A phase 1 clinical trial of the selective BTK inhibitor ONO/GS-4059 in relapsed and refractory mature B-cell malignancies

Abstract

We report the results of a multicenter phase 1 dose-escalation study of the selective Bruton tyrosine kinase (BTK) inhibitor ONO/GS-4059 in 90 patients with relapsed/refractory B-cell malignancies. There were 9 dose-escalation cohorts ranging from 20 mg to 600 mg once daily with twice-daily regimens of 240 mg and 300 mg. Twenty-four of 25 evaluable chronic lymphocytic leukemia (CLL) patients (96%) responded to ONO/GS-4059, with a median treatment duration of 80 weeks; 21 CLL patients remain on treatment. Lymph node responses were rapid and associated with a concurrent lymphocytosis. Eleven of 12 evaluable patients with mantle cell lymphoma (92%) responded (median treatment duration, 40 weeks). Eleven of 31 non-germinal center B-cell diffuse large B-cell lymphoma patients (35%) responded but median treatment duration was 12 weeks due to development of progressive disease. ONO/GS-4059 was very well tolerated with 75% of adverse events (AEs) being Common Toxicity Criteria for Adverse Events version 4.0 grade 1 or grade 2. Grade 3/4 AEs were mainly hematologic and recovered spontaneously during therapy. One CLL patient experienced a grade 3 treatment-related bleeding event (spontaneous muscle hematoma) but no clinically significant diarrhea, cardiac dysrhythmias, or arthralgia were observed. No maximal tolerated dose (MTD) was reached in the CLL cohort. In the non-Hodgkin lymphoma cohort, 4 patients developed a dose-limiting toxicity, yielding an MTD of 480 mg once daily. ONO/GS-4059 has significant activity in relapsed/refractory B-cell malignancies without major drug-related toxicity. The selectivity of ONO/GS-4059 should confer advantages in combination therapies. This trial was registered at www.clinicaltrials.gov as #NCT01659255.

Figure 1

Patient enrollment by disease subtype and disposition within the trial. Seven CLL patients were withdrawn due to AEs; 2 of the CLL patients withdrawn due to an AE also had concurrent PD. AEs were considered to be either related (R) or not related (NR) to study drug. In the CLL cohort, these AEs comprised: fever (NR), Escherichia coli septicemia (NR), worsening heart failure (NR), neutropenic sepsis (R), purpura, lymphocytic infiltration (R), spontaneous psoas hematoma (R), idiopathic thrombocytopenia (R). Three DLBCL patients were withdrawn due to AEs: myelodysplastic syndrome (NR), tubulopathy myeloma (renal tubular necrosis) (NR), and confusional state (NR). Two WM patients were withdrawn due to AEs: urticarial reaction (R), nonimmune drug reaction (R). Other reasons for discontinuation included investigator decision (2 DLBCL cases), patient decision (1 FL case), 1 case of MCL proceeding to allograft and DLTs in 2 WM patients. The majority of deaths especially in the DLBCL cohort were due to PD.

Figure 2

PFS curves for CLL, MCL, and DLBCL patients. Results are shown for CLL, MCL, and DLBCL patients as separate curves. Estimated mean PFS for each cohort: CLL = 874 days, MCL = 341 days, and DLBCL = 54 days.

Figure 3

Efficacy of ONO/GS-4059 in patients with CLL. (A) Duration on treatment for all CLL patients (n = 28) according to dose cohort. *Ongoing patients. (B) Waterfall plot for all CLL patients by dose cohort (n = 25), showing response evaluated by CT imaging. Changes from baseline scan (sum of the largest diameter of each target lesion) are shown. Negative values indicate tumor response. **Patients with TP53/17p deletion; @patients with ATM/11q deletion. (C) Rate of response of lymph nodes in CLL patients up to cycle 7 (n = 23). Measured by the percentage change in tumor SPD. (D) Mean blood concentrations of hemoglobin (g/dL) and platelet count (×10⁹/L) showing recovery of normal hemopoiesis in CLL patients up to cycle 31. (E) Case example: CT axial images from a CLL patient. (i) Pretreatment CT imaging showing large volume intra-abdominal lymphadenopathy. (ii) CT imaging during cycle 3 following treatment with ONO/GS-4059 600 mg once daily shows considerable reduction in lymphadenopathy. SPD, sum of perpendicular dimensions.

Figure 4

Efficacy of ONO/GS-4059 in patients with MCL. (A) Waterfall plot for all MCL patients by dose cohort (n = 12), showing response evaluated by CT imaging. Changes from baseline scan (sum of the largest diameter of each target lesion) are shown. Negative values indicate tumor response. (B) Duration on treatment for all MCL patients (n = 16) according to dose cohort. *Ongoing patients.

Figure 5

Efficacy of ONO/GS-4059 in patients with DLBCL. (A) Waterfall plot for all DLBCL patients by dose cohort (n = 17), showing response evaluated by CT imaging. Changes from baseline scan (sum of the largest diameter of each target lesion) are shown. Negative values indicate tumor response. (B) Duration on treatment for all DLBCL patients (n = 35) according to dose cohort. *Ongoing patients.

Figure 6

Pharmacokinetic studies of ONO/GS-4059. Plasma concentration-time profiles of ONO/GS-4059 on day 1 (A) and day 28 (B) after once-daily oral administration. Graphs show the mean plasma concentration of ONO/GS-4059 (ng/mL) for all patients in both CLL and NHL cohorts according to dose cohort. Error bars represent the standard deviation.