Clinical trial NCT02073487: Neoadjuvant TDM1 With Lapatinib and Abraxane Compared With Trastuzumab Plus Pertuzumab With Paclitaxel
Official title: Randomized Open Label PhII Trial of Neoadjuvant Trastuzumab Emtansine(Te) in Combination w/Lapatinib(L) Followed by Abraxane (A) Compared w/Trastuzumab Plus Pertuzumab Followed by Paclitaxel in Her2/Neu Over-Expressed Breast Cancer Patients
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Breast Cancer
Keywords: Neoadjuvant Breast Cancer
HER2 positive Breast Cancer
Lead sponsor: The Methodist Hospital Research Institute
Sponsor class: OTHER
Collaborators: name: Celgene Corporation
name: Novartis
First posted: 2014-02-27
Enrollment: 32
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This is a randomized, open label Phase II neoadjuvant study comparing the efficacy and safety of trastuzumab emtansine (T-DM1) plus lapatinib (L)followed by abraxane (A) versus trastuzumab plus pertuzumab followed by paclitaxel in patients with HER2-overexpressing breast cancer.

Detailed description: This is a randomized, open label Phase II neoadjuvant study comparing the efficacy and safety of trastuzumab emtansine (T-DM1) plus lapatinib (L) followed by abraxane (A) versus trastuzumab plus pertuzumab followed by paclitaxel in patients with HER2-overexpressing breast cancer. Patients will be randomized (1:1) to one of the two treatment arms: arm 1, trastuzumab emtansine plus lapatinib for 6 weeks, followed by trastuzumab emtansine plus lapatinib plus abraxane for 12 weeks; arm 2, trastuzumab plus pertuzumab for six weeks, followed by trastuzumab plus pertuzumab plus paclitaxel for 12 weeks. Patients will undergo surgery after neoadjuvant therapy. All patients will have a core needle biopsy at baseline, after week 6, and at the time of disease progression. Surgical specimens will be obtained after week 18.

Eligibility criteria: Inclusion Criteria:

* Female gender;
* Age ≥18 years;
* Performance Status- Eastern Cooperative Oncology Group (ECOG) 0-1
* Histologically confirmed invasive breast cancer:
* Primary tumor greater than 1 cm diameter, measured by clinical examination and mammography or ultrasound.
* Any N,
* No evidence of metastasis (M0) (isolated supra-clavicular node involvement allowed);
* Over expression and/or amplification of HER2 in the invasive component of the primary tumor and confirmed by a certified laboratory prior to randomization.
* Known hormone receptor status.
* Hematopoietic status:
* CBC not less than .75 of institutional lower limit. Absolute neutrophil count ≥ 1,5 x 10\^9/L, Platelet count ≥ 100 x 10\^9/L, Hemoglobin at least 9 g/dl,
* Hepatic status:

Serum total bilirubin ≤ 2 x upper limit of normal (ULN). In the case of known Gilbert's syndrome, a higher serum total bilirubin (\< 1.5 x ULN) is allowed, Aspartate Aminotransferase (AST) and Alanine Aminotransferase (ALT) ≤ 3.5 times ULN, Alkaline phosphatase ≤ 2.5 times ULN, • Renal status: Creatinine ≤ 1.5mg/dL,

• Cardiovascular: Baseline left ventricular ejection fraction (LVEF) ³ ≥50% measured by echocardiography (ECHO) or Multiple Gate Acquisition (MUGA) scan,

* Negative serum or urine β-hCG pregnancy test at screening for patients of childbearing potential within 2-weeks (preferably 7 days) prior to randomization.
* Fertile patients must use effective contraception (barrier method - condoms, diaphragm - also in conjunction with spermicidal jelly, or total abstinence. Oral, injectable, or implant hormonal contraceptives are not allowed)
* Signed informed consent form (ICF)
* Patient accepts to make available tumor samples for submission to central laboratory to conduct translational studies as part of this protocol.

Exclusion Criteria:

* Previous (less than 5 years) or current history of malignant neoplasms, except for curatively treated: Basal and squamous cell carcinoma of the skin; Carcinoma in situ of the cervix.
* Patients with a prior malignancy diagnosed more than 5 years prior to randomization may enter the study.
* Preexisting peripheral neuropathy ≥ grade 2
* Known history of uncontrolled or symptomatic angina, clinically significant arrhythmias, congestive heart failure, transmural myocardial infarction, uncontrolled hypertension (≥180/110), unstable diabetes mellitus, dyspnea at rest, or chronic therapy with oxygen;
* Concurrent disease or condition that would make the subject inappropriate for study participation or any serious medical disorder that would interfere with the subject's safety;
* Unresolved or unstable, serious adverse events from prior administration of another investigational drug;
* Dementia, altered mental status, or any psychiatric condition that would prevent the understanding or rendering of ICF;
* Malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel. Subjects with ulcerative colitis are also excluded;
* Concurrent neoadjuvant cancer therapy (chemotherapy, radiation therapy, immunotherapy, biologic therapy other than the trial therapies);
* Concurrent treatment with an investigational agent or participation in another therapeutic clinical trial;
* Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to trastuzumab Emtansine, trastuzumab, lapatinib, paclitaxel, abraxane or their components;
* Pregnant or lactating women;
* Concomitant use of CYP3A4 inhibitors or inducers
* Other concurrent severe and/or uncontrolled concomitant medical conditions (e.g. active or uncontrolled infection, uncontrolled diabetes) that could cause unacceptable safety risks or compromise compliance with the protocol
* Patients have an active infection and require IV or oral antibiotics.
* Pregnant or breast-feeding women
* Patients unwilling or unable to comply with the protocol

Primary outcomes:
measure: Pathological Complete Response (pCR) RCB-0 or RCB-1
timeFrame: From date of randomization until the date of surgery, approximately 16 weeks
Secondary outcomes:
measure: Breast Imaging Response to Treatment: Number of Eventual Responders in Standard Arm
timeFrame: From date of randomization until 6 weeks post treatment
Other outcomes:
measure: Determine Predictive Markers
timeFrame: approximately 1 year
Locations:
city: Houston
country: United States
facility: Houston Methodist Hospital
state: Texas
city: Houston
country: United States
facility: Houston Methodist Hospital Willowbrook
state: Texas
city: Sugar Land
country: United States
facility: Houston Methodist Hospital Sugar Land
state: Texas
Study officials:
affiliation: The Methodist Hospital Research Institute
name: Jenny C Chang, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Patel TA, Ensor JE, Creamer SL, Boone T, Rodriguez AA, Niravath PA, Darcourt JG, Meisel JL, Li X, Zhao J, Kuhn JG, Rosato RR, Qian W, Belcheva A, Schwartz MR, Kaklamani VG, Chang JC. A randomized, controlled phase II trial of neoadjuvant ado-trastuzumab emtansine, lapatinib, and nab-paclitaxel versus trastuzumab, pertuzumab, and paclitaxel in HER2-positive breast cancer (TEAL study). Breast Cancer Res. 2019 Sep 2;21(1):100. doi: 10.1186/s13058-019-1186-0.