2nd Line Patients Research Articles

Recombinant IL-21 (rIL-21) in combination with sorafenib: Interim results from a phase 1/2 study in patients with metastatic renal cell cancer (mRCC)

16008 Background: Despite the impact of tyrosine kinase inhibitors on the outcome for mRCC, complete responses are rare and long term survival remains poor. rIL-21, a cytokine that enhances CD8+ T cell and NK cell activity, demonstrated single agent anti-tumor activity in Phase 1 studies. To explore the combined use of rIL-21 with sorafenib in patients with mRCC, a Phase 1/2 dose escalation study was initiated. Results from the Phase 1 dose escalation are reported here. Methods: First or 2nd-line patients received sorafenib at 400 mg BID plus rIL-21 at 1 of 4 dose levels (10, 30, 40, or 50 μg/kg IV) on days 1–5 and 15–19 of a 6-week treatment course. Safety, pharmacokinetics (PK), and tumor response per RECIST were assessed. In Phase 2, 30 patients will receive 2nd or 3rd-line therapy with rIL-21 at the maximum tolerated dose + sorafenib. Results: 14 patients were treated at 3 consecutive dose levels of 10, 30, and 50 μg/kg. After documentation of DLT in 2 subjects at 50 μg/kg, an intermediate dose level cohort at 40 μg/kg was opened. 3 patients have currently been treated at this dose level. Most adverse events (AEs) were Grade 1 or 2, and consistent with the known toxicity of rIL-21 and sorafenib. Treatment-related Grade 3 AEs were hypophosphatemia (n=6), hand-foot syndrome (n=5), rash (n=2), fatigue (n=2), hyponatremia (n=2), elevated liver transaminases (n=2), fever (n=1), and dehydration (n=1). DLTs of diffuse erythroderma with hand-foot syndrome were reported in 1 of 6 patients at 10 μg/kg and 2 of 4 patients at 50 μg/kg. Sorafenib and rIL-21 PK estimates were within the expected range for single agent therapy. To date, 10 patients have been evaluable for tumor response. Per investigator assessment, all 10 had tumor shrinkage at first evaluation, and all received additional courses (2–5). 5 patients had ≥ 30% tumor shrinkage as best response to date, including one confirmed PR at 50 μg/kg. 11 subjects continue on study. Conclusions: rIL-21 plus sorafenib can be administered in the outpatient setting and is associated with anti-tumor activity. Sorafenib PK data suggests that rIL-21 does not increase plasma levels of sorafenib. The Phase 1 results have justified initiation of the Phase 2 portion to confirm the anti-tumor effect of the combination. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration ZymoGenetics, Inc. ZymoGenetics, Inc. ZymoGenetics, Inc. ZymoGenetics, Inc.

Final results of CONFIRM 2: A multinational, randomized, double-blind, phase III study in 2nd line patients (pts) with metastatic colorectal cancer (mCRC) receiving FOLFOX4 and PTK787/ZK 222584 (PTK/ZK) or placebo

4033 Background: PTK/ZK, a novel, oral, anti-angiogenic compound that inhibits all VEGF receptors has been investigated in two multinational randomized phase 3 studies in 1st (CONFIRM 1) and 2nd line (CONFIRM 2) mCRC. Interim analyses (IA) have been presented at ASCO 2005 and 2006, respectively. Methods: In CONFIRM 2, 855 pts were randomized to FOLFOX4 plus PTK/ZK (1250 mg, qd), or placebo. Eligibility included histologically documented mCRC, pre-treatment for metastatic disease with irinotecan-/fluoropyrimidine- based therapy, measurable disease by RECIST, PS of 0–2 and adequate organ function. Pts were stratified based on PS (0 vs. 1–2) and baseline serum Lactate Dehydrogenase (LDH = vs. >1.5 × ULN). The primary endpoint is overall survival (OS). Secondary endpoints included OS and PFS in high LDH pts (LDH > 1.5 × ULN). Results: At the time of IA in July 2005, OS was 12.1 mo in the PTK/ZK and 11.8 mo in the placebo arm (HR: 0.94; p=0.511). PFS was significantly longer in the PTK/ZK arm (5.5 mo vs. 4.1 mo; HR: 0.83; p=0.026). LDH, a marker for poor prognosis in mCRC, is predictive of the outcome in the PTK/ZK arm. When treated with PTK/ZK, high LDH pts showed a strong improvement in PFS (5.6 mo vs. 3.8 mo; HR: 0.63; p<0.001) and in OS (9.6 mo vs. 7.5 mo; HR: 0.78; p=0.10). Adverse events (AE) were similar to that of the CONFIRM 1 trial. Final analysis for OS, PFS and safety is planned for Feb. 2007 after 732 events (compared to 413 in the IA) and will be presented at the meeting. Conclusions: While the primary endpoint for OS was not met in the IA, PTK/ZK improves PFS significantly in the overall population, and shows strong activity (improved PFS and OS) in patients with high baseline serum LDH. Final results of the study will be presented at the meeting. No significant financial relationships to disclose.