Researchers are combining the novel CD20-targeting agent ublituximab (TG-1101) with ibrutinib to determine whether the regimen can improve outcomes in CLL, particularly for patients whose disease has high-risk features.
Jeff Sharman, MD
The FDA’s approval of ibrutinib (Imbruvica) in February 2014 was a significant step forward in the management of chronic lymphocytic leukemia (CLL). However, the Bruton tyrosine kinase inhibitor is not curative, and relapse and resistance remain clinical challenges.
Now, researchers are combining the novel CD20-targeting agent ublituximab (TG-1101) with ibrutinib to determine whether the regimen can improve outcomes in CLL, particularly for patients whose disease has high-risk features.
“Patients usually do very well on ibrutinib; however, those patients who exhibit chromosome changes that designate high risk, such as 17p or 11q deletions and TP53 mutations, do not derive the same benefit as patients who lack these markers,” said Jeff Sharman, MD, medical director of Hematology Research for The US Oncology Network and director of research at the Willamette Valley Cancer Institute in Springfield, Oregon.
Sharman is principal investigator of the phase III GENUINE trial in which patients with previously treated high-risk CLL are being randomized to treatment with ublituximab in combination with ibrutinib versus ibrutinib alone.1
Ublituximab is a novel, chimeric monoclonal antibody targeting a unique epitope on the CD20 antigen and is glycoengineered to contain a low fucose content, according to Sharman and colleagues.2
The open-label GENUINE study, currently accruing patients at the Willamette Valley Cancer Institute and 150 other locations throughout the United States, is evaluating whether the addition of ublituximab to ibrutinib improves outcomes for patients with relapsed or refractory high-risk CLL whose disease exhibits at least one of the three high-risk cytogenetic features that Sharman described.
Patients who exhibit these high-risk markers tend to progress at a faster rate than patients without those features, said Sharman. “The median progression-free survival [PFS] in those with the 17p deletion is about 2 years. We’re trying to see if we can improve that with the addition of the CD20 antibody,” he said.
Previously treated patients with CLL will either receive ibrutinib as standard of care, or ibrutinib plus ublituximab on days 1, 8, and 15, and monthly thereafter. At baseline, patients will undergo fluorescence in situ hybridization (FISH) testing to determine the presence of high-risk markers. FISH status can change during the course of therapy.
“Deletions like 17p or 11q can be present at the time of diagnosis in 5% to 7% of patients, but it can rise to as much as 30% at relapse,” stated Sharman. “That’s a similar story with 11q deletions, which are present in about 10% of patients upfront and reach up to 30% in patients with relapse/refractory disease.”
Sharman noted that the TP53 gene resides on chromosome 17p, but FISH only detects loss, not mutation. Patients screened for this study also have sequencing performed on the TP53 gene, and those with mutations are allowed to enroll. Study endpoints include overall response rate (ORR) and PFS. The FDA has granted the study sponsor, TG Therapeutics, Inc, a special protocol assessment (SPA). The SPA allows the sponsor to evaluate the ORR among the first two-thirds of participants enrolled, or approximately 200 patients.
If the ORR is better with the addition of the antibody than standard care alone, “it could lead to an accelerated approval of ublituximab with PFS serving as confirmation,” said Sharman. The trial, which seeks to enroll 330 participants, is aiming for a primary completion date of September 2016.
The groundwork for the GENUINE study was established through a phase II study in which patients with high-risk relapsed/refractory CLL received the combination of ibrutinib and ublituximab. 2 Overall, the study enrolled 44 patients including 48% (21 patients) with the high-risk features of 17p del, 11 q del, or mutated p53. Among 40 patients with CLL evaluable for efficacy at months 2 and 5, the ORR was 88%, with all but 4 responses classified as partial responses. The ORR rose to 95% among the 20 patients with high-risk CLL, with 3 patients achieving negative minimal residual disease status within 6 months of therapy.
The regimen was well tolerated, with the most common all-grade adverse events (AEs) among 44 patients evaluable for safety consisting of infusion reactions (45%), diarrhea (36%), and fatigue (30%). The most common grade 3-4 AEs included anemia and neutropenia (11% each) and infusion reactions (7%).
A number of studies have shown that adding ibrutinib to standard of care therapy has improved outcomes. Previously, the phase III HELIOS study3 combined ibrutinib with standard bendamustine and rituximab. Results indicated that the agent lowered the risk of disease progression by 80% in patients with relapsed/refractory CLL and small lymphocytic lymphoma (SLL).
“A reasonable criticism of the HELIOS trial is that it is unclear whether patients in the ibrutinib arm would have done better if they had received ibrutinib alone. So the question is, ‘Are these additional agents necessary over ibrutinib?’ I don’t think we have answered that yet,” said Sharman.