Pharmacokinetic study of gemcitabine, given as prolonged infusion at fixed dose rate, in combination with cisplatin in patients with advanced non-small-cell lung cancer

Caffo, Orazio; Fallani, Stefania; Marangon, Elena; Nobili, Stefania; Cassetta, Maria Iris; Murgia, V.; Sala, Federica; Novelli, Andréa; Mini, Enrico; Zucchetti, Massimo; Galligioni, Enzo

doi:10.1007/s00280-010-1255-7

Cited by 12 publications

(6 citation statements)

References 21 publications

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“…In another study published by the same group, an apparent numerically superior activity and lower toxicity compared to the standard dose gemcitabine was reported [13]. Multiple phase 2 studies (at the time of planning this study) with PLDG echoed these findings of superior to similar activity in comparison with standard dose of gemcitabine [14], [15].…”

Section: Introductionmentioning

confidence: 64%

Phase III Non-inferiority Study Evaluating Efficacy and Safety of Low Dose Gemcitabine Compared to Standard Dose Gemcitabine With Platinum in Advanced Squamous Lung Cancer

et al. 2019

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Background Prolonged infusion of low dose gemcitabine (PLDG) in combination with platinum has shown promising activity in terms of improved response rate and progression free survival (PFS); especially in squamous non-small cell lung cancer (NSCLC). Hence, we conducted a phase 3 randomized non-inferiority study with the primary objective of comparing the overall survival (OS) between PLDG and standard dose of gemcitabine with platinum. Methodology Adult subjects (age ≥ 18 years), with stages IIIB–IV, NSCLC (squamous) and ECOG performance status of ≤ 2 were randomized 1:1 into either carboplatin with standard dose gemcitabine (1000 mg/m 2 intravenous over 30 min, days 1 and 8) (STD-G arm) or carboplatin along with low dose gemcitabine (250 mg/m 2 intravenous over 6 h, days 1 and 8) (LOW-G arm) for a maximum of 6 cycles. Tumor response was assessed by RECIST criteria version 1.1 every 2 cycles till 6th cycle and thereafter at 2 monthly intervals till progression. The primary endpoint was overall survival. 308 patients were randomized, 155 in STD-G arm and 153 in LOW-G arm, respectively. Results The median overall survival in STD-G arm was 6.8 months (95%CI 5.3–8.5) versus 8.4 months (95%CI 7–10.3) in the LOW-G arm (HR-0.890 (90%CI 0.725–1.092). The results with per protocol analysis were in line with these results. There was no statistical difference in progression free survival (HR-0.949; 90%CI 0.867–1.280) and adverse event rate between the 2 arms. Conclusion This study suggests that PLDG is an alternative to the standard gemcitabine schedule in squamous NSCLC, and either of these can be selected subject to patient convenience.

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Section: Introductionmentioning

confidence: 64%

Phase III Non-inferiority Study Evaluating Efficacy and Safety of Low Dose Gemcitabine Compared to Standard Dose Gemcitabine With Platinum in Advanced Squamous Lung Cancer

et al. 2019

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“…13-14 The fixed dose rate improves intracellular accumulation of the active triphosphate form of the drug, and was associated with improved outcomes when compared to the standard 30-minute infusion time in several solid tumors, including bladder cancer. 15 We administered doxorubicin as a short infusion and always before paclitaxel to minimize the effect of drug interaction on cardiac toxicity.…”

Section: Commentmentioning

confidence: 99%

Front-line Treatment with Gemcitabine, Paclitaxel, and Doxorubicin for Patients With Unresectable or Metastatic Urothelial Cancer and Poor Renal Function: Final Results from a Phase II Study

