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-DRCD11b+) 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.

Original languageEnglish (US)
Pages (from-to)111-124
Number of pages14
JournalClinical and Experimental Metastasis
Volume32
Issue number2
DOIs
StatePublished - Feb 6 2015

Fingerprint

Castration
Cyclophosphamide
Prostatic Neoplasms
Circulating Neoplastic Cells
Immunosuppressive Agents
lenalidomide
Maximum Tolerated Dose
Immunosuppression
B-Lymphocytes
Biomarkers
Tissue Donors
T-Lymphocytes
Drug Therapy

Keywords

  • Circulating tumor cells
  • FoxP3 T-regulatory (T-reg) cell
  • Lenalidomide
  • Metastatic castration-resistant prostate cancer
  • Metronomic chemotherapy
  • Myeloid-derived suppressor cell

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

@article{5869572eccd74f97b34f81eedf413c37,
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.",
keywords = "Circulating tumor cells, FoxP3 T-regulatory (T-reg) cell, Lenalidomide, Metastatic castration-resistant prostate cancer, Metronomic chemotherapy, Myeloid-derived suppressor cell",
author = "J. Wang and McGuire, {Timothy R} and Britton, {H. C.} and Schwarz, {James K} and Loberiza, {F. R.} and Meza, {Jane L} and Talmadge, {James E}",
year = "2015",
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language = "English (US)",
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T1 - Lenalidomide and cyclophosphamide immunoregulation in patients with metastatic, castration-resistant prostate cancer

AU - Wang, J.

AU - McGuire, Timothy R

AU - Britton, H. C.

AU - Schwarz, James K

AU - Loberiza, F. R.

AU - Meza, Jane L

AU - Talmadge, James E

PY - 2015/2/6

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N2 - 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.

AB - 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.

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