Ignite Creation Date:
2024-05-06 @ 3:58 AM
Last Modification Date:
2024-10-26 @ 11:42 AM
Study NCT ID:
NCT02426281
Status:
COMPLETED
Last Update Posted:
2023-02-15
First Post:
2015-04-15
Brief Title:
Nab-pacliatxel Plus Gemcitabine in Korean Patients With Metastatic Pancreatic Ductal Adenocarcinoma
Sponsor:
Samsung Medical Center
Organization:
Samsung Medical Center
Study Overview
Official Title:
A Phase 2 Study to Evaluate the Safety and Efficacy of Nab-pacliatxel Plus Gemcitabine in Korean Patients With Metastatic Pancreatic Ductal Adenocarcinoma
Status:
COMPLETED
Status Verified Date:
2023-02
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
Nab-paclitaxel interchangeable with ABRAXANE and ABI-007 is a unique protein formulation of a noncrystalline amorphous form of paclitaxel in an insoluble particle state Nab-paclitaxel was designed to improve the chemotherapeutic effects of paclitaxel by exploiting endogenous transport pathways to deliver higher doses of paclitaxel to the tumor and to reduce the solvent-related hypersensitivity and other toxicities associated with Taxol paclitaxel injections the solvent Cremophor EL and ethanol vehicle Nab-paclitaxel provides more rapid tissue distribution and increased tumor accumulation compared to cremophor-EL paclitaxel Mechanistically albumin receptor-mediated transport across the endothelium binding to interstitial proteins and macropinocytic or receptor-mediated uptake into tumor cells as well as sequestration of paclitaxel by cremophor-EL may contribute to the observed differences Furthermore nab-paclitaxel synergizes with gemcitabine in preclinical models The Cremophor EL-free medium enables nab-paclitaxel to be given at a higher dose and in a shorter duration without the need for premedication to prevent solvent-related hypersensitivity reactions As of March 2014 nab-paclitaxel is approved under the trade name of ABRAXANE in over 45 countriesregions including the US Canada India European UnionEuropean Economic Area South Korea China Australia Bhutan United Arab Emirates Nepal New Zealand Japan Russia Sri Lanka Argentina Hong Kong and Lebanon for the treatment of patients with metastatic breast cancer ABRAXANE is also approved for the first-line treatment of locally advanced or metastatic non small cell lung cancer NSCLC in the US Japan Argentina Australia and New Zealand for treatment of advanced gastric cancer in Japan and for first-line treatment of metastatic adenocarcinoma of the pancreas in the US EUEEA Australia New Zealand and Argentina
Detailed Description:
Preclinical studies have demonstrated that nab-paclitaxel may play a role in sensitizing the tumor to chemotherapeutic agents and specifically increases the antitumor efficacy when combined with gemcitabine While the mechanism of action for the synergy is unclear preclinical studies have generated hypothetical models One hypothesis is a remodeling and weakening of the stroma barrier allowing the chemotherapeutic agents to have better access to the tumor cells Weakening the tumor-stroma barrier is particularly important in cancer that is characterized by dense stroma such as pancreatic cancer In mice with primary patient derived pancreatic tumor xenografts nab-paclitaxel plus gemcitabine versus gemcitabine alone resulted in increased tumor regression and depleted the desmoplastic stroma as observed by the less dense disorganized wisps of collagen type1 fibers after 4 weeks of treatment In this study the intratumoral concentration of gemcitabine was increased by 28-fold after 5 days of treatment when nab-paclitaxel was added to gemcitabine It was hypothesized that nab-paclitaxel may play a role in reducing the dense stroma and may have contributed to the increased intratumoral gemcitabine uptake Additional preclinical studies in a genetically engineered mouse model of pancreatic adenocarcinoma coadministration of nab-paclitaxel and gemcitabine also demonstrated tumor regression and increased intratumoral gemcitabine levels after 8 days of treatment Apoptosis of tumor epithelial cells were observed however there were no changes in stromal components or collagen density in this short term treatment model The increased intratumoral gemcitabine levels were attributed to a marked decrease in the primary gemcitabine metabolizing enzyme cytidine deaminase by nab-paclitaxel Finally a recent clinical study in subjects with resectable pancreatic cancer treated with neoadjuvant nab-paclitaxel plus gemcitabine showed reduction in fibrotic collagenous stroma further supporting a stroma active mechanism for nab-paclitaxel
In a clinical Phase 12 dose ranging study CA040 NCT003980860 nab-paclitaxel plus gemcitabine CA040 NCT003980860 antitumor activity and tolerability were established in patients who had no prior treatment for metastatic pancreatic cancer The maximum tolerated dose and recommended dose for further studies was determined to be 125 mgm2 nab-paclitaxel in combination with 1000 mgm2 gemcitabine
