RESUMO
OBJECTIVE: This trial compared the efficacy/safety of two IV doses of AZD9773, a polyclonal antibody to tumor necrosis factor-α, in adult patients with severe sepsis/septic shock. DESIGN: Multicenter, randomized, double-blind, placebo-controlled phase IIb trial. SETTING: ICUs in seven countries (Australia, Belgium, Canada, Czech Republic, Finland, France, and Spain). PATIENTS: Patients 18 years old or older with severe sepsis and/or septic shock. Patients were required to have 1) objective clinical evidence of infection; 2) at least two of four systemic inflammatory response syndrome criteria; and 3) cardiovascular and/or respiratory sepsis-related failure. INTERVENTIONS: Patients were randomized 1:1:1 to a single loading infusion of AZD9773 250 U/kg followed by 50 U/kg every 12 hours (low dose, n = 100), a single loading infusion of AZD9773 500 U/kg followed by 100 U/kg every 12 hours (high dose, n = 100), or placebo (n = 100) for 5 days. Follow-up assessments were performed up to day 90. MEASUREMENTS AND MAIN RESULTS: Mean number of ventilator-free days (primary endpoint) did not differ between low-dose (19.7 d) or high-dose AZD9773 (17.3 d) and placebo (18.3 d) (one-sided p = 0.18 and 0.74, respectively). Mortality rates were comparable across treatment groups; relative risk of death versus placebo at day 29 was 0.80 for low-dose AZD9773 (one-sided p = 0.25) and 1.64 for high-dose AZD9773 (p = 0.97). Most patients experienced at least one treatment-emergent adverse event (87.8% in AZD9773-treated patients, 92.9% in placebo patients) although most were mild/moderate in nature. No differences in the incidence of adverse events or laboratory or vital sign abnormalities were observed between groups. CONCLUSIONS: AZD9773 rapidly and efficiently decreased plasma tumor necrosis factor-α concentration in patients with severe sepsis/septic shock, but this effect did not translate into clinical benefit.
Assuntos
Fragmentos Fab das Imunoglobulinas/administração & dosagem , Sepse/tratamento farmacológico , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Adulto , Idoso , Intervalos de Confiança , Relação Dose-Resposta a Droga , Método Duplo-Cego , Esquema de Medicação , Estudos de Avaliação como Assunto , Feminino , Seguimentos , Humanos , Infusões Intravenosas , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Medição de Risco , Sepse/diagnóstico , Sepse/mortalidade , Choque Séptico/diagnóstico , Choque Séptico/tratamento farmacológico , Choque Séptico/mortalidade , Estatísticas não Paramétricas , Taxa de Sobrevida , Resultado do Tratamento , Fator de Necrose Tumoral alfa/administração & dosagemRESUMO
Comparisons of duration of response (DoR) and duration of clinical benefit (DoCB) within clinical trials are prone to biases. To address these biases, we used new methodology to prospectively analyze expected DoR and expected DoCB. Objective response rate and clinical benefit rate were calculated for fulvestrant 500 and 250 mg, and used to calculate expected DoR and expected DoCB for each dose group. The ratios for expected DoR and expected DoCB (expected DoR500/expected DoR250 and expected DoCB500/expected DoCB250) were then calculated, thereby allowing statistical comparisons of these endpoints between each arm of the COmparisoN of Faslodex In Recurrent or Metastatic breast cancer (CONFIRM) trial. Expected DoRs for fulvestrant 500 and 250 mg were 3.2 and 3.6 months, respectively. The expected DoR ratio between fulvestrant 500 and 250 mg was not statistically significant (0.89; 95 % CI, 0.48-1.67, P = 0.724). The expected DoCBs for fulvestrant 500 and 250 mg were 9.8 and 7.2 months, respectively. The expected DoCB ratio showed that the expected DoCB for fulvestrant 500 mg was significantly improved compared with the expected DoCB for fulvestrant 250 mg (1.36; 95 % CI, 1.07-1.73, P = 0.013). Analysis of the expected DoR and expected DoCB showed fulvestrant 500 mg significantly increased expected DoCB compared with fulvestrant 250 mg in the CONFIRM trial.
Assuntos
Antineoplásicos Hormonais/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Estradiol/análogos & derivados , Antineoplásicos Hormonais/administração & dosagem , Estradiol/administração & dosagem , Estradiol/uso terapêutico , Feminino , Fulvestranto , Humanos , Fatores de Tempo , Resultado do TratamentoRESUMO
Oral selective estrogen receptor degraders (SERD) could become the backbone of endocrine therapy (ET) for estrogen receptor-positive (ER+) breast cancer, as they achieve greater inhibition of ER-driven cancers than current ETs and overcome key resistance mechanisms. In this study, we evaluated the preclinical pharmacology and efficacy of the next-generation oral SERD camizestrant (AZD9833) and assessed ER-co-targeting strategies by combining camizestrant with CDK4/6 inhibitors (CDK4/6i) and PI3K/AKT/mTOR-targeted therapy in models of progression on CDK4/6i and/or ET. Camizestrant demonstrated robust and selective ER degradation, modulated ER-regulated gene expression, and induced complete ER antagonism and significant antiproliferation activity in ESR1 wild-type (ESR1wt) and mutant (ESR1m) breast cancer cell lines and patient-derived xenograft (PDX) models. Camizestrant also delivered strong antitumor activity in fulvestrant-resistant ESR1wt and ESR1m PDX models. Evaluation of camizestrant in combination with CDK4/6i (palbociclib or abemaciclib) in CDK4/6-naive and -resistant models, as well as in combination with PI3Kαi (alpelisib), mTORi (everolimus), or AKTi (capivasertib), indicated that camizestrant was active with CDK4/6i or PI3K/AKT/mTORi and that antitumor activity was further increased by the triple combination. The response was observed independently of PI3K pathway mutation status. Overall, camizestrant shows strong and broad antitumor activity in ER+ breast cancer as a monotherapy and when combined with CDK4/6i and PI3K/AKT/mTORi. SIGNIFICANCE: Camizestrant, a next-generation oral SERD, shows promise in preclinical models of ER+ breast cancer alone and in combination with CDK4/6 and PI3K/AKT/mTOR inhibitors to address endocrine resistance, a current barrier to treatment.
