Paclitaxel, an Active Agent in Nonsquamous Carcinomas of the Uterine Cervix: A Gynecologic Oncology Group Study

PURPOSE: A phase II trial of paclitaxel was initiated in advanced nonsquamous carcinoma of the cervix to determine its activity in patients who had failed standard chemotherapy. PATIENTS AND METHODS: Eligible patients had at least one measurable lesion. The starting dose of paclitaxel was 170 mg/m2 (135 mg/m2 for patients with prior pelvic radiation) given as a 24-hour continuous intravenous infusion with courses repeated every 3 weeks. Dose escalation to 200 mg/m2 and de-escalation to 110 mg/m2 were allowed based on adverse effects. RESULTS: In this trial, 42 assessable patients were initially entered onto the study, and 13 responses were seen; four patients had a complete response, and nine patients had a partial response. The overall response rate was 31%. The primary and dose-limiting toxicity was neutropenia. CONCLUSION: The response rate to paclitaxel exceeds the rates reported using other single agents in nonsquamous carcinoma of the cervix.

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Paclitaxel and concurrent radiation for locally advanced pancreatic and gastric cancer: a phase I study.

Journal of Clinical Oncology ◽

10.1200/jco.1997.15.3.901 ◽

1997 ◽

Vol 15 (3) ◽

pp. 901-907 ◽

Cited By ~ 54

Author(s):

H Safran ◽

T P King ◽

H Choy ◽

P J Hesketh ◽

B Wolf ◽

...

Keyword(s):

Gastric Cancer ◽

Overall Response Rate ◽

Response Rate ◽

Phase Ii Trial ◽

Locally Advanced ◽

Maximum Tolerated Dose ◽

Upper Abdominal ◽

Adenocarcinoma Of The Pancreas ◽

Dose Limiting Toxicity ◽

Potential Antitumor

PURPOSE To determine the maximum-tolerated dose (MTD), dose-limiting toxicities, and potential antitumor activity of weekly paclitaxel with concurrent radiation (RT) for locally advanced pancreatic and gastric cancer. PATIENTS AND METHODS Thirty-four patients with locally advanced adenocarcinoma of the pancreas or stomach were studied. The initial dose of paclitaxel was 30 mg/m2 by 3-hour intravenous (I.V.) infusion repeated every week for 6 weeks with 50 Gy RT. Doses were escalated at 10-mg/m2 increments in successive cohorts of three new patients until dose-limiting toxicity was observed. RESULTS The dose-limiting toxicities at 60 mg/m2/wk were abdominal pain within the RT field, nausea, and anorexia. Of 23 patients with assessable disease, 11 (seven with gastric, four with pancreatic cancer) had objective responses for an overall response rate of 48%. CONCLUSION Concurrent paclitaxel with upper abdominal RT is well tolerated at dosages that have substantial activity. A phase II trial of neoadjuvant paclitaxel and RT at the MTD of 50 mg/m2/wk is underway.

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Phase II multicenter open-label study of karenitecin in previously treated epithelial ovarian and primary peritoneal cancer: a Gynecologic Oncology Group Study

International Journal of Gynecological Cancer ◽

10.1136/j.1525-1438.2007.01053.x ◽

2008 ◽

Vol 18 (3) ◽

pp. 460-464 ◽

Cited By ~ 1

Author(s):

J. J. KAVANAGH ◽

M. W. SILL ◽

P. T. RAMIREZ ◽

D. WARSHAL ◽

M. L. PEARL ◽

...

Keyword(s):

Ovarian Cancer ◽

Phase Ii ◽

Topoisomerase I ◽

Response Rate ◽

Gynecologic Oncology ◽

Complete Response ◽

Gynecologic Oncology Group ◽

Open Label ◽

Peritoneal Cancer ◽

Previously Treated

The topoisomerase I agents are established as a therapy in recurrent ovarian cancer. Karenitecin, an analog of topotecan with solubility and pharmacologic advantages, was tested in a phase II trial in previously treated patients with recurrent or persistent ovarian cancer. The drug was administered intravenously over 1 h at a dose of 1.0 mg/m2 daily for 5 days every 21 days. Patients were treated until disease progression, intolerable toxicity, or voluntary withdrawal. Response was evaluated according to modified RECIST criteria. Twenty-seven patients were entered into the study. One patient was inevaluable for not receiving any treatment. Of the 26 evaluable patients, there were two partial responses and one complete response for a total response rate of 12%. This response rate was insufficient to justify accrual to the second stage. The most common grade 3 or 4 toxicities were neutropenia (19%) and gastrointestinal (15%). Karenitecin is a well-tolerated topoisomerase compound but has minimal activity in extensively pretreated ovarian cancer with the dose-schedule employed.

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Bendamustine Combined With Rituximab in Patients With Relapsed and/or Refractory Chronic Lymphocytic Leukemia: A Multicenter Phase II Trial of the German Chronic Lymphocytic Leukemia Study Group

Journal of Clinical Oncology ◽

10.1200/jco.2010.33.8061 ◽

2011 ◽

Vol 29 (26) ◽

pp. 3559-3566 ◽

Cited By ~ 265

Author(s):

Kirsten Fischer ◽

Paula Cramer ◽

Raymonde Busch ◽

Stephan Stilgenbauer ◽

Jasmin Bahlo ◽

...

