologically heterogeneous. Around 50% of the HER2+ tumors co-express ER, 
dividing HER2+ patients in two main subgroups (HR-neg/HER2+ and HR+/HER2+).  
Patients with HR+/HER2+ BC represent a unique group of patients with an unmet clinical need. 
This population is the focus of this trial. 
4.2. 
Neoadjuvant treatment in HR+ and HER2+ BC 
Neoadjuvant therapy (NAT) (also called preoperative or primary systemic therapy) is delivered 
before surgical treatment and has historically been used mainly for locally advanced or 
inflammatory BC, because of its ability to downstage the disease and to favor operability in 
primary inoperable breast tumors. 
More recently, NAT use has become increasingly common also for patients with operable disease 
for a number of reasons including: a) tumor downsizing with a subsequent increased chance to 
achieve breast conserving surgery b) early treatment of distant micro-metastases c) selection of 
individualized therapy by early detection of treatment failures. NAT also offers a unique platform 
in clinical research to rapidly evaluate new drugs or treatment modalities to be further studied in 
other clinical settings. 
One of the main therapeutic goals of NAT is pathological complete response (pCR). The 
frequency of pCR following NAT varies among, and also within, BC subtypes.  
Triple negative and HER2+ BCs have the highest pCR rates after NAT, while HR+ tumors 
achieve lower pCR rates. Within HR+ tumors, pCR rates are particularly low for patients with 
low-grade tumors, while they are more than doubled for patients with high-grade tumors. Within 
HER2+ tumors, HR status also affects the pCR rates after neoadjuvant chemotherapy, pCR being 
less common for HR+ compared to HR negative BCs [1].  
Several studies revealed an association between pCR and improved survival. However, pCR rate 
has a clear prognostic value only in particular BC subgroups. A recent meta-analysis from von 
Minckwitz and colleagues [2] including more than 6000 patients showed that, among HER2+ 
patients, pCR after NAT is prognostic for survival in HR negative BC but not in HR+ BC, 
irrespective of trastuzumab treatment.  
Bhargava and colleagues divided HER2+ BC into three subgroups based on the levels of 
expression of ER and PgR [3]. These authors reported that the pCR rate and the level of ER 
expression are inversely correlated.  
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Recently, clinical trials of NAT in HER2+ disease (NeoALTTO, NeoSphere, CALGB40601, see 
below) also showed different response rates to anti-HER2 agents in HR+ vs HR- tumors. 
Available current data in the NAT setting suggest that HR+/HER2+ BC behaves differently from 
HR negative/HER2+ BC, achieving lower pCR rates after neoadjuvant chemotherapy with or 
without anti-HER2 agents; pCR may not be predictive of outcome in this subtype of BC. 
4.3. 
Endocrine treatment 
Endocrine treatment (ET) with aromatase inhibitors (AI), tamoxifen or fulvestrant represents the 
mainstay of HR+ BC treatment given its efficacy and very limited toxicity. HER2 is a major and 
well-recognized factor of primary resistance to ET and therefore HR+/HER2+ BC patients are 
seldom treated with ET alone. 
Extensive preclinical and clinical data have shown a complex bi-directional cross talk between 
ER and HER2 signaling pathways that may have important implication in resistance of 
HR+/HER2+ tumors to endocrine therapy and anti-HER2 agents [4]. HER2 overexpression or 
amplification affects endocrine therapy responsiveness; indeed, HR+/HER2+ BC patients treated 
with letrozole or tamoxifen, showed less Ki67 suppression when compared to HR+/HER2 
negative patients, despite similar short-term clinical efficacy [5].  
Combining targeted treatments that simultaneously block both signaling pathways is a promising 
approach to prevent or overcome either endocrine or anti-HER2 therapy resistance in some 
HR+/HER2+ tumors. 
Indeed, several clinical trials have explored this concept both in the metastatic and in the NAT 
setting. A small phase II trial of trastuzumab and letrozole enrolled 31 evaluable post-menopausal 
patients with HR+/HER2+ metastatic BC. More than 80% of included patients had received prior 
tamoxifen [6]. This trial showed an objective response rate of 26% and a clinical benefit rate 
(CBR) of 52%. The median time to progression was 5.8 months and the median duration of 
response was 20.6 months, suggesting that durable responses can be seen with combined ET and 
anti-HER2 therapy. 
In the randomized phase II TAnDEM trial, 207 patients with ER+/HER2+ metastatic breast 
cancer (MBC) were treated with either anastrozole alone or in combination with trastuzumab as 
first-line therapy. This trial demonstrated that the 2-year progression-free survival (PFS) rate was 
about 15% with anastrozole plus trastuzumab and only 5% with anastrozole alone. No difference 
in overall survival was seen. Clinical Benefit Rate (CBR) was about 43% with trastuzumab plus 
anastrozole compared to about 28% with anastrozole alone. Combination treatment was well 
tolerated with mostly mild to moderate side effects including fatigue (21%), diarrhea (20%), 
vomiting (21%), and pyrexia (17.5%) [7]. 
The eLEcTRA trial, compared letrozole alone or with trastuzumab as first line therapy and 
showed a non-significant trend toward longer PFS with combination therapy. CBR was 65% in 
the combination arm and 39% in the letrozole alone arm. Also in this trial, the more commonly 
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reported symptoms included fatigue (27%), diarrhea (19%), vomiting (19%) and peripheral 
edema (19%) [8]. 
The dual HER1/2 (EGFR/HER2) kinase inhibitor lapatinib has also been investigated in 
combination with hormonal therapy. The EGF30008 trial randomized 1286 patients with ER+ 
MBC to receive letrozole in combination with lapatinib or placebo as first line therapy. Of these, 
219 patients had HER2+ tumors. In the ER+/HER2+ population, there was a large and 
statistically significant improvement in PFS and the CBR was significantly improved from 29 to 
48% with the combination [9].  
All these trials in the MBC setting have confirmed that ET and anti-HER2 therapy can be safely 
and effectively combined. 
Only two published trials in early disease setting tested the combination of ET and anti-HER2 
agents in HR+/HER2+ BC. In the phase II TBCRC006 study [10], 64 patients with stages I–III 
HER2+ BC, received lapatinib plus trastuzumab for 12 weeks in the NAT setting. The 39 women 
with HR+ disease also received letrozole (plus luteinizing hormone-releasing hormone (LHRH) 
agonist if premenopausal). HR+/HER2+ patients achieved a pCR rate of 21% which was 
remarkable, given the absence of chemotherapy in the study regimen. 
The TBCRC023 trial compared lapatinib plus trastuzumab, adding letrozole (along with ovarian 
suppression if premenopausal) in HR+ patients, for 12 weeks vs 24 weeks. Longer treatment 
duration of endocrine therapy and anti-HER2 therapy (without chemotherapy) led to a 
meaningful increase in pCR rate in HR+/HER2+ BC (33% with 24 weeks vs 9% with 12 weeks 
of therapy) while pCR rates were quite similar for the ER negative patients, independently from 
treatment duration [11]. 
Regarding the choice of ET agent in ER+/HER2+ BC, data suggest a superiority of AI over 
tamoxifen. The advantage of the AI letrozole over tamoxifen in HR+/HER2+ BC, was shown in 
a phase III study including 330 postmenopausal women; the difference in response rate (RR) 
between the two treatment arms, was more evident in HER2+ patients (RR= 88% vs 21%), than 
in HER2- patients (RR=54% vs 42%) [12]. 
These results were confirmed in the IMPACT trial, comparing the AI anastrozole vs tamoxifen 
vs the combination of the two agents; patients with HER2 overexpressing tumors presented a 
higher response rate with the AI when compared with tamoxifen although the difference was not 
statistically significant (58% vs 22% vs 31% with anastrozole, tamoxifen, and combination 
therapy, respectively) [13]. 
4.4. 
Chemotherapy 
Chemotherapy in combination with anti-HER2 agents remains the most frequently used treatment 
for HR+/HER2+ BC patients. 
pCR rates and outcomes of patients treated with chemotherapy and anti-HER2 agents vary 
between trials according to the type of chemotherapy and the anti-HER2 agent under study. 
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The addition of trastuzumab to primary chemotherapy has significantly improved the pCR rate 
in HER2+ BC. The first randomized trial was reported by Buzdar and colleagues in 2005 [14]. 
