Adding Surgery and Radiation to the Usual Treatment for HER2-Positive Breast Cancer That Had Already Spread at Diagnosis
Randomized Phase III Trial of Multimodality Therapy Versus Standard of Care Systemic Therapy in HER2 Positive (HER2+) De Novo (AJCC Stage IV) Oligometastatic Breast Cancer With Response to Initial Chemotherapy
調査の概要
状態
介入・治療
- 手順：生物標本コレクション
- 手順：磁気共鳴画像
- 放射線：放射線治療
- 放射線：定位放射線治療
- 手順：陽電子放出断層撮影
- 手順：コンピュータ断層撮影
- 放射線：定位放射線治療
- 手順：マンモグラフィー
- 手順：超音波画像診断
- 手順：心エコー検査
- 手順：生検手順
- 生物学的：パーツズマブ
- 生物学的：トラスツズマブ
- 薬：HER2-targeted Therapy
- 手順：Breast Conservation Treatment
- 薬：Cyclin-Dependent Kinase 4 Inhibitor
- 薬：Cyclin-Dependent Kinase 6 Inhibitor
- 薬：Hormone Therapy
- 放射線：Radiation Boost
- 薬：Taxane Compound
- 手順：Total Mastectomy
- 生物学的：Trastuzumab Deruxtecan
- 生物学的：Trastuzumab Emtansine
詳細な説明
PRIMARY OBJECTIVES:
I. To compare overall survival (OS) between participants with de novo stage IV oligometastatic HER2+ breast cancer who experience at least a partial response (PR) after initial systemic therapy similar to those used in stage III disease with curative intent, and are randomized to a multimodality approach including definitive locoregional therapy with surgery and radiotherapy and ablative intent stereotactic radiotherapy to detectable metastatic lesions followed by additional HER2-directed systemic therapy, similar to those used for residual disease after neoadjuvant therapy, (Cohort A, Arm 1) versus those who are randomized to physician's choice standard of care HER2-directed systemic therapies without local and metastasis directed ablative therapies (Cohort A, Arm 2). (Randomized Cohort A) II. To evaluate the distribution of progression-free survival (PFS) and overall survival (OS) among participants with de novo stage IV oligometastatic HER2+ breast cancer who do not experience a response after systemic therapy. (Observational Cohort B)
SECONDARY OBJECTIVES:
I. To compare progression-free survival (PFS) in Cohort A, Arm 1 (randomized to multimodality therapy) versus Cohort A, Arm 2 (randomized to standard of care HER2-directed systemic therapy). (Randomized Cohort) II. To compare PFS in Cohort A, Arm 1 per protocol (received all multimodality therapy as planned) versus Cohort A, Arm 2. (Randomized Cohort) III. To compare OS in Cohort A, Arm 1 per protocol (received all multimodality therapy as planned) versus Cohort A, Arm 2. (Randomized Cohort) IV. To assess duration of standard of care first line systemic therapy received from time of response assessment in Cohort B. (Observational Cohort)
BANKING OBJECTIVE:
I. To bank specimens for future correlative studies.
OUTLINE:
STEP 1: Patients receive physician's choice of HER2-targeted systemic therapy according to National Comprehensive Cancer Network (NCCN)/American Society of Clinical Oncology (ASCO) guidelines until completion of at least 12 weeks (4 cycles) or up to 24 weeks (8 cycles) of HER2-targeted therapy prior to Step 2 registration. Patients with brain metastases may also undergo stereotactic radiosurgery (SRS)/stereotactic radiotherapy (SRT) at the discretion of the treating physician.
STEP 2: Patients with partial or complete response in the breast following completion of Step 1 are assigned to Cohort A. Patients with clinically stable or progressive disease following completion of Step 1 are assigned to Cohort B.
COHORT A: Patients are randomized to 1 of 2 arms.
ARM 1:
LOCOREGIONAL THERAPY: Patients undergo breast surgery (either breast conserving therapy or total mastectomy) within 4-6 weeks of completion of Step 1 systemic therapy. Within 8 weeks of breast surgery, patients undergo locoregional radiation therapy (RT) to the breast, with or without RT to the breast/chest wall and/or regional lymph nodes, over 5-16 fractions. Patients may undergo RT boost to the lumpectomy bed over 4-5 fractions at the discretion of the treating physician.
