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1.
Lisa M. McGregor MD PhD Sheri L. Spunt MD Wayne L. Furman MD Clinton F. Stewart PharmD Paula Schaiquevich PhD Mark D. Krailo PhD RoseAnne Speights BA CCRP Percy Ivy MD Peter C. Adamson MD Susan M. Blaney MD 《Cancer》2009,115(8):1765-1775
BACKGROUND:
For this report, the authors estimated the maximum tolerated dose (MTD) and investigated the toxicities of oxaliplatin combined with irinotecan in children with refractory solid tumors.METHODS:
Oxaliplatin was administered on Days 1 and 8 in combination with irinotecan on Days 1 through 5 and Days 8 through 12 of a 21‐day cycle. An oral cephalosporin was administered daily to ameliorate irinotecan‐associated diarrhea. Pharmacokinetic studies of oxaliplatin and uridine diphosphate glucuronosyltransferase 1 family, polypeptide A1 (UGT1A1) genotyping were performed.RESULTS:
Thirteen patients were enrolled. Dose‐limiting diarrhea (n = 3), serum lipase elevation (n = 3), serum amylase elevation (n = 2), colitis, abdominal pain, and headache (n = 1 each) occurred at the first dose level (oxaliplatin at a dose of 60 mg/m2; irinotecan at a dose of 20 mg/m2). Only 1 of 7 patients who received reduced doses of both agents (40 mg/m2/dose oxaliplatin; 15 mg/m2/dose irinotecan) experienced a dose‐limiting toxicity (DLT): diarrhea. When the oxaliplatin dose was re‐escalated (60 mg/m2) with irinotecan at a dose of 15 mg/m2, 2 of 3 patients had a DLT (1 episode of diarrhea, 1 episode of hypokalemia). Myelosuppression was minimal. One patient had a complete response, and another patient had stable disease for 6 cycles of therapy. The median oxaliplatin area under the concentration versus time curve (AUC0→∞) was 5.9 μg · hour/mL (range, 1.8‐7.6 μg · hour/mL). The frequency of the 6/6, 6/7, and 7/7 UGT1A1 promoter genotypes was 5 of 10, 4 of 10, and 1 of 10, respectively.CONCLUSIONS:
The oxaliplatin MTD was 40 mg/m2 per dose on Days 1 and 8 in combination with irinotecan 15 mg/m2 per dose on Days 1‐5 and Days 8‐12. There was some evidence of antitumor activity; however, severe toxicity, both expected (diarrhea) and unexpected (elevation in pancreatic enzymes), was observed. Cancer 2009. © 2009 American Cancer Society. 相似文献2.
Reardon DA Desjardins A Peters KB Vredenburgh JJ Gururangan S Sampson JH McLendon RE Herndon JE Coan A Threatt S Friedman AH Friedman HS 《Cancer》2011,117(23):5351-5358
BACKGROUND:
The efficacy of carboplatin, irinotecan, and bevacizumab among recurrent glioblastoma (GBM) patients after prior progression on bevacizumab therapy in a phase 2, open‐label, single‐arm trial was evaluated.METHODS:
Eligible patients received carboplatin (area under the plasma curve [AUC] 4 mg/ml‐min) on day 1, whereas bevacizumab (10 mg/kg) and irinotecan (340 mg/m2 for patients on CYP3A enzyme‐inducing anti‐epileptics [EIAEDs] and 125 mg/m2 for patients not on EIAEDs) were administered on days 1 and 14 of every 28‐day cycle. Patients were evaluated after each of the first 2 cycles and then after every other cycle. Treatment continued until progressive disease, unacceptable toxicity, noncompliance, or voluntary withdrawal. The primary end point was progression‐free survival at 6 months (PFS‐6), and secondary end points included safety and median overall survival (OS).RESULTS:
All patients had progression on at least 1 prior bevacizumab regimen and 56% enrolled after either second or third overall progression. The median OS was 5.8 months (95% confidence interval [CI], 4.0‐7.0 months) and PFS‐6 rate was 16% (95% CI, 5.0%‐32.5%). The most common grade 3 or 4 events were hematologic and occurred in 29% of cycles. Nine patients (38%) required dose modification. There were no treatment‐related deaths.CONCLUSIONS:
Carboplatin, irinotecan, and bevacizumab was associated with modest activity and adequate safety among recurrent GBM patients who progressed on bevacizumab previously. Cancer 2011;. © 2011 American Cancer Society. 相似文献3.
