Neoplasms

All Conditions

Skin and Connective Tissue Diseases

Rare Diseases

Carcinoma

Breast Neoplasms

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Breast Diseases

Skin Diseases

Myotonic Dystrophy Type 1

Antineoplastic Agents

All Drugs and Chemicals

Anti-Arrhythmia Agents

Vasodilator Agents

Analgesics

Trastuzumab

Ado-Trastuzumab Emtansine

Tucatinib

Adenosine

Maytansine

Antineoplastic Agents, Immunological

Tubulin Modulators

Antimitotic Agents

Immunotoxins

Immunoconjugates

Immunologic Factors

Protein Kinase Inhibitors

Enzyme Inhibitors

Patients receive T-DM1 IV over 30-90 minutes on day 1 and placebo PO BID on days 1-21. Treatment repeats every 21 days for up to 14 cycles in the absence of disease progression or unacceptable toxicity.

Patients receive T-DM1 IV over 30-90 minutes on day 1 and tucatinib PO BID on days 1-21. Treatment repeats every 21 days for up to 14 cycles in the absence of disease progression or unacceptable toxicity.

Trastuzumab Emtansine

Placebo Administration

Questionnaire Administration

Quality-of-Life Assessment

Ciara C. O'Sullivan, MB, BCh, BAO

Site Public Contact

Katia Khoury

Jose N. Galeas

Nicholas DiBella

Shakeela W. Bahadur

John A. Ellerton

Philip E. Lammers

Sri Obulareddy

Kristie A. Bobolis

Hope S. Rugo

Jin Sun L. Bitar

Shahzad Siddique

Uzair B. Chaudhary

Ritesh Parajuli

Joanne E. Mortimer

Jennifer M. Suga

Bogdan S. Eftimie

David J. Park

Priya Jayachandran

Timothy E. Byun

Kim M. Phan

Melinda L. Telli

Steven H. Applebaum

Manasa Vulchi

Tyler Y. Kang

Hong Zhao

Alison K. Conlin

This phase III trial studies how well trastuzumab emtansine (T-DM1) and tucatinib work in preventing breast cancer from coming back (relapsing) in patients with high risk, HER2 positive breast cancer. T-DM1 is a monoclonal antibody, called trastuzumab, linked to a chemotherapy drug, called DM1. Trastuzumab is a form of targeted therapy because it attaches to specific molecules (receptors) on the surface of cancer cells, known as HER2 receptors, and delivers DM1 to kill them. Tucatinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving T-DM1 and tucatinib may work better in preventing breast cancer from relapsing in patients with HER2 positive breast cancer compared to T-DM1 alone.

PRIMARY OBJECTIVE:

I. To determine if the invasive disease-free survival (iDFS) with T-DM1 and tucatinib is superior to the iDFS in the control arm (T-DM1 + placebo) when administered to high risk patients with HER2-positive breast cancer and residual disease after neoadjuvant HER2-directed therapy.

SECONDARY OBJECTIVES:

I. To evaluate whether treatment with tucatinib plus T-DM1 compared to treatment with T-DM1 alone (T-DM1 plus placebo) improves the following:

Ia. Breast cancer free survival (BCFS). Ib. Distant recurrence-free survival (DRFS). Ic. Brain metastases-free survival (BMFS). Id. Overall survival (OS). II. To evaluate whether treatment with tucatinib plus T-DM1 compared to treatment with T-DM1 alone (T-DM1 plus placebo) reduces the incidence of brain metastases.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM I: Patients receive T-DM1 intravenously (IV) over 30-90 minutes on day 1 and placebo orally (PO) twice daily (BID) on days 1-21. Treatment repeats every 21 days for up to 14 cycles in the absence of disease progression or unacceptable toxicity.

ARM II: Patients receive T-DM1 IV over 30-90 minutes on day 1 and tucatinib PO BID on days 1-21. Treatment repeats every 21 days for up to 14 cycles in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days, then every 6 months for 10 years.

