Clinical trial NCT04893109: ATEMPT 2.0: Adjuvant T-DM1 vs TH
Official title: A Randomized Phase II Trial of Adjuvant Trastuzumab Emtansine (T-DM1) Followed by Subcutaneous Trastuzumab Versus Paclitaxel in Combination With Subcutaneous Trastuzumab for Stage I HER2-positive Breast Cancer (ATEMPT 2.0)
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Breast Cancer
HER2-positive Breast Cancer
Keywords: Breast Cancer
HER2-positive Breast Cancer
Lead sponsor: Dana-Farber Cancer Institute
Sponsor class: OTHER
Collaborators: name: Genentech, Inc.
First posted: 2021-05-19
Enrollment: 500
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: participants are randomized in a 2-1 fashion to Arm A vs. Arm B
Primary purpose: TREATMENT

Brief summary: This research study is studying how well newly diagnosed breast cancer that has tested positive for a protein called HER2 responds using one of two different combination of HER2-directed therapies as a treatment after surgery.

The name of the study drugs involved are:

* Trastuzumab-emtansine (T-DM1, Kadcyla)
* Trastuzumab SC (Herceptin Hylecta)
* Paclitaxel

Detailed description: This is a randomized phase II adjuvant study for women and men with Stage I HER2-positive invasive breast cancer. Participants will be randomized into one of two treatment arms in this study and receive:

* Arm 1: trastuzumab-emtansine (T-DM1, Kadcyla) and trastuzumab SC (Herceptin Hylecta)
* Arm 2: paclitaxel and trastuzumab SC (Herceptin Hylecta) This research study is looking to see if the study drug T-DM1 followed by trastuzumab SC will have less side-effects than traditional HER2-positive breast cancer treatment of trastuzumab and paclitaxel.The study is also looking to learn about the long-term benefits and disease-free survival of participants who are treated with T-DM1 followed by trastuzumab SC.

T-DM1 is an antibody-drug conjugate; it is made up of an antibody (trastuzumab) linked to a cytotoxic drug, DM1 (chemotherapy). T-DM1 functions as a targeted cancer therapy because it targets HER2-positive breast cancer cells directly, limiting exposure of the rest of the body to chemotherapy. More specifically, the trastuzumab in T-DM1 first binds to the HER2 protein on the surface of the breast cancer cells and the DM1 then enters the cells and can cause them to die, preventing tumor growth. The FDA (the U.S. Food and Drug Administration) has not approved T-DM1 for use on its own in patients with stage I, II, or III breast cancer. However, it has been approved for use in (a) advanced or metastatic, previously treated breast cancer and (b) in some patients receiving postoperative treatment after preoperative chemotherapy and surgery have been completed.

Trastuzumab SC is a subcutaneous form of trastuzumab.Trastuzumab is a monoclonal antibody, which are disease-fighting proteins made by cloned immune cells. Paclitaxel and trastuzumab are considered a standard-of-care regimen in early breast cancer. Trastuzumab is FDA-approved to be administered as an IV (intravenous) or subcutaneous (muscular injection).

The research study procedures include screening for eligibility and study treatment including laboratory evaluations and follow up visits.

Participants will receive study treatment for a year in total and will be followed for 5 years after treatment.

It is expected that about 500 people will take part in this research study.

Genentech is supporting this research study by providing funding for the study and supplying trastuzumab-emtansine (T-DM1) and trastuzumab SC (subcutaneous).

Eligibility criteria: Inclusion Criteria:

* Patients must have HER2-positive Stage I histologically confirmed invasive carcinoma of the breast. Patients must have node-negative (N0) or micrometastases (N1mic) breast cancer according to the 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. If an axillary dissection without sentinel lymph node biopsy is performed to determine nodal status, at least six axillary lymph nodes must be removed and analyzed, and determined to be negative, for the patient to be considered node-negative. Axillary nodes with single cells or tumor clusters ≤ 0.2 mm by either 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 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 a T1aN0, ER+ (defined as \>10%), HER2-negative cancer in addition to their primary HER2-positive tumor are eligible.
* HER2-positive by ASCO CAP 2018 guidelines, confirmed by central testing. NOTE: HER-2 status must be confirmed to be positive by central review by NeoGenomics prior to patient starting protocol therapy. Patients previously having had HER2 immunohistochemical testing by NeoGenomics do not need to undergo retesting for central confirmation of HER2 status.

