Abstract
Abstract 1783
Background:
The PI3K/Akt/mTOR signaling pathway is an attractive target to inhibit for cancer therapy because it is altered in many cancers and is vital to essential biological processes. While inhibition of specific PI3K isoforms, such as δ, has demonstrated efficacy in B-cell malignancies, recent studies suggest that inhibition of all Class IA isoforms (α, β, and δ) is essential to produce maximal inhibition of cell proliferation and to induce apoptosis. For example, the pan PI3K inhibitor LY294002 has been shown to inhibit both the viability and chemotaxis of chronic lymphocytic leukemia (CLL) B-cells, whereas a PI3K δ inhibitor did not. Dual PI3K and mTOR inhibition is also expected to offer a therapeutic advantage, as several mTOR inhibitors have demonstrated promising activity in B-cell malignancies, including the mobilization of CLL cells from tissue sites into the circulation that could enhance the cytotoxicity of other agents.
Objectives:
The role of PI3K in a wide range of normal biologic processes raises potential safety concerns about dual inhibition of mTOR and all PI3K Class I isoforms. The objective of this Phase I study is to demonstrate that SF1126 can overcome these concerns by accumulating preferentially in tumor tissue to both maximize efficacy and minimize toxicity. SF1126 is a peptidic prodrug that converts to LY294002, one of the most widely studied dual PI3K/mTOR inhibitors. LY294002 is conjugated to an Arg-Gly-Asp (RGD) peptide via a cleavable linker to form SF1126, which has improved properties for clinical use. As a prodrug with improved solubility and site selectivity due to targeting of RGD-recognizing integrin receptors, SF1126 opened up a new avenue for the clinical development of LY294002. Furthermore, the fact that proliferation of CLL cells requires stromal support mediated through cytokines and adhesion molecules (eg, integrins) provides additional biological rationale for testing a RGD-targeted agent as a treatment for CLL.
Methods:
Based on translational studies demonstrating that LY294002 induces apoptosis in CLL cells and sensitize CLL cells to cytotoxic drugs, patients with CLL and other B-cell malignancies will be enrolled on this expanded Phase I trial at the maximum administered dose of SF1126 (1110 mg/m2) as determined by 47 patients treated to date in dose-escalation studies. SF1126 will be administered intravenously over 90-minutes on days 1 and 4 weekly in cycles of 4 weeks. Patients with CLL will be assessed using the International Workshop on CLL (IWCLL) criteria and patients with indolent non-Hodgkin's lymphoma (NHL) or mantle cell lymphoma (MCL) will be assessed using the International Workshop Group (IWG) criteria. Correlative pharmacodynamic studies will also be conducted to evaluate the potential inhibition of PI3K in tumor cells from patients enrolled in this trial.
Results:
At the maximum administered dose of 1110 mg/m2, SF1126 appears to be well tolerated and demonstrates activity in relapsed and refractory CLL patients treated to date in this ongoing Phase I study. Similar to the tumor flare reaction (TFR) demonstrated in CLL patients treated with immune-modulating agents, such as lenalidomide, two patients treated with SF1126 experienced TFR during the cycle one, day 1–4 time period. TFR has been postulated to be associated with a drug-induced, immune-mediated anti-tumor response and is manifested as an acute onset of swelling of involved lymph nodes that is not associated with disease progression. Time course analysis by flow cytometry of isolated lymphocytes from the first two CLL patients treated demonstrate consistent increases in late apoptosis over time relative to baseline following the first dose of SF1126. Western blot analyses of isolated lymphocytes from the first CLL patient treated demonstrate decreased pAKT (473) signaling and increased PARP cleavage over time relative to baseline. One CLL patient with a 17p deletion genotype demonstrated clinical activity as indicated by stable disease and significant lymph node decreases accompanied by an increases in absolute lymphocyte count (ALC) as seen with the mTOR inhibitor everolimus. The trial continues to enroll patients and updated results from this study will be presented. In view of SF1126's ability to mobilize CLL cells into the circulation, combination studies with synergistic agents that are effective against circulating CLL cells are also being planned.
Disclosures:
Garlich: Semafore Pharmaceuticals: Employment, Patents & Royalties. Becker:Semafore Pharmaceuticals: Consultancy, Patents & Royalties. Shelton:Semafore Pharmaceuticals: Consultancy. Qi:Seamfore Pharmaceuticals: Research Funding. Liu:Semafore Pharmaceuticals: Research Funding. Cooke:Semafore Pharmaceuticals: Research Funding. Mahadevan:semafore pharmaceuticals: Research Funding.
