Enhanced treatment regimens using pi3k Alpha inhibitors
An alpha inhibitor and scheme technology, applied in the directions of medical preparations, pharmaceutical formulations, and drug combinations containing active ingredients, can solve the problem that estrogen receptor antagonists are not particularly effective, and achieve improved therapeutic efficacy and good therapeutic efficacy. Effect
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Embodiment 1
[0350] Example 1. Antitumor Activity of Compound A in Breast Cancer Model
[0351] Objective of the study: To determine the in vivo antitumor activity of Compound A in MDA-MB-361 human breast cancer xenografts at various doses and schedules following oral (PO) administration in female nude mice.
[0352] Compound A was prepared according to the methods disclosed in WO2011 / 022439 and WO2013 / 071272, and stored at about 25°C in the dark. The control used in this study was 100% PEG400.
[0353] MDA-MB-361 cells of low passage were cultured in Dulbecco's modified Eagle's medium (DMEM) supplemented with 20% fetal bovine serum (FBS) and 1X penicillin / streptomycin (Invitrogen [Carlsbad, CA, USA]). ) medium until reaching approximately 80% confluency. Before injection, cells were detached with trypsin (Invitrogen), washed twice with phosphate-buffered saline (PBS), and resuspended in RPMI (Roswell Park Memorial Institute) medium (Invitrogen) without supplements. Cells were resuspe...
Embodiment 2
[0356] Example 2. Clinical research using compound A as a single agent
[0357] Initiate a Phase 1 clinical study to evaluate safety, tolerability, PK, pharmacodynamics; determine the maximum tolerated dose (MTD) in each of the 3 schedules described below; and evaluate patients with advanced solid Antitumor activity in patients with malignant disease.
[0358] suitability
[0359] Eligible age for research: 18 years or older
[0360] Suitable gender for study: both
[0361] Accept healthy volunteers: No
[0362] standard
[0363] standard constrain
[0364] ■ Subjects have been assessed for PIK3CA gene mutation status prior to enrollment in this study
[0365] ■The subject's disease progression must have been documented prior to enrollment into the study
[0366] ■Locally advanced or metastatic solid tumors other than in situ brain tumors for which standard of care therapy has failed or is not amenable to standard of care therapy.
[0367] ■Age ≥ 18 years old, incl...
Embodiment 3
[0396] Example 3. Antitumor activity of compound A in combination with fulvestrant in human breast cancer xenograft T47-D sex
[0397] Objective of this study: To determine the antitumor activity of Compound A administered on an intermittent schedule in combination with fulvestrant in T47D (PIK3CA mutant, ER / PR+) human breast cancer xenografts.
[0398] Compound A was prepared according to the methods disclosed in WO2011 / 022439 and WO2013 / 071272, and was formulated in 100% PEG400, and stored at about 25°C in the dark. The control used in this study was 100% PEG400 + 0.9% saline. Fulvestrant was formulated in 0.9% saline.
[0399]Low passage T47-D cells were grown in RPMI1640 medium supplemented with 10% fetal bovine serum (FBS). Before injection, cells were detached with trypsin (Invitrogen), washed twice with phosphate-buffered saline (PBS), and resuspended in RPMI (Roswell Park Memorial Institute) medium (Invitrogen) without supplements. Resuspend cells to 10.0 x 10 i...
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