Navitoclax (ABT-263) Plus Rituximab: Interim Results of a Phase 1 Study In Patients with CD20-Positive Lymphoid Malignancies

Navitoclax (ABT-263) is a novel, orally bioavailable, small molecule that binds with high affinity (Ki ≤1nM) to Bcl-2, Bcl-xL, and Bcl-w, promoting apoptosis. Navitoclax shows potent targeted cytotoxicity (EC₅₀ ≤1μM) in vitro against T and B lymphoid malignancies that over-express Bcl-2. As monotherapy in phase 1 trials, oral navitoclax is well-tolerated and with daily dosing has shown activity in patients (pts) with lymphoid malignancies and many pts (response rate approximately 35%) with chronic relapsed or refractory lymphocytic leukemia (CLL). Thrombocytopenia is the dose-limiting toxicity (DLT). Rituximab mono- or combination therapy is an established treatment for pts with indolent, CD20-positive B-cell malignancies. In multiple preclinical models of B-cell lymphoma, the efficacy of rituximab (monotherapy and in combination with chemotherapy) was enhanced by the addition of navitoclax. Methods: This international, phase 1, dose-escalation study employing a modified Fibonacci 3+3 design, assessed the safety and pharmacokinetics (PK), and determined the maximum tolerated dose (MTD) and the recommended phase 2 dose (RPTD) of oral navitoclax added to standard rituximab monotherapy in pts with CD20-positive malignancies. Secondary objectives were evaluation of progression-free survival, response rate, duration of response, and overall survival. Patient eligibility included ≥1 lesion ≥1.5 cm, ECOG score ≤1, and platelet count of ≥100,000/mm³. For all dose cohorts, after a 7–14 day 150 mg/day dose lead-in, navitoclax was given once daily at 200 mg (Cohort 1), 250 mg (Cohort 2), or 325 mg (Cohort 3). At least 3 pts were enrolled in each cohort. At MTD determination, a safety expansion cohort of up to 12 pts was added. Pts proceeded from lead-in to the combination regimen, if the pre-dose platelet count on Lead-in Day 7 was ≥50,000/mm³. Rituximab was given 375 mg/m² IV once weekly for 4 doses, starting Day 1 of Week 1. A cycle was 28 days of therapy. Patients were allowed to continue on navitoclax therapy for 2 years in the absence of progressive disease or significant toxicity. Safety was assessed by NCI-CTCAE v3.0, and tumor responses by IWG or NCI-WG criteria (for CLL pts) every 2 months by CT or MRI. Results: As of July 2010, 19 pts, median age 58 years (range 45–92), have been enrolled (11 with follicular lymphoma [FL], 3 with CLL/SLL, and 1 each with diffuse large B-cell lymphoma, transformed disease, lymphoplasmacytic lymphoma [LPL], lymphoblastic lymphoma, and Hodgkin lymphoma, respectively); 4 in the 200 mg, 7 in the 250 mg, 3 in the 325 mg, and 5 in the 250 mg expanded safety cohort. The median number of prior therapies was 3. Seventeen pts had navitoclax-related AEs, the most common being diarrhea (11 pts), nausea (11), and fatigue (8). DLTs were Grade 3 diarrhea (1 pt in the 250 mg cohort), Grade 3 fatigue (1 pt in the 325 mg cohort), and Grade 4 thrombocytopenia (1 pt in the 325 mg cohort). MTD was defined as 250 mg. Preliminary antitumor activity and best response data are available for 12 pts. Eight pts responded (ORR 67%) with 4 CRs (all FL), 4 PRs (SLL, FL, CLL, LPL), 1 SD, and 3 PDs. Five other pts are continuing treatment but have not yet reached the first tumor assessment at 12 weeks. One pt discontinued due to disease progression prior to the first tumor assessment, and 1 pt discontinued after 3 days of dosing due to the taste of the oral drug solution. Twelve pts remain on study at a median of 19.4 weeks (4.4–49.1 weeks). Preliminary PK results indicated that navitoclax PK at doses of 200–325 mg in this combination study was comparable to that in the navitoclax monotherapy study. Conclusions: The combination of navitoclax and rituximab is well tolerated and shows encouraging preliminary evidence of activity. The MTD of navitoclax in combination with rituximab is 250 mg. An expanded cohort of pts is being enrolled at 250 mg of navitoclax to further assess tolerability, confirm this dose as the RPTD, and to better define efficacy.

Kahl:Abbott: Consultancy, Research Funding. Roberts:Abbott: Research Funding. Seymour:Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Advani:Abbott: Research Funding. Persky:Millennium, Takeda: Consultancy, Research Funding. Yang:Abbott: Employment. Cui:Abbott: Employment. Busman:Abbott: Employment. Krivoshik:Abbott: Employment. Enschede:Abbott: Employment. Humerickhouse:Abbott: Employment.