NOTE: DCIS components will not be counted in the determination of HER2 status

* ER/PR determination is required. ER and PR assays should be performed by immunohistochemical methods according to the local institution standard protocol.
* Bilateral breast cancers that individually meet eligibility criteria are allowed.
* Patients with multifocal or multicentric disease are eligible, as long as each tumor individually meets eligibility criteria. Central confirmation is needed for any site of disease that is tested to be HER2-positive by local testing (unless testing was previously done by NeoGenomics).
* Patients with a history of ipsilateral DCIS are eligible if they were treated with wide excision alone, without radiation therapy, or treated with a mastectomy for this current breast cancer. Patients with a history of contralateral DCIS are not eligible.
* ≤ 90 days between the planned treatment start date and the patient's most recent breast surgery for this breast cancer
* ≥ 18 years of age with any menopausal status.
* ECOG Performance Status 0 or 1
* 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.
* Patients undergoing breast conservation therapy (i.e. lumpectomy) must not have any contraindications to radiation therapy. Radiation to the conserved breast is required.
* Patients may have received up to 4 weeks of tamoxifen therapy, or other hormonal therapy, for adjuvant therapy for this cancer. Patients cannot receive adjuvant hormonal therapy during protocol treatment for the first 12 weeks.
* Prior oophorectomy for cancer prevention is allowed.
* Patients who have undergone partial breast radiation (duration ≤ 14 days) prior to registration are eligible. Partial breast radiation must be completed prior to 2 weeks before starting protocol therapy. Patients who have undergone whole breast radiation are not eligible.
* 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.
* Adequate bone marrow function:

  * ANC ≥ 1000/mm3,
  * Hemoglobin ≥ 9 g/dl
  * Platelets ≥ 100,000/mm3
* Adequate hepatic function:

  * Total bilirubin ≤ 1.2mg/dL
  * AST and ALT ≤ 1.5x Institutional ULN
  * For patients with Gilbert syndrome, the direct bilirubin should be within the institutional normal range. Serum alkaline phosphatase should be ≤ 1.5x Institutional ULN.
* Left ventricular ejection fraction (LVEF) ≥ 50%
* Premenopausal patients must have a negative serum or urine pregnancy test, including women who have had a tubal ligation and for women less than 12 months after the onset of menopause.
* Women of childbearing potential and men with partners of childbearing potential must be willing to use one highly effective form of nonhormonal contraception or two effective forms of nonhormonal contraception by the patient and/or partner. Contraceptive use must be continued for the duration of the study treatment and for 7 months after the last dose of study treatment. Hormonal birth control methods are not permitted.
* Patients should have tumor tissue available, and a tissue block of sufficient size to make 15 slides, which must be sent to DFCI for correlative research. If a tissue block is unavailable, sites may send one H\&E-stained slide and 15 unstained sections of paraffin-embedded tissue on uncharged slides. Slide sections should be 4-5 microns in thickness. It is also acceptable to submit 2 cores from a block of invasive tissue using a 1.2 mm diameter coring tool. If tumor is not available, the investigator must document why tissue is not available in the patient medical record, and that efforts have been made to obtain tissue.
* Willing and able to sign informed consent
* Must be able to read and understand English in order to participate in the quality of life surveys. If patient does not read and understand English, the patient is still eligible, but cannot participate in the quality of life surveys.

