Extended phase I trial of the oral pan-Bcl-2 inhibitor AT-101 by multiple dosing schedules in patients with advanced cancers
Document Type
Article
Department
Haematology and Oncology, East Africa
Abstract
Background: Over-expression of Bcl-2 family proteins is common in human cancers. Initial trials of the oral pan-Bcl-2 inhibitor AT-101 showed acute dose limiting toxicity of Gr 3–4 AST/ALT (MTD 40 mg/d), and ileus with prolonged dosing daily (QD) for 21/28 days per cycle (Saleh, NCI_EORTC, 2005; James, ASCO, 2006). Our ongoing Phase 1 study tests different dosing schedules of AT-101 in adults with advanced cancers.
Methods: Serial patient (pt) cohorts received AT-101 at escalating doses twice a day for three days every other week (BIDx3dEOW) or once weekly (QW). Adverse events (AEs) were graded by the NCI CTCAE v. 3.0.
Results: 24 pts have received pulse dosing; safety data are available for 20 pts (30–70 mg BIDx3dEOW, N=13; 80–160 mg QW, N=7). For comparison, 38 pts received 5–60 mg QD. Median number of cycles (range): BIDx3dEOW_2(1–9); QW_3(1–3), QD_2(1–12). AST/ALT is not yet dose limiting, nor the MTD reached, at 70 mg BIDx3dEOW or 160 mg QW. Ileus occurred in 4/38 pts dosed daily but in no pts on either pulse schedule. Other potentially related Gr 3–4 AEs were: BIDx3dEOW (6 pts)–AST (1 pt), abdominal pain (2 pts), elevated CK/right ventricular dysfunction (1 pt w/history of COPD/doxil therapy), hypokalemia (1 pt);QW: none; QD: AST/ALT (5 pts), nausea/vomiting/diarrhea (3 pts each) fatigue (2 pts), hypocalcemia (2 pts), hypokalaemia/anorexia/dehydration/hypophosphatemia (1 pt), elevated GGT (1 pt). The most common Gr 1–2 AEs_nausea/vomiting/fatigue_occurred in over 50% of QD and BIDx3dEOW pts but only 1/7 QW pts. Plasma Cmax (mean ± SD, μM): 70 mg BIDx3d EOW, 2.4 ± 0.9; 160 mg QW, 3.5 ± 1.3; 40 mg/d (MTD, 21/28 d), 2.6 ± 2.0. T ½ was approx. 3 hours on all schedules.
Conclusions: Pulse dosing of AT-101 appears associated with reduced toxicity than more continuous daily dosing, and may be preferable in combination regimens.
Publication (Name of Journal)
Journal of Clinical Oncology
DOI
https://doi.org/10.1200/jco.2007.25.18_suppl.3583
Recommended Citation
Pitot, H.,
Saleh, M.,
Holmlund, J.,
Maleski, J.,
Forero, A.
(2007). Extended phase I trial of the oral pan-Bcl-2 inhibitor AT-101 by multiple dosing schedules in patients with advanced cancers. Journal of Clinical Oncology, 25(18).
Available at:
https://ecommons.aku.edu/eastafrica_fhs_mc_haematol_oncol/24
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 International License.
Comments
This work was published before the author joined Aga Khan University.