To Reduce the Use of Chemotherapy in Postmenopausal Patients With ER-positive and HER2-positive Breast Cancer (TOUCH)
To Reduce the Use of Chemotherapy in Postmenopausal Patients With ER-positive and HER2-positive Breast Cancer (TOUCH)
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.
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.
Inclusion Criteria:

 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).

 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
 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

 3. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1

 4. Primary tumor must have positive estrogen receptor (ER) ≥10%

 5. Primary tumor must be HER2-positive (by IHC and/or ISH)

 6. Baseline LVEF ≥55% measured by Echocardiography (preferred) or MUGA scan

 7. Normal hematologic status:

 -  Absolute neutrophil count ≥1500/mm3 (1.5 × 109/L);

 -  Platelets ≥100 × 109/L;

 -  Hemoglobin ≥9 g/dL (≥90 g/L).

 8. Normal renal function: serum creatinine ≤1.5 ULN

 9. 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.

 10. Written Informed Consent (IC) must be signed and dated by the patient and the
 Investigator prior to randomization.

 11. The patient has been informed of and agrees to data transfer and handling, in
 accordance with national data protection guidelines.

 12. 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.

 Exclusion Criteria:

 1. 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)

 2. Inflammatory breast cancer

 3. Bilateral invasive breast cancer

 4. Received any prior treatment for primary invasive breast cancer

 5. Any active tumor of non-breast-cancer histology

 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), cerebrovascular
 accident including transient ischemic attack, or symptomatic pulmonary embolism.

 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

 8. Contraindications or known hypersensitivity to any of the trial medications or
 excipients

 9. Treatment with any investigational agents within 30 days prior to expected start of
 trial treatment

 10. Any GI disorder that may affect absorption of oral medications, such as malabsorption
 syndrome or status post major bowel resection

 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)

 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.