A Phase 2 Study of Ofatumumab in Combination with a Pan-AKT Inhibitor (Afuresertib) in Previously Treated Patients with Chronic Lymphocytic Leukemia (CLL)
Bibliographic record
Abstract
Abstract Introduction: Ofatumumab is an anti-CD20 monoclonal antibody with single-agent responses of 47-58% in refractory CLL (Wierda et al 2010) and a median response duration ranging from 5.6-7.1 months. In order to improve upon these results, we combined ofatumumab with afuresertib, a pan-AKT kinase inhibitor. The AKT pathway plays a centralized role in tumor differentiation, migration, proliferation and survival and is frequently aberrantly activated in CLL (Longo et al 2007). Single agent afuresertib is very well-tolerated with minimal myelotoxicity in hematologic malignancies (Spencer et al ASH 2011). We present results from 27 of 31 planned patients (pts) in a trial of ofatumumab and afuresertib in relapsed/refractory CLL. Methods: Pts withCLL relapsed/refractory to at least one fludarabine-containing regimen were eligible. During the initial 6 month Treatment Phase, ofatumumab 2000mg IV was administered weekly for 8 doses, then once every 4 weeks for 4 doses (dose/schedule identical to the pivotal phase 2 trial) with afuresertib 125mg orally daily. An initial 10 day Lead-in Phase with afuresertib alone allowed for evaluation of pharmacodynamic (PD) and pharmacokinetic (PK) studies. Patients achieving SD, PR or CR by the end of the Treatment Phase proceeded to the Maintenance Phase with single-agent afuresertib for a maximum of 12 4-week cycles. Results: Demographics: Of the 27 patients enrolled, the median age was 63 yrs (range 43-76), absolute lymphocytes 60.4 x109 /L (range 1.0-464), β2M 5.1mg/L (range 1.1-16.6). High risk features included: FISH with del17p/del11q in 10 pts (37%), ZAP70+ in 20 pts (74%) and unmutated IgVH status in 18 pts (72%). The median number of prior therapies was 2 (range 1-6). Eleven pts (41%) were fludarabine-refractory but only 3 (11%) had received prior alemtuzumab. Toxicity: Hematologic: Gr 3-4 neutropenia occurred in 10 pts (37%) and thrombocytopenia (without bleeding) in 8 pts (30%) during at least 1 cycle of treatment. Only 1 pt (4%) developed febrile neutropenia. Nonhematologic toxicity: Most common toxicities (all grades) were infusion reactions (70%), upper respiratory infections (74%), dyspepsia (59%), cough (70%), and diarrhea (56%). Dyspepsia was temporally related to oral afuresertib and managed symptomatically. Of the 19 pts (70%) who had infusion reactions to the ofatumumab, only 3 were grade 3-4 (non-fatal, all cycle 1). Grade 3-4 non-infectious pneumonitis, attributed to ofatumumab, occurred in 3 pts (11%), with 2 pts requiring hospitalization. Two pts with preexisting atrial arrhythmias sustained exacerbation during weekly ofatumumab infusions. Most infections were mild, with grade 3 upper respiratory infections (2 pts), pneumonia (4 pts), and skin infection (1 pt). There were no grade 4 infections. Efficacy: The median number of study cycles was 8 (2-19). Of all 27 response-evaluable pts, 12 pts (44%) achieved a PR, 14 SD (52%), and 1 CR (4%) = overall response rate 48%. Response onset was rapid (median 1.4 mos). Nineteen pts did not complete treatment protocol due to: disease progression 12 pts (44%), toxicity 5 pts (19%), and patient preference 2 pts (7%). At a median follow-up of 9.5 mos, the median PFS is 8.6 mos (95% CI: 7.4-13.9) and OS not yet reached. PD Studies: CD19+ cells were assayed for phosphorylated AKT and downstream targets RAS40 and GSK3, in addition to phospho-proteins of alternative pathways including ERK and pS6 by multiplexed phospho-flow cytometry. Blood samples collected at screening demonstrated constitutive AKT phosphorylation. Partial inhibition of AKT signaling evidenced by increased phosphorylation of AKT and inhibition of GSK3 and/or RAS40 phosphorylation in response to BCR stimulation was observed post-treatment, indicating target engagement by afuresertib. PK Studies: Afuresertib exposure (Cmax and AUC) was similar when afuresertib was administered alone or in combination with ofatumumab. Conclusion: This phase 2 study of 27 previously treated CLL pts, 40% with fludarabine-refractory disease, demonstrates that the addition of an oral AKT inhibitor, afuresertib, to ofatumumab has anti-tumor activity and is generally well-tolerated with minimal myelotoxicity. Although this combination works rapidly with a response onset of 1.4 mos, the moderate response rate of 48% and PFS of 8.6 mos suggest that this combination may not provide significant benefit over single agent ofatumumab. Disclosures Chen: Glaxo Smith Kline: Honoraria; Lundbeck: Honoraria; Roche: Honoraria; Janssen: Honoraria; Sanofi: Research Funding; Celgene: Honoraria, Research Funding. Off Label Use: Afuresertib is not currently approved for use in CLL.. Trudel:BMS: Honoraria; Amgen: Honoraria, Speakers Bureau; Celgene: Consultancy, Equity Ownership, Honoraria, Speakers Bureau; GSK: Honoraria, Research Funding; Merck: Research Funding; Novartis: Consultancy, Honoraria.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".