STEREOTACTIC BODY RADIATION THERAPY (SBRT): Within 4-6 weeks of completion of locoregional therapy, patients undergo SBRT, with or without concurrent adjuvant therapy (pertuzumab and trastuzumab, or trastuzumab emtansine [T-DM1], or trastuzumab deruxtecan [T-DXd] with or without pertuzumab), to all targetable metastatic lesions every other day for 1, 3, or 5 fractions over a maximum of 3 weeks.
POST-LOCOREGIONAL THERAPY AND SBRT: Following recovery from surgery, patients resume systemic therapy (T-DXd, or T-DM1, or T-DXd with or without pertuzumab, or taxane with trastuzumab and pertuzumab, or trastuzumab with pertuzumab) according to NCCN/ASCO guidelines for at least 1 year in the absence of disease progression or unacceptable toxicity. Patients who are estrogen receptor positive may also receive endocrine therapy, with or without CDK4/6 inhibitors, at the discretion of the treating physician for at least 5 years, in the absence of disease progression or unacceptable toxicity.
ARM 2: Patients continue systemic therapy (T-DXd, or T-DM1, or T-DXd with or without pertuzumab, or taxane with trastuzumab and pertuzumab, or trastuzumab with pertuzumab) according to NCCN/ASCO guidelines for at least 1 year in the absence of disease progression or unacceptable toxicity. Patients may receive locoregional therapy and/or SBRT according to standard of care only if required for palliative purposes.
COHORT B: Patients continue systemic therapy (T-DXd, or T-DM1, or T-DXd with or without pertuzumab, or taxane with trastuzumab and pertuzumab, or trastuzumab with pertuzumab) according to NCCN/ASCO guidelines in the absence of disease progression or unacceptable toxicity.
All patients also undergo echocardiography (ECHO), magnetic resonance imaging (MRI), mammography, ultrasound, computed tomography (CT), and/or positron emission tomography (PET)/CT throughout the trial. Patients may undergo optional biopsy and/or collection of blood samples throughout the trial.
After completion of study treatment, patients registered to Step 2 are followed up for 10 years.
研究の種類
入学 (推定)
段階
- フェーズ 3
参加基準
適格基準
就学可能な年齢
- 大人
- 高齢者
健康ボランティアの受け入れ
説明
Inclusion Criteria:
- REGISTRATION STEP 1 - SCREENING & INITIAL TREATMENT:
Participants must have histologically confirmed de novo metastatic (i.e. American Joint Committee on Cancer [AJCC] stage IV, no prior history of breast cancer) HER2+ breast cancer with 1 to 5 distant metastatic lesions (oligometastatic). Metastatic breast cancer must be histologically confirmed through biopsy of a distant metastatic lesion unless it is not feasible or safe to biopsy a metastatic lesion, then there must be unequivocal evidence of metastasis on imaging and laboratory studies. HER2+ status must be confirmed in the breast tumor and distant metastatic site as defined per NCCN guidelines version 4.2025
- NOTE: If HER2 positivity at metastatic site is equivocal due to limitations in HER2 analysis in bone, or it is not feasible or safe to biopsy the metastatic lesion, then HER2 positivity based on breast tumor only is acceptable. If there is no breast lesion, HER2+ must be confirmed in at least one metastatic site
Participants with brain metastases are eligible if they meet all of the following criteria at baseline:
- There are 5 or fewer intracranial lesions
- Each intracranial lesions is no larger than 2cm in longest dimension
- NOTE: The brain is counted as 1 distant site towards the oligometastatic definition. Brain imaging is not required for participants who have no neurological signs or symptoms suggestive of central nervous system (CNS) involvement; however, assessment of neurological symptoms and brain MRI is strongly encouraged to rule out CNS disease
- Participants must have no known leptomeningeal disease
Participants must meet one of the following criteria prior to Step 1 registration:
- Treatment naïve and planning to initiate standard of care systemic HER2+ targeted treatment OR
Have already initiated standard of care systemic HER2+ targeted treatment and have completed at least one (≥ 1) but no more than three (≤ 3) cycles prior to enrollment, without progression
- NOTE: Standard of care scans for baseline disease assessment must have been performed within 28 days prior to initiation of treatment
- Participants must not be receiving or planning to receive any investigational systemic therapy during study before disease progression
Participants must not have received whole brain irradiation
- NOTE: Participants with up to five brain metastases may have received SRS/SRT either before or after initiation of systemic therapy. If lesions are small and asymptomatic and the participant is receiving CNS penetration they may be managed with observation
- Participants must be ≥ 18 years old at the time of registration
- Participants must have Zubrod performance status of 0-2
