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A phase I trial of azacitidine and nanoparticle albumin bound paclitaxel in patients with advanced or metastatic solid tumors.

ABSTRACT: Secreted protein acidic and rich in cysteine (SPARC), an albumin-binding protein, is downregulated by hypermethylation in many cancers. Hypomethylating agents such as azacitidine can upregulate SPARC in tumors, which may enhance the accumulation of albumin-bound drugs at tumor site. The objectives of this phase I trial was to determine the safety and maximum tolerated dose and to assess any clinical activity of the combination of azacytidine and weekly nanoparticle-albumin-bound (nab®) paclitaxel.Patients received escalating azacytidine doses daily for 5 days, followed by nab-paclitaxel at the standard 100mg/m2 weekly dose for 3 weeks in 4-week cycles. Dose-limiting toxicities (DLTs) were monitored during the first cycle. Serum was obtained at baseline, during and after treatment for correlative study.All sixteen total patients enrolled were evaluable for toxicity, while 13 patients were evaluable for response. Two of five patients treated with 100mg/m2 of azacytidine had DLT of prolonged grade 4 neutropenia. Therefore, the MTD of azacitidine in this regimen is 75 mg/m2. Three additional patients were treated with no grade 4 toxicity in cycle 1. Clinical activity included 1 complete response (CR) in refractory DLBCL, 2 CR in ovarian cancer, 4 partial responses (PR) in ovarian and endometrial cancer, 4 stable diseases (SD) in lung, sarcoma and pancreatic cancer, 1 unconfirmed PR in breast cancer, and 1 progression of disease in CLL/SLL.Priming with azacitidine 75 mg/m2 daily for 5 days, followed by weekly nab-paclitaxel 100 mg/m2 weekly was well tolerated and results in dramatic responses pre-treated cancer patients.

SUBMITTER: Cohen AL

PROVIDER: S-EPMC5581038 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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A phase I trial of azacitidine and nanoparticle albumin bound paclitaxel in patients with advanced or metastatic solid tumors.

Cohen Adam L AL Ray Abhijit A Van Brocklin Matthew M Burnett David M DM Bowen Randy C RC Dyess Donna L DL Butler Thomas W TW Dumlao Theresa T Khong Hung T HT

Oncotarget 20161226 32

<h4>Background</h4>Secreted protein acidic and rich in cysteine (SPARC), an albumin-binding protein, is downregulated by hypermethylation in many cancers. Hypomethylating agents such as azacitidine can upregulate SPARC in tumors, which may enhance the accumulation of albumin-bound drugs at tumor site. The objectives of this phase I trial was to determine the safety and maximum tolerated dose and to assess any clinical activity of the combination of azacytidine and weekly nanoparticle-albumin-bou ...[more]

PMID: 28881739

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Project description:BackgroundThis phase I/II study aimed to determine the maximum tolerated dose (MTD) of nanoparticle albumin-bound paclitaxel (nab (®)-paclitaxel) plus cisplatin as treatment for metastatic nasopharyngeal carcinoma (NPC).MethodsPatients were enrolled into 1 of 3 dose cohorts, each with 21-day treatment cycles: 1) intravenous (IV) nab-paclitaxel 260 mg/m(2) on day 1; 2) IV nab-paclitaxel 140 mg/m(2) on days 1 and 8; 3) IV nab-paclitaxel 100 mg/m(2) on days 1, 8, and 15. All patients received IV cisplatin 75 mg/m(2) on day 1. Treatment continued for 4-6 cycles, or until progression or unacceptable toxicity. If more than one-third of the patients in a cohort experienced a dose-limiting toxicity (DLT), the dose used in the previous cohort would be designated the MTD. Secreted protein acidic and rich in cysteine (SPARC) expression was detected by immunohistochemistry staining.ResultsSixty-nine patients were enrolled, of whom 64 and 67 were eligible for efficacy and safety analysis, respectively. Two DLTs occurred in cohort 1 (grade 4 febrile neutropenia, grade 3 myalgia), none occurred in cohort 2, and 2 occurred in cohort 3 (both grade 3 fatigue). The MTD was not reached. Partial responses were achieved by 42 patients, 15 had stable disease, and 7 had progressive disease, giving an overall response rate of 66 %. Median progression-free survival was 9 months (95 % CI, 6-12 months). Grade ≥ 3 adverse events were mainly hematologic. There was no significant difference between the 3 cohorts with respect to efficacy or safety. Biomarker analyses indicated that stromal, rather than tumoral, SPARC may predict the response to nab-paclitaxel in NPC.ConclusionsOur findings suggest that nab-paclitaxel plus cisplatin is a highly active regimen with moderate toxicity for the treatment of metastatic NPC, which warrants further investigation in a phase III study.Trial registrationsClinicalTrials.gov ID: NCT01735409 . The trial was registered on November 20th, 2012.

