gdc-0068 and Neoplasms

To examine the single- and multiple-dose pharmacokinetics (PK), CYP3A inhibition potential of ipatasertib, and effect of food on PK of ipatasertib in patients with refractory solid tumors and a dedicated food effect assessment in healthy subjects.. The Phase I dose-escalation study enrolled patients with solid tumors in a standard 3 + 3 design with a 1 week washout after the first dose, followed by once-daily dosing on a 3-week-on/1-week-off schedule. In the expansion cohort, the effect of ipatasertib on CYP3A substrate (midazolam) was assessed by examining the change in midazolam exposure when dosed in the absence and presence of steady-state ipatasertib at 600 mg. The effect of food on ipatasertib PK was studied with ipatasertib administered in fed or fasted state (6 patients from Phase I patient study and 18 healthy subjects from the dedicated food effect study).. Ipatasertib was generally well tolerated at doses up to 600 mg given daily for 21 days. Ipatasertib showed rapid absorption (t. Ipatasertib exhibited rapid absorption and was dose-proportional over a broad dose range. Ipatasertib appeared to be a moderate CYP3A inhibitor when administered at 600 mg and could be administered with or without food in clinical studies.. NCT01090960 (registered March 23, 2010); NCT02536391 (registered August 31, 2015).

Topics: Administration, Oral; Antineoplastic Agents; Case-Control Studies; Cytochrome P-450 CYP3A; Cytochrome P-450 CYP3A Inhibitors; Eating; Female; Follow-Up Studies; Food-Drug Interactions; Healthy Volunteers; Humans; Male; Neoplasms; Piperazines; Prognosis; Pyrimidines; Tissue Distribution

This Phase Ib study explored combination dosing of the allosteric MEK1/2 inhibitor cobimetinib and the ATP-competitive pan-AKT inhibitor ipatasertib.. Patients with advanced solid tumors were enrolled to two dose escalation arms, each using a 3 + 3 design in 28-day cycles. In Arm A, patients received concurrent cobimetinib and ipatasertib on days 1-21. In Arm B, cobimetinib was administered intermittently with ipatasertib for 21 days. Primary objectives evaluated dose-limiting toxicities (DLTs), maximum tolerated doses (MTD), and the recommended Phase II dose (RP2D). Secondary objectives included analysis of pharmacokinetic parameters, MAPK and PI3K pathway alterations, changes in tissue biomarkers, and preliminary anti-tumor efficacy. Expansion cohorts included patients with PTEN-deficient triple-negative breast cancer and endometrial cancer.. Among 66 patients who received ≥1 dose of study drug, all experienced an adverse event (AE). Although no DLTs were reported, 6 patients experienced Cycle 1 DLT-equivalent AEs. The most common treatment-related AEs were diarrhea, nausea, vomiting, dermatitis acneiform, and fatigue. Thirty-five (53%) patients experienced drug-related AEs of ≥ grade 3 severity. Cobimetinb/ipatasertib MTDs were 60/200 mg on Arm A and 150/300 mg on Arm B; the latter was chosen as the RP2D. No pharmacokinetic interactions were identified. Biomarker analyses indicated pathway blockade and increases in IFNγ and PD-L1 gene expression following the combination. Three patients with endometrial or ovarian cancer achieved partial response, all with PTEN-low disease and two with tumor also harboring KRAS mutation.. There was limited tolerability and efficacy for this MEK and AKT inhibitor combination. Nonetheless, pharmacodynamic analyses indicated target engagement and suggest rationale for further exploration of cobimetinib or ipatasertib in combination with other anticancer agents. ClinicalTrials.gov identifier: NCT01562275.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Azetidines; Dose-Response Relationship, Drug; Female; Humans; Male; Maximum Tolerated Dose; Middle Aged; Mitogen-Activated Protein Kinases; Neoplasms; Phosphatidylinositol 3-Kinases; Piperazines; Piperidines; Pyrimidines

Ipatasertib is a selective AKT kinase inhibitor currently in development for the treatment of several solid tumors, including breast and prostate cancers. This study was undertaken to characterize pharmacokinetic profiles of ipatasertib and its metabolite M1 (G-037720) and to understand the sources of variability. Population pharmacokinetic models of ipatasertib and M1 were developed separately using data from 342 individuals with cancer from 5 phase 1 and 2 studies. The final population pharmacokinetic models for ipatasertib and M1 were 3-compartmental, with first-order elimination and sequential zero- and first-order absorption. Ipatasertib bioavailability and M1 formation increased after multiple dosing, resulting in an increase in exposure beyond that expected from accumulation alone. Covariate effects of ipatasertib include decreased oral clearance with increasing age and with coadministration of abiraterone, as well as decreased bioavailability with increasing weight. For ages 37 and 80 years, steady-state area under the curve (AUC

Topics: Adult; Age Factors; Aged; Aged, 80 and over; Androstenes; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Area Under Curve; Dose-Response Relationship, Drug; Female; Humans; Male; Middle Aged; Models, Biological; Neoplasm Metastasis; Neoplasms; Paclitaxel; Piperazines; Prednisolone; Pyrimidines

