Ibrutinib, Ublituximab, TGR-1202 Triplet Active in Relapsed B-Cell Malignancies

Loretta Nastoupil, MD

A chemotherapy-free combination of the anti-CD20 antibody ublituximab, ibrutinib (Imbruvica), and the PI3K delta inhibitor TGR-1202 demonstrated robust clinical activity in patients with relapsed/refractory chronic lymphocytic leukemia (CLL) or B-cell non-Hodgkin lymphoma (B-NHL), according to data presented at the 13th International Conference on Malignant Lymphoma (ICML) in Lugano, Switzerland.¹

The overall response rate (ORR) in 13 patients evaluable for efficacy was 86% by week 8 of treatment. A complete response (CR) was achieved by one patient with mantle cell lymphoma (MCL), with partial responses (PR) observed in one patient with marginal zone lymphoma (MZL), 1 with MCL, 2 with follicular lymphoma (FL), 3 with CLL, and in 1 patient with small lymphocytic lymphoma (SLL). 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 greater than 9 months. Patients remained on study a median of 4 months (range, 1-9+).

“There was a rapid response with the majority of patients showing a greater than 50% reduction in disease burden by 8 weeks,” said lead investigator Loretta Nastoupil, MD, Hematology Department, MD Anderson Cancer Center. “The primary focus of this small study was safety. Not many complete responses were observed but it must be remembered that 76% of the study population was heavily pre-treated. 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 I trial, the triplet of CD20, PI3K delta, and BTK inhibition was administered to 16 patients, including 4 patients with FL, 4 patients with CLL, 1 with SLL, 3 with diffuse large B cell lymphoma (DLBCL), 1 with MZL, 2 with MCL, and 1 patient with Richter’s Transformation. The study included patients that had not responded to prior treatment with PI3K delta or BTK inhibitors. The median patient age was 63 years (range, 51-85). The 12 male and 4 female patients had received a median of 4 prior regimens (range, 1-5).

Safety and dose limiting toxicities (DLTs) in the CLL and NHL cohorts were evaluated independently in a 3 + 3 dose escalation design. Patients received ublituximab at 900 mg and ibrutinib was administered each evening at 420 mg in CLL patients or at 560 mg in patients with NHL. TGR-1202 was administered each morning at 400 mg in cohort 1, 600 mg in cohort 2, and at 800 mg in cohort 3. Scans were done at week 8 and every 12 weeks thereafter.

At data cutoff, all 16 patients were evaluable for safety. One DLT occurred in the 400 mg TGR-1202 cohort that was unrelated to treatment and consisted of a reactivation of varicella zoster; no other DLTs have been reported to date.

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.

However, given the short duration of follow-up, it could be too soon to judge whether common treatment-related AEs like colitis would emerge. “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,” Nastoupil said.

In a separate phase II presentation at the ICML conference, the combination of ublituximab and ibrutinib demonstrated an ORR of 95% in high-risk patients with previously treated CLL.² At 6 months, the median nodal reduction was 85% with the combination. This 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. In the full population, the ORR was 88%.

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. In the study, labeled GENUINE, high-risk will be defined as 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.

"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."

Ublituximab is a novel glycoengineered, type 1 chimeric IgG1 monoclonal antibody targeting a unique epitope on the CD20 antigen that demonstrated activity in rituximab refractory patients (O’Connor et al. ASCO 2014). TGR-1202 is a next generation PI3K delta inhibitor with a pharmacokinetic profile that supports once-daily dosing and has demonstrated a 93% nodal PR rate in patients with relapsed/refractory CLL (Burris et al. ASCO 2015, Abstract 7069). This triplet is expected to be active against a broad spectrum of B-cell malignancies.

The FDA initially approved ibrutinib in November 2013 for patients with MCL following at least one prior therapy. In February 2014, the FDA expanded this approval to include patients with previously treated CLL, which was then followed by a full FDA approval and a new indication for high-risk patients with 17p deletions in July 2014. Ibrutinib was granted an approval for Waldenström’s macroglobulinemia in January 2015, and continues to be explored across a number of hematologic malignancies.

References:

1. Nastoupil L, Lunning MA, Vose JM, et al. The chemotherapy-free triplet of ublituximab, TGR-1202, and ibrutinib is safe and highly active in relapsed B-cell malignancies. Presented at: 13th International Conference on Malignant Lymphoma; June 16-20, 2015; Lugano, Switzerland. Abstract 106.
2. Sharman J, Farber CM, Mahadevan D, et al. Ublituximab (TG-1101), a novel glycoengineered anti-CD20 mAb, in combination with ibrutinib achieves 95% ORR in patients with high-risk relapsed/refractory CLL. Presented at: 13th International Conference on Malignant Lymphoma; June 16-20, 2015; Lugano, Switzerland. Abstract 105.

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