Siefker-Radtke

Campbell

Munsell

et al. 2016

Urology

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Objectives To estimate the response rate to gemcitabine, paclitaxel, and doxorubicin in patients with advanced urothelial carcinoma, we conducted a phase II clinical trial. Patients with renal insufficiency cannot receive standard cisplatin-based chemotherapy for urothelial carcinoma, and carboplatin-based regimens have proved unsatisfactory. Secondary end points for this study included overall survival, safety of the regimen, and safety of same-day pegfilgrastim dosing. Methods A two-stage design was chosen with target response rate of 40%. Key inclusion criteria were metastatic or unresectable urothelial carcinoma, no prior chemotherapy, glomerular filtration rate <60 mL/min, and no dialysis. Gemcitabine (900 mg/m2), paclitaxel (135 mg/m2), and doxorubicin (40 mg/m2) were administered on day 1 of each 14-day cycle. Pegfilgrastim was given with every cycle on either day 1 or optionally day 2. Results Forty patients were enrolled and 39 were treated. Median age was 72 years (range, 51–89). There were 7 complete and 15 partial responses, for a response rate of 56.4% (95% CI, 39.6-72.2). Most (82.8%) cycles were given with same-day pegfilgrastim. Notable grade 3 and 4 non-hematologic toxicities were fatigue and mucositis (10.3% each). There were 4 episodes of neutropenic fever (4/198 cycles [2%]; 4/39 patients [10.3%]) and no treatment related deaths. Median overall survival was 14.4 months. Conclusions The combination of gemcitabine, paclitaxel, and doxorubicin is effective first-line chemotherapy for patients with advanced urothelial carcinoma and renal insufficiency. Neutropenic prophylaxis was acceptable whether pegfilgrastim was given immediately or 24 hours after chemotherapy.

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“…It must be taken into account that the total number of subjects was rather small. Nevertheless, such a PK modification over time has never been reported for prolonged administration of gemcitabine so far [35] and may reflect an interaction with continuous capecitabine administration since both drugs are metabolized by the enzyme CDA. Due to the rather long elimination half-life of erlotinib, approximately 36 h [36], AUC 0–4.5 h does not reflect total systemic exposure, and this PK parameter needs to be considered with caution.…”

Section: Discussionmentioning

confidence: 99%

Phase I Trial of Gemcitabine Combined with Capecitabine and Erlotinib in Advanced Pancreatic Cancer: A Clinical and Pharmacological Study

François

Bennouna²,

Chamorey

et al. 2012

Chemotherapy

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Background: The aim of this phase I trial was to define the maximum tolerated dose (MTD), the dose-limiting toxicity (DLT) and the recommended dose of erlotinib combined with capecitabine and gemcitabine in the treatment of advanced pancreatic cancer (APC). Methods: Gemcitabine was administered intravenously at 1,000 mg/m²/week (days 1, 8 and 15) and oral capecitabine from day 1 to day 21 at 1,660 mg/m²/day. Oral erlotinib was administered daily continuously at escalating doses (28-day cycle). Dose levels (DLs) 1, 2, 3 and 4 were 50, 75, 100 and 125 mg/day, respectively. Pharmacokinetic analysis of the three drugs was performed in the first cycle. Results: Nineteen patients were enrolled. At the MTD (DL4; 125 mg/day erlotinib), 100% of patients developed DLT consisting of grade 4 febrile neutropenia and nonhematological grade 3 events (vomiting, diarrhea, stomatitis, rash). The most common toxicities, regardless of grade, were neutropenia, anemia, rash and diarrhea. Erlotinib systemic exposure was significantly related to the administered dose. Of note, toxicity was significantly associated with elevated systemic exposure of capecitabine anabolites. Conclusion: When combined concurrently with 1,000 mg/m²/week gemcitabine and 1,660 mg/m²/day capecitabine, erlotinib can be administered safely at a daily dose of 100 mg in APC patients.

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Pharmacokinetic study of gemcitabine, given as prolonged infusion at fixed dose rate, in combination with cisplatin in patients with advanced non-small-cell lung cancer

Cited by 12 publications

References 21 publications

Phase III Non-inferiority Study Evaluating Efficacy and Safety of Low Dose Gemcitabine Compared to Standard Dose Gemcitabine With Platinum in Advanced Squamous Lung Cancer

Phase III Non-inferiority Study Evaluating Efficacy and Safety of Low Dose Gemcitabine Compared to Standard Dose Gemcitabine With Platinum in Advanced Squamous Lung Cancer

Front-line Treatment with Gemcitabine, Paclitaxel, and Doxorubicin for Patients With Unresectable or Metastatic Urothelial Cancer and Poor Renal Function: Final Results from a Phase II Study

Phase I Trial of Gemcitabine Combined with Capecitabine and Erlotinib in Advanced Pancreatic Cancer: A Clinical and Pharmacological Study

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