Chemotherapy-free Trastuzumab and Pertuzumab in HER2-positive Breast Cancer: FDG-PET Response-adapted Strategy.

Study Overview
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Brief Summary
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The study assess the early metabolic effects of neoadjuvant treatment with trastuzumab and pertuzumab (± endocrine therapy) on the primary tumor and axillary lymph nodes and their predictive value for pathologic complete response (pCR) in the breast and axilla. And also assess 3-year invasive disease-free survival (iDFS) in patients with HER2-positive (HER: human epidermal receptor) breast cancer treated with neoadjuvant trastuzumab and pertuzumab (± endocrine therapy) using a FDG-PET response-adapted strategy.

Detailed Description
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Investigational Medicinal Products (IMPs) will be trastuzumab and pertuzumab, carboplatin, and docetaxel, as well as all endocrine therapy drugs to be administered according to HR status (hormone receptor). For cohort C, trastuzumab SC (subcutaneous) and pertuzumab IV will be IMPs until a maximum of 18 cycles. Patients will be randomly assigned in a 1:4 ratio, with a randomization stratified by HR status to receive trastuzumab and pertuzumab with docetaxel and carboplatin (cohort A) or trastuzumab and pertuzumab ± endocrine therapy according to HR status (cohort B). A F-FDG PET/CT will be performed at baseline (total body) and after 2 cycles of neoadjuvant therapy. Central review of F-FDG PET/CT will be mandatory. Patients allocated into cohort A will continue with the same treatment for a total of six cycles regardless of 18F-FDG PET/CT results. Patients enrolled into cohort B showing at least 40% reduction of the SUVmax of F-FDG PET/CT respect to baseline (PET responders) will continue with the same treatment for a total of 8 cycles. PET-non responders patients will also receive neoadjuvant chemotherapy based on six cycles of docetaxel and carboplatin concurrently with trastuzumab and pertuzumab for all cycles. Following surgery, cohort B/PET responders patients who do not achieve a pCR will additionally receive six cycles of docetaxel and carboplatin concurrently with trastuzumab and pertuzumab for all cycles. Moreover, all patients from cohorts A/B must complete 18 cycles of trastuzumab and pertuzumab, along with adjuvant endocrine therapy and radiotherapy according to HR status (hormone receptor) and institutional practices, respectively. An additional exploratory cohort (cohort C) will include patients with evidence of subclinic M1 at baseline 18F-FDG PET/CT, but not previously detected by routine clinical assessment. These patients will receive trastuzumab and pertuzumab with docetaxel and carboplatin for a total of six cycles. After first six cycles, these patients will receive trastuzumab and pertuzumab ± endocrine.therapy according to HR status for at least 12 additional cycles after surgery (only if surgery is performed). According to institutional practices, it will be allowed to continue treatment with trastuzumab and pertuzumab, along endocrine therapy on the basis of HR status, as maintenance therapy until disease progression or unacceptable toxicity. A sub-set of 42 patients (35 patients from cohort A and 7 patients from cohort B) from 5 sites in Spain are participating in the LINGain sub-study Prospective evaluation of predictive/prognostic immunogenicity biomarkers for target therapy in HER2-positive early breast cancer within the PHERGain study : Hospital General de Valencia, Hospital Clínico Universitario de Valencia, IVO, Hospital La Fe and Hospital Arnau de Vilanova.

