AT-101, a small molecule Bcl-2 antagonist, in treatment naïve CLL patients (pts) with high risk features; Preliminary results from an ongoing phase I trial

Abstract

6605 Background: CLL pts with early stage disease are often observed under a “watch and wait” approach. Unmutated immunoglobulin variable-region gene (IgVH); expression of zeta chain associated kinase (ZAP-70); CD38 expression; and cytogenetics abnormalities identify pts with a tendency for early disease progression. Whether pts with these high-risk features may benefit from early intervention warrants investigation in clinical trials. Gossypol, a naturally occurring compound in cotton seeds has been extensively studied in clinical trials and is well tolerated with a favorable safety profile. AT-101, a derivative of R-(-)-gossypol binds to Bcl-2 family proteins and induces apoptosis of CLL cells in vitro. Dysregulated expression of Bcl-2 proteins is critical for CLL leukemogenesis and is an attractive therapeutic target. Methods: We conducted a phase I study to evaluate the safety and tolerability of single agent AT-101 in treatment naïve CLL pts with high-risk features. Clinical activity, pharmacokinetics, and pharmacodynamics were assessed. Results: 7 pts were treated with AT-101 at doses of 20–40mg daily. Pt characteristics: median age 55, median Rai stage II, elevated ZAP-70 (57%), high CD38 (71%), unmutated IgVH (57%), trisomy 12 (43%), and loss of 17p (43%). AT-101 was well tolerated with no grade 4 toxicities, hospitalizations, deaths. Maximum toxicity in 6 evaluable pts was grade III transaminase elevation at week 7, with complete resolution following discontinuation of AT-101. Other most common adverse events, all Grade 1–2 include: elevated transaminases; nausea; fatigue; diarrhea; and hypokalemia. No hematologic toxicity was observed. 5/6 pts had decrease in lymphocyte count, 6/6 had reduction in lymphadenopathy, and 5/5 with palpable spleens had reduction in spleen size. Cmax for 30mg (n=3) and 40mg (n=2) dose of AT-101 was 570ng/ml and 660ng/ml at a Tmax of 4.3 and 4.4 hrs. Tmax correlated with in vivo apoptosis studies revealing maximum leukemic cell apoptosis occurring at 4hrs and poly(ADP-ribose) polymerase cleavage. Conclusions: AT-101 is safe and well tolerated, induces in vivo leukemia cell apoptosis, and may have clinical activity in previously untreated pts with CLL and high risk features. No significant financial relationships to disclose.

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“…The isomer AT-101 proved to be even more active and capable of overcoming stroma-mediated Mcl-1 induction and apoptosis prevention [52]. Phase I/ II trials of AT-101 in CLL have indicated only limited single-agent therapeutic efficacy [36,53]. Several gossypol derivatives (acting predominantly through BH3 mimicry) are currently in preclinical studies [48]; these include apogossypolone (ApoG2) which was recently reported to induce apoptosis in CLL cells [54].…”

AT‐101 downregulates BCL2 and MCL1 and potentiates the cytotoxic effects of lenalidomide and dexamethasone in preclinical models of multiple myeloma and Waldenström macroglobulinaemia

“…This shift restores the intrinsic apoptotic pathways thereby disarming the tumour cells' survival mechanism (Wang et al , ; Kitada et al , ; Zhang et al , ). Among blood cancers, AT‐101 has been investigated in lymphoma and CLL (James et al , ; Castro et al , ; Kingsley et al , ) and, in the latter, has produced anti‐leukaemic effects with a favourable toxicity profile in patients (James et al , ). However, a limited number of clinical responses in these malignancies restricted its development as a single agent.…”

Phase I/II Study of AT-101 with Topotecan in Relapsed and Refractory Small Cell Lung Cancer

“…Because other concurrently conducted studies showed that total doses of AT-101 of 60 mg/d were associated with dose-limiting elevation in liver enzymes, the dose of AT-101 was not increased further. 15 Therefore, if 40 mg was tolerated, it was planned to be the maximum tolerated dose of AT-101 in combination with topotecan 1.25 mg/m 2 . One dose deescalation of AT-101 to 30 mg/d was allowed, based on AT-101 tolerability.…”