T-DM1 vs Paclitaxel/Trastuzumab for Breast (ATEMPT Trial)

Study Overview
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Brief Summary
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This research study is a Phase II clinical trial. Phase II clinical trials test the effectiveness of an investigational drug to learn whether the drug works in treating a specific cancer. Investigational means that the drug is still being studied and that research doctors are trying to find out more about it-such as the safest dose to use, the side effects it may cause, and if the drug is effective for treating different types of cancer. It also means that the FDA has not approved this drug for use patients undergoing adjuvant treatment for HER2+ breast cancer. Trastuzumab emtansine (T-DM1) is a drug that may stop cancer cells from growing. This drug has been used in other research studies and information from those other research studies suggests that this drug may help to prevent the recurrence of breast cancer in this research study. The use of T-DM1 in this research study is experimental, which means it is not approved by any regulatory authority for the adjuvant treatment of HER2-positive breast cancer. However, it FDA-approved for metastatic HER2-positive breast cancer. T-DM1 has caused cancer cells to die in laboratory studies. In preclinical studies, this drug has prevented or slowed the growth of breast cancer. The breast cancer treatments (paclitaxel and Trastuzumab) used in this study are considered part of standard-of-care regimens in early breast cancer. A standard treatment means that this is a treatment that would be accepted by the majority of the medical community as a suitable treatment for your type of breast cancer. In this research study, the investigators are looking to see if the study drug T-DM1 will have less side effects than traditional HER2-positive breast cancer treatment of trastuzumab and paclitaxel. The investigators are also hoping to learn about the long term benefits and disease-free survival of participants who take the study drug T-DM1 in comparison to those participants to take the combination of trastuzumab and paclitaxel.

Detailed Description
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If a participant agrees to participate in this study she will be asked to undergo some screening tests or procedures to confirm that she is eligible. Many of these tests and procedures are likely to be part of regular cancer care and may be done even if turns out that she does not take part in this research study. If she has had some of these tests or procedures recently, they may or may not have to be repeated. These tests and procedures will include: a medical history, performance status, assessment of your tumor, blood tests, cardiac tests, pregnancy test and a collection of tumor tissue. If these tests show that she is eligible to participate in the research study, she will begin the study treatment. If she does not meet the eligibility criteria, she will not be able to participate in this research study. Because no one knows which of the study options is best, the participant will be randomized into one of the study groups after she has had her breast surgery: Group 1 or Group 2. Randomization means that she is put into a group by chance. Neither the participant nor the research doctor will choose what group she will be in. The participant will have a one in three chance of being placed in any group. Approximately 375 study participants will receive the study drug, while 125 study participants will receive the standard therapy of trastuzumab and paclitaxel. Group 1 participants will receive the study drug T-DM1 every three weeks by IV (intravenous injection) for 17 treatments (total of 51 weeks). Group 2 participants will receive the FDA-approved drugs Paclitaxel and Trastuzumab once per week by IV for 12 weeks. Then beginning week 13, participants will receive Trastuzumab only by IV injection every three weeks for the next 13 treatments. During all cycles the participant will have a physical exam and tumor assessment. The investigators would like to keep track of the participant's medical condition for the next five years after the final dose of study drug. The investigators would like to do this by regular visits every 6 months for 3 years after completion of study treatment, and then once a year for the next two years. The investigators may ask for additional follow-up by phone after completion of these visits. Participants who undergo lumpectomy (breast conserving surgery) need to receive breast radiation therapy to participate in this study. Participants who have undergone a mastectomy may receive chest wall and lymph node radiation (as determined by discussion with their physician). Radiation Therapy will begin after the conclusion of all study paclitaxel doses, and after 12 weeks fo the study drug T-DM1.