Exclusion Criteria:

* Any of the following due to teratogenic potential of the study drugs:

  * Pregnant women
  * Nursing women
  * Women of childbearing potential who are unwilling to employ adequate contraception (condoms, diaphragms, IUDs, surgical sterilization, abstinence, etc.).
  * Men who are unwilling to employ adequate contraception (condoms, surgical sterilization, abstinence, etc.).
* Locally advanced tumors at diagnosis, including tumors fixed to the chest wall, peau d'orange, skin ulcerations/nodules, or clinical inflammatory changes (diffuse brawny cutaneous induration with an erysipeloid edge)
* Patients with a history of previous invasive breast cancer.
* History of prior chemotherapy in the past 5 years.
* History of paclitaxel therapy
* Patients with active liver disease, for example due to hepatitis B virus, hepatitis C virus, autoimmune hepatic disorder, or sclerosing cholangitis
* Individuals with a history of a different malignancy are ineligible except for the following circumstances:

  * Individuals with a history of other malignancies are eligible if they have been disease-free for at least 5 years and are deemed by the investigator to be at low risk for recurrence of that malignancy.
  * Individuals with the following cancer are eligible regardless of when they were diagnosed and treated: cervical cancer in situ, and non-melanoma cancer of the skin.
* Intercurrent illness including, but not limited to: ongoing or active, unresolved systemic infection, renal failure requiring dialysis, active cardiac disease, prior myocardial infarction (asymptomatic changes on EKG suggestive of old MI is not an exclusion), history of CHF, current use of any therapy specifically for CHF, uncontrolled hypertension, significant psychiatric illness, or other conditions that in the opinion of the investigator limit compliance with study requirements.

