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Pharmacology: Pharmacodynamics: Mechanism of action: Capivasertib is a potent, selective inhibitor of the kinase activity of all 3 isoforms of serine/threonine kinase AKT (AKT1, AKT2 and AKT3). AKT is a pivotal node in the phosphatidylinositol 3-kinase (PI3K) signalling cascade regulating multiple cellular processes including cellular survival, proliferation, cell cycle, metabolism, gene transcription and cell migration. AKT activation in tumours is a result of upstream activation from other signalling pathways, mutations of AKT, loss of Phosphatase and Tensin Homolog (PTEN) function and mutations in the catalytic subunit of PI3K (PIK3CA).
Capivasertib inhibits the phosphorylation of downstream AKT substrates such as glycogen synthase kinase 3-β (GSK3β) and proline-rich AKT substrate of 40 kilodaltons (PRAS40). Capivasertib reduces growth of a range of cell lines derived from solid tumours and haematological disease. Multiple breast cancer cell lines were sensitive to capivasertib monotherapy. Within cell lines showing greater sensitivity to capivasertib there was an enrichment of PIK3CA or AKT1 mutations, or loss of PTEN. Some cell lines lacking such mutations were also sensitive to capivasertib.
In vivo, monotherapy capivasertib inhibits growth of human cancer xenograft models representative of different tumour types including estrogen receptor positive (ER+) and triple negative breast cancer models with PIK3CA, AKT1 mutations, PTEN loss and HER2 amplification. Combined treatment with capivasertib and fulvestrant demonstrated a greater anti-tumour response in a range of human breast cancer PDX models representative of different breast cancer subsets. This included models without detectable mutations or alterations in PIK3CA, PTEN or AKT, as well as models with mutations or alterations in PIK3CA, PTEN or AKT.
Cardiac Electrophysiology: Based on an exposure-response analysis of data from 180 patients with advanced solid malignancies who received capivasertib doses from 80 to 800 mg, the predicted QTcF prolongation was 3.87 ms at the mean steady state Cmax following 400 mg twice daily. No clinically relevant effect of capivasertib on QT prolongation associated with pro-arrhythmic effect was observed at the recommended dose of 400 mg twice daily.
Clinical efficacy: The efficacy of TRUQAP with fulvestrant was evaluated in CAPItello-291 (NCT04305496), a randomized, double-blind, placebo-controlled, multicenter trial that enrolled 708 adult patients with locally advanced (inoperable) or metastatic HR-positive, HER2-negative (defined as IHC 0 or 1+, or IHC 2+/ISH-) breast cancer of which 289 patients had tumors with eligible PIK3CA/AKT1/PTEN-alterations. Eligible PIK3CA/AKT1 activating mutations or PTEN loss of function alterations were identified in the majority of FFPE tumor specimens using FoundationOne CDx next-generation sequencing (n=686). All patients were required to have progression on an aromatase inhibitor (AI) based treatment in the metastatic setting or recurrence on or within 12 months of completing (neo)adjuvant treatment with an AI. Patients could have received up to two prior lines of endocrine therapy and up to 1 line of chemotherapy for locally advanced (inoperable) or metastatic disease. Patients were excluded if they had clinically significant abnormalities of glucose metabolism (defined as patients with diabetes mellitus Type 1, Type 2, requiring insulin treatment, or HbA1c ≥8% (63.9 mmol/mol)).
Patients were randomized (1:1) to receive either 400 mg of TRUQAP (n=355) or placebo (n=353), given orally twice daily for 4 days followed by 3 days off treatment each week of 28-day treatment cycle. Fulvestrant 500 mg intramuscular injection was administered on cycle 1 days 1 and 15, and then at day 1 of each subsequent 28-day cycle. Patients were treated until disease progression, or unacceptable toxicity. Randomization was stratified by presence of liver metastases (yes vs. no), prior treatment with CDK4/6 inhibitors (yes vs. no) and geographical region (region 1: US, Canada, Western Europe, Australia, and Israel vs region 2: Latin America, Eastern Europe and Russia vs Region 3: Asia).
The major efficacy outcomes were investigator-assessed progression-free survival (PFS) in the overall population, and in the population of patients whose tumors have PIK3CA/AKT1/PTEN-alterations evaluated according to Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1. Additional efficacy outcome measures were overall survival (OS), investigator assessed objective response rate (ORR) and duration of response (DoR).
A statistically significant difference in PFS was observed in the overall population and the population of patients whose tumors have PIK3CA/AKT1/PTEN-alteration. An exploratory analysis of PFS in the 313 (44%) patients whose tumors did not have a PIK3CA/AKT1/PTEN-alteration showed a HR of 0.79 (95% CI:0.61, 1.02), indicating that the difference in the overall population was primarily attributed to the results seen in the population of patients whose tumors have PIK3CA/AKT1/PTEN-alteration.
