论文部分内容阅读
Background: GDCE0917 is a small molecule that triggers tumor cell apoptosis by selectively antagonizing IAP proteins.Preclinical studies demonstrated antitumor efficacy of GDC-0917 alone or in combination with chemotherapeutic agents.Methods: Oral GDC-0917 was given on Day(d)1 followed by 2d off and a 2-week(w)on/1w off treatment(tx)schedule(21d cycle)starting d4.A modified continual reassessment method was used for dose escalation.Dose-limiting toxicity(DLT,assessed d1-24),PK,adverse events(AEs),pharmacodynamics(PD),and clinical activity were evaluated.Results: 42 pts of age 36-86(median 60.5)were enrolled in 11 cohorts(5-600 mg)and received 1-15 cycles(median 2)of GDC-0917.One DLT,Grade(G)3 fatigue,was observed at 450 mg.The maximum tolerated dose was not determined although plasma concentrations of preclinically defined IC90 were reached.The most frequent AEs were diarrhea,fatigue and nausea(26.2%each),vomiting(23.8%),and constipation(19%).The most frequent AEs reported as tx-related were mostly G1-2 and included fatigue and nausea(21.4%each),vomiting(14.3%),rash(11.9%)and pruritus(9.5%).AEs reported as tx-related that were ≥ G3 in > 1 pt were elevated AST and ALT(2 pts,at 450 and 600 mg).AEs reported as tx-related that resulted in tx discontinuation were G3 fatigue,G2 QTc prolongation,G2 drug hypersensitivity,G2 pneumonitis(1 pt each),and G3 pruritus/G2 rash(same pt).GDC-0917 peak concentrations were observed 2-3h post dosing.Exposure was dose-proportional with a mean plasma elimination t1/2of 4-8h and no apparent accumulation at steady state.Rapid down-modulation of cIAP1 was observed in PBMCs at all dose levels.Evaluation of tumor biopsies demonstrated decreases in cIAP1(2 pts total,at 40 and 200 mg)and increases in activated caspase-3 and cPARP(1 pt at 200 mg).Two pts(4.8%)had a complete response(both unconfirmed,ovarian Ca and MALT lymphoma [PET]); 4 pts(9.5%)had stable disease for ≥ 3 months.Conclusions: GDC-0917 had a favorable safety,PK and PD profile in pts with advanced malignancies.These encouraging results support further clinical evaluation of this agent.