GA NCORP

NCORP Trials

Testing the Ability to Decrease Chemotherapy in Patients with HER2-Positive Breast Cancer Who Have No Remaining Cancer at Surgery after Limited Pre-operative Chemotherapy and HER2-Targeted Therapy

Status
Active
Cancer Type
Breast Cancer
Trial Phase
Phase II
Eligibility
18 Years and older, Male and Female
Study Type
Treatment
NCD ID
NCT04266249
Protocol IDs
EA1181 (primary)
EA1181
NCI-2019-07439
Study Sponsor
ECOG-ACRIN Cancer Research Group

Summary

This clinical trial studies how well paclitaxel, trastuzumab, and pertuzumab work in eliminating further chemotherapy after surgery in patients with HER2-positive stage II-IIIa breast cancer who have no cancer remaining at surgery (either in the breast or underarm lymph nodes) after pre-operative chemotherapy and HER2-targeted therapy. Drugs used in chemotherapy, such as paclitaxel, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Trastuzumab is a form of “targeted therapy” because it works by attaching itself to specific molecules (receptors) on the surface of tumor cells, known as HER2 receptors. When trastuzumab attaches to HER2 receptors, the signals that tell the cells to grow are blocked and the tumor cell may be marked for destruction by the body’s immune system. Pertuzumab is a monoclonal antibody that may interfere with the ability of tumor cells to grow and spread. Giving paclitaxel, trastuzumab, and pertuzumab may enable fewer chemotherapy drugs to be given without compromising patient outcomes compared to the usual treatment.

Objectives

PRIMARY OBJECTIVES:
I. To determine if 3-year recurrence-free survival (RFS) is greater than 92% among clinical stages II or IIIa patients (by American Joint Committee on Cancer [AJCC] cancer staging manual anatomic staging table, 8th edition) with HER2-positive/ER-positive breast cancer who achieve pathologic complete response (pCR) (ypT0/is ypN0) after preoperative therapy with 12 weeks of a taxane, trastuzumab (or Food and Drug Administration [FDA] approved biosimilar) and pertuzumab (THP x 12). Post-operatively, patients will receive standard of care adjuvant locoregional therapy, plus completion of 12 months of HER2-targeted therapy (and standard adjuvant endocrine therapy for patients with estrogen receptor-positive disease).
II. To determine if 3-year recurrence-free survival (RFS) is greater than 92% among clinical stages II or IIIa patients (by AJCC cancer staging manual anatomic staging table, 8th edition) with HER2-positive/ER-negative breast cancer who achieve pCR (ypT0/is ypN0) after preoperative therapy with 12 weeks of a taxane, trastuzumab (or FDA approved biosimilar) and pertuzumab (THP x 12). Post-operatively, patients will receive standard of care adjuvant locoregional therapy, plus completion of 12 months of HER2-targeted therapy (and no adjuvant endocrine therapy for patients with estrogen receptor-negative disease).

SECONDARY OBJECTIVES:
I. To determine 3-year IDFS (invasive disease-free survival), DDFS (distant disease-free survival), DRFS (distant relapse-free survival), RFI (recurrence-free interval), OS (overall survival) and breast cancer-specific survival in patients who achieve pCR (and by pretreatment clinical stage). (Secondary Clinical Objective)
II. To determine 3-year EFS (event-free survival) in all patients from time of study registration. (Secondary Clinical Objective)
III. To evaluate safety and tolerability for all patients during the pre-operative phase and for patients who attain pCR and de-escalate therapy (Arm A) until the completion of post-surgery protocol assigned therapy (i.e., until the end of trastuzumab and pertuzumab [HP] therapy). (Secondary Clinical Objective)
IV. To evaluate the association of estrogen receptor (ER) status in the untreated primary tumor with pathologic response and with long-term survival outcomes (including RFS, EFS, IDFS, DDFS, DRFS, RFI, OS, and breast cancer-specific survival). (Secondary Correlative Objective)
V. To evaluate the associations of detection of circulating tumor cells (CTCs) in the blood at baseline with pCR. (Secondary Correlative Objective)
VI. To evaluate the association of detection of CTCs in the blood at baseline, after 3 weeks of THP, after 12 weeks of THP (before surgery), after surgery before any additional therapy, and after completion of HER2-targeted therapy with RFS in patients who achieve pCR or not. (Secondary Correlative Objective)