Official Title
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A Randomized Phase II Study of Trastuzumab Emtansine (T-DM1) vs. Paclitaxel in Combination With Trastuzumab for Stage I HER2-Positive Breast Cancer (ATEMPT Trial)

Conditions
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Breast Cancer

Intervention / Treatment
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* Drug: Trastuzumab
* Drug: Paclitaxel
* Drug: Trastuzumab emtansine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: HER2-positive Stage I histologically confirmed invasive carcinoma of the breast ER/PR determination is required HER2 positive, confirmed by central testing: IHC 3+, FISH HER2/CEP17 <2.0 with an average HER2 copy number >/=6.0, or FISH HER2/CEP17 >/= 2.0 Bilateral breast cancers that individually meet eligibility criteria are allowed Subjects with multifocal or multicentric disease are eligible as long as each tumor individually meets eligibility criteria Subjects with a history of ipsilateral DCIS are eligible if they were treated with wide-excision alone, without radiation therapy; Patients with a history of contralateral DCIS are not eligible. Should have tumor tissue available and a tissue block of sufficient size to make 15 slides, which must be sent to a DFCI site for testing Less than or equal to 90 days since most recent breast surgery for this breast cancer 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 May have received up to 4 weeks of tamoxifen therapy or other hormonal therapy, for adjuvant therapy for this cancer Prior oophorectomy for cancer prevention is allowed Subjects who have undergone partial breast radiation (duration </= 7 days) prior to registration are eligible. Partial breast radiation must be completed prior to 2 weeks before starting protocol therapy. Must have discontinued any investigational drug at least 2 weeks prior to participation Willing to use one highly effective from of nonhormonal contraception or two effective forms of nonhormonal contraception while on study and for 7 months after end of study treatment Subjects undergoing lumpectomy must have no contraindications to radiation therapy Exclusion Criteria: Pregnant or breastfeeding Use of potent CYP3A4 inhibitors during the study treatment period Excessive alcohol intake (more than 3 alcoholic beverages per day) Locally advanced tumors at diagnosis History of previous invasive breast cancer History of prior chemotherapy in the past 5 years History of prior trastuzumab or prior paclitaxel therapy Active, unresolved infection Active liver disease History of a different malignancy except for the following: disease free for at least 5 years and at low risk for recurrence; cervical cancer in situ, basal or squamous cell carcinoma of the skin Active cardiac disease

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Trastuzumab emtansine (T-DM1)<br>T-DM1 3.6mg/kg every three weeks by IV for 17 doses for a total of 51 weeks | Drug: Trastuzumab emtansine<br> <br> * Other names: T-DM1;|
| Active Comparator: Paclitaxel + Trastuzumab<br>paclitaxel 80 mg/m2 IV weekly and trastuzumab 4 mg/kg IV load, followed by 2 mg/kg IV weekly for 12 weeks, followed by trastuzumab 6 mg/kg IV every 3 weeks for 13 treatments | Drug: Trastuzumab<br> <br> Drug: Paclitaxel<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants of Clinically Relevant Toxicities (CRT) | Clinically relevant toxicities will include the composite incidence of grade 3 or higher non-hematologic toxicity, grade 2 or higher neurotoxicity, and grade 4 or higher hematologic toxicity. These toxicities will only be assessed at the pre-specified toxicity-assessment visits. In addition, the following events, regardless of timing of their occurrence, will also count towards the composite endpoint: febrile neutropenia, any toxicity requiring dose-delay, discontinuation of any study treatment (Paclitaxel, Trastuzumab, or T-DM1) for toxicity, and any serious adverse event (SAE). | 5 years after completion of study treatment or until death, whichever occurs first. | 
| 3-year Disease Free Survival (DFS) Rate of Trastuzumab Emtansine (TDM-1) | Disease-free survival (DFS) is evaluated and defined per protocol: from the time of randomization until the to the occurrence of the first of the following events: Local/regional recurrence: a recurrent or new invasive ipsilateral breast cancer, invasive breast cancer in the axilla, regional lymph nodes, chest wall, or skin of the ipsilateral breast. Contralateral invasive breast cancer, Distant recurrence: metastatic disease that has either been biopsy confirmed or clinically diagnosed as recurrent invasive breast cancer. A single new lesion on a bone scan without evidence of lytic disease on x-ray and without symptoms does not in and of itself constitute distant recurrence, but multiple new bone lesions, or increased isotope uptake associated with new bone symptoms are more likely due to metastases. Bone metastases must be documented with x-rays and clinical description. Death from any cause | 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence Rate of Grade 3-4 Treatment-Related Toxicity | All grade 3 - 4 adverse events (AE) with treatment attribution of possibly, probably or definite based on CTCAEv4 as reported on case report forms were counted. Incidence is the number of patients experiencing at least one treatment-related grade >=3 AE of any type during the time of observation. | AE is reported every 3 weeks for the first 12 weeks, then every 9 weeks for the subsequent 39 weeks, then follow-up up to 5 years after completion of study treatment or until death, whichever occurs first. Median follow-up 3.1 years. | 
