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JOURNAL ONKOLOGIE – STUDIE
SASCIA

Sacituzumab Govitecan in Primary HER2-negative Breast Cancer

Rekrutierend

NCT-Nummer:
NCT04595565

Studienbeginn:
Oktober 2020

Letztes Update:
02.03.2023

Wirkstoff:
Capecitabine, Carboplatin, Cisplatin, Sacituzumab govitecan

Indikation (Clinical Trials):
Breast Neoplasms, Triple Negative Breast Neoplasms

Geschlecht:
Alle

Altersgruppe:
Erwachsene (18+)

Phase:
Phase 3

Sponsor:
German Breast Group

Collaborator:
Gilead Sciences, Austrian Breast & Colorectal Cancer Study Group, Spanish Breast Cancer Research Group (GEICAM), ETOP IBCSG Partners Foundation, Cancer Trials Ireland, UNICANCER,

Studienleiter

Frederik Marmé, MD, Prof.
Principal Investigator
ASCO, ESMO, GBG, AGO, DKG, DGS, DKG

Kontakt

Studienlocations
(3 von 179)

LKH Hochsteiermark Leoben
8700 Leoben
AustriaAktiv, nicht rekrutierend» Google-Maps
Ordensklinikum Linz GmbH - BHS
4010 Linz
AustriaAktiv, nicht rekrutierend» Google-Maps
MUW - Med. Univ.-Klinik AKH Wien
1090 Wien
AustriaAktiv, nicht rekrutierend» Google-Maps
Institut Jules Bordet
1000 Brussels
BelgiumAktiv, nicht rekrutierend» Google-Maps
CHU UCL Namur/Site Sainte Elisabeth
5000 Namur
BelgiumAktiv, nicht rekrutierend» Google-Maps
Polyclinique Bordeaux Nord Aquitaine
33077 Bordeaux
FranceAktiv, nicht rekrutierend» Google-Maps
CH Fleyriat
1000 Bourg En Bresse
FranceAktiv, nicht rekrutierend» Google-Maps
Centre Jean Perrin 5
63011 Clermont Ferrand
FranceAktiv, nicht rekrutierend» Google-Maps
GHBS hôpital du Scorff
56322 Lorient
FranceAktiv, nicht rekrutierend» Google-Maps
St James's Hospital
D08 NHY1 Dublin
IrelandAktiv, nicht rekrutierend» Google-Maps
Hospital Universitario de Cruces
48903 Barakaldo
SpainAktiv, nicht rekrutierend» Google-Maps
COMPLEJO HOSPITALARIO UNIVERSITARIO A CORUÑA-Hospital Teresa Herrera (CHUAC)
15009 A Coruña
SpainAktiv, nicht rekrutierend» Google-Maps
Hospital de Mataró
8304 Barcelona
SpainAktiv, nicht rekrutierend» Google-Maps
Clinica Universidad de Navarra
28027 Madrid
SpainAktiv, nicht rekrutierend» Google-Maps
Hospital Universitario Quirónsalud Madrid
28223 Madrid
SpainAktiv, nicht rekrutierend» Google-Maps
Hospital Universitario Fundación Alcorcón
28922 Madrid
SpainAktiv, nicht rekrutierend» Google-Maps
Hospital General Universitario Morales Meseguer
3008 Murcia
SpainAktiv, nicht rekrutierend» Google-Maps
Hospital Universitari Son Llátzer
'07198 Palma de Mallorca
SpainAktiv, nicht rekrutierend» Google-Maps
Clinica Universidad de Navarra
31008 Pamplona
SpainAktiv, nicht rekrutierend» Google-Maps
Hospital Universitario de Salamanca
37007 Salamanca
SpainAktiv, nicht rekrutierend» Google-Maps
Hospital Universitario Ntra.Sra. de Candelaria
38010 Santa Cruz de Tenerife
SpainAktiv, nicht rekrutierend» Google-Maps
Complejo Hospitalario Universitario de Santiago (Chus)
15706 Santiago De Compostela
SpainAktiv, nicht rekrutierend» Google-Maps
Hospital Universitario Araba-Txagorritxu
01009 Vitoria
SpainAktiv, nicht rekrutierend» Google-Maps
Kantonsspital Graubünden
7000 Chur
SwitzerlandAktiv, nicht rekrutierend» Google-Maps
Breast Center KSSG
9007 St. Gallen
SwitzerlandAktiv, nicht rekrutierend» Google-Maps
Kantonsspital Winterthur
8400 Winterthur
SwitzerlandAktiv, nicht rekrutierend» Google-Maps
Alle anzeigen