- Participants with known human immunodeficiency virus (HIV)-infection must be on effective anti-retroviral therapy and have undetectable viral load test on the most recent test results obtained within 6 months prior to registration
- Participants must be able to safely receive the physician's choice of standard of care systemic HER2+ targeted treatment per the current Food and Drug Administration (FDA)-approved package insert(s), treating physician's discretion, and institutional guidelines
- Participants must be candidates for definitive surgical and radiotherapeutic management of locoregional disease opinion per the discretion of the treating physician
- Participants must be able to receive ablative dose stereotactic body radiation therapy (SBRT) to all metastatic lesions identified at baseline, in the opinion of the treating physician
- Participants must be offered the opportunity to participate in specimen banking
NOTE: As a part of the Oncology Patient Enrollment Network (OPEN) registration process the treating institution's identity is provided in order to ensure that the current (within 365 days) date of institutional review board approval for this study has been entered in the system
- Participants must be informed of the investigational nature of this study and must sign and give informed consent in accordance with institutional and federal guidelines For participants with impaired decision-making capabilities, legally authorized representatives may sign and give informed consent on behalf of study participants in accordance with applicable federal, local, and CIRB regulations
- REGISTRATION STEP 2 - COHORT ASSIGNMENT AND RANDOMIZATION:
- COHORT A: Participants must be registered to Step 2 within 14 days of staging scans performed after completing Step 1 systemic therapy
- COHORT A: Participants must have standard of care (SOC) staging scans and breast imaging performed following 12-24 weeks (minimum of 4 cycles) of initial systemic therapy and within 14 days prior to Step 2 registration
COHORT A: Participants must have experienced partial or complete response in the breast (in the opinion of the treating physician) following 12-24 weeks of initial systemic therapy based on staging scans performed within 14 days prior to Step 2 registration
- Participants with breast lesion(s) at diagnosis must have a clinical response on breast imaging per the treating physician
- Metastatic lesions, as assessed by Response Evaluation Criteria in Solid Tumors (RECIST) and bone response criteria, must have at least stable disease
- Brain metastases treated with SRS/SRT must have at least stable disease as per Response Assessment in Neuro-Oncology Brain Metastases (RANO BM) and must not require steroid treatment
- Participants with no known breast lesions at diagnosis must have at least partial response in the metastatic sites as assessed by RECIST and bone response criteria
- NOTE: The same imaging modality must be used as in Step 1
- COHORT A: Participants must be eligible for definitive surgical and radiotherapeutic management of locoregional disease per the discretion of the treating physician
COHORT A: Participants must not have metastatic lesions that are not amenable to ablative dose stereotactic body radiation therapy (SBRT)
- Lung lesions that completely resolve after systemic therapy will not be targeted with SBRT, as it is not possible to achieve dose build-up
- The development of new sclerotic bone lesions after systemic therapy is not to be interpreted as disease progression, and all such lesions should be targeted with SBRT
- COHORT B: Participants must be registered to Step 2 within 14 days of staging scans performed after completing Step 1 systemic therapy
- COHORT B: Participants must have standard of care (SOC) staging and breast imaging performed following 12-24 weeks (minimum of 4 cycles) of initial systemic therapy and within 14 days prior to Step 2 registration
COHORT B: Participants must experience clinically stable disease or progression following 12-24 weeks (minimum of 4 cycles) of initial systemic therapy and within 14 days prior to Step 2 registration
- Participants must have progression in metastatic lesions as assessed by RECIST and bone response criteria or may have stable disease in metastatic lesions by RECIST and bone response criteria if there is progression or no clinical response in the breast
- Participants with known breast lesion must have progression or no clinical response on breast imaging as per the treating physician
- NOTE: The same modality must be used as in Step 1
研究計画
研究はどのように設計されていますか？
デザインの詳細
- 主な目的：処理
- 割り当て：ランダム化
- 介入モデル：並列代入
- マスキング：なし（オープンラベル）
武器と介入
参加者グループ / アーム |
介入・治療 |
|---|---|
|
実験的：Step 1 (HER2-targeted systemic therapy, STS/SRT)
Patients receive physician's choice of HER2-targeted systemic therapy according to NCCN/ASCO guidelines until completion of at least 12 weeks (4 cycles) or up to 24 weeks (8 cycles) of HER2-targeted therapy prior to Step 2 registration.
