Abstract

Background: MGd is a novel anti-cancer agent that selectively accumulates in tumor cells and disrupts redox dependent pathways by targeting oxidative stress related proteins such as thioredoxin reductase and metallothioneins. MGd induces apoptosis in lymphoma cells and is additive or synergistic with radiation, chemotherapy and rituximab in pre-clinical studies. In solid tumor clinical trials, there has been no evidence of hematopoietic toxicity with MGd at doses of 5 mg/kg x 10 days. In rituximab-refractory follicular NHL, single-agent Zevalin® produces a response rate (RR) of 74% (15% complete response [CR]). We reasoned that MGd and Zevalin® would be synergistic and provide higher response rates that are more durable.

Method: To test this hypothesis, we are conducting a phase I/II dose escalation trial for patients with relapsed/refractory NHL using fixed dose 90Yttrium-Zevalin (0.4 mCi/kg) with increasing doses of MGd (2.5 mg/kg, 3.5 mg/kg and 5.0 mg/kg) based on a modified Fibonacci scheme. Patients receive MGd days 1 to 4 (with 111Indium-Zevalin given day 1) and days 8 to 11 (with 90Yttrium-Zevalin given day 8). Since MGd contains the paramagnetic metal ion, gadolinium, the molecule is detectable by MRI, which may be used to visualize tumor selective localization.

Results: Seven of 10 treated patients are evaluable (3 female, 4 male) at 2.5 mg/kg and 3.5 mg/kg MGd dose levels. Median age is 57 (range, 37 to 80). The histologies include: 5 follicular, 1 transformed (follicular to diffuse large B-cell [DLBCL]), 1 mantle-cell. Median number of prior therapies is 3 (range, 2–4), and 7/7 patients were refractory to rituximab (defined as no response or time to treatment progression of less than 6 months). No dose limiting toxicity (grade 3 or 4 non-hematologic or grade 4 hematologic) has been seen. Response has been seen in 6/7 patients. Response by histology is shown in the table.

Response According to Histology

HistologyNumberOverall RRCR
follicular 5/5 4/5 
transformed 1/1 1/1 
mantle-cell 0/1 0/1 
HistologyNumberOverall RRCR
follicular 5/5 4/5 
transformed 1/1 1/1 
mantle-cell 0/1 0/1 

Of the 6 responders, response (by CT scan) was documented at 4 weeks in all patients (5 CR/Cru and 1 partial remission). One patient relapsed at 8 months (at dose level 1), while the other patients remain in remission at 13, 12, 7, 7, 6 and 2 months. In one patient, where MRI data were obtained, the day 4 non-contrast MRI of a superficial scalp mass showed 30% increase in MRI signal intensity (compared with a pre-MGd scan) indicating tumor-selective uptake of MGd.

Conclusion: We found that MGd at doses of 2.5 and 3.5 mg/kg x 8, when given with Zevalin®, is safe and does not appear to increase hematologic or other toxicity. Moreover, we have observed prompt tumor responses and complete remission in a very high proportion of rituximab-refractory follicular lymphoma patients (overall RR for these histologies was 100%, CR 80%). These data suggest possible synergistic effects of MGd and Zevalin® RIT.

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