A phase I trial combining carboplatin/doxorubicin with tocilizumab, an anti-IL-6R monoclonal antibody, and interferon-α2b in patients with recurrent epithelial ovarian cancer

Ann Oncol. 2015 Oct;26(10):2141-9. doi: 10.1093/annonc/mdv309. Epub 2015 Jul 27.

Abstract

Background: The immune system is important in epithelial ovarian cancer (EOC). Interleukin-6 is associated with chemoresistance and an immune-suppressive tumor microenvironment. We investigated whether a combination of chemotherapeutics, blockade of interleukin 6 (IL-6) receptor (IL-6R; tocilizumab), and immune enhancer interferon-α (Peg-Intron) is feasible, safe, and able to enhance immunity in patients with recurrent EOC.

Patients and methods: In this dose-escalation study, patients received tocilizumab 1, 2, 4, or 8 mg/kg i.v., q4 weeks during the first three cycles of carboplatin (AUC5) plus doxorubicin [pegylated liposomal doxorubicin (PLD) 30 mg/m(2) or doxorubicin 50 mg/m(2) i.v., day 1, q4 weeks, for six cycles]. At the highest tocilizumab dose (8 mg/kg), Peg-Intron (1 µg/kg s.c.) was added. Peripheral blood mononuclear cells were collected for immunomonitoring at baseline, after three and six cycles. Dose-limiting toxicity (DLT), CA-125, and radiologic response were evaluated.

Results: In the 23 patients enrolled, no DLT was established. The most frequent grade 3/4 adverse events (CTCAE v4.03) were neutropenia (23%), febrile neutropenia (19%), and ileus (19%). No treatment-related deaths occurred. Using CT evaluation, 11 of 21 assessable patients responded, 6 had stable disease and 3 progressive disease. Patients receiving highest dose tocilizumab showed a functional blockade of IL-6R with increased levels of serum IL-6 (P = 0.02) and soluble IL-6R (P = 0.008). Consequently, immune cells displayed decreased levels of pSTAT3, myeloid cells produced more IL-12 and IL-1β while T cells were more activated and secreted higher amounts of effector cytokines interferon-γ and tumor necrosis factor-α. An increase in sIL-6R was potentially associated with a survival benefit (P = 0.03).

Conclusions: Functional IL-6R blocking is feasible and safe in EOC patients treated with carboplatin/(pegylated liposomal)doxorubicin, using 8 mg/kg tocilizumab. This combination is recommended for phase II evaluation based on immune parameters.

Clinical trial register: NCT01637532.

Keywords: chemoresistance; immunotherapy; interleukin-6; ovarian cancer; tumor immunity.

Publication types

  • Clinical Trial, Phase I
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma, Clear Cell / blood
  • Adenocarcinoma, Clear Cell / drug therapy*
  • Adenocarcinoma, Clear Cell / pathology
  • Adenocarcinoma, Mucinous / blood
  • Adenocarcinoma, Mucinous / drug therapy*
  • Adenocarcinoma, Mucinous / pathology
  • Adult
  • Aged
  • Antibodies, Monoclonal, Humanized / administration & dosage
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Biomarkers, Tumor / blood
  • CA-125 Antigen / blood
  • Carboplatin / administration & dosage
  • Cystadenocarcinoma, Serous / blood
  • Cystadenocarcinoma, Serous / drug therapy*
  • Cystadenocarcinoma, Serous / pathology
  • Dose-Response Relationship, Drug
  • Doxorubicin / administration & dosage
  • Doxorubicin / analogs & derivatives
  • Endometrial Neoplasms / blood
  • Endometrial Neoplasms / drug therapy*
  • Endometrial Neoplasms / pathology
  • Enzyme-Linked Immunosorbent Assay
  • Female
  • Follow-Up Studies
  • Humans
  • Interferon alpha-2
  • Interferon-alpha / administration & dosage
  • Interferon-gamma / blood
  • Interleukin-6 / blood
  • Middle Aged
  • Neoplasm Invasiveness
  • Neoplasm Recurrence, Local / blood
  • Neoplasm Recurrence, Local / drug therapy*
  • Neoplasm Recurrence, Local / pathology
  • Neoplasm Staging
  • Ovarian Neoplasms / blood
  • Ovarian Neoplasms / drug therapy*
  • Ovarian Neoplasms / pathology
  • Polyethylene Glycols / administration & dosage
  • Prognosis
  • Receptors, Interleukin-6 / antagonists & inhibitors
  • Recombinant Proteins / administration & dosage

Substances

  • Antibodies, Monoclonal, Humanized
  • Biomarkers, Tumor
  • CA-125 Antigen
  • IL6 protein, human
  • Interferon alpha-2
  • Interferon-alpha
  • Interleukin-6
  • Receptors, Interleukin-6
  • Recombinant Proteins
  • liposomal doxorubicin
  • Polyethylene Glycols
  • Doxorubicin
  • Interferon-gamma
  • Carboplatin
  • peginterferon alfa-2b
  • tocilizumab

Associated data

  • ClinicalTrials.gov/NCT01637532