Francisco Robert Karen Harper Judie Ackerman Sunil Gupta 《Cancer chemotherapy and pharmacology》2010,65(2):227-234
Purpose
This primary objective of this phase I dose-escalation study was to define the maximum tolerated dose (MTD) and dose limiting toxicity (DLT) of larotaxel administered in combination with carboplatin in chemotherapy-naïve patients with advanced/metastatic non-small cell lung cancer (NSCLC).Methods
Eighteen patients with stage IIIB or IV NSCLC, in cohorts of three to six evaluable patients, were to receive every 3 weeks: larotaxel beginning at 45 mg/m2 administered as a 1-h infusion, followed after 30 min by carboplatin (area under the concentration–time curve (AUC) = 6 mg/mL × min, later AUC = 5) as a 1-h infusion. Dose escalation of larotaxel up to 90 mg/m2 was permitted according to DLT occurrence. Patients received ondansetron as prophylactic anti-emetic premedication.Results
In view of the toxicity encountered, the carboplatin dose was decreased for the later part of the study to AUC = 5 mg/mL × min. Eight of 18 treated patients experienced DLTs in the first cycle, including neutropenia and associated complications, diarrhea and fatigue. The MTD of the combination was defined as larotaxel 60 mg/m2 with a carboplatin AUC of 6 mg/mL × min. Neutropenia, reported at grade 3/4 in 15/18 patients (83%), was the most common severe adverse event, reaching grade 4 in 14 patients (78%). Eleven patients (61%) experienced grade 3/4 non-hematological toxicity, predominantly dehydration, fatigue, infection, nausea and vomiting. One patient (6%) achieved a partial response and 11 (61%) had stable disease.Conclusions
The combination of larotaxel and carboplatin is feasible and shows modest activity in chemotherapy-naïve patients with advanced/metastatic NSCLC. The principal toxicity was grade 3/4 neutropenia. 相似文献4.
Razelle Kurzrock MD Sanjay Goel MD Jennifer Wheler MD David Hong MD Siqing Fu MD PhD Keyvan Rezai PhD Sonia K. Morgan‐Linnell PhD Saik Urien MD PhD Sridhar Mani MD Imran Chaudhary MD Mohammed H. Ghalib MD Aby Buchbinder MD CM François Lokiec PhD Mary Mulcahy MD 《Cancer》2012,118(24):6144-6151
BACKGROUND:
EZN‐2208 is a water‐soluble, polyethylene glycol drug conjugate of SN38, which is the active moiety of irinotecan. In this study, the authors evaluated the tolerability, pharmacokinetics (PK), and activity of EZN‐2208 in adult patients with advanced solid tumors.METHODS:
Patients in sequential cohorts (3 + 3 design) received intravenous EZN‐2208 at doses between 1.25 mg/m2 and 25 mg/m2 once every 21 days.RESULTS:
Thirty‐nine patients received EZN‐2208. The median number of prior therapies was 2 (range, 0‐10 prior therapies). Seventeen patients received prior irinotecan. Two maximum tolerated doses (MTDs) were defined: EZN‐2208 with (16.5 mg/m2) and without (10 mg/m2) granulocyte‐colony–stimulating factor (G‐CSF). The dose‐limiting toxicity (DLT) was febrile neutropenia. Two of 19 patients who were heterozygous for a polymorphism in the uridine diphosphate glucuronosyltransferase 1 family, polypeptide A1 (UGT1A1) gene (UGT1A1*28) developed DLTs (dose, 25 mg/m2 with G‐CSF), and 2 patients who were homozygous for UGT1A1*28 were treated without DLTs (dose, 5 mg/m2). PK analysis indicated a mean terminal half‐life of 19.4 ± 3.4 hours. Sixteen patients (41%) achieved stable disease, including 6 of 39 patients (15%) who had stable disease that lasted ≥4 months. One patient with cholangiocarcinoma (no prior irinotecan) achieved a short‐lived 32% tumor regression. Among 6 patients who had stable disease that lasted for ≥4 months, 3 had received prior irinotecan, and 1 had KRAS‐positive colorectal cancer.CONCLUSIONS:
EZN‐2208 was well tolerated and produced stable disease that lasted for ≥4 months/unconfirmed partial responses in 7 of 39 heavily pretreated patients (18%) with advanced solid tumors, including those who had failed prior irinotecan therapy. Cancer 2012. © 2012 American Cancer Society. 相似文献5.
Jeanne Schilder MD Timothy Breen MS Shu Zhang MD PhD Changyu Shen PhD Lang Li PhD Carol Kulesavage Anthony J. Snyder BS Kenneth P. Nephew PhD Daniela E. Matei MD 《Cancer》2010,116(17):4043-4053
BACKGROUND:
Aberrant DNA methylation is a hallmark of cancer, and DNA methyltransferase inhibitors have demonstrated clinical efficacy in hematologic malignancies. On the basis of preclinical studies indicating that hypomethylating agents can reverse platinum resistance in ovarian cancer cells, the authors conducted a phase 1 trial of low‐dose decitabine combined with carboplatin in patients with recurrent, platinum‐resistant ovarian cancer.METHODS:
Decitabine was administered intravenously daily for 5 days, before carboplatin (area under the curve, 5) on Day 8 of a 28‐day cycle. By using a standard 3 + 3 dose escalation, decitabine was tested at 2 dose levels: 10 mg/m2 (7 patients) or 20 mg/m2 (3 patients). Peripheral blood mononuclear cells (PBMCs) and plasma collected on Days 1 (pretreatment), 5, 8, and 15 were used to assess global (LINE‐1 repetitive element) and gene‐specific DNA methylation.RESULTS:
Dose‐limiting toxicity (DLT) at the 20‐mg/m2 dose was grade 4 neutropenia (2 patients), and no DLTs were observed at 10 mg/m2. The most common toxicities were nausea, allergic reactions, neutropenia, fatigue, anorexia, vomiting, and abdominal pain, the majority being grades 1‐2. One complete response was observed, and 3 additional patients had stable disease for ≥6 months. LINE‐1 hypomethylation on Days 8 and 15 was detected in DNA from PBMCs. Of 5 ovarian cancer‐associated methylated genes, HOXA11 and BRCA1 were demethylated in plasma on Days 8 and 15.CONCLUSIONS:
Repetitive low‐dose decitabine is tolerated when combined with carboplatin in ovarian cancer patients, and demonstrates biological (ie, DNA‐hypomethylating) activity, justifying further testing for clinical efficacy. Cancer 2010. © 2010 American Cancer Society. 相似文献6.