Project description:Purposenab-paclitaxel demonstrates improved clinical efficacy compared with conventional Cremophor EL (CrEL)-paclitaxel in multiple tumor types. This study explored the distinctions in drug distribution between nab-paclitaxel and CrEL-paclitaxel and the underlying mechanisms.MethodsUptake and transcytosis of paclitaxel were analyzed by vascular permeability assay across human endothelial cell monolayers. The tissue penetration of paclitaxel within tumors was evaluated by local injections into tumor xenografts and quantitative image analysis. The distribution profile of paclitaxel in solid-tumor patients was assessed using pharmacokinetic modeling and simulation.ResultsLive imaging demonstrated that albumin and paclitaxel were present in punctae in endothelial cells and could be observed in very close proximity, suggesting cotransport. Uptake and transport of albumin, nab-paclitaxel and paclitaxel were inhibited by clinically relevant CrEL concentrations. Further, nab-paclitaxel causes greater mitotic arrest in wider area within xenografted tumors than CrEL- or dimethyl sulfoxide-paclitaxel following local microinjection, demonstrating enhanced paclitaxel penetration and uptake by albumin within tumors. Modeling of paclitaxel distribution in patients with solid tumors indicated that nab-paclitaxel is more dependent upon transporter-mediated pathways for drug distribution into tissues than CrEL-paclitaxel. The percent dose delivered to tissue via transporter-mediated pathways is predicted to be constant with nab-paclitaxel but decrease with increasing CrEL-paclitaxel dose.ConclusionsCompared with CrEL-paclitaxel, nab-paclitaxel demonstrated more efficient transport across endothelial cells, greater penetration and cytotoxic induction in xenograft tumors, and enhanced extravascular distribution in patients that are attributed to carrier-mediated transport. These observations are consistent with the distinct clinical efficacy and toxicity profile of nab-paclitaxel.

Project description:PurposeThis study aimed to assess the effect of nanoparticle albumin-bound paclitaxel (nab-PTX) chemotherapy regimens in elderly patients (≥70 years old) with advanced squamous non-small-cell lung cancer (NSCLC).Patients and methodsThe clinical records of elderly patients aged ≥70 years with advanced squamous NSCLC were reviewed retrospectively. All of these patients received nab-PTX, with or without combination of chemotherapy in Shandong Cancer Hospital and Institute between 1 July 2012 and 30 June 2017. We analyzed the toxicity profiles, progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and disease control rate (DCR).ResultsTotally, 52 elderly patients with squamous NSCLC were included in the analysis. For all patients, the ORR was 34.6%, the DCR was 80.8%, median PFS was 5.9 months (95% confidence interval [CI]: 4.0-7.8 months), and median OS was 14.3 months (95% CI: 11.0-17.8 months). Combination with chemotherapy significantly prolonged OS (19.3 vs 11.2 months, P = .016), despite a nonsignificant improvement in PFS (7.1 vs 4.2 months, P = .060) vs monotherapy. For patients who received nab-PTX as first-line treatment, the median PFS and OS were 6.7 months and 17.2 months, respectively, and the median OS in combination therapy subgroup was significantly higher than that in monotherapy group (20.3 vs 11.2 months, P = .013). Meanwhile, the median PFS and OS of patients with nab-PTX as second- or later-line treatment were 4.4 months and 13.3 months, respectively, but no survival benefit was achieved by the combination chemotherapy when compared with single-agent chemotherapy. Hematologic toxicities were the most common adverse events (AEs), which include grade 3 or 4 neutropenia (13.7%), thrombocytopenia (4.1%), and anemia (6.8%). The main nonhematologic toxicities were peripheral sensory neuropathy (39.7%), followed by anorexia and nausea/vomiting.ConclusionIn elderly advanced squamous NSCLC patients, the treatment of nab-PTX was effective and well tolerated.

Dataset Information

A phase I trial of azacitidine and nanoparticle albumin bound paclitaxel in patients with advanced or metastatic solid tumors.

Publications

A phase I trial of azacitidine and nanoparticle albumin bound paclitaxel in patients with advanced or metastatic solid tumors.

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