Abstract
BackgroundPharmacokinetic 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.MethodsA 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 ≤ 1 cm were registered for the treatment phase 2–5 weeks post surgery. The effect of IP rIL-12 on the expression of TNFα , INFα , IL-10, IP-10, IL-8, FGF, VEGF was also studied.ResultsThirty-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 ≥ 3 fold relative increase post-rhIL-12: IFN-γ, 5/5 pts; TNF-α , 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-γ , IP-10) or pro-tumor growth effects (VEGF, IL-8) were detected.ConclusionIP 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.
Highlights
The limited success of systemic chemotherapy for the treatment of Mullerian type carcinomas involving the peritoneum has promoted interest in the intraperitoneal (IP) route of administration of therapeutic agents for this condition
IP IL-12 can safely be administered at this dose and schedule to patients after first line chemotherapy for ovarian/peritoneal carcinoma
In a Phase I study [9] of IP IL-12 in patients with peritoneal carcinomatosis from Mullerian and gastrointestinal primary tumors who were not responding to standard chemotherapy treatment, rhIL-12 was given weekly on 4 week cycles
Summary
The limited success of systemic chemotherapy for the treatment of Mullerian type carcinomas involving the peritoneum has promoted interest in the intraperitoneal (IP) route of administration of therapeutic agents for this condition. In a Phase I study [9] of IP IL-12 in patients with peritoneal carcinomatosis from Mullerian and gastrointestinal primary tumors who were not responding to standard chemotherapy treatment, rhIL-12 was given weekly on 4 week cycles. Of the 26 patients entered in the phase study, none were removed because of dose-limiting toxicities. In that study one patient experienced a CR laparoscopically documented and 7 patients had stable disease Based on these results the dose of 300 ng/kg administered weekly was selected for the phase 2 study. 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
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