| Quality of Life (QOL) FACT B Total Score at Baseline | The QOL assessments questionnaire should be completed via the tablet provided by the study or on any available computer with an internet connection. The FACT-B questionnaire consists of five subscale, listed below: Physical well being(PWB): range 0-28 Social/Family well being(SWB): range 0-28 Emotional well being(EWB): range 0-24 Functional well being(FWB): range 0-28 Breast cancer subscale(BCS): range 0-40 The total score (FACTB) is calculated by summarizing all the subscales listed above, therefore it ranges from 0 to 148. The higher the score the better the outcome (applies to all sub-scales as well). | at baseline | 
| Quality of Life (QOL) FACT B Total Score at Week 3 | The QOL assessments questionnaire should be completed via the tablet provided by the study or on any available computer with an internet connection. The FACT-B questionnaire consists of five subscale, listed below: Physical well being(PWB): range 0-28 Social/Family well being(SWB): range 0-28 Emotional well being(EWB): range 0-24 Functional well being(FWB): range 0-28 Breast cancer subscale(BCS): range 0-40 The total score (FACTB) is calculated by summarizing all the subscales listed above, therefore it ranges from 0 to 148. The higher the score the better the outcome (applies to all sub-scales as well). | at week 3 | 
| Quality of Life (QOL) FACT B Total Score at Week 12 | The QOL assessments questionnaire should be completed via the tablet provided by the study or on any available computer with an internet connection. The FACT-B questionnaire consists of five subscale, listed below: Physical well being(PWB): range 0-28 Social/Family well being(SWB): range 0-28 Emotional well being(EWB): range 0-24 Functional well being(FWB): range 0-28 Breast cancer subscale(BCS): range 0-40 The total score (FACTB) is calculated by summarizing all the subscales listed above, therefore it ranges from 0 to 148. The higher the score the better the outcome (applies to all sub-scales as well). | at week 12 | 
| Quality of Life (QOL) FACT B Total Score at 6 Months | The QOL assessments questionnaire should be completed via the tablet provided by the study or on any available computer with an internet connection. The FACT-B questionnaire consists of five subscale, listed below: Physical well being(PWB): range 0-28 Social/Family well being(SWB): range 0-28 Emotional well being(EWB): range 0-24 Functional well being(FWB): range 0-28 Breast cancer subscale(BCS): range 0-40 The total score (FACTB) is calculated by summarizing all the subscales listed above, therefore it ranges from 0 to 148. The higher the score the better the outcome (applies to all sub-scales as well). | at 6 months | 
| Quality of Life (QOL) FACT B Total Score at 1 Year | The QOL assessments questionnaire should be completed via the tablet provided by the study or on any available computer with an internet connection. The FACT-B questionnaire consists of five subscale, listed below: Physical well being(PWB): range 0-28 Social/Family well being(SWB): range 0-28 Emotional well being(EWB): range 0-24 Functional well being(FWB): range 0-28 Breast cancer subscale(BCS): range 0-40 The total score (FACTB) is calculated by summarizing all the subscales listed above, therefore it ranges from 0 to 148. The higher the score the better the outcome (applies to all sub-scales as well). | at 1 year | 
| Quality of Life (QOL) FACT B Total Score at 18 Months | The QOL assessments questionnaire should be completed via the tablet provided by the study or on any available computer with an internet connection. The FACT-B questionnaire consists of five subscale, listed below: Physical well being(PWB): range 0-28 Social/Family well being(SWB): range 0-28 Emotional well being(EWB): range 0-24 Functional well being(FWB): range 0-28 Breast cancer subscale(BCS): range 0-40 The total score (FACTB) is calculated by summarizing all the subscales listed above, therefore it ranges from 0 to 148. The higher the score the better the outcome (applies to all sub-scales as well). | at 18 months | 
| Quality of Life (QOL) FACT B Total Score at 24 Months | The QOL assessments questionnaire should be completed via the tablet provided by the study or on any available computer with an internet connection. The FACT-B questionnaire consists of five subscale, listed below: Physical well being(PWB): range 0-28 Social/Family well being(SWB): range 0-28 Emotional well being(EWB): range 0-24 Functional well being(FWB): range 0-28 Breast cancer subscale(BCS): range 0-40 The total score (FACTB) is calculated by summarizing all the subscales listed above, therefore it ranges from 0 to 148. The higher the score the better the outcome (applies to all sub-scales as well). | at 24 months | 
| Number of Patients Has Neuropathy | Neuropathy evaluated by Patient Neurotoxicity Questionnaire (PNQ) defined per protocol. | Surveys are took at week 3, 12 and month 6 and 12 during treatment, and month 18. The data cutoff date is 18 month. | 
| Percentage of Work Time Missed Because of Health | Effects of therapy on work productivity and activity - work time missed because of health, evaluated using the Work Productivity and Activity Impairment Questionnaire (WPAI-SHP), which defined per protocol. | Surveys are took at week 3, 12 and month 6 and 12 during treatment, and month 18, 24, 30 and 36 during follow up. | 
