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Journal of Clinical Oncology : Official... Dec 2022To compare taxane maintenance chemotherapy, paclitaxel (P) and paclitaxel poliglumex (PP), with surveillance (S) in women with ovarian, peritoneal, or fallopian tube... (Randomized Controlled Trial)
Randomized Controlled Trial
Phase III Randomized Trial of Maintenance Taxanes Versus Surveillance in Women With Advanced Ovarian/Tubal/Peritoneal Cancer: A Gynecologic Oncology Group 0212:NRG Oncology Study.
PURPOSE
To compare taxane maintenance chemotherapy, paclitaxel (P) and paclitaxel poliglumex (PP), with surveillance (S) in women with ovarian, peritoneal, or fallopian tube (O/PC/FT) cancer who attained clinical complete response after first-line platinum-taxane therapy.
METHODS
Women diagnosed with O/PC/FT cancer who attained clinical complete response after first-line platinum-taxane-based chemotherapy were randomly allocated 1:1:1 to S or maintenance, P 135 mg/m once every 28 days for 12 cycles, or PP at the same dose and schedule. Overall survival (OS) was the primary efficacy end point.
RESULTS
Between March 2005 and January 2014, 1,157 individuals were enrolled. Grade 2 or worse GI adverse events were more frequent among those treated with taxane (PP: 20%, P: 27% S: 11%). Grade 2 or worse neurologic adverse events occurred more often with taxane treatment (PP: 46%, P: 36% S: 14%). At the fourth scheduled interim analysis, both taxane regimens passed the OS futility boundary and the Data Monitoring Committee approved an early release of results. With a median follow-up of 8.1 years, 653 deaths were reported; none were attributed to the study treatment. Median survival durations were 58.3, 56.8, and 60.0 months for S, P, and PP, respectively. Relative to S, the hazard of death for P was 1.091 (95% CI, 0.911 to 1.31; = .343) and for PP, it was 1.033 (95% CI, 0.862 to 1.24; = .725). The median times to first progression or death (PFS) were 13.4, 18.9, and 16.3 months for S, P, and PP, respectively. Hazard ratio = 0.801; 95% CI, 0.684 to 0.938; = .006 for P and hazard ratio = 0.854; 95% CI, 0.729 to 1.00; = .055 for PP.
CONCLUSION
Maintenance therapy with P and PP did not improve OS among patients with newly diagnosed O/tubal/peritoneal cancer, but may modestly increase PFS. GI and neurologic toxicities were more frequent in the taxane treatment arms.
Topics: Female; Humans; Platinum; Medical Futility; Neoplasms
PubMed: 35759733
DOI: 10.1200/JCO.22.00146 -
Scientific Reports Jun 2017The conventional chemotherapeutics could not be traced in vivo and provide timely feedback on the clinical effectiveness of drugs. In this study,...
The conventional chemotherapeutics could not be traced in vivo and provide timely feedback on the clinical effectiveness of drugs. In this study, poly(L-γ-glutamyl-glutamine)-paclitaxel (PGG-PTX), as a model polymer, was chemically conjugated with Gd-DTPA (Gd-diethylenetriaminepentaacetic acid), a T-contrast agent of MRI, to prepare a Gd-DTPA-conjugated PGG-PTX (PGG-PTX-DTPA-Gd) delivery system used for tumor theranostics. PGG-PTX-DTPA-Gd can be self-assembled to NPs in water with a z-average hydrodynamic diameter about 35.9 nm. The 3 T MRI results confirmed that the relaxivity of PGG-PTX-DTPA-Gd NPs (r = 18.98 mMS) was increased nearly 4.9 times compared with that of free Gd-DTPA (r = 3.87 mMS). The in vivo fluorescence imaging results showed that PGG-PTX-DTPA-Gd NPs could be accumulated in the tumor tissue of NCI-H460 lung cancer animal model by EPR effect, which was similar to PGG-PTX NPs. The MRI results showed that compared with free Gd-DTPA, PGG-PTX-DTPA-Gd NPs showed significantly enhanced and prolonged signal intensity in tumor tissue, which should be attributed to the increased relaxivity and tumor accumulation. PGG-PTX-DTPA-Gd NPs also showed effective antitumor effect in vivo. These results indicated that PGG-PTX-DTPA-Gd NPs are an effective delivery system for tumor theranostics, and should have a potential value in personalized treatment of tumor.
