A Phase Ib/II Study of Combined Obinutuzumab and High-Dose Methylprednisolone (HDMP) As Treatment for Patients with Chronic Lymphocytic Leukemia (CLL)

Chronic lymphocytic leukemia (CLL) is not curable and ultimately patients (pts) relapse and require additional treatment. In addition, most of CLL pts are older than 65 years old or are unfit to receive chemotherapy. Because of these reasons there is a need for the development of novel therapeutic strategies.

Obinutuzumab, a third-generation anti-CD20 mAb, in combination with chlorambucil is currently approved by the FDA for previously untreated pts. Studies have demonstrated that most of the clinical benefit of this regimen is derived from obinutuzumab rather than chlorambucil, and also that obinutuzumab has superior clinical activity than rituximab. Because of these and our previous clinical studies that have shown synergism between HDMP and anti-CD20 antibodies, we initiated an open label phase Ib/II clinical study of obinutuzumab with HDMP for therapy of pts with CLL.

The study is divided in two cohorts of 20 pts each, front-line (FL) and relapsed / refractory (RR) CLL. Pts receive HDMP 1g/m² on Day 1-3 of cycles 1-4 (28 days / cycle) and obinutuzumab administered based on FDA dosing recommendations for 6 cycles. All pts received prophylactic medications (trimethoprim/sulfamethoxazole, acyclovir, fluconazole and allopurinol). 85% of target accrual has been completed (RR cohort=19 pts; FL cohort=15 pts). Here we present a preliminary analysis of safety /tolerability of this regimen.

The median age in the RR cohort was 68 years +/- 7.8 and 62 years +/- 7.3 in the FL cohort. 84% and 87% of the pts in the RR and FL cohorts had a CIRS > 6, respectively. The median baseline absolute lymphocyte count was 32.9 +/- 32.6 x10³/mm³ for pts in the RR cohort and 49.3 +/- 98.1 x10³/mm³ for pts in the FL cohort. Pts showed the following cytogenetic abnormalities: del(17p) in 32% RR vs. 0% FL, del(13q) in 63% RR vs.67% FL, del(11q) in 21% RR vs. 33% FL, and trisomy 12 in 16% RR vs. 20% FL.

All 34 pts were assessed for adverse events (AEs). Most AEs were grade 1-2 (RR=88%; FL=92%) without development of dose-limiting toxicities (DLTs). One pt in the RR cohort developed asymptomatic metformin-associated lactic acidosis that required overnight inpatient observation without therapy discontinuation.

Grade 1-2 obinutuzumab-infusion-related reactions (IRR) were observed in 42% and 87% of pts in the RR and FL cohort, respectively. We did not observe grade 3-4 IRR. Only one patient has required therapy discontinuation due to asymptomatic GI bleeding that required blood transfusion and resolved spontaneously.

We observed neutropenia (RR: all grades: 63%, grade 3-4: 26%; FL: all grades: 53%, grade 3-4: 33%), thrombocytopenia (RR: all grades: 68%, grade 3-4: 37%; FL: all grades: 80%, grade 3-4: 40%) and anemia (RR: all grades: 58%; FL: all grades: 53%). There were no cases of febrile neutropenia. Three pts (16%) in the RR cohort developed community-acquired pneumonia, requiring outpatient treatment with oral antibiotics but not study treatment discontinuation. The most frequent non-hematological AEs were transaminitis, hyperglycemia, and electrolyte alterations (grade 1-2).

All 34 pts have had favorable clinical and hematological responses. Six pts (4 pts in the RR cohort and 2 pts in the FL cohort) were evaluable for response assessment by iwCLL criteria. The four pts in the RR cohort achieved a PR. In the FL cohort, 1 pt achieved a CR MRD^neg (<0.01% CLL in the marrow), and the other pt achieved a PR.

Overall, obinutuzumab with HDMP has been well tolerated with no evidence of DLTs. The profile of AEs appears favorable compared to those noted with obinutuzumab in combination with chlorambucil, particularly in terms of grade 3-4 IRR (0% vs 20%) or rate of therapy discontinuation (3% vs 7%). Enrollment continues and updated information will be presented during the meeting.