Clinical Trials /

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

NCT03161353

Description:

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.

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

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

Clinical Trial IDs

  • ORG STUDY ID: MedOPP096
  • NCT ID: NCT03161353

Conditions

  • Breast Cancer

Interventions

DrugSynonymsArms
PerjetaPertuzumabCohort A
HerceptinTrastuzumabCohort A
DocetaxelCohort A
CarboplatinCohort A
LetrozoleCohort A
TamoxifenCohort A

Purpose

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 breast cancer (human epidermal receptor) treated with neoadjuvant trastuzumab and pertuzumab (± endocrine therapy) using a FDG-PET response-adapted strategy.

Detailed Description

      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 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.
    

Trial Arms

NameTypeDescriptionInterventions
Cohort AExperimentalCohorts 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
  • Perjeta
  • Herceptin
  • Docetaxel
  • Carboplatin
  • Letrozole
  • Tamoxifen
Cohort BExperimentalcohorts 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 (tamoxifen or letrozole) 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 (tamoxifen or letrozole) 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 (tamoxifen or letrozole) during 10 cycles.
  • Perjeta
  • Herceptin
  • Docetaxel
  • Carboplatin
  • Letrozole
  • Tamoxifen
Cohort CExperimentalcohorts 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.
  • Perjeta
  • Herceptin
  • Docetaxel
  • Carboplatin
  • Letrozole
  • Tamoxifen

Eligibility Criteria

        Inclusion Criteria:

          1. Written informed consent prior to beginning specific protocol procedures.

          2. Female or male patients ≥ 18 years of age.

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

          4. Histologically proven invasive breast cancer.

          5. Operable breast cancer (cT1-3 and/or cN0-2 tumors) (breast cancer TNM classification)

          6. 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 standardized 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:

          1. Histological confirmation of at least two lesions.

          2. All tumors must be HER2-positive.

          3. 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 2013 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:

          1. Previous treatment with chemotherapy, anti-HER2 therapy, radiation therapy, or
             endocrine therapy for invasive breast cancer.

          2. cT4 and/or cN3 tumors (TNM breast cancer classification)

          3. Bilateral breast cancer.

          4. 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.

          5. Known hypersensitivity reaction to any investigational or therapeutic compound or
             their incorporated substances.

          6. 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.

          7. Left ventricular ejection fraction (LVEF) below 55% as determined by multiple-gated
             acquisition (MUGA) scan or echocardiography (ECHO).

          8. Uncontrolled hypertension (systolic > 150 mm Hg and/or diastolic > 100 mm Hg) despite
             adequate antihypertensive treatment.

          9. 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].

         10. Active uncontrolled infection at the time of enrollment.

         11. Current known infection with HIV, hepatitis B virus, or hepatitis C virus.

         12. Patients with pulmonary disease requiring continuous oxygen therapy.

         13. Previous history of bleeding diathesis.

         14. Patient is currently receiving anti-coagulant therapy, chronic treatment with
             corticosteroids, or another immunosuppressive agent (standard premedication for
             chemotherapy and local applications are allowed).

         15. 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.

         16. Patient has other concurrent severe and/or uncontrolled medical conditions that
             would, in the investigator´s judgment, contraindicate her participation in the
             clinical study.

         17. Concurrent participation in other clinical trial, except other translational studies.

         18. History of receiving any investigational treatment within 28 days prior to
             randomization.

         19. Pregnant or breast-feeding women or patients not willing to apply highly effective
             contraception as defined in the protocol.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Evaluate the rate of pCR
Time Frame:After Cycle 6 or 8 (each cycle 21 days- After 4.2 or 5.6 months)
Safety Issue:
Description: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].

Secondary Outcome Measures

Measure:pCR rates in the breast and axilla (ypTO/isN0)
Time Frame:After Cycle 6 or 8 (each cycle 21 days- After 4.2 or 5.6 months)
Safety Issue:
Description:pCR rates in the breast and axilla (ypT0/isN0) (cohort A; cohort B; cohort B/PET non-responders).
Measure:pCR rates in the breast (ypT0/is)
Time Frame:After Cycle 6 or 8 (each cycle 21 days- After 4.2 or 5.6 months)
Safety Issue:
Description:pCR rates in the breast (ypT0/is) (cohort A; cohort B; cohort B/PET responders; cohort B/PET non-responders).
Measure:RCB score (residual cancer burden)
Time Frame:After Cycle 6 or 8 (each cycle 21 days- After 4.2 or 5.6 months)
Safety Issue:
Description:RCB score (cohort A; cohort B; cohort B/PET responders; cohort B/PET non-responders
Measure:pCR rates in the breast and axilla
Time Frame:After Cycle 6 or 8 (each cycle 21 days- After 4.2 or 5.6 months)
Safety Issue:
Description: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).
Measure:Rate of breast conserving surgery
Time Frame:After Cycle 6 or 8 (each cycle 21 days- After 4.2 or 5.6 months)
Safety Issue:
Description:Rate of breast conserving surgery (cohort A; cohort B; cohort B/PET responders; cohort B/PET non-responders).
Measure:18F-FDG PET/CT response rate (18F-fluorodeoxyglucose)
Time Frame:After cycle 2 (each cycle 21 days- After 42 days approximately)
Safety Issue:
Description:18F-FDG PET/CT response rate (according to the adapted EORTC criteria) (cohort A; cohort B).
Measure:Optimal 18F-FDG PET/CT cut-off for pCR
Time Frame:After cycle 2 (each cycle 21 days-After 42 days approximately)
Safety Issue:
Description:Optimal 18F-FDG PET/CT cut-off for pCR (cohort A; cohort B).
Measure:Other 18FDG PET quantification parameters
Time Frame:After cycle 2 (each cycle 21 days- After 42 days approximately)
Safety Issue:
Description: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.
Measure:MRI response rate
Time Frame:After two cycles of neoadjuvant therapy, and prior to surgery (each cycle 21 days)
Safety Issue:
Description: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).
Measure:Health-related quality of life
Time Frame:Baseline, cycle 3 (after 63 days approximately), before surgery and end of study through study completion (after cycle 18- after 12 months approximately)
Safety Issue:
Description: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.
Measure:3-year iDFS (cohort A).
Time Frame:After 3 years (After 36 months)
Safety Issue:
Description:3-year iDFS (cohort A).
Measure:3-year DDFS (cohort A; cohort B) (DDFS:Distant disease-free survival)
Time Frame:After 3 years (After 36 months)
Safety Issue:
Description:3-year DDFS (cohort A; cohort B).
Measure:3-year DFS (cohort A; cohort B) (DFS:Disease-free survival)
Time Frame:After 3 years (After 36 months)
Safety Issue:
Description:3-year DFS (cohort A; cohort B).
Measure:OS (cohort A; cohort B; cohort C) (OS: overall survival)
Time Frame:After 3 years (After 36 months)
Safety Issue:
Description:OS (cohort A; cohort B; cohort C).
Measure:PFS (cohort C) (PFS: Progression-free survival)
Time Frame:After 3 years (After 36 months)
Safety Issue:
Description:PFS (cohort C).

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:MedSIR

Last Updated

May 22, 2017