In the subsequent randomized international Phase 3 study MPACT CA046 NCT00394251 that enrolled 861 patients with metastatic pancreatic cancer nab-paclitaxel in combination with gemcitabine exhibited a clinically meaningful statistically significant improvement in OS and progression-free survival PFS The median OS primary endpoint in the intent-to-treat population was 85 months 95 CI 789-953 with nab-paclitaxelgemcitabine compared with 67 months 95 CI 601-723 with gemcitabine p 00001 HR 072 95 CI 0617-0835 Long-term survival was improved in the nab-paclitaxelgemcitabine arm versus gemcitabine alone with a 59 increase at 1 year 35 versus 22 and doubling at 2 years 9 versus 4 The secondary PFS overall response rate ORR and all other efficacy endpoints showed consistent statistically significant improvements with nab-paclitaxelgemcitabine supporting the results from the primary analysis of OS Specifically PFS by independent review was 55 months 95 CI 447-595 versus 37 months 95 CI 361-404 in the nab-paclitaxelgemcitabine arm versus gemcitabine alone arms respectively p 00001 HR 0 69 95 CI 0581-0821 The improvement in PFS corresponded to a 31 reduction in the risk of progression or death with nab-paclitaxelgemcitabine Furthermore in this study of metastatic unresectable adenocarcinoma of the pancreas subjects in the combination arm were on therapy longer than those receiving single agent gemcitabine indicating disease improvement and tolerable treatment The suitability of the dosing regimen was confirmed by the observation that the majority of patients did not require a dose reduction and that 71 of nab-paclitaxel doses were delivered at the starting dose of 125 mgm2 The safety profile for both regimens was consistent with previous reports Serious life threatening toxicities were not increased AEs were acceptable and manageable The most notable differences in toxicity between the 2 treatment arms was peripheral neuropathy which was cumulative and rapidly reversible with dose delay and reduction and neutropenia which was manageable with dose delays and dose reductions The incremental risks of sepsis and pneumonitis were managed by protocol amendments to increase awareness and for early diagnosis and treatment to reduce the risk of fatal outcomes Since the above described initial analysis of the MPACT study the updated OS with a cutoff of May 2013 showed that the benefit continued to improve with nab-paclitaxel in combination with gemcitabine with 87 versus 66 median months respectively The updated survival rates also significantly favored nab-paclitaxel plus gemcitabine at year 1 35 versus 22 year 2 10 versus 5 and year 3 4 versus 0 as compared with gemcitabine alone
In a clinical Phase 12 dose ranging study CA040 NCT003980860 nab-paclitaxel plus gemcitabine CA040 NCT003980860 antitumor activity and tolerability were established in patients who had no prior treatment for metastatic pancreatic cancer The maximum tolerated dose and recommended dose for further studies was determined to be 125 mgm2 nab-paclitaxel in combination with 1000 mgm2 gemcitabine
In the subsequent randomized international Phase 3 study MPACT CA046 NCT00394251 that enrolled 861 patients with metastatic pancreatic cancer nab-paclitaxel in combination with gemcitabine exhibited a clinically meaningful statistically significant improvement in OS and progression-free survival PFS The median OS primary endpoint in the intent-to-treat population was 85 months 95 CI 789-953 with nab-paclitaxelgemcitabine compared with 67 months 95 CI 601-723 with gemcitabine p 00001 HR 072 95 CI 0617-0835 Long-term survival was improved in the nab-paclitaxelgemcitabine arm versus gemcitabine alone with a 59 increase at 1 year 35 versus 22 and doubling at 2 years 9 versus 4 The secondary PFS overall response rate ORR and all other efficacy endpoints showed consistent statistically significant improvements with nab-paclitaxelgemcitabine supporting the results from the primary analysis of OS Specifically PFS by independent review was 55 months 95 CI 447-595 versus 37 months 95 CI 361-404 in the nab-paclitaxelgemcitabine arm versus gemcitabine alone arms respectively p 00001 HR 0 69 95 CI 0581-0821 The improvement in PFS corresponded to a 31 reduction in the risk of progression or death with nab-paclitaxelgemcitabine Furthermore in this study of metastatic unresectable adenocarcinoma of the pancreas subjects in the combination arm were on therapy longer than those receiving single agent gemcitabine indicating disease improvement and tolerable treatment The suitability of the dosing regimen was confirmed by the observation that the majority of patients did not require a dose reduction and that 71 of nab-paclitaxel doses were delivered at the starting dose of 125 mgm2 The safety profile for both regimens was consistent with previous reports Serious life threatening toxicities were not increased AEs were acceptable and manageable The most notable differences in toxicity between the 2 treatment arms was peripheral neuropathy which was cumulative and rapidly reversible with dose delay and reduction and neutropenia which was manageable with dose delays and dose reductions The incremental risks of sepsis and pneumonitis were managed by protocol amendments to increase awareness and for early diagnosis and treatment to reduce the risk of fatal outcomes Since the above described initial analysis of the MPACT study the updated OS with a cutoff of May 2013 showed that the benefit continued to improve with nab-paclitaxel in combination with gemcitabine with 87 versus 66 median months respectively The updated survival rates also significantly favored nab-paclitaxel plus gemcitabine at year 1 35 versus 22 year 2 10 versus 5 and year 3 4 versus 0 as compared with gemcitabine alone
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None