Topics: Animals; Cell Line, Tumor; Drug Delivery Systems; Gadolinium; Humans; Lung Neoplasms; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Paclitaxel; Pentetic Acid; Polyglutamic Acid; Theranostic Nanomedicine; Xenograft Model Antitumor Assays
PubMed: 28630436
DOI: 10.1038/s41598-017-03633-9 -
International Journal of Medical... 2014Increasing evidence reveals that traditional pharmacokinetics parameters based on plasma drug concentrations are insufficient to reliably demonstrate accurate...
Increasing evidence reveals that traditional pharmacokinetics parameters based on plasma drug concentrations are insufficient to reliably demonstrate accurate pharmacological effects of drugs in target organs or cells in vivo. This underscores the increasing need to improve the types and qualities of cellular pharmacokinetic information for drug preclinical screening and clinical efficacy assessments. Here we report a whole cell-based method to assess drugs that disturb microtubule dynamics to better understand different formulation-mediated intracellular drug release profiles. As proof of concept for this approach, we compared the well-known taxane class of anti-microtubule drugs based on paclitaxel (PTX), including clinically familiar albumin nanoparticle-based Abraxane™, and a polymer nanoparticle-based degradable paclitaxel carrier, poly(L-glutamic acid)-paclitaxel conjugate (PGA-PTX, also known as CT-2103) versus control PTX. This in vitro cell-based evaluation of PTX efficacy includes determining the cellular kinetics of tubulin polymerization, relative populations of cells under G2 mitotic arrest, cell proliferation and total cell viability. For these taxane tubulin-binding compounds, the kinetics of cell microtubule stabilization directly correlate with G2 arrest and cell proliferation, reflecting the kinetics and amounts of intracellular PTX release. Each individual cell-based dose-response experiment correlates with published, key therapeutic parameters and taken together, provide a comprehensive understanding of drug intracellular pharmacokinetics at both cellular and molecular levels. This whole cell-based evaluating method is convenient, quantitative and cost-effective for evaluating new formulations designed to optimize cellular pharmacokinetics for drugs perturbing tubulin polymerization as well as assisting in explaining drug mechanisms of action at cellular levels.
Topics: Albumin-Bound Paclitaxel; Albumins; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Cell Survival; Drug Evaluation; Drug Resistance, Neoplasm; Humans; Microtubules; Neoplasms; Paclitaxel; Polyglutamic Acid; Tubulin
PubMed: 24688312
DOI: 10.7150/ijms.8340 -
American Journal of Clinical Oncology Apr 2014Capecitabine and paclitaxel are established effective treatments, alone and combined with other cytotoxic and targeted agents, for metastatic breast cancer (MBC)....
BACKGROUND
Capecitabine and paclitaxel are established effective treatments, alone and combined with other cytotoxic and targeted agents, for metastatic breast cancer (MBC). Paclitaxel polyglumex (a macromolecular conjugate of paclitaxel bound to poly-L-glutamic acid) has potential advantages over conventional paclitaxel, including little alopecia, short infusion time with no premedication, enhanced tumor permeability/retention effect, and improved tolerability. We therefore examined tolerability and efficacy of paclitaxel polyglumex with capecitabine in patients with MBC.
