title: Lenalidomide and cyclophosphamide immunoregulation in patients with metastatic, castration-resistant prostate cancer.
abstract: Lenalidomide (LEN) and metronomic cyclophosphamide (CTX) regulate angiogenesis and immunosuppressive cells linked to the progression of metastatic castration-resistant prostate cancer (mCRPC). A phase-I/II, dose-escalation trial of LEN plus oral CTX was conducted in patients with previously treated mCRPC. In the phase-I study, CTX was given at 50 mg (day 1-28) and LEN at 10-25 mg (day 1-21) on a 28-day cycle using a "3+3" study design. In phase II, patients received LEN at 25 mg (day 1-21) with CTX at 50 mg PO QD (day 1-28) on a 28-day cycle. Nineteen patients in phase I were evaluable for toxicity. The maximum tolerated dose (MTD) was not observed at any of the dose levels (DLs) tested. Six patients received treatment in phase II before the trial was closed. A ≥ 50% reduction in PSA was observed in 31.7% evaluable patients. Radiographically, one patient had a partial response. Stable disease was documented in 68% of evaluable patients after two therapy cycles. Circulating tumor cells (CTCs) decreased in 22.7% and remained stable in 31.8% of patients. Baseline numbers of peripheral MDSCs (MDSC; Lin-DR(-)CD11b(+)) were significantly increased in patients versus normal donors, and were decreased by chemotherapy. At baseline, MDSCs correlated directly with CTCs, and inversely with T- and B cell frequency supporting their immunosuppressive activity. The combination of LEN and metronomic CTX can be safely administered, reversing cellular immunosuppression in this group of elderly patients with mCRPC. Further research is required to identify responsive subgroup(s) and validate the biomarkers.
authors.affiliation: Internal Medicine Oncology/Hematology, 987680 Nebraska Medical Center, Omaha, NE, 68198, USA, Jue.Wang@DignityHealth.org.
authors.forename: J
authors.initials: J
authors.lastname: Wang
authors.forename: T R
authors.initials: TR
authors.lastname: McGuire
authors.forename: H C
authors.initials: HC
authors.lastname: Britton
authors.forename: J K
authors.initials: JK
authors.lastname: Schwarz
authors.forename: F R
authors.initials: FR
authors.lastname: Loberiza
authors.forename: J L
authors.initials: JL
authors.lastname: Meza
authors.forename: J E
authors.initials: JE
authors.lastname: Talmadge
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use; D003520:Cyclophosphamide / Q000627:therapeutic use*; D016207:Cytokines / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D053208:Kaplan-Meier Estimate; D000077269:Lenalidomide; D007962:Leukocytes / Q000166:cytology; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D022423:Myeloid Cells / Q000166:cytology; D009360:Neoplastic Cells, Circulating; D017430:Prostate-Specific Antigen / Q000378:metabolism; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy* / Q000276:immunology; D013792:Thalidomide / Q000031:analogs & derivatives* / Q000627:therapeutic use; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D016207:Cytokines; D007166:Immunosuppressive Agents; D013792:Thalidomide; D003520:Cyclophosphamide; D017430:Prostate-Specific Antigen; D000077269:Lenalidomide