Studien-Informationen

Detailed Description:

Neoadjuvant chemotherapy (NACT) allows monitoring of tumor response to treatment and a

pathological complete response (pCR) is associated with superior survival. This association

is strongest in the most aggressive subtype, i.e. in patients with triple-negative breast

cancer (TNBC). Patients with TNBC not achieving a pCR have a 5-year event free survival rate

of about 50%. The association between pCR and prognosis is less pronounced in

HR-positive/HER2-negative patients. However, the CPS+EG scoring system for prognosis after

neoadjuvant chemotherapy, taking into account clinical stage, post treatment pathological

stage, estrogen receptor status and grade, leads to an improved estimate of prognosis

allowing to select patients at high risk of relapse for post-neoadjuvant therapy. Patients

with TNBC not achieving a pCR as well as those with HR-positive/HER2-negative tumors and a

CPS+EG score of 3 or 2/ypN+ are at high risk of relapse, warranting additional experimental

therapies after NACT.

There is proof of concept, that post-neoadjuvant therapy can significantly improve survival.

First data was provided by the CREATE X trial, randomizing patients with residual tumor after

neoadjuvant chemotherapy to either capecitabine or observation. CREATE X included

HER2-negative patients and demonstrated a significant improvement in disease-free survival

(DFS) and overall survival (OS) in the overall population, which was confined to the TNBC

subgroup.

Recently, the randomized post-neoadjuvant phase III KATHERINE study demonstrated an improved

invasive disease-free survival in HER2-positive patients without pCR after trastuzumab +/-

pertuzumab treated postoperatively with T-DM1, an antibody-drug-conjugate compared to

trastuzumab.

Sacituzumab govitecan has demonstrated unprecedented activity in heavily pretreated patients

with metastatic triple-negative and HR-positive/HER2-negative breast cancer, even after prior

immune-checkpoint inhibitors or CDK4/6 and mTOR inhibitors. Based on the results of the phase

I/II study, sacituzumab govitecan was granted a breakthrough therapy designation for the

treatment of patients with advanced or metastatic TNBC who have received at least two

previous lines of treatment for metastatic disease. The efficacy of sacituzumab govitecan in

advanced TNBC was confirmed in the phase III ASCENT trial. Based on this study, sacituzumab

govitecan received regular approval. Additionally, the TROPiCS-02 study showed an improvement

in progression-free survival and OS over single-agent chemotherapy and a manageable safety

profile in patients with heavily pre-treated HR-positive/HER2-negative endocrine-resistant,

unresectable locally advanced or metastatic BC.

Ein-/Ausschlusskriterien

Inclusion Criteria:

1. Written informed consent prior to beginning specific protocol procedures, including

expected cooperation of the patients for the treatment and follow-up, must be obtained

and documented according to the local regulatory requirements.

2. Age at diagnosis at least 18 years.

3. Willingness and ability to provide archived formalin fixed paraffin embedded tissue

(FFPE) block from surgery after neoadjuvant chemotherapy and from core biopsy before

start of neoadjuvant chemotherapy, which will be used for centralized prospective

confirmation of HR status, HER2 status, Ki-67 and tumor-infiltrating lymphocytes

(TILs) and for retrospective exploratory correlation between genes, proteins, and

mRNAs relevant to sensitivity/resistance to the investigational agents. For patients

with bilateral carcinoma, FFPE blocks from both sides have to be provided for central

testing.

