Clinical trial NCT03644186: To Reduce the Use of Chemotherapy in Postmenopausal Patients With ER-positive and HER2-positive Breast Cancer (TOUCH)
Official title: Phase II Open-label, Multicentre, Randomized Trial of Neoadjuvant Palbociclib in Combination With Hormonal Therapy and HER2 Blockade Versus Paclitaxel in Combination With HER2 Blockade for Postmenopausal Patients With Hormone Receptor Positive/HER2 Positive Early Breast Cancer
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Breast Cancer
Estrogen Receptor Positive Tumor
HER2-positive Breast Cancer
Keywords: hormone receptor positive early breast cancer
HER2 receptor positive early breast cancer
Lead sponsor: ETOP IBCSG Partners Foundation
Sponsor class: NETWORK
Collaborators: name: Pfizer
name: Hoffmann-La Roche
First posted: 2018-08-23
Enrollment: 147
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Pathological Complete Response (pCR)
timeFrame: Assessed within 30 days of the time of breast surgery after completion of a treatment period of up to 16 weeks; up to 21 weeks. If the patient does not undergo surgery, assessment will occur within 30 days after all treatment is stopped; up to 30 weeks.
Secondary outcomes:
measure: Pathological Complete Response (pCR) in the Breast
timeFrame: Assessed within 30 days of the time of breast surgery after completion of a treatment period of up to 16 weeks; up to 21 weeks. If the patient does not undergo surgery, assessment will occur within 30 days after all treatment is stopped; up to 30 weeks.
measure: Objective Response
timeFrame: Tumor assessments were performed by ultrasound and mammography at screening (prior to treatment start), and before surgery; measurements by caliper were assessed at the same time points and at the end of cycle 2 (28 days/cycle), approximately 56 days.
measure: Rate of Breast Conserving Surgery (BCS)
timeFrame: From randomization until completion of study, up to 20 months
Other outcomes:
Locations:
city: Brasschaat
country: Belgium
facility: AZ Klina, Augustijinslei 100
city: Brussels
country: Belgium
facility: Jules Bordet Institute
city: Liège
country: Belgium
facility: CHR de la Citadelle, Boulevard du XIIe de Ligne, 1
city: Liège
country: Belgium
facility: Clinique Saint- Joseph, Rue de Hesbaye 75
city: Namur
country: Belgium
facility: Clinique Saint Elizabeth, Place Louise Godin 15
city: Sint-Niklaas
country: Belgium
facility: AZ Nikolaas, Moerlandstrat 1
city: Avignon
country: France
facility: Institut Sainte Catherine
city: Bordeaux
country: France
facility: Institut Bergonié
city: Le Mans
country: France
facility: Centre Hospitalier Le Mans
city: Lyon
country: France
facility: Centre Léon Berard
city: Montpellier
country: France
facility: ICM Val d'Aurelle
city: Nantes
country: France
facility: Institut de Cancérologie de l'Ouest (ICO)
city: Nice
country: France
facility: Centre Antoine Lacassagne
city: Paris
country: France
facility: Groupe Hospitalier Diaconesses Croix Saint Simon
city: Paris
country: France
facility: Institut Curie - Site de Paris
city: Pringy
country: France
facility: Centre Hospitalier Annecy Genevois
city: Rennes
country: France
facility: Centre Eugène Marquis
city: Rouen
country: France
facility: Centre Henri Becquerel
city: Saint-Cloud
country: France
facility: Institut Curie - Site Saint Cloud
city: Toulouse
country: France
facility: Clinique Pasteur
city: Toulouse
country: France
facility: Institut Claudius Regaud