Phase 1 study of veliparib with carboplatin and weekly paclitaxel in Japanese patients with newly diagnosed ovarian cancer
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Shin Nishio Munetaka Takekuma Satoshi Takeuchi Kouichirou Kawano Naotake Tsuda Kazuto Tasaki Nobutaka Takahashi Masakazu Abe Aki Tanaka Takayuki Nagasawa Tadahiro Shoji Hao Xiong Silpa Nuthalapati Terri Leahy Hideyuki Hashiba Tsukasa Kiriyama Philip Komarnitsky Yasuyuki Hirashima Kimio Ushijima 《Cancer science》2017,108(11):2213-2220
This phase 1, open‐label, dose‐escalation study was conducted to determine the safety, tolerability, pharmacokinetics and preliminary efficacy of veliparib with carboplatin and weekly paclitaxel in Japanese women with newly diagnosed, advanced ovarian cancer. Patients received veliparib at 100 or 150 mg b.i.d. on days 1–21 with carboplatin (area under the concentration–time curve 6 mg/mL?min) on day 1 and paclitaxel 80 mg/m2 on days 1, 8 and 15 every 3 weeks for up to 6 21‐day cycles. Dose escalation followed a 3 + 3 design to determine dose‐limiting toxicities, maximum tolerated dose and the recommended phase 2 dose. Nine patients (median age 62 [range 27–72] years) received a median of 5 (range 3–6) cycles of treatment (3 at 100 mg, 6 at 150 mg). There were no dose‐limiting toxicities. The most common adverse events of any grade were neutropenia (100%), alopecia (89%), peripheral sensory neuropathy (78%), and anemia, nausea and malaise (67% each). Grade 3 or 4 adverse events were associated with myelosuppression. Pharmacokinetics of carboplatin/paclitaxel were similar at both veliparib doses. Response, assessed in five patients, was partial in four and complete in one (objective response rate 100%). The response could not be assessed in four patients who had no measurable disease at baseline. The recommended phase 2 dose of veliparib, when combined with carboplatin/paclitaxel, is 150 mg b.i.d. Findings from this phase 1 trial demonstrate the tolerability and safety of veliparib with carboplatin/paclitaxel, a regimen with potential clinical benefit in Japanese women with ovarian cancer. 相似文献
7.
Lisa M. McGregor MD PhD Sheri L. Spunt MD Victor M. Santana MD Clinton F. Stewart PharmD Deborah A. Ward PharmD Amy Watkins MS Fred H. Laningham MD Percy Ivy MD Wayne L. Furman MD Maryam Fouladi MD 《Cancer》2009,115(3):655-664
BACKGROUND:
The combination of a platinating agent and etoposide has induced responses in various pediatric tumors. The study estimated the maximum tolerated dose (MTD) of an oxaliplatin and etoposide regimen in children with recurrent solid tumors.METHODS:
Oxaliplatin was administered on Day 1 and etoposide on Days 1 to 3 of each 21‐day course. Cohorts of 3 to 6 patients were enrolled at 3 dose levels: 1) oxaliplatin at a dose of 130 mg/m2 and etoposide at a dose of 75 mg/m2, 2) oxaliplatin at a dose of 130 mg/m2 and etoposide at a dose of 100 mg/m2, and 3) oxaliplatin at a dose of 145 mg/m2 and etoposide at a dose of 100 mg/m2. Calcium and magnesium infusions were used at dose level 3 in an attempt to escalate the oxaliplatin dose past the single‐agent MTD.RESULTS:
The 16 patients received a total of 63 courses. At dose level 1, dose‐limiting epistaxis, neuropathy, and neutropenia occurred in 1 of 6 patients. No dose‐limiting toxicity (DLT) occurred at dose level 2 (n = 6). At dose level 3, 2 of 4 patients experienced dose‐limiting neutropenia; none experienced grade 3 or 4 acute neuropathy. Six patients required prolongation of the oxaliplatin infusion because of acute sensory neuropathy. Responses were observed in patients with medulloblastoma (1 complete response) and pineoblastoma (1 partial response); 3 others with atypical teratoid rhabdoid tumor, ependymoma, and soft tissue sarcoma had prolonged disease stabilization.CONCLUSIONS:
The MTD of this regimen was found to be oxaliplatin at a dose of 130 mg/m2 given on Day 1 and etoposide at a dose of 100 mg/m2/d given on Days 1 to 3. Neutropenia was found to be the DLT. Calcium and magnesium infusions did not allow escalation of the oxaliplatin dose. The combination was well‐tolerated and demonstrated antitumor activity. Cancer 2009. © 2008 American Cancer Society. 相似文献8.