T-DM1 and Tucatinib Compared With T-DM1 Alone in Preventing Relapses in People With High Risk HER2-Positive Breast Cancer, the CompassHER2 RD Trial

The CompassHER2 Trials (Comprehensive Use of Pathologic Response Assessment to Optimize Therapy in HER2-Positive Breast Cancer) CompassHER2 Residual Disease (RD), a Double-Blinded, Phase III Randomized Trial of T-DM1 Compared With T-DM1 and Tucatinib

Will be assessed by the Functional Assessment of Cancer Therapy (FACT)-Breast Cancer (B) Trial Outcome Index questionnaire. The mixed model will compare the cycle 9 day 1 and cycle 14 day 1 time points between randomized arms. In addition to a randomized arm covariate, the model will include a randomized arm-by-time interaction term and will use the planned cycle of assessment as the categorical time value. Unstructured covariance will initially be used, though alternative covariance structures will be investigated with the final covariance structure selected based on minimization of the Akaike information criterion. A contrast will be used to compare mean change from baseline at cycle 9 day 1 between arms. If the two-sided 95% confidence interval excludes a difference of 5 favoring the trastuzumab emtansine (T-DM1) + placebo arm, then non-inferiority will be concluded.

Will be assessed by the Functional Assessment of Cancer Therapy (FACT)-Breast Cancer (B) Trial Outcome Index questionnaire. The mixed model will compare the mean change from baseline at cycle 14 day 1 between arms. If the two-sided 95% confidence interval excludes a difference of 5 favoring the T-DM1 + placebo arm, then non-inferiority will be concluded at this time point.

A Kaplan-Meier method will be used to estimate the survival curves and a stratified log-rank test will be used to compare the invasive disease-free survival (iDFS) of the two arms. A stratified Cox model will be used to estimate the hazard ratio. If there appears to be clinically significant imbalances of baseline variables between the treatment arms, a secondary analysis of the primary endpoint will use stratified Cox model to compare the treatment effects that include the variables that are deemed imbalanced between the arms as adjusting variables. The randomization stratification variables will be the stratified variables in the model.

Will be defined as the time from randomization to one of the following events: invasive local, regional or distant recurrence, invasive contralateral breast cancer secondary primary invasive cancer (other than basal or squamous cell carcinoma of the skin, or carcinoma in situ of the cervix), or death from any cause, assessed up to 10 years. A Kaplan-Meier method will be used to estimate the survival curves and a stratified log-rank test will be used to compare the iDFS of the two arms. A stratified Cox model will be used to estimate the hazard ratio.

Will be summarized with Kaplan-Meier curves and compared between the arms using a stratified log-rank test and stratified Cox model. If there are clinically significant imbalances in baseline characteristics between the treatment arms, a second analysis will be done using a stratified Cox model with the variables that are imbalance added as adjusting variables.

An incident of brain metastases is documentation of involvement of the central nervous system by metastatic cancer including parenchymal brain and spinal cord metastases as well as leptomeningeal carcinomatosis. The cumulative incidence of brain metastases will be determined as the crude cumulative incidence as well as with incidence with competing risks where the competing event is death.

National Cancer Institute (NCI)

Seagen Inc.

Alliance for Clinical Trials in Oncology

Symptoms and General Pathology

Recurrence

Carcinoma in Situ

Carcinoma, Ductal

Carcinoma, Intraductal, Noninfiltrating

Carcinoma, Ductal, Breast

Adenocarcinoma

Breast Carcinoma In Situ

Bone Density Conservation Agents

Anticoagulants

Other Dietary Supplements

Tamoxifen

Hormones

Exemestane

Letrozole

Citric Acid

Sodium Citrate

Anastrozole

Aromatase Inhibitors

Estrogens

Estrogen Antagonists

Estrogen Receptor Antagonists

Hormone Antagonists

Antineoplastic Agents, Hormonal

Selective Estrogen Receptor Modulators

Estrogen Receptor Modulators

Citrate

Patients receive a protocol-approved chemotherapy regimen based on the patient and/or physician preference. Patients then receive a protocol-approved adjuvant endocrine therapy comprising tamoxifen citrate, an aromatase inhibitor (anastrozole, letrozole, or exemestane), or both for 5-10 years in the absence of disease progression or unacceptable toxicity.

Patients receive a protocol-approved endocrine therapy comprising tamoxifen citrate, an aromatase inhibitor (anastrozole, letrozole, or exemestane), or both for 5-10 years in the absence of disease progression or unacceptable toxicity.

