A Phase I/II Trial of Radioimmunotherapy (RIT) with 90Yttrium-Ibritumomab Tiuxetan (Zevalin®; 90Y-Zevalin) Combined with the Redox-Active Agent Motexafin Gadolinium (MGd): Prompt and High Remission Rates in Patients with Rituximab-Refractory Non-Hodgkin's Lymphoma (NHL).

Abstract

MGd is a novel anti-cancer agent that induces apoptosis in NHL cell lines in part by targeting oxidative stress related proteins and has been shown in solid tumor studies to enhance ionizing radiation. We reasoned that response rates could be improved by combining MGd concurrently with RIT in NHL. We conducted a phase I/II trial for patients (pts) with relapsed/refractory NHL using fixed-dose Zevalin® with increasing doses of MGd (2.5 mg/kg, 3.5 mg/kg, 5.0 mg/kg). Pts received 8 MGd doses on days 1 to 4 (111Indium-Zevalin day 1) and days 8 to 11 (90Y-Zevalin day 8). Restaging CTs were performed 4 weeks after MGd/ 90Y-Zevalin. Response was assessed by the International Workshop NHL response criteria (Cheson, 1999). 30 pts enrolled, and 28 are evaluable for toxicity and response (see table). 23 of 28 pts (82%) were rituximab-refractory (Rit-Ref) (defined as no response or time to progression (TTP) of <6 months). 4 pts received 0.3 mCi/kg 90Y-Zevalin (due to thrombocytopenia), while the remainder (n=24) received 0.4 mCi/kg. No dose limiting toxicity was seen and treatment was well-tolerated. No grade 4 non-hematologic toxicities were seen; hematologic toxicities included: 29% with grade 3/4 neutropenia (7% grade 4), 46% grade 3/4 thrombocytopenia (0% grade 4), and 18% grade 3/4 anemia (0% grade 4), which were similar to single-agent zevalin®.Overall response rate (ORR), complete remission (CR), and overall survival (OS) rates are shown (see table). Of note, all responses seen in this trial were documented at 4 weeks following MGd/90Y-Zevalin therapy. Among Rit-Ref follicular lymphoma (FL) pts, 5 responses are ongoing (9+, 9+, 11+, 27+, 31+). Moreover, these data in Rit-Ref FL compares favorably to prior reported data with single-agent Zevalin® (ORR 74%- CR 15%, median TTP 6.8 mo, Witzig, 2002). In conclusion, we found that MGd, when given with Zevalin®, is safe and does not appear to increase hematologic or other toxicity. Responses here were prompt, all seen by 4 weeks following MGd/90Y-Zevalin therapy. Moreover, we observed a high rate of durable remission in Rit-Ref FL pts (ORR 86%/CR 64%). Further studies designed to combine novel therapeutic agents with RIT are warranted.Pt Characteristics, Response, and SurvivalAll Patients (n=28)*Rituximab-Refractory FL (n=14)Aggressive NHL (n=10)*Median age, years (range)65 (47–87)- 32% >age 7560 (47–85)77 (48–87)Median prior treatments (range)3 (1–5)3 (1–4)2 (1–4)Stage III/IV at study entry19/28 (68%)11/14 (79%)7/10 (70%)Bulky disease (>5cm) at study entry15/28 (54%)9/14 (64%)4/10 (40%)Elevated LDH at study entry10/28 (36%)6/14 (43%)4/10 (40%)Best ORR (CR rate)57% (46% CR)86% (64% CR)20% (20% CR)ORR (CR rate) at 4 Weeks57% (21% CR)86% (21% CR)20% (20% CR)TTP, months (range)9 (2–31+)10 (2–31+)4 (2–29+)2-year OS76%93%50%*Histologies enrolled: 17 FL, 1 marginal zone, and 10 aggressive NHL (3 mantle-cell, 4 transformed large-cell, + 3 DLBCL)