Clinical Trials /

Sacituzumab Govitecan in Primary HER2-negative Breast Cancer

NCT04595565

Description:

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 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.

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 3

Trial Eligibility

Document

Title

  • Brief Title: Sacituzumab Govitecan in Primary HER2-negative Breast Cancer
  • Official Title: 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

Clinical Trial IDs

  • ORG STUDY ID: GBG102 - SASCIA
  • NCT ID: NCT04595565

Conditions

  • HER2-negative Breast Cancer
  • Triple Negative Breast Cancer

Interventions

DrugSynonymsArms
CapecitabineXelodaTreatment of physician´s choice
CarboplatinParaplatinTreatment of physician´s choice
CisplatinPlatinolTreatment of physician´s choice
Sacituzumab govitecanTrodelvySacituzumab govitecan

Purpose

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 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.

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.
    

Trial Arms

NameTypeDescriptionInterventions
Sacituzumab govitecanExperimentalSacituzumab govitecan is administered intravenously 10 mg/kg body weight on days 1, 8 q3w for eight cycles.
  • Sacituzumab govitecan
Treatment of physician´s choiceOtherTPC, defined as capecitabine or platinum-based chemotherapy for eight cycles or Observation.
  • Capecitabine
  • Carboplatin
  • Cisplatin

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

               -  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. Germline BRCA1/2 mutated or wildtype/unknown.

          8. 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 is not required in
             patients with a negative sentinel-node biopsy before (pN0, pN+(mic)) or after (ypN0,
             ypN+(mic)) neoadjuvant chemotherapy. Histologic complete resection (R0) of all
             invasive and in situ tumors is required.

          9. 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).

         10. 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.

         11. In case of local progression during neoadjuvant therapy, distant metastases must be
             excluded by adequate imaging (CT/MRI recommend) prior to entering the trial.

         12. Immune checkpoint inhibitor / immunotherapy during neoadjuvant therapy is allowed.

         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.

        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 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.

          4. 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.

          5. 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-Syndrom, known hepatitis B, hepatitis C, known HIV positivity or known
             autoimmune disease (other than diabetes, vitiligo, or stable thyroid disease) and
             infection requiring intravenous antibiotic use within 1 week of enrolment.

          6. 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.

          7. 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.

          8. History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g. bronchiolitis
             obliterans), drug-induced pneumonitis, idiopathic pneumonitis or active pneumonitis on
             chest CT scan.

          9. Receipt of live attenuated vaccination within 30 days prior to study entry or within
             30 days of receiving chemotherapy.

         10. History of significant neurological or psychiatric disorders including psychotic
             disorders, dementia or seizures that would prohibit the understanding and giving of
             informed consent.

         11. Any condition that, in the opinion of the investigator, would interfere with
             evaluation of study treatment or interpretation of patient safety or study results.

         12. Known allergic reactions to irinotecan.

         13. 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.
      
Maximum Eligible Age:99 Years
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Invasive disease free survival (iDFS) between patients treated with sacituzumab govitecan vs. treatment of physician's choice.
Time Frame:Assuming 3 years of recruitment with 12 months ramp-up and 42 patients per month at peak and 3.2 years of follow-up after the last patient in, 385 events will be needed and final analysis is expected 75 months after study start.
Safety Issue:
Description: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 Measures

Measure:To compare overall survival (OS) between patients treated with sacituzumab govitecan vs. treatment of physician's choice.
Time Frame:Assuming 3 years of recruitment 386 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).
Safety Issue:
Description: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.
Measure: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)
Safety Issue:
Description: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.
Measure: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.
Safety Issue:
Description: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.
Measure:iDFS in stratified subgroups.
Time Frame:Will be analyzed at the time of the final iDFS analysis (is expected 75 months after study start)
Safety Issue:
Description:HR-negative vs. HR-positive ypN+ vs. ypN0.
Measure: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)
Safety Issue:
Description:HR-negative vs. HR-positive ypN+ vs. ypN0.
Measure:iDFS in exploratory subgroups.
Time Frame:Will be analyzed at the time of the final iDFS analysis (is expected 75 months after study start)
Safety Issue:
Description:Prior platinum therapy (TNBC) Prior immune-checkpoint inhibitor therapy (TNBC) Experimental arm vs. active TPC in TNBC low vs. high TROP2-expression
Measure: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)
Safety Issue:
Description:Prior platinum therapy (TNBC) Prior immune-checkpoint inhibitor therapy (TNBC) Experimental arm vs. active TPC in TNBC low vs. high TROP2-expression
Measure: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)
Safety Issue:
Description: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.
Measure: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 Issue:
Description: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.
Measure:Patient reported outcomes: Quality of life - FACT-B Quality of life - FACT-Cog Quality of life - EQ-5D-5L
Time Frame:Through study completion and until 12 months after End of treatment of single patients.
Safety Issue:
Description: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, FACT-cog scales and for the EQ-5D-5L instrument, 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.

Details

Phase:Phase 3
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:German Breast Group

Last Updated

October 14, 2020