Patients were randomized to receive taxane and anthracycline-based chemotherapy with or 
without weekly trastuzumab for a total of 24 weeks. The results were strongly in favor of 
trastuzumab combination therapy in both the whole population (pCR rate=65.2% versus 26%), 
and in patients selected by HR status. The updated safety and efficacy data from this trial [15] 
confirmed the initial findings and showed an improved disease-free survival among trastuzumab-
treated patients without clinical cardiac dysfunctions or other relevant toxicities.  
In the NOAH trial, neoadjuvant chemotherapy with doxorubicin, paclitaxel, cyclophosphamide, 
methotrexate and fluorouracil, was administered alone or in combination with trastuzumab. The 
study included 235 patients with HER2+ BC, 151 of whom had HR+ status. In the overall 
population, the pCR rate was higher in patients receiving trastuzumab, but the difference between 
the two treatment arms was more evident in HR negative tumors compared to HR+ tumors 
(Hazard ratios= 0,46 vs 0,87 in HR- and HR+ respectively). Equally, in terms of event free 
survival, HR negative patients had a more pronounced benefit from trastuzumab than HR+ 
patients [16, 17]. 
The GeparQuattro study [18] evaluated the incorporation of capecitabine into an 
anthracycline/taxane-based regimen and the concurrent use of trastuzumab in HER2+ patients. 
Also in this case, HR status was the only factor independently associated with pCR in a univariate 
and multivariate analysis (pCR rate= 43.5% in HR negative vs 23.4% in HR+). 
The phase III ACOSOG Z1041 trial [19] randomized patients to paclitaxel and trastuzumab 
followed by concurrent 5-fluorouracil + epirubicin + cyclophosphamide (FEC) and trastuzumab 
compared with FEC alone followed by concurrent paclitaxel and trastuzumab. No difference in 
pCR rate was found between the two arms, irrespective of hormone receptor status, and pCR rates 
were lower in those patients with HR+ status (pCR rate=70.4% and 77.6% in HR negative vs. 
47.6% and 38.1% in HR+).  
Collectively, these data show that, among patients with HER2 + disease, those with HR+ BC 
derive less benefit from combination of chemotherapy and anti-HER2 agents, compared to 
patients with HR negative disease. 
4.5. 
Anti-HER2 treatment 
Clinically approved anti-HER2 agents include monoclonal antibodies (trastuzumab and 
pertuzumab), tyrosine kinase inhibitors (lapatinib) or antibody–drug conjugates (T-DM1).  
Trastuzumab was the first anti-HER2 agent used as chemotherapy partner in HR+/HER2+ 
tumors. However, preclinical data have suggested that a more complete inhibition of the HER2 
pathway by means of dual blockade with trastuzumab and lapatinib could be a more efficacious 
treatment strategy. 
The dual combination of the anti-HER2 agents lapatinib and trastuzumab with chemotherapy was 
used in the in the NSABP B-41 [20], NeoALTTO trial [21], CALGB 40601 trial [22], and CHER-
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LOB trial [23], and was associated with higher pCR rates compared with single-agent anti-HER2 
treatments independent of the receptor status.  
Regarding toxicity, all the trials including a lapatinib + trastuzumab arm showed consistently that 
the addition of lapatinib increases the incidence of class-specific side effects such as diarrhea, 
rash and liver toxicity.  
The positive results in the NAT setting in terms of activity of the dual blockade with trastuzumab 
and lapatinib were not replicated in the post-operative adjuvant setting. In the phase III ALTTO 
trial, a total of 8,331 patients with operable HER2+ BC were randomized to receive either 
lapatinib concurrently with trastuzumab, trastuzumab followed by lapatinib, lapatinib alone, or 
trastuzumab alone. The lapatinib-alone arm was closed early due to demonstrated superiority of 
trastuzumab over lapatinib alone. No significant difference between the lapatinib plus 
trastuzumab and the trastuzumab alone arms was observed in terms of the primary endpoint 
disease free survival (DFS) [24]. 
Given these unexpected results, along with the tolerability data from the NAT studies, the dual 
blockade with trastuzumab and lapatinib is not clinically indicated in the NAT setting. 
Trastuzumab has also been evaluated in combination with pertuzumab in the NAT setting. 
In the phase II NeoSphere trial 417 patients with HER2+ BC were randomized to one of the four 
following treatment arms: 1) trastuzumab + docetaxel; 2) pertuzumab + docetaxel; 
3) trastuzumab and pertuzumab + docetaxel; or 4) trastuzumab and pertuzumab without 
chemotherapy prior to breast surgery. After surgery, all groups received additional chemotherapy 
+ trastuzumab. This study showed that patients who were given the dual blockade of pertuzumab 
and trastuzumab plus docetaxel had a significantly improved pCR (45.8%) compared with those 
given trastuzumab with docetaxel (29%) or pertuzumab with docetaxel (24%). In this study, pCR 
rates in the docetaxel-trastuzumab-pertuzumab arm were higher in patients with HR negative 
(63.2%) compared to HR+ (26%) tumors. This was also observed in the chemo-free dual HER2 
blockade arm (27.3% vs 5.9%) [25]. 
In the phase II TRYPHAENA study, pertuzumab and trastuzumab were combined with different 
chemotherapy regimens. Patients randomized to arms A and B received three cycles of FEC 
followed by three cycles of docetaxel and were randomized to start the combination of 
pertuzumab and trastuzumab with cycle 1 of FEC (Arm A) or with cycle 1 of docetaxel (Arm B). 
Patients randomized in Arm C received six cycles of concurrent docetaxel, carboplatin and 
pertuzumab plus trastuzumab [26]. 
All three treatment regimens were highly active; indeed a pCR was seen in 50.7% (Arm A), 
45.3% (Arm B) and 51.9% (Arm C). Higher pCR rates were observed in patients with HR 
negative disease (79.4%, 65% and 83.8% for arms A, B and C, respectively) than in patients with 
HR+ disease (46.1 %, 48.6% and 50% for Arm A,B and C, respectively). TRYPHAENA was not 
intended to evaluate superiority of any arm, with all three arms being experimental. However this 
study showed that pertuzumab does not increase the rate of cardiac dysfunction observed with 
the combination of trastuzumab plus standard chemotherapy. 
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The results from the NeoSphere trial drove the FDA approval of pertuzumab for neoadjuvant 
treatment of HER2+ BC.  
The combination of trastuzumab and pertuzumab was also tested in the APHINITY trial, a 
randomized, double-blind, placebo controlled study, evaluating adjuvant pertuzumab plus 
trastuzumab plus chemotherapy vs trastuzumab plus placebo plus chemotherapy [27]. The study 
met the primary objective, indeed the addition of pertuzumab to trastuzumab was shown to lower 
the chance of developing recurrent invasive BC by 19% compared to trastuzumab alone. 
However the absolute benefit from adding pertuzumab was lower than 1% against increased 
toxicity and costs. A bigger benefit was observed only in high risk patients with node positive or 
ER-negative disease. 
Since August 2013, a subcutaneous formulation of trastuzumab has been available for patients 
with HER2-positive early and MBC. The subcutaneous formulation is administered as a fixed 
dose of 600 mg over a period of up to 5 minutes. The efficacy of subcutaneous versus intravenous 
trastuzumab as neoadjuvant/adjuvant therapy in patients with HER2-positive BC was evaluated 
in the HannaH study [28, 29]. This phase III, open-label, multinational study compared 
subcutaneous with intravenous administration and found comparable pharmacokinetics, efficacy 
and tolerability for both administration forms of trastuzumab. Furthermore, in the randomized, 
open-label, multinational, crossover study PrefHer, neoadjuvant/adjuvant or adjuvant 
subcutaneous administration of trastuzumab was preferred over intravenous administration by 
patients, mainly because it was time saving and induced less pain and discomfort [30, 31]. 
In the recent Phase III KATHERINE study, 1486 patients with HER2-positive early breast cancer 
who were found to have residual disease in the breast or axilla at surgery after neoadjuvant 
taxane-containing chemotherapy were randomized to receive adjuvant trastuzumab emtansine 
(T-DM1) or trastuzumab for 14 cycles. T-DM1 reduced the risk of recurrence of invasive breast 
cancer or death by 50% compared to adjuvant trastuzumab alone (95% CI, 0.39-0.64, p<0.001), 
with a 3-year invasive disease-free survival rate of 88.3% in the T-DM1 group, versus 77% in 
the trastuzumab group [32]. 
4.6. 