PATIENTS AND METHODS
This was a single-stage phase 2 study, with interim analysis conducted with endpoints of tumor response, adverse events (toxicities), time to progression, and overall survival. The main eligibility criteria were: age >18 years, no prior MBC chemotherapy, Eastern Cooperative Oncology Group performance score <2, disease measurable by RECIST criteria, no HER2 overexpression or amplification, no brain metastases or peripheral sensory neuropathy. Treatment consisted of paclitaxel polyglumex (135 mg/m) by intravenous infusion on day 1+capecitabine (825 mg/m) orally twice daily on days 1 to 14, repeated on a 3-week cycle. Forty-one evaluable patients were required to test the null hypothesis that the complete and partial tumor response rate (CR+PR) was at the most 40% against the alternative of at least 60%. Paclitaxel polyglumex+capecitabine would be considered promising in this population if ≥21 responses were observed among first 41 evaluable patients.
RESULTS
Forty-eight patients were enrolled between April 2006 and April 2007; all patients were evaluable. The median number of treatment cycles administered was 6. Eighteen patients [38%; 95% confidence interval (CI), 24%-53%] had a confirmed tumor response (2 CR, 16 PR) by RECIST criteria. Fifteen (38%; 95% CI, 23%-53%) responses occurred in first 41 patients, falling short of prespecified goal of 21 responses. Median duration of tumor response was 13.2 months. Three of the responders were progression free at last follow-up with a median follow-up of 43 months. Median progression-free survival was 5.1 months (95% CI, 4.0-7.6 mo). Six-month progression-free survival was 42% (95% CI, 30%-58%). Median dose level administered was paclitaxel polyglumex (135 mg/m) and capecitabine (825 mg/m) for cycles 1 to 7. Most common severe (grade 3/4) toxicities (at least possibly related to study drug) were: leukopenia 9 (19%), neutropenia 8 (17%), neurosensory 4 (8%), skin reaction-hand/foot 4 (8%), and dyspnea 2 (4%). Forty-six percent (22/47) of patients experienced grade ≥3 toxicity and 8% (4/48) experienced grade ≥4 toxicity. No alopecia was reported.
CONCLUSIONS
Although the trial failed to reach goal of 21 confirmed tumor responses among the first 41 evaluable patients, paclitaxel polyglumex and capecitabine is well tolerated and effective in MBC.
Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Capecitabine; Deoxycytidine; Disease-Free Survival; Drug Administration Schedule; Female; Fluorouracil; Follow-Up Studies; Humans; Leukopenia; Middle Aged; Neutropenia; Paclitaxel; Polyglutamic Acid; Proportional Hazards Models; Treatment Outcome
PubMed: 23211220
DOI: 10.1097/COC.0b013e31826e0550 -
Clinical Cancer Research : An Official... Nov 2011To investigate the associations between baseline and posttreatment circulating tumor cell (CTC) gene expression and outcome of patients enrolled in four North Central...
Cytokeratin-19 and mammaglobin gene expression in circulating tumor cells from metastatic breast cancer patients enrolled in North Central Cancer Treatment Group trials, N0234/336/436/437.
PURPOSE
To investigate the associations between baseline and posttreatment circulating tumor cell (CTC) gene expression and outcome of patients enrolled in four North Central Cancer Treatment Group metastatic breast cancer (MBC) trials in which specimens were shipped (at 4°C) from community-based sites to a reference laboratory (Mayo Clinic, Rochester, MN).
EXPERIMENTAL DESIGN
Blood was collected at treating sites from MBC patients before (baseline), during, and at the end of treatment with erlotinib + gemcitabine (N0234), sorafenib (N0336), irinotecan + cetuximab (N0436), or paclitaxel-poliglumex + capecitabine (N0437). CTCs from 10 mL of EDTA blood were enriched with CD45 depletion, 24 to 30 hours postblood collection. Reverse transcription/quantitative PCR was used to determine cytokeratin-19 (CK19) and mammaglobin (MGB1) mRNA levels in CTCs from up to 13 (N0234), 16 (N0336), 18 (N0436), and 39 (N0437) patients. The gene expressions were normalized to β(2)-microglobulin and calibrated to healthy blood using the 2(-ΔΔCq) algorithm; positivity was defined as 2 or more.
