TEAL: Neoadjuvant TDM1 With Lapatinib and Abraxane Compared With Trastuzumab Plus Pertuzumab With Paclitaxel

• Sponsor: The Methodist Hospital Research Institute (Other)
• Overall Status: Completed
• CT.gov ID: NCT02073487
• Collaborator: Celgene Corporation (Industry), Novartis (Industry)
• Enrollment: 32
• Locations: 3
• Arms: 2
• Duration (Months): 59
• Patients Per Site: 10.7
• Patients Per Site Per Month: 0.2

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Breast Cancer	Drug: T-DM1; Drug: Trastuzumab; Drug: Lapatinib; Drug: Abraxane; Drug: Paclitaxel; Drug: Pertuzumab	Phase 2

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 32 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• 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 Start Date: Feb 1, 2014
• Actual Primary Completion Date: Jan 1, 2019
• Actual Study Completion Date: Jan 1, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: T-DM1 + Lapatinib + Abraxane T-DM1 intravenously (IV) every three weeks plus L orally once daily for 6 weeks followed by abraxane IV weekly for 12 weeks.	Drug: T-DM1; antibody-drug conjugate of trastuzumab and emtansine; Other Names: trastuzumab emtansine Kadcyla ; Drug: Lapatinib; Dual tyrosine kinase inhibitor (HER2 and EGFR); Other Names: tykerb ; Drug: Abraxane; albumin-bound paclitaxel. chemotherapy - microtubule inhibitor.; Other Names: nab-paclitaxel
Active Comparator: Trastuzumab + Pertuzumab + Paclitaxel Trastuzumab IV weekly plus pertuzumab IV every 3 weeks for 6 weeks, followed by paclitaxel IV weekly for 12 weeks.	Drug: Trastuzumab; anti-Her2 monoclonal antibody; Other Names: Herceptin ; Drug: Paclitaxel; chemotherapy - microtubule inhibitor; Other Names: Taxol ; Drug: Pertuzumab; anti-HER2 monoclonal antibody; Other Names: Perjeta

Outcome Measures

Primary Outcome Measures

1. Pathological Complete Response (pCR) RCB-0 or RCB-1 [From date of randomization until the date of surgery, approximately 16 weeks]

   To evaluate the pathological complete response (pCR) in the breast after treatment with Trastuzumab Emtansine plus Lapatinib follow by Abraxane in women with HER2 Neu over-expressed breast cancer patients per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.", or similar definition that is accurate and appropriate. Residual cancer burden (RCB)-0 was synonymous with pCR, indicating no residual disease present.

Secondary Outcome Measures

1. Breast Imaging Response to Treatment: Number of Eventual Responders in Standard Arm [From date of randomization until 6 weeks post treatment]

   To determine the change in tumor size by MRI at 6 weeks post treatment using RECIST v1.0. Criteria. Since all patients in the experimental arm achieved RCB-0 or RCB-1 (pCR), changes in tumor size by MRI were only evaluated in patients on the standard arm.

Other Outcome Measures

1. Determine Predictive Markers [approximately 1 year]

   To determine predictive markers for sensitivity and resistance to Trastuzumab Emtansine when combined with Lapatinib follow by Abraxane

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Houston Methodist Hospital	Houston	Texas	United States	77030
2	Houston Methodist Hospital Willowbrook	Houston	Texas	United States	77070
3	Houston Methodist Hospital Sugar Land	Sugar Land	Texas	United States	77479

Sponsors and Collaborators

• The Methodist Hospital Research Institute
• Celgene Corporation
• Novartis

Investigators

• Principal Investigator: Jenny C Chang, MD, The Methodist Hospital Research Institute

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Jan 23, 2014

More Information

Publications

None provided.

• Responsible Party: Jenny C. Chang, MD, Principal Investigator, The Methodist Hospital Research Institute
• ClinicalTrials.gov Identifier: NCT02073487
• Other Study ID Numbers: Pro00010074; 1013-0164
• First Posted: Feb 27, 2014
• Last Update Posted: Sep 22, 2021
• Last Verified: Aug 1, 2021

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Keywords provided by Jenny C. Chang, MD, Principal Investigator, The Methodist Hospital Research Institute: Neoadjuvant Breast Cancer; HER2 positive Breast Cancer
• Additional relevant MeSH terms: Breast Neoplasms; Paclitaxel; Ado-Trastuzumab Emtansine; Albumin-Bound Paclitaxel; Trastuzumab; Lapatinib; Pertuzumab

Study Results

Participant Flow

Recruitment Details	16 patients were enrolled into each arm of the study, for a total of 32 patients. The trial was closed early due to superiority, with 14 patients completing the experimental arm and 16 patients completing the standard, control arm.