Jennifer A. Quinn MD Sara Xiaoyin Jiang David A. Reardon MD Annick Desjardins MD James J. Vredenburgh MD Sridharan Gururangan MRCP John H. Sampson MD PhD Roger E. McLendon MD James E. Herndon II PhD Henry S. Friedman MD 《Cancer》2009,115(13):2964-2970
BACKGROUND:
The current study was a phase 1 clinical trial conducted with patients who had recurrent or progressive malignant glioma (MG). The trial was designed to determine the maximum tolerated dose (MTD) and toxicity of irinotecan (CPT‐11) when administered with temozolomide (TMZ) and O6‐benzylguanine (O6‐BG).METHODS:
All 3 drugs, CPT‐11, TMZ, and O6‐BG, were administered on Day 1 of a 21‐day treatment. First, patients were treated with a 1‐hour bolus infusion of O6‐BG at a dose of 120 mg/m2 followed immediately by a 48‐hour continuous infusion of O6‐BG at a dose of 30 mg/m2/d. Second, within 60 minutes of the end of the 1‐hour bolus infusion of O6‐BG, TMZ was administered orally at a dose of 355 mg/m2. Third, 1 hour after administration of TMZ, CPT‐11 was infused over 90 minutes. Patients were accrued to 1 of 2 strata based on CYP3A1‐ and CYP3A4‐inducing antiepileptic drug (EIAED) use; dose escalation was conducted independently within these strata.RESULTS:
Fifty‐five patients were enrolled. In both strata, the dose‐limiting toxicities were hematologic and included grade 4 neutropenia, febrile neutropenia, leukopenia, and/or thrombocytopenia. For Stratum 1 (EIAEDs), when TMZ was administered at a dose of 355 mg/m2, the MTD of CPT‐11 was determined to be 120 mg/m2. In contrast, for Stratum 2 (no EIAEDs), when TMZ was administered at a dose of 200 mg/m2, the MTD of CPT‐11 was determined to be 80 mg/m2.CONCLUSIONS:
The authors believe that the results of the current study provide the foundation for a phase 2 trial of O6‐BG in combination with CPT‐11 and TMZ in patients with MG. Cancer 2009. © 2009 American Cancer Society. 相似文献9.
R. C. Brennan W. Furman S. Mao J. Wu D. C. Turner C. F. Stewart V. Santana L. M. McGregor 《Cancer chemotherapy and pharmacology》2014,74(6):1191-1198
Purpose
This phase I study endeavored to estimate the maximum tolerated dose and describe the dose-limiting toxicities (DLTs) of oral irinotecan with gefitinib in children with refractory solid tumors.Methods
Oral irinotecan was administered on days 1–5 and 8–12 with oral gefitinib (fixed dose, 150 mg/m2/day) on days 1–12 of a 21-day course. The escalation with overdose control method guided irinotecan dose escalation (7 dose levels, range 5–40 mg/m2/day).Results
Sixteen of 19 patients were evaluable, with serial pharmacokinetic studies in ten patients. Diagnoses included osteosarcoma (N = 5), neuroblastoma (N = 3), sarcoma (N = 3), and others (N = 5). Patients received a median of two courses (range 1–20), with at least two patients treated on dose levels 2–7. Three patients had five DLTs; the most common being metabolic (hypokalemia, N = 2 and hypophosphatemia, N = 1) at dose levels two (10 mg/m2) and four (20 mg/m2). One patient experienced grade 3 diarrhea (40 mg/m2). Irinotecan bioavailability was 2.5-fold higher when co-administered with gefitinib, while the conversion rate of irinotecan to SN-38 lactone was unaffected. The study closed due to poor accrual before evaluation of the next recommended irinotecan dose level (35 mg/m2). Of 11 patients receiving at least two courses of therapy, three had stable disease lasting two to four courses and one patient maintained a complete response through 18 courses.Conclusions
The combination of oral gefitinib and irinotecan has acceptable toxicity and anti-tumor activity in pediatric patients with refractory solid tumors. Pharmacokinetic analysis confirms that co-administration of gefitinib increases irinotecan bioavailability leading to an increased SN-38 lactone systemic exposure. 相似文献10.
