European journal of cancer (Oxford, England : 1990) · 2017
PIKHER2: A phase IB study evaluating buparlisib in combination with lapatinib in trastuzumab-resistant HER2-positive advanced breast cancer.
Клиническое исследование I фазыСтатьяМногоцентровое исследованиеНазвание и аннотация: Перевод пока не подготовлен
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Guerin Mathilde, Rezai Keyvan, Isambert Nicolas, Campone Mario, Autret Aurélie, Pakradouni Jihane, Provansal Magali, Camerlo Jacques, Sabatier Renaud, Bertucci François, Charafe-Jauffret Emmanuelle, Hervieu Alice, Extra Jean-Marc, Viens Patrice, Lokiec François, Boher Jean-Marie, Gonçalves Anthony
Аннотация
BACKGROUND: Phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin pathway is frequently activated in HER2-positive breast cancer and may play a major role in resistance to trastuzumab. Buparlisib is a pan-class-I PI3K inhibitor with potent and selective activity against wild-type and mutant PI3K p110 isoforms.
PATIENTS AND METHODS: PIKHER2 phase IB study aimed primarily to determine a maximum tolerated dose (MTD) and propose a recommended phase II dose (RP2D) for buparlisib in combination with lapatinib in HER2-positive, trastuzumab-resistant, advanced breast cancer. Oral buparlisib (40, 60 or 80 mg) and lapatinib (750, 1000 or 1250 mg) were administered daily. A modified continuous reassessment method using an adaptive Bayesian model guided the dose escalation of both agents. Secondary end-points included antitumour activity and pharmacokinetic (PK) assessments.
RESULTS: A total of 24 patients were treated across five dose levels. Dose-limiting toxicities included transaminases elevation, vomiting, stomatitis, hyperglycemia and diarrhoea. MTD was declared at buparlisib 80 mg/d + lapatinib 1250 mg/d, but toxicities and early treatment discontinuation rate beyond cycle 1 led to select buparlisib 80 mg + lapatinib 1000 mg/d as the RP2D. Main drug-related adverse events included diarrhoea, nausea, skin rash, asthenia, depression, anxiety and transaminases increase. There was no significant evidence for drug-drug PK interaction. Disease control rate was 79% [95% confidence interval [CI] 57-92%], one patient obtained a complete remission, and six additional patients experienced stable disease for ≥ 24 weeks (clinical benefit rate of 29% [95% CI 12-51%]).
CONCLUSION: Combining buparlisib and lapatinib in HER2-positive trastuzumab-resistant advanced breast cancer was feasible. Preliminary evidence of antitumour activity was observed in this heavily pre-treated population.
TRIAL REGISTRATION ID: NCT01589861.
PATIENTS AND METHODS: PIKHER2 phase IB study aimed primarily to determine a maximum tolerated dose (MTD) and propose a recommended phase II dose (RP2D) for buparlisib in combination with lapatinib in HER2-positive, trastuzumab-resistant, advanced breast cancer. Oral buparlisib (40, 60 or 80 mg) and lapatinib (750, 1000 or 1250 mg) were administered daily. A modified continuous reassessment method using an adaptive Bayesian model guided the dose escalation of both agents. Secondary end-points included antitumour activity and pharmacokinetic (PK) assessments.
RESULTS: A total of 24 patients were treated across five dose levels. Dose-limiting toxicities included transaminases elevation, vomiting, stomatitis, hyperglycemia and diarrhoea. MTD was declared at buparlisib 80 mg/d + lapatinib 1250 mg/d, but toxicities and early treatment discontinuation rate beyond cycle 1 led to select buparlisib 80 mg + lapatinib 1000 mg/d as the RP2D. Main drug-related adverse events included diarrhoea, nausea, skin rash, asthenia, depression, anxiety and transaminases increase. There was no significant evidence for drug-drug PK interaction. Disease control rate was 79% [95% confidence interval [CI] 57-92%], one patient obtained a complete remission, and six additional patients experienced stable disease for ≥ 24 weeks (clinical benefit rate of 29% [95% CI 12-51%]).
CONCLUSION: Combining buparlisib and lapatinib in HER2-positive trastuzumab-resistant advanced breast cancer was feasible. Preliminary evidence of antitumour activity was observed in this heavily pre-treated population.
TRIAL REGISTRATION ID: NCT01589861.
Предметные рубрики MeSH
Administration, OralAdultAgedAminopyridinesAntineoplastic Agents, ImmunologicalAntineoplastic Combined Chemotherapy ProtocolsBreast NeoplasmsDrug Administration ScheduleDrug Dosage CalculationsDrug Resistance, NeoplasmFemaleFranceHumansLapatinibMaximum Tolerated DoseMiddle AgedMorpholinesPhosphatidylinositol 3-KinasePhosphoinositide-3 Kinase InhibitorsProtein Kinase InhibitorsQuinazolinesErb-b2 Receptor Tyrosine KinasesTrastuzumabTreatment Outcome