RESULTS
CK19+mRNA cells were detected in 56% to 75% and MGB1+mRNA cells in 23% to 38% of 86 patients at baseline. CK19+mRNA cells were detected in 30% to 67% and MGB1+mRNA cells in 14% to 64% of 110 postbaseline serial samples. The presence of baseline CK19+mRNA cells (P = 0.01) but not MGB1+mRNA cells (P = 0.14) was significantly associated with shorter overall survival. A decrease in MGB1+mRNA levels (baseline-week 8) seemed to be associated with clinical response (P = 0.05).
CONCLUSIONS
CTC gene expression analysis conducted by a reference laboratory is feasible when blood is collected from treating sites and processed 24 to 30 hours postcollection. The presence of baseline CK19+mRNA CTCs was associated with poor prognosis; a decrease in MGB1+mRNA CTCs may help predict response to therapy of MBC patients.
Topics: Adult; Aged; Breast Neoplasms; Female; Gene Expression; Humans; Keratin-19; Mammaglobin A; Middle Aged; Neoplasm Metastasis; Neoplastic Cells, Circulating; Prognosis; RNA, Messenger; Treatment Outcome
PubMed: 21976532
DOI: 10.1158/1078-0432.CCR-11-0981 -
Annals of Oncology : Official Journal... Mar 2012Despite current trend of targeted therapy development, cytotoxic agents are a mainstay of treatment of patients with breast cancer. We reviewed recent advances in... (Review)
Review
BACKGROUND
Despite current trend of targeted therapy development, cytotoxic agents are a mainstay of treatment of patients with breast cancer. We reviewed recent advances in cytotoxic therapy for patients with metastatic breast cancer (MBC).
MATERIALS AND METHODS
Medline searches were conducted for English language studies using the term 'MBC' and 'cytotoxic drugs'. The data search was restricted to the period 2000-2011.
RESULTS
Several novel cytotoxic compounds, all microtubule inhibitors, have been approved for clinical use in MBC: (i) nab-paclitaxel, reported to improve tumour response and decrease hypersensitivity reactions in comparison with other taxanes; (ii) ixabepilone, shown to have clinical benefit in taxane- and anthracycline-resistant disease and (iii) eribulin, shown to improve overall survival in heavily pre-treated patients, when compared with best available standard treatment. Agents, such as larotaxel, vinflunine, trabectidin and formulations, including cationic liposomal paclitaxel or paclitaxel poliglumex, are currently under evaluation in phase II/III trials.
CONCLUSION
Toxicity and chemotherapy resistance are still major limitations in the treatment of patients with MBC. Further research into new cytotoxic compounds is needed in order to maximise benefit, whilst minimising toxicity.
Topics: Antineoplastic Agents; Breast Neoplasms; Clinical Trials as Topic; Cytotoxins; Female; Humans
PubMed: 21896541
DOI: 10.1093/annonc/mdr382 -
International Journal of General... Dec 2010In Phase I evaluation of CT-2103 (paclitaxel poliglumex), prolongation of prothrombin time (PT) and activated thromboplastin time (aPTT) was observed, without clinical...
BACKGROUND
In Phase I evaluation of CT-2103 (paclitaxel poliglumex), prolongation of prothrombin time (PT) and activated thromboplastin time (aPTT) was observed, without clinical consequence, with doses 1.3-1.5 times higher than the current clinical dose of 175 mg/m(2). This Phase I, open-label, nonrandomized pilot study was performed to study the effect of the standard dose regimen on blood coagulation.