4. Histologically confirmed unilateral or bilateral primary invasive carcinoma of the

breast, confirmed histologically by core biopsy. The lead tumor has to be defined by

the investigator based on the inclusion criteria for the respective subtype and on the

risk status.

5. Centrally confirmed HER2-negative (IHC score 0-1 or FISH negative according to

ASCO/CAP guideline) and either

- HR-positive (≥1% positive stained cells) disease or

- HR-negative (<1% positive stained cells) assessed preferably on tissue from

postneoadjuvant residual invasive disease of the breast, or if not possible, of

residual nodal invasion. If not evaluable, core of diagnostic biopsy will be

used. In case of bilateral breast cancer, HER2-negative status has to be

confirmed for both sides.

6. Patients with residual invasive disease after neoadjuvant chemotherapy at high risk of

recurrence defined by either:

- For HR-negative: any residual invasive disease > ypT1mi and/or ypN1>1mm

- For HR-positive disease: a CPS+EG score ≥ 3 or CPS+EG score 2 and ypN+ using

local ER and grade assessed on core biopsies taken before start of neoadjuvant

treatment.

7. Adequate surgical treatment including resection of clinically evident disease and

ipsilateral axillary lymph node dissection. SNB before NACT is discouraged. Axillary

dissection before NACT is not permitted. Axillary dissection, including Targeted

Axillary Dissection (TAD) should be performed according to guidelines. Histologic

complete resection (R0) of all invasive and in situ tumors is required.

8. Patients must have received neoadjuvant taxane-based chemotherapy for 16 weeks

(anthracyclines are permitted). This period must include 6 weeks of a taxane

containing neoadjuvant chemotherapy (exception: for patients with progressive disease

that occurred after at least 6 weeks of taxane-containing neoadjuvant chemotherapy, a

total treatment period of less than 16 weeks is also eligible).

9. No clinical evidence for locoregional or distant relapse during or after preoperative

chemotherapy. Local progression during chemotherapy is not an exclusion criterion if

adequate local control could be obtained.

10. In case of local progression during neoadjuvant therapy, distant metastases must be

excluded by adequate imaging (CT/MRI recommend) prior to entering the trial.

11. Immune checkpoint inhibitor / immunotherapy during (neo)adjuvant therapy is allowed

until the completion of radiotherapy.

12. Patients with known gBRCA1/2 mutation without indication to adjuvant olaparib therapy

are allowed to participate in the trial.

13. An interval of less than 16 weeks since the date of final surgery or less than 10

weeks from completing radiotherapy (whichever occurs last) and the date of

randomization is required.

14. Radiotherapy should be delivered before the start of study treatment. Radiotherapy to

the breast is indicated in all patients with breast conserving surgery and to the

chest wall and lymph nodes according to local guidelines as well as in all patients

with cT3/4 or ypN+ disease treated by mastectomy.

15. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1.

16. Resolution of all acute toxic effects of prior anti-cancer therapy or surgical

procedure or radiotherapy to NCI CTCAE v 5.0 grade ≤ 1 (except alopecia or other

toxicities not considered a safety risk for the patients at the investigator´s

discretion).

17. Estimated life expectancy of at least 5 years irrespective of the diagnosis of breast

cancer.

18. The patient must be accessible for scheduled visits, treatment and follow-up.

19. Normal cardiac function after neoadjuvant chemotherapy must be confirmed according to

local guidelines. Results for LVEF must be above the normal limit of the institution.

20. Laboratory requirements:

Hematology

- Absolute neutrophil count (ANC) ≥1.5 x 109 / L

- Platelets ≥100 x 109 / L

- Hemoglobin ≥10 g/dL (≥6.2 mmol/L) Hepatic function

- Total bilirubin <1.25x UNL

- AST and ALT ≤1.5x UNL

- Alkaline phosphatase ≤2.5x UNL Renal Function

- <1.25x ULN creatinine or creatinine clearance ≥30 ml/min (according to

Cockroft-Gault, if creatinine is above UNL).

