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Patients with relapsed/refractory B-cell malignancies treated with cerdulatinib, a dual Syk-JAK inhibitor, have rapid tumor responses

During the EHA the interim results of the phase II study evaluating the efficacy and safety profile of cerdulatinib were presented. The overall response rate (ORR) was 50% for patients with relapsed/refractory B-cell malignancies treated with cerdulatinib. Moreover, cerdulatinib is well-tolerated, the most common adverse events being diarrhea, fatigue and anemia.

Cerdulatinib is an oral, dual Syk-JAK inhibitor with a unique mechanism of action. It inhibits 2 key signaling pathways that promote cancer cell growth in certain hematologic malignancies: the B-cell receptor pathway via Syk and key cytokine receptors via JAK. Preclinical data suggested that cerdulatinib may have anti-tumor activity in patients who did not adequately respond to, or relapsed on, other treatments.

The aim of the multi-center, open label phase II study is to evaluate the safety and efficacy of cerdulatinib in patients with certain types of non-Hodgkin lymphoma. Up to 40 patients each will be enrolled in 3 cohorts: (1) patients with relapsed/refractory (r/r) chronic lymphocytic leukemia (CLL) or small lymphocytic leukemia (SLL), and (2) r/r indolent lymphomas such as follicular lymphoma (FL) and peripheral T cell lymphoma (PTCL) and (3) relapsed DLBCL, MCL and transformed FL. During the EHA 2017 the efficacy data of the first 40 patients were presented. Adverse events were analyzed for the first 47 patients (for 7 patients it was too early to analyze the efficacy). The median age of the patients is 70 years (range: 45-93) and the median number of prior therapies is 3 (range 1-7), of which 14 patients had prior BTK or PI3K inhibitor therapy.

The interim results presented at EHA 2017 demonstrated evidence of differentiated clinical activity in patients with r/r B-cell malignancies. Twelve out of 18 (67%) patients with r/r CLL/SLL had a partial response, 5 out of 9 patients (56%) of the patients with r/r FL had a partial response, and 1 out of 7 patients (14%) with r/r iNHL had a partial response. A complete response (CR) was seen in the first r/r PTCL patient evaluated in the study. Partial responses have been seen in heavily pre-treated patients, including a patient with FL who relapsed on ibrutinib, and a patient with SLL who relapsed on venetoclax, both of whom remain on drug after 10 months of therapy. Responses occur after a median of 2 cycles, are predominantly partial remissions, with 15 patients continuing on drug (4 patients >300 days).

Furthermore, the results showed that cerdulatinib was generally well-tolerated in these heavily pre-treated patients. However, 3 patients at 35 mg BID achieved higher than expected drug concentrations and had severe adverse events including two grade 5 infections and one case of grade 3 pancreatitis. The dose was subsequently reduced to 30 mg BID and a PK monitoring strategy was implemented. This has resulted in an improved safety profile and more consistent PK, while still maintaining clinical activity. The most common adverse events of any grade have been diarrhea (9/47), fatigue (18/47) and anemia (14/47). The most common grade ≥3 adverse events were neutropenia (6/47), thrombocytopenia (5/47), diarrhea, anemia, pneumonia and hypertension (all 4/47).

Overall, cerdulatinib demonstrates clinical activity in patients with CLL, FL, and other B-cell malignancies with 12 of 18 CLL/SLL patients having an partial response and 5 of 9 FL patients having a partial response. Moreover, the treatment is generally well-tolerated. Enrollment in this trial is still ongoing and updated results are expected at the end of this year.

Reference

Hamlin P, Farber C, Fenske T, et al. The dual Syk/JAK inhibitor cerdulatinib demonstrates complete inhibition of Syk and JAK and rapid tumor responses in a phase 2 study in patients with relapsed/refractory B-cell malignancies. EHA 2017, oral presentation, abstract S773.

 

Speaker Paul A. Hamlin

Hamlin

Paul A. Hamlin, MD, PhD, Memorial Sloan Kettering Cancer Center New York, USA

 

See: Keyslides

 

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