Laboratory Biomarker Analysis

Systemic Chemotherapy

Tamoxifen Citrate

Kevin M Kalinsky

This randomized phase III clinical trial studies how well tamoxifen citrate, anastrozole, letrozole, or exemestane with or without chemotherapy work in treating patients with breast cancer that has spread from where it began in the breast to surrounding normal tissue (invasive). Estrogen can cause the growth of breast cancer cells. Hormone therapy, using tamoxifen citrate, may fight breast cancer by blocking the use of estrogen by the tumor cells. Aromatase inhibitors, such as anastrozole, letrozole, and exemestane, may fight breast cancer by lowering the amount of estrogen the body makes. Drugs used in chemotherapy work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. It is not yet known whether giving tamoxifen citrate, anastrozole, letrozole, or exemestane is more effective with combination chemotherapy in treating patients with breast cancer.

PRIMARY OBJECTIVE:

I. To determine the effect of chemotherapy in patients with node positive breast cancer who do not have high recurrence scores (RS) by Oncotype DX.

SECONDARY OBJECTIVES:

I. To compare overall survival (OS), distant disease-free survival (DDFS) and local disease-free interval (LDFI) by receipt of chemotherapy or not and its interaction with RS.

II. To compare the toxicity across the treatment arms. III. To perform other molecular assays or test other signatures that measure prognosis and potential benefit of chemotherapy and compare them to Oncotype DX.

IV. To determine the impact of management with Oncotype DX on patient-reported anxiety (co-primary Health-Related Quality of Life \[HRQL\] outcome) prior to screening, after disclosure of test results, and during the randomized trial.

V. To determine the impact of Oncotype DX on the initial management cost of node-positive, hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer.

VI. To compare patient-reported utilities (e.g., quality of life \[QOL\]) for those randomized to chemotherapy versus no chemotherapy.

VII. Using modeling and DFS information from the trial, to estimate the cost-effectiveness of management with Oncotype DX vs usual care.

VIII. To determine the role of other assays as predictors of DFS, DDFS, and LDFI for patients randomized to chemotherapy versus no chemotherapy.

IX. To determine the impact of treatment with chemotherapy versus no chemotherapy on patient-reported fatigue and cognitive concerns (secondary HRQL outcomes).

X. To determine the impact of management with Oncotype DX on patient-reported decision conflict, perceptions regarding Oncotype DX testing, and survivor concerns prior to screening, after disclosure of test results, and during the randomized trial (secondary HRQL outcomes).

XI. The presence of circulating tumor cells (CTC+) using two CTC platforms will be assessed at up to two time points to assess late recurrence in those still at risk for the primary outcome.

XII. To compare clinically reported menopausal status with status categorized by serum hormone levels determined from baseline serum in women under age 55 years and to assess subsequent association with outcomes.

BANKING OBJECTIVE:

I. To bank specimens for future correlative studies.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive a protocol-approved chemotherapy regimen based on the patient and/or physician preference. Patients then receive a protocol-approved adjuvant endocrine therapy comprising tamoxifen citrate, an aromatase inhibitor (anastrozole, letrozole, or exemestane), or both for 5-10 years in the absence of disease progression or unacceptable toxicity.

ARM II: Patients receive a protocol-approved endocrine therapy comprising tamoxifen citrate, an aromatase inhibitor (anastrozole, letrozole, or exemestane), or both for 5-10 years in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 1 year, every 6 months for 4 years, and then yearly for 15 years.

Tamoxifen Citrate, Letrozole, Anastrozole, or Exemestane With or Without Chemotherapy in Treating Patients With Invasive RxPONDER Breast Cancer

A Phase III, Randomized Clinical Trial of Standard Adjuvant Endocrine Therapy +/- Chemotherapy in Patients With 1-3 Positive Nodes, Hormone Receptor-Positive and HER2-Negative Breast Cancer With Recurrence Score (RS) of 25 or Less. RxPONDER: A Clinical Trial Rx for Positive Node, Endocrine Responsive Breast Cancer

From date of randomization (2nd Registration) to date of first invasive recurrence (local, regional or distant), second invasive primary cancer (breast or not), or death due to any cause. Patients last known to be alive who have not experienced recurrence or second primary cancer are censored at their last contact date. This is the STEEP definition of invasive disease-free survival. Kaplan-Meier estimates were calculated for the 5-year IDFS rate.