Arm/Group Title	T-DM1 + Lapatinib + Abraxane	Trastuzumab + Pertuzumab + Paclitaxel
Arm/Group Description	T-DM1 intravenously (IV) every three weeks plus L orally once daily for 6 weeks followed by abraxane IV weekly for 12 weeks. T-DM1: antibody-drug conjugate of trastuzumab and emtansine Lapatinib: Dual tyrosine kinase inhibitor (HER2 and EGFR) Abraxane: albumin-bound paclitaxel. chemotherapy - microtubule inhibitor.	Trastuzumab IV weekly plus pertuzumab IV every 3 weeks for 6 weeks, followed by paclitaxel IV weekly for 12 weeks. Trastuzumab: anti-Her2 monoclonal antibody Paclitaxel: chemotherapy - microtubule inhibitor Pertuzumab: anti-HER2 monoclonal antibody
Period Title: Overall Study
STARTED	16	16
COMPLETED	14	16
NOT COMPLETED	2	0

Baseline Characteristics

Arm/Group Title	T-DM1 + Lapatinib + Abraxane	Trastuzumab + Pertuzumab + Paclitaxel	Total
Arm/Group Description	T-DM1 intravenously (IV) every three weeks plus Lapatinib orally once daily for 6 weeks followed by abraxane IV weekly for 12 weeks. T-DM1: antibody-drug conjugate of trastuzumab and emtansine Lapatinib: Dual tyrosine kinase inhibitor (HER2 and EGFR) Abraxane: albumin-bound paclitaxel. chemotherapy - microtubule inhibitor.	Trastuzumab IV weekly plus pertuzumab IV every 3 weeks for 6 weeks, followed by paclitaxel IV weekly for 12 weeks. Trastuzumab: anti-Her2 monoclonal antibody Paclitaxel: chemotherapy - microtubule inhibitor Pertuzumab: anti-HER2 monoclonal antibody	Total of all reporting groups
Overall Participants	14	16	30
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	53.1	57.2	55.1
Sex: Female, Male (Count of Participants)
Female	14 100%	16 100%	30 100%
Male	0 0%	0 0%	0 0%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	5 35.7%	4 25%	9 30%
Not Hispanic or Latino	9 64.3%	12 75%	21 70%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	1 7.1%	1 6.3%	2 6.7%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	1 7.1%	0 0%	1 3.3%
White	12 85.7%	15 93.8%	27 90%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
United States	14 100%	16 100%	30 100%
Invasive ductal carcinoma (Count of Participants)
Count of Participants [Participants]	13 92.9%	14 87.5%	27 90%
Tumor grade: 2 (Count of Participants)
Count of Participants [Participants]	7 50%	8 50%	15 50%
Tumor grade: 3 (Count of Participants)
Count of Participants [Participants]	7 50%	8 50%	15 50%
Tumor stage: II (Count of Participants)
Count of Participants [Participants]	7 50%	8 50%	15 50%
Tumor stage: III (Count of Participants)
Count of Participants [Participants]	7 50%	8 50%	15 50%

Outcome Measures

1. Primary Outcome

Title	Pathological Complete Response (pCR) RCB-0 or RCB-1
Description	To evaluate the pathological complete response (pCR) in the breast after treatment with Trastuzumab Emtansine plus Lapatinib follow by Abraxane in women with HER2 Neu over-expressed breast cancer patients per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.", or similar definition that is accurate and appropriate. Residual cancer burden (RCB)-0 was synonymous with pCR, indicating no residual disease present.
Time Frame	From date of randomization until the date of surgery, approximately 16 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	T-DM1 + Lapatinib + Abraxane	Trastuzumab + Pertuzumab + Paclitaxel
Arm/Group Description	T-DM1 intravenously (IV) every three weeks plus L orally once daily for 6 weeks followed by abraxane IV weekly for 12 weeks. T-DM1: antibody-drug conjugate of trastuzumab and emtansine Lapatinib: Dual tyrosine kinase inhibitor (HER2 and EGFR) Abraxane: albumin-bound paclitaxel. chemotherapy - microtubule inhibitor.	Trastuzumab IV weekly plus pertuzumab IV every 3 weeks for 6 weeks, followed by paclitaxel IV weekly for 12 weeks. Trastuzumab: anti-Her2 monoclonal antibody Paclitaxel: chemotherapy - microtubule inhibitor Pertuzumab: anti-HER2 monoclonal antibody
Measure Participants	14	16
Count of Participants [Participants]	14 100%	10 62.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	T-DM1 + Lapatinib + Abraxane, Trastuzumab + Pertuzumab + Paclitaxel
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.01
	Comments
	Method	Fisher Exact
	Comments

