title: A modular Phase I study of lenalidomide and paclitaxel in metastatic castration-resistant prostate cancer following prior taxane therapy.
abstract: OBJECTIVE
  Lenalidomide, a highly potent immunomodulatory derivative of thalidomide, potentiates the action of paclitaxel in vitro against prostate cancer cell lines in co-culture with mononuclear cells. A modular Phase I study of lenalidomide and paclitaxel in men with metastatic castration-resistant prostate cancer (CRPC) was conducted to assess PSA kinetics with lead-in lenalidomide and the feasibility of the combination.
  
  
  METHODS
  Men with metastatic CRPC with prior taxane chemotherapy were planned for single-agent "lead-in" lenalidomide for 21/28 days at dose-levels: -1 (5 mg), 0 (10 mg), +1 (15 mg), +2 (20 mg), +3 (25 mg); followed by lenalidomide at the same dose and schedule in combination with weekly intravenous paclitaxel 100 mg/m(2) over 3 h on days 1, 8, 15 every 28 days utilizing a 3 + 3 dose-escalation design.
  
  
  RESULTS
  Dose-limiting toxicity was observed in 4/6 patients with first-cycle combination therapy at the 10 mg dose-level and 3/6 patients at the 5 mg dose-level of lenalidomide, respectively. These included Grade 3 neutropenia precluding planned paclitaxel therapy (n = 3), grade 3 gastrointestinal toxicity (n = 2), chest pain (n = 1) and pulmonary embolism (n = 1). With lead-in lenalidomide, two patients with lymph-node dominant CRPC had a PSA-decline and regression in lymph node disease, respectively. Two of seven evaluable patients had PSA declines by 50% with combination therapy. Progression-free survival was 13 weeks (range 4-35 weeks).
  
  
  CONCLUSIONS
  The high dose-limiting toxicity rates observed with lenalidomide and weekly paclitaxel require exploration of alternate dose-schedules of the combination in the second-line setting of CRPC. These early observations suggest distinctive toxicity and efficacy outcomes from thalidomide in combination with paclitaxel.
authors.affiliation: Department of Genitourinary Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA. pmathew@tuftsmedicalcenter.org
authors.forename: P
authors.initials: P
authors.lastname: Mathew
authors.forename: N
authors.initials: N
authors.lastname: Tannir
authors.forename: S M
authors.initials: SM
authors.lastname: Tu
authors.forename: C M
authors.initials: CM
authors.lastname: Carter
authors.forename: N B
authors.initials: NB
authors.lastname: Bekele
authors.forename: L
authors.initials: L
authors.lastname: Pagliaro
mesh_terms: D000368:Aged; D000740:Anemia / Q000139:chemically induced; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D001952:Bridged-Ring Compounds / Q000008:administration & dosage; D003131:Combined Modality Therapy; D003967:Diarrhea / Q000139:chemically induced; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D006801:Humans; D000077269:Lenalidomide; D008297:Male; D008875:Middle Aged; D009325:Nausea / Q000139:chemically induced; D009503:Neutropenia / Q000139:chemically induced; D009919:Orchiectomy; D017239:Paclitaxel / Q000008:administration & dosage / Q000009:adverse effects; D017430:Prostate-Specific Antigen / Q000097:blood; D011471:Prostatic Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000601:surgery; D016019:Survival Analysis; D043823:Taxoids / Q000008:administration & dosage; D013792:Thalidomide / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives; D016896:Treatment Outcome; D014839:Vomiting / Q000139:chemically induced
chemical_list: D001952:Bridged-Ring Compounds; D043823:Taxoids; C080625:taxane; D013792:Thalidomide; D017430:Prostate-Specific Antigen; D000077269:Lenalidomide; D017239:Paclitaxel