Interim Analysis of a Phase 1 Study of the Antibody-Drug Conjugate SGN-CD19A in Relapsed or Refractory B-Lineage Non-Hodgkin Lymphoma

Background

CD19, a B-cell specific marker, is expressed in the majority of patients with B-cell non-Hodgkin lymphoma (NHL). SGN-CD19A is a novel antibody-drug conjugate (ADC) composed of a humanized anti-CD19 monoclonal antibody conjugated to the microtubule-disrupting agent monomethyl auristatin F (MMAF) via a maleimidocaproyl linker.

Methods

This ongoing phase 1, open-label, dose-escalation study investigates the safety, tolerability, pharmacokinetics, and antitumor activity of SGN-CD19A in patients with relapsed or refractory B-cell NHL (NCT 01786135). Eligible patients are ≥12 years of age and must have a confirmed diagnosis of diffuse large B-cell lymphoma (DLBCL), including transformed follicular histology; mantle cell lymphoma (MCL); follicular lymphoma grade 3 (FL3); Burkitt lymphoma; or B-cell lymphoblastic lymphoma. Patients must be relapsed or refractory to at least 1 prior systemic regimen. Patients with DLBCL or FL3 must have also received intensive salvage therapy with or without autologous stem cell transplant (SCT), unless they refused or were deemed ineligible. A modified continual reassessment method is used for dose allocation and maximum tolerated dose (MTD) estimation. SGN-CD19A is administered IV on Day 1 of 21-day cycles (0.5–6 mg/kg). Response is assessed with CT and PET scans according to the Revised Response Criteria for Malignant Lymphoma (Cheson 2007).

Results

To date, 44 patients have been treated: 39 patients (89%) with DLBCL (including 10 with transformed DLBCL), 4 (9%) with MCL, and 1 (2%) with FL3. Median age was 65 years (range, 33–81). Patients had a median of 2 prior systemic therapies (range, 1–7), and 10 patients (23%) had autologous SCT. Twenty-six patients (59%) were refractory to their most recent prior therapy, and 18 (41%) were relapsed. Patients received a median of 3 cycles of treatment (range, 1–12) at doses from 0.5–6 mg/kg. Eleven patients (25%) remain on treatment, and 33 have discontinued treatment (18 due to progressive disease [PD], 5 for investigator decision, 5 for adverse events [AE], 4 because of patient decision/non-AE, and 1 for SCT). No dose-limiting toxicity (DLT) in Cycle 1 has been reported. Treatment-emergent AEs reported in ≥20% of patients were blurred vision (59%), dry eye (39%), fatigue (39%), constipation (32%), keratopathy (23%), and pyrexia (20%). Corneal exam findings consistent with superficial microcystic keratopathy were observed in 25 patients (57%) and were mostly Grade 1/2. Grade 3/4 corneal AEs were observed in 4 patients at the higher doses; the majority resolved or improved to Grade 1/2 at last follow-up. Corneal AEs were treated with ophthalmic steroids, and during the trial steroid eye drop prophylaxis was instituted with each dose of study drug. SGN-CD19A ADC plasma exposures were approximately dose-proportional. Accumulation was observed following multiple dose administrations, consistent with a mean terminal half-life of about 2 weeks, suggesting less frequent dosing might be possible. In the 43 efficacy-evaluable patients, the objective response rate (ORR) is 30% (95% CI [17, 46]), including 7 complete responses (CRs; 16%) and 6 partial responses (PRs; 14%). Of the 13 patients with an objective response, 8 are still on study with follow-up times of 0.1–31 weeks; 2 are no longer on study; and 3 had subsequent PD or death with response durations of 14, 19, and 31 weeks.

Conclusions

To date, SGN-CD19A has shown evidence of clinical activity with an ORR of 30% and CR rate of 16%. Enrollment in the trial is ongoing to further refine optimal dose and schedule. SGN-CD19A is generally well-tolerated. No DLTs have been observed in tested dose levels. Observed ocular AEs are manageable with steroid eye drops and dose modifications. The high response rate (53%) in relapsed patients and low rate of bone marrow suppression or neuropathy suggest that SGN-CD19A could be incorporated into novel combination regimens in earlier lines of therapy.