Assuntos
Neoplasias da Mama , Humanos , Feminino , Neoplasias da Mama/patologia , Receptores de Estrogênio/metabolismo , Proteínas Proto-Oncogênicas c-akt , Fosfatidilinositol 3-Quinases/metabolismo , Antagonistas de Estrogênios , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Quinase 4 Dependente de Ciclina , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêuticoRESUMO
Fulvestrant fIRst-line Study comparing endocrine Treatments is a phase II, randomized, open-label study comparing fulvestrant 500 mg with anastrozole 1 mg as first-line endocrine therapy for postmenopausal women with hormone receptor-positive (HR+) advanced breast cancer. At data cut-off, only 36 % of patients had progressed and the median time to progression (TTP) had not been reached for fulvestrant. Here, we report follow-up data for TTP for fulvestrant 500 mg versus anastrozole 1 mg. Key inclusion criteria were postmenopausal women with estrogen receptor-positive and/or progesterone receptor-positive locally advanced or metastatic breast cancer and no prior endocrine therapy. Key exclusion criteria were presence of life-threatening metastases and prior treatment with a non-approved drug. Fulvestrant was administered 500 mg/month plus 500 mg on day 14 of month 1; anastrozole was administered 1 mg/day. TTP was defined by modified Response Evaluation Criteria in Solid Tumors v1.0 before data cut-off for the primary analysis, and investigator opinion after data cut-off. Best overall response to subsequent therapy and serious adverse events are also reported. In total, 205 patients received fulvestrant 500 mg (n = 102) or anastrozole (n = 103). Follow-up analysis was performed when 79.5 % of patients had discontinued study treatment. Median TTP was 23.4 months for fulvestrant versus 13.1 months for anastrozole; a 34 % reduction in risk of progression (hazard ratio 0.66; 95 % confidence interval: 0.47, 0.92; P = 0.01). Best overall response to subsequent therapy and clinical benefit rate for subsequent endocrine therapy was similar between the treatment groups. No new safety concerns for fulvestrant 500 mg were documented. These longer-term, follow-up results confirm efficacy benefit for fulvestrant 500 mg versus anastrozole as first-line endocrine therapy for HR+ advanced breast cancer in terms of TTP, and, importantly, show similar best overall response rates to subsequent endocrine therapy.
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Antineoplásicos Hormonais/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Estradiol/análogos & derivados , Nitrilas/administração & dosagem , Triazóis/administração & dosagem , Anastrozol , Antineoplásicos Hormonais/efeitos adversos , Estradiol/administração & dosagem , Estradiol/efeitos adversos , Feminino , Seguimentos , Fulvestranto , Humanos , Estadiamento de Neoplasias , Nitrilas/efeitos adversos , Resultado do Tratamento , Triazóis/efeitos adversosRESUMO
Nearly all estrogen receptor (ER)-positive (POS) metastatic breast cancers become refractory to endocrine (ET) and other therapies, leading to lethal disease presumably due to evolving genomic alterations. Timely monitoring of the molecular events associated with response/progression by serial tissue biopsies is logistically difficult. Use of liquid biopsies, including circulating tumor cells (CTC) and circulating tumor DNA (ctDNA), might provide highly informative, yet easily obtainable, evidence for better precision oncology care. Although ctDNA profiling has been well investigated, the CTC precision oncology genomic landscape and the advantages it may offer over ctDNA in ER-POS breast cancer remain largely unexplored. Whole-blood (WB) specimens were collected at serial time points from patients with advanced ER-POS/HER2-negative (NEG) advanced breast cancer in a phase I trial of AZD9496, an oral selective ER degrader (SERD) ET. Individual CTC were isolated from WB using tandem CellSearch® /DEPArray™ technologies and genomically profiled by targeted single-cell DNA next-generation sequencing (scNGS). High-quality CTC (n = 123) from 12 patients profiled by scNGS showed 100% concordance with ctDNA detection of driver estrogen receptor α (ESR1) mutations. We developed a novel CTC-based framework for precision medicine actionability reporting (MI-CTCseq) that incorporates novel features, such as clonal predominance and zygosity of targetable alterations, both unambiguously identifiable in CTC compared to ctDNA. Thus, we nominated opportunities for targeted therapies in 73% of patients, directed at alterations in phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA), fibroblast growth factor receptor 2 (FGFR2), and KIT proto-oncogene, receptor tyrosine kinase (KIT). Intrapatient, inter-CTC genomic heterogeneity was observed, at times between time points, in subclonal alterations. Our analysis suggests that serial monitoring of the CTC genome is feasible and should enable real-time tracking of tumor evolution during progression, permitting more combination precision medicine interventions.
