A Phase I Study of LSZ102, an Oral Selective Estrogen Receptor Degrader, with or without Ribociclib or Alpelisib, in Patients with Estrogen Receptor-Positive Breast Cancer.

PURPOSE: Data are sparse for oral selective estrogen receptor (ER) degraders (SERD) in cancer treatment. The investigational oral SERD LSZ102 was assessed in monotherapy and combination use in a phase I study. PATIENTS AND METHODS: A phase I, multicenter, open-label dose-escalation study (NCT02734615) of LSZ102 alone (arm A; n = 77) or with ribociclib (arm B; n = 78) or alpelisib (arm C; n = 43) in heavily pretreated adults with histologically confirmed ER-positive breast cancer and prior disease progression. Arm A received LSZ102 200-900 mg/day; arm B, LSZ102 200-600 mg/day plus ribociclib 300-600 mg/day; arm C, LSZ102 300-450 mg/day plus alpelisib 200-300 mg/day. Key outcomes were dose-limiting toxicities (DLT) in the first 28-day treatment cycle, adverse events (AE), laboratory parameters, pharmacokinetics, biopsy ER protein, and investigator-assessed clinical response (RECIST v1.1). RESULTS: The most common AEs were gastrointestinal. Treatment-related serious AEs occurred in 10% of participants (19/198), mostly in arm C [10/43 (23%)]. DLTs occurred in: arm A, 5% (4/77); arm B, 3% (2/78); and arm C, 19% (8/43). LSZ102 exposure was slightly greater than dose proportional. On-treatment biopsy ER reductions were observed, with a trend toward an LSZ102 dose response. Objective response rates (95% confidence interval) were: arm A, 1.3% (0.0-7.0); arm B, 16.9% (9.3-27.1); and arm C, 7.0% (1.5-19.1), and clinical benefit rates 7.8% (2.9-16.2), 35.1% (24.5-46.8), and 20.9% (10.0-36.0), respectively. CONCLUSIONS: LSZ102 was well tolerated alone and with ribociclib and had a manageable safety profile with alpelisib. Preliminary clinical activity was observed in combination use.

Unexpected hepatotoxicity in a phase I study of TAS266, a novel tetravalent agonistic Nanobody® targeting the DR5 receptor.

PURPOSE: TAS266 is a novel agonistic tetravalent Nanobody(®) targeting the DR5 receptor. In preclinical studies, TAS266 was more potent than a cross-linked DR5 antibody or TRAIL. This first-in-human study was designed to evaluate the safety and tolerability, maximum tolerated dose, pharmacokinetics, pharmacodynamics, immunogenicity, and preliminary efficacy of TAS266. METHODS: Adult patients with advanced solid tumors were to receive assigned doses of TAS266 (3, 10, 15, or 20 mg/kg) intravenously on days 1, 8, 15, and 22 of a 28-day treatment cycle. RESULTS: Grade ≥3 elevations in aspartate aminotransferase and/or alanine aminotransferase levels, occurring during cycle 1 in three of four patients at the 3 mg/kg dose level, were attributed to TAS266 and led to early study termination. Liver enzyme levels quickly returned to grade ≤1 following TAS266 discontinuation. Evidence of preexisting antibodies able to bind to TAS266 was found in the three patients who experienced these dose-limiting toxicities. Immunogenic responses remained elevated and strengthened at end-of-treatment (EOT). In the one patient who did not develop hepatotoxicity, no evidence of immunogenicity was observed at baseline or following administration of 4 TAS266 doses; however, incipient positive immunogenicity was observed at the EOT visit. CONCLUSION: TAS266 was associated with unexpected, significant but reversible hepatotoxicity. Although the underlying mechanism is not fully elucidated, factors including the molecule's high potency, immunogenicity to TAS266, and possibly increased DR5 expression on hepatocytes further enhancing the activity of the Nanobody(®) may have contributed to enhanced DR5 clustering and activation of hepatocyte apoptosis.