Official Title
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Chemotherapy-free Trastuzumab and Pertuzumab in HER2-positive (Human Epidermal Receptor) Breast Cancer: FDG-PET Response-adapted Strategy. The PHERGain Study

Conditions
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Breast Cancer

Intervention / Treatment
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* Drug: Perjeta
* Drug: Herceptin
* Drug: Docetaxel
* Drug: Carboplatin
* Drug: Letrozole
* Drug: Tamoxifen


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Written informed consent prior to beginning specific protocol procedures. Female or male patients ≥ 18 years of age. Eastern Cooperative Oncology Group (ECOG) performance status of 0-1. Histologically proven invasive breast cancer. Operable breast cancer (cT1-3 and/or cN0-2 tumors) (breast cancer TNM classification) Tumor size larger than or equal to 1.5 centimeter (cm) in diameter by magnetic resonance imaging (MRI) or ultrasound with a significant 18F-FDG uptake defined as maximum standarized uptake value (SUVmax: maximum standarized uptake value) ≥1.5 x SUVmean (mean standarized uptake value) liver + 2 SD (standard deviation. Multicentric/multifocal tumors will be allowed only if: Histological confirmation of at least two lesions. All tumors must be HER2-positive. Largest lesion must be larger than or equal to 1.5 cm in diameter by MRI or ultrasound. 7)Centrally confirmed HER2-positive disease according to the 2018 American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) criteria. 8)Patient must have known estrogen receptor (ER) and progesterone receptor (PR) status locally determined prior to study entry. Patient has adequate bone marrow, liver, and renal function: 9)Hematological: White blood cell (WBC) count > 3.0 x 109/L, absolute neutrophil count (ANC) ≥ 1.5 x 109/L, platelet count ≥ 100.0 x109/L, and hemoglobin ≥ 10.0 g/dL (≥ 6.2 mmol/L). 10)Hepatic: total bilirubin ≤ institutional upper limit of normal (ULN) (except for Gilbert's syndrome); alkaline phosphatase (ALP) ≤ 2.5 times ULN; aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 1.5 times ULN. 11)Renal: serum creatinine ≤ 1.5 x ULN or creatinine clearance ≥ 50 mL/min/1.73 m2 for patients with creatinine levels above institutional normal. 12)Patient must be accessible for treatment and follow-up. Exclusion Criteria: Previous treatment with chemotherapy, anti-HER2 therapy, radiation therapy, or endocrine therapy for invasive breast cancer. cT4 and/or cN3 tumors (TNM breast cancer classification) Bilateral breast cancer. Evidence of metastatic disease by routine clinical assessment chest x-ray, liver ultrasound, and bone scan; or computed tomography (CT) scan of thorax and abdomen and bone scan, except patients with subclinic M1 (metastases) at baseline only according to 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) that will be allowed to be included into cohort C. Known hypersensitivity reaction to any investigational or therapeutic compound or their incorporated substances. History of other malignancy within the last five years prior to first dose of study drug administration, except for curatively treated basal and squamous cell carcinoma of the skin and/or in situ cervical carcinoma. Left ventricular ejection fraction (LVEF) below 55% as determined by multiple-gated acquisition (MUGA) scan or echocardiography (ECHO). Uncontrolled hypertension (systolic > 150 mm Hg and/or diastolic > 100 mm Hg) despite adequate antihypertensive treatment. Clinically significant cardiovascular disease [stroke, unstable angina pectoris, or documented myocardial infarction within six months prior to study entry; history of documented congestive heart failure (CHF) (New York Heart Association II-III-IV); symptomatic pericarditis; documented cardiomyopathy; ventricular arrythmias with the exception of benign premature ventricular contractions; conduction abnormality requiring a pacemaker; other arrhythmias not controlled with medication]. Active uncontrolled infection at the time of enrollment. Current known infection with HIV, hepatitis B virus, or hepatitis C virus. Patients with pulmonary disease requiring continuous oxygen therapy. Previous history of bleeding diathesis. Patient is currently receiving anti-coagulant therapy, chronic treatment with corticosteroids, or another immunosuppressive agent (standard premedication for chemotherapy and local applications are allowed). Major surgical procedure or significant traumatic injury within 14 days