Assuntos
Neoplasias da Mama , DNA Tumoral Circulante , Células Neoplásicas Circulantes , Biomarcadores Tumorais/genética , Neoplasias da Mama/patologia , DNA Tumoral Circulante/genética , Antagonistas de Estrogênios , Estudos de Viabilidade , Feminino , Genômica , Humanos , Mutação/genética , Células Neoplásicas Circulantes/patologia , Medicina de PrecisãoRESUMO
Five to ten percent of ER+ metastatic breast cancer (MBC) tumors harbor somatic PTEN mutations. Loss of function of this tumor-suppressor gene defines a highly aggressive, treatment-refractory disease for which new therapies are urgently needed. This Phase I multipart expansion study assessed oral capivasertib with fulvestrant in patients with PTEN-mutant ER+ MBC. Safety and tolerability were assessed by standard methods. Plasma and tumor were collected for NGS and immunohistochemistry analyses of PTEN protein expression. In 31 eligible patients (12 fulvestrant naive; 19 fulvestrant pretreated), the 24-week clinical benefit rate was 17% in fulvestrant-naive and 42% in fulvestrant-pretreated patients, with objective response rate of 8% and 21%, respectively. Non-functional PTEN was centrally confirmed in all cases by NGS or immunohistochemistry. Co-mutations occurred in PIK3CA (32%), with less ESR1 (10% vs 72%) and more TP53 (40% vs 28%) alterations in fulvestrant-naive versus fulvestrant-pretreated patients, respectively. PTEN was clonally dominant in most patients. Treatment-related grade ≥3 adverse events occurred in 32% of patients, most frequently diarrhea and maculopapular rash (both n = 2). In this clinical study, which selectively targeted the aggressive PTEN-mutant ER+ MBC, capivasertib plus fulvestrant was tolerable and clinically active. Phenotypic and genomic differences were apparent between fulvestrant-naive and -pretreated patients.Trial registration number for the study is NCT01226316.
RESUMO
The Faslodex Investigation of Dose evaluation in Estrogen Receptor-positive advanced breast cancer (FINDER)2 study evaluated the efficacy, safety, and pharmacokinetics (PK) of three fulvestrant dosing regimens. FINDER2 enrolled Western postmenopausal women recurring or progressing after prior endocrine therapy. Primary endpoint: objective response rate (ORR); secondary endpoints: time to progression (TTP), clinical benefit rate (CBR), tolerability, and PK parameters. Patients were randomized to receive fulvestrant: 250 mg/month (approved dose [AD]); 250 mg plus loading dose (loading dose [LD]; 500 mg on day 0, 250 mg on days 14, 28, and monthly thereafter); or 500 mg (high dose [HD]; 500 mg/month plus 500 mg on day 14 of Month 1). Treatment continued until disease progression or discontinuation. 144 patients were randomized: fulvestrant AD (n = 47); LD (n = 51); HD (n = 46). ORRs were: 8.5% (95% confidence interval [CI]: 2.4, 20.4%), 5.9% (1.2, 16.2%), and 15.2% (6.3, 28.9%) in the AD, LD, and HD arms, respectively. CBRs were: 31.9% (95% CI: 19.1, 47.1%), 47.1% (32.9, 61.5%), and 47.8% (32.9, 63.1%) for the AD, LD, and HD arms, respectively. Median TTP (months) was numerically longer for HD (6.0) and LD (6.1) versus AD (3.1). Tolerability was similar across dosing regimens. Steady-state plasma fulvestrant concentrations were predictable and achieved earlier with LD and HD. While there appeared to be a trend toward improved efficacy with HD and LD versus AD, no significant differences could be shown. A parallel study (FINDER1) has reported similar findings in Japanese patients.
