LSZ102

Selective estrogen receptor degraders (SERDs) like fulvestrant provide new strategies for endocrine therapy combinations due to unique mechanisms. In general, compound 40 showed much better pharmacological profiles than the lead LSZ102, exhibiting growth inhibition of wild-type or tamoxifen-resistant MCF-7 cells, potent ERα degradation, together with superior pharmacokinetic properties, directional target tissue distribution including the brain, and robust antitumor efficacy in the mice breast cancer xenograft model. Currently, 40 is being evaluated in preclinical trials.

As LSZ102 is metabolized by a number of different sulfotransferases, drug-drug interactions resulting from the inhibition of one sulfotransferase are unlikely.5. Despite the observed species difference in metabolism, the major human metabolites of LSZ102, sulfate M5, glucuronide M4, and secondary glucuronide/sulfate metabolite M12, have no or weak pharmacological activity and are not considered a toxicity risk as they are phase II conjugative metabolites.

P1, N=199, Terminated, Novartis Pharmaceuticals | Active, not recruiting --> Terminated; Sponsor's decision

LSZ102 was well tolerated alone and with ribociclib and had a manageable safety profile with alpelisib. Preliminary clinical activity was observed in combination use.

No abstract available

P1, N=200, Active, not recruiting, Novartis Pharmaceuticals | Trial completion date: Oct 2020 --> Mar 2021 | Trial primary completion date: Oct 2020 --> Mar 2021

P1, N=198, Active, not recruiting, Novartis Pharmaceuticals | N=420 --> 198

LSZ plus RIB or ALP showed manageable safety and encouraging clinical activity in heavily pre-treated ER+ BC pts, regardless of ESR1 and PIK3CA mutations. This is the first report of an oral SERD in combination with both CDK4/6 and PI3Kα inhibitors.Legal entity responsible for the study: Novartis Pharmaceuticals Funding: Novartis Pharmaceuticals Clinical trial identification: NCT02734615.

P1, N=420, Active, not recruiting, Novartis Pharmaceuticals | Recruiting --> Active, not recruiting

Finally, ten novel compounds were designed based on above findings, where the predicted activity of compound D8 was equivalent to that of the compound LSZ102. 3D-QSAR, ADMET and bioavailability predictions indicated that all designed compounds with good predicted activity, good physicochemical and bioavailability could be potential candidates for SERDs. These results and combinations of computational methods provided guidance for the rational drug design of novel potential SERDs.

This phase 1/1b, open-label study evaluates single-agent LSZ102 (Arm A) and LSZ102 in combination with ribociclib (Arm B) or alpelisib (Arm C) in pts with ER+ ABC who had progressed after ET. The combination of LSZ102 and ribociclib was well-tolerated and demonstrated antitumor activity in heavily pre-treated pts with ER+ ABC many of whom had progressed after fulvestrant and/or CDK4/6 inhibitor therapy.