Phase I Trial of Nanoparticle Albumin-Bound Paclitaxel in Combination with Gemcitabine in Patients with Thoracic Malignancies

Stinchcombe, Thomas E.; Socinski, Mark A.; Lee, Carrie B.; Hayes, D. Neil; Moore, Dominic T.; Goldberg, Richard M.; Dees, Elizabeth Claire

doi:10.1097/jto.0b013e31816de2a7

Cited by 25 publications

(20 citation statements)

References 28 publications

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“…S1A-B) . Consistent with clinical reports (18, 19), both nab -paclitaxel monotherapy and nab -paclitaxel/gemcitabine treatments were well-tolerated with blood counts in acceptable ranges ( Fig. 1A, S1C ).…”

Section: Resultssupporting

confidence: 88%

nab-Paclitaxel Potentiates Gemcitabine Activity by Reducing Cytidine Deaminase Levels in a Mouse Model of Pancreatic Cancer

et al. 2012

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nab-paclitaxel, an albumin-stabilized paclitaxel formulation, demonstrates clinical activity when administered in combination with gemcitabine in patients with metastatic pancreatic ductal adenocarcinoma (PDA). The limited availability of patient tissue and exquisite sensitivity of xenografts to chemotherapeutics have limited our ability to address the mechanistic basis of this treatment regimen. Here, we used a mouse model of PDA to show that the co-administration of nab-paclitaxel and gemcitabine uniquely demonstrates evidence of tumor regression. Combination treatment increases intratumoral gemcitabine levels due to a marked decrease in the primary gemcitabine metabolizing enzyme, cytidine deaminase (Cda). Correspondingly, paclitaxel reduced Cda protein levels in cultured cells through reactive oxygen species-mediated degradation, resulting in the increased stabilization of gemcitabine. Our findings support the concept that suboptimal intratumoral concentrations of gemcitabine represent a crucial mechanism of therapeutic resistance in PDA and highlight the advantages of genetically engineered mouse models in preclinical therapeutic trials.

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Section: Resultssupporting

confidence: 88%

nab-Paclitaxel Potentiates Gemcitabine Activity by Reducing Cytidine Deaminase Levels in a Mouse Model of Pancreatic Cancer

et al. 2012

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“…In a recent phase I trial in NSCLC, 300 mg/m 2 was confirmed as the MTD and Grade 3 skin rash was one of the DLTs [25]. …”

Section: Discussionmentioning

confidence: 99%

Higher rate of skin rash in a phase II trial with weekly nanoparticle albumin-bound paclitaxel and cisplatin combination in Chinese breast cancer patients

et al. 2013

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AbstractsBackgroundThe aim of this sub-study is to explore the incidence of skin rash among advanced breast cancer(ABC) patients in a phase II trial treated with weekly nab-paclitaxel and cisplatin combination.MethodsNab-paclitaxel(125 mg/m2) was administered on days 1, 8, 15, followed by cisplatin(75 mg/m2) on day 1 every 28 day cycle until disease progression, intolerable toxicities or the maximum of 6 cycles. Patients who received at least one injection of the study drug were included in this analysis of the incidence of skin rash among Chinese patients. Toxicity was graded using the CTCAE4.0 criteria. Statistical analysis was carried out by using SPSS 16.0 (SPSS Inc, Chicago, IL).ResultsSeventy three patients were enrolled and eligible for analysis. A total of 384 cycles were administered at the time of this analysis. Rash was presented in 27 patients (37.0%). The most common sites involved were face (14/27), neck (14/27), limbs (18/27) and frictional parts of the trunk (10/27). Macular and papular rash with pruritus commonly occurred 2 (95% CI: 1–7) days after the first day of chemotherapy. Only one patient developed Grade 3 skin toxicity with generalized erythroderma and disfigurement of the face requiring dose reduction. The rash gradually regressed 2 (95% CI: 1–10) days after antihistamines used, but pigmentation remained in 13/27 cases. The incidence rate of skin rash was significantly higher than what has been described for western patients (approximate 4%, P < 0.0001).ConclusionA higher rate of maculo-papular rash occurred in Chinese breast cancer patients treated with weekly nab-paclitaxel compared to western patients. The albumin component of nab-paclitaxel might be the cause of the skin disorder.Trial registrationNCT01149798

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“…Efficacy has also been reported in the front-line treatment of advanced NSCLC, both as a single agent[8, 10] and in combination with other agents[11-13]. CA031 was a randomized phase III trial that compared carboplatin plus nab -paclitaxel with carboplatin plus solvent-based paclitaxel as frontline chemotherapy in patients with advanced stage NSCLC.…”

Section: Introductionmentioning

confidence: 99%

Treatment of recurrent and platinum-refractory stage IV non-small cell lung cancer with nanoparticle albumin-bound paclitaxel (nab-paclitaxel) as a single agent

et al. 2016

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Background The role of single-agent nab-paclitaxel in relapsed or platinum-refractory advanced non-small cell lung cancer (NSCLC) has not been well reported in Western populations. We reviewed our own institution's experience using nab-paclitaxel in these settings. Patients and Methods We analyzed the records of stage IV NSCLC patients with relapsed or platinum-refractory disease treated with single-agent nab-paclitaxel at Weill Cornell Medical College between October 2008 and December 2013. The primary endpoint of the study was treatment failure-free survival (TFFS), defined as the time from the start of nab-paclitaxel therapy to discontinuation of the drug for any reason. The best overall response was recorded for each patient and overall response and disease control rates were calculated. Results Thirty-one stage IV NSCLC patients received a median of 4 cycles (range 1-40) of nab-paclitaxel. Dose reduction or drug discontinuation due to toxicity occurred in 10 patients, mainly because of grade 2/3 fatigue or peripheral neuropathy. The overall response rate was 16.1% and the disease control rate was 64.5%. Median TFFS was 3.5 months (95% CI = 1.3-5.3 months). No statistically significant difference in TFFS based on line of therapy or prior taxane exposure was identified. There was a statistically significant decrease in TFFS for patients with non-adenocarcinoma histology, although there were only 5 patients in this group. There was a trend toward reduction in the risk of treatment failure with increasing age. One patient remained on nab-paclitaxel therapy for over 3 years. Conclusions Single-agent nab-paclitaxel was well tolerated and demonstrated efficacy in advanced NSCLC patients with relapsed or platinum-refractory disease. Further prospective clinical trials with nab-paclitaxel in these settings are warranted.

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Phase I Trial of Nanoparticle Albumin-Bound Paclitaxel in Combination with Gemcitabine in Patients with Thoracic Malignancies

Abstract: The maximum tolerated dose of nab-paclitaxel is 300 mg/m in combination with gemcitabine 1000 mg/m on days 1, 8 every 21 days. This combination demonstrated activity in previously treated NSCLC and SCLC patients.

Cited by 25 publications

References 28 publications

nab-Paclitaxel Potentiates Gemcitabine Activity by Reducing Cytidine Deaminase Levels in a Mouse Model of Pancreatic Cancer

nab-Paclitaxel Potentiates Gemcitabine Activity by Reducing Cytidine Deaminase Levels in a Mouse Model of Pancreatic Cancer

Higher rate of skin rash in a phase II trial with weekly nanoparticle albumin-bound paclitaxel and cisplatin combination in Chinese breast cancer patients

Treatment of recurrent and platinum-refractory stage IV non-small cell lung cancer with nanoparticle albumin-bound paclitaxel (nab-paclitaxel) as a single agent

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