Assuntos
Neoplasias da Mama/tratamento farmacológico , Estradiol/análogos & derivados , Antagonistas de Estrogênios/administração & dosagem , Receptores de Estrogênio/efeitos dos fármacos , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/química , Neoplasias da Mama/patologia , Canadá , Progressão da Doença , Método Duplo-Cego , Estradiol/administração & dosagem , Estradiol/efeitos adversos , Estradiol/farmacocinética , Antagonistas de Estrogênios/efeitos adversos , Antagonistas de Estrogênios/farmacocinética , Europa (Continente) , Feminino , Fulvestranto , Humanos , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Pós-Menopausa , Receptores de Estrogênio/análise , Fatores de Tempo , Resultado do TratamentoRESUMO
PURPOSE: The activating mutation AKT1 E17K occurs in approximately 7% of estrogen receptor-positive (ER+) metastatic breast cancer (MBC). We report, from a multipart, first-in-human, phase I study (NCT01226316), tolerability and activity of capivasertib, an oral AKT inhibitor, as monotherapy or combined with fulvestrant in expansion cohorts of patients with AKT1 E17K-mutant ER+ MBC. PATIENTS AND METHODS: Patients with an AKT1 E17K mutation, detected by local (next-generation sequencing) or central (plasma-based BEAMing) testing, received capivasertib 480 mg twice daily, 4 days on, 3 days off, weekly or 400 mg twice daily combined with fulvestrant at the labeled dose. Study endpoints included safety, objective response rate (ORR; RECIST v1.1), progression-free survival (PFS), and clinical benefit rate at 24 weeks (CBR24). Biomarker analyses were conducted in the combination cohort. RESULTS: From October 2013 to August 2018, 63 heavily pretreated patients received capivasertib (20 monotherapy, 43 combination). ORR was 20% with monotherapy, and within the combination cohort was 36% in fulvestrant-pretreated and 20% in fulvestrant-naïve patients, although the latter group may have had more aggressive disease at baseline. AKT1 E17K mutations were detectable in plasma by BEAMing (95%, 41/43), droplet digital PCR (80%, 33/41), and next-generation sequencing (76%, 31/41). A ≥50% decrease in AKT1 E17K at cycle 2 day 1 was associated with improved PFS. Combination therapy appeared more tolerable than monotherapy [most frequent grade ≥3 adverse events: rash (9% vs. 20%), hyperglycemia (5% vs. 30%), diarrhea (5% vs. 10%)]. CONCLUSIONS: Capivasertib demonstrated clinically meaningful activity in heavily pretreated patients with AKT1 E17K-mutant ER+ MBC, including those with prior disease progression on fulvestrant. Tolerability and activity appeared improved by the combination.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias da Mama/terapia , Fulvestranto/administração & dosagem , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Pirimidinas/administração & dosagem , Pirróis/administração & dosagem , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Mama/patologia , Mama/cirurgia , Neoplasias da Mama/genética , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Quimioterapia Adjuvante/efeitos adversos , Quimioterapia Adjuvante/métodos , Feminino , Fulvestranto/efeitos adversos , Humanos , Mastectomia , Pessoa de Meia-Idade , Mutação , Intervalo Livre de Progressão , Proteínas Proto-Oncogênicas c-akt/genética , Pirimidinas/efeitos adversos , Pirróis/efeitos adversos , Receptores de Estrogênio/análise , Receptores de Estrogênio/metabolismo , Critérios de Avaliação de Resposta em Tumores SólidosRESUMO
PURPOSE: Fulvestrant, the first-in-class selective estrogen receptor (ER) degrader (SERD), is clinically effective in patients with ER+ breast cancer, but it has administration and pharmacokinetic limitations. Pharmacodynamic data suggest complete ER degradation is not achieved at fulvestrant's clinically feasible dose. This presurgical study (NCT03236974) compared the pharmacodynamic effects of fulvestrant with AZD9496, a novel, orally bioavailable, nonsteroidal, potent SERD, in treatment-naïve patients with ER+ HER2- primary breast cancer awaiting curative intent surgery. PATIENTS AND METHODS: Patients were randomized 1:1 to receive AZD9496 250 mg twice daily from day 1 for 5-14 days, or fulvestrant 500 mg on day 1. On-treatment imaging-guided core tumor biopsies were taken between day 5 and 14 and compared with pretreatment diagnostic biopsies. The primary objective was to compare the effects of AZD9496 and fulvestrant on ER expression. Secondary objectives included changes in progesterone receptor (PR) and Ki-67 pharmacokinetic/pharmacodynamic relationships and safety. RESULTS: Forty-six women received treatment (AZD9496 n = 22; fulvestrant n = 24); 35 paired biopsies were evaluable (AZD9496 n = 15; fulvestrant n = 20). The least square mean estimate for ER H-score reduction was 24% after AZD9496 versus 36% after fulvestrant treatment (P = 0.86). AZD9496 also reduced PR H-scores (-33.3%) and Ki-67 levels (-39.9%) from baseline, but was also not superior to fulvestrant (PR: -68.7%, P = 0.97; Ki-67: -75.4%, P = 0.98). No new safety findings were identified. CONCLUSIONS: This was the first presurgical study to demonstrate that an oral SERD affects its key biological targets. However, AZD9496 was not superior to fulvestrant at the dose tested.
Assuntos
Neoplasias da Mama/tratamento farmacológico , Cinamatos/administração & dosagem , Receptor alfa de Estrogênio/genética , Fulvestranto/administração & dosagem , Indóis/administração & dosagem , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Cinamatos/efeitos adversos , Estradiol/genética , Feminino , Fulvestranto/efeitos adversos , Humanos , Indóis/efeitos adversos , Pessoa de Meia-Idade , Receptor ErbB-2/genética , Receptores de Progesterona/genéticaRESUMO
PURPOSE: The STAKT study examined short-term exposure (4.5 days) to the oral selective pan-AKT inhibitor capivasertib (AZD5363) to determine if this drug can reach its therapeutic target in sufficient concentration to significantly modulate key biomarkers of the AKT pathway and tumor proliferation. PATIENTS AND METHODS: STAKT was a two-stage, double-blind, randomized, placebo-controlled, "window-of-opportunity" study in patients with newly diagnosed ER+ invasive breast cancer. Stage 1 assessed capivasertib 480 mg b.i.d. (recommended monotherapy dose) and placebo, and stage 2 assessed capivasertib 360 and 240 mg b.i.d. Primary endpoints were changes from baseline in AKT pathway markers pPRAS40, pGSK3ß, and proliferation protein Ki67. Pharmacologic and pharmacodynamic properties were analyzed from blood sampling, and tolerability by adverse-event monitoring. RESULTS: After 4.5 days' exposure, capivasertib 480 mg b.i.d. (n = 17) produced significant decreases from baseline versus placebo (n = 11) in pGSK3ß (H-score absolute change: -55.3, P = 0.006) and pPRAS40 (-83.8, P < 0.0001), and a decrease in Ki67 (absolute change in percentage positive nuclei: -9.6%, P = 0.031). Significant changes also occurred in secondary signaling biomarker pS6 (-42.3, P = 0.004), while pAKT (and nuclear FOXO3a) also increased in accordance with capivasertib's mechanism (pAKT: 81.3, P = 0.005). At doses of 360 mg b.i.d. (n = 5) and 240 mg b.i.d. (n = 6), changes in primary and secondary biomarkers were also observed, albeit of smaller magnitude. Biomarker modulation was dose and concentration dependent, and no new safety signals were evident. CONCLUSIONS: Capivasertib 480 mg b.i.d. rapidly modulates key biomarkers of the AKT pathway and decreases proliferation marker Ki67, suggesting future potential as an effective therapy in AKT-dependent breast cancers.