Fury MG Sherman E Ho A Katabi N Sima C Kelly KW Nwankwo O Haque S Pfister DG 《Cancer chemotherapy and pharmacology》2012,70(1):121-128
Purpose
The mammalian target of rapamycin complex 1 (mTORC1) is aberrantly activated in many head and neck squamous cell carcinomas (HNSCCs). This phase I study combines the mTORC1 inhibitor temsirolimus with carboplatin and paclitaxel.Methods
This was a single institution phase I study for patients with R/M HNSCC with a standard 3?+?3 design. Three doses of temsirolimus were planned: 15, 20, and 25?mg. Due to excessive toxicity with the original study regimen, the protocol was amended to carboplatin AUC 1.5, paclitaxel 80?mg/m2, and temsirolimus (according to dose escalation plan), all on days 1 and 8 of a 21-day cycle.Results
18 patients (14 male, 4 female) enrolled, with median age 56?years (range 33?C78). The most common toxicities were anemia, leukopenia, thrombocytopenia, and hyperglycemia. Among all patients treated, the confirmed objective partial response (cPR) rate was 22?%. DLT was not exceeded among 6 patients treated at dose level 3 of the revised protocol, and 4 of 6 subjects treated at this dose level had cPRs.Conclusion
The phase II recommended regimen is temsirolimus 25?mg, carboplatin AUC 1.5, and paclitaxel 80?mg/m2, all on days 1 and 8 of a 21-day cycle. A phase II study of this regimen in R/M HNSCC is ongoing. 相似文献11.
Elizabeth A. Poplin David S. Alberts John J. Rinehart Harriet O. Smith James A. Neidhart Evan M. Hersh 《Cancer chemotherapy and pharmacology》1994,33(4):340-346
Dose intensification has the potential to increase the response frequency of chemosensitive tumors to chemotherapy. G-CSF and GM-CSF offer the possibility of dose-intensifying chemotherapy without prohibitive myelosuppression. A phase I study was undertaken to identify the maximum tolerated dose (MTD) of carboplatin that could be administered with a fixed dose of doxorubicin, 60 mg/m2, administered every 28 days. Further escalation of the carboplatin dose was then attempted, with the concomitant addition of GM-CSF 10 mg/kg per day on days 1–21. We had 21 patients, 13 with prior therapy, who were eligible. In all, 60 courses of therapy were delivered, all with doxorubicin and with carboplatin doses of 250 mg/m2, 325 mg/m2 and 400 mg/m2. At carboplatin 400 mg/m2 and doxorubicin 60 mg/m2, thrombocytopenia was dose limiting. The addition of GM-CSF did not allow further escalation. Of the 6 patients treated with carboplatin 400 mg/m2, doxorubicin 60 mg/m2, and GM-CSF, grade 4 granulocytopenia and thrombocytopenia were seen in 4 and 5 patients, respectively. The severity of thrombocytopenia was related to the calculated carboplatin AUC and also to baseline platelet count and prior therapy. In addition, the interaction of GM-CSF and chemotherapy, especially carboplatin-based, may be more complex than originally anticipated.This investigation was supported in part by the following PHS Cooperative Agreement grant numbers awarded by the National Cancer Institute, DHHS: CA-14028, CA-28862, CA-12213, CA-13612, CA-32102 相似文献
12.
Matthew D. Galsky Marshall Posner Randall F. Holcombe Karen M. Lee Krzysztof Misiukiewicz Che-Kai Tsao James Godbold Rothschild Soto Kiev Gimpel-Tetra Nancy Lowe William K. Oh 《Cancer chemotherapy and pharmacology》2014,74(3):465-471
Purpose
Dovitinib is a small molecule kinase inhibitor with activity against the fibroblast growth factor and vascular endothelial growth factor receptor families. The purpose of this phase Ib study was to define the recommended phase 2 dose of the combinations of gemcitabine and cisplatin or gemcitabine and carboplatin plus dovitinib.Methods
Patients with advanced solid tumors were enrolled in two parallel dose escalation arms (cisplatin- or carboplatin-based regimens). Treatment was administered with gemcitabine (1,000 mg/m2 on days 1 and 8), cisplatin (70 mg/m2), or carboplatin (AUC 5) on day 1, and dovitinib (orally on days 1–5, 8–12, and 15–19), every 21 days. The starting dose of dovitinib was 300 mg and was dose escalated in successive cohorts using 3 + 3 dose escalation rules.Results
Fourteen patients with advanced solid tumors were enrolled, five to the cisplatin arm and nine to the carboplatin arm. Patients enrolled in the cisplatin arm received a median of two cycles of treatment (range 1–5), and patients enrolled in the carboplatin arm received a median of one cycle of treatment (range 1–4). There were no protocol-defined dose-limiting toxicities in the cisplatin arm. However, the cohort was closed due to the need for frequent dose delays and/or reductions and two patients experiencing severe thromboembolic events. There were two dose-limiting toxicities in the carboplatin arm at the starting dose level of dovitinib (both prolonged neutropenia), and the dose of dovitinib was de-escalated to 200 mg. Two additional dose-limiting toxicities (prolonged neutropenia and febrile neutropenia) occurred in the lower dose cohort, and the study was closed. No patients achieved an objective response to treatment.Conclusions
Dovitinib in combination with gemcitabine plus cisplatin or gemcitabine plus carboplatin was poorly tolerated due to myelosuppression. 相似文献13.