EXPLORATORY OBJECTIVES:
I. To determine 3-year RFS, IDFS (invasive disease-free survival), DDFS (distant disease-free survival), DRFS (distant relapse-free survival), RFI (recurrence-free interval), OS (overall survival) and breast cancer-specific survival in patients who do not achieve pCR (and by pretreatment clinical stage). (Exploratory Clinical Objective)
II. To determine the pathologic response to THP neoadjuvant therapy, as assessed by residual cancer burden (RCB). (Exploratory Clinical Objective)
III. To determine the association between residual cancer burden (RCB) and all described standardized definitions for efficacy end points (STEEP) criteria outcomes. (Exploratory Clinical Objective)
IV. To determine the false negative rate (FNR) of limited staging procedures (defined as sentinel lymph node biopsy [SLNB] plus removal of clipped node) in patients who undergo such procedures with a planned axillary lymph node dissection (ALND). (Exploratory Clinical Objective)
V. To determine axillary pCR rates as a function of the burden of disease at presentation as determined on pre-treatment ultrasound (US) and the axillary staging technique (SLNB plus ensuring removal of clipped node versus ALND). (Exploratory Clinical Objective)
VI. To evaluate the associations between plasma tumor cell-free deoxyribonucleic acid (DNA) (cfDNA) tumor-specific mutations (baseline and after therapy) with pathologic response and long-term outcomes (including RFS, EFS, IDFS, DDFS, DRFS, RFI, OS, and breast cancer-specific survival). (Exploratory Correlative Objective)
VII. To evaluate the associations between tumor infiltrating lymphocytes (TILs) in the baseline tumor with pathologic and long-term outcomes (including RFS, EFS, IDFS, DDFS, DRFS, RFI, OS and breast cancer-specific survival) and in the residual tumor with long-term outcomes. (Exploratory Correlative Objective)
VIII. To evaluate the associations between immune activation gene signatures in the baseline tumor and pathologic response as well as outcomes (including RFS, EFS, IDFS, DDFS, DRFS, RFI, OS and breast cancer-specific survival). (Exploratory Correlative Objective)
IX. To evaluate the association of intrinsic subtype at baseline with outcomes (pathologic response and survival). (Exploratory Correlative Objective)
X. To determine the frequency of change in intrinsic subtype between pretreatment tumor specimen and residual disease at the time of surgery and to evaluate any association with survival. (Exploratory Correlative Objective)
XI. To evaluate the associations between DNA copy number, DNA mutations, ribonucleic acid (RNA) expression and protein expression in the baseline tumor and changes from baseline to post-THP therapy with pathologic response and long-term outcomes (including RFS, EFS, IDFS, DDFS, DRFS, RFI, OS, and breast cancer-specific survival). (Exploratory Correlative Objective)

OUTLINE:

PRE-OPERATIVE/NEOADJUVANT THERAPY: Patients receive either paclitaxel or nab-paclitaxel intravenously (IV) on days 1, 8 and 15, or docetaxel IV on day 1 at the discretion of the treating oncologist. Patients also receive trastuzumab IV on day 1 and weekly thereafter, and pertuzumab IV on day 1. Patients may substitute trastuzumab-hyaluronidase subcutaneously (SC) over 2-5 minutes on day 1 in place of trastuzumab or pertuzumab-trastuzumab-hyaluronidase SC over 8 minutes on day 1 of cycle 1 and over 5 minutes on day 1 of cycles 2-4 in place of trastuzumab and pertuzumab. Treatment repeats every 21 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. However, if surgery occurs later than 21 days after the 4th cycle of trastuzumab and pertuzumab, patients receive an additional cycle of trastuzumab and pertuzumab before surgery.

SURGERY: Within 126 days (18 weeks) after the first dose of neoadjuvant therapy, patients undergo standard of care lumpectomy and/or mastectomy.

POST-OPERATIVE/ADJUVANT THERAPY: Patients are assigned to 1 of 2 arms.

ARM A: Patients with pCR after surgery receive trastuzumab and pertuzumab IV on day 1. Patients may substitute trastuzumab-hyaluronidase SC over 2-5 minutes on day 1 in place of trastuzumab or pertuzumab-trastuzumab-hyaluronidase SC over 5 minutes on day 1 in place of trastuzumab and pertuzumab. Treatment repeats every 21 days for up to 13 cycles in the absence of disease progression or unacceptable toxicity. Patients may also undergo standard of care radiation therapy and receive hormone therapy if appropriate.

ARM B: Patients with remaining tumor after surgery receive standard of care trastuzumab emtansine for 14 doses in the absence of disease progression or unacceptable toxicity. Patients may also receive additional standard of care chemotherapy, as well as hormone therapy if appropriate.

After completion of study treatment, patients are followed up every 3 months for 2 years, every 6 months for 2-5 years, then annually for 5-15 years from date of surgery.