Assuntos
Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/tratamento farmacológico , Receptor alfa de Estrogênio/metabolismo , Antígeno Ki-67/metabolismo , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Pirimidinas/farmacocinética , Pirimidinas/uso terapêutico , Pirróis/farmacocinética , Pirróis/uso terapêutico , Neoplasias da Mama/patologia , Proliferação de Células , Método Duplo-Cego , Feminino , Humanos , Pessoa de Meia-Idade , Inibidores de Proteínas Quinases/farmacocinética , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Distribuição Tecidual , Resultado do TratamentoRESUMO
Preclinical studies have demonstrated synergy between PARP and PI3K/AKT pathway inhibitors in BRCA1 and BRCA2 (BRCA1/2)-deficient and BRCA1/2-proficient tumors. We conducted an investigator-initiated phase I trial utilizing a prospective intrapatient dose- escalation design to assess two schedules of capivasertib (AKT inhibitor) with olaparib (PARP inhibitor) in 64 patients with advanced solid tumors. Dose expansions enrolled germline BRCA1/2-mutant tumors, or BRCA1/2 wild-type cancers harboring somatic DNA damage response (DDR) or PI3K-AKT pathway alterations. The combination was well tolerated. Recommended phase II doses for the two schedules were: olaparib 300 mg twice a day with either capivasertib 400 mg twice a day 4 days on, 3 days off, or capivasertib 640 mg twice a day 2 days on, 5 days off. Pharmacokinetics were dose proportional. Pharmacodynamic studies confirmed phosphorylated (p) GSK3ß suppression, increased pERK, and decreased BRCA1 expression. Twenty-five (44.6%) of 56 evaluable patients achieved clinical benefit (RECIST complete response/partial response or stable disease ≥ 4 months), including patients with tumors harboring germline BRCA1/2 mutations and BRCA1/2 wild-type cancers with or without DDR and PI3K-AKT pathway alterations. SIGNIFICANCE: In the first trial to combine PARP and AKT inhibitors, a prospective intrapatient dose- escalation design demonstrated safety, tolerability, and pharmacokinetic-pharmacodynamic activity and assessed predictive biomarkers of response/resistance. Antitumor activity was observed in patients harboring tumors with germline BRCA1/2 mutations and BRCA1/2 wild-type cancers with or without somatic DDR and/or PI3K-AKT pathway alterations.This article is highlighted in the In This Issue feature, p. 1426.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Proteína BRCA1/metabolismo , Proteína BRCA2/metabolismo , Ftalazinas/uso terapêutico , Piperazinas/uso terapêutico , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Pirimidinas/uso terapêutico , Pirróis/uso terapêutico , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Feminino , Humanos , Pessoa de Meia-Idade , Ftalazinas/farmacologia , Piperazinas/farmacologia , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Pirimidinas/farmacologia , Pirróis/farmacologiaRESUMO
Purpose: AZD9496 is an oral nonsteroidal, small-molecule inhibitor of estrogen receptor alpha (ERα) and a potent and selective antagonist and degrader of ERα. This first-in-human phase I study determined the safety and tolerability of ascending doses of oral AZD9496 in women with estrogen receptor (ER)+/HER2- advanced breast cancer, characterized its pharmacokinetic (PK) profile, and made preliminary assessment of antitumor activity.Patients and Methods: Forty-five patients received AZD9496 [20 mg once daily (QD) to 600 mg twice daily (BID)] in a dose-escalation, dose-expansion "rolling 6" design. Safety, tolerability, and PK activity in each cohort were reviewed before escalating to the next dose. PK was determined by mass spectrometry. Adverse events (AEs) were graded according to the Common Terminology Criteria for Adverse Events (CTCAE) v4.0. Objective tumor response was evaluated by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1.Results: Most common causally related AEs were diarrhea (35.6%), fatigue (31.1%), and nausea (22.2%), and seven patients had grade ≥3 AEs. Three patients experienced a dose-limiting toxicity: one each at 150 mg BID (abnormal hepatic function), 400 mg BID (diarrhea and elevated liver function tests), and 600 mg BID (diarrhea), and all were reversible. The maximum tolerated dose was not reached. Partial response was confirmed in one patient, who also had decreased tumor marker Ca15.3. Four patients had stable disease at 12 months' follow-up.Conclusions: AZD9496 is well tolerated with an acceptable safety profile, showing evidence of prolonged disease stabilization in heavily pretreated patients with ER+/HER2- advanced breast cancer. Clin Cancer Res; 24(15); 3510-8. ©2018 AACRSee related commentary by Jordan, p. 3480.
