EP is a next-generation topoisomerase I inhibitor-polymer conjugate that provides continuous exposure to SN-38, the active metabolite of irinotecan. A BM mouse model showed high penetration and retention of SN-38 in CNS lesions, resulting in decreased size of CNS lesions and improved survival at concentrations achieved at the recommended dose in pts (Adkins BMC Cancer 2015). Although a phase 3 trial (BEACON) of EP vs TPC in 852 pts with advanced BC did not meet its primary endpoint of overall survival (OS) (HR 0.87; P = 0.08), a pre-planned subset analysis of 67 pts with stable BM showed improved OS (HR 0.51 [95% CI 0.30-0.86]; P < 0.01) (Perez Lancet Oncol 2015). The current phase 3 trial (ATTAIN) was designed to further study this subpopulation of pts.
Pts with MBC with locally treated stable BM will be randomized 1:1 to EP or TPC in an open-label phase 3 study. Eligibility includes: ECOG PS 0 or 1; adequate organ function; prior ATC therapy (any setting); ≥1 prior cytotoxic regimen for pts with triple negative MBC; ≥2 prior cytotoxic regimens for pts with HR+ or HER2+ BC (pts with HR+/HER2+ BC must have received prior hormone therapy/HER2 targeted therapy); prior definitive local therapy of BM (whole brain radiation [RT], stereotactic RT or surgical resection as single-agent or combination); and stable signs/symptoms of BM with steroids (ie, unchanged or decreasing ≥7 days prior to randomization). Primary endpoint is OS. Key secondary endpoints are ORR and PFS by RECIST v1.1 and RANO-BM, CBR (ORR+SD ≥ 6 months) and QoL. Pts randomized to TPC will receive 1 of 7 IV agents. Pts are stratified by region, PS and receptor status. An independent data monitoring committee will assess interim data and determine final number of events needed to provide 80% conditional power to detect a statistically significant improvement in OS based on the promising zone adaptive design (Mehta & Pocock, 2011). Up to 220 pts will be randomized. PK sampling and UGT1A1 testing will be performed in the EP arm; plasma ctDNA will be assessed for predictive markers of efficacy.
Clinical trial identification
Legal entity responsible for the study
Nektar Therapeutics, San Francisco, CA.
Nektar Therapeutics, San Francisco, CA.
D. Tripathy: Consulting or advisory role: Novartis, Nektar, Pfizer, Puma Biotechnology; Travel, Accommodations, Expenses: Novartis; Research funding: Genentech/Roche (to institution), Novartis (to institution). S.M. Tolaney: Consulting or advisory role: Novartis, Pfizer, Merck, Lilly, Nanostring Technologies AstraZeneca, Puma Biotechnology, Genentech; Research funding (to institution): Genentech/Roche, Merck, Exelixis, Pfizer, Lilly, Novartis, Bristol-Myers Squibb; Research funding (to author): Eisai. A.D. Seidman: Honoraria: Eisai, Genentech, Genomic Health, Novartis; Consulting or advisory role: Nektar, Eisai; Speaker's bureau: Eisai, Genentech, Genomic Health, Novartis; Research funding: Bayer, Novartis. C.K. Anders: Consulting or advisory role: Sanofi, Novartis, Merrimack, Genentech/Roche, to-BBB technologies BV, Lilly, Nektar, Kadmon, Angiochem Patents, royalties, other intellectual property: Up to Date.com, Jones and Bartlell; Research funding (to institution): Sanofi, Novartis, to-BBB technologies BV, Puma Biotechnology, Angiochem, Merrimack, Lilly, Merck, Cascadian Therapeutics, Nektar, Tesaro. N.K. Ibrahim: Speakers' bureau: Celgene, Roche, Novartis; Travel, accommodations, expenses: Roche, Novartis; Honoraria: Celgene, Roche, Novartis; Research funding (to institution): GenomeDx, Newlink Genetics, Archer Biosciences. H.S. Rugo: Consulting or advisory role: Amgen; Speakers' bureau: Genomic Health; Travel, accommodations, expenses: Novartis, Roche/Genentech, OBI Pharma, Pfizer, Puma Biotechnology, Mylan; Honoraria: Genomic Health; Research funding (to institution): Plexxikon, Macrogenics, OBI Pharma, Eisai, Pfizer, Novartis, Lilly, Genentech, Merck, GTx, Incyte, Immunomedics. C.J. Twelves: Honoraria: Daiichi Sankyo, Eisai, Nektar. V. Dieras: Consulting or advisory role: Abbvie, Novartis, Pfizer, Roche/Genentech, Lilly Pharma; Speakers' bureau: Novartis, Pfizer, Roche; Travel, accommodations, expenses: Novartis, Pfizer, Roche. V. Müller: Consulting or advisory role: AstraZeneca, Celgene, Daiichi Sankyo, Eisai, Nektar, Roche/Genentech, Novartis; Travel, accommodations, expenses: Pfizer, Roche Pharma AG. A.L. Hannah: Leadership: NeoGenomics Laboratories; Stock ownership interests: NeoGenomics Laboratories Consulting; Advisory role: Nektar, Pfizer, BeiGene. M.A. Tagliaferri: Employment: Nektar Leadership, Nektar Stock; Ownership interests: Nektar Consulting or advisory role (immediate family member): Bluebird Bio, Nektar Patents, royalties, other intellectual property: Nektar; Travel, accommodations, expenses: Nektar; Travel, accommodations, expenses (an immediate family member): Bluebird Bio, Nektar. J. Cortes Castan: Stock and other ownership interests: MedSIR; Honoraria: Celgene, Eisai, Novartis, Pfizer, Roche; Consulting or advisory role: AstraZeneca, Biothera, Celgene, Cellestia Biotech, Roche.