Purpose Trop-2, expressed in most triple-negative breast cancers (TNBCs), may be a potential target for antibody-drug conjugates. Sacituzumab govitecan, an antibody-drug conjugate, targets Trop-2 for the selective delivery of SN-38, the active metabolite of irinotecan. Patients and Methods We evaluated sacituzumab govitecan in a single-arm, multicenter trial in patients with relapsed/refractory metastatic TNBC who received a 10 mg/kg starting dose on days 1 and 8 of 21-day repeated cycles. The primary end points were safety and objective response rate; secondary end points were progression-free survival and overall survival. Results In 69 patients who received a median of five prior therapies (range, one to 12) since diagnosis, the confirmed objective response rate was 30% (partial response, n = 19; complete response, n = 2), the median response duration was 8.9 (95% CI, 6.1 to 11.3) months, and the clinical benefit rate (complete response + partial response + stable disease ≥ 6 months) was 46%. These responses occurred early, with a median onset of 1.9 months. Median progression-free survival was 6.0 (95% CI, 5.0 to 7.3) months, and median overall survival was 16.6 (95% CI, 11.1 to 20.6) months. Grade ≥ 3 adverse events included neutropenia (39%), leukopenia (16%), anemia (14%), and diarrhea (13%); the incidence of febrile neutropenia was 7%. The majority of archival tumor specimens (88%) were moderately to strongly positive for Trop-2 by immunohistochemistry. No neutralizing antibodies to the ADC or antibody were detected, despite repeated cycles developed. Conclusion Sacituzumab govitecan was well tolerated and induced early and durable responses in heavily pretreated patients with metastatic TNBC. As a therapeutic target and predictive biomarker, Trop-2 warrants further research.

Sacituzumab govitecan has a predictable pharmacokinetic profile and manageable toxicity at doses of 8 and 10 mg/kg. With objective responses and a good therapeutic index at 10 mg/kg, this dose was chosen for future development. Cancer 2017;123:3843-3854. © 2017 American Cancer Society.

Purpose Sacituzumab govitecan (IMMU-132) is an antibody-drug conjugate (ADC) targeting Trop-2, a surface glycoprotein expressed on many epithelial tumors, for delivery of SN-38, the active metabolite of irinotecan. This Phase I trial evaluated this ADC as a potential therapeutic for pretreated patients with a variety of metastatic solid cancers. Experimental Design Sacituzumab govitecan was administered on days 1 and 8 of 21-day cycles, with cycles repeated until dose-limiting toxicity or progression. Dose escalation followed a standard 3 + 3 scheme with 4 planned dose levels and dose delay or reduction allowed. Results Twenty-five patients (52-60 years old, 3 median prior chemotherapy regimens) were treated at dose levels of 8 (N=7), 10 (N=6), 12 (N=9), and 18 (N=3) mg/kg. Neutropenia was dose-limiting, with 12 mg/kg the maximum tolerated dose for cycle 1, but too toxic with repeated cycles. Lower doses were acceptable for extended treatment with no treatment-related grade 4 toxicities and grade 3 toxicities limited to fatigue (N=3), neutropenia (N=2), diarrhea (N=1), and leukopenia (N=1). Using CT-based RECIST 1.1, two patients achieved partial responses (triple-negative breast cancer, colon cancer) and 16 others had stable disease as best response. Twelve patients maintained disease control with continued treatment for 16-36 weeks; 6 survived 15-20+ months. No pre-selection of patients based on tumor Trop-2 expression was done. Conclusion Sacituzumab govitecan had acceptable toxicity and encouraging therapeutic activity in patients with difficult-to-treat cancers. The 8 and 10 mg/kg doses were selected for Phase II studies.

Tea has received a great deal of attention because tea polyphenols are strong antioxidants, and tea preparations have inhibitory activity against tumorigenesis. The bioavailability and biotransformation of tea polyphenols, however, are key factors limiting these activities in vivo. The inhibition of tumorigenesis by green or black tea preparations has been demonstrated in animal models on different organ sites such as skin, lung, oral cavity, esophagus, forestomach, stomach, small intestine, colon, pancreas, and mammary gland. Epidemiological studies, however, have not yielded clear conclusions concerning the protective effects of tea consumption against cancer formation in humans. The discrepancy between the results from humans and animal models could be due to 1) the much higher doses of tea used in animals in comparison to human consumption, 2) the differences in causative factors between the cancers in humans and animals, and 3) confounding factors limiting the power of epidemiological studies to detect an effect. It is possible that tea may be only effective against specific types of cancer caused by certain etiological factors. Many mechanisms have been proposed for the inhibition of carcinogenesis by tea, including the modulation of signal transduction pathways that leads to the inhibition of cell proliferation and transformation, induction of apoptosis of preneoplastic and neoplastic cells, as well as inhibition of tumor invasion and angiogenesis. These mechanisms need to be evaluated and verified in animal models or humans in order to gain more understanding on the effect of tea consumption on human cancer.

The present study investigates the bioavailability of resveratrol and quercetin in humans, mice, and rats after oral ingestion of grape juice preparations or pure aglycones. Oral administration of resveratrol and quercetin to humans yielded detectable levels of resveratrol, quercetin, and their derivatives in the plasma and urine. Urinary levels of resveratrol, quercetin, and their metabolites were observed in human subjects receiving 600 and 1200 mL of grape juice, whereas quercetin metabolites were identified in urine samples even after receiving 200 mL of grape juice. The cumulative amounts of resveratrol and quercetin excreted in the urine of mice receiving concentrated grape juice for 4 days were 2.3 and 0.7% of the ingested doses, respectively. After i.g. administration of resveratrol to rats (2 mg/kg), up to 1.2 microM resveratrol was observed in the plasma. The study demonstrates that the glycoside forms of resveratrol and quercetin in grape juice are absorbed to a lesser extent than the aglycones.