Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT02426281 |
| Other study ID # |
2014-10-061 |
| Secondary ID |
|
| Status |
Completed |
| Phase |
Phase 2
|
| First received |
|
| Last updated |
|
| Start date |
June 4, 2015 |
| Est. completion date |
September 30, 2022 |
Study information
| Verified date |
February 2023 |
| Source |
Samsung Medical Center |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial 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 countries/regions, including the US, Canada, India, European
Union/European 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, EU/EEA, Australia, New Zealand and Argentina.
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
2.8-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 1/2 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 mg/m2 nab-paclitaxel
in combination with 1000 mg/m2 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 8.5 months (95% CI = 7.89-9.53) with nab-paclitaxel/gemcitabine compared with
6.7 months (95 % CI = 6.01-7.23) with gemcitabine, p < 0.0001, HR = 0.72 (95% CI =
0.617-0.835). Long-term survival was improved in the nab-paclitaxel/gemcitabine 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-paclitaxel/gemcitabine,
supporting the results from the primary analysis of OS. Specifically, PFS (by independent
review) was 5.5 months (95% CI = 4.47-5.95) versus 3.7 months (95% CI = 3.61-4.04) in the
nab-paclitaxel/gemcitabine arm versus gemcitabine alone arms, respectively p < 0.0001; HR =0
.69; 95% CI = 0.581-0.821). The improvement in PFS corresponded to a 31% reduction in the
risk of progression or death with nab-paclitaxel/gemcitabine. 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 mg/m2. 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 8.7 versus 6.6 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.
