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Hormonal Therapy after Pertuzumab and Trastuzumab for the Treatment of Hormone Receptor Positive, HER2 Positive Breast Cancer, the ADEPT study

Status
Active
Cancer Type
Breast Cancer
Trial Phase
Phase II
Eligibility
18 Years and older, Male and Female
Study Type
Treatment
NCT ID
NCT04569747
Protocol IDs
20-347 (primary)
NCI-2020-13971
Study Sponsor
Dana-Farber Harvard Cancer Center

Summary

This phase II trial studies the effect of hormonal therapy given after (adjuvant) combination pertuzumab/trastuzumab in treating patients with hormone receptor positive, HER2 positive breast cancer. The drugs trastuzumab and pertuzumab are both monoclonal antibodies, which are disease-fighting proteins made by cloned immune cells. Estrogen can cause the growth of breast cancer cells. Hormonal therapy, such as letrozole, anastrozole, exemestane, and tamoxifen, block the use of estrogen by the tumor cells. Giving hormonal therapy after pertuzumab and trastuzumab may kill any remaining tumor cells in patients with breast cancer.

Objectives

PRIMARY OBJECTIVE:
I. To evaluate 3-year invasive disease-free survival (iDFS) in patients with stage I hormone receptor positive (HR+) HER2+ breast cancer treated with adjuvant hyaluronidase-zzxf/pertuzumab/trastuzumab (HP) plus endocrine therapy.

SECONDARY OBJECTIVES:
I. To evaluate iDFS at 7 and 10 years in patients with stage I HR+ HER2+ breast cancer treated with adjuvant HP plus endocrine therapy, in:
Ia. All patients.
Ib. Patient subgroups according to intrinsic subtype (HER2-enriched, luminal, basal).
II. To evaluate recurrence-free interval (RFI) at 3, 7, and 10 years in patients with stage I HR+ HER2+ breast cancer treated with adjuvant HP plus endocrine therapy, in:
IIa. All patients.
IIb. Patient subgroups according to intrinsic subtype (HER2-enriched, luminal, basal).
III. To evaluate breast cancer-specific survival (BCSS) at 3, 7, and 10 years in patients with stage I HR+ HER2+ breast cancer treated with adjuvant HP plus endocrine therapy, in:
IIIa. All patients.
IIIb. Patient subgroups according to intrinsic subtype (HER2-enriched, luminal, basal).
IV. To evaluate overall survival (OS) at 3, 7, and 10 years in patients with stage I HR+ HER2+ breast cancer treated with adjuvant HP plus endocrine therapy, in:
IVa. All patients
IVb. Patient subgroups according to intrinsic subtype (HER2-enriched, luminal, basal)
V. To assess safety and tolerability of one year of subcutaneous HP plus endocrine therapy.
VI. To estimate the mean difference in total patient chair time of drug administration and observation, comparing treatment with HP fixed dose combination (FDC) subcutaneously (SC) and treatment with intravenous (IV) administration of HP as part of the Time and Motion substudy.

EXPLORATORY AND CORRELATIVE OBJECTIVES:
I. To evaluate quality of life, patient satisfaction, financial concerns, patient acceptance of subcutaneous administration at home, and hormonal therapy adherence over time in patients treated with HP plus endocrine therapy.
II. To explore how the presence, absence, and characteristics (i.e. presence of certain mutations) of detectable circulating tumor deoxyribonucleic acid (DNA) correlates with long-term outcomes (iDFS, RFI, OS) on HP plus hormonal therapy.
III. To explore how features of the pre-treatment immune microenvironment correlate with long-term outcomes (iDFS, RFI, OS) on HP plus hormonal therapy.
IV. To estimate the mean difference in overall patient treatment experience time (comparing FDC HP to IV HP) as part of the Time and Motion substudy.
V. To estimate the mean difference (comparing FDC HP to IV HP) in drug administration time, as part of the Time and Motion substudy.
VI. To estimate the mean difference (comparing FDC HP to IV HP) in pharmacist time commitment for drug preparation, as part of the Time and Motion substudy.

OUTLINE:
Patients receive HP SC over 5-8 minutes on day 1. Treatment repeats every 21 days for up to 18 cycles in the absence of disease progression or unacceptable toxicity. Postmenopausal women also receive either letrozole orally (PO) once daily (QD), anastrozole PO QD, or exemestane PO QD, and pre- and postmenopausal women and men receive tamoxifen PO QD on days 1-21. Treatment repeats every 21 days for at least 5 years in the absence of disease progression or unacceptable toxicity. Premenopausal or male patients may receive gonadotropin-releasing hormone analog intramuscularly (IM) once monthly or every 3 months for at least 5 years in the absence of disease progression or unacceptable toxicity. NOTE: Patients able to tolerate SC trastuzumab but unable to tolerate SC pertuzumab may receive trastuzumab/hyaluronidase-oysk SC together with pertuzumab intravenously (IV). Patients unable to tolerate SC trastuzumab may receive IV trastuzumab.

TIME AND MOTION SUB-STUDY: Patients receive HP SC over 5-8 minutes on day 1 in cycles 1 and 4-18, and pertuzumab IV and trastuzumab IV in cycles 2-3. Treatment repeats every 21 days for up to 18 cycles in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up annually until 10 years after trial registration.