Assuntos
Neoplasias da Mama/tratamento farmacológico , Cinamatos/administração & dosagem , Indóis/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Neoplasias da Mama/sangue , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Cinamatos/efeitos adversos , Relação Dose-Resposta a Droga , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/classificação , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Receptor alfa de Estrogênio/genética , Feminino , Humanos , Indóis/efeitos adversos , Dose Máxima Tolerável , Pessoa de Meia-Idade , Náusea/induzido quimicamente , Náusea/patologia , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Receptor ErbB-2/genética , Moduladores Seletivos de Receptor Estrogênico/administração & dosagem , Moduladores Seletivos de Receptor Estrogênico/efeitos adversosRESUMO
PURPOSE: AZD5363 is a potent pan-AKT inhibitor originally formulated as a capsule; a tablet was developed for patient convenience and manufacturing ease. This study assessed the PK comparability of both formulations (Part A) and the effect of food (Part B) on the PK/safety of the tablet. METHODS: Adults with advanced solid tumours received AZD5363 480 mg bid in a partially fasted state by tablet (Week 1) and capsule (Week 2) in a '4-days-on/3-days-off' schedule (Part A). PK parameters were evaluated using pre-defined 90% CIs for AUCτ and Cmax ratios of 0.75-1.33 to assess comparability. In Part B, AZD5363 tablet was given to a new cohort of patients under the same conditions as Part A, except on the morning of PK assessment days, when it was administered after an overnight fast (Week 1) and standard meal (Week 2). RESULTS: In evaluable patients (N = 11), the geometric least-squares mean ratios (tablet:capsule) for AUCτ and Cmax were 0.90 (0.77-1.06) and 1.02 (0.86-1.20), respectively, demonstrating comparable PK in the partially fasted state. Tablet and capsule safety data were also comparable. Tablet PK profiles indicated later tmax and lower Cmax after food versus overnight fast. Fed and fasted AUCτ and Cmax ratios were 0.89 (0.76-1.05) and 0.67 (0.55-0.82), respectively (N = 9). The safety/tolerability profile of the tablet was comparable between fed and fasted states. CONCLUSIONS: PK and safety/tolerability of AZD5363 tablet and capsule were comparable. Food did not affect the bioavailability of AZD5363, but reduced the absorption rate without discernibly affecting safety/tolerability.
Assuntos
Antineoplásicos/farmacocinética , Interações Alimento-Droga , Neoplasias/tratamento farmacológico , Pirimidinas/farmacocinética , Pirróis/farmacocinética , Adulto , Idoso , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Disponibilidade Biológica , Cápsulas , Estudos Cross-Over , Jejum , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pirimidinas/administração & dosagem , Pirimidinas/efeitos adversos , Pirróis/administração & dosagem , Pirróis/efeitos adversos , ComprimidosRESUMO
PURPOSE: Common resistance mechanisms to endocrine therapy (ET) in estrogen receptor (ER)-positive metastatic breast cancers include, among others, ER loss and acquired activating mutations in the ligand-binding domain of the ER gene (ESR1LBDm). ESR1 mutational mediated resistance may be overcome by selective ER degraders (SERD). During the first-in-human study of oral SERD AZD9496, early changes in circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA) were explored as potential noninvasive tools, alongside paired tumor biopsies, to assess pharmacodynamics and early efficacy. EXPERIMENTAL DESIGN: CTC were enumerated/phenotyped for ER and Ki67 using CellSearch in serial blood draws. ctDNA was assessed for the most common ESR1LBDm by droplet digital PCR (BioRad). RESULTS: Before starting AZD9496, 11 of 43 (25%) patients had ≥5 CTC/7.5 mL whole blood (WB), none of whom underwent reduction to <5 CTC/7.5 mL WB on C1D15. Five of 11 patients had baseline CTC-ER+, two of whom had CTC-ER+ reduction. CTC-Ki67 status did not change appreciably. Patients with ≥5 CTC/7.5 mL WB before treatment had worse progression-free survival (PFS) than patients with <5 CTC (P = 0.0003). Fourteen of 45 (31%) patients had ESR1LBDm + ctDNA at baseline, five of whom had ≥2 unique mutations. Baseline ESR1LBDm status was not prognostic. Patients with persistently elevated CTC and/or ESR1LBDm + ctDNA at C1D15 had worse PFS than patients who did not (P = 0.0007). CONCLUSIONS: Elevated CTC at baseline was a strong prognostic factor in this cohort. Early on-treatment changes were observed in CTC-ER+ and ESR1LBDm + ctDNA, but not in overall CTC number. Integrating multiple biomarkers in prospective trials may improve outcome prediction and ET resistance mechanisms' identification over a single biomarker.
