Micrograph showing CLL
LUGANO, SWITZERLAND—Results of a phase 1 study suggest a 2-drug combination may be safe and effective in patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) and follicular lymphoma (FL).
The ongoing study is a test of the BTK inhibitor BGB-3111 and the anti-CD20 antibody obinutuzumab.
The overall response rate (ORR) with this combination was 81% in the entire study population, 89% in treatment-naïve CLL/SLL patients, 92% in relapsed/refractory CLL/SLL patients, and 73% in relapsed/refractory FL patients.
The rate of serious adverse events (AEs) was 24% in both CLL/SLL and FL patients.
These results were presented at the 14th International Conference on Malignant Lymphoma (ICML). The research was sponsored by BeiGene, Ltd.
“This clinical trial is supported by preclinical work suggesting that BGB-3111 may combine well with antibodies that rely on antibody-dependent cell-mediated cytotoxicity, such as obinutuzumab, because of less off-target inhibition of interleukin-2-inducible T-cell kinase,” said study investigator Constantine Tam, MD, of St. Vincent’s Hospital in Melbourne, Australia.
“The preliminary clinical results to date suggest that the combination is well tolerated and highly active in patients with CLL or SLL and FL. Complete responses have already been observed in patients with both disease types, including CLL or SLL patients with high-risk features, despite a very short follow-up time.”
The trial consists of a dose-escalation phase and a dose-expansion phase in disease-specific cohorts, which include treatment-naive or relapsed/refractory CLL/SLL and relapsed/refractory FL.
The dose-escalation component is testing BGB-3111 at 320 mg once daily or 160 mg twice daily in 28-day cycles, in combination with obinutuzumab. Obinutuzumab is administered in line with standard CLL dosing (3 loading doses of 1000 mg weekly, followed by 1000 mg on day 1 of cycles 2 to 6).
The ongoing dose-expansion component is testing doses of BGB-3111 at 160 mg twice daily with the same obinutuzumab schedule.
As of the data cutoff (March 31, 2017), 45 patients with CLL/SLL and 17 patients with FL were enrolled in the trial.
Patient characteristics
The median age was 68 (range, 28-82) in the CLL/SLL patients and 56 (range, 41-86) in the FL patients.
ECOG performance status was 0 in 42% of CLL/SLL patients, 1 in 56% of these patients, and 2 in 2%. ECOG performance status was 0 in 82% of FL patients, 1 in 12% of these patients, and 2 in 6%.
Twenty CLL/SLL patients were treatment-naïve, and 25 had relapsed/refractory disease. All 17 FL patients had relapsed/refractory disease.
The median number of prior therapies was 1 (range, 1-4) in the relapsed/refractory CLL/SLL patients and 3 (range, 1-7) in the FL patients.
Safety
At the time of the data cutoff, BGB-3111 was deemed well tolerated in patients with CLL/SLL and FL.
The most frequent AEs of any cause occurring in at least 15% of patients with CLL/SLL were petechiae/purpura/contusion (33%), neutropenia (31%), thrombocytopenia (22%), fatigue (18%), pyrexia (18%), upper respiratory tract infection (18%), and diarrhea (16%).
Most of these events were grade 1/2. The exceptions were grade 3/4 neutropenia (20%) and grade 3/4 thrombocytopenia (4%).
The most frequent AEs in FL patients were petechiae/purpura/contusion (35%), fatigue (29%), cough (18%), diarrhea (18%), dizziness (18%), headache (18%), insomnia (18%), nausea (18%), and upper respiratory tract infection (18%). All of these events were grade 1/2.
Serious AEs occurred in 24% of both the CLL/SLL patients and the FL patients.
Infusion-related reactions occurred in 24% of CLL/SLL patients and 6% of FL patients. Nearly all cases were grade 1/2. The exception was 1 grade 4 case in a CLL/SLL patient.
There were no cases of serious hemorrhage (≥ grade 3 hemorrhage or central nervous system hemorrhage of any grade) or atrial fibrillation.
One patient discontinued treatment due to an AE—squamous cell carcinoma. This patient had a prior history of squamous cell carcinoma.
Efficacy
At the time of the data cutoff, 43 patients with CLL/SLL (18 treatment-naive, 25 relapsed/refractory) and 15 patients with relapsed/refractory FL had greater than 12 weeks of follow-up and were evaluable for efficacy.
In treatment-naive CLL/SLL, after a median follow-up of 7.0 months (range, 2.8–11.8 months), the ORR was 89%. The complete response (CR) rate was 22%, the rate of partial response (PR) was 67%, and the rate of stable disease (SD) was 11%.
In relapsed/refractory CLL/SLL, at a median follow-up of 8.0 months (range, 3.8–14.0 months) the ORR was 92%. The CR rate was 16%, the PR rate was 76%, and 4% of patients had SD.
One patient (4%) with relapsed/refractory CLL/SLL had progressive disease (Richter’s transformation).
In relapsed/refractory FL, at a median follow-up of 6.2 months (range, 1.2–10.7 months), the ORR was 73%. The CR rate was 33%, the PR rate was 40%, and 13% of patients had SD.
Two patients (13%) with relapsed/refractory FL had progressive disease.
On the basis of these data, BeiGene plans to expand its global registrational program for BGB-3111 to include a phase 2 trial of BGB-3111 in combination with obinutuzumab compared to obinutuzumab alone in patients with relapsed/refractory FL.
The company is also planning a phase 3 trial comparing BGB-3111 with bendamustine plus rituximab in patients with treatment-naive CLL.