CDK inhibition 
Cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitors are bringing great improvements in the 
management of patients with HR+/HER2neg advanced BC. Three different CDK4/6 inhibitors 
(palbociclib, abemaciclib and ribociclib) are in clinical development in this patient subgroup, 
mostly in combination with endocrine therapy.  
CDK4 and 6 control transition from the G1 to the S phase of the cell cycle by binding to D-type 
cyclins. A primary target of CDK action is the retinoblastoma susceptibility gene product (Rb), 
which mediates G1 arrest through sequestration of transcriptional factors of the E2F family. 
Phosphorylation of Rb (pRb) by active cyclin-CDK complexes leads to release of E2F 
transcription factors and transcription of requisite genes for S-phase entry. CDK4/6 inhibitors, by 
inhibiting Rb phosphorylation, induce a cell cycle arrest in Rb proficient cancer cells [33]. 
CyclinD1-CDK4/6-Rb pathway is critical for the development and maintenance not only of ER+ 
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but also of HER2+ tumors [34] and molecular alterations involving the Rb pathway frequently 
occur both in ER+ and in HER2+ BC [35]. Indeed, preclinical studies demonstrated that ER+ or 
HER2+ cell lines are the most sensitive to inhibition by CDK4/6 inhibitors and that combination 
of CDK4/6 inhibitors and ET or CDK4/6 inhibitors and anti-HER2 agents are synergistic in ER+ 
or HER2+ BC models, respectively [36]. CDK4/6 pathway activation is a well-known 
mechanism of resistance to endocrine therapy [37], indeed CDK4/6 inhibitors have shown 
activity in cellular models of acquired resistance to endocrine therapies [38]. Little is known 
about the role of CDK4/6 pathways in anti-HER2-targeted therapies resistance. However 
palbociclib showed activity in cellular models of acquired resistance to lapatinib indicating that 
activation of the pathway might be implicated in resistance to such agents [39]. These data 
collectively indicate that CDK4/6 is a therapeutic target that functions downstream of both ER 
and HER2 pathways. Therefore tumors co-expressing ER and HER2 might be more sensitive to 
CDK4/6 inhibition.  
Notwithstanding this rationale, to date there is a lack of data on the effect of the addition of 
CDK4/6 inhibitors to the combination of endocrine and HER2-targeted therapies in tumors co-
expressing ER and HER2 and there are only very few clinical trials assessing the combination in 
patients with ER+/HER2+ BC. 
4.7. 
Palbociclib 
Palbociclib has been granted approval both in the U.S. and more recently in Europe for the 
treatment of HR+/HER2neg advanced BC in combination with the hormonal treatments letrozole 
and fulvestrant given the unprecedented results in terms of efficacy of two pivotal clinical trials 
(PALOMA-2 and PALOMA-3) [40, 41]. Palbociclib and other CDK4/6 inhibitors, have also 
shown a good toxicity profile.  
Palbociclib is a selective ATP-competitive, orally-administered inhibitor of CDK4 and CDK6 
and was the first compound of this class to be developed and tested in clinical trials. Palbociclib 
is highly specific for CDK4 (IC50, 0.011 mol/L) and CDK6 (IC50, 0.016 mol/L). It exerts G1 
arrest with consequent anti-proliferative activity in vitro and prevents tumor growth in vivo in an 
array of Rb-positive tumor cells [42, 43]. Palbociclib was first studied in two phase I dose 
escalation trials in patients with advanced solid tumor or non-Hodgkin’s lymphoma with 
histologically proven Rb tumor expression [44, 45]. These studies revealed that hematological 
toxicity in general is common with this agent. Grade 3 or 4 hematological adverse events 
consisted of lymphopenia (36%), neutropenia (24%), leucopenia (21%), thrombocytopenia (9%) 
and anemia seen in a single patient (3%). The most common non-hematological adverse events 
were fatigue, nausea and diarrhea. However, treatment was generally well tolerated and no patient 
discontinued treatment permanently because of treatment-related adverse events [44]. Tumor 
responses were observed in non-seminomatous germ cell testicular tumor, liposarcomas, thyroid 
tumor, melanoma, cholangiosarcoma and angiomyxoma. The recommended phase II dose of 
palbociclib was 125 mg once daily. Palbociclib subsequently moved into Phase II and III clinical 
trials in different tumor types, including BC. 
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Clinical data from several trials confirmed the activity of CDK4/6 inhibitors in patients with HR 
positive BC. Although palbociclib showed modest activity (CBR of 21%) when used as a single-
agent in a phase II trial (NCT01037790) in heavily pre-treated advanced BC patients, partial 
responses and stable disease were observed in patients with ER positive tumors [46].  
Additional clinical data for palbociclib in combination with endocrine therapy in the metastatic 
setting come from the seminal randomized phase II PALOMA-1/TRIO-18 trial where the 
combination of palbociclib plus letrozole was compared to single-agent letrozole in the first line 
treatment setting for post-menopausal patients with ER-positive/HER2 negative MBC. The study 
was composed of two parts: Part 1 enrolled patients with ER+/HER2 negative disease with no 
further biomarker assessment, while Part 2 enrolled patients with tumor harboring Cyclin D1 
gene amplification and/or loss of p16. The primary endpoint was Investigator-assessed PFS. A 
total of 165 patients were randomized in this study (66 patients in Part 1 and 99 patients in Part 
2).  
The final analysis of primary endpoint showed a statistically significant improvement in PFS for 
the combination arm (20.2 months) compared to the letrozole (10.2 months) with hazard ratio 
0.488 (95% CI: 0.319 to 0.748, 1-sided p=0.0004). Significant improvements in PFS were also 
seen in both Part 1 and Part 2 when analyzed separately (hazard ratio=0.299 [95% CI: 0.156, 
0.572]; 1-sided p=0.0001 for Part 1 and hazard ratio =0.508 [95% CI: 0.303, 0.853]; 1-sided 
p=0.0046 for Part 2) [47].  
These results were further confirmed in a larger phase III, double-blind, registration trial with the 
same design, namely the PALOMA-2 trial. In this trial, 666 postmenopausal women with ER-
positive, HER2-negative BC, who had not received prior treatment for advanced disease, were 
randomized in a 2:1 fashion to receive palbociclib plus letrozole or placebo plus letrozole. The 
primary end point was PFS, as assessed by the Investigators. Results showed that the median PFS 
was 24.8 months (95% confidence interval [CI], 22.1 to not estimable) in the palbociclib–
letrozole group, as compared with 14.5 months (95% CI, 12.9 to 17.1) in the placebo–letrozole 
group (hazard ratio, 0.58; 95% CI, 0.46 to 0.72; P<0.001). Subgroup analysis did not reveal any 
subset of patients who received benefit from the combination [41].  
In the setting of endocrine pre-treated MBC, results from the phase III PALOMA-3 trial have 
recently been published [48]. This trial involved patients with ER-positive/HER2-negative MBC 
that had relapsed or progressed during prior ET. Patients were randomized in a 2:1 ratio favoring 
the combination arm, to receive palbociclib and fulvestrant or placebo and fulvestrant. 
Premenopausal or perimenopausal women were eligible and also received the LHRH agonist 
goserelin. Patients who had received one line of prior chemotherapy for the treatment of 
metastatic disease were eligible for this trial. A total of 521 patients were randomized in this 
study, 347 in the palbociclib and fulvestrant arm and 174 in the palbociclib and placebo arm. The 
majority of the patients were post-menopausal (79.3% in both arms) and had received one or 
more prior lines of therapy for metastatic disease (patients who had received no prior treatment 
for metastatic disease represented 24.2% and 25.9% of the trial population in the palbociclib + 
fulvestrant and the placebo + fulvestrant arms, respectively). The study met its primary objective, 
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showing improved median PFS of 9.2 months with palbociclib and fulvestrant and 3.8 months 
with placebo and fulvestrant, corresponding to a hazard ratio 0.42 (95% CI, 0.32 to 0.56, p<0.001) 
[48].  
Overall survival analysis of the phase II PALOMA 1 ([49] Finn R.S. ASCO 2017) showed a 
numerical but not statistically significant superiority of the combination treatment versus the 
single agent arm. However, it must be noted that this study was not powered to detect a significant 
difference in overall survival. PALOMA-3 demonstrated a statistically insignificant 
improvement in median overall survival of 34.9 months for palbociclib plus fulvestrant, versus 
28.0 months for fulvestrant plus placebo (hazard ratio for death, 0.81; 95% CI 0.64-1.03; p=0.09) 
[50]. Overall survival data from the first-line PALOMA-2 study are not yet mature. 