Koukourakis MI Giatromanolaki A Kakolyris S Froudarakis M Georgoulias V Retalis G Bahlitzanakis N 《Medical oncology (Northwood, London, England)》2000,17(2):135-143
Taxanes have been shown to interact with anti-apoptotic proteins. In the present study we investigated whether the addition
of taxane in combination with DNA damaging drugs can further enhance tumor shrinkage in cases with incomplete response to
radiotherapy. Since the dose of docetaxel in combination with carboplatin is not known, the above hypothesis was tested in
the context of a dose escalation phase I study.
Twenty-eight patients with locally advanced chest or pelvic tumors, showing residual disease on CT scans performed 40 d following
docetaxel radio-chemotherapy, were recruited in a dose escalation protocol of docetaxel/carboplatin supported with amifostine
and GM-CSF. The starting dose of docetaxel was 40 mg/m2 every 2 weeks. Carboplatin dose was calculated using the Calvert formula and was escalated in cohorts of 4 patients (starting
dose AUC2 every two weeks; AUC0.5 increments up to AUC3). Thereafter the docetaxel dose was increased to 50 and 60 mg/m2, while carboplatin was escalated (by AUC0.5 increments) starting from AUC3 and AUC4 respectively. Amifostine (600 mg/m2) was administered i.v. before carboplatin and GM-CSF (480μg) was injected s.c. on days 5, 6 and 10, 11 of each cycle. Six
cycles were given and response was assessed 2 weeks after the end of chemotherapy.
None out of four patients treated in the 6th dose level cohort (50mg/m2 of docetaxel and AUC4 of carboplatin every 2 weeks) showed any grade 2–4 hematologic toxicity. Mild non-hematologic toxicity
such as neuropathy, leg edema, pleural effusion, pyrexia, alopecia grade 2 and hypersensitivity was observed in 4–12% of patients.
Out of four patients treated in a 7th cohort (docetaxel 60mg/m2 and carboplatin AUC4), one developed grade IV neutropenia and two developed grade 3 severe asthenia requiring treatment delay
for 2 weeks. Out of 11 patients with PR following docetaxel radio-chemotherapy, 7 (63%) showed CR after docetaxel/carboplatin
additional chemotherapy. Eight out of 17 patients with MR following docetaxel radio-chemotherapy showed PR (47%) and one showed
CR (6%) after additional chemotherapy.
High dose combined docetaxel (50 mg/m2) and carboplatin (AUC4) chemotherapy can be safely administered on a two-weekly basis if supported with amifostine and GM-CSF.
Such an additional therapy may be important in patients with incomplete response after chemo-RT. Broad spectrum cytoprotection
with amifostine and GM-CSF may also contribute to the reduction of incidence of neurosensory reactions and asthenia in patients
treated with taxanes. 相似文献
14.
Kyu-pyo Kim Ho-Sook Kim Sun Jin Sym Kyun Seop Bae Yong Sang Hong Heung-Moon Chang Jae Lyun Lee Yoon-Koo Kang Jung Shin Lee Jae-Gook Shin Tae Won Kim 《Cancer chemotherapy and pharmacology》2013,71(6):1609-1617
Purpose
UGT1A1 genotypes are important when considering treatment with irinotecan-containing regimens. In this study, we determined the dose, efficacy, and tolerability of irinotecan according to UGT1A1 genotypes when combined with capecitabine in patients with metastatic colorectal cancer.Methods
Patients with histologically confirmed metastatic adenocarcinoma of the colon or rectum were enrolled into a UGT1A1 genotype-directed dose-escalation trial of irinotecan plus fixed-dose capecitabine (2,000 mg/m2/day). The starting dose of irinotecan was different for each genotype group and ranged from 200 to 280 mg/m2. Pharmacokinetic concentrations of irinotecan and metabolites were determined by LC/MS/MS.Results
Fifty patients were genotyped for UGT1A1 *28 and *6, and grouped according to the numbers of defective alleles (DA): 0, 1, and 2. Plasma concentrations of irinotecan, SN-38, and SN-38G were measured. The maximum tolerated dose of irinotecan was 350 mg/m2 for the 0 and 1 DA groups, and 200 mg/m2 for the 2 DA group. For the 0, 1, and 2 DA groups, mean AUClast ratios of SN-38G to SN-38 were 7.72, 5.71, and 2.72 (P = 0.0023) and relative dose intensities at recommended dose were 85, 83, and 97 %.Conclusion
Irinotecan dosing based on UGT1A1*28 and *6 is feasible, and higher doses of irinotecan can be safely administered in patients with 0 or 1 DA, compared to those with 2 DA. 相似文献15.
