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1.
Ann Oncol ; 2024 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-38729567

RESUMO

BACKGROUND: SERENA-1 (NCT03616587) is a phase I, multi-part, open-label study of camizestrant in pre- and post-menopausal women with estrogen receptor-positive (ER+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer. Parts A and B aim to determine the safety and tolerability of camizestrant monotherapy and define doses for clinical evaluation. PATIENTS AND METHODS: Women aged ≥18 years with metastatic or recurrent ER+, HER2- breast cancer, refractory (or intolerant) to therapy, were assigned 25 mg up to 450 mg once daily (QD; escalation) or 75, 150, or 300 mg QD (expansion). Safety and tolerability, antitumor efficacy, pharmacokinetics, and impact on mutations in the estrogen receptor gene (ESR1m) circulating tumor (ct)DNA levels were assessed. RESULTS: By 9 March 2021, 108 patients received camizestrant monotherapy at 25-450 mg doses. Of these, 93 (86.1%) experienced treatment-related adverse events (TRAEs), 82.4% of which were grade 1 or 2. The most common TRAEs were visual effects (56%), (sinus) bradycardia (44%), fatigue (26%), and nausea (15%). There were no TRAEs grade 3 or higher, or treatment-related serious adverse events at doses ≤150 mg. Median tmax was achieved ∼2-4 h post-dose at all doses investigated, with an estimated half-life of 20-23 h. Efficacy was observed at all doses investigated, including in patients with prior cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) and/or fulvestrant treatment, with and without baseline ESR1 mutations, and with visceral disease, including liver metastases. CONCLUSIONS: Camizestrant is a next-generation oral selective ER antagonist and degrader (SERD) and pure ER antagonist with a tolerable safety profile. The pharmacokinetics profile supports once-daily dosing, with evidence of pharmacodynamic and clinical efficacy in heavily pre-treated patients, regardless of ESR1m. This study established 75-, 150-, and 300-mg QD doses for phase II testing (SERENA-2, NCT04214288 and SERENA-3, NCT04588298).

3.
Nat Commun ; 13(1): 3246, 2022 06 10.
Artigo em Inglês | MEDLINE | ID: mdl-35688802

RESUMO

We conducted a phase IIa, multi-centre, open label, single arm study (RADICAL; NCT01791985) of AZD4547 (a potent and selective inhibitor of Fibroblast Growth Factor Receptor (FGFR)-1, 2 and 3 receptor tyrosine kinases) administered with anastrozole or letrozole in estrogen receptor positive metastatic breast cancer patients who had become resistant to aromatase inhibitors. After a safety run-in study to assess safety and tolerability, we recruited 52 patients. The primary endpoint was change in tumour size at 12 weeks, and secondary endpoints were to assess response at 6 weeks, 20 weeks and every 8 weeks thereafter and tolerability of the combined treatment. Two partial responses (PR) and 19 stable disease (SD) patients were observed at the 12-week time point. At 28 weeks, according to centrally reviewed Response Evaluation Criteria in Solid Tumours (RECIST) criteria, five PR and 8 SD patients were observed in 50 assessable cases. Overall, objective response rate (5 PR) was of 10%, meeting the pre-specified endpoint. Fourteen patients discontinued due to adverse events. Eleven patients had retinal pigment epithelial detachments which was asymptomatic and reversible in all but one patient. Exploratory ribonucleic acid sequencing (RNA-Seq) analysis was done on patients' samples: 6 differentially-expressed-genes could distinguish those who benefited from the addition of AZD4547.


Assuntos
Benzamidas , Neoplasias da Mama , Piperazinas , Pirazóis , Antineoplásicos/efeitos adversos , Benzamidas/efeitos adversos , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Feminino , Humanos , Piperazinas/efeitos adversos , Pirazóis/efeitos adversos , Resultado do Tratamento
4.
Eur J Cancer ; 103: 17-23, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30196106