METHODS
Seven previously treated solid tumor patients received CT-2103 175 mg/m(2) intravenously on day 1 of 21-day cycles for a mean of 5.4 cycles (median 4, range 2-14). Plasma samples were collected for cycle 1 predose and at hours 1, 24, 48, and 72 after the end of administration for drug levels, and for PT and aPTT assays.
RESULTS
No coagulopathy-related adverse events were documented. Bleeding time remained normal in the six patients tested, with transient increases in PT and aPTT noted but resolving within 72 hours. Titration studies at 100 μg/mL of CT-2103 (corresponding to the standard clinical dose) prolonged PT and aPTT clotting times, produced a modest dose-dependent reduction of thrombin and factor Xa, and no significant changes in factors IXa, XIa, or XIIa. Two patients achieved stable disease for ≥10 cycles.
CONCLUSION
CT-2103 is associated with transient prolongation of PT and aPTT without clinical sequelae.
PubMed: 21403785
DOI: 10.2147/IJGM.S12170 -
Biomaterials May 2011Angiogenesis plays a prominent role in cancer progression. Anti-angiogenic therapy therefore, either alone or in combination with conventional cytotoxic therapy, offers...
Angiogenesis plays a prominent role in cancer progression. Anti-angiogenic therapy therefore, either alone or in combination with conventional cytotoxic therapy, offers a promising therapeutic approach. Paclitaxel (PTX) is a widely-used potent cytotoxic drug that also exhibits anti-angiogenic effects at low doses. However, its use, at its full potential, is limited by severe side effects. Here we designed and synthesized a targeted conjugate of PTX, a polymer and an integrin-targeted moiety resulting in a polyglutamic acid (PGA)-PTX-E-[c(RGDfK)(2)] nano-scaled conjugate. Polymer conjugation converted PTX to a macromolecule, which passively targets the tumor tissue exploiting the enhanced permeability and retention effect, while extravasating via the leaky tumor neovasculature. The cyclic RGD peptidomimetic enhanced the effects previously seen for PGA-PTX alone, utilizing the additional active targeting to the α(v)β(3) integrin overexpressed on tumor endothelial and epithelial cells. This strategy is particularly valuable when tumors are well-vascularized, but they present poor vascular permeability. We show that PGA is enzymatically-degradable leading to PTX release under lysosomal acidic pH. PGA-PTX-E-[c(RGDfK)(2)] inhibited the growth of proliferating α(v)β(3)-expressing endothelial cells and several cancer cells. We also showed that PGA-PTX-E-[c(RGDfK)(2)] blocked endothelial cells migration towards vascular endothelial growth factor; blocked capillary-like tube formation; and inhibited endothelial cells attachment to fibrinogen. Orthotopic studies in mice demonstrated preferential tumor accumulation of the RGD-bearing conjugate, leading to enhanced anti-tumor efficacy and a marked decrease in toxicity as compared with free PTX-treated mice.
Topics: Animals; Antineoplastic Agents, Phytogenic; Cathepsin B; Cell Line, Tumor; Cell Proliferation; Drug Delivery Systems; Humans; Integrins; Mice; Mice, Inbred BALB C; Neoplasms; Neovascularization, Pathologic; Oligopeptides; Paclitaxel; Polyglutamic Acid; Rats; Rats, Wistar
PubMed: 21376390
DOI: 10.1016/j.biomaterials.2011.01.073 -
International Journal of Nanomedicine Oct 2010The purpose of this study was to develop a novel, highly water-soluble poly(L-γ-glutamyl-glutamine)-paclitaxel nanoconjugate (PGG-PTX) that would improve the...
