Phase III Study of Sacituzumab Govitecan (IMMU-132) in Refractory/Relapsed Triple-Negative Breast Cancer
This is an international, multi-center, open-label, randomized, Phase III study in patients with metastatic TNBC refractory or relapsing after at least 2 prior chemotherapies (including a taxane) for their metastatic disease. Patients meeting eligibility will be randomized 1:1 to receive either sacituzumab govitecan or treatment of physician choice (TPC) Patients will be treated until progression, unacceptable toxicity, study withdrawal, or death, whichever comes first. Tumor progression leading to treatment withdrawal will be assessed by the investigator. Starting with the initial dose of sacituzumab govitecan or TPC, Imaging assessments will be obtained at least every 8 weeks until the occurrence of progression of disease requiring discontinuation of further treatment. All patients, will be followed every 4 weeks during the first year and every 8 weeks thereafter for survival follow-up.
The primary objective of this study is to compare the efficacy of sacituzumab govitecan to the treatment of physician's choice (TPC) as measured by progression-free survival (PFS) in patients with metastatic TNBC previously treated with at least two systemic chemotherapy regimens.
The secondary objectives of the study are to compare between the two treatment groups for:
- Overall Survival (OS)
- Independently-determined Objective Response Rate (ORR), duration of response and time to onset of response per RECIST 1.1 criteria
- Quality of life
- Safety (adverse events, safety laboratories, incidence of dose delays and dose reductions, treatment discontinuations due to adverse events) Exploratory objectives include exposure-response analysis for the efficacy (PFS and OS) and safety (incidence of Grade 3-5 adverse events, related to UGT1A1 endpoints).
Four-Hundred and eighty-eight patients are anticipated to be enrolled. Approximately 150 institutions will participate in this study, including sites in North America and Europe.
Clinical sites will use standard ASCO/CAP criteria for the pathological diagnosis of TNBC, defined as negative for estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2). Receptor results will be based on local assessment. TNBC status will be reviewed centrally but these results are not required prior to determining eligibility.
BRCA 1&2 mutational status will be collected, if known. Baseline serum biomarkers (CA15-3, CA27-29, and CEA) will be measured. A single whole-blood sample will be also collected from all patients for determination of UGT1A1 genotype for retrospective assessment predicting of toxicity.
The Sponsor will request slides from prior (archived) biopsy or surgical specimens, particularly for immunohistology documentation of tumor Trop-2 expression and other appropriate tumor markers, including topoisomerase 1.
Patients meeting eligibility will be randomized 1:1 to receive either sacituzumab govitecan or treatment of physician choice (TPC), which needs to be selected prior to randomization from one of the 4 allowed regimens. Randomization will be stratified by number of prior chemotherapies for advanced disease (2-3 vs > 3) and geographical location (North America vs Europe).
Patients will be treated until progression, unacceptable toxicity, study withdrawal, or death, whichever comes first. Tumor progression leading to treatment withdrawal will be assessed by the investigator.
No crossover to sacituzumab govitecan treatment will be allowed after discontinuing treatment in the TPC arm, but otherwise there is no restriction on subsequent therapies that a patient may receive after discontinuing the study.
All patients, including those prematurely terminating study participation, will be followed every 4 weeks for survival follow-up.
18 Years and up
Accepting Healthy Volunteers?
- Female or male patients, >18 years of age, able to understand and give written informed consent.
- Histologically or cytologically confirmed TNBC based on the most recent analyzed biopsy or other pathology specimen. TNBC determination as per local institution as per standard guidelines.
- Refractory to or relapsed after at least two prior standard therapeutic regimens for advanced/metastatic TNBC.
- Prior exposure to a taxane (paclitaxel or docetaxel)-based regimen in localized or advanced/metastatic setting.
- Eligible for one of the chemotherapy options listed as TPC (Eribulin, capecitabine, gemcitabine, or vinorelbine) as per investigator assessment.
- ECOG performance score of 0 or 1 .
- Measurable disease by CT or MRI as per RECIST 1.1. Bone-only disease is not permitted.
- At least 2 weeks beyond prior treatment (chemotherapy, investigational drugs including small molecular inhibitors, endocrine therapy, immunotherapy and/or radiation therapy) or major surgery, and recovered from all acute toxicities to Grade 1 or less (except alopecia and peripheral neuropathy).
- At least 2 weeks beyond high dose systemic corticosteroids (however, low dose corticosteroids < 20 mg prednisone or equivalent daily are permitted).
- Adequate hematology without ongoing transfusional support (hemoglobin > 9 g/dL, ANC > 1,500 per mm3, platelets > 100,000 per mm3).
- Adequate renal and hepatic function (creatinine ≤ 2.0 x IULN, bilirubin ≤ 1.5 IULN, AST and ALT ≤ 3.0 x IULN or 5 x IULN if known liver metastases).
- Otherwise, all toxicity at study entry < Grade 1 by NCI CTCAE v4.00 (Patients with ≤ Grade 2 neuropathy are eligible).
- Patients with treated, non-progressive brain metastases, off high-dose steroids (>20 mg prednisone or equivalent) for at least 4 weeks can be enrolled in the trial.
- Women who are pregnant or lactating.
- Women of childbearing potential or fertile men unwilling to use effective contraception during study until conclusion of 4-week post-treatment evaluation period.
- Patients with Gilbert's disease.
- Patients with active ≥ grade 2 anorexia, nausea or vomiting, and/or signs of intestinal obstruction.
- Patients with non-melanoma skin cancer or carcinoma in situ of the cervix are eligible, while patients with other prior malignancies must have had at least a 3-year disease-free interval.
- Patients known to be HIV positive, hepatitis B positive, or hepatitis C positive.
- Infection requiring intravenous antibiotic use within one week of enrollment.
- Patients with a history of an anaphylactic reaction to irinotecan.
- Other concurrent medical or psychiatric conditions that, in the Investigator's opinion, may be likely to confound study interpretation or prevent completion of study procedures and follow-up examinations.