RESUMO

BACKGROUND: Dose-escalation of epertinib (S-222611), a new potent oral EGFR/HER2 inhibitor, has established a recommended daily dose of 800 mg in patients with solid tumours. In this study, we have recruited a larger number of patients to assess further the safety, tolerability, pharmacokinetics (PKs) and antitumour activity. PATIENTS AND METHODS: Patients with solid tumours expressing EGFR or HER2 received a single dose of epertinib at 800 mg on Day 1 to assess PK over 7 days, followed by continuous once-daily dosing from Day 8. RESULTS: We treated 76 patients with breast (n = 27), upper gastrointestinal (GI; n = 30), head and neck (n = 12) or renal cancers (n = 7). Epertinib was well-tolerated with mostly grade I and II adverse events (AEs). The most frequent AE was diarrhoea, which was generally manageable with loperamide. The objective response rate (ORR) in patients with heavily pretreated breast and upper GI cancers was 16.0% (4 PRs) and 8.3% (1CR, 1PR), respectively. All six responding patients had HER2-positive tumours; the ORR for HER2-positive breast and upper GI cancer populations was 19.0% and 20.0%. Partial response in the brain disease of one breast cancer patient lasted 7.5 months. CONCLUSION: Once-daily dosing of epertinib at 800 mg was well-tolerated and demonstrated promising antitumour activity in patients with heavily pretreated HER2-positive breast and upper GI cancer, including those with brain metastases. EUDRACT NUMBER: 2009-017817-31.


Assuntos
Neoplasias/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Quinazolinas/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/patologia , Inibidores de Proteínas Quinases/farmacologia , Quinazolinas/farmacologia , Resultado do Tratamento
6.
Eur J Gynaecol Oncol ; 33(2): 211-3, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22611966

RESUMO

OBJECTIVE: While gynaecological cancer patients who participate in Phase I clinical trials are not routinely considered for elective surgery because of a short life expectancy, this should not be overlooked in carefully selected responding patients. METHODS/RESULTS: We describe two cases of patients with different gynaecological cancers, who received treatment within separate phase I trials, and who then proceeded to surgical resection of their cancers, resulting in complete remission. CONCLUSION: Surgery, when feasible, should be taken into consideration as a potential management option, even when patients are receiving treatment within a phase I trial.


Assuntos
Adenocarcinoma Papilar/tratamento farmacológico , Carcinoma de Células Escamosas/tratamento farmacológico , Ensaios Clínicos Fase I como Assunto , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Pulmonares/cirurgia , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Pélvicas/cirurgia , Neoplasias do Colo do Útero/tratamento farmacológico , Adenocarcinoma Papilar/secundário , Adulto , Afatinib , Idoso , Anticorpos Monoclonais Humanizados/administração & dosagem , Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bevacizumab , Carcinoma de Células Escamosas/secundário , Feminino , Humanos , Neoplasias Hepáticas/secundário , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/secundário , Excisão de Linfonodo , Metástase Linfática , Neoplasias Ovarianas/patologia , Paclitaxel/administração & dosagem , Neoplasias Pélvicas/secundário , Ftalazinas/uso terapêutico , Piperazinas/uso terapêutico , Quinazolinas/administração & dosagem , Neoplasias do Colo do Útero/patologia
7.
Eur J Cancer ; 39(17): 2450-61, 2003 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-14602131

RESUMO

Clinical drug resistance is a major barrier to overcome before chemotherapy can become curative for most patients presenting with metastatic cancer. Rational attempts to tackle clinical drug resistance need to be based on an understanding of the mechanisms involved; these are likely to be complex and multifactorial, and may be due to inadequate drug exposure or alterations in the cancer cell itself. This article reviews a number of strategies used to tackle drug resistance, focussing on work in our institution related to the treatment of ovarian cancer and resistance to platinum and taxane-based chemotherapy. Further progress towards drug resistance reversal will require a three-pronged approach, namely: the development of novel cytotoxics which exploit selectively expressed targets; modulation of resistance to conventional agents and, most importantly, a serious attempt to understand resistance mechanisms in tumour samples taken both pre- and post-chemotherapy.


Assuntos
Antineoplásicos/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Neoplasias Ovarianas/tratamento farmacológico , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Pareamento Incorreto de Bases , Carboplatina/química , Carboplatina/uso terapêutico , Linhagem Celular Tumoral , Dano ao DNA/efeitos dos fármacos , Reparo do DNA/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Humanos , Repetições de Microssatélites , Mutação/genética , Paclitaxel/química , Paclitaxel/uso terapêutico , Compostos de Platina/química , Compostos de Platina/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Tubulina (Proteína)/genética
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