Redox biology · 2025
Phase IB trial of high dose ascorbic acid + nab-paclitaxel + cisplatin + gemcitabine in patients with untreated metastatic pancreatic cancer.
СтатьяКлиническое исследование I фазыПоддержка исследования: вне правительства СШАПоддержка NIH: внешняя программаНазвание 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.
Jameson Gayle S, LeGrand S Danielle, Gordon Michael S, Roe Denise J, Wertheim Betsy C, Olszewski Kellen, Rabinowitz Josh, Evans Ron, Downes Michael, Truitt Morgan, Korn Ron, Han Haiyong, Miller Richard M, Barrett Michael T, Propper David, Von Hoff Daniel D, Borazanci Erkut
Аннотация
BACKGROUND: Preclinical studies suggest that cancer cells take up oxidized vitamin C (dehydroascorbate, DHA) via the GLUT1 transporter, leading to oxidative stress and glutathione depletion. This mechanism may offer a therapeutic strategy for KRAS-mutated cancers. This Phase IB trial evaluated high-dose intravenous ascorbic acid (AA) combined with nab-paclitaxel, cisplatin, and gemcitabine (NABPLAGEM) in patients with untreated metastatic pancreatic ductal adenocarcinoma (PDAC).
METHODS: Eligible patients (≥18 years, ECOG 0-1, measurable PDAC, adequate organ function) received AA (25, 37.5, or 56.25 g/m2 twice weekly) plus NABPLAGEM on Days 1 and 8 of 21-day cycles. The primary endpoint was determining the maximum tolerated dose (MTD) of AA.
RESULTS: Seventeen patients were enrolled (median age 63.9; 70.6 % female; 82.4 % white). No MTD was reached; AA up to 56.25 g/m2 twice weekly was feasible. Patients on the lowest AA dose remained on treatment longer. Grade ≥3 treatment-related adverse events (TRAEs) included thrombocytopenia (82.4 %), anemia (35.3 %), neutropenia (29.4 %), hypokalemia (29.4 %), diarrhea (11.8 %), and colitis (11.8 %), with no significant differences between dose groups. Peak AA levels >20 mM were achieved in 57 % of patients at the highest dose. Median progression-free survival (PFS) and overall survival (OS) were 7.1 and 14.2 months, respectively, with no significant differences by AA dose. Textural imaging showed decreased liver fat in 3 of 4 patients with baseline steatosis.
CONCLUSION: High-dose AA with NABPLAGEM was tolerable in patients with advanced PDAC but did not improve disease response compared to historical data for chemotherapy alone. A separate study suggests AA may enhance gemcitabine and nab-paclitaxel efficacy without cisplatin. AA and cisplatin may have overlapping DNA-damaging effects, or differences in AA dosing frequency and exposure may influence outcomes - variables to consider in future trials.
TRIAL REGISTRATION: NCT03410030.
METHODS: Eligible patients (≥18 years, ECOG 0-1, measurable PDAC, adequate organ function) received AA (25, 37.5, or 56.25 g/m2 twice weekly) plus NABPLAGEM on Days 1 and 8 of 21-day cycles. The primary endpoint was determining the maximum tolerated dose (MTD) of AA.
RESULTS: Seventeen patients were enrolled (median age 63.9; 70.6 % female; 82.4 % white). No MTD was reached; AA up to 56.25 g/m2 twice weekly was feasible. Patients on the lowest AA dose remained on treatment longer. Grade ≥3 treatment-related adverse events (TRAEs) included thrombocytopenia (82.4 %), anemia (35.3 %), neutropenia (29.4 %), hypokalemia (29.4 %), diarrhea (11.8 %), and colitis (11.8 %), with no significant differences between dose groups. Peak AA levels >20 mM were achieved in 57 % of patients at the highest dose. Median progression-free survival (PFS) and overall survival (OS) were 7.1 and 14.2 months, respectively, with no significant differences by AA dose. Textural imaging showed decreased liver fat in 3 of 4 patients with baseline steatosis.
CONCLUSION: High-dose AA with NABPLAGEM was tolerable in patients with advanced PDAC but did not improve disease response compared to historical data for chemotherapy alone. A separate study suggests AA may enhance gemcitabine and nab-paclitaxel efficacy without cisplatin. AA and cisplatin may have overlapping DNA-damaging effects, or differences in AA dosing frequency and exposure may influence outcomes - variables to consider in future trials.
TRIAL REGISTRATION: NCT03410030.