Sacituzumab Govitecan and Talazoparib for the Treatment of Stage IV Triple-Negative Breast Cancer
- Histologically or cytologically confirmed stage IV (metastatic) breast cancer. Principal investigator (PI) approval is needed for patients who do not have source documentation of histologically confirmed stage IV (metastatic) breast cancer, but otherwise have known metastatic breast cancer
- Participants must have biopsy proven triple negative, i.e. estrogen receptor (ER) negative (ER-), progesterone receptor (PR) negative (PR-), HER2 negative, invasive breast cancer, by American Joint Committee on Cancer (AJCC) 7th edition staging. ER, PR, and HER2 positivity would be determined per institutional (local) testing, with triple negative status for this trial determined as per 2020 American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) guidelines, in a biopsy/surgical specimen analyzed for ER/PR/HER2. Patients with “ER or PR low positive” as per updated ASCO/CAP 2020 guidelines can be considered after approval of PI. Confirmation of adequate (15-20 unstained slides cut at 5-10 um or 1 block) archival tissue (primary or metastatic) required before study entry. If adequate tissue not available, PI approval is required prior to study entry
- Previously treated with no more than one prior therapeutic regimens for metastatic disease during dose-expansion (no limit on prior therapeutic regimens in dose-escalation). In patients with disease recurrence within 12 months of (neo)adjuvant therapy, the (neo)adjuvant therapy would count as one prior regimen for this criterion. Radiation therapy or local therapy/surgery would not count as prior regimen for this criterion
- Pre- and postmenopausal women are eligible
- Eastern Cooperative Oncology Group (ECOG) performance status = 0-1
- Measurable disease as per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1
- Ability to understand and the willingness to sign a written informed consent document. Patient has signed the informed consent (ICF) prior to any screening procedures being performed and is able to comply with protocol requirements
- At least 2 weeks beyond treatment (chemotherapy, targeted therapy, immunotherapy, and/or radiation therapy) or major surgery and recovered from all acute toxicities (adverse events from prior anti-cancer agents need to be grade 1 or lower; grade 2 alopecia or peripheral neuropathy is permitted)
- At least 2 weeks beyond corticosteroids (however, low dose corticosteroids < 20 mg prednisone or equivalent daily are permitted. Also, use of steroid prophylaxis for contrast allergy does not count toward this criterion and the use is permitted)
- Absolute neutrophil count >= 1.5 x 10^9/L
- Platelets >= 100 x 10^9/L
- Hemoglobin >= 10.0 g/dL (transfusion permitted)
- Institutional normalized ratio (INR) =< 1.5
- Glomerular filtration rate (GFR) or creatinine clearance >= 50 mL/min (either permitted)
- In the absence of liver metastases, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) < 2.5 x upper limit of normal (ULN). If the patient has liver metastases, ALT and AST < 5 x ULN
- Total bilirubin =< 1.5 x ULN or direct bilirubin =< 3 x ULN in patients with well-documented Gilbert’s syndrome
- Participants who have had anti-cancer therapy including targeted therapy or chemotherapy or radiotherapy (including stereotactic radiosurgery/SRS) within 2 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study, or those who have not recovered from adverse events (clinically significant grade 2 or higher adverse events; grade 2 alopecia or peripheral neuropathy is permitted) due to prior anti-cancer agents
- Participants who have received prior PARP inhibitor (allowed in phase 1b), and/or sacituzumab govitecan (allowed in phase 1b). Participants who have received prior irinotecan or ADC backbone with SN-38 or topoisomerase-1 inhibitor (allowed in phase 1b)
- Participants with increasing/progressive central nervous system (CNS) metastatic disease. Patients with asymptomatic or stable CNS metastasis would be eligible, provided metastasis radiologically non-progressing for at least two weeks, and patient is not actively taking steroids (more than 20 mg of prednisone or equivalent dose)
- Current use of strong CYP3A inhibitors/inducers, or P-glycoprotein (P-gp) inhibitors within 7 days prior to talazoparib use.