The toxicity profile of palbociclib appears very favorable. In the above-mentioned single agent 
trial [46], side effects were mainly hematological, in line with data from the phase 1 trials. Grade 
3 and 4 toxicities were limited to transient neutropenia (50%) and thrombocytopenia (21%), and 
all other toxicities were grade 1/2. Similarly, in the PALOMA-1 study, the most common adverse 
events in the combination arm were neutropenia, leucopenia, fatigue and anemia [47]. In 
particular, grade 3-4 neutropenia was reported in 54% of the patients in the combination arm 
versus 1% of the patients in the letrozole arm. Of note, no cases of febrile neutropenia or 
neutropenia-related infections were reported and discontinuation rates due to adverse events were 
13% in the combination arm versus 2% in the letrozole arm. This was further confirmed in the 
larger PALOMA -2 trial where the most common grade 3 or 4 adverse events were neutropenia 
(occurring in 66.4% of the patients in the palbociclib– letrozole group vs. 1.4% in the placebo–
letrozole group), leukopenia (24.8% vs. 0%), anemia (5.4% vs. 1.8%), and fatigue (1.8% vs. 
0.5%). Febrile neutropenia was reported in 1.8% of patients in the palbociclib–letrozole group 
and in none of the patients in the placebo–letrozole group. Permanent discontinuation of any trial 
treatment as a result of adverse events occurred in 43 patients (9.7%) in the palbociclib–letrozole 
group and in 13 patients (5.9%) in the placebo–letrozole group [41]. Also in PALOMA-3, similar 
figures were observed in terms of adverse events with toxicities being in line with previous data. 
The rate of discontinuation due to adverse events was 2.6% with palbociclib and 1.7% with 
placebo. Hematological toxicities, especially neutropenia, are the most frequently reported 
adverse events for palbociclib [48]. A recent work investigated the mechanism of palbociclib-
induced bone marrow suppression and compared it to that induced by cytotoxic chemotherapeutic 
agents [51]. The authors demonstrated that, in contrast to chemotherapeutic agents which caused 
DNA damage and apoptotic cell death in human bone marrow mononuclear cells (hBMNCs), 
palbociclib did not induce senescence, with hBMNCs resuming proliferation following 
palbociclib withdrawal. These data, along with clinical data, confirm that the hematological 
toxicity induced by palbociclib is intrinsically different from the one observed with chemotherapy 
and is more clinically manageable, inducing less morbidity and complications. 
Severe, life-threatening, or fatal interstitial lung disease (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 
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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. 
4.8. 
Elderly patients 
Around 40% of BCs occur in women aged 65 and older and 20% in women over 75. Older 
patients have tumors with more favorable biological characteristics when compared with younger 
postmenopausal patients, i.e., a higher degree of ER and PgR expression, less peritumoral 
vascular invasion, less HER2 expression, lower proliferative rates, diploidy, and normal p53 [52]. 
However, some studies suggest that BC in the elderly is not more indolent. In a single-institution 
analysis by Sigh et al. in a subgroup of elderly patients (>70 years of age) with lymph node-
negative disease, BC appeared to be more aggressive, with a greater risk of developing distant 
metastases compared with younger patients [53]. Similarly, in another single-institution analysis 
smaller tumors seemed to be associated with increased axillary lymph node involvement [54]. 
The hypothesis made by the authors was that small BCs in older patients have different behavior 
because of decreased immune defense mechanisms related to aging. Overexpression of HER2 is 
reported in 10-15% of older BC patients [33, 40]. Jenkins et al. recently showed that among 
patients with HR+/HER2+ tumors, BC subtypes vary with age with luminal B tumors ranging 
from 20% in patients aged <60 years to 50% in patients over 60 [55]. 
HER2 directed therapy in combination with chemotherapy is the standard of care for HER2 
overexpressing BC. Elderly patients are generally underrepresented in clinical trials; only 16% 
of patients in the key studies of adjuvant trastuzumab were 60 and above [56, 57]. Subgroup 
analyses have shown that they benefit from anti-HER2 agents as much as the younger population 
[58-60]. However, in elderly populations, there is a concern for increasing toxicity, especially 
cardiotoxicity, when these patients also receive anthracycline-based chemotherapy regimens. In 
a large and recent meta-analysis of randomized and cohort studies including 29,000 women, 
cardiotoxicity increased from 2.3% in individuals <50 years to 3.5% and 4.9% in those 50-59 
years and >60 years of age [61]. In a single-arm study, patients with HER2+ node-negative BC 
received weekly paclitaxel × 12 and trastuzumab. This regimen has not been evaluated in older 
cancer patients specifically but, given its safety profile, is an attractive option [62]. Elderly 
patients are almost unrepresented in neoadjuvant trials. In Geparquinto, for example, only five of 
307 patients in the trastuzumab arm were older than 70 [63]. Due to the limited participation of 
older patients in neoadjuvant trials subgroup analyses by age are not performed. 
Limited data are available on the safety and efficacy of pertuzumab in patients ≥65 years of age. 
NeoSPHERE randomized patients up to the age of 80; no subgroup analysis by age was 
performed in this study in which patients’ median age was 50 [25]. In the Cleopatra trial no 
significant differences in efficacy of pertuzumab were observed between elderly patients aged 65 
to 75 years and adult patients aged <65 years. Diarrhea, fatigue, asthenia, decreased appetite, 
vomiting, and dysgeusia were reported more frequently in patients 65 years of age or older 
compared with younger patients. The safety profile of a Cleopatra-like regimen can be improved 
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by substituting docetaxel with paclitaxel. No febrile neutropenia or symptomatic left ventricular 
systolic dysfunction were reported in a phase II study that evaluated paclitaxel in combination 
with trastuzumab and pertuzumab as first-line treatment for advanced BC (patients median age 
53, range 26-84) [64]. No dose adjustment is necessary when pertuzumab is used in the elderly 
population ≥65 years of age [59].  
Subgroup analyses looking at the efficacy and the safety profile of the combination of CDK 4/6 
inhibitors with ET have been conducted and recently published [65, 66]. Focusing on palbociclib, 
Rugo and colleagues have conducted a pooled analysis of data from elderly patients enrolled in 
randomized phase 2 and 3 trials of palbociclib (PALOMA studies). Overall, among 872 patients 
treated with palbociclib plus ET, 221 patients (25%) were aged ≥65-74 years while 83 (10%) 
were aged ≥75 years. Amongst patients aged ≥65 years, 218 (of whom 56 were 75 years old or 
older) were treated with palbociclib plus letrozole (PL) as first-line therapy, while 86 (of whom 
27 were aged ≥75 years) were treated with palbociclib plus fulvestrant. In patients treated with 
PL, median PFS was significantly improved with the addition of palbociclib to the AI in all age 
groups. No new safety concerns were identified for palbociclib in elderly patients. Hematologic 
toxicities were the most frequently registered AEs during palbociclib treatment across all age 
groups. Most events were of grade 1 or 2 severity, with the exception of neutropenia and 
leukopenia: neutropenia was reported in 81% of patients treated with palbociclib vs 5% of 
patients in control group, with similar incidence among patients aged 65-74 years (77% vs 1%) 
and higher incidence in the ≥75 years-old subgroup (90% vs 3%). Febrile neutropenia was 
reported in 11 patients receiving palbociclib, including 2 (1%) aged 65-74 years and 2 (1%) aged 
≥75 years. Treatment discontinuation due to AE occurred in 77 (9%) in the palbociclib group vs 
22 (5%) in the control group. Among patients aged ≥65-74 years, 28 (13%) in the palbociclib 
group and 8 (6%) in the control group discontinued because of AEs, compared with 16 patients 
(19%) and 4 (13%) aged ≥75 years. The most common AE leading to permanent discontinuation 
across all age groups was neutropenia. The authors presented also pharmacokinetics data 
indicating that no dose adjustment of palbociclib based solely on age is required in elderly 
patients.  
Elderly patients are under-represented in clinical trials and as such, inclusion of older women and 
the prospective utilization of geriatric assessment instruments in those 65 years will produce 
valuable safety and efficacy data within this subpopulation. 
4.9. 
