Phase I study of a novel oral Janus kinase 2 inhibitor, SB1518, in patients with relapsed lymphoma: evidence of clinical and biologic activity in multiple lymphoma subtypes

Abstract

Purpose: The Janus kinase 2/signal transducers and activators of transcription (JAK2/STAT) pathway plays an important role in the pathogenesis of hematologic malignancies. We conducted a phase I dose-finding and pharmacokinetic/pharmacodynamic study of SB1518, a potent JAK2 inhibitor, in patients with relapsed lymphoma.

Patients and methods: Patients with relapsed or refractory Hodgkin or non-Hodgkin lymphoma of any type except Burkitt's or CNS lymphoma were enrolled. Patient cohorts received escalating doses of SB1518 orally once daily for 28-day cycles. Response was evaluated after 8 weeks.

Results: Thirty-four patients received doses of 100 to 600 mg/d. The maximum tolerated dose was not reached. Treatment was well tolerated, with mostly grade 1 and 2 toxicities. Gastrointestinal toxicities were the most common treatment-related events. Cytopenias were infrequent and modest. Pharmacologically active concentrations were achieved at all doses. Dose-related linear increases in area under the concentration-time curve were seen on day 1, with no significant accumulation on day 15. Mean terminal half-life was 1 to 4 days, and mean time to peak concentration ranged from 5 to 9 hours. SB1518 inhibited JAK2 signaling at 4 hours postdose at all levels. Increases in fms-like tyrosine kinase-3 (FLT-3) ligand, reflecting FLT-3 inhibition, were seen in most patients. There were three partial responses (≥300 mg/d) and 15 patients with stable disease (SD), with most responses lasting longer than 2 months. Seven of 13 SDs had tumor reductions of 4% to 46%.

Conclusion: SB1518 has encouraging activity in relapsed lymphoma, providing the first proof-of-principle of the potential therapeutic value of targeting the JAK/STAT pathway in lymphoma in the clinical setting.

Trial registration: ClinicalTrials.gov NCT00741871.

Conflict of interest statement

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

Figures

Fig 1.

(A) Mean plasma concentration-time profiles of SB1518 on day 1 following single oral doses of 100, 200, 300, 400, and 600 mg. The error bars represent the SEM. The potencies of SB1518 on the target enzymes and cell line are indicated with horizontal dashed lines. (B) Relationship between log mean area under the concentration-time curve (AUC0-24; day 1) and log dose. The linearity was assessed at the 95% confidence level. The error bars represent the SEM. The estimated values of the slope and the regression coefficient are also shown in the inset along with the P values. FLT-3L, fms-like tyrosine kinase-3 ligand; JAK2, Janus kinase 2.

Fig 2.

Plasma levels of fms-like tyrosine kinase-3 ligand (FLT-3L) after 29 days of SB1518 treatment were significantly higher compared with those on day 1 (P < .001; paired t test; n = 22).

Fig 3.

Waterfall plot demonstrating percent change from baseline in target tumor dimensions (best response) among evaluable patients (n = 31). (A) Best responses by dose level. (B) Best responses by prior rituximab exposure. Labels in the x axis identify the histologic subtypes. BC, unclassified B-cell lymphoma; FL, follicular lymphoma; DLBC, diffuse large B-cell lymphoma; MCL, mantle-cell lymphoma; CLL, small lymphocytic lymphoma/chronic lymphocytic leukemia; HL, Hodgkin lymphoma.