21. Negative pregnancy test (urine or serum) within 14 days prior to randomization for all

women of childbearing potential. A woman is considered to be of childbearing potential

if she is not postmenopausal. Postmenopausal is defined as:

- Age ≥60 years

- Age <60 years and ≥12 continuous months of amenorrhea with no identified cause

other than menopause

- Surgical sterilization (bilateral oophorectomy and/or hysterectomy).

22. For women of childbearing potential and males with partners of childbearing potential:

agreement to remain abstinent (refrain from heterosexual intercourse) or use

contraceptive methods that result in a failure rate of < 1% per year during the

treatment period and for at least 6 months after the last dose of sacituzumab

govitecan for female patients and for at least 3 months for male patients; for at

least 6 months after the last dose of capecitabine or carboplatin/cisplatin for female

patients and for at least 3 months after the last dose of capecitabine or 6 months

after the last dose of carboplatin/cisplatin for male patients. Examples of

non-hormonal contraceptive methods with a failure rate of < 1% per year include:

bilateral tubal ligation; male partner sterilization; intrauterine devices.

23. Complete staging work-up prior to the initiation of neoadjuvant chemotherapy. Missing

staging investigations must be performed prior to randomization.

Exclusion Criteria:

1. Known hypersensitivity reaction to one of the compounds or substances used in this

protocol.

2. Patients with definitive clinical or radiologic evidence of stage IV cancer

(metastatic disease) are not eligible.

3. Patients with known gBRCA1/2 mutation and indicated or planned adjuvant olaparib

therapy if available.

4. Patients with a history of any malignancy are ineligible with the following

exceptions:

- Patient has been disease-free for at least 5 years and is at low risk for

recurrence of that malignancy

- CIS of the cervix, basal cell and squamous cell carcinomas of the skin.

5. Female patients: pregnancy or lactation at the time of randomization or intention to

become pregnant during the study and up to 6 months after sacituzumab govitecan and up

to 6 months after treatment with capecitabine or carboplatin/cisplatin.

6. Severe and relevant co-morbidity that would interact with the application of cytotoxic

agents or the participation in the study, including Gilbert´s disease,

Crigler-Najjar-Syndrome, known hepatitis B, hepatitis C, known HIV positivity or known

autoimmune disease other than diabetes, vitiligo, or stable thyroid disease, vitiligo,

or other autoimmune skin disease with dermatologic manifestations only are permitted

provided all of the following conditions are met:

- Rash must cover < 10% of body surface area

- Disease is well controlled at baseline and requires only low-potency topical

corticosteroids

- No occurrence of acute exacerbations of the underlying condition requiring

psoralen plus ultraviolet A radiation (PUVA), methotrexate, retinoids, biologic

agents, oral calcineurin inhibitors, or high-potency or oral corticosteroids

within the previous 12 months.

7. Any condition that interferes with the safe administration of the treatment of

physician´s choice in case the patient is randomized into the TPC arm.

8. Known or suspected congestive heart failure (>NYHA I) and/or coronary heart disease,

angina pectoris requiring antianginal medication, previous history of myocardial

infarction, evidence of prior infarction on ECG, uncontrolled or poorly controlled

arterial hypertension (i.e. BP >150/90 mmHg under treatment with at maximum three

antihypertensive drugs), rhythm abnormalities requiring permanent treatment (excluding

chronic atrial fibrillation not requiring a pacemaker), clinically significant

valvular heart disease, supraventricular and nodal arrhythmias requiring a pacemaker

or not controlled with medication;conduction abnormality requiring a pacemaker.

9. History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g. bronchiolitis

obliterans), drug-induced pneumonitis, idiopathic pneumonitis or active pneumonitis on

chest CT scan.

10. Receipt of live attenuated vaccination within 30 days prior to study entry or within

30 days of receiving chemotherapy.

11. History of significant neurological or psychiatric disorders including psychotic

disorders, dementia or seizures that would prohibit the understanding and giving of

informed consent.

