title: 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.
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.
  
  
  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.
  NCT01637532.
authors.affiliation: Department of Clinical Oncology, Leiden University Medical Center, Leiden.
authors.forename: E M
authors.initials: EM
authors.lastname: Dijkgraaf
authors.affiliation: Department of Clinical Oncology, Leiden University Medical Center, Leiden.
authors.forename: S J A M
authors.initials: SJ
authors.lastname: Santegoets
authors.affiliation: Department of Clinical Oncology.
authors.forename: A K L
authors.initials: AK
authors.lastname: Reyners
authors.affiliation: Department of Clinical Oncology, Leiden University Medical Center, Leiden.
authors.forename: R
authors.initials: R
authors.lastname: Goedemans
authors.affiliation: Department of Gynecologic Oncology, University Medical Center Groningen, Groningen.
authors.forename: M C A
authors.initials: MC
authors.lastname: Wouters
authors.affiliation: Department of Gynecologic Oncology, Center for Gynecological Oncology Amsterdam, Amsterdam.
authors.forename: G G
authors.initials: GG
authors.lastname: Kenter
authors.affiliation: Department of Radiology.
authors.forename: A R
authors.initials: AR
authors.lastname: van Erkel
authors.affiliation: Department of Gynecology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: M I E
authors.initials: MI
authors.lastname: van Poelgeest
authors.affiliation: Department of Clinical Oncology.
authors.forename: H W
authors.initials: HW
authors.lastname: Nijman
authors.affiliation: Department of Clinical Oncology, Leiden University Medical Center, Leiden.
authors.forename: J J M
authors.initials: JJ
authors.lastname: van der Hoeven
authors.affiliation: Department of Clinical Oncology, Leiden University Medical Center, Leiden.
authors.forename: M J P
authors.initials: MJ
authors.lastname: Welters
authors.affiliation: Department of Clinical Oncology, Leiden University Medical Center, Leiden.
authors.forename: S H
authors.initials: SH
authors.lastname: van der Burg
authors.affiliation: Department of Clinical Oncology, Leiden University Medical Center, Leiden j.r.kroep@lumc.nl.
authors.forename: J R
authors.initials: JR
authors.lastname: Kroep
mesh_terms: D018262:Adenocarcinoma, Clear Cell / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D002288:Adenocarcinoma, Mucinous / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D000328:Adult; D000368:Aged; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000097:blood; D018394:CA-125 Antigen / Q000097:blood; D016190:Carboplatin / Q000008:administration & dosage; D018284:Cystadenocarcinoma, Serous / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000008:administration & dosage / Q000031:analogs & derivatives; D016889:Endometrial Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000008:administration & dosage; D007371:Interferon-gamma / Q000097:blood; D015850:Interleukin-6 / Q000097:blood; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D009364:Neoplasm Recurrence, Local / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D009367:Neoplasm Staging; D010051:Ovarian Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D011092:Polyethylene Glycols / Q000008:administration & dosage; D011379:Prognosis; D019947:Receptors, Interleukin-6 / Q000037:antagonists & inhibitors; D011994:Recombinant Proteins / Q000008:administration & dosage
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D014408:Biomarkers, Tumor; D018394:CA-125 Antigen; C508600:IL6 protein, human; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D015850:Interleukin-6; D019947:Receptors, Interleukin-6; D011994:Recombinant Proteins; C506643:liposomal doxorubicin; D011092:Polyethylene Glycols; D004317:Doxorubicin; D007371:Interferon-gamma; D016190:Carboplatin; C417083:peginterferon alfa-2b; C502936:tocilizumab
keywords: chemoresistance; immunotherapy; interleukin-6; ovarian cancer; tumor immunity