Biomarkers for CDK4/6 inhibitor activity 
Currently, there is a lack of biomarkers to identify patients more likely to achieve a response to 
CDK4/6 inhibitors. Efforts have been made towards the identification of single biomarkers in the 
CyclinD1/CDK4-6/RB1 pathway itself or in other co-activating pathways such as the PI3K 
pathway, but have proven unsuccessful so far. This suggests that single biomarkers may not 
capture the complex biology of resistance to CDK4/6 inhibitors and that a more thorough 
evaluation of the pathway activity may be necessary. 
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Genetic loss of RB1 is a marker of primary resistance to CDK4/6 inhibitors but it is uncommon 
in HR+ or HER2+ subtypes. Recent studies have shown that functional loss of the 
CyclinD1/CDK4-6/Rb pathway can be measured by gene-expression studies [67]. Several gene-
signatures of RB-loss have been developed which have shown to be prognostic in BC subtypes 
as well as predictive of response to neoadjuvant chemotherapy [68, 69]. 
A recently developed gene signature of functional loss of Rb (RBsig) that is prognostic in luminal 
BC subtypes can predict response to the CDK4/6 inhibitor palbociclib in cell line models of BC 
[70]. In particular, cell lines with increased levels of RBsig (RBsig HIGH) are among the most 
resistant to palbociclib treatment. 
Additionally, preliminary data suggest that the RBsig might be also predictive of response to 
chemotherapy + trastuzumab in ER+/HER2+ BC patients. Indeed, we performed a retrospective 
in-silico study using publicly available datasets of gene-expression data (10 studies) obtained 
from a total of 514 HER2+ BC patients treated with neo-adjuvant chemotherapy +/- anti-HER2 
therapy. For these patients, we computed the RBsig and correlated the RBsig expression with 
clinical outcome. The pCR rate to neoadjuvant CT + anti-HER2 for patients with RBsig LOW 
expression was significantly lower than the pCR rate for patients with RBsig HIGH expression. 
Results were similar for patients receiving neoadjuvant CT alone. Of note, the relationship 
between RBsig and pCR was observed only in HER2+/ER+, and not in HER2+/ER− tumors, 
suggesting that, as expected, RBsig seems to be relevant only in tumors with a luminal phenotype. 
These data suggest that RBsig identifies a subset of HR+/HER2+ patients (RBsig LOW) who 
derive little benefit from chemotherapy. 
Further validation of RBsig has been shown within the phase III NeoALTTO study, a neoadjuvant 
trial involving women with HER2+ primary breast cancer, which originally showed that 
pathological complete response (pCR) rates were significantly improved in patients receiving 
paclitaxel plus dual HER2 blockade in the form of trastuzumab and lapatinib compared with 
paclitaxel given with either of the two anti-HER2 agents alone[21]. RNA sequencing data from 
pre-treatment biopsies derived from NeoALTTO were collected, with RBsig status subsequently 
correlated with pCR. Overall, the pCR rate was significantly higher in patients with RBsig HIGH 
tumours than those with RBsig LOW (35% versus 18% respectively; p=0.01). In the subset of 
patients with HR+/HER2+ disease, a remarkably low pCR rate was observed in those with RBsig 
LOW status (11%), versus those with RBsig HIGH status (28%) [71]. 
Taken together, our data suggest that, among patients with ER+/HER2+ BC, those with RBsig 
HIGH derive benefit from chemotherapy and might be resistant to CDK4/6 inhibitors. On the 
other end, patients with RBsig LOW who derive little benefit from chemotherapy may benefit 
from CDK4/6 inhibitors. 
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4.10. Trial hypothesis 
Based on this rationale, we hypothesize that the CDK4/6 inhibitor palbociclib in combination 
with the anti-HER2 trastuzumab and the ET letrozole may be active as neoadjuvant therapy in 
patients with ER+/HER2+ BC, especially in the subset of RBsig LOW patients. 
We also hypothesize that patients with RBsig HIGH ER+/HER2+ BC might be particularly 
sensitive to neoadjuvant chemotherapy with paclitaxel and trastuzumab. 
4.11. Overall risk-benefit assessment 
Patients with operable HR+/HER2+ BC represent a population for whom standard treatment 
options include either surgery, most of the time followed by adjuvant chemotherapy + anti-HER2 
agents, or NAT. In patients considered fit for chemotherapy, the latter would consist of 
chemotherapy plus anti-HER2 agents in most cases, as per current recommendations. 
We hypothesize that chemotherapy could be safely avoided in this population by using a 
combination of ET, trastuzumab plus pertuzumab and palbociclib. This regimen would be 
substantially less toxic compared to standard chemotherapy. 
The setting of the NAT is particularly suitable to test our hypothesis because it supports easy 
monitoring of the effects of therapy therefore minimizing the risk of offering a sub-optimal 
treatment in the experimental arm. Also, tissue biopsies for the evaluation of the RBsig from each 
patient may be acquired as part of routine clinical practice, therefore limiting the need for invasive 
procedures to obtain tissue samples. 
The available data provide scientific rationale for the combination of palbociclib, letrozole and 
trastuzumab plus pertuzumab in this patient population. 
4.12. Rationale for the trial design 
This is an open label, international, phase II neoadjuvant trial with the primary objective to 
explore the interaction between the RBsig status (HIGH or LOW, as determined centrally on the 
mandatory pre-treatment biopsy collected as FFPE specimen) and treatment activity, assessed by 
pathological complete response (pCR), of palbociclib + letrozole versus paclitaxel when 
administered in combination with trastuzumab plus pertuzumab for ER+/HER2+ primary BC. 
The neo-adjuvant setting was chosen to evaluate these therapy combinations in a short time-frame 
and to provide access to biomaterial both at baseline and after the end of the treatment, at surgery. 
Palbociclib is a potent, highly selective, reversible, orally active, inhibitor of CDK 4/6. This 
compound prevents progression of the cell cycle from G1 into the S phase, therefore inhibiting 
cell growth. CDK4/6 is a key downstream effector of both the ER and HER2 pathways, 
representing a major driver of the proliferation and growth of HR+/HER2+ BC cells. In 
preclinical experiments, palbociclib synergizes with anti-estrogens and also with trastuzumab to 
cause tumor regression in ER + and HER2+ BC cell lines.  
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Clinical data from the HR+/HER2 negative setting show that combinations of palbociclib and 
letrozole are safe and effective. These combinations have not yet been tested in the HR+/HER2+ 
population that we include in this trial. However, combinations of trastuzumab and ET, including 
letrozole have shown to be safe and to have some additional activity compared to ET alone in the 
HR+/HER2+ population. Therefore, the role of palbociclib in addition to letrozole and 
trastuzumab plus pertuzumab needs to be further studied. Of note the combination of 
trastuzumab, pertuzumab, palbociclib and fulvestrant has been recently evaluated in the context 
of a neoadjuvant trial. The four drug regimen was well tolerated and led to a 30% pCR in breast 
and 27% in breast and axilla and to a 97% clinical response rate. The authors concluded that 
overall the data support further evaluation of the approach of multi-signaling block including 
CDK4/6 inhibition in HER2+ and ER+ BC [72]. 
Current standard of care for treatment of HER2+ BC incorporates chemotherapy and anti-HER2 
agents, with chemotherapy regimens of sequential anthracyclines and taxanes, used as single 
agents or in combination with other chemotherapy drugs. Trastuzumab is often administered 
concurrently with a single agent taxane to avoid the possible additive cardiac toxicity of 
combinations of anthracycline containing regimens and trastuzumab. Additional chemotherapy, 
depending on the schedule used pre-operatively, can be administered following surgery. 
Combinations of chemotherapy and anti-HER2 therapy may result in excessive toxicity in 
patients with ER+ and HER2+ disease, and a non-chemotherapy-based treatment may provide a 
less toxic treatment without compromising efficacy. However, endocrine therapy alone may not 
be a sufficient partner for anti-HER2 agents. 
A regimen of weekly paclitaxel and trastuzumab plus pertuzumab was chosen as the comparator 
arm in this trial. This was based on a twofold rationale: i) the particular features of patients 
included (patients with ER+ and HER2+ BC of limited stage), representing a population where 
more aggressive chemotherapy may not be justified, and ii) considering that patients participating 
in the trial may receive additional treatment after surgery, at the discretion of the Investigator. As 
outlined in the background section, previous trials in this setting have used different schedules of 
paclitaxel and trastuzumab, and there is no currently defined standard schedule. Duration of the 
preoperative trastuzumab + paclitaxel treatment varies among clinical trials, ranging from 12 
(neoALTTO) to 16 weeks (CALGB40601) of continuous treatment.  