Of the 289 patients whose tumors were PIK3CA/AKT1/PTEN-altered, the median age was 59 years (range 34 to 90); female (99%); White (52%), Asian (29%), Black (1%), American Indian/Alaska Native (0.7%), other races (17%) and 9% were Hispanic/Latino. Eastern Cooperative Oncology Group (ECOG) performance status was 0 (66%) or 1 (34%), and 18% were premenopausal or perimenopausal. Seventy-six percent of patients had an alteration in PIK3CA, 13% had an alteration in AKT1, and 17% had an alteration in PTEN. All patients received prior endocrine-based therapy (100% AI based treatment and 44% received tamoxifen). Seventy-one percent of patients were previously treated with a CDK4/6 inhibitor and 18% received prior chemotherapy for locally advanced (inoperable) or metastatic disease.
Efficacy results for PIK3CA/AKT1/PTEN-altered subgroup are presented in Table 1 and figure. Results from the blinded independent review committee (BICR) assessment were consistent with the investigator assessed PFS results. Overall survival results were immature at the time of the PFS analysis (30% of the patients died). (See Table 1 and figure.)
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Click on icon to see table/diagram/imagePharmacokinetics: Capivasertib pharmacokinetics have been characterized in healthy subjects and patients with solid tumours. The systemic exposure (AUC and Cmax) increased approximately proportionally to the dose over the 80 to 800 mg dose range when given to patients. Following intermittent dosing of capivasertib 400 mg twice daily, 4 days on, 3 days off, steady-state levels are predicted to be attained on every 3rd and 4th dosing day each week, starting from week 2. During the off-dosing days, the plasma concentrations are low (approximately 0.5% to 15% of the steady state Cmax).
Absorption: Capivasertib is rapidly absorbed with peak concentration (Cmax) observed at approximately 1-2 hours in patients. The mean absolute bioavailability is 29%.
Food Effect: When capivasertib was administered after a high-fat, high-calorie meal (approximately 1000 kcal), the fed to fasted ratio was 1.32 and 1.23, for AUC and Cmax, respectively, compared to when given after an overnight fast. When capivasertib was administered after a low-fat, low-calorie (approximately 400 kcal), the exposure was similar to that after fasted administration with fed to fasted ratios of 1.14 and 1.21, for AUC and Cmax, respectively. Co-administration with food did not result in clinically relevant changes to the exposure.
Distribution: The mean volume of distribution (Vss) was 205 L after intravenous administration to healthy subjects. Capivasertib is not extensively bound to plasma protein (percentage unbound 22%) and the plasma to blood ratio is 0.71.
Elimination: The effective half-life after multiple dosing in patients was 8.3 hours. The mean total plasma clearance was 38 L/h after a single intravenous administration to healthy subjects. The mean total oral plasma clearance was 60 L/h after single oral administration and decreased by 8% after repeated dosing of 400 mg twice daily.
Following single oral dose of 400 mg, the mean total recovery of radioactive dose was 45% from urine and 50% from faeces. Renal clearance was 21% of total clearance. Capivasertib is primarily eliminated by metabolism.
Biotransformation: Capivasertib is primarily metabolised by CYP3A4 and UGT2B7 enzymes. The major metabolite in human plasma was an ether glucuronide that accounted for 83% of total drug-related material. A minor oxidative metabolite was quantified at 2% and capivasertib accounted for 15% of total circulating drug-related material. No active metabolites have been identified.
Special populations: Effect of race, age, gender and weight: There were no clinically significant differences in pharmacokinetics of capivasertib based on race/ethnicity (including White and Asian patients), gender or age. There was a statistically significant correlation of apparent oral clearance of capivasertib to body weight. Compared to a patient with a body weight of 66 kg, a 47 kg patient is predicted to have 12% higher AUC. There is no basis for dose modification based on body weight as the predicted effect on capivasertib exposure was small.
Renal impairment: Based on population pharmacokinetic analyses, AUC and Cmax were 1% higher in patients with mild renal impairment (creatinine clearance 60 to 89 mL/min), compared to patients with normal renal function. AUC and Cmax were 16% higher in patients with moderate renal impairment (creatinine clearance 30 to 59 mL/min), compared to patients with normal renal function.
There is no data in severe renal impairment or end-stage renal disease (creatinine clearance <30 ml/min).
Hepatic impairment: Based on population pharmacokinetic analyses, AUC and Cmax were 5% higher in patients with mild hepatic impairment (bilirubin ≤ ULN and AST > ULN, or bilirubin >1 ULN to ≤1.5 ULN), compared to patients with normal hepatic function. No dose adjustment is required for patients with mild hepatic impairment.
