title: A phase I weekly dosing study of brentuximab vedotin in patients with relapsed/refractory CD30-positive hematologic malignancies.
abstract: OBJECTIVE
  The antibody-drug conjugate (ADC) brentuximab vedotin comprises a CD30-directed antibody covalently attached to the potent antimicrotubule agent monomethyl auristatin E (MMAE) via a protease-cleavable linker. This study explored the safety, maximum-tolerated dose (MTD), and activity of weekly dosing of brentuximab vedotin in patients with relapsed or refractory CD30-positive hematologic malignancies.
  
  
  METHODS
  In this phase I dose-escalation study, brentuximab vedotin was administered intravenously on Days 1, 8, and 15, of each 28-day cycle at doses ranging from 0.4 to 1.4 mg/kg. Forty-four patients were enrolled: 38 with Hodgkin lymphoma, five with systemic anaplastic large cell lymphoma, and one with peripheral T-cell lymphoma not otherwise specified. Doses were escalated in increments of 0.2 mg/kg until dose-limiting toxicity (DLT) was observed. Patients were monitored for antitherapeutic antibodies and pharmacokinetic parameters. Antitumor assessments were carried out every two cycles.
  
  
  RESULTS
  The MTD was 1.2 mg/kg. The most common adverse events were peripheral sensory neuropathy, fatigue, nausea, diarrhea, arthralgia, and pyrexia; and the majority of events were mild to moderate in severity. Tumor regression occurred in 85% of patients and the overall objective response rate was 59% (n = 24), with 34% (n = 14) complete remissions. The median duration of response was not reached at a median follow-up of 45 weeks on study.
  
  
  CONCLUSIONS
  Weekly administration of brentuximab vedotin resulted in tumor regression and durable remissions in patients with CD30-positive malignancies. This ADC was associated with manageable toxicity, including peripheral neuropathy. Further study in CD30-positive malignancies is warranted.
authors.affiliation: Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA. mfanale@mdanderson.org
authors.forename: Michelle A
authors.initials: MA
authors.lastname: Fanale
authors.forename: Andres
authors.initials: A
authors.lastname: Forero-Torres
authors.forename: Joseph D
authors.initials: JD
authors.lastname: Rosenblatt
authors.forename: Ranjana H
authors.initials: RH
authors.lastname: Advani
authors.forename: Anna R
authors.initials: AR
authors.lastname: Franklin
authors.forename: Dana A
authors.initials: DA
authors.lastname: Kennedy
authors.forename: Tae H
authors.initials: TH
authors.lastname: Han
authors.forename: Eric L
authors.initials: EL
authors.lastname: Sievers
authors.forename: Nancy L
authors.initials: NL
authors.lastname: Bartlett
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000079963:Brentuximab Vedotin; D002648:Child; D004305:Dose-Response Relationship, Drug; D005260:Female; D005500:Follow-Up Studies; D019337:Hematologic Neoplasms / Q000188:drug therapy* / Q000401:mortality; D006801:Humans; D018796:Immunoconjugates / Q000493:pharmacokinetics / Q000627:therapeutic use*; D017730:Ki-1 Antigen / Q000378:metabolism*; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D011379:Prognosis; D015996:Survival Rate; D014018:Tissue Distribution; D055815:Young Adult
chemical_list: D018796:Immunoconjugates; D017730:Ki-1 Antigen; D000079963:Brentuximab Vedotin