12. Any condition that, in the opinion of the investigator, would interfere with

evaluation of study treatment or interpretation of patient safety or study results.

13. Known allergic reactions to irinotecan.

14. Concurrent treatment with:

- Chronic corticosteroids prior to study entry with the exceptions of intranasal

and inhaled corticosteroids or systemic corticosteroids at physiological doses,

which are not to exceed 10 mg/day of prednisone, or equivalent corticosteroid.

Studien-Rationale

Primary outcome:

1. Invasive disease free survival (iDFS) between patients treated with sacituzumab govitecan vs. treatment of physician's choice. (Time Frame - Assuming 3.25 years of recruitment with 12 months ramp-up and 42 patients per month at peak and 3 years of follow-up after the last patient in, 396 events will be needed and final analysis is expected 75 months after study start.):
iDFS is defined as time from randomization until first iDFS event: local invasive recurrence following mastectomy, local invasive recurrence in the ipsilateral breast following lumpectomy, regional recurrence, distant recurrence, contralateral invasive breast cancer, second non-breast primary cancer (excluding squamous or basal cell carcinoma of the skin), or death from any cause. (according to Hudis (J Clin Oncol 2007) ) There will be one interim analysis for efficacy after 2/3 of the events to allow for early stopping of the trial due to overwhelming efficacy.



Secondary outcome:

1. To compare overall survival (OS) between patients treated with sacituzumab govitecan vs. treatment of physician's choice. (Time Frame - Assuming 3.25 years of recruitment 398 events will be needed with a power of 80% and final analysis is expected after 99 months (8.3 years after first patient in, 2 years after final analysis of iDFS).):
OS is defined as the time from randomization until death from any cause. One interim analysis of the key secondary endpoint OS will be performed at the time of the final analysis of the iDFS.

2. Distant disease-free survival (DDFS) between patients treated with sacituzumab govitecan vs. treatment of physician's choice. (Time Frame - DDFS will be analyzed at the time of the final iDFS analysis (is expected 75 months after study start)):
DDFS is defined as the time from randomization until distant recurrence of disease, second primary invasive cancer (non-breast, excluding squamous or basal cell carcinoma of the skin), and death due to any cause.

3. To compare the invasive breast cancer-free survival (iBCFS) between both groups. (Time Frame - iBCFS will be analyzed at the time of the final iDFS analysis (is expected 75 months after study start)):
iBCFS is defined as the time from randomization until first iDFS event excluding any second non-breast primary cancer.

4. Locoregional recurrences-free interval between patients treated with sacituzumab govitecan vs. treatment of physician's choice. (Time Frame - Time-to-Event Outcome Measure up to 75 month after study start.):
LRRFI is defined as the time from randomization until any loco-regional (ipsilateral breast (invasive), chest wall, local/regional lymph nodes) recurrence of disease or any invasive contralateral breast cancer whichever occurs first. Distant recurrence, secondary malignancy and death are considered as competing risks and will be accounted for in the analysis.

5. iDFS in stratified subgroups. (Time Frame - Will be analyzed at the time of the final iDFS analysis (is expected 75 months after study start)):
HR-negative vs. HR-positive ypN+ vs. ypN0.

6. OS in stratified subgroups. (Time Frame - Will be analyzed after 99 months (8.3 years after first patient in, 2 years after final analysis of iDFS)):
HR-negative vs. HR-positive ypN+ vs. ypN0.

7. iDFS in exploratory subgroups. (Time Frame - Will be analyzed at the time of the final iDFS analysis (is expected 75 months after study start)):
Prior platinum therapy (TNBC) Prior immune-checkpoint inhibitor therapy (TNBC) Experimental arm vs. active TPC in TNBC, overall and in subgroups of different active TPC low vs. high TROP2-expression

8. OS in exploratory subgroups. (Time Frame - Will be analyzed after 99 months (8.3 years after first patient in, 2 years after final analysis of iDFS)):
Prior platinum therapy (TNBC) Prior immune-checkpoint inhibitor therapy (TNBC) Experimental arm vs. active TPC in TNBC, overall and in subgroups of different active TPC low vs. high TROP2-expression

9. Safety - To compare safety between patients treated with sacituzumab govitecan vs. treatment of physician's choice. (Time Frame - Final safety analysis will take place when interim analysis of the primary endpoint is performed (all patients will have completed treatment, estimated 54 months from study start)):
Frequency and severity of adverse events graded according to the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. One interim analysis for safety will be performed after first 50 patients completed 4 cycles of treatment.

