Credit: Linda Bartlett
KOHALA COAST, HAWAII—Early results of a small, phase 1 study suggest a novel combination treatment is active and generally well-tolerated in relapsed or refractory patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) or non-Hodgkin lymphomas (NHLs).
The treatment consists of ublituximab (TG-1101), a monoclonal antibody that targets a unique epitope on the CD20 antigen, and TGR-1202, a next-generation PI3K delta inhibitor.
The combination appeared to be well tolerated overall, although infusion-related reactions were common, and nearly a quarter of patients experienced grade 3/4 neutropenia.
Four of 5 CLL/SLL patients experienced a partial response (PR), and the remaining patient had stable disease (SD). Among the 10 NHL patients, 1 had progressive disease, 7 had SD, and 2 achieved a PR.
Matthew Lunning, DO, of the University of Nebraska Medical Center in Omaha, and his colleagues presented these results in a poster at the 2014 Pan Pacific Lymphoma Conference.
The study is sponsored by TG Therapeutics, the company developing both drugs.
The researchers presented results from 8 patients with CLL/SLL, 7 patients with diffuse large B-cell lymphoma (DLBCL), 5 with follicular lymphoma (FL), and 1 patient with Richter’s syndrome (RS).
Patients had a median age of 64 years (range, 35-82), and they had received a median of 3 prior therapies (range, 1-9). Fifty-seven percent of patients had received 3 or more prior therapies, and 38% were refractory to their prior therapy.
The patients received escalating doses of TGR-1202, with a fixed dose of ublituximab—900 mg for patients with NHL and 600 mg for patients with CLL.
As of the data cutoff, all 21 patients were evaluable for safety, but only 15 were evaluable for efficacy.
Adverse events
The most common adverse event was infusion-related reactions, which occurred in 48% of patients. All of these events were manageable without dose reductions, and all but 1 event was grade 1 or 2 in severity.
Neutropenia was also common, occurring in 38% of patients. Grade 3/4 neutropenia occurred in 24% of patients. One CLL patient required a dose delay for neutropenia in cycle 1, which met the criteria for a dose-limiting toxicity.
No additional dose-limiting toxicities have been observed to date. Likewise, none of the patients has required dose reductions for either drug, and there were no drug-related AST/ALT elevations.
On the other hand, 1 patient did come off the study due to grade 1 itching that was possibly related to TGR-1202.
Other common adverse events associated with treatment included diarrhea (29%), nausea (29%), hoarseness (10%), muscle aches (10%), and fatigue (10%).
Activity in CLL/SLL
Of the 8 CLL/SLL patients enrolled to date, 5 were evaluable for efficacy. Four patients achieved a PR at the first efficacy assessment. The remaining patient, a CLL patient with both 17p and 11q del, achieved SD with a 44% nodal reduction at the first assessment.
All 5 patients achieved a greater-than-50% reduction in ALC by the first efficacy assessment. One patient achieved complete normalization of ALC (less than 4000/uL), and the other 4 patients achieved at least an 80% reduction by the first efficacy assessment.
The lymphocytosis generally observed in CLL patients treated with TGR-1202, similar to other PI3K delta and BTK inhibitors, appears to be mitigated by the addition of ublituximab.
Activity in NHL
Of the 13 patients in this group, 10 were evaluable for efficacy, including 5 with DLBCL, 4 with FL, and 1 with RS. Results were not as favorable in this group as they were among CLL/SLL patients, but, as the researchers pointed out, these patients were heavily pretreated.
Among the DLBCL patients, 2 achieved PRs with TGR-1202 and ublituximab. Both of these responses occurred at the higher dose of TGR-1202.
Two DLBCL patients had SD, and 1 patient progressed. DLBCL patients had a median of 3 prior treatment lines, and 3 patients had GCB DLBCL, with 1 patient classified as triple-hit lymphoma (overexpression of BCL2, BCL6, and MYC rearrangements).
In the FL group, all 4 patients had SD after treatment and exhibited a reduction in tumor mass at the first assessment. These patients had advanced disease and a median of 6 prior lines of therapy.
The RS patient also had SD following TGR-1202 and ublituximab.
“We have been very impressed with the safety profile and the level of activity observed to date in all patient groups with TGR-1202 in combination with ublituximab, particularly given the advanced stage of disease . . . ,” said Susan O’Brien, MD, a professor at MD Anderson Cancer Center in Houston and study chair for the CLL patient group.
“Of particular interest is the absence of observed elevations in AST/ALT with TGR-1202, which is a known adverse event associated with other PI3K delta inhibitors. We look forward to continuing enrollment at all trial centers of this exciting combination and presenting data on more patients at upcoming medical meetings.”
