Mature Results of a Phase 1-2 Open-Label, Dose-Escalation Study of Intravenous SNS01-T in Patients (pts) with Relapsed or Refractory B-Cell Malignancies

Background

Eukaryotic translation initiation factor 5A (eIF5A) has been implicated in the regulation of cell proliferation, apoptosis, and inflammation. SNS01-T is a novel therapeutic with a dual mechanism of eIF5A modulation: inducing cell death via siRNA-mediated inhibition of hypusinated eIF5A while simultaneously causing over-expression of pro-apoptotic eIF5A_K50R via a DNA plasmid with a B-cell promoter to induce tumor cell death, using a PEI vector. SNS01-T significantly inhibits tumor growth and increases survival in mouse models of myeloma (MM), mantle cell and diffuse large B-cell lymphoma.

Methods

This is an open label, phase 1-2 dose escalation study in pts with refractory B-cell cancers, comprising 4 SNS01-T dose cohorts: 0.0125, 0.05, 0.2 and 0.375 mg/kg twice weekly IV for 6 weeks. Key inclusion criteria are: MM per IMWG criteria or lymphomas or plasma cell leukemia with histologic confirmation; measurable disease, relapsed or refractory after ≥2 prior regimens; not eligible for standard therapy known to extend life expectancy. Primary endpoints are safety and tolerability of SNS01-T. Secondary endpoints include pharmacokinetics, tumor response (M protein, % plasma cells, radiologic response) and time to relapse or progression. Efficacy assessments were performed at baseline and after 12 infusions in all pts (week 6); myeloma pts were also assessed at week 3.

Results

All cohorts will have completed enrollment in August 2014 and dosing in cohort 4 will be complete by September. A total of 21 pts have been treated, of whom 18 currently have data available. Demographics are provided in Table 1.

Treatment-emergent adverse events (TEAE) were reported for all pts. The most frequently reported System Organ Classes were General Disorders and Administration Site Conditions (72%) and Gastrointestinal Disorders (56%), with somewhat higher reporting frequency in dose cohorts 3 and 4. The most commonly reported AEs were fatigue (50%), nausea (33%), infusion-related reaction (33%), chills (28%), thrombocytopenia (22%) and pyrexia (17%). Thrombocytopenia, nausea, fatigue, infusion reaction appeared to show some degree of dose relationship. Grade ≥3 TEAEs occurred in 50% of pts with no obvious dose relationship. The only grade ≥3 TEAE reported in >1 pt was thrombocytopenia (17%). There have been no treatment-related deaths. There was 1 DLT at dose level 4 (0.375 mg/kg). Pt 51-001 did not receive premedication prior to the third infusion of SNS01-T and consequently experienced a grade 4 infusion reaction, from which all symptoms resolved within 24 hours. Study treatment was discontinued and the protocol was amended to require the following premedication at each SNS01-T infusion: a corticosteroid, antihistamine and acetaminophen are obligatory, plus an opioid as clinically indicated.

Preliminary efficacy was explored. To date, 2 pts have shown stable disease of myeloma at week 3 with some decrease in serum and urine disease markers and one pt with DLBCL had a 15% decrease in small lymph node disease with approximately a 5 month duration. These patients were in cohorts 3 and 4.

Conclusions

SNS01-T administration was feasible in all 4 dose cohorts with prophylaxis for infusion reactions. Early signs of potential efficacy are encouraging. Expansion of efficacy testing to more patients and combination studies are planned.