Lopez AM Ketchum M Nichols H Xu MJ Peng YM Dorr R Alberts DS 《Cancer chemotherapy and pharmacology》2000,46(5):411-415
The effect of the addition of G-CSF to carboplatin, ifosfamide and doxorubicin (CIA) at the maximally tolerated dose (MTD)
was studied in a phase I clinical trial. Nine patients with incurable solid tumors were treated: six endometrial and epithelial
ovarian cancers, one colon cancer with pelvic masses and two unknown primary cancers. The carboplatin dose was calculated
using the Calvert formula and administered in a standard 30-min intravenous infusion. The initial carboplatin dose was AUC
4.0 mg/ml per min. Fixed doses of ifosfamide (1.25 g/m2 per day), mesna (1.0 g/m2 per day, and doxorubicin (15 mg/m2 per day) were combined and given as a 4-day continuous intravenous infusion in an attempt to decrease nonhematologic toxicity.
The dose-limiting toxicity of CIA was myelosuppression, mainly neutropenia and thrombocytopenia. Nonhematologic toxicities
were hemorrhagic cystitis, weakness, fatigue, and nausea and vomiting. The MTD for CIA was established at the first dose level
of carboplatin (4.0 mg/ml per min). Following this, G-CSF was added to the regimen in an unsuccessful effort to escalate the
carboplatin dose. Free and total carboplatin pharmacokinetics were determined using flameless atomic absorption spectroscopy.
There was one complete response and one partial response among eight evaluable patients. Both responding patients had advanced
ovarian cancer. We conclude that carboplatin dose intensification beyond an AUC of 4.0 mg/ml per min is not made feasible
by the addition of G-CSF to infusional doxorubicin and ifosfamide in patients with advanced gynecologic cancer.
Received: 22 December 1999 / Accepted: 28 April 2000 相似文献
16.
Deborah A. Thomas MD Hagop M. Kantarjian MD Wendy Stock MD Leonard T. Heffner MD Stefan Faderl MD Guillermo Garcia‐Manero MD Alessandra Ferrajoli MD William Wierda MD PhD Sherry Pierce RN Biao Lu PhD Steven R. Deitcher MD Susan O'Brien MD 《Cancer》2009,115(23):5490-5498
BACKGROUND:
Dose intensification of chemotherapy has improved outcome for younger adults with de novo acute lymphoblastic leukemia (ALL). Novel formulations of standard chemotherapy agents may further reduce the incidence of disease recurrence after frontline chemotherapy. Vincristine (VCR) sulfate liposomes injection (VSLI) is a sphingomyelin/cholesterol nanoparticle encapsulated VCR formulation that improves the pharmacokinetic profile of VCR without augmenting neurotoxicity.METHODS:
A phase 1 trial of weekly, intravenous VSLI at 1.5 mg/m2, 1.825 mg/m2, 2.0 mg/m2, 2.25 mg/m2, or 2.4 mg/m2 was conducted to determine the maximum tolerated dose (MTD) using a standard, 3 + 3 dose‐escalation design. Dexamethasone (40 mg) was given on Days 1 through 4 and on Days 11 through 14 of each 4‐week cycle.RESULTS:
Thirty‐six adults with relapsed/refractory ALL, all previously treated with conventional VCR, received at least 1 dose of VSLI. The MTD of VSLI was 2.25 mg/m2 based on dose‐limiting toxicities of grade 3 motor neuropathy, grade 4 seizure, and grade 4 hepatotoxicity in 1 patient each at the 2.4 mg/m2 dose level. The most common toxicities attributed to VSLI included peripheral neuropathy (55%) and constipation (53%). A complete response (CR) was achieved in 7 of 36 patients (19%) based on an intent‐to‐treat analysis; the CR rate was 29% for the 14 patients who underwent therapy as their first salvage attempt. Four of 7 patients who achieved a CR underwent subsequent allogeneic stem cell transplantation in remission.CONCLUSIONS:
In this study, VSLI plus dexamethasone appeared to be an effective salvage therapy option for relapsed/refractory ALL. A phase 2, international, multicenter clinical trial assessing the efficacy of single‐agent VSLI as second salvage therapy for patients with previously treated ALL is underway. Cancer 2009. © 2009 American Cancer Society. 相似文献17.
Jean Maroun Horia Marginean Derek Jonker Christine Cripps Rakesh Goel Timothy Asmis Rachel Goodwin Gabriela Chiritescu 《Clinical colorectal cancer》2018,17(2):e257-e268
Background
The objective of the present phase I study was to define the dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD) of irinotecan, capecitabine, and oxaliplatin given in combination (IXO regimen) to patients with previously untreated, unresectable advanced or metastatic colorectal cancer (CRC).Patients and Methods
Patients received oxaliplatin followed by irinotecan as intravenous infusions on day 1, with oral capecitabine taken twice daily (BID) on days 2 to 15 of a 3-week cycle. The dose ranges were explored as follows: oxaliplatin, 75 to 120 mg/m2; irinotecan, 160 to 230 mg/m2; capecitabine, 750 to 1000 mg/m2 BID. Dose escalation was performed individually for each drug at each dose level according to the type and severity of toxicity encountered in the previous cohort.Results
A total of 39 patients were enrolled at 7 dose levels and the MTD. The recommended doses for phase II evaluation were oxaliplatin 100 mg/m2, irinotecan 160 mg/m2, and capecitabine 950 mg/m2 BID. Diarrhea and febrile neutropenia were DLTs. Of the 39 enrolled patients, 26 (67%) had confirmed objective responses. The median progression-free survival was 11 months, and the median overall survival was 25 months. The survival rate at 5 years was 23%.Conclusion
The IXO regimen has a manageable toxicity profile with promising antitumor activity as first-line treatment of advanced and metastatic CRC. 相似文献18.