city: Torrette
country: Italy
facility: Clinica Oncologica-Ospedali Riuniti Ancona, Via Conca n.71,
state: Ancona
city: Meldola
country: Italy
facility: Istituto scientifico Romagnolo per lo studio e la cura,Via Piero Maroncelli 40
state: Forli
city: Carpi
country: Italy
facility: U.O Medicina Oncologica Ospedale di Carpi, Via G. Molinari, 2
state: Modena
city: Aviano
country: Italy
facility: Centro di Riferimento Oncologico (CRO), Via Franco Gallini 2
state: Pordenone
city: Alessandria
country: Italy
facility: ASO "SS Antonio e Biagio Cesare Arrigo, Via Venezia 16
city: Bergamo
country: Italy
facility: Ospedali Riuniti di Bergamo, A.O.Papa Giovanni XXIII, Piazza OMS1
city: Bologna
country: Italy
facility: Ospedale S. Orsola-Malpighi, Viale Ercolani 4/2
city: Bolzano
country: Italy
facility: Comprensorio Sanitario Bolzano, Via Lorenz Bohler, 5
city: Brescia
country: Italy
facility: ASST Spedali Civili Brescia, Piazzale Spedali Civili n.1
city: Genova
country: Italy
facility: E.O. Ospedali Galliera, Mura delle Cappuccine, 14
city: Genova
country: Italy
facility: Ospedale Policlinico San Martino,Largo Rosanna Benzi,10
city: Lecco
country: Italy
facility: Ospedale Civile di Lecco,Via della Filanda 14
city: Milano
country: Italy
facility: Milano, IEO, Via Ripamonti 435
city: Novara
country: Italy
facility: Università del Piemonte Orientale - SCDU Oncologia, Corso Mazzini 18
city: Parma
country: Italy
facility: Azienda Ospedaliero-Universitaria di Parma, via Gramsci 14
city: Pavia
country: Italy
facility: Istituti Clinici Scientifici Maugeri SpA-SB,Via Salvatore Maugeri N° 10
city: Pisa
country: Italy
facility: A.O. Universitaria Pisana Ospedale Santa Chiara Pisa, Via Roma 67
city: Prato
country: Italy
facility: Hospital of Prato, Via Dolce dei Mazzamuti, 7
city: Ravenna
country: Italy
facility: Santa Maria delle Croci Hospital, Viale Randi 5
city: Rimini
country: Italy
facility: UO Oncologia, Rimini Hospital, Via Settembrini 2
city: Udine
country: Italy
facility: Azienda Ospedaliero-Universitaria di Udine, Piazzale S.M. Misericordia 15
city: Varese
country: Italy
facility: AO Universitaria Ospedale Di Circolo e Fondazione,v.le L. Borri, 57
city: Baden
country: Switzerland
facility: Kantonsspital Baden AG
state: Aarau
city: Basel
country: Switzerland
facility: Universitatsspital Basel, Petersgraben 4
state: Basel-Stadt
city: Frauenfeld
country: Switzerland
facility: Brustzentrum Thurgau / Kantonsspital Frauenfeld, Pfaffenholzstrasse 4
state: Thurgau
city: Bellinzona
country: Switzerland
facility: Oncology Institute of Southern Switzerland (IOSI), Ospedale San Giovanni, IOSI
state: Ticino
city: Zürich
country: Switzerland
facility: University Hospital Zurich, Frauenklinikstrasse 10
state: Zurich
city: Winterthur
country: Switzerland
facility: Kantonsspital Winterthur
state: Zürich
city: Bern
country: Switzerland
facility: Inselspital Bern
city: Freiburg
country: Switzerland
facility: HFR Freiburg - Kantonsspital
city: Geneva
country: Switzerland
facility: University Hospital Geneva
city: Saint Gallen
country: Switzerland
facility: Kantonsspital St. Gallen, Rorschacher Strasse 95
city: Zurich
country: Switzerland
facility: Brust-Zentrum AG, Seefeldstrasse 214
Study officials:
affiliation: USL4 Hospital of Prato, Italy
name: Laura Biganzoli, MD
role: STUDY_CHAIR
affiliation: Institut Curie, Paris, France
name: Etienne Brain, MD
role: STUDY_CHAIR
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