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Anti-cancer Drugs May 2014Since their addition to paclitaxel in the oncologists' armamentarium in the early 1990s, several new taxane formulations have been developed. Besides docetaxel and... (Review)
Review
Since their addition to paclitaxel in the oncologists' armamentarium in the early 1990s, several new taxane formulations have been developed. Besides docetaxel and nab-paclitaxel, new analogs with better therapeutic profiles are being investigated. The goals of this next generation of taxanes are to improve the toxicity profile and efficacy, and to overcome resistance patterns. Several new taxanes, including cabazitaxel, paclitaxel poliglumex, paclitaxel+endotag, and polymeric-micellar paclitaxel, have shown clinical efficacy. These chemotherapeutics are part of many ongoing phase II and III studies on various cancer types. In addition, there are immunotoxins that link key antibodies to mitotic spindle inhibitors (trastuzumab emtansine and brentuximab vedotin). Through this mechanism, novel formulations increase cytotoxicity, improve specificity, and create possibilities for drug enhancement.
Topics: Antineoplastic Agents, Phytogenic; Drug Therapy, Combination; Humans; Immunotoxins; Neoplasms; Taxoids
PubMed: 24374330
DOI: 10.1097/CAD.0000000000000053 -
American Journal of Clinical Oncology Oct 2014Paclitaxel poliglumex (PPX), a drug conjugate that links paclitaxel to poly-L-glutamic acid, is a potent radiation sensitizer. Prior studies in esophageal cancer have...
OBJECTIVES
Paclitaxel poliglumex (PPX), a drug conjugate that links paclitaxel to poly-L-glutamic acid, is a potent radiation sensitizer. Prior studies in esophageal cancer have demonstrated that PPX (50 mg/m/wk) can be administered with concurrent radiation with acceptable toxicity. The primary objective of this study was to determine the safety of the combination of PPX with temozolomide and concurrent radiation for high-grade gliomas.
METHODS
Eligible patients were required to have WHO grade 3 or 4 gliomas. Patients received weekly PPX (50 mg/m/wk) combined with standard daily temozolomide (75 mg/m) for 6 weeks with concomitant radiation (2.0 Gy, 5 d/wk for a total dose of 60 Gy).
RESULTS
Twenty-five patients were enrolled, 17 with glioblastoma and 8 with grade 3 gliomas. Seven of 25 patients had grade 4 myelosuppression. Hematologic toxicity lasted up to 5 months suggesting a drug interaction between PPX and temozolomide. For patients with glioblastoma, the median progression-free survival was 11.5 months and the median overall survival was 18 months.
CONCLUSIONS
PPX could not be safely combined with temozolomide due to grade 4 hematologic toxicity. However, the favorable progression-free and overall survival suggest that PPX may enhance radiation for glioblastoma. A randomized study of single agent PPX/radiation versus temozolomide/radiation for glioblastoma without MGMT methylation is underway.
Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Brachytherapy; Brain Neoplasms; Chemoradiotherapy; Combined Modality Therapy; Dacarbazine; Disease-Free Survival; Female; Glioma; Humans; Male; Middle Aged; Paclitaxel; Polyglutamic Acid; Survival Analysis; Temozolomide
PubMed: 23388562
DOI: 10.1097/COC.0b013e31827de92b -
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 -
Medicine and Health, Rhode Island May 2012
Topics: Antineoplastic Agents, Alkylating; Antineoplastic Agents, Phytogenic; Brain Neoplasms; Dacarbazine; Glioma; Humans; Magnetic Resonance Angiography; Male; Middle Aged; Necrosis; Paclitaxel; Polyglutamic Acid; Temozolomide
PubMed: 22808637
DOI: No ID Found -
Evolution of the Gynecologic Oncology Group protocols in the treatment of epithelial ovarian cancer.Clinical Obstetrics and Gynecology Mar 2012This chapter reviews some of the sentinel Gynecologic Oncology Group (GOG) ovarian trials, describes their rationale, provides summary tables for reference, and is... (Review)
Review
This chapter reviews some of the sentinel Gynecologic Oncology Group (GOG) ovarian trials, describes their rationale, provides summary tables for reference, and is organized into early ovarian cancer (GOG 1, 7601, 7602, 95, 157, 175, 212), advanced ovarian cancer optimal (2, 25, 52, 104, 114, 158, 172, 182, 178, 212, 252), and suboptimal disease (3, 22, 47, 97, 111, 162, 182, 218, 252, 262).
Topics: Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Clinical Trials as Topic; Female; Humans; Laparotomy; Neoplasm Staging; Neoplasms, Glandular and Epithelial; Ovarian Neoplasms; Paclitaxel; Polyglutamic Acid; Second-Look Surgery
PubMed: 22343234
DOI: 10.1097/GRF.0b013e318248050d -
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 -
Expert Opinion on Investigational Drugs Jun 2011Despite an 80% initial response rate to the standard primary regimen of carboplatin and paclitaxel, most women with ovarian cancer will experience recurrence with... (Review)
Review
INTRODUCTION
Despite an 80% initial response rate to the standard primary regimen of carboplatin and paclitaxel, most women with ovarian cancer will experience recurrence with incurable disease within five years and will be treated with several successive palliative regimens. Consequently, a significant need exists for chemotherapeutic agents, which are not only clinically efficacious, but have acceptable side-effect profiles. Paclitaxel poliglumex (PPX) is a recently developed taxane in which paclitaxel is conjugated to poly(l-glutamic acid), which renders it water soluble, reduces hypersensitivity reactions and preferentially targets it to the tumor.
AREAS COVERED
This review covers pre-clinical pharmacokinetic data and key Phase I and II clinical trial results in ovarian cancer.
EXPERT OPINION
While PPX is active in ovarian cancer, it is unclear at present whether it offers significant benefit in terms of its side-effect profile or outcomes over a standard taxane-based regimen as first-line therapy, or what role it will have in maintenance therapy as studies are ongoing.
Topics: Animals; Antineoplastic Agents, Phytogenic; Drug Delivery Systems; Female; Humans; Neoplasm Recurrence, Local; Ovarian Neoplasms; Paclitaxel; Palliative Care; Polyglutamic Acid; Solubility; Time Factors; Treatment Outcome
PubMed: 21470062
DOI: 10.1517/13543784.2011.576666 -
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