Phase II study of intraperitoneal recombinant interleukin-12 (rhIL-12) in patients with peritoneal carcinomatosis (residual disease < 1 cm) associated with ovarian cancer or primary peritoneal carcinoma

J Transl Med. 2007 Dec 12;5:66. doi: 10.1186/1479-5876-5-66.

Abstract

Background: Pharmacokinetic advantages of intraperitoneal (IP) rhIL-12, tumor response to IP delivery of other cytokines as well as its potential anti-angiogenic effect provided the rationale for further evaluation of IPrhIL-12 in patients with persistent ovarian or peritoneal carcinoma.

Methods: A phase 2 multi-institutional trial (NCI Study #2251) of IP rIL-12 (300 nanogram/Kg weekly) was conducted in patients with ovarian carcinoma or primary peritoneal carcinoma. Patients treated with primary therapy for ovarian cancer who had no extraabdominal/parenchymal disease or bulky peritoneal disease were eligible. Four to 8 weeks from last chemotherapy, eligible patients underwent a laparotomy/laparoscopy. Patients with residual disease < or = 1 cm were registered for the treatment phase 2-5 weeks post surgery. The effect of IP rIL-12 on the expression of TNFalpha , INFalpha , IL-10, IP-10, IL-8, FGF, VEGF was also studied.

Results: Thirty-four patients were registered for the first screening phase of the study. Median age was 56.6 years (range: 31-71); 12 completed the second phase and were evaluable for response/toxicity. Performance scores of IL-12 treated patients were 0 (11 pts) and 1 (1 pt). There were no treatment related deaths, peritonitis or significant catheter related complications. Toxicities included grade 4 neutropenia (1), grade 3 fatigue (4), headache (2), myalgia (2), non-neutropenic fever (1), drug fever (1), back pain (1), and dizziness (1). The best response observed was SD. Two patients had SD and 9 had PD, and 1 was evaluable for toxicity only. Peritoneal fluid cytokine measurements demonstrated a > or = 3 fold relative increase post-rhIL-12: IFN-gamma, 5/5 pts; TNF-alpha , 1/5; IL-10, 4/5; IL-8, 5/5; and VEGF, 3/5. IP10 levels were increased in 5/5 patients. Cytokine response profiles suggest either NK or T-cell mediated effects of IP rhIL-12. Cytokine/chemokine results also suggest a pleiotropic response since proteins with potential for either anti-tumor (IFN-gamma , IP-10) or pro-tumor growth effects (VEGF, IL-8) were detected.

Conclusion: IP IL-12 can safely be administered at this dose and schedule to patients after first line chemotherapy for ovarian/peritoneal carcinoma. The maximum response was stable disease. Future IP therapies with rhIL-12 will require better understanding and control of pleiotropic effects of IL-12.

Publication types

  • Clinical Trial, Phase II
  • Multicenter Study
  • Research Support, N.I.H., Extramural

MeSH terms

  • Adult
  • Aged
  • Ascitic Fluid / chemistry
  • Clinical Trials, Phase I as Topic
  • Cytokines / analysis
  • Female
  • Humans
  • Interleukin-12 / therapeutic use*
  • Interleukin-12 / toxicity*
  • Middle Aged
  • Neoplasm, Residual / drug therapy*
  • Ovarian Neoplasms / drug therapy*
  • Peritoneal Neoplasms / drug therapy*
  • Recombinant Proteins / therapeutic use
  • Recombinant Proteins / toxicity
  • Safety

Substances

  • Cytokines
  • Recombinant Proteins
  • Interleukin-12