Phase 1 Study of Radiosensitization Using Bortezomib in Patients with Relapsed Non-Hodgkin's Lymphoma Receiving Radioimmunotherapy,

Radioimmunotherapy (RIT) is effective treatment for relapsed and refractory indolent lymphomas. Results in aggressive lymphomas such as diffuse large B cell lymphoma (DLBCL) and mantle cell lymphoma (MCL) have been less impressive, with low response rates and short duration of remission. We hypothesized that administration of the proteasome inhibitor bortezomib as a radiosensitizer in patients receiving RIT would be tolerable and potentially improve efficacy in both aggressive and indolent lymphomas.

We performed a Phase 1 dose escalation study to evaluate the maximum tolerated dose (MTD) of bortezomib in combination with ¹³¹I-tositumomab. The studies underwent review and was approved by each institution's Institutional Review Board. Dose escalation proceeded using a Time to Event-Continuous Reassessment Model (TiTE-CRM) design. Patients with relapsed or refractory DLBCL, MCL or indolent B cell non-Hodgkin's lymphoma were eligible if they had not undergone prior stem cell transplant, organ function was preserved, and bone marrow involvement by lymphoma was less than 25% of the intertrabecular space. Neutrophil count at least 1500/uL and platelet count at least 150 × 10³/uL were required. A dosimetric dose of ¹³¹I-tositumomab was administered on day 1, followed by three whole body gamma camera scans for purposes of dose calculation and evaluation of biodistribution. After an initial cohort received a step down dose level of 50 cGy ¹³¹I-tositumomab, patients received RIT at the standard dose of 75 cGy on day 8. Patients were treated with escalating doses of bortezomib (0.3 to 1.2 mg/m²) on days 6, 10, 13, 16 and 20. Dose limiting toxicity (DLT) was defined as any grade 3 or 4 non-hematologic toxicity, or grade 4 hematologic toxicity.

Twenty patients have been enrolled, of whom 15 have received study treatment. These include 5 patients with DLBCL, 5 with MCL and 5 with follicular lymphoma (FL). Median age is 68 (range 48–80). Median number of prior therapies is 2 (range 1–3), and all but one had received prior rituximab. Fourteen patients are evaluable for response, while one patient has not yet undergone restaging. Of the 5 enrolled patients that were not treated, three patients were deemed ineligible due to excessive bone marrow involvement by lymphoma or inadequate organ function, one patient had abnormal biodistribution of ¹³¹I-tositumomab, and one patient was not treated due to lack of drug availability. Fourteen patients are evaluable for the primary endpoint of MTD. One treated patient was not evaluable for toxicity due to early progression of disease and need for further therapy prior to the end of the observation period. Of 14 patients evaluable, 3 experienced DLT (Table), all at dose level 5 (1.2 mg/m²). These events included grade 3 hyponatremia, herpes zoster, and grade 4 thrombocytopenia. Grade 3 hematologic toxicities included two patients with leukopenia, one with neutropenia, one with anemia, and three with thrombocytopenia. Three patients treated at dose level 4 (0.9 mg/m²) have not experienced DLT, and enrollment is continuing at this dose level to ensure tolerability and to expand efficacy data. Nine of 14 (64%) evaluable patients have responded, including 3/5 with DLBCL, 3/5 with MCL, and 3/4 with FL. Five patients have achieved complete remission, including one patient with DLBCL, one with MCL, and 3 with FL.

Bortezomib can be safely administered in combination with ¹³¹I-tositumomab. Responses were seen in a majority of patients, including those with aggressive histology. This strategy of radiosensitization using bortezomib shows promise, and efficacy should be further evaluated in a Phase 2 trial.

Elstrom:GlaxoSmithKline: Research Funding. Off Label Use: bortezomib and 131I-tositumomab. Leonard:GlaxoSmithKline: Consultancy; Millennium: Consultancy. Furman:GlaxoSmithKline: Speakers Bureau. Kaminski:GlaxoSmithKline: Consultancy, Patents & Royalties, Research Funding.