- Uncontrolled inter-current illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements. Patient has impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of the study drugs (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection)
- Clinically significant, uncontrolled heart disease and/or cardiac repolarization abnormality including any of the following: * History of angina pectoris, symptomatic pericarditis, coronary artery bypass graft (CABG) or myocardial infarction within 6 months prior to study entry * Documented cardiomyopathy * History of cardiac failure, significant/symptomatic bradycardia, long QT syndrome, family history of idiopathic sudden death or congenital long QT syndrome or any of the following: ** Known risk to prolong the QT interval or induce Torsades de Pointes ** Uncorrected hypokalemia ** Systolic blood pressure (SBP) > 160 mmHg or < 90 mmHg ** Bradycardia (heart rate < 50 at rest), by electrocardiography (ECG) or pulse ** On screening, the corrected QT interval by Fridericia's correction formula (QTcF) > 470 screening ECG
- Human immunodeficiency virus (HIV)-positive participants on combination antiretroviral therapy are ineligible. These participants are at increased risk of lethal infections when treated with marrow-suppressive therapy. Appropriate studies will be undertaken in participants receiving combination antiretroviral therapy when indicated
- Pregnant women are excluded from this study because the safety of study medications is not established in pregnant women
- Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, or fertile men, unless they are using highly effective methods of contraception throughout the study and after study drug discontinuation (till seven months in women and four months in males, post-study). Male patient should not donate sperm while on treatment and up to 6 months after last dose. Women are considered post-menopausal and not of child bearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy (with or without hysterectomy) or tubal ligation at least six weeks ago. In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment is she considered not of child bearing potential. Highly effective contraception methods include: * Total abstinence when this is in line with the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception * Female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy), total hysterectomy, or tubal ligation at least six weeks before taking study treatment. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment * Use of oral, injected or implanted hormonal methods of contraception or placement of an intrauterine device (IUD) or intrauterine system (IUS), or other forms of hormonal contraception that have comparable efficacy (failure rate < 1%), for example hormone vaginal ring or transdermal hormone contraception * In case of use of oral contraception, women should have been stable on the same pill for a minimum of 3 months before taking study treatment. Note: While oral contraceptives are allowed, they should be used in conjunction with a barrier method of contraception due to unknown effect of drug-drug interaction
I. To assess the dose-limiting toxicity (DLT) rate and maximum tolerated dose (MTD) of sacituzumab govitecan in combination with talazoparib in patients with metastatic triple-negative breast cancer (mTNBC) to select the recommended phase 2 dose (RP2D) of this combination, in patients with mTNBC. (Phase Ib)
II. To assess the confirmed overall response rate (ORR) of sacituzumab govitecan in combination with talazoparib at the R2PD, in patients with mTNBC. (Phase II)
I. To obtain preliminary evidence of efficacy with progression-free survival (PFS) of sacituzumab govitecan in combination with talazoparib at R2PD, in patients with mTNBC.
II. To evaluate safety and tolerability, including health-related quality of life (HRQoL), of sacituzumab govitecan in combination with talazoparib at RP2D, in patients with mTNBC.
I. To evaluate predictive biomarkers, including trop-2 expression homologous recombinant deficiency (HRD) and BRCA mutation, associated with efficacy of sacituzumab govitecan in combination with talazoparib, in patients with mTNBC.
II. To evaluate mechanism of resistance of sacituzumab govitecan in combination with talazoparib, in patients with mTNBC.
OUTLINE: This is a phase I, dose-escalation study followed by a phase II study.
Patients receive either sacituzumab govitecan intravenously (IV) over 1-3 hours on days 1 and 8 and talazoparib orally (PO) on days 1-21; or sacituzumab govitecan IV on days 1 and 15 over 1-3 hours and talazoparib PO on days 8-14 and 22-28. Cycles repeat every 21 or 28 days (depending on schedule) in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up for 30 days and then every 8 weeks thereafter.
Trial Phase Phase I/II
Trial Type Treatment
Dana-Farber Harvard Cancer Center
- Primary ID 19-239
- Secondary IDs NCI-2019-07939
- Clinicaltrials.gov ID NCT04039230