Abstract 2830

Introduction:

The Janus kinase 2 (JAK2) signal transducers and activators of transcription (STAT) pathway plays an important role in the proliferation and pathogenesis of hematological malignancies. In vitro inhibition of JAK2 results in antiproliferative activity in a variety of lymphoma cell lines. We have completed dose-escalation in a Phase-I study of the novel small molecule JAK2 inhibitor SB1518 in patients with relapsed Hodgkin lymphoma (HL) and Non-Hodgkin lymphoma (NHL).

Patients and Methods:

The primary objectives were to examine the safety and efficacy of SB1518 in this patient population. Patients were eligible if they had relapsed or refractory HL or NHL of any type except Burkitt's, any number of prior treatment regimens as well as adequate organ function and performance status. They were excluded if they had HIV infection or CNS lymphoma. Cohorts of 3–6 patients received escalating dose levels of SB1518 orally once daily for 28-day cycles. Response was first evaluated after 8 weeks (2 cycles) of therapy.

Results:

Thirty patients have been enrolled (14 HL, 3 mantle cell [MCL], 8 follicular [FL], 4 diffuse large B-cell [DLBCL], 1 small lymphocytic [SLL]). Patients have been treated orally once daily at 5 dose levels, 100 mg (n=3), 200 mg (n=7), 300 mg (n=6), 400 mg (n=7) and 600 mg (n=7). Twenty of 30 patients were male and 10 were female. 28 have received SB1518 of which twenty-six are evaluable for tumor response and all 28 are evaluable for safety. The median number of prior treatment regimens was 5.5 (range 2–15), Prior treatment included an autologous transplant in 12 patients and an allogeneic stem cell transplant in 2. Treatment was well tolerated, with the most common Grade 1–2 toxicities (≥10% in frequency) being: constipation 43% (n=12), diarrhea 43% (n=12), pyrexia 32% (n=9), nausea 29% (n=8), cough and fatigue 21% (n=6), decreased appetite 18% (n=5) and anemia, anorexia, chills, dyspnea, headache, peripheral edema, peripheral neuropathy 11% (n=3). Grade 3–4 toxicities included: neutropenia 7% (n=2), abdominal distension, anemia, bacteremia, cellulitis, cerebral vascular accident, dyspnea, fatigue, hyperbilirubinemia, hypotension, lymphopenia, musculoskeletal pain, peripheral edema, pneumonia, pulmonary embolism, pyelonephritis, retroperitoneal hemorrhage and thrombocytopenia 4% (n=1). Dose escalation has been halted at 600 mg without identification of the MTD and enrollment continues in an expanded 600 mg cohort to confirm the recommended Phase II dose. There were no CRs, 3 patients had PRs (2 MCL, 1 FL at 300, 400, 600 mg), and 13 patients had SD (7 FL, 5 HL, 1 SLL), with the majority of responses sustained for >2 months. Of the patients with SD 7/13 had reduction in tumor mass of 4–46%. Serial plasma samples were collected for PK analysis. Pharmacologically active concentrations were achieved at the lowest dose level (100 mg). Dose related increases in AUC were seen on C1D1 and C1D15 up to 400mg. The terminal half-life was 1–3 days, and mean Tmax ranged between 5–9 hours. The effect of drug treatment on pJAK2, pSTAT3, and pSTAT5 was examined in PBMCs and whole blood before and after the first dose of SB1518. SB1518 inhibited the JAK/STAT pathway as early as 4 hrs after the first dose at all dose levels. Plasma was collected at each cycle to assess changes in cytokines, chemokines and growth factors. Data show marked reductions in inflammatory cytokines such as IFNalpha, as well as in PDGFalpha and beta, VEGF and RANTES in >50% of patients with samples tested (SB1518 dose levels of 100, 200, and 300 mg). Samples from higher dose levels are being tested and results will be correlated to response. Efficacy and biomarker data confirm the activity of SB1518 in multiple lymphoma subtypes and show the safety of chronic administration at doses up to 600 mg daily. Collectively these data suggest that targeting the JAK2 pathway has therapeutic value in patients with relapsed lymphoma. A Phase II trial of SB1518 in selected lymphomas is being initiated.

Disclosures:

Zhu:S*BIO: Employment.

Author notes

*

Asterisk with author names denotes non-ASH members.

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