Assuntos
Antineoplásicos Hormonais/farmacologia , Biomarcadores Tumorais/sangue , Neoplasias da Mama/sangue , Neoplasias da Mama/patologia , Resistencia a Medicamentos Antineoplásicos , Antineoplásicos Hormonais/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , DNA Tumoral Circulante , Antagonistas de Estrogênios/farmacologia , Antagonistas de Estrogênios/uso terapêutico , Receptor alfa de Estrogênio/antagonistas & inibidores , Receptor alfa de Estrogênio/genética , Receptor alfa de Estrogênio/metabolismo , Feminino , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Biópsia Líquida , Mutação , Metástase Neoplásica , Estadiamento de Neoplasias , PrognósticoRESUMO
Purpose: This phase I, open-label study (Study 1, D3610C00001; NCT01226316) was the first-in-human evaluation of oral AZD5363, a selective pan-AKT inhibitor, in patients with advanced solid malignancies. The objectives were to investigate the safety, tolerability, and pharmacokinetics of AZD5363, define a recommended dosing schedule, and evaluate preliminary clinical activity.Experimental Design: Patients were aged ≥18 years with World Health Organization (WHO) performance status of 0 to 1. Dose escalation was conducted within separate continuous and intermittent [4 days/week (4/7) or 2 days/week (2/7)] schedules with safety, pharmacokinetic, and pharmacodynamic analyses. Expansion cohorts of approximately 20 patients each explored AZD5363 activity in PIK3CA-mutant breast and gynecologic cancers.Results: MTDs were 320, 480, and 640 mg for continuous (n = 47), 4/7 (n = 21), and 2/7 (n = 22) schedules, respectively. Dose-limiting toxicities were rash and diarrhea for continuous, hyperglycemia for 2/7, and none for 4/7. Common adverse events were diarrhea (78%) and nausea (49%) and, for Common Terminology Criteria for Adverse Events grade ≥3 events, hyperglycemia (20%). The recommended phase II dose (480 mg bid, 4/7 intermittent) was assessed in PIK3CA-mutant breast and gynecologic expansion cohorts: 46% and 56% of patients, respectively, showed a reduction in tumor size, with RECIST responses of 4% and 8%. These responses were less than the prespecified 20% response rate; therefore, the criteria to stop further recruitment to the PIK3CA-mutant cohort were met.Conclusions: At the recommended phase II dose, AZD5363 was well tolerated and achieved plasma levels and robust target modulation in tumors. Proof-of-concept responses were observed in patients with PIK3CA-mutant cancers treated with AZD5363. Clin Cancer Res; 24(9); 2050-9. ©2017 AACRSee related commentary by Costa and Bosch, p. 2029.
Assuntos
Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Classe I de Fosfatidilinositol 3-Quinases/genética , Neoplasias dos Genitais Femininos/tratamento farmacológico , Neoplasias dos Genitais Femininos/genética , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Pirimidinas/uso terapêutico , Pirróis/uso terapêutico , Adulto , Idoso , Área Sob a Curva , Biomarcadores Tumorais , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Feminino , Neoplasias dos Genitais Femininos/metabolismo , Neoplasias dos Genitais Femininos/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Terapia de Alvo Molecular , Mutação , Metástase Neoplásica , Estadiamento de Neoplasias , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/farmacocinética , Pirimidinas/administração & dosagem , Pirimidinas/efeitos adversos , Pirimidinas/farmacocinética , Pirróis/administração & dosagem , Pirróis/efeitos adversos , Pirróis/farmacocinética , Resultado do TratamentoRESUMO
High-throughput analyses have revealed the presence of activating mutations in the AKT1 gene in a subpopulation of meningiomas. We report a female patient with multiple intracranial tumor manifestations and histologically verified meningotheliomatous meningioma in the lung. The tumor was continuously growing at multiple sites despite six surgical resections, radiotherapy, and two lines of systemic therapy. Following detection of an AKT1E17K mutation in three independent tumor samples by sequencing, treatment with AZD5363, a selective AKT inhibitor, was initiated. Ex vivo cultured meningioma cells exhibited sensitivity to the drug as shown by pAKT accumulation on immunoblots. Treatment with AZD5363 resulted, for the first time, in stable disease and minor radiographic response. The patient has been on that treatment for more than one year with ongoing clinical and radiographic response. This is the first report of an AKT1-mutant meningioma responding to AKT inhibition, suggesting that molecular screening may result in clinical benefit.
Assuntos
Antineoplásicos/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Meníngeas/tratamento farmacológico , Meningioma/tratamento farmacológico , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Pirimidinas/uso terapêutico , Pirróis/uso terapêutico , Adulto , Antineoplásicos/farmacologia , Feminino , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/secundário , Neoplasias Meníngeas/genética , Neoplasias Meníngeas/patologia , Meningioma/genética , Meningioma/secundário , Mutação , Gradação de Tumores , Proteínas Proto-Oncogênicas c-akt/genética , Pirimidinas/farmacologia , Pirróis/farmacologia , Células Tumorais Cultivadas/efeitos dos fármacosRESUMO
Personalized healthcare relies on accurate companion diagnostic assays that enable the most appropriate treatment decision for cancer patients. Extensive assay validation prior to use in a clinical setting is essential for providing a reliable test result. This poses a challenge for low prevalence mutations with limited availability of appropriate clinical samples harboring the mutation. To enable prospective screening for the low prevalence AKT1 E17K mutation, we have developed and validated a competitive allele-specific TaqMan® PCR (castPCR™) assay for mutation detection in formalin-fixed paraffin-embedded (FFPE) tumor tissue. Analysis parameters of the castPCR™ assay were established using an FFPE DNA reference standard and its analytical performance was assessed using 338 breast cancer and gynecological cancer FFPE samples. With recent technical advances for minimally invasive mutation detection in circulating tumor DNA (ctDNA), we subsequently also evaluated the OncoBEAM™ assay to enable plasma specimens as additional diagnostic opportunity for AKT1 E17K mutation testing. The analysis performance of the OncoBEAM™ test was evaluated using a novel AKT1 E17K ctDNA reference standard consisting of sheared genomic DNA spiked into human plasma. Both assays are employed at centralized testing laboratories operating according to quality standards for prospective identification of the AKT1 E17K mutation in ER+ breast cancer patients in the context of a clinical trial evaluating the AKT inhibitor AZD5363 in combination with endocrine (fulvestrant) therapy.