Preclinical and clinical rationale exists to support the proposal that palbociclib may represent a 
valuable option for increasing the activity of ET and anti-HER2 agents, such that a triple 
combination with these agents could prove superior to a standard treatment with chemotherapy 
and anti-HER2 agents. 
Additionally, further data suggest that the substantial heterogeneity in response observed within 
the HR+/HER2+ population may be in part resolved by classifying these tumors by means of the 
RBsig status. This marker may represent a tool to identify the patients who are more likely to 
benefit from a chemotherapy-free regimen in this population 
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The optimal duration of endocrine + anti-HER2 therapy in the pre-operative setting has not been 
finally determined, with studies suggesting that extending the duration of the combination 
treatment from 12 to 24 weeks led to improved outcomes (TBCR-023). We hypothesize that the 
combination of palbociclib, letrozole and trastuzumab plus pertuzumab proposed in this trial will 
be more efficacious compared to the combinations of anti-HER2 agents and ET reported in other 
trials. Therefore, we set the duration of treatment in the experimental arm to 16 weeks, consisting 
of 4 cycles of palbociclib. 
The choice of administering paclitaxel in 12 weekly doses over a 16 week period (day 1,8,15 
every 28 days) was chosen to match the minimum number of weekly paclitaxel administrations 
with the total duration of 16 weeks of treatment in the experimental arm. It also matches the 
paclitaxel + trastuzumab schedule used in the NSABP B-41 trial. 
Around 40% of BCs occur in women aged 65 and older. Of these, 10-15% have tumors that 
overexpress HER2 [33, 40]. Jenkins et al. recently showed that among patients with HR+/HER2+ 
tumors, BC subtypes vary with age with luminal B tumors ranging from 20% in patients aged 
<60 years to 50% in patients over 60 [55]. Elderly patients are generally underrepresented in 
clinical trials; subgroup analyses have shown that they benefit from anti-HER2 agents as much 
as the younger population [58, 59, 73]. Overall a higher incidence of adverse events has been 
observed in the elderly mainly related to the chemotherapy backbone of the treatment [59]. For 
this trial, we have therefore chosen 4 cycles of weekly paclitaxel with a 3 out of 4 weeks schedule 
[74]. Palbociclib can be safely and effectively administered to older patients without need for 
dose adjustment based solely on age [66]. Treatment de-escalation, namely harnessing and taking 
maximum advantage of targeted therapies vs conventional treatment (chemotherapy) in order to 
limit side effects, is particularly appealing in the older population. Active enrollment of older 
women and prospective utilization of geriatric assessment instruments in all participating women 
aged 65 will provide much-needed safety and efficacy data in this under-represented population. 
5. 
Trial objectives and endpoints 
5.1. 
Primary objective 
The primary objective is to explore the interaction between the RBsig status (HIGH or LOW, as 
determined centrally on the mandatory pre-treatment biopsy collected as an FFPE specimen) and 
treatment activity, assessed by pathological complete response (pCR), of palbociclib + letrozole 
versus paclitaxel when given with trastuzumab plus pertuzumab for ER+/HER2+ primary BC. 
The pre-treatment biopsy will be analyzed at the end of the trial by gene-expression profiling to 
assess RBsig status. 
5.2. 
Primary endpoint 
Pathological complete response pCR, defined as absence of invasive tumor cells in the breast and 
in the axillary lymph nodes at the time of surgery (ypT0/ypTis ypN0). 
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5.3. 
Secondary objectives 
To evaluate: 
 pCR in breast only (ypT0/ypTis) 
 Objective response prior to surgery, defined as partial or complete response assessed 
physically and by ultrasound and mammography 
 Tolerability, as defined by adverse events according to CTCAE version 5 
 Rate of breast-conserving surgery 
5.4. 
Correlative objectives 
Evaluations may be done to identify: 
 molecular characteristics of responding tumors by immunohistochemistry (IHC), 
fluorescence in situ hybridization (FISH), gene expression 
 factors at baseline and prior to surgery predictive of response to randomized treatments 
 Ki67 proliferation marker changes between baseline and residual invasive tumor at 
surgery 
 For subgroup of women aged 65 years, features in geriatric assessments which correlate 
with (lack of) tolerability of trial treatment 
6. 
Trial design, duration and termination 
6.1. 
Trial design 
This is an international, multi-center, randomized phase II trial that will randomize 
postmenopausal women with histologically confirmed ER+, HER2+ primary breast cancer to 
receive the combination of palbociclib plus letrozole plus trastuzumab plus pertuzumab or 
paclitaxel plus trastuzumab plus pertuzumab during a treatment period of 16 weeks prior to 
surgery. Patients will be randomized in a ratio of 1:1. 
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6.2. 
Trial schema 
 
6.3. 
Treatment 
Patients will be randomized in a 1:1 fashion to: 
Arm A: Paclitaxel 80 mg/m2 i.v. on day 1, 8, 15 every 28 days for 4 cycles 
Trastuzumab 600 mg s.c. every 3 weeks for a total of 5 doses 
Pertuzumab 840 mg i.v. loading dose followed by 420 mg i.v. every 3 weeks for a total 
of 5 doses 
 
Arm B: Palbociclib 125 mg/day orally for 21 days followed by 7 days’ rest, for four 28-day 
cycles 
 
Letrozole 2.5 mg/day orally for 16 weeks 
Trastuzumab 600 mg s.c. every 3 weeks for a total of 5 doses 
Pertuzumab 840 mg i.v. loading dose followed by 420 mg i.v. every 3 weeks for a total 
of 5 doses 
Definitive surgery should be performed not later than 4 weeks after the final dose of any of the 
drugs in the combinations described above. 
6.4. 
Clinical evaluations 
Tumor assessments will be performed by ultrasound and mammography at screening (prior to 
start of protocol therapy), and before surgery. Tumor measurements by caliper will be assessed 
at the same time points and after 2 cycles (8 weeks) of therapy. All patients who are discontinued 
from the protocol therapy for any reason will be documented within 30 days after surgery. If a 
patient does not undergo surgery, the end of treatment visit should take place within 30 days after 
her last dose of trial treatment.  
Early BC, 
ER+, HER2+,
postmenopausal,
Neo-adj. 
treatment 
planned
R
A:
paclitaxel
trastuzumab
pertuzumab
B:
palbociclib
letrozole
trastuzumab
pertuzumab
surgery
surgery
Week   
1     2     3     4     5     6     7     8     9    10    11   12   13   14   15   16  
+
+
staging
FFPE sample
FFPE sample
Pertuzumab: 
loading dose
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6.5. 
Biological evaluations 
An FFPE tumor specimen of the pre-treatment biopsy must be submitted for all patients. At 
surgery, one FFPE tumor specimen for central review and translational research has to be 
retained, unless no residual invasive tumor is found at surgery. Both specimens will be submitted 
to the IBCSG Central Pathology Office in Milan, Italy, and will be analyzed by gene-expression 
profiling to assess RBsig status. The laboratory analyzing RBsig will be defined and carefully 
selected closer to the time of the analysis, based on their scientific track record. 
Gene-expression profiling will also be utilized to explore potential biomarkers of response or 
resistance to treatment.  
Additionally, studies on proteins and genes involved in the ER and RB1 pathway will be 
conducted using immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) on 
both pre-treatment and surgical samples. 
6.6. 
Sample size and trial duration 
A total of 144 patients will be randomized by approximately 30 sites in Belgium, Italy, France 
and Switzerland. 
The enrollment is expected to occur over a period of 24 months after a start-up period of 6 months 
as the trial is being activated by participating Centers. Individual patient’s trial participation ends 
with the End of Treatment visit to be done within 30 days after surgery. The final trial analysis is 
expected 41 months after the randomization of the first patient. 
7. 
Patient selection 
7.1. 
Inclusion criteria  
7.1.1. 
Histologically confirmed invasive breast cancer, with the following characteristics: 
- Early breast cancer with tumor size >1 cm (as measured by at least one of the required 
examination methods of clinical examination, mammography and ultrasonography) 
- No clinical evidence of regional lymph node metastasis (via physical and/or 
radiological exam) (cN0) OR  
- Clinical evidence of cN1 status, defined by nodal involvement limited to clinically or 
radiologically detectable metastasis to movable ipsilateral level I, II axillary lymph 
node(s) 
- No evidence of metastasis (M0) 
7.1.2. 