2. Secondary Outcome

Title	Breast Imaging Response to Treatment: Number of Eventual Responders in Standard Arm
Description	To determine the change in tumor size by MRI at 6 weeks post treatment using RECIST v1.0. Criteria. Since all patients in the experimental arm achieved RCB-0 or RCB-1 (pCR), changes in tumor size by MRI were only evaluated in patients on the standard arm.
Time Frame	From date of randomization until 6 weeks post treatment

Outcome Measure Data

Analysis Population Description

Since all patients in the experimental arm achieved RCB-0 or RCB-1 (pCR), changes in tumor size by MRI were only evaluated in patients on the standard arm. Of 16 patients enrolled in the standard arm, 5 had incomplete imaging data. Therefore, 11 patients were analyzed.

Arm/Group Title	Trastuzumab + Pertuzumab + Paclitaxel
Arm/Group Description	Trastuzumab IV weekly plus pertuzumab IV every 3 weeks for 6 weeks, followed by paclitaxel IV weekly for 12 weeks. Trastuzumab: anti-Her2 monoclonal antibody Paclitaxel: chemotherapy - microtubule inhibitor Pertuzumab: anti-HER2 monoclonal antibody
Measure Participants	11
Count of Participants [Participants]	5 35.7%

3. Other Pre-specified Outcome

Title	Determine Predictive Markers
Description	To determine predictive markers for sensitivity and resistance to Trastuzumab Emtansine when combined with Lapatinib follow by Abraxane
Time Frame	approximately 1 year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

Adverse Events

Time Frame	From time of informed consent through 30 days after the last treatment dose.
Arm/Group Title	T-DM1 + Lapatinib + Abraxane		Trastuzumab + Pertuzumab + Paclitaxel
Arm/Group Description	T-DM1 intravenously (IV) every three weeks plus L orally once daily for 6 weeks followed by abraxane IV weekly for 12 weeks. T-DM1: antibody-drug conjugate of trastuzumab and emtansine Lapatinib: Dual tyrosine kinase inhibitor (HER2 and EGFR) Abraxane: albumin-bound paclitaxel. chemotherapy - microtubule inhibitor.		Trastuzumab IV weekly plus pertuzumab IV every 3 weeks for 6 weeks, followed by paclitaxel IV weekly for 12 weeks. Trastuzumab: anti-Her2 monoclonal antibody Paclitaxel: chemotherapy - microtubule inhibitor Pertuzumab: anti-HER2 monoclonal antibody
All Cause Mortality
	T-DM1 + Lapatinib + Abraxane		Trastuzumab + Pertuzumab + Paclitaxel
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/14 (0%)		0/16 (0%)
Serious Adverse Events
	T-DM1 + Lapatinib + Abraxane		Trastuzumab + Pertuzumab + Paclitaxel
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/14 (0%)		0/16 (0%)
Other (Not Including Serious) Adverse Events
	T-DM1 + Lapatinib + Abraxane		Trastuzumab + Pertuzumab + Paclitaxel
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	14/14 (100%)		16/16 (100%)
Blood and lymphatic system disorders
Hypokalemia	3/14 (21.4%)		6/16 (37.5%)
Hypomagnesemia	0/14 (0%)		1/16 (6.3%)
Platelet count decreased	1/14 (7.1%)		0/16 (0%)
Neutrophil count decreased	1/14 (7.1%)		0/16 (0%)
Cardiac disorders
Myocardial infarction	1/14 (7.1%)		0/16 (0%)
Gastrointestinal disorders
Diarrhea	7/14 (50%)		7/16 (43.8%)
Constipation	1/14 (7.1%)		0/16 (0%)
General disorders
Fatigue	7/14 (50%)		8/16 (50%)
Mucositis	1/14 (7.1%)		1/16 (6.3%)
Nail discoloration	1/14 (7.1%)		0/16 (0%)
Nausea	0/14 (0%)		3/16 (18.8%)
Epistaxis	2/14 (14.3%)		0/16 (0%)
Chest pain	0/14 (0%)		1/16 (6.3%)
Breast pain	0/14 (0%)		1/16 (6.3%)
Hepatobiliary disorders
Liver Function Abnormality	9/14 (64.3%)		11/16 (68.8%)
Musculoskeletal and connective tissue disorders
Musculoskeletal pain	0/14 (0%)		1/16 (6.3%)
Nervous system disorders
Neuropathy	3/14 (21.4%)		3/16 (18.8%)
Psychiatric disorders
Depression	1/14 (7.1%)		1/16 (6.3%)
Anxiety	0/14 (0%)		1/16 (6.3%)
Skin and subcutaneous tissue disorders
Rash	3/14 (21.4%)		3/16 (18.8%)
Skin Discoloration	1/14 (7.1%)		0/16 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.