This phase Ib study evaluated the safety, tolerability, pharmacokinetics, and preliminary efficacy of the oral AKT inhibitor ipatasertib and chemotherapy or hormonal therapy in patients with advanced or metastatic solid tumors to determine combined dose-limiting toxicities (DLTs), maximum tolerated dose, and recommended phase II doses and schedules.. The clinical study comprised four combination treatment arms: arm A (with docetaxel), arm B [with mFOLFOX6 (modified leucovorin, 5-fluorouracil, and oxaliplatin)], arm C (with paclitaxel), and arm D (with enzalutamide). Primary endpoints were safety and tolerability; secondary endpoints were pharmacokinetics, clinical activity per Response Evaluation Criteria in Solid Tumors v1.1, and prostate-specific antigen levels.. In total, 122 patients were enrolled. Common adverse events were diarrhea, nausea, vomiting, decreased appetite, and fatigue. The safety profiles of the combination regimens were consistent with those of the background regimens, except for diarrhea, hyperglycemia, and rash, which were previously observed with ipatasertib treatment. The only combination DLT across all treatment arms was one event of grade 3 dehydration (ipatasertib 600 mg and paclitaxel). Recommended phase II doses for ipatasertib were 600 mg (and mFOLFOX6) and 400 mg (and paclitaxel), respectively. The maximum assessed dose of ipatasertib 600 mg combined with docetaxel or enzalutamide was well tolerated. Coadministration with enzalutamide (a cytochrome P450 3A inducer) resulted in approximately 50% lower ipatasertib exposure.. Ipatasertib in combination with chemotherapy or hormonal therapy was well tolerated with a safety profile consistent with that of ATP-competitive AKT inhibitors.. NCT01362374.

Topics: Antineoplastic Combined Chemotherapy Protocols; Humans; Male; Maximum Tolerated Dose; Neoplasms; Piperazines; Pyrimidines

Activation of AKT signaling by PTEN loss or PIK3CA mutations occurs frequently in human cancers, but targeting AKT has been difficult due to the mechanism-based toxicities of inhibitors that target the inactive conformation of AKT. Ipatasertib (GDC-0068) is a novel selective ATP-competitive small-molecule inhibitor of AKT that preferentially targets active phosphorylated AKT (pAKT) and is potent in cell lines with evidence of AKT activation. In this phase I study, ipatasertib was well tolerated; most adverse events were gastrointestinal and grade 1-2 in severity. The exposures of ipatasertib ≥200 mg daily in patients correlated with preclinical TGI. Potent inhibition of AKT signaling with ipatasertib was associated with a tolerable safety profile and meaningful disease control in a subgroup of patients. Targeting pAKT with an ATP-competitive inhibitor provides a greater therapeutic window than allosteric inhibitors. Further investigation with ipatasertib is ongoing in phase II studies. Cancer Discov; 7(1); 102-13. ©2016 AACR.This article is highlighted in the In This Issue feature, p. 1.

Topics: Administration, Oral; Adult; Aged; Cell Line, Tumor; Drug Administration Schedule; Female; Humans; Male; Middle Aged; Neoplasms; Piperazines; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Pyrimidines; Xenograft Model Antitumor Assays

Rash is one of the primary dose-limiting toxicities of Akt (protein kinase B) inhibitors in clinical trials. Here, we demonstrate the inhibition of Akt2 isozyme may be a driver for keratinocyte apoptosis, which promotes us to search for new selective Akt inhibitors with an improved cutaneous safety property. According to our previous research, compound

Topics: Animals; Benzamides; Cell Line, Tumor; Cell Proliferation; Dogs; Exanthema; Female; HEK293 Cells; Humans; Keratinocytes; Male; Mice, Inbred BALB C; Mice, Nude; Molecular Docking Simulation; Molecular Dynamics Simulation; Molecular Structure; Neoplasms; Protein Binding; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Pyrazoles; Rats, Sprague-Dawley; Structure-Activity Relationship

Ipatasertib is a potent small molecule Akt kinase inhibitor currently being tested in Phase III clinical trials for the treatment of metastatic castration-resistant prostate cancer and triple negative metastatic breast cancer. In this paper an overview of the development achievements towards the commercial manufacturing process is given. The convergent synthesis consists of ten steps with eight isolated intermediates and utilizes a wide range of chemical techniques and technologies to build-up this complex drug. All three stereocenters are introduced using enzyme or metal catalysis.

Topics: Antineoplastic Combined Chemotherapy Protocols; Humans; Male; Neoplasms; Piperazines; Pyrimidines

We describe the preclinical pharmacology and antitumor activity of GDC-0068, a novel highly selective ATP-competitive pan-Akt inhibitor currently in clinical trials for the treatment of human cancers.. The effect of GDC-0068 on Akt signaling was characterized using specific biomarkers of the Akt pathway, and response to GDC-0068 was evaluated in human cancer cell lines and xenograft models with various genetic backgrounds, either as a single agent or in combination with chemotherapeutic agents.. GDC-0068 blocked Akt signaling both in cultured human cancer cell lines and in tumor xenograft models as evidenced by dose-dependent decrease in phosphorylation of downstream targets. Inhibition of Akt activity by GDC-0068 resulted in blockade of cell-cycle progression and reduced viability of cancer cell lines. Markers of Akt activation, including high-basal phospho-Akt levels, PTEN loss, and PIK3CA kinase domain mutations, correlate with sensitivity to GDC-0068. Isogenic PTEN knockout also sensitized MCF10A cells to GDC-0068. In multiple tumor xenograft models, oral administration of GDC-0068 resulted in antitumor activity ranging from tumor growth delay to regression. Consistent with the role of Akt in a survival pathway, GDC-0068 also enhanced antitumor activity of classic chemotherapeutic agents.. GDC-0068 is a highly selective, orally bioavailable Akt kinase inhibitor that shows pharmacodynamic inhibition of Akt signaling and robust antitumor activity in human cancer cells in vitro and in vivo. Our preclinical data provide a strong mechanistic rationale to evaluate GDC-0068 in cancers with activated Akt signaling.

Topics: Animals; Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Cell Proliferation; Disease Models, Animal; Enzyme Activation; Female; Humans; Male; Mice; Neoplasms; Piperazines; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Pyrimidines; Signal Transduction; Xenograft Model Antitumor Assays