Postmenopausal, defined by women with: 
- Prior bilateral surgical oophorectomy; OR 
- Amenorrhea and age 60 years; OR 
- Age <60 years and amenorrhea for 12 or more consecutive months in the absence of 
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alternative pathological or physiological cause (including chemotherapy, tamoxifen, 
toremifene, ovarian suppression, or hormonally-based contraception) plus FSH and 
serum estradiol levels within the laboratory’s reference ranges for postmenopausal 
women 
7.1.3. 
Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 (see Table 1) 
7.1.4. 
Primary tumor must have positive estrogen receptor (ER) ≥10%  
7.1.5. 
Primary tumor must be HER2-positive (by IHC and/or ISH) 
7.1.6. 
Baseline LVEF ≥55% measured by Echocardiography (preferred) or MUGA scan 
7.1.7. 
Normal hematologic status: 
- Absolute neutrophil count ≥1500/mm3 (1.5 × 109/L) 
- Platelets ≥100 × 109/L 
- Hemoglobin ≥9 g/dL (≥90 g/L). 
7.1.8. 
Normal renal function: serum creatinine ≤1.5 upper limit of normal (ULN). 
7.1.9. 
Normal liver function: 
- Serum total bilirubin ≤1.5 × ULN. In the case of known Gilbert’s syndrome, a higher 
serum total bilirubin (<2 × ULN) is allowed 
- AST or ALT ≤2.5 × ULN 
- Alkaline phosphatase ≤2.5 × ULN 
7.1.10. Written Informed Consent (IC) must be signed and dated by the patient and the 
Investigator prior to randomization. 
7.1.11. The patient has been informed of and agrees to data transfer and handling, in accordance 
with national data protection guidelines. 
7.1.12. The patient agrees in writing to make tumor samples (mandatory diagnostic core biopsy 
and surgical specimen) available for submission for central pathology review and to 
conduct translational studies as part of this protocol. 
NOTE: Central Pathology Review on the primary tumor is mandatory for this trial, but 
patients will be evaluated for eligibility according to tumor characteristics as determined 
by the local pathologist. Both the diagnostic breast core biopsy specimen and the 
final breast surgical specimen (unless no residual invasive tumor is found at surgery) 
must be submitted for Central Pathology Review which will be done by the IBCSG 
Central Pathology Office in Milan, Italy. 
7.2. 
Exclusion criteria 
7.2.1. 
Tumor of any size with direct extension to the chest wall and/or to the skin (ulceration 
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or skin nodules) (T4 according to AJCC 8th edition cancer staging TNM) 
7.2.2. 
Inflammatory breast cancer 
7.2.3. 
Bilateral invasive breast cancer 
7.2.4. 
Received any prior treatment for primary invasive breast cancer 
7.2.5. 
Any active tumor of non-breast-cancer histology 
7.2.6. 
Any of the following in the previous 6 months: myocardial infarction, severe/unstable 
angina pectoris, ongoing cardiac dysrhythmias of NCI CTCAE grade ≥2, atrial 
fibrillation of any grade, coronary/peripheral artery bypass graft, symptomatic 
congestive heart failure (NYHA functional classification ≥II, see Table 2 below), 
cerebrovascular accident including transient ischemic attack, or symptomatic pulmonary 
embolism. 
7.2.7. 
Concurrent disease or condition that would make the subject inappropriate for study 
participation or any serious medical disorder that would interfere with the subject’s 
safety. 
7.2.8. 
Contraindications or known hypersensitivity to any of the trial medications or 
excipients. 
7.2.9. 
Treatment with any investigational agents within 30 days prior to expected start of trial 
treatment. 
7.2.10. Any GI disorder that may affect absorption of oral medications, such as malabsorption 
syndrome or status post major bowel resection. 
7.2.11. Evidence via physical and/or radiological exam of cN2 or cN3 nodal involvement 
defined by: metastasis to ipsilateral level I, II axillary lymph nodes that are clinically 
fixed or matted, OR involvement of ipsilateral infraclavicular, internal mammary and/or 
supraclavicular lymph node(s) 
7.2.12. History of extensive disseminated/bilateral or known presence of interstitial fibrosis or 
interstitial lung disease, including a history of pneumonitis, hypersensitivity 
pneumonitis, interstitial pneumonia, obliterative bronchiolitis, and pulmonary fibrosis. 
A history of prior radiation pneumonitis is not considered an exclusion criterion. 
 
 
Table 1. 
ECOG Performance Status 
PS 0 
Fully active, able to carry on all pre-disease performance without restriction. 
PS 1 
Restricted in physically strenuous activity but ambulatory and able to carry out work 
of a light or sedentary nature, e.g., light housework, office work. 
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PS 2 
Ambulatory and capable of all self-care but unable to carry out any work activities. 
Up and about more than 50% of waking hours. 
PS 3 
Capable of only limited self-care, confined to bed or chair more than 50% of waking 
hours. 
PS 4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair. 
 
Table 2. 
NYHA functional classification 
Class 
Functional Capacity: How a patient with cardiac disease feels during physical 
activity. 
I 
Patients with cardiac disease but resulting in no limitation of physical activity. 
Ordinary physical activity does not cause undue fatigue, palpitation, dyspnea or 
anginal pain. 
II 
Patients with cardiac disease resulting in slight limitation of physical activity. 
They are comfortable at rest. Ordinary physical activity results in fatigue, 
palpitation, dyspnea or anginal pain. 
III 
Patients with cardiac disease resulting in marked limitation of physical activity. 
They are comfortable at rest. Less than ordinary activity causes fatigue, 
palpitation, dyspnea or anginal pain. 
IV 
Patients with cardiac disease resulting in inability to carry on any physical 
activity without discomfort. Symptoms of heart failure or the anginal syndrome 
may be present even at rest. If any physical activity is undertaken, discomfort 
increases. 
8. 
Randomization and stratification 
This trial will use a web-based randomization system. Specific details for randomization are in 
the “IBCSG Registration/Randomization Procedures Manual” which is available on the IBCSG 
website (www.ibcsg.org). 
8.1. 
Randomization  
8.1.1. 
Patient needs to give informed consent to trial participation, screening procedures and 
biomaterial submission. 
8.1.2. 
Verify eligibility (see Section 7). Screening procedures need to be done within 28 days 
(hematology within 14 days) before randomization. 
8.1.3. 
For subgroup of women aged 65 years: Complete the Geriatric Assessment G8 
questionnaire (Form 55-G8) and calculate the total score needed for the stratification. 
8.1.4. 
Access the IBCSG Registration/Randomization System (Registration: Step 1) and 
provide the requested information as indicated on the Confirmation of Randomization 
(55-A) Form. The date the Informed Consent Form was signed by the patient and the 
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date signed by the Investigator are both required to complete randomization. 
The IBCSG Registration/Randomization System will provide the Patient ID 
(randomization number) and treatment assignment via email. 
8.1.5. 
Submit the Confirmation of Randomization (55-A) electronic case report form (eCRF) 
via DFexplore. 
8.2. 
Randomization Help Desk 
The IBCSG Data Management Center (located at Frontier Science and Technology Research 
Foundation (FSTRF)) is responsible for developing and maintaining the IBCSG 
Registration/Randomization System. The Help Desk includes technical personnel and 
administrators of the registration programs at the Data Management Center in Amherst, NY, 
USA. 
The Help Desk is available round the clock 7 days per week, except for New Year's Eve, 
Memorial Day, Independence Day, Thanksgiving Day, Christmas Day. 
FSTRF Randomization Help Desk 
Frontier Science & Technology Research Foundation (FSTRF) 
4033 Maple Rd, Amherst, NY 14226 USA 
Phone: +1 716 834 0900 Extension 7301 
Fax: +1 716 832-8437 
Email: bc.helpdesk@frontierscience.org  
8.3. 
Stratification 
For randomization, patients will be stratified by 
 Age and G8 score (<65 years vs ≥65y and G8 score >14 vs ≥65y and G8 score ≤14), 
see 14.1.14 
 No 
clinical 
evidence 
of 
regional 
lymph 
nodes 
metastasis 
(cN0) 
vs  
nodal involvement limited to clinically detectable metastasis to movable ipsilateral 
level I, II axillary lymph node(s) (cN1) 
Dynamic institution balancing will be used in order to balance randomized assignments within 
institutions. 
9. 
Trial drugs formulation and handling 
Palbociclib is the Investigational Medicinal Product (IMP) used in this trial; IMP will be supplied. 