Sakakibara-Konishi J Oizumi S Kinoshita I Shinagawa N Kikuchi J Kato M Inoue T Katoh N Onimaru R Shirato H Dosaka-Akita H Nishimura M 《Lung cancer (Amsterdam, Netherlands)》2011,74(2):248-252
Introduction
Although paclitaxel with carboplatin and thoracic radiotherapy has improved survival for patients with locally advanced unresectable non-small cell lung cancer (NSCLC), the optimal dose of paclitaxel has not been well defined in Japan. This study was conducted to determine the maximum tolerated dose (MTD) and recommended dose (RD) of paclitaxel in combination with carboplatin and concurrent real-time tumor-tracking thoracic radiation therapy (thoracic RTRT).Patients and methods
Previously untreated patients with histologically confirmed, locally advanced unresectable NSCLC were eligible. Before treatment, gold markers were inserted into the lung and the mediastinum of all patients. RTRT comprised a total of 66 Gy at 2 Gy/fraction, 5 days/week, for 7 weeks. Patients received paclitaxel at a starting dose of 40 mg/m2 followed by carboplatin at a fixed area under the curve (AUC) of 2, as a weekly regimen with RTRT. The dose of paclitaxel was escalated by 5 mg/m2 per level.Results
Eight patients with locally advanced unresectable NSCLC were enrolled and treated with two dose levels of paclitaxel (40 mg/m2 and 45 mg/m2), carboplatin (AUC = 2) and RTRT. No dose limiting toxicities (DLTs) were observed at Level 1 (paclitaxel, 40 mg/m2 and carboplatin, AUC = 2). At Level 2 (paclitaxel, 45 mg/m2 and carboplatin, AUC = 2), two of five patients experienced DLTs, in the form of esophagitis and discontinuation of chemotherapy more than twice. The MTD and RD of paclitaxel were thus defined as 45 mg/m2 and 40 mg/m2, respectively.Conclusions
This phase I study was well tolerated and the RD of paclitaxel and carboplatin with RTRT is 40 mg/m2 at AUC = 2, respectively. Further studies are warranted to evaluate the efficacy of this regimen. 相似文献19.
Adam J. Olszewski Michael L. Grossbard Michael S. Chung Sree B. Chalasani Stephen Malamud Tahir Mirzoyev Peter S. Kozuch 《Journal of gastrointestinal cancer》2013,44(2):182-189
Purpose
The aims of this study were to establish the maximum tolerated dose (MTD) of oxaliplatin in combination with fixed doses of gemcitabine, irinotecan, and 5-fluorouracil/leucovorin (G-FLIE) in solid tumors, including advanced pancreatic cancer, and to evaluate the toxicity of the regimen.Methods
Patients with metastatic solid tumors were treated with a regimen consisting of gemcitabine (500 mg/m2 by fixed-dose-rate infusion), irinotecan (120 mg/m2), leucovorin 300 mg, bolus/infusion 5-fluorouracil (400 and 1,500 mg/m2, respectively), and oxaliplatin at doses from 50 to 85 mg/m2 according to the escalation schema. Treatment was repeated every 14 days.Results
The study enrolled 25 patients with a median age of 64 years and median Karnofsky performance score of 80. Patients had metastatic adenocarcinomas of pancreas (n?=?9), as well as gastroesointestinal, hepatobiliary, or unknown primary tumors. With only one dose limiting toxicity (neutropenia and constipation), the MTD of oxaliplatin was not reached up to the pre-specified maximum level of 85 mg/m2. Other toxicities predictably included cytopenias, fatigue, sensory neuropathy, nausea/vomiting, diarrhea, and constipation. Four partial responses and ten disease stabilizations were observed. The overall median time to disease progression was 17 weeks (2–110 weeks) with median overall survival of 31.5 weeks (7–139 weeks).Conclusions
G-FLIE is a tolerable multi-agent chemotherapy regimen with the oxaliplatin dose up to 85 mg/m2. The combination of full-dose oxaliplatin with gemcitabine, irinotecan, and 5-fluorouracil is feasible with attenuated doses of the drugs, but further optimization is necessary before assessment of efficacy. 相似文献20.
Shimada M Fujiwara H Sato S Oishi T Itamochi H Machida S Takei Y Harada T Suzuki M Kigawa J 《Cancer chemotherapy and pharmacology》2012,70(1):33-38