Eligibility

  1. HER2-positive T1 histologically confirmed invasive carcinoma of the breast. Patients must have node-negative (N0) or micrometastases (N1mi) breast cancer according to the American Joint Committee on Cancer (AJCC) 8th edition anatomic staging table * If the patient has had a negative sentinel node biopsy, then no further axillary dissection is required, and the patient is determined to be node-negative. Axillary nodes with single cells or tumor clusters =< 0.2 mm by either hematoxylin and eosin (H&E) or immunohistochemistry (IHC) will be considered node-negative * Any axillary lymph node with tumor clusters between 0.02 and 0.2 cm is considered a micrometastasis. Patients with a micrometastasis are eligible. An axillary dissection is not required to be performed in patients with a micrometastasis found by sentinel node evaluation. In cases where the specific pathologic size of lymph node involvement is subject to interpretation, the overall principal investigator will make the final determination as to eligibility. The investigator must document approval in the patient medical record * Patients who have an area of T1aN0, estrogen receptor (ER)+ (defined as >= 10%), HER2-negative cancer in either breast, in addition to their primary HER2 positive tumor, are eligible
  2. For unifocal disease, all invasive disease must have been tested for ER and progesterone receptor (PR) (for multifocal disease, see below). Either ER or PR must be positive, defined as ER >= 10% or PR >= 10%. ER- and PR-assays should be performed by immunohistochemical methods according to the local institution standard protocol
  3. HER2-positive by American Society of Clinical Oncology (ASCO) College of American Pathologists (CAP) 2018 guidelines, confirmed by central testing * NOTE: Ductal carcinoma in situ (DCIS) components will not be counted in the determination of HER2 status * NOTE: HER-2 status must be confirmed to be positive by central review prior to patient starting protocol therapy. Patients previously having had HER2 testing by NeoGenomics do not need to undergo retesting for central confirmation of HER2 status. A pathology report documenting testing by NeoGenomics should be provided at time of patient registration
  4. Bilateral breast cancers that individually meet eligibility criteria are allowed
  5. Patients with multifocal or multicentric disease are eligible as long as each tumor individually meets eligibility criteria, with the following exceptions: (1) central confirmation of HER2 status is needed only for any site of disease that is tested to be HER2-positive by local testing (unless original testing was done by NeoGenomics); (2) all areas that were locally tested for ER and PR status must be ER/PR positive (as defined above)
  6. Patients with a history of ipsilateral DCIS are eligible as long as the patient has not received prior hormonal therapy. Patients with a history of contralateral DCIS are not eligible
  7. =< 95 days between the date of protocol registration and the patient’s most recent breast surgery for this breast cancer
  8. Patients must have undergone definitive breast surgery for the current malignancy. All tumor should be removed by either a modified radical mastectomy or a segmental mastectomy (lumpectomy), with either a sentinel node biopsy or axillary dissection * All margins should be clear of invasive cancer or DCIS (i.e. no tumor on ink). The local pathologist must document negative margins of resection in the pathology report. If all other margins are clear, a positive posterior (deep) margin is permitted, provided the surgeon documents that the excision was performed down to the pectoral fascia and all tumor has been removed. Likewise, if all other margins are clear, a positive anterior (superficial; abutting skin) margin is permitted provided the surgeon documents that all tumor has been removed. Radiation therapy to the conserved breast is required
  9. May have received up to 8 weeks of hormonal therapy as adjuvant treatment for this cancer. Patients should otherwise not have received prior hormonal therapy
  10. Prior oophorectomy (including for cancer therapy) is allowed
  11. Patients undergoing breast conservation therapy (i.e. lumpectomy) must not have any contraindications to radiation therapy
  12. Patients who have participated in a window study (treatment with an investigational agent prior to surgery for =< 2 weeks) are eligible. Patients must have discontinued the investigational agent at least 14 days before participation
  13. Any menopausal status >= 18 years of age
  14. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1
  15. Absolute neutrophil count (ANC) >= 1000/mm^3
  16. Hemoglobin >= 8 g/dl
  17. Platelets >= 75,000/mm^3
  18. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) both =< 5 x institutional upper limit of normal (ULN)
  19. Total bilirubin =< 1.5 mg/dL. For patients with Gilbert syndrome, the direct bilirubin should be =< institutional ULN
  20. Serum creatinine =< 2.0 mg/dL OR calculated glomerular filtration rate (GFR) >= 30 mL/min
  21. Left ventricular ejection fraction (LVEF) >= 50%
  22. Post-menopausal patients must meet one of the following criteria: * Prior bilateral ovariectomy/oophorectomy * Age >= 60 years * Age < 60 years with intact uterus and amenorrhoeic for >= 12 consecutive months prior to chemotherapy and/or endocrine therapy exposure (medication-induced amenorrhea is not acceptable to meet this criterion) * Age < 60 years hysterectomized and follicle-stimulating hormone (FSH) and plasma estradiol levels in the post-menopausal range according to local policies prior to chemotherapy and/or endocrine therapy exposure
  23. Willingness to discontinue contraceptive hormonal therapy, e.g. birth control pills, prior to registration and while on study
  24. Premenopausal patients must have a negative serum or urine pregnancy test, including women who have had a tubal ligation and women less than 12 months from their last menstrual period
  25. Women of childbearing potential and men with partners of childbearing potential must be willing to use one highly effective form of nonhormonal contraception with the exception of hormonal IUDs or two effective forms of nonhormonal contraception by the patient and/or partner and continue its use for the duration of the study treatment and for 7 months after the last dose of antibody treatment and 3 months after the last dose of hormonal treatment
  26. Patients must be willing and able to sign informed consent
  27. Patients must be willing to provide archival tissue for research purposes
  28. If patient is English-speaking, must be willing to fill out patient questionnaires
  29. Time and Motion Substudy: Participant must be enrolled at Dana-Farber Cancer Institute
  30. Time and Motion Substudy: Participant must NOT have discontinued pertuzumab following treatment cycle 1
  31. Time and Motion Substudy: Participant must be able to tolerate subcutaneous administration following cycle 1
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