STOCKHOLM—The dual SYK/JAK inhibitor cerdulatinib has demonstrated efficacy in a phase 2 trial of patients with heavily pretreated B- and T-cell non-Hodgkin lymphomas (NHLs).
There were a few deaths due to sepsis or septic shock that were considered related to cerdulatinib, but investigators have taken steps to prevent additional deaths.
Cerdulatinib produced responses in patients with peripheral T-cell lymphoma (PTCL), cutaneous T-cell lymphoma (CTCL), chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL), follicular lymphoma (FL), and other NHLs.
The 5 deaths due to sepsis or septic shock (3 concomitant with pneumonia) occurred early on in the trial, and dose reductions, monitoring, and antibiotic prophylaxis appeared to be effective in preventing additional deaths.
Results from this trial were presented in a poster (abstract PF437) at the 23rd Congress of the European Hematology Association (EHA).
The research was sponsored by Portola Pharmaceuticals, Inc.
The trial enrolled 114 patients. They had FL (grade 1-3A; n=39), PTCL (n=25), CTCL (n=5), CLL/SLL (n=28), other indolent NHLs (Waldenstrom’s macroglobulinemia and marginal zone lymphoma; n=12), or aggressive NHL (defined as diffuse large B-cell lymphoma [DLBCL], grade 3B FL, mantle cell lymphoma, and transformed NHL with relapsed disease; n=5).
The patients’ median age was 68 (range, 34-93), and 59% were male. The median number of prior treatment regimens was 3 (range, 1-13), and 37% of patients had refractory disease.
Patients received cerdulatinib at 25, 30, or 35 mg twice daily (BID). A total of 101 patients were evaluable as of May 4, 2018.
The objective response rate (ORR) was 47% in the entire population. Thirteen patients achieved a complete response (CR), and 34 had a partial response (PR). Thirty-four patients remained on cerdulatinib at the data cut-off.
The ORR was 46% in the FL patients, with 3 patients achieving a CR and 13 achieving a PR. Thirteen FL patients remained on cerdulatinib.
In the CLL/SLL patients, the ORR was 61%. Two patients had a CR, and 15 had a PR. Four CLL/SLL patients remained on cerdulatinib.
In PTCL, the ORR was 35%. All 7 responders had a CR. Eleven PTCL patients remained on cerdulatinib.
Only 1 CTCL patient was evaluable, but this patient achieved a CR and remained on cerdulatinib.
The ORR was 42% for patients with other indolent NHLs, with 5 PRs and no CRs. Only 1 patient in this group remained on cerdulatinib.
For aggressive NHL, the ORR was 20%, with 1 PR and no CRs. None of the patients in this group stayed on cerdulatinib.
“Cerdulatinib continues to demonstrate promising results across a wide range of B- and T-cell malignancies, including early indications of the potential for durable responses,” said study investigator Paul Hamlin, MD, of Memorial Sloan Kettering Cancer Center in New York, New York.
“The new signals in relapsed/refractory PTCL and CTCL are particularly compelling when you consider the limited treatment options for patients that fail frontline therapy.”
Grade 3 or higher adverse events included lipase increase (18%), neutropenia (17%), pneumonia/lung infection (11%), diarrhea (8%), fatigue (6%), amylase increase (5%), sepsis/septic shock (4%), hypertension (4%), anemia (4%), thrombocytopenia (4%), and hypophosphatemia (4%).
The 5 deaths due to sepsis or septic shock (3 of which were concomitant with pneumonia) were considered related to cerdulatinib. Three of the deaths occurred in patients with CLL, 1 in a DLBCL patient, and 1 in an FL patient.
“One of the things we have seen [with CLL patients] is the background infection rate is quite a bit higher,” said John T. Curnutte, MD, PhD, interim co-president and head of research and development at Portola Pharmaceuticals.
“You see this with multiple other agents, so we were not particularly surprised to see [sepsis/septic shock in CLL].”
Dr Curnutte noted that grade 5 sepsis/septic shock tended to occur in patients who were pre-colonized and/or had high plasma levels of cerdulatinib.
So, to prevent these adverse events, the starting dose of cerdulatinib was lowered, investigators began monitoring patients’ plasma levels, and all patients began receiving antibiotic prophylaxis. (Previously, only CLL patients had received this prophylaxis.)
The investigators found that lowering the starting dose from 35 mg BID to 30 mg or even 25 mg BID reduced plasma levels.
“At the 35 mg dose, 1 out of every 4 patients showed accumulation of the drug,” Dr Curnutte said. “In general, the use of the 30 mg BID or step-down 25 mg BID did not result in accumulation of drug.”
Dr Curnutte also noted that enrollment of CLL/SLL patients is complete, and investigators would be “very careful” if the study were to be re-opened to these patients.
For now, Portola is focused on completing enrollment in other patient groups on this phase 2 trial. The company is also hoping to conduct a phase 3 trial of cerdulatinib in PTCL that could begin as early as the end of this year.