Clinical trial NCT03716180: DAPHNe: Paclitaxel/Trastuzumab/Pertuzumab in HER2-Positive BC
Official title: DAPHNe: De-escalation to Adjuvant Antibodies Post-pCR to Neoadjuvant THP (Paclitaxel/Trastuzumab/Pertuzumab)-a Pilot Study in HER2-positive Breast Cancer
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE1
Conditions: Breast Cancer
Keywords: Breast Cancer
Lead sponsor: Dana-Farber Cancer Institute
Sponsor class: OTHER
Collaborators: name: Susan G. Komen Breast Cancer Foundation
name: Breast Cancer Research Foundation
name: Terri Brodeur Breast Cancer Foundation
First posted: 2018-10-23
Enrollment: 100
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: This research study is studying whether participants and their doctors are willing to determine post-surgery treatment on the basis of response to pre-surgery treatment, and studying blood and tissue collected from participants treated with a combination of drugs as a treatment for breast cancer.

The names study drugs involved in this study are:

* Paclitaxel (also called Taxol)
* Trastuzumab (also called Herceptin)
* Pertuzumab (also called Perjeta)

Detailed description: This research study is a Pilot Study, which means investigators are looking at the feasibility of a new approach for deciding the optimal medical treatment for this type of breast cancer. The FDA (the U.S. Food and Drug Administration) has approved paclitaxel, trastuzumab, and pertuzumab as part of a pre-operative treatment option for this disease.

The purpose of this study is to evaluate whether participants and their doctors are willing to accept a treatment recommendation for post-operative chemotherapy, on the basis of the participant's response to pre-operative treatment with paclitaxel, trastuzumab, and pertuzumab.

In addition, the investigators are evaluating how the body's immune system works with paclitaxel, trastuzumab, and pertuzumab to kill cancer cells. For this reason, the investigators will collect samples of the participant's breast tumor and samples of the participant's blood over time to understand the reaction of the immune system to the participant's tumor.

Eligibility criteria: Inclusion Criteria:

* Patients must have Stage II or III (according to AJCC cancer staging manual anatomic staging table, 8th edition) histologically confirmed invasive carcinoma of the breast. A minimum tumor size of 1.5 cm determined by physical exam or imaging (whichever is larger) is required. Patients with inflammatory breast carcinoma (T4d) are NOT eligible.
* Tumors must be HER-2 positive, as assessed by standard local institutional protocol (central testing is not required):

  * IHC 3+
  * FISH positive based on one of the three following criteria:

Single-probe average HER2 copy number ≥ 6.0 signals/cell; OR

* Dual-probe HER2/CEP17 ratio \<2.0 with an average HER2 copy number ≥ 6.0 signals/cell; OR
* Dual-probe HER2/CEP17 ratio ≥2.0

  * 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 are allowed as long as both cancers are HER2-positive (as defined in 3.1.2), or the contralateral cancer is a \<1 cm, ER+, and HER2- tumor.
  * Patients with multifocal or multicentric disease are eligible as long as all tumor foci that were tested for HER2 status at the local institution are HER2-positive, and at least one tumor focus meets eligibility criteria.
  * Breast imaging should include dedicated ultrasound of the ipsilateral axilla. For subjects with a clinically positive axilla based on exam or imaging, a fine needle aspiration or core biopsy procedure will be performed to determine the presence of metastatic disease in the lymph nodes (though lymph node sampling procedure need not be resulted prior to patient's registration on trial, as long as all other eligibility are met).
  * Men and women (with any menopausal status) ≥ 18 years of age are eligible.
  * ECOG PS 0 or 1.
* Required laboratory values:
* ANC ≥ 1000/mm3
* Hemoglobin ≥ 9 g/dl
* Platelets ≥ 100,000/mm3
* Serum creatinine \< 1.5 x ULN (institutional) OR calculated GFR ≥60mL/min.

  -Total bilirubin ≤ 1.5 x ULN (institutional). For patients with Gilbert Syndrome, the direct bilirubin should be within the institutional normal range OR total bilirubin ≤ 2.0 mg/dL.
* AST and ALT ≤ 2.5x ULN (institutional)

  * Left ventricular ejection fraction (LVEF) ≥ 50%.
  * Premenopausal women must have a negative serum pregnancy test within 14 days of registration, 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 non-hormonal contraception or two effective forms of non-hormonal 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 study treatment.
  * Patients with a history of ipsilateral DCIS are eligible.
  * Patients undergoing breast conservation therapy (i.e. lumpectomy) must not have any contraindications to radiation therapy.
  * Willing and able to sign informed consent.
  * Willing to provide tissue for research purposes

Exclusion Criteria:

* Pregnant or nursing women due to the teratogenic potential of the study drugs.
* Active, unresolved infection.
* Receipt of intravenous antibiotics for infection within 7 days prior to registration.
* Uncontrolled hypertension (systolic \>180 mm Hg and/or diastolic \>100 mm Hg) or clinically significant (i.e. active) cardiovascular disease: cerebrovascular accident/stroke or myocardial infarction within 6 months prior to first study medication, unstable angina, congestive heart failure (CHF) of New York Heart Association (NYHA) Class II or higher (see Appendix B), or serious cardiac arrhythmia requiring medication.
* Significant symptoms (Grade ≥ 2) from peripheral neuropathy.
* Other concurrent serious diseases that may interfere with planned treatment, including severe pulmonary conditions/illness, uncontrolled infections, uncontrolled diabetes.
* Any prior treatment for the current breast cancer, including chemotherapy, hormonal therapy, radiation, or experimental therapy

Primary outcomes:
measure: Adjuvant chemotherapy Received
timeFrame: 2.5 years
Secondary outcomes:
measure: pCR rate
timeFrame: 2 years
measure: Residual Cancer Burden (RCB) scores
timeFrame: 2 years
measure: Reasons for Off-Protocol Escalation per study-specific questionnaires
timeFrame: 2 years
measure: Reasons for Off-Protocol De-Escalation per study-specific questionnaires
timeFrame: 2 years
measure: One Year of Trastuzumab and Pertuzumab
timeFrame: 3 years
measure: Event-Free Survival (EFS)
timeFrame: 12 years
measure: Recurrence-Free Interval (RFI)
timeFrame: 12 years
measure: Overall survival (OS)
timeFrame: 12 years
measure: Post-THP (Paclitaxel/Trastuzumab/Pertuzumab) imaging findings and pathology findings in the surgical specimen
timeFrame: 2 years
Other outcomes:
Locations:
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
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: Milford
country: United States
facility: DF/BWCC at Milford Regional Medical Center
state: Massachusetts
city: South Weymouth
country: United States
facility: DF/BWCC in clinical affiliation with South Shore Hospital
state: Massachusetts
Study officials:
affiliation: Dana-Farber Cancer Institute
name: Adrienne G Waks, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Waks AG, Desai NV, Li T, Poorvu PD, Partridge AH, Sinclair N, Spring LM, Faggen M, Constantine M, Metzger O, Alberti J, Deane J, Rosenberg SM, Frank E, Tolaney SM, Krop IE, Tung NM, Tayob N, King TA, Mittendorf EA, Winer EP. A prospective trial of treatment de-escalation following neoadjuvant paclitaxel/trastuzumab/pertuzumab in HER2-positive breast cancer. NPJ Breast Cancer. 2022 May 10;8(1):63. doi: 10.1038/s41523-022-00429-7.