Assuntos
Mutação , Neoplasias/enzimologia , Proteínas Proto-Oncogênicas c-akt/genética , Humanos , Neoplasias/sangue , Neoplasias/genética , Inclusão em Parafina , Reação em Cadeia da Polimerase , Padrões de Referência , Reprodutibilidade dos TestesRESUMO
Purpose AKT1 E17K mutations are oncogenic and occur in many cancers at a low prevalence. We performed a multihistology basket study of AZD5363, an ATP-competitive pan-AKT kinase inhibitor, to determine the preliminary activity of AKT inhibition in AKT-mutant cancers. Patients and Methods Fifty-eight patients with advanced solid tumors were treated. The primary end point was safety; secondary end points were progression-free survival (PFS) and response according to Response Evaluation Criteria in Solid Tumors (RECIST). Tumor biopsies and plasma cell-free DNA (cfDNA) were collected in the majority of patients to identify predictive biomarkers of response. Results In patients with AKT1 E17K-mutant tumors (n = 52) and a median of five lines of prior therapy, the median PFS was 5.5 months (95% CI, 2.9 to 6.9 months), 6.6 months (95% CI, 1.5 to 8.3 months), and 4.2 months (95% CI, 2.1 to 12.8 months) in patients with estrogen receptor-positive breast, gynecologic, and other solid tumors, respectively. In an exploratory biomarker analysis, imbalance of the AKT1 E17K-mutant allele, most frequently caused by copy-neutral loss-of-heterozygosity targeting the wild-type allele, was associated with longer PFS (hazard ratio [HR], 0.41; P = .04), as was the presence of coincident PI3K pathway hotspot mutations (HR, 0.21; P = .045). Persistent declines in AKT1 E17K in cfDNA were associated with improved PFS (HR, 0.18; P = .004) and response ( P = .025). Responses were not restricted to patients with detectable AKT1 E17K in pretreatment cfDNA. The most common grade ≥ 3 adverse events were hyperglycemia (24%), diarrhea (17%), and rash (15.5%). Conclusion This study provides the first clinical data that AKT1 E17K is a therapeutic target in human cancer. The genomic context of the AKT1 E17K mutation further conditioned response to AZD5363.
Assuntos
Antineoplásicos/efeitos adversos , DNA de Neoplasias/sangue , Mutação , Neoplasias/tratamento farmacológico , Neoplasias/genética , Inibidores de Proteínas Quinases/efeitos adversos , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-akt/genética , Pirimidinas/efeitos adversos , Pirróis/efeitos adversos , Adulto , Idoso , Alelos , Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/sangue , Biomarcadores Tumorais/genética , Diarreia/induzido quimicamente , Intervalo Livre de Doença , Toxidermias/etiologia , Exantema/induzido quimicamente , Feminino , Humanos , Hiperglicemia/induzido quimicamente , Perda de Heterozigosidade , Masculino , Pessoa de Meia-Idade , Neoplasias/sangue , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Proteínas Quinases/uso terapêutico , Pirimidinas/uso terapêutico , Pirróis/uso terapêutico , Critérios de Avaliação de Resposta em Tumores Sólidos , Transdução de Sinais/genéticaRESUMO
PURPOSE: Investigate the safety and tolerability of AZD5363 and define a recommended dose for evaluation in Japanese patients with advanced solid malignancies. METHODS: AZD5363 was administered orally as a single dose, and then the dose was escalated to twice daily (bid) in separate continuous (every day) and intermittent (4 days on, 3 days off [4/3] or 2 days on, 5 days off [2/5]) dosing schedules to reach recommended doses defined by dose-limiting toxicity (DLT). Doses for continuous, 4/3, and 2/5 intermittent dosing schedules were 80-400, 360-480, and 640 mg, respectively, and were informed by results from an equivalent study in Caucasian patients. RESULTS: Forty-one patients received AZD5363. DLTs were only experienced with continuous dosing. 97.6 % of patients reported at least one adverse event (AE); most common were diarrhea (78.0 %), hyperglycemia (68.3 %), nausea (56.1 %), and maculopapular rash (56.1 %). Grade ≥3 AEs were reported by 63.4 % of patients. Exposure of AZD5363 was generally dose proportional for both single and multiple doses. Single-dose pharmacokinetics of AZD5363 was generally predictive of multiple-dose pharmacokinetics. Confirmed partial responses were reported by two patients, both of whom were Akt1 (E17K) mutation positive. One patient in the 480 mg bid 4/3 dosing cohort maintained partial response for >2 years. CONCLUSIONS: Intermittent dosing of AZD5363 was more tolerable than continuous dosing. 480 mg bid intermittent 4/3 dosing for AZD5363 monotherapy was selected for further investigation. Preliminary evidence of antitumor activity was observed. Akt1 (E17K) is a potent driver mutation that may predict clinical response to AZD5363.