Primary outcomes:
measure: Incidence of clinically relevant toxicities (CRT)
timeFrame: First 18 weeks of treatment
measure: Disease Free Survival (DFS)
timeFrame: Time from randomization to first Disease Free Survival (DFS) event up to 72 months
Secondary outcomes:
measure: Grade 3 and 4 adverse events
timeFrame: Enrollment to end of treatment up to 1 year
measure: Quality of Life Assessment: FACT B
timeFrame: Enrollment to end of treatment up to 1 year
measure: Symptoms related to therapy
timeFrame: Enrollment to end of treatment up to 1 year
measure: Symptoms related to therapy
timeFrame: Enrollment to end of treatment up to 1 year
measure: Effects of therapy on work productivity
timeFrame: Enrollment to end of treatment up to 1 year
measure: Effect of alopecia on patients
timeFrame: Enrollment to end of treatment up to 1 year
measure: Incidence of Side Effects
timeFrame: Enrollment to end of treatment up to 1 year
measure: Incidence of grade 3-4 cardiac left ventricular dysfunction
timeFrame: Enrollment to end of treatment up to 1 year
measure: Incidence of trastuzumab-emtansine-induced grade 2-4 thrombocytopenia
timeFrame: Enrollment to end of treatment up to 1 year
measure: Percentage of patients with amenorrhea
timeFrame: Enrollment to end of treatment up to 1 year
measure: Evaluation of gene predictors of trastuzumab-emtansine-induced grade 2-4
timeFrame: Enrollment to end of treatment up to 1 year
measure: Gene Profiling
timeFrame: Enrollment to end of treatment up to 1 year
measure: Radiation therapy Toxicity
timeFrame: Enrollment to end of treatment up to 1 year
measure: Overall survival
timeFrame: Enrollment to end of treatment up to 1 year
Other outcomes:
Locations:
city: San Francisco
country: United States
facility: UCSF Helen Diller Family Comprehensive Cancer Center
state: California
city: Derby
country: United States
facility: Smilow Cancer Hospital Care center at Derby
state: Connecticut
city: Fairfield
country: United States
facility: Smilow Cancer Hospital Care center at Fairfield
state: Connecticut
city: Glastonbury
country: United States
facility: Smilow Cancer Hospital Care center at Glastonbury
state: Connecticut
city: Greenwich
country: United States
facility: Smilow Cancer Hospital Care center at Greenwich
state: Connecticut
city: Guilford
country: United States
facility: Smilow Cancer Hospital Care center at Guilford
state: Connecticut
city: Hartford
country: United States
facility: Smilow Cancer Hospital Care center at St. Francis
state: Connecticut
city: Long Ridge
country: United States
facility: Smilow Cancer Hospital Care center at Long Ridge
state: Connecticut
city: New Haven
country: United States
facility: Yale Cancer Center at Yale University School of Medicine
state: Connecticut
city: North Haven
country: United States
facility: Smilow Cancer Hospital Care center at North Haven
state: Connecticut
city: Stamford
country: United States
facility: Stamford Hospital
state: Connecticut
city: Torrington
country: United States
facility: Smilow Cancer Hospital Care center at Torrington
state: Connecticut
city: Trumbull
country: United States
facility: Smilow Cancer Hospital Care center at Trumbull
state: Connecticut
city: Waterbury
country: United States
facility: Smilow Cancer Hospital Care center at Waterbury
state: Connecticut
city: Waterford
country: United States
facility: Smilow Cancer Hospital Care center at Waterford
state: Connecticut
city: Miami
country: United States
facility: Miami Cancer Institute/Baptist Hospital of Miami
state: Florida
city: Plantation
country: United States
facility: Miami Cancer Institute - Plantation (MCIP)
state: Florida
city: Chicago
country: United States
facility: The University of Chicago Medical Center
state: Illinois
city: Carmel
country: United States
facility: Indiana University Health Joe & Shelly Schwarz Cancer Center
state: Indiana
city: Carmel
country: United States
facility: IU Health North Hospital
state: Indiana
city: Indianapolis
country: United States
facility: Indiana University Melvin and Bren Simon Comprehensive Cancer Center
state: Indiana
city: Indianapolis
country: United States
facility: Indiana University Sidney and Lois Eskenazi Hospital
state: Indiana
city: Brewer
country: United States
facility: Eastern Maine Medical Center (Northern Light)
state: Maine
city: Scarborough
country: United States
facility: New England Cancer Specialists
state: Maine
city: Boston
country: United States
facility: Beth Israel Deaconess Medical Center
state: Massachusetts
city: Boston
country: United States
facility: Dana Farber Cancer Institute
state: Massachusetts
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Brighton
country: United States
facility: Dana-Farber at St. Elizabeth's Medical Center
state: Massachusetts
city: Danvers
country: United States
facility: Mass General North Shore Cancer Center
state: Massachusetts
city: Foxborough
country: United States
facility: Dana-Farber Brigham Cancer Center - Foxborough
state: Massachusetts
city: Methuen
country: United States
facility: Dana-Farber Cancer Instiute - Merrimack Valley
state: Massachusetts
city: Milford
country: United States
facility: Dana-Farber at Milford
state: Massachusetts
city: Newton
country: United States
facility: Newton Wellesley Hospital
state: Massachusetts
city: Pittsfield
country: United States
facility: Berkshire Medical Center
state: Massachusetts
city: Weymouth
country: United States
facility: Dana Farber at South Shore Hospital
state: Massachusetts
city: Concord
country: United States
facility: NH Oncology-Hematology, PA - Payson Center for Cancer Care
state: New Hampshire
city: Londonderry
country: United States
facility: Dana-Farber Cancer Insitute at Londonderry Hospital
state: New Hampshire
city: Manchester
country: United States
facility: Solinsky Center for Cancer Care (NH Oncology-Hematology, PA)
state: New Hampshire
city: Portsmouth
country: United States
facility: New England Cancer Specialists - Portsmouth
state: New Hampshire
city: Brooklyn
country: United States
facility: New York University Langone Hospital -Brooklyn
state: New York
city: Mineola
country: United States
facility: New York University Langone Hospital - Long Island
state: New York
city: New York
country: United States
facility: New York University Langone Health
state: New York
city: Durham
country: United States
facility: Duke University Medical Center
state: North Carolina
city: Raleigh
country: United States
facility: Duke Women's Cancer Care Raleigh
state: North Carolina
city: Columbus
country: United States
facility: Stefanie Spielman Comprehensive Breast Center
state: Ohio
city: Philadelphia
country: United States
facility: University of Pennsylvania, Abramson Cancer Center
state: Pennsylvania
city: Westerly
country: United States
facility: Smilow Cancer Hospital Care center at Westerly
state: Rhode Island
city: Nashville
country: United States
facility: SCRI Oncology Partners
state: Tennessee
city: Nashville
country: United States
facility: Tennessee Oncology - Nashville
state: Tennessee
city: Houston
country: United States
facility: MD Anderson Cancer Center
state: Texas
Study officials:
affiliation: Dana-Farber Cancer Institute
name: Sara Tolaney, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References: