Phase III Postneoadjuvant Study Evaluating Sacituzumab Govitecan, an Antibody Drug Conjugate in Primary HER2-negative Breast Cancer Patients With High Relapse Risk After Standard Neoadjuvant Treatment - SASCIA

Official Summary

Phase III, prospective, multi-center, randomized, open label, parallel group, study in patients with HER2-negative breast cancer with residual disease after neoadjuvant chemotherapy with 1:1 allocation to: * Arm A: Sacituzumab govitecan (days 1, 8 q3w for eight cycles); * Arm B: treatment of physician´s choice (TPC, defined as capecitabine or platinum-based chemotherapy for eight cycles or observation. Treatment in either arm will be given for eight cycles. In patients with HR-positive breast cancer, endocrine-based therapy, which includes the use of CDK4/6 inhibitors, will be administered according to local guidelines. The start of endocrine therapy will be at the discretion of the investigator; however, it will be encouraged to start after surgery/radiotherapy in patients without additional cytotoxic agents. Adjuvant pembrolizumab can be given until the completion of radiotherapy before randomization. Within the study the use of pembrolizumab in patients with TNBC who received pembrolizumab as neoadjuvant therapy is allowed as monotherapy in the TPC arm, according to the approval of pembrolizumab in this setting.

Eligibility Requirements

• Minimum Age: 18 Years
• Maximum Age: 99 Years

Study Design

• Study Type: INTERVENTIONAL
• Allocation: RANDOMIZED
• Model: PARALLEL
• Masking: NONE
• Enrollment: 1,332 participants

Study Arms

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

Interventions

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

Primary Outcomes

• Invasive disease free survival (iDFS) between patients treated with sacituzumab govitecan vs. treatment of physician's choice. (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.)

Secondary Outcomes

• To compare overall survival (OS) between patients treated with sacituzumab govitecan vs. treatment of physician's choice. (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).)
• Distant disease-free survival (DDFS) between patients treated with sacituzumab govitecan vs. treatment of physician's choice. (DDFS will be analyzed at the time of the final iDFS analysis (is expected 75 months after study start))
• To compare the invasive breast cancer-free survival (iBCFS) between both groups. (iBCFS will be analyzed at the time of the final iDFS analysis (is expected 75 months after study start))
• Locoregional recurrences-free interval between patients treated with sacituzumab govitecan vs. treatment of physician's choice. (Time-to-Event Outcome Measure up to 75 month after study start.)
• iDFS in stratified subgroups. (Will be analyzed at the time of the final iDFS analysis (is expected 75 months after study start))

Eligibility Criteria

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 creat

Trial Locations

• MUG - Univ.-Klinik f. Frauenheilkunde u. Geburtshilfe Graz, Graz, Austria
• MUG - Univ.-Klinik f. Innere Medizin Graz, Graz, Austria
• MUI - Univ. Klinik f. Frauenheilkunde Innsbruck, Innsbruck, Austria
• Ordensklinikum Linz GmbH - BHS, Linz, Austria
• TumorZentrum Kepler Uniklinikum Linz, Linz, Austria
• LKH Salzburg - PMU, Salzburg, Austria
• Universitätsklinikum St. Pölten, Sankt Pölten, Austria
• MUW - AKH Wien, Vienna, Austria
• MUW - Med. Univ.-Klinik AKH Wien, Vienna, Austria
• Salzkammergut-Klinikum Vöcklabruck, Vöcklabruck, Austria
• ...and 10 more locations

Study Officials

• Frederik Marmé, MD, Prof. — PRINCIPAL_INVESTIGATOR
  ASCO, ESMO, GBG, AGO, DKG, DGS, DKG

More HER2-negative Breast Cancer Trials

View all HER2-negative Breast Cancer clinical trials