prior to randomization or anticipation of need for major surgery within the course of the study treatment. Patient has other concurrent severe and/or uncontrolled medical conditions that would, in the investigator´s judgment, contraindicate her participation in the clinical study. Concurrent participation in other clinical trial, except other translational studies. History of receiving any investigational treatment within 28 days prior to randomization. Pregnant or breast-feeding women or patients not willing to apply highly effective contraception as defined in the protocol. LINGain sub-study: The LINGAIN project intends to include a total of 126 blood samples from PHERGain trial, as follows: 105 from patients treated with trastuzumab and pertuzumab ± endocrine therapy (according to HR status); 21 from patients treated with trastuzumab and pertuzumab + carboplatin and docetaxel.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: This randomized, open-label phase II study will assess the efficacy of the combination of trastuzumab and pertuzumab, ± endocrine therapy according to HR (hormone receptor) status, as exclusive neoadjuvant and adjuvant treatment in patients with HER2-positive breast cancer through a FDG-PET response-adapted strategy.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort A<br>Cohorts A/B if there is no evidence of subclinic M1 assessed by 18F-FDG PET/CT at screening. Interventional: Perjeta+Herceptin+Carboplatin+Docetaxel (during 4 cycles): PET responders or not responders after surgery: Continue with Perjeta+Herceptin+ Endocrine therapy (tamoxifen or letrozole) during 12 cycles A sub-set of 42 patients (35 patients from cohort A and 7 patients from cohort B) from 5 sites in Spain are participating in the LINGain sub-study Prospective evaluation of predictive/prognostic immunogenicity biomarkers for target therapy in HER2-positive early breast cancer within the PHERGain study. | Drug: Perjeta<br>* All patients will receive Perjeta® as an IV infusion on Day 1 of the first treatment cycle as a loading dose of 840 mg, followed by 420 mg on Day 1 of each subsequent 3-week cycle. Perjeta® IV should be administered 60 minutes after the end of Herceptin® SC (subcutaneous) administration. An observation period of 30-60 minutes is recommended after each Perjeta® infusion.<br>* Other names: Pertuzumab;Drug: Herceptin<br>* All patients will receive a fixed dose of 600 mg, irrespective of the patient's weight, will be administered throughout the treatment phase. All doses of Herceptin® SC will be administered as an SC injection into the thigh by a trained health care professional over a period of 2-5 minutes. No loading dose is required with Herceptin® SC.<br>* Other names: Trastuzumab;Drug: Docetaxel<br>* Docetaxel will be administered in line with the respective product information and/or recognized clinical practice guidelines. It will be administered after Herceptin® SC, Perjeta® IV, and carboplatin<br>Drug: Carboplatin<br>* Carboplatin will be administered in line with the respective product information and/or recognized clinical practice guidelines. It will be administered after Herceptin® SC and Perjeta® IV.<br>Drug: Letrozole<br>* Postmenopausal women will receive letrozole 2.5 mg tablet orally once daily beginning on Day 1 and continuing through Day 21 of a 21-day cycle as neoadjuvant therapy.<br>Drug: Tamoxifen<br>* Premenopausal women will receive tamoxifen 20 mg tablet orally once daily beginning on Day 1 and continuing through Day 21 of a 21-day cycle as neoadjuvant therapy. Male patients will receive tamoxifen 20 mg tablet orally once daily beginning on Day 1 and continuing through Day 21 of a 21-day cycle as neoadjuvant therapy.<br>|
| Experimental: Cohort B<br>Cohorts A/B if there is no evidence of subclinic M1 assessed by 18F-FDG PET/CT at screening. Interventional: Perjeta+Herceptin+Endocrine therapy (tamoxifen or letrozole) during 2 cycles. PET responders: Perjeta+Herceptin+Endocrine therapy during 6 cycles. -Complete response: continue with Perjeta+Herceptin+ Endocrine therapy during 10 cycles -Non-complete response: Perjeta+Herceptin+ Carboplatin+ Docetaxel during 6 cycles and Perjeta+Herceptin+Endocrine therapy during 4 cycles. PET non-responders: Perjeta+Herceptin+Carboplatin+Docetaxel during 6 cycles. Patients with or without complete response will continue with Perjeta+Herceptin+Endocrine therapy during 10 cycles. A sub-set of 42 patients (35 patients from cohort A and 7 patients from cohort B) from 5 sites in Spain are participating in the LINGain sub-study Prospective evaluation of predictive/prognostic immunogenicity biomarkers for target therapy in HER2-positive early breast cancer within the PHERGain study. | Drug: Perjeta<br>* All patients will receive Perjeta® as an IV infusion on Day 1 of the first treatment cycle as a loading dose of 840 mg, followed by 420 mg on Day 1 of each subsequent 3-week cycle. Perjeta® IV should be administered 60 minutes after the end of Herceptin® SC (subcutaneous) administration. An observation period of 30-60 minutes is recommended after each Perjeta® infusion.<br>* Other names: Pertuzumab;Drug: Herceptin<br>* All patients will receive a fixed dose of 600 mg, irrespective of the patient's weight, will be administered throughout the treatment phase. All doses of Herceptin® SC will be administered as an SC injection into the thigh by a trained health care professional over a period of 2-5 minutes. No loading dose is required with Herceptin® SC.<br>* Other names: Trastuzumab;Drug: Docetaxel<br>* Docetaxel will be administered in line with the respective product information and/or recognized clinical practice guidelines. It will be administered after Herceptin® SC, Perjeta® IV, and carboplatin<br>Drug: Carboplatin<br>* Carboplatin will be administered in line with the respective product information and/or recognized clinical practice guidelines. It will be administered after Herceptin® SC and Perjeta® IV.<br>Drug: Letrozole<br>* Postmenopausal women will receive letrozole 2.5 mg tablet orally once daily beginning on Day 1 and continuing through Day 21 of a 21-day cycle as neoadjuvant therapy.<br>Drug: Tamoxifen<br>* Premenopausal women will receive tamoxifen 20 mg tablet orally once daily beginning on Day 1 and continuing through Day 21 of a 21-day cycle as neoadjuvant therapy. Male patients will receive tamoxifen 20 mg tablet orally once daily beginning on Day 1 and continuing through Day 21 of a 21-day cycle as neoadjuvant therapy.<br>|
| Experimental: Cohort C<br>cohorts C if there is evidence of subclinic M1 assessed by 18F-FDG PET/CT at screening Interventional: Perjeta+Herceptin+Carboplatin+Docetaxel during 6 cycles. Patients will continue with Perjeta+Herceptin+Endocrine therapy (tamoxifen or letrozole) after surgery or no surgery. | Drug: Perjeta<br>* All patients will receive Perjeta® as an IV infusion on Day 1 of the first treatment cycle as a loading dose of 840 mg, followed by 420 mg on Day 1 of each subsequent 3-week cycle. Perjeta® IV should be administered 60 minutes after the end of Herceptin® SC (subcutaneous) administration. An observation period of 30-60 minutes is recommended after each Perjeta® infusion.<br>* Other names: Pertuzumab;Drug: Herceptin<br>* All patients will receive a fixed dose of 600 mg, irrespective of the patient's weight, will be administered throughout the treatment phase. All doses of Herceptin® SC will be administered as an SC injection into the thigh by a trained health care professional over a period of 2-5 minutes. No loading dose is required with Herceptin® SC.<br>* Other names: Trastuzumab;Drug: Docetaxel<br>* Docetaxel will be administered in line with the respective product information and/or recognized clinical practice guidelines. It will be administered after Herceptin® SC, Perjeta® IV, and carboplatin<br>Drug: Carboplatin<br>* Carboplatin will be administered in line with the respective product information and/or recognized clinical practice guidelines. It will be administered after Herceptin® SC and Perjeta® IV.<br>Drug: Letrozole<br>* Postmenopausal women will receive letrozole 2.5 mg tablet orally once daily beginning on Day 1 and continuing through Day 21 of a 21-day cycle as neoadjuvant therapy.<br>Drug: Tamoxifen<br>* Premenopausal women will receive tamoxifen 20 mg tablet orally once daily beginning on Day 1 and continuing through Day 21 of a 21-day cycle as neoadjuvant therapy. Male patients will receive tamoxifen 20 mg tablet orally once daily beginning on Day 1 and continuing through Day 21 of a 21-day cycle as neoadjuvant therapy.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evaluate the rate of pCR | evaluate the rate of pCR as defined by the absence of invasive disease in the breast and axilla (ypT0/isN0) at the time of surgery achieved with the combination of trastuzumab and pertuzumab (± endocrine therapy) as exclusive neoadjuvant treatment in PET responders patients (cohort B/PET responders) [PET/CT positive predictive value (PPV) for a pCR among patients who are PET responders]. | After Cycle 6 or 8 (each cycle 21 days- After 4.2 or 5.6 months) | 