Patients with brain metastases may also undergo SRS/SRT at the discretion of the treating physician.
All patients also undergo ECHO, MRI, mammography, ultrasound, CT, and/or PET/CT throughout the trial.
Patients may undergo optional biopsy and/or collection of blood samples throughout the trial.
|
血液サンプルの採取を受ける
他の名前：
MRIを受ける
他の名前：
PET/CTを受ける
他の名前：
CTおよび/またはPET/CTを受ける
他の名前：
SRS/SRTを受ける
他の名前：
マンモグラフィーを受けてください
他の名前：
超音波検査を受ける
他の名前：
エコーを受ける
他の名前：
生検を受けます
他の名前：
Receive HER2-targeted systemic therapy
|
|
実験的：Step 2 Cohort A, Arm 1 (locoregional, SBRT, systemic therapy)
See Detailed Description.
|
血液サンプルの採取を受ける
他の名前：
MRIを受ける
他の名前：
RTを受ける
他の名前：
SBRTを受ける
他の名前：
PET/CTを受ける
他の名前：
CTおよび/またはPET/CTを受ける
他の名前：
マンモグラフィーを受けてください
他の名前：
超音波検査を受ける
他の名前：
エコーを受ける
他の名前：
生検を受けます
他の名前：
パーツズマブ投与下
他の名前：
トラスツズマブ投与
他の名前：
Undergo breast conserving therapy
他の名前：
Given CDK4/6 inhibitor
他の名前：
Given CDK4/6 inhibitor
他の名前：
Given endocrine therapy
他の名前：
Undergo RT boost
他の名前：
Given taxane therapy
他の名前：
Undergo total mastectomy
他の名前：
Given T-DXd
他の名前：
Given T-DM1
他の名前：
|
|
実験的：Step 2 Cohort A, Arm 2 (systemic therapy)
Patients continue systemic therapy (T-DXd, or T-DM1, or T-DXd with or without pertuzumab, or taxane with trastuzumab and pertuzumab, or trastuzumab with pertuzumab) according to NCCN/ASCO guidelines for at least 1 year in the absence of disease progression or unacceptable toxicity.
Patients may receive locoregional therapy and/or SBRT according to standard of care only if required for palliative purposes.
All patients also undergo ECHO, MRI, mammography, ultrasound, CT, and/or PET/CT throughout the trial.
Patients may undergo optional biopsy and/or collection of blood samples throughout the trial.
|
血液サンプルの採取を受ける
他の名前：
MRIを受ける
他の名前：
RTを受ける
他の名前：
SBRTを受ける
他の名前：
PET/CTを受ける
他の名前：
CTおよび/またはPET/CTを受ける
他の名前：
マンモグラフィーを受けてください
他の名前：
超音波検査を受ける
他の名前：
エコーを受ける
他の名前：
生検を受けます
他の名前：
パーツズマブ投与下
他の名前：
トラスツズマブ投与
他の名前：
Undergo breast conserving therapy
他の名前：
Undergo RT boost
他の名前：
Given taxane therapy
他の名前：
Undergo total mastectomy
他の名前：
Given T-DXd
他の名前：
Given T-DM1
他の名前：
|
|
実験的：Step 2 Cohort B (systemic therapy)
Patients continue systemic therapy (T-DXd, or T-DM1, or T-DXd with or without pertuzumab, or taxane with trastuzumab and pertuzumab, or trastuzumab with pertuzumab) according to NCCN/ASCO guidelines in the absence of disease progression or unacceptable toxicity.