Trastuzumab and pertuzumab are Non-Investigational Medicinal Products (NIMPs) and used as 
background treatment in both arms. Both will be supplied. 
Letrozole and paclitaxel are part of standard neoadjuvant treatment and will be sourced locally. 
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Complete details of the trial drug logistics, distribution, packaging, labeling, storage and handling 
as well as accountability are described in a separate Drug Supply Manual. This document is 
available for reference by the pharmacist and trial personnel. 
9.1. 
Palbociclib 
9.1.1. 
Formulation 
Refer to the current version of the palbociclib SPC (Summary of Product Characteristics) for 
pharmaceutical formulation information. 
9.1.2. 
Packaging and labeling 
IMP will be affixed with a clinical label in accordance with regulatory requirements. 
9.1.3. 
Storage and handling 
Supplies must be stored at 15°C to 30°C in a secure, limited-access location under the storage 
conditions specified on the label. The Investigator shall take responsibility for and shall take all 
steps to maintain appropriate records and ensure appropriate supply, storage, handling, 
distribution and usage of investigational product in accordance with the protocol and any 
applicable laws and regulations.  
9.2. 
Trastuzumab  
Trastuzumab is used in accordance with the currently approved SPC (Summary of Product 
Characteristics), and with the applicable EU legislation and current guidelines.  
9.2.1. 
Packaging and labeling 
Supplies will be packaged and labeled in accordance with regulatory requirements. 
9.2.2. 
Storage and handling 
Supplies must be stored at 2°C to 8°C in a secure, limited-access location under the storage 
conditions specified on the label. 
9.3. 
Pertuzumab 
Pertuzumab is used in accordance with the currently approved SPC (Summary of Product 
Characteristics), and with the applicable EU legislation and current guidelines. Supplies will be 
packaged and labelled in accordance with regulatory requirements. 
9.3.1. 
Packaging and labeling 
Supplies will be packaged and labelled in accordance with regulatory requirements. 
9.3.2. 
Storage and handling 
Supplies must be stored at 2°C to 8°C in a secure, limited-access location under the storage 
conditions specified on the label. 
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9.4. 
Paclitaxel 
Paclitaxel is used in accordance with the currently approved SPC (Summary of Product 
Characteristics), and with the applicable EU legislation and current guidelines. 
9.5. 
Letrozole 
Letrozole is used in accordance with the currently approved SPC (Summary of Product 
Characteristics), and with the applicable EU legislation. 
10. 
Treatment 
10.1. Trial treatments 
Trial treatment should start within one week after randomization. Trial treatments will be 
administered in four 28-day cycles, or until protocol treatment is discontinued (see Section 10.8).  
Treatment administration should comply with the protocol; compliance will be monitored by the 
Monitoring Team and Data Management Center. Complete details of dispensation and dosing are 
recorded on the eCRF.  
10.2. Treatment Administration 
10.2.1. Palbociclib administration 
Palbociclib will be administered orally at a dose of 125 mg per day continuously dosed for 
21 days followed by 7 days rest; repeated at each subsequent cycle. The duration of a cycle of 
treatment is 28 days. A deviation of 1-3 days from this schedule is permitted. On treatment day 
1, patients will be provided with trial treatment for self-administration at home. Sufficient 
capsules should be provided to cover administration until next scheduled visit. The patients will 
be instructed to take the trial treatment exactly as prescribed, promoting compliance. 
Palbociclib intake should be documented by the patient on the patient diary which will be 
dispensed for each cycle. 
Patients should be instructed to take the palbociclib with food. Concomitant intake of proton 
pump inhibitors does not significantly affect the overall exposure to palbociclib when taken with 
food. Patients should be instructed to swallow palbociclib capsules whole and not to chew them 
prior to swallowing. No capsule should be ingested if it is broken, cracked, or otherwise not intact. 
Patients should be encouraged to take their dose at approximately the same time each day. 
Patients should be instructed to record daily administration of the trial drug in the patient diary, 
and to bring the diary to the clinic at each visit. The Investigator should keep a copy in the patient 
file. 
10.2.2. Trastuzumab administration 
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Trastuzumab will be administered at a dose of 600 mg, irrespectively of the patient body weight 
for a total of 5 doses. Trastuzumab will be administered by s.c. injection according to local 
guidelines.  
10.2.3. Pertuzumab administration 
Pertuzumab will be administered at a loading dose of 840 mg on day 1 of cycle 1, and then every 
3 weeks at a dose of 420 mg for a total of 5 doses. Pertuzumab will be administered over 30-60 
minutes (60 minutes for 840 mg/kg loading dose) by i.v. infusion according to local guidelines.  
10.2.4. Paclitaxel administration 
Paclitaxel will be administered at a dose of 80 mg/m2 on days 1, 8, and 15 of every cycle. The 
administration is by i.v. infusion according to local guidelines.  
10.2.5. Letrozole administration 
Letrozole will be taken as one tablet of 2.5 mg/day orally continuously during four cycles of 28 
days each for a total of 16 weeks. On day 1 of each cycle, one bottle of letrozole tablets will be 
dispensed to the patient. 
Letrozole intake should be documented by the patient on the patient diary which will be dispensed 
for each cycle. 
10.3. Dose delays and modifications for palbociclib 
In the event of significant treatment-related toxicity, palbociclib dosing may be interrupted or 
delayed and/or reduced as described below. In the event of multiple toxicities, dose modification 
should be based on the worst toxicity observed. Patients are to be instructed to notify Investigators 
at the first occurrence of any adverse sign or symptom. 
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. 
Permanently discontinue palbociclib in patients with severe ILD or pneumonitis. 
10.3.1. Dose delays 
Patients experiencing the following adverse events should have their treatment of palbociclib 
interrupted/delayed until criteria for retreatment (see below) are met:  
 Grade 3 or 4 neutropenia (ANC<1000/mm3) associated with a documented infection 
or fever 38.5C; 
 Grade 3 or 4 thrombocytopenia (Platelet count <50,000/mm3); 
 Non-hematologic toxicity persisting despite optimal medical treatment if either grade 
2 lasting more than 3 weeks, or grade 3 (including nausea, vomiting, diarrhea, and 
hypertension). Patients should not hold or discontinue palbociclib for non-
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hematological side effects potentially or likely related to concomitant antihormonal 
therapy (e.g., grade 3 or long lasting grade 2 joint pain) as per the Investigator’s 
judgment; 
 In case of concurrent >3×ULN ALT and 2×ULN total bilirubin, the dose needs to be 
held while the cause is being investigated. 
Appropriate follow up assessments should be done until adequate recovery occurs as assessed by 
the Investigator. Criteria required before treatment can resume are described in the Retreatment 
Criteria Section (see below). 
Doses may be held as needed until toxicity resolution. Depending on when the adverse event 
resolved, a treatment interruption may lead to the patient missing all subsequent planned doses 
within that same cycle or delayed initiation of the subsequent cycle.  
If the adverse event that led to the treatment interruption recovers within the same cycle, then 
resuming treatment in that cycle is allowed. Doses omitted for toxicity are not replaced within 
the same cycle. The need for a dose reduction at the time of treatment resumption should be based 
on the criteria defined in the Section 10.3.2, unless expressly agreed otherwise following 
discussion 
between 
the 
Investigator 
and 
IBCSG 
(please 
contact 
ibcsg55_touch@frontierscience.org). If a dose reduction is applied in the same cycle, the patient 
will need to return to the clinic to receive new drug supply. 
In the event of a treatment interruption due to toxicity and for reasons other than treatment-related 
toxicity (e.g., non-cancer related surgery) lasting >3 weeks, treatment resumption will be decided 
in consultation with IBCSG (please contact ibcsg55_touch@frontierscience.org). 
In the event of palbociclib 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 total delay is >4 
weeks, palbociclib should be stopped and treatment should continue with the other drugs. 
Retreatment Criteria 
Retreatment with palbociclib following treatment interruption for treatment related toxicity or at 
the start of any new cycle may not occur until all of the following parameters have been met: 
 Platelet count 50’000/mm3;  
 ANC 1000/mm3 and no fever; 
 Grade 3 or higher treatment-related non-hematologic AEs considered related to 
palbociclib (including, nausea, vomiting, diarrhea, and hypertension only if persisting 
despite optimal medical treatment), have recovered to grade ≤1 or baseline. 
If a treatment delay results from decline in hematologic parameters, the frequency of blood count 
assessments should be adjusted as clinically indicated. 
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