Based on limited data the AUC and Cmax was 17% and 13% higher respectively in patients with moderate hepatic impairment (bilirubin >1.5 ULN to ≤3 ULN), compared to patients with normal hepatic function. There is limited data in patients with moderate hepatic impairment and no data in severe hepatic impairment.
Drug-Drug Interaction: Effects of Other Medicinal Products on capivasertib: In vitro studies have demonstrated that capivasertib is primarily metabolised by CYP3A4 and UGT2B7 enzymes.
In a study in healthy subjects, co-administration of multiple 200 mg doses of the strong CYP3A4 inhibitor itraconazole with a single 80 mg capivasertib dose increased capivasertib AUC and Cmax by 95% and 70%, respectively, relative to a single 80 mg capivasertib dose given alone. At the therapeutic dose regimen, the predicted increase in capivasertib AUC and Cmax by itraconazole is between 52% and 56%, and between 30% and 35%, respectively, over a dosing cycle.
In a study in patients with prostate cancer, the strong CYP3A4 inducer enzalutamide decreased the capivasertib AUC by approximately 40% to 50% and rifampicin is predicted to decrease capivasertib AUC by approximately 70%.
Co-administration of a single dose of capivasertib 400 mg after repeated dosing of acid-reducing agent rabeprazole 20 mg twice daily for 3 days in healthy subjects did not result in clinically relevant changes of the capivasertib exposure. The capivasertib AUC and Cmax decreased by 6% and 27% respectively when administered with and without rabeprazole. In addition, a population pharmacokinetic analysis showed no significant impact of co-administration of acid reducing agents on the pharmacokinetics of capivasertib in patients. Capivasertib can be taken with acid reducing agents.
Based on physiologically based pharmacokinetic models, the predicted increase in capivasertib AUC by the moderate inhibitors verapamil and erythromycin is approximately 40%, with less impact on Cmax. Co-administration with the UGT2B7 inhibitor probenecid is predicted to cause an increase in capivasertib AUC of 23 to 37% over a dosing cycle.
Effects of capivasertib on Other Medicinal Products: Co-administration of TRUQAP at the recommended dose with midazolam (CYP3A substrate), increased the AUC of midazolam by 15% on the 3rd off-dosing day and by 77% on the 4th on-dosing day of capivasertib which shows that capivasertib is a weak CYP3A inhibitor.
Capivasertib inhibited CYP2C9, CYP2D6, CYP3A4 and UGT1A1 metabolizing enzymes and BCRP, OATP1B1, OATP1B3, OAT3, OCT2, MATE1 and MATE2K drug transporters in in vitro studies.
Based on in vitro data and physiologically based modelling, capivasertib was predicted to have no effect on the AUC of CYP2C9, CYP2D6 or UGT1A1 substrates, atorvastatin or rosuvastatin. No meaningful interaction was predicted for metformin (2% to 40% AUC increase, depending on the capivasertib dosing day).
Toxicology: Preclinical safety data: Non-clinical/Repeat-dose toxicity: The major target organs or systems for toxicity were insulin signalling (increased levels of glucose and insulin in rats and dogs), the male reproductive organs (tubular degeneration in in rats and dogs), and the renal system in rats (polyuria, decreased tubular epithelial cell size, decreased kidney size and weight). The findings present following 1 month of dosing were largely reversible within 1 month of cessation of dosing. Findings occurred at plasma concentrations lower or similar to those in humans (approximately 0.14 to 2 times) at the recommended dose of 400 mg twice daily (based on total AUC).
Mutagenicity and carcinogenicity: Capivasertib showed no mutagenic or genotoxic potential in vitro. When dosed orally to rats, capivasertib induced micronuclei in the bone marrow via an aneugenic mode of action.
Carcinogenicity studies have not been conducted with capivasertib.
Reproductive toxicity: Embryofetal/Developmental toxicity: In a rat embryo-fetal study, capivasertib caused an increase in post implantation loss, an increase in early embryonic deaths, together with reduced gravid uterine and fetal weights, and minor fetal visceral variations. These effects were seen at a dose level of 150 mg/kg/day which caused maternal toxicity, and where plasma concentrations were approximately 0.8 times the exposure in humans at the recommended dose of 400 mg twice daily (based on total AUC). When capivasertib was administered to pregnant rats at 150 mg/kg/day throughout gestation and through early lactation, there was a reduction in litter and pup weights.
Exposure to capivasertib was confirmed in suckling pups which may indicate the potential for excretion of capivasertib in human milk.
Fertility: Capivasertib had no effect on fertility in male rats. Effects on female fertility have not been studied in animals.