Due to the results of the third prespecified interim analysis, prespecified separate analyses were conducted for all outcomes by menopausal status (see Statistical Analysis 2). The NCI and data and safety monitoring committee recommended early reporting of the data. After the primary analysis, changes in eligibility status were identified for three participants, making the population of eligible and evaluable participants different between the reporting of this outcome and both the Participant Flow section and the Adverse Events section.

Only adverse events that are possibly, probably, or definitely related to study drug are reported. Assessed at 6, 12, 24, and 36 months after randomization.

Time from date of randomization (2nd Registration) to date of death due to any cause. Participants last known to be alive are censored at their last contact date.

Time from date of randomization (2nd Registration) to date of invasive distant disease recurrence, second invasive primary cancer (breast or not) or death due to any cause. Participants last known to be alive who have not experienced distant recurrence, or second primary cancer are censored at their last contact date. This secondary outcome requires continuing to follow the patient after local recurrence in order to ascertain subsequent distant recurrence.

Invasive recurrence is defined as: appearance of any new invasive lesion(s) during or after protocol treatment. Whenever possible, recurrences should be documented histologically. Invasive recurrence includes local, regional, or distant recurrence with an invasive component. A new diagnosis of ipsilateral or contralateral DCIS without an invasive component is not considered to be a recurrence.

Time from date of randomization (2nd Registration) to date of invasive local or regional recurrence. Participants last known to be alive without recurrence are censored at their last contact date. Participants with distant recurrence, second primary cancer or death are censored at the time of that event.

Invasive recurrence is defined as: appearance of any new invasive lesion(s) during or after protocol treatment. Whenever possible, recurrences should be documented histologically. Invasive recurrence includes local, regional, or distant recurrence with an invasive component. A new diagnosis of ipsilateral or contralateral DCIS without an invasive component is not considered to be a recurrence.

Anxiety is evaluated with the Patient-Reported Outcomes Measurement Information System (PROMIS) Emotional Distress-Anxiety Short Form. Raw PROMIS scores can be re-scaled into T-scores based on a reference population with a mean score of 50 and a standard deviation of 10. Higher scores reflect greater anxiety.

PROMIS Anxiety scores at the 6 month timepoint will be compared between the two randomized study arms separately by menopausal status.

Assessed using the EuroQol-5D (EQ-5D), in which participants rate their health status in five different health-related domains: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. The raw scores can be converted to index scores on a scale of 0 to 1, where a higher index score represents better health.

EQ-5D index scores at the 6-month timepoint will be compared between the two randomized study arms separately by menopausal status.

Only participants who received protocol treatment and assessed for adverse event were included in the adverse event result: 2062 in the Chemo and Endocrine Therapy arm and 2342 in the Endocrine Therapy Alone arm.

All-Cause mortality is reported for all eligible and evaluable participants (2487 in the Chemo and Endocrine arm and 2497 in the endocrine therapy arm). Due to eligibility changes found after the primary analysis, the number at risk differs from the Outcomes Section.

Participants receive a protocol-approved chemotherapy regimen based on the participant and/or physician preference. Participants then receive a protocol-approved adjuvant endocrine therapy for 5-10 years in the absence of disease progression or unacceptable toxicity.

Chemo and Endocrine Therapy

Participants receive a protocol-approved endocrine therapy for 5-10 years in the absence of disease progression or unacceptable toxicity.

Endocrine Therapy Alone

Total

Age, Continuous

Age, Customized

This trial only included female participants.

Sex: Female, Male

Ethnicity (NIH/OMB)

Race/Ethnicity, Customized

Premenopausal was defined as: \< 6 months since last menstrual period and no prior bilateral oophorectomy and not on estrogen replacement.

Postmenopausal was defined as: prior bilateral oophorectomy, or \> 12 months since last menstrual period with no prior hysterectomy.

If these categories did not apply, premenopausal was defined as age \< 50 and postmenopausal was defined as age \>= 50.

Menopausal Status

The Oncotype DX® Recurrence Score is based on a 21-gene breast cancer assay. The score ranges from 0-100, with higher scores indicating a worse prognosis. This study included participants with a score of 0-25.

Recurrence Score

Axillary Surgery

Positive Nodes

Randomized participants who were eligible for the study.

Breast Committee Statistician

This test describes the interaction of the treatment arm with the recurrence score in the analysis of invasive disease-free survival in the overall study population, to determine whether chemotherapy benefit depends on the recurrence score. If the interaction was statistically significant, the interaction term was planned to be included in the Cox model to evaluate the invasive disease-free survival outcome.