The purpose of this study was to develop a novel, highly water-soluble poly(L-γ-glutamyl-glutamine)-paclitaxel nanoconjugate (PGG-PTX) that would improve the therapeutic index of paclitaxel (PTX). PGG-PTX is a modification of poly(L-glutamic acid)- paclitaxel conjugate (PGA-PTX) in which an additional glutamic acid has been added to each glutamic side chain in the polymer. PGG-PTX has higher water-solubility and faster dissolution than PGA-PTX. Unlike PGA-PTX, PGG-PTX self-assembles into nanoparticles, whose size remains in the range of 12-15 nm over the concentration range from 25 to 2,000 μg/mL in saline. Its critical micellar concentration in saline was found to be ~25 μg/mL. The potency of PGG-PTX when tested in vitro against the human lung cancer H460 cell line was comparable to other known polymer-PTX conjugates. However, PGG-PTX possesses lower toxicity compared with PGA-PTX in mice. The maximum tolerated dose of PGG-PTX was found to be 350 mg PTX/kg, which is 2.2-fold higher than the maximum tolerated dose of 160 mg PTX/kg reported for the PGA-PTX. This result indicates that PGG-PTX was substantially less toxic in vivo than PGA-PTX.
Topics: Animals; Antineoplastic Agents, Phytogenic; Cell Line, Tumor; Drug Delivery Systems; Humans; Lung Neoplasms; Mice; Mice, Nude; Nanoconjugates; Nanomedicine; Paclitaxel; Particle Size; Polyglutamic Acid; Proteins; Solubility
PubMed: 21042550
DOI: 10.2147/IJN.S13482 -
Methods and Findings in Experimental... 2010A-3309, Abobotulinumtoxin A, Adalimumab, AIDSVAX gp120 B/E, ALVAC E120TMG, Atorvastatin calcium; Bepridil, Bevacizumab; Candesartan cilexetil, Capecitabine, Cetuximab,...
A-3309, Abobotulinumtoxin A, Adalimumab, AIDSVAX gp120 B/E, ALVAC E120TMG, Atorvastatin calcium; Bepridil, Bevacizumab; Candesartan cilexetil, Capecitabine, Cetuximab, Clopidogrel; Dapagliflozin, Dasatinib, Denosumab, Dexmedetomidine hydrochloride, Diacetylmorphine, Diannexin, Docetaxel, Dutasteride; Entecavir, Eplerenone, Erlotinib hydrochloride, Escitalopram oxalate, Everolimus, Ezetimibe; Fesoterodine fumarate, Flagellin.HuM2e, Fluzone; Glimepiride/rosiglitazone maleate; Hyaluronic acid-paclitaxel bioconjugate; IDX-184, Imatinib mesylate, Infliximab, Insulin glargine, Irbesartan; JX-594; Landiolol, Latrunculin B, Levocetirizine dihydrochloride, Liraglutide, Lyprinol; Metformin, Metronidazole/tetracycline hydrochloride/bismuth biskalcitrate, Mipomersen sodium, Mycophenolic acid sodium salt; Nalfurafine hydrochloride, Nilotinib hydrochloride monohydrate; Paclitaxel nanoparticles, Paclitaxel poliglumex, Peginterferon alfa-2a, Peginterferon alfa-2b, Perospirone hydrochloride, Pimavanserin tartrate, Pirfenidone, Pitavastatin calcium, Prasterone, Prasugrel, Pregabalin, Ranelic acid distrontium salt, Ranibizumab, Remimazolam, Risedronate, Rosuvastatin calcium; Silodosin, Silybin phosphatidylcholine complex, Sirolimus-eluting stent, Sitagliptin phosphate monohydrate, Sorafenib, Sunitinib malate; Tadalafil, Tamsulosin hydrochloride, Technosphere/insulin, Telmisartan, Temsirolimus, Teriparatide, Thymalfasin, Ticagrelor, Toltedorine-XR, Tramadol-XR, Triphosadenine, Trospium-XR; Val8-GLP-1(7-37)OH, Valsartan, Vardenafil hydrochloride hydrate, Varenicline tartrate, Velaglucerase alfa; Zoledronic acid monohydrate.
Topics: Clinical Trials as Topic; Humans
PubMed: 20852754
DOI: 10.1358/mf.2010.32.6.1538165