title: Sargramostim (GM-CSF) and lenalidomide in castration-resistant prostate cancer (CRPC): results from a phase I-II clinical trial.
abstract: BACKGROUND
  Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a pleiotropic cytokine that stimulates dendritic cells (DCs) and promotes uptake of tumor antigens by DCs leading to T-cell cross-priming. Lenalidomide (Revlimid) is an immunomodulatory analog of thalidomide with significant T-cell stimulatory and antiangiogenic properties. GM-CSF in combination with thalidomide induces prostate-specific antigen (PSA) responses in 20% to 25% of patients with castration-resistant prostate cancer (CRPC). In an effort to further evaluate the clinical and immune activity of GM-CSF and lenalidomide, we conducted a phase I-II trial in patients with CRPC.
  
  
  METHODS
  Asymptomatic patients with CRPC were enrolled. Prior immunotherapy or chemotherapy was not allowed. All the patients received 250 μg of GM-CSF administered subcutaneously 3 times weekly along with 25mg/d of lenalidomide administered orally on days 1 to 21 of a 28-day cycle. The primary end points were objective, PSA response, and safety. Exploratory end points included activation of circulating DCs, regulatory T cells, and Th1 cytokine production.
  
  
  RESULTS
  Thirty-two patients were enrolled in the study. No dose-limiting toxicities occurred in the phase I portion of the study. Although 81% of the patients achieved a decline in the levels of PSA while on therapy, only 4 achieved a PSA level decline of ≥ 50%. The overall response rate among 11 patients with response evaluation criteria in solid tumors-defined measurable disease was 18%. Overall toxicity was G1 and G2 in nature and included fatigue observed in 69% of the patients, nausea/vomiting in 34%, and diarrhea in 28% of the patients. Grade 3 or 4 toxicities occurred in 22% of the patients and were primarily thrombocytopenia (9%) or neutropenia (19%) or both.
  
  
  CONCLUSIONS
  Administration of GM-CSF and lenalidomide in patients with CRPC is safe with modest evidence of antitumor activity and no immune changes observed.
authors.affiliation: Department of Solid Tumor Oncology, Cleveland Clinic, Taussig Cancer Institute, Cleveland, OH; Department of Biostatistics, Cleveland Clinic, Taussig Cancer Institute, Cleveland, OH. Electronic address: Garciaj4@ccf.org.
authors.forename: Jorge A
authors.initials: JA
authors.lastname: Garcia
authors.affiliation: Department of Solid Tumor Urology, Cleveland Clinic, Glickman Urological and Kidney Institute, Cleveland, OH.
authors.forename: Paul
authors.initials: P
authors.lastname: Elson
authors.affiliation: Department of Solid Tumor Oncology, Cleveland Clinic, Taussig Cancer Institute, Cleveland, OH.
authors.forename: Allison
authors.initials: A
authors.lastname: Tyler
authors.affiliation: Department of Solid Tumor Oncology, Cleveland Clinic, Taussig Cancer Institute, Cleveland, OH.
authors.forename: Pierre
authors.initials: P
authors.lastname: Triozzi
authors.affiliation: Department of Solid Tumor Oncology, Cleveland Clinic, Taussig Cancer Institute, Cleveland, OH; Department of Biostatistics, Cleveland Clinic, Taussig Cancer Institute, Cleveland, OH.
authors.forename: Robert
authors.initials: R
authors.lastname: Dreicer
mesh_terms: D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000166:cytology; D004334:Drug Administration Schedule; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000008:administration & dosage*; D006801:Humans; D007155:Immunologic Factors / Q000008:administration & dosage*; D007167:Immunotherapy / Q000379:methods; D000077269:Lenalidomide; D008297:Male; D008875:Middle Aged; D017430:Prostate-Specific Antigen / Q000097:blood*; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy* / Q000601:surgery*; D011994:Recombinant Proteins / Q000008:administration & dosage; D016019:Survival Analysis; D050378:T-Lymphocytes, Regulatory / Q000166:cytology; D013792:Thalidomide / Q000008:administration & dosage / Q000031:analogs & derivatives*; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D016207:Cytokines; D007155:Immunologic Factors; D011994:Recombinant Proteins; D013792:Thalidomide; C081222:sargramostim; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D017430:Prostate-Specific Antigen; D000077269:Lenalidomide
keywords: Castration-resistant prostate cancer (CRPC); Granulocyte-macrophage colony-stimulating factor (GM-CSF); Immunomodulation; Lenalidomide