Summary

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 independently-reviewed
Independent Review Committee (IRC) progression-free survival (PFS) in participants with
locally advanced or metastatic triple-negative breast cancer (TNBC) previously treated
with at least two systemic chemotherapy regimens for unresectable, locally advanced or
metastatic disease, and without brain metastasis at baseline.

Objectives

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. Earlier adjuvant or neoadjuvant treatment for more limited disease is allowed, but not included in the "at least two prior therapies" count. 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). Three-hundred and twenty-eight (328) patients are anticipated to be enrolled. Approximately 100 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 of the most recent biopsy findings (or other pathology reports). HER2 negative is defined as one of the following: 0 or 1+ by immunohistochemistry (IHC), or if IHC 2+, then fluorescence in situ hybridization (FISH) ratio of HER2 gene: chromosome 17 being less than 2, as per standard guidelines. ER- and PR-negative is defined as < 1% of cells expressing hormonal receptors by IHC, as per standard guidelines. 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; however, these results are not required prior to determining eligibility. 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. Starting with the initial dose of sacituzumab govitecan or TPC, CT scans (or MRI if contrast allergic) will be obtained at least every 8 weeks until the occurrence of progression of disease requiring discontinuation of further treatment. All images will be evaluated locally at the study site for tumor status as per RECIST1.1. Confirmatory CT/MRI scans are to be obtained in any patient within 4 to 6 weeks of an initial partial response. Additional CT or MRI scans may be performed at the discretion of the physician to assess disease status as medically indicated. Other study procedures during treatment include quality of life questionnaires, physical examination and vital signs, CBC (with differential and platelet counts), routine serum chemistries, serum samples for levels of sacituzumab govitecan, anti-drug antibodies (HAHA), concomitant medications, and adverse events. (See Study Procedures). A final study visit will be conducted 4 weeks after the last dose of sacituzumab govitecan or TPC for patients discontinuing study participation unless an earlier termination is required. The reason for study discontinuation will be documented and any adverse events or abnormal laboratories at that time will be followed until resolution or stabilization. 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 during the first year and every 8 weeks thereafter for survival follow-up. This may be by telephone and will include documentation of any further anti-cancer therapy they may receive. Survival status may be also documented from public databases . The use of prophylactic antipyretics, antihistamines, antiemetics, sedatives or and corticosteroids has not been regularly required with sacituzumab govitecan and thus should be used only if medically necessary. The use of such medications for patients receiving TPC is at the discretion of the treating physician, but must be recorded.All patients on study will receive best supportive care, which includes the use of growth factors or blood transfusions, continuing or initiating the use of corticosteroids, other palliative medications for complications of disease (including medications for pain and dietary support), treatment of any active infections, and palliative external radiation therapy for bone metastases, or medications for other ongoing medical conditions.The use of other anti-cancer treatment (besides IMMU-132 or TPC) is not permitted during this study. However, palliative and/or supportive medications such as bone-modifying medications (bisphosphonates or denosumab), and/or procedures such as radiation and surgery will be allowed at the investigator's discretion. After discontinuing the study, the patient may not receive any more sacituzumab govitecan; otherwise, there is no restriction on subsequent therapies or interventions that a patient may receive. Any further anti-cancer therapy should be documented. A 67% improvement in PFS in this relapsed/refractory metastatic TNBC patient population would be considered to be clinically meaningful. PFS estimates in this patient population vary from 1.7 to 4.2 months (3 months average). For an estimate of median PFS of 3 months in the control TPC group, a 1:1 randomization and a 67% improvement of median PFS in the IMMU-132 group from 3 to 5 months (corresponding to a hazard ratio of 0.6), a total sample size of 328 patients (305 events) equally randomized between the two arms would achieve 99% power with a two-sided type 1 error rate of 5%, based on an accrual rate of 18.2 patients per month (18-month enrollment period) and a minimum follow-up of 9 months. For the secondary endpoint of overall survival, with an enrollment of 328 patients (and 204 expected events), and a two-sided 5% type 1 error rate, the study will have 82.5% power to detect an increase in overall survival from 10 months in the control arm to 15 months in the IMMU-132 arm (corresponding to a hazard ratio of 0.67).

Eligibility

1. Histologically or cytologically confirmed TNBC based on the most recent analyzed biopsy or other pathology specimen. Triple negative is defined as <1% expression for estrogen receptor (ER) and progesterone receptor (PR) and negative for human epidermal growth factor receptor 2 (HER2) by in-situ hybridization.
2. Refractory to or relapsed after at least two prior standard therapeutic regimens for advanced/metastatic TNBC.
3. Prior exposure to a taxane in localized or advanced/metastatic setting.
4. Eligible for one of the chemotherapy options listed as TPC (eribulin, capecitabine, gemcitabine, or vinorelbine) as per investigator assessment.
5. Eastern Cooperative Oncology Group (ECOG) performance score of 0 or 1.
6. Measurable disease by computed tomography (CT) or magnetic resonance imaging (MRI) as per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1). Bone-only disease is not permitted.
7. At least 2 weeks beyond prior anti-cancer treatment (chemotherapy, endocrine therapy, radiotherapy, and/or major surgery), and recovered from all acute toxicities to Grade 1 or less (except alopecia and peripheral neuropathy).
8. At least 2 weeks beyond high dose systemic corticosteroids (however, low dose corticosteroids < 20 mg prednisone or equivalent daily are permitted provided the dose is stable for 4 weeks).
9. Adequate hematology without ongoing transfusional support (hemoglobin > 9 g/dL, absolute neutrophil count (ANC) > 1,500 per mm^3, platelets > 100,000 per mm^3).
10. Adequate renal and hepatic function (creatinine clearance [CrCL] > 60 mL/min, bilirubin = 1.5 institutional upper limit of normal [IULN], aspartate aminotransferase [AST] and alanine aminotransferase [ALT] = 2.5 x IULN or = 5 x IULN if known liver metastases and serum albumin =3 g/dL).
11. Recovered from all toxicities to Grade 1 or less by National Cancer Institute common terminology criteria for adverse events (NCI CTCAE) v4.03 (except alopecia or peripheral neuropathy that may be Grade 2 or less) at the time of randomization. Participants with Grade 2 neuropathy are eligible but may not receive vinorelbine as TPC.
12. Participants 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. Key