Treatment with ibrutinib plus the anti-CD20 antibody ublituximab was shown to be safe with an objective response rate of 95% in patients with chronic lymphocytic leukemia.
Jeff Sharman, MD
Treatment with ibrutinib plus the anti-CD20 antibody ublituximab was shown to be safe with an objective response rate of 95% in patients with chronic lymphocytic leukemia (CLL), according to phase II findings. Additionally, when the investigational PI3K delta inhibitor TGR-1202 was added to the doublet, an ORR of 86% was seen in patients with various pretreated non-Hodgkin lymphomas (NHL), in a phase I study.
Both studies were presented at the 13th International Conference on Malignant Lymphoma (ICML) in Lugano, Switzerland. Based on these findings, TG Therapeutics, the developer of ublituximab announced the initiation of a phase III study to assess the combination in patients with high-risk CLL.
"The updated phase II data continues to demonstrate that adding ublituximab to ibrutinib can induce not only significant response rates for high-risk CLL patients, but has the potential to impact depth of response, with higher CR and MRD negative rates observed compared to historical data with ibrutinib monotherapy," Jeff Sharman, MD, medical director of Hematology Research for the US Oncology Network and study chair the phase II/III studies, said in a statement. "The phase III study is now up and running, and we look forward to a strong collaboration with all investigators, as this is a very attractive protocol for patients with high-risk CLL."
The phase II study enrolled 44 patients with relapsed and/or refractory CLL, with 40 patients evaluable for efficacy. Half of these patients (n = 20) were previously treated with high-risk CLL. The median age of patients in the study was 71 years. Patients had received a median of 2 prior treatments.
The combination of ublituximab and ibrutinib demonstrated an objective response rate (ORR) of 95% in high-risk patients with previously treated CLL.2 At 6 months, the median nodal reduction was 85% with the combination. In the full population, the ORR was 88%.
No dose limiting toxicities (DLTs) were observed in the study. With anemia and neutropenia representing the most common grade 3/4 adverse events. Additionally, the addition of ublituximab appeared to mitigate ibrutinib-related lymphocytosis.
In the phase I trial, the triplet was administered to 16 patients with NHL. The study included patients that had not responded to prior treatment with PI3K delta or BTK inhibitors. The median patient age was 63 years and the median number of prior therapies was 4.
The ORR was 86% following 8 weeks of treatment in 13 evaluable patients. A complete response (CR) was achieved by one patient with mantle cell lymphoma (MCL), with partial responses (PR) observed across all other NHL subtypes. An average 83% reduction in tumor burden was seen at the first scan.
One patient with stage IV FL who was previously refractory to ibrutinib and rituximab achieved a partial response by week 8 that remained durable for 9+ months. Patients remained on study median 4 months.
The most commonly reported adverse event (AE) was Grade 1/2 infusion reaction, which was reported by 25% of patients. Diarrhea, nausea, fatigue and rash have each been reported by 19% of patients. One (6%) patient each reported Grade 3/4 leukopenia and neutropenia.
“I think of this phase I study as a pilot study to evaluate whether it is safe to proceed farther, and the evidence is promising,” said lead investigator Loretta Nastoupil, MD, from MD Anderson Cancer Center. "We know from this study that the triplet appears to be safe but the mechanism and whether synergy is present are unknown.”
In the phase III study, labeled GENUINE, high-risk patients will be defined as those with the presence of a 17p del, 11q del, and/or p53 mutation. The study will be conducted under a special protocol assessment, with an agreement between the company and the FDA to evaluate a biologics license application for the combination based on a primary endpoint of ORR.