This test describes the interaction of the treatment arm with menopausal status (one of the study stratification factors) in the analysis of invasive disease-free survival in the overall study population, to determine whether chemotherapy benefit depends on menopausal status. If the interaction was statistically significant, separate analyses of IDFS were planned to be conducted by menopausal status.

This analysis includes only premenopausal participants.

This analysis includes only postmenopausal participants.

Premenopausal

Postmenopausal

For the participants flow and baseline characteristics summary, 5018 eligible participants were included. However, among them, there were 34 participants (10 in the chemo and endocrine arm, and 24 in the endocrine alone arm) that withdrew consent immediately after randomization; thus these participants were excluded from the survival analyses.

Invasive Disease-Free Survival (IDFS)

Abdominal infection

Abdominal pain

Acute kidney injury

Alanine aminotransferase increased

Alkaline phosphatase increased

Allergic reaction

Anemia

Anorexia

Anxiety

Arthralgia

Aspartate aminotransferase increased

Atrial fibrillation

Back pain

Blood and lymphatic system disorders - Other

Bone marrow hypocellular

Bone pain

Breast infection

Bronchial infection

CD4 lymphocytes decreased

Cardiac arrest

Cataract

Catheter related infection

Chest pain - cardiac

Chest wall pain

Colitis

Constipation

Death NOS

Dehydration

Depression

Dermatitis radiation

Device related infection

Diarrhea

Dizziness

Dry mouth

Dry skin

Dyspareunia

Dyspepsia

Dyspnea

Ear pain

Edema limbs

Ejection fraction decreased

Erythema multiforme

Erythroderma

Esophagitis

Fatigue

Febrile neutropenia

Fever

Flank pain

Flu like symptoms

GGT increased

Gastric hemorrhage

Gastric ulcer

Gastrointestinal disorders - Other, specify

Eligible participants who received at least one dose of protocol treatment and assessed for Adverse Event.

Number of Participants With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
T-DM1 and Tucatinib Compared With T-DM1 Alone in Preventing Relapses in People With High Risk HER2-Positive Breast Cancer, the CompassHER2 RD Trial	NCT04457596	Anatomic Stage ... Anatomic Stage ... Anatomic Stage ... Anatomic Stage ... Anatomic Stage ... Anatomic Stage ... Anatomic Stage ... Anatomic Stage ... HER2 Positive B... Invasive Breast... Multifocal Brea... Prognostic Stag... Prognostic Stag... Prognostic Stag... Prognostic Stag... Prognostic Stag... Prognostic Stag... Prognostic Stag... Prognostic Stag... Prognostic Stag... Prognostic Stag... Synchronous Bil...	Trastuzumab Emt... Placebo Adminis... Tucatinib Questionnaire A... Quality-of-Life...	18 Years -	Alliance for Clinical Trials in Oncology
Tamoxifen Citrate, Letrozole, Anastrozole, or Exemestane With or Without Chemotherapy in Treating Patients With Invasive RxPONDER Breast Cancer	NCT01272037	Breast Ductal C... Invasive Breast... Multicentric Br... Multifocal Brea... Synchronous Bil...	Anastrozole Exemestane Laboratory Biom... Letrozole Quality-of-Life... Systemic Chemot... Tamoxifen Citra...	18 Years -	National Cancer Institute (NCI)
T-DM1 and Tucatinib Compared With T-DM1 Alone in Preventing Relapses in People With High Risk HER2-Positive Breast Cancer, the CompassHER2 RD Trial	NCT04457596	Anatomic Stage ... Anatomic Stage ... Anatomic Stage ... Anatomic Stage ... Anatomic Stage ... Anatomic Stage ... Anatomic Stage ... Anatomic Stage ... HER2 Positive B... Invasive Breast... Multifocal Brea... Prognostic Stag... Prognostic Stag... Prognostic Stag... Prognostic Stag... Prognostic Stag... Prognostic Stag... Prognostic Stag... Prognostic Stag... Prognostic Stag... Prognostic Stag... Synchronous Bil...	Trastuzumab Emt... Placebo Adminis... Tucatinib Questionnaire A... Quality-of-Life...	18 Years -	Alliance for Clinical Trials in Oncology

Spots Global Cancer Trial Database for synchronous bilateral breast carcinoma