All patients also undergo ECHO, MRI, mammography, ultrasound, CT, and/or PET/CT throughout the trial.
Patients may undergo optional biopsy and/or collection of blood samples throughout the trial.
|
血液サンプルの採取を受ける
他の名前：
MRIを受ける
他の名前：
PET/CTを受ける
他の名前：
CTおよび/またはPET/CTを受ける
他の名前：
マンモグラフィーを受けてください
他の名前：
超音波検査を受ける
他の名前：
エコーを受ける
他の名前：
生検を受けます
他の名前：
パーツズマブ投与下
他の名前：
トラスツズマブ投与
他の名前：
Given T-DXd
他の名前：
Given T-DM1
他の名前：
|
この研究は何を測定していますか？
主要な結果の測定
結果測定 |
メジャーの説明 |
時間枠 |
|---|---|---|
|
Overall survival (OS) (Cohort A)
時間枠：From date of Step 2 registration to date of death, assessed up to 10 years
|
The primary analysis to evaluate the primary objective in the randomized cohort will be an intent-to treat (ITT) comparison of Arm 1 versus Arm 2 using a stratified log-rank test including all randomized, eligible participants.
The hazard ratio and 95% confidence interval (CI) will be estimated by Cox regression including the stratification factors as variables in the model.
Primary analyses will be repeated among individuals with brain metastases to understand whether the effect of the intervention differs in this subgroup.
|
From date of Step 2 registration to date of death, assessed up to 10 years
|
|
Progression-free survival (PFS) (Observational Cohort B)
時間枠：From date of Step 2 registration to date of first documentation of progression or recurrence or death, assessed at 3 and 5 years
|
In the observational cohort, the primary objective will be evaluated by estimating 3- and 5-year survival and corresponding 95% CIs using the Kaplan-Meier estimator.
All analyses in the observational cohort will be descriptive.
Primary analyses will be repeated among individuals with brain metastases to understand whether the effect of the intervention differs in this subgroup.
|
From date of Step 2 registration to date of first documentation of progression or recurrence or death, assessed at 3 and 5 years
|
|
Overall survival (Observational Cohort B)
時間枠：From date of Step 2 registration to date of death, assessed at 3 and 5 years
|
In the observational cohort, the primary objective will be evaluated by estimating 3- and 5-year survival and corresponding 95% CIs using the Kaplan-Meier estimator.
All analyses in the observational cohort will be descriptive.
Primary analyses will be repeated among individuals with brain metastases to understand whether the effect of the intervention differs in this subgroup.
|
From date of Step 2 registration to date of death, assessed at 3 and 5 years
|
二次結果の測定
結果測定 |
メジャーの説明 |
時間枠 |
|---|---|---|
|
Progression free survival (Cohort A)
時間枠：From date of Step 2 registration to date of first documentation of progression or recurrence or death, assessed at 3 and 5 years and then up to 10 years
|
The primary analysis will be an ITT comparison of Arm 1 versus Arm 2 using a stratified log-rank test including all randomized, eligible participants.
The hazard ratio and 95% CI will be estimated by Cox regression including the stratification factors as variables in the model.
In addition to the primary analyses, will estimate PFS at 3 years and 5 years in Arm 1 and Arm 2 and corresponding 95% CIs using the Kaplan-Meier estimator.
|
From date of Step 2 registration to date of first documentation of progression or recurrence or death, assessed at 3 and 5 years and then up to 10 years
|
|
Overall survival (Cohort A)
時間枠：From date of Step 2 registration to date of death, assessed at 3 and 5 years and then up to 10 years
|
The primary analysis will be an ITT comparison of Arm 1 versus Arm 2 using a stratified log-rank test including all randomized, eligible participants.
The hazard ratio and 95% CI will be estimated by Cox regression including the stratification factors as variables in the model.
