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

Sponsor

ETOP IBCSG Partners Foundation (Other)

Overall Status

Recruiting

CT.gov ID

NCT03644186

Collaborator

Pfizer (Industry), Hoffmann-La Roche (Industry)

144

Enrollment

Locations

Arms

39.5

Anticipated Duration (Months)

2.6

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Breast Cancer Estrogen Receptor Positive Tumor HER2-positive Breast Cancer	Drug: Paclitaxel Drug: Trastuzumab Drug: Pertuzumab Drug: Palbociclib Drug: Letrozole Drug: Trastuzumab Drug: Pertuzumab	Phase 2

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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

144 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

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

Actual Study Start Date :

Apr 16, 2019

Anticipated Primary Completion Date :

Apr 1, 2022

Anticipated Study Completion Date :

Aug 1, 2022

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Paclitaxel plus trastuzumab and pertuzumab 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.	Drug: Paclitaxel Chemotherapy plus HER2 Blockade Other Names: Paclitaxel Sandoz Drug: Trastuzumab Chemotherapy plus HER2 Blockade Other Names: Herceptin Drug: Pertuzumab Chemotherapy plus HER2 Blockade Other Names: Perjeta
Experimental: Palbociclib plus letrozole plus trastuzumab and pertuzumab 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.	Drug: Palbociclib CDK Inhibition plus Hormonal Therapy plus HER2 Blockade Other Names: Ibrance Drug: Letrozole CDK Inhibition plus Hormonal Therapy plus HER2 Blockade Other Names: Femara Drug: Trastuzumab CDK Inhibition plus Hormonal Therapy plus HER2 Blockade Other Names: Herceptin Drug: Pertuzumab CDK Inhibition plus Hormonal Therapy plus HER2 Blockade Other Names: Perjeta

Arm

Intervention/Treatment

Active Comparator: Paclitaxel plus trastuzumab and pertuzumab

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.

Drug: Paclitaxel

Chemotherapy plus HER2 Blockade

Other Names:

Paclitaxel Sandoz

Drug: Trastuzumab

Chemotherapy plus HER2 Blockade

Other Names:

Herceptin

Drug: Pertuzumab

Chemotherapy plus HER2 Blockade

Other Names:

Perjeta

Experimental: Palbociclib plus letrozole plus trastuzumab and pertuzumab

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.

Drug: Palbociclib

CDK Inhibition plus Hormonal Therapy plus HER2 Blockade

Other Names:

Ibrance

Drug: Letrozole

CDK Inhibition plus Hormonal Therapy plus HER2 Blockade

Other Names:

Femara

Drug: Trastuzumab

CDK Inhibition plus Hormonal Therapy plus HER2 Blockade

Other Names:

Herceptin

Drug: Pertuzumab

CDK Inhibition plus Hormonal Therapy plus HER2 Blockade

Other Names:

Perjeta

Outcome Measures

Primary Outcome Measures

Pathological complete response (pCR) [Assessed within 30 days of the time of breast surgery after completion of a treatment period of up to 16 weeks. If the patient does not undergo surgery, assessment will occur within 30 days after all treatment is stopped.]
Defined as absence of invasive tumour cells in the breast and in the axillary lymph nodes at the time of surgery (ypT0/ypTis ypN0) determined from the local histopathologic evaluation according to the American Joint Committee on Cancer Staging Manual. The presence of in situ cancer after trial treatment in the absence of residual invasive disease constitutes a pCR.

Secondary Outcome Measures

Pathological complete response (pCR) in the breast [Assessed at the time of breast surgery within 30 days of completion of a treatment period of up to 16 weeks. All patients who are discontinued from treatment for any reason will be documented within 30 days after surgery.]
Defined as the absence of invasive tumour cells in the breast at the time of surgery (ypT0/ypTis) determined from the local histopathologic evaluation according to the American Joint Committee on Cancer Staging Manual..
Objective response [Tumour assessments will be performed by ultrasound and mammography at screening (prior to start of treatment), and before surgery. Tumour measurements by caliper will be assessed at the same time points and at the end of cycle 2 (each cycle is 28 days).]
Defined as the number of patients with partial or complete response measured physically by caliper and by ultrasound and mammography. Response will be assessed using World Health Organisation tumour measurement and response criteria.
Frequency of reported adverse events [From the time informed consent is signed, during treatment and until 30 days after surgery. If there is no surgery, adverse events will be collected until 30 days after treatment stops.]
Defined by frequency of all grades for targeted adverse events, all grade 3 for non-targeted events and grade ≥2 for non-targeted events requiring medical attention according to CTCAE version 5. For each adverse event, the frequency of patients by worst grade of the adverse event will be summarized and tabulated by treatment.
Rate of breast conserving surgery (BCS) [Assessed at 35 months after randomization of the first patient.]
Defined as the number of patients undergoing BCS, divided by the number of patients in the assessable population (subset of the randomized population with RBsig status successfully determined who received at least 1 dose of medication).

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

Female

Accepts Healthy Volunteers:

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 or radiologically detectable metastasis to movable ipsilateral level I, II axillary lymph node(s)
No evidence of metastasis (M0).

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

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
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.