10. Compliance - To compare dose-density, dose reductions, dose delays, treatment interruptions and treatment discontinuation rates between patients treated with sacituzumab govitecan vs. treatment of physician's choice. (Time Frame - Analysis with final safety analysis expected 54 months after study start.):
Safety, tolerability, and treatment compliance: the number and percentage of patients whose treatment had to be reduced, delayed or permanently stopped will be summarized for each treatment arm, reasons for dose modification, delay and premature termination will be categorized according to the main reason and will be presented in frequency tables. Treatment arms will be compared regarding the occurrence of any adverse events (AE) (grade 1-5), low grade AE (grade 1-2), and high grade AE (grade 3-5) using Fisher's exact test. Those tests are descriptive in nature and no adjustments for multiple comparisons will be made.

11. Patient reported outcome: Functional Assessment of Cancer Therapy - Breast Cancer (FACT-B) (Time Frame - Through study completion and until 12 months after End of treatment of single patients.):
For each treatment group and at each time point, the number and percentage of patients who completed the instrument will be summarized, as well as the reasons for non-completion of these questionnaires, if known. For each of the FACT-B scales (37 items; 5 point Likert-typ scale; scale from 0-148; the higher the score, the better the QOL) the results will be summarized using descriptive statistics for each treatment group at each time point. Results based on the observed values as well as changes from baseline (including both within group and between group differences) will be displayed.

12. Patient reported outcome: Functional Assessment of Cancer Therapy - Cognitive function issues (FACT-Cog) (Time Frame - Through study completion and until 12 months after End of treatment of single patients.):
For each treatment group and at each time point, the number and percentage of patients who completed the instrument will be summarized, as well as the reasons for non-completion of these questionnaires, if known. For each of the FACT-cog scales (37 items; 5 point Likert-type scale; scale from 0-126; the higher the score, the better the QOL) the results will be summarized using descriptive statistics for each treatment group at each time point. Results based on the observed values as well as changes from baseline (including both within group and between group differences) will be displayed.

13. Patient reported outcome: Health Questionnaire 5-Level EQ-5D (EQ-5D-5L) (Time Frame - Through study completion and until 12 months after End of treatment of single patients.):
For each treatment group and at each time point, the number and percentage of patients who completed the instrument will be summarized, as well as the reasons for non-completion of the questionnair, if known. For the EQ-5D-5L instrument (6 items; 5 times 5 point Likert-type scale; 1-digit number that expresses the level selected for the item; 1 visual analogue scale (0-100mm); the higher the score, the better the QOL) the results will be summarized using descriptive statistics for each treatment group at each time point. Results based on the observed values as well as changes from baseline (including both within group and between group differences) will be displayed.

Studien-Arme

  • Experimental: Sacituzumab govitecan
    Sacituzumab govitecan is administered intravenously 10 mg/kg body weight on days 1, 8 q3w for eight cycles.
  • Other: Treatment of physician´s choice
    TPC, defined as capecitabine or platinum-based chemotherapy for eight cycles or Observation.

Geprüfte Regime

  • Capecitabine (Xeloda):
    2000 mg/m² day 1-14 q21 day cycle for eight cycles
  • Carboplatin (Paraplatin):
    AUC 5 q3w or AUC 1.5 weekly for eight 3 weekly cycles
  • Cisplatin (Platinol):
    25mg/m3 weekly or 75 mg/m3 q3w
  • Sacituzumab govitecan (Trodelvy):
    10 mg/kg body weight on days 1, 8 q3w

Quelle: ClinicalTrials.gov


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