American journal of clinical oncology · 2019
Phase I Study of IGF-Methotrexate Conjugate in the Treatment of Advanced Tumors Expressing IGF-1R.
Клиническое исследование I фазыСтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод пока не подготовлен
Обработка статьи · этапы, ошибки и управление
Загрузка состояния…
Ошибки и ограничения
История · было → стало
Состояние обновляется каждые 5 секунд, пока блок открыт. Процент показывается только там, где известен объём работы. Пауза останавливает продолжение этапа; текущий запрос к источнику может завершиться.
Venepalli Neeta K, Emmadi Rajyasree, Danciu Oana C, Chowdhery Rozina, Cabay Robert J, Gaitonde Sujata, Aardsma Nathan, Kothari Rajul, Liu Li C, Fischer James H, Zaidi Ayesha, Russell Meredith J, Dudek Arkadiusz Z
Аннотация
OBJECTIVES: Insulin-like growth factor-methotrexate (IGF-MTX) is a conjugate of methotrexate and 765IGF, a variant of IGF-1 with high affinity for insulin-like growth factor type 1 receptor. The study aim was to determine the maximum tolerated dose of IGF-MTX in refractory solid organ and hematologic malignancies expressing insulin-like growth factor type 1 receptor.
MATERIALS AND METHODS: This phase I trial used a modified toxicity probability interval design with 5 cohort dose levels, and expansion cohort at maximum tolerated dose. IGF-MTX was given intravenously over 90 minutes on days 1, 8, and 15 of a 28-day cycle.
RESULTS: A total of 17 patients were enrolled. The highest tolerated dose tested was 0.80 µEq/kg with dose-limiting toxicity of grade 3 hypoglycemia. Drug-related grade 3 and 4 toxicities included abdominal pain (26%), hypoglycemia (10%), and hypotension (10%). Of the 15 evaluable for response, 3 patients (20%) had stable disease, including the patient with Hodgkin lymphoma with stable disease for 12 cycles of therapy. IGF-MTX concentrations declined rapidly, with half-lives of 5.2 to 14 minutes for the initial distribution phase and 6.5 to 7.5 hours for the terminal elimination phase. Higher IGF-R1 expression did not correlate with better outcome.
CONCLUSIONS: IGF-MTX is well tolerated. IGF-MTX pharmacokinetics suggest rapid cellular uptake. The activity of IGF-MTX in Hodgkin lymphoma should be explored.
MATERIALS AND METHODS: This phase I trial used a modified toxicity probability interval design with 5 cohort dose levels, and expansion cohort at maximum tolerated dose. IGF-MTX was given intravenously over 90 minutes on days 1, 8, and 15 of a 28-day cycle.
RESULTS: A total of 17 patients were enrolled. The highest tolerated dose tested was 0.80 µEq/kg with dose-limiting toxicity of grade 3 hypoglycemia. Drug-related grade 3 and 4 toxicities included abdominal pain (26%), hypoglycemia (10%), and hypotension (10%). Of the 15 evaluable for response, 3 patients (20%) had stable disease, including the patient with Hodgkin lymphoma with stable disease for 12 cycles of therapy. IGF-MTX concentrations declined rapidly, with half-lives of 5.2 to 14 minutes for the initial distribution phase and 6.5 to 7.5 hours for the terminal elimination phase. Higher IGF-R1 expression did not correlate with better outcome.
CONCLUSIONS: IGF-MTX is well tolerated. IGF-MTX pharmacokinetics suggest rapid cellular uptake. The activity of IGF-MTX in Hodgkin lymphoma should be explored.
Предметные рубрики MeSH
AdultAgedDisease-Free SurvivalDose-Response Relationship, DrugDrug Administration ScheduleFemaleGene Expression Regulation, NeoplasticHematologic NeoplasmsHumansIllinoisKaplan-Meier EstimateMaleMaximum Tolerated DoseMethotrexateMiddle AgedMolecular Targeted TherapyNeoplasmsPatient SelectionPrognosisReceptor, IGF Type 1Risk AssessmentSurvival Analysis