In addition to the primary analyses, will estimate OS at 3 years and 5 years in Arm 1 and Arm 2 and corresponding 95% CIs using the Kaplan-Meier estimator.
|
From date of Step 2 registration to date of death, assessed at 3 and 5 years and then up to 10 years
|
|
Duration of standard of care first line systemic therapy (Cohort B)
時間枠：From time of response assessment at end of Step 1 up to 10 years
|
From time of response assessment at end of Step 1 up to 10 years
|
その他の成果指標
結果測定 |
メジャーの説明 |
時間枠 |
|---|---|---|
|
Primary outcome treatment effect by sex
時間枠：Up to 10 years
|
Will estimate the primary outcome treatment effect and corresponding 95% CI by sex.
|
Up to 10 years
|
|
Primary outcome treatment effect by race
時間枠：Up to 10 years
|
Will estimate the primary outcome treatment effect and corresponding 95% CI by race.
|
Up to 10 years
|
|
Primary outcome treatment effect by ethnicity
時間枠：Up to 10 years
|
Will estimate the primary outcome treatment effect and corresponding 95% CI by ethnicity.
|
Up to 10 years
|
協力者と研究者
捜査官
- 主任研究者：Mariya Rozenblit、SWOG Cancer Research Network
研究記録日
主要日程の研究
研究開始 (推定)
一次修了 (推定)
研究の完了 (推定)
試験登録日
最初に提出
QC基準を満たした最初の提出物
最初の投稿 (実際)
学習記録の更新
投稿された最後の更新 (実際)
QC基準を満たした最後の更新が送信されました
最終確認日
詳しくは
本研究に関する用語
追加の関連 MeSH 用語
- 薬物の生理学的影響
- ホルモン、ホルモン代替品、ホルモン拮抗薬
- ペプチド
- アミノ酸、ペプチド、およびタンパク質
- タンパク質
- 有機化学物質
- 調査手法
- 治療
- 臨床検査技術
- 診断技術と手順
- 診断
- 外科的処置、手術
- 細胞学的技術
- 細胞診断
- 薬理学的行動
- 化学作用と用途
- 炭化水素
- シクロパラフィン
- 炭化水素、環状
- 炭化水素、周期的
- テルペン
- 物理現象
- 多環式化合物
- 抗体、モノクローナル、ヒト化
- 抗体、モノクローナル
- 抗体
- 免疫グロブリン
- 免疫タンパク質
- 血液タンパク質
- 血清グロブリン
- グロブリン
- シクロデカン
- Diterpenes
- 融合リング化合物
- 乳房切除術
- 診断技術、外科的
- 化学技術、分析
- マクロライド
- ラクトン
- スペクトル分析
- 定位技術
- 脳神経外科手術
- ラクタム、大環状
- 大環性化合物
- 放射線、非イオン化
- メイタンシン
- 細胞内シグナル伝達ペプチドとタンパク質
- 超音波
- 音
- 細胞周期タンパク質
- 腫瘍抑制タンパク質
- 新生物タンパク質
- サイクリン依存性キナーゼ阻害剤タンパク質
- トラスツズマブ
- Ado-トラスツズマブ エムタンシン
- ホルモン
- 放射線療法
- 放射線
- 乳房切除術、セグメント
- 生検
- 標本処理
- ペルズマブ
- 磁気共鳴分光法
- 放射線手術
- タキャン
- トラスツズマブderuxtecan
- ステロイド
- 高エネルギーショック波
- 2C4抗体
- CT-P6
- PF-05280014
- トラスツズマブバイオシミラーHLX02
- オギブリ
- Ontruzant
- サイクリン依存性キナーゼ阻害剤P18
- サイクリン依存性キナーゼ阻害剤P16
- タキソイド
- Mastectomy, Simple
その他の研究ID番号
- S2511 (その他の識別子：CTEP)
- U10CA180888 (米国 NIH グラント/契約)
- NCI-2026-02627 (レジストリ識別子：CTRP (Clinical Trial Reporting Program))
医薬品およびデバイス情報、研究文書
米国FDA規制医薬品の研究
米国FDA規制機器製品の研究
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