| Percentage of Impairment While Working Because of Health (Mean, SD) | Effects of therapy on work productivity and activity - Impairment While Working because of health, evaluated using the Work Productivity and Activity Impairment Questionnaire (WPAI-SHP), which defined per protocol. | Surveys are took at week 3, 12 and month 6 and 12 during treatment, and month 18, 24, 30 and 36 during follow up. | 
| Percentage of Overall Work Impairment Because of Health | Effects of therapy on work productivity and activity - Work Impairment because of health, evaluated using the Work Productivity and Activity Impairment Questionnaire (WPAI-SHP), which defined per protocol. | Surveys are took at week 3, 12 and month 6 and 12 during treatment, and month 18, 24, 30 and 36 during follow up. | 
| Percentage of Activity Impairment Because of Health | Effects of therapy on work productivity and activity - Activity Impairment because of health, evaluated using the Work Productivity and Activity Impairment Questionnaire (WPAI-SHP), which defined per protocol. | Surveys are took at week 3, 12 and month 6 and 12 during treatment, and month 18, 24, 30 and 36 during follow up. | 
| Number of Patients Have Alopecia | alopecia assessment is a 5-item questionnaire that will assess the impact alopecia has had on these patients and will be conducted electronically at pre-specified study visits. If electronic evaluation is not possible, paper evaluation will be conducted. | Median follow-up was 3.9 years. The AE data cutoff date is 21 April 2020. | 
| 3-year T-DM1 iDFS Percentage by Tumor Size and Hormone Receptor (HR) Status | Disease-free survival (DFS) is evaluated in patients treated with trastuzumab emtansine, which is defined per protocol: from the time of randomization until the to the occurrence of the first of the following events: Local/regional recurrence: a recurrent or new invasive ipsilateral breast cancer, invasive breast cancer in the axilla, regional lymph nodes, chest wall, or skin of the ipsilateral breast. Contralateral invasive breast cancer, Distant recurrence: metastatic disease that has either been biopsy confirmed or clinically diagnosed as recurrent invasive breast cancer. A single new lesion on a bone scan without evidence of lytic disease on x-ray and without symptoms does not in and of itself constitute distant recurrence, but multiple new bone lesions, or increased isotope uptake associated with new bone symptoms are more likely due to metastases. Bone metastases must be documented with x-rays and clinical description. Death from any cause | 3 years | 
| Number of Incidence of Grade 3-4 Cardiac Left Ventricular Dysfunction | All grade 3 - 4 adverse events (AE) with treatment attribution of possibly, probably or definite based on CTCAEv4 as reported on case report forms were counted. Incidence is the number of patients experiencing at least one treatment-related grade >=3 AE of any type during the time of observation | AE is reported every 3 weeks for the first 12 weeks, then every 9 weeks for the subsequent 39 weeks, then follow-up up to 5 years after completion of study treatment or until death, whichever occurs first. Median follow-up 3.1 years. | 
| Number of Incidence of T-DM1 Induced Grade 2-3 Thrombocytopenia | Reversible Grade 1-4 thrombocytopenia has been observed in ongoing studies with trastuzumab emtansine. | AE is reported every 3 weeks for the first 12 weeks, then every 9 weeks for the subsequent 39 weeks, then follow-up up to 5 years after completion of study treatment or until death, whichever occurs first. Median follow-up 3.1 years. | 
| Number of SNPs With Top Associations of Trastuzumab Emtansine-induced Grade 2-4 Thrombocytopenia in the T-DM1 Arm | DNA will be genotyped for SNPs and CNV markers using the Infinium Human Omni1 array (1.2 million SNP platform) from Illumina. A gene-based association analyses for thrombocytopenia or bleeding is applied with significancy (p-value). This analysis was only conducted in the T-DM1 arm. | DNA sample collected at pre-treatment. AE is reported every 3 weeks for the first 12 weeks, then every 9 weeks for the subsequent 39 weeks. | 
| Percentage of Patients With Amenorrhea | All grade 3 - 4 adverse events (AE) with treatment attribution of possibly, probably or definite based on CTCAEv4 as reported on case report forms were counted. Incidence is the number of patients experiencing at least one treatment-related grade >=3 AE of any type during the time of observation. For those who were premenopausal pre-chemotherapy, at each follow-up visit (every six months) in order to assess for duration of amenorrhea and also premature ovarian failure. | Surveys are took at month 6 and 12 during treatment, and month 18, 24, 30 and 36 during follow up. | 
| Gene Mutation Assessed Using High-throughput Mutation Profiling System (Oncomap) | Archival tumor tissue from all patients will be assessed using a high-throughput mutation profiling system (Oncomap) to query a large panel of cancer gene mutations. | After treatment | 
| Median Overall Survival (OS) | OS is evaluated in patients with Stage I HER2-positive breast cancer treated with trastuzumab emtansine | Reported every 3 weeks for the first 12 weeks, then every 9 weeks for the subsequent 39 weeks, then follow-up up to 5 years after completion of study treatment or until death, whichever occurs first. |