title: 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.
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.
  
  
  CONCLUSIONS
  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.
authors: Department of GI Medical Oncology, The University of Texas M,D, Anderson Cancer Center, Houston, Texas, USA. rlenzi@mdanderson.org
authors: Renato
authors: R
authors: Lenzi
authors: Robert
authors: R
authors: Edwards
authors: Carl
authors: C
authors: June
authors: Michael V
authors: MV
authors: Seiden
authors: Michael E
authors: ME
authors: Garcia
authors: Michael
authors: M
authors: Rosenblum
authors: Ralph S
authors: RS
authors: Freedman
mesh_terms: D000328:Adult; D000368:Aged; D001202:Ascitic Fluid / Q000737:chemistry; D017321:Clinical Trials, Phase I as Topic; D016207:Cytokines / Q000032:analysis; D005260:Female; D006801:Humans; D018664:Interleukin-12 / Q000627:therapeutic use* / Q000633:toxicity*; D008875:Middle Aged; D018365:Neoplasm, Residual / Q000188:drug therapy*; D010051:Ovarian Neoplasms / Q000188:drug therapy*; D010534:Peritoneal Neoplasms / Q000188:drug therapy*; D011994:Recombinant Proteins / Q000627:therapeutic use / Q000633:toxicity; D012449:Safety
chemical_list: D016207:Cytokines; D011994:Recombinant Proteins; D018664:Interleukin-12