| 3-year iDFS rate | time from the first date of no disease (i.e., date of surgery) to invasive recurrence, new invasive disease, or death by any cause. Recurrence will be defined in accordance with the standardized efficacy endpoints (STEEP) criteria. The primary analysis will be to estimate 3-year iDFS rate in cohort B. | After 3 years (36 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| pCR rates in the breast and axilla (ypTO/isN0) | pCR rates in the breast and axilla (ypT0/isN0) (cohort A; cohort B; cohort B/PET non-responders). | After Cycle 6 or 8 (each cycle 21 days- After 4.2 or 5.6 months) | 
| pCR rates in the breast (ypT0/is) | pCR rates in the breast (ypT0/is) (cohort A; cohort B; cohort B/PET responders; cohort B/PET non-responders). | After Cycle 6 or 8 (each cycle 21 days- After 4.2 or 5.6 months) | 
| RCB score (residual cancer burden) | RCB score (cohort A; cohort B; cohort B/PET responders; cohort B/PET non-responders | After Cycle 6 or 8 (each cycle 21 days- After 4.2 or 5.6 months) | 
| pCR rates in the breast and axilla | pCR rates in the breast and axilla (ypT0/isN0) according to HR status and tumor stage (cohort A; cohort B; cohort B/PET responders; cohort B/PET non-responders). | After Cycle 6 or 8 (each cycle 21 days- After 4.2 or 5.6 months) | 
| Rate of breast conserving surgery | Rate of breast conserving surgery (cohort A; cohort B; cohort B/PET responders; cohort B/PET non-responders). | After Cycle 6 or 8 (each cycle 21 days- After 4.2 or 5.6 months) | 
| 18F-FDG PET/CT response rate (18F-FDG: 18F-fluorodeoxyglucose) | 18F-FDG PET/CT response rate (according to the adapted EORTC criteria) (cohort A; cohort B). | After cycle 2 (each cycle 21 days- After 42 days approximately) | 
| Optimal 18F-FDG PET/CT cut-off for pCR | Optimal 18F-FDG PET/CT cut-off for pCR (cohort A; cohort B). | After cycle 2 (each cycle 21 days-After 42 days approximately) | 
| Other 18FDG PET quantification parameters | Other 18F-FDG PET quantification parameters beside SUVmax for pCR (cohort A; cohort B). We will consider alternative measures to SUVmax in order to improve the ability to predict pCR; The best predictive parameter will be selected by means of logistic regressions models. For all tests, we will use two sided p-values with alpha ≤ 0.05 level of significance. The p-values emerging from these analyses will not be interpreted in a confirmative sense; they will be considered of descriptive nature only. | After cycle 2 (each cycle 21 days- After 42 days approximately) | 
| MRI response rate | MRI response rate [according to the Response Criteria in Solid Tumors (RECIST) criteria version 1.1] (cohort A; cohort B; cohort B/PET responders; cohort B/PET non-responders). | After two cycles of neoadjuvant therapy, and prior to surgery (each cycle 21 days) | 
| Health-related quality of life | Health-related quality of life (EORTC QLQ-C30- quality of life questionnaire and EORTC QLQ-BR23 quality of life questionnaires) (cohort A; cohort B; cohort C).All of the scales and single-item measures range in score from 0 to 100. A high scale score represents a higher response level. The EORTC QLQ-C30 is composed of both multi-item scales and single-item measures. These include five functional scales, three symptom scales, a global health status/quality of life scale, and six single itemsThe QLQ-BR23 (quality of life questionnaire) breast cancer module is meant for use among patients varying in disease stage and treatment modality.The scoring approach for the QLQ-BR23 (quality of life questionnaire) is identical in principle to that for the function and symptom scales/single items of the QLQ-C30. | Baseline, cycle 3 (after 63 days approximately), before surgery and end of study through study completion (after cycle 18- after 12 months approximately) | 
| 3-year iDFS (cohort A). | 3-year iDFS (cohort A). | After 3 years (After 36 months) | 
| 3-year DDFS (cohort A; cohort B) (DDFS:Distant disease-free survival) | 3-year DDFS (cohort A; cohort B). | After 3 years (After 36 months) | 
| 3-year DFS (cohort A; cohort B) (DFS:Disease-free survival) | 3-year DFS (cohort A; cohort B). | After 3 years (After 36 months) | 
| OS (cohort A; cohort B; cohort C) (OS: overall survival) | OS (cohort A; cohort B; cohort C). | After 3 years (After 36 months) | 
| PFS (cohort C) (PFS: Progression-free survival) | PFS (cohort C). | After 3 years (After 36 months) |