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. A history of prior radiation pneumonitis is not considered an exclusion criterion.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	AZ Klina, Augustijinslei 100	Brasschaat		Belgium	2930
2	Jules Bordet Institute	Brussels		Belgium	1000
3	CHR de la Citadelle, Boulevard du XIIe de Ligne, 1	Liège		Belgium	4000
4	Clinique Saint- Joseph, Rue de Hesbaye 75	Liège		Belgium	4000
5	Clinique Saint Elizabeth, Place Louise Godin 15	Namur		Belgium	5000
6	AZ Nikolaas, Moerlandstrat 1	Sint-Niklaas		Belgium	9100
7	Institut Sainte Catherine	Avignon		France
8	Institut Bergonié	Bordeaux		France
9	Centre Hospitalier Le Mans	Le Mans		France
10	Centre Léon Berard	Lyon		France
11	ICM Val d'Aurelle	Montpellier		France
12	Institut de Cancérologie de l'Ouest (ICO)	Nantes		France
13	Centre Antoine Lacassagne	Nice		France
14	Groupe Hospitalier Diaconesses Croix Saint Simon	Paris		France
15	Institut Curie - Site de Paris	Paris		France
16	Centre Hospitalier Annecy Genevois	Pringy		France
17	Centre Eugène Marquis	Rennes		France
18	Centre Henri Becquerel	Rouen		France
19	Institut Curie - Site Saint Cloud	Saint-Cloud		France	92210
20	Clinique Pasteur	Toulouse		France
21	Institut Claudius Regaud	Toulouse		France
22	Clinica Oncologica-Ospedali Riuniti Ancona, Via Conca n.71,	Torrette	Ancona	Italy	60020
23	Istituto scientifico Romagnolo per lo studio e la cura,Via Piero Maroncelli 40	Meldola	Forli	Italy	47014
24	U.O Medicina Oncologica Ospedale di Carpi, Via G. Molinari, 2	Carpi	Modena	Italy	41012
25	Oncologia Medica Fano Italy,V.le Vittorio Veneto 2	Fano	Pesaro	Italy	31032
26	Centro di Riferimento Oncologico (CRO), Via Franco Gallini 2	Aviano	Pordenone	Italy	33081
27	ASO "SS Antonio e Biagio Cesare Arrigo, Via Venezia 16	Alessandria		Italy	15121
28	Ospedali Riuniti di Bergamo, A.O.Papa Giovanni XXIII, Piazza OMS1	Bergamo		Italy	24127
29	Ospedale S. Orsola-Malpighi, Viale Ercolani 4/2	Bologna		Italy	40138
30	Comprensorio Sanitario Bolzano, Via Lorenz Bohler, 5	Bolzano		Italy	39100
31	ASST Spedali Civili Brescia, Piazzale Spedali Civili n.1	Brescia		Italy	25123
32	E.O. Ospedali Galliera, Mura delle Cappuccine, 14	Genova		Italy	16128
33	Ospedale Policlinico San Martino,Largo Rosanna Benzi,10	Genova		Italy	16132
34	Ospedale Civile di Lecco,Via della Filanda 14	Lecco		Italy	23900
35	Milano, IEO, Via Ripamonti 435	Milano		Italy	20141
36	Università del Piemonte Orientale - SCDU Oncologia, Corso Mazzini 18	Novara		Italy	28100
37	Azienda Ospedaliero-Universitaria di Parma, via Gramsci 14	Parma		Italy	43126
38	Istituti Clinici Scientifici Maugeri SpA-SB,Via Salvatore Maugeri N° 10	Pavia		Italy	27100
39	A.O. Universitaria Pisana Ospedale Santa Chiara Pisa, Via Roma 67	Pisa		Italy	56125
40	Hospital of Prato, Via Dolce dei Mazzamuti, 7	Prato		Italy	59100
41	Santa Maria delle Croci Hospital, Viale Randi 5	Ravenna		Italy	48121
42	UO Oncologia, Rimini Hospital, Via Settembrini 2	Rimini		Italy	47037
43	Azienda Ospedaliero-Universitaria di Udine, Piazzale S.M. Misericordia 15	Udine		Italy	33100
44	AO Universitaria Ospedale Di Circolo e Fondazione,v.le L. Borri, 57	Varese		Italy	21100
45	Kantonsspital Baden AG	Baden	Aarau	Switzerland	5400
46	Universitatsspital Basel, Petersgraben 4	Basel	Basel-Stadt	Switzerland	4031
47	Brustzentrum Thurgau / Kantonsspital Frauenfeld, Pfaffenholzstrasse 4	Frauenfeld	Thurgau	Switzerland	8501
48	Oncology Institute of Southern Switzerland (IOSI), Ospedale San Giovanni, IOSI	Bellinzona	Ticino	Switzerland	6500
49	University Hospital Zurich, Frauenklinikstrasse 10	Zürich	Zurich	Switzerland	8091
50	Kantonsspital Winterthur	Winterthur	Zürich	Switzerland	8401
51	Inselspital Bern	Bern		Switzerland
52	HFR Freiburg - Kantonsspital	Freiburg		Switzerland	1708
53	University Hospital Geneva	Geneva		Switzerland
54	Kantonsspital St. Gallen, Rorschacher Strasse 95	Saint Gallen		Switzerland	9007
55	Brust-Zentrum AG, Seefeldstrasse 214	Zurich		Switzerland	8008