Keyword(s):

Chronic Lymphocytic Leukemia ◽

Partial Response ◽

Phase Ii ◽

Overall Response Rate ◽

Response Rate ◽

Phase Ii Trial ◽

Complete Response ◽

Lymphocytic Leukemia ◽

Refractory Disease ◽

Overall Response

Purpose The objective of this trial was to evaluate safety and efficacy of bendamustine combined with rituximab (BR) in patients with relapsed and/or refractory chronic lymphocytic leukemia (CLL). Patients and Methods Seventy-eight patients, including 22 patients with fludarabine-refractory disease (28.2%) and 14 patients (17.9%) with deletion of 17p, received BR chemoimmunotherapy. Bendamustine was administered at a dose of 70 mg/m2 on days 1 and 2 combined with rituximab 375 mg/m2 on day 0 of the first course and 500 mg/m2 on day 1 during subsequent courses for up to six courses. Results On the basis of intent-to-treat analysis, the overall response rate was 59.0% (95% CI, 47.3% to 70.0%). Complete response, partial response, and nodular partial response were achieved in 9.0%, 47.4%, and 2.6% of patients, respectively. Overall response rate was 45.5% in fludarabine-refractory patients and 60.5% in fludarabine-sensitive patients. Among genetic subgroups, 92.3% of patients with del(11q), 100% with trisomy 12, 7.1% with del(17p), and 58.7% with unmutated IGHV status responded to treatment. After a median follow-up time of 24 months, the median event-free survival was 14.7 months. Severe infections occurred in 12.8% of patients. Grade 3 or 4 neutropenia, thrombocytopenia, and anemia were documented in 23.1%, 28.2%, and 16.6% of patients, respectively. Conclusion Chemoimmunotherapy with BR is effective and safe in patients with relapsed CLL and has notable activity in fludarabine-refractory disease. Major but tolerable toxicities were myelosuppression and infections. These promising results encouraged us to initiate a further phase II trial evaluating the BR regimen in patients with previously untreated CLL.

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Phase II trial of ifosfamide and mesna in advanced ovarian carcinoma: a Gynecologic Oncology Group Study.

Journal of Clinical Oncology ◽

10.1200/jco.1989.7.11.1672 ◽

1989 ◽

Vol 7 (11) ◽

pp. 1672-1676 ◽

Cited By ~ 89

Author(s):

G P Sutton ◽

J A Blessing ◽

H D Homesley ◽

M L Berman ◽

J Malfetano

Keyword(s):

Ovarian Carcinoma ◽

Overall Response Rate ◽

Phase Ii Trial ◽

Chemotherapy Regimen ◽

Gynecologic Oncology ◽

Response Duration ◽

Gynecologic Oncology Group ◽

Oncology Group ◽

Prior Chemotherapy Regimen ◽

Grade 3

Ifosfamide (isophosphamide) and mesna (2-mercaptoethane sodium sulfonate) were administered intravenously at monthly intervals to 46 patients with advanced epithelial ovarian carcinoma refractory to or recurrent after cisplatin-containing combination chemotherapy. Initially, ifosfamide was given as 1.5 g/m2/d x 5 days and mesna as 300 mg/m2 every 4 hours for three doses following ifosfamide, but the initial dose of ifosfamide was reduced to 1.2 g/m2 because of toxicity. Four of the patients initially entered were found to be ineligible: two who had had more than one prior chemotherapy regimen and two who did not have ovarian primaries. One patient received an inadequate trial and four patients had discontinuation of therapy because of toxicity, leaving 41 evaluable for response. Three patients (7.0%) had complete responses and five (13.0%) had partial responses for an overall response rate of 20.0%. Response duration ranged from 2.1 to 20.3 + months with a median of 6.9 + months. Two patients died of renal failure, one of whom had no known renal disease and received 1.5 g/m2/d x 5 days ifosfamide. The second patient received the 1.2 g/m2 dose and was found to have chronic pyelonephritis and pyonephrosis at autopsy. Gynecologic Oncology Group (GOG) grade 3 or 4 granulocytopenia was seen in eight (19.5%), grade 3 or 4 thrombocytopenia in four (9.8%), and grade 3 or 4 neurotoxicity in six (14.6%) of the 41 patients evaluable for toxicity. Ifosfamide/mesna is active in epithelial ovarian cancer. GOG trials in untreated patients are being initiated and toxicity is being evaluated.

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A novel pharmacodynamically based approach to dose optimization of carboplatin when used in combination with etoposide.

Journal of Clinical Oncology ◽

10.1200/jco.1989.7.12.1896 ◽

1989 ◽

Vol 7 (12) ◽

pp. 1896-1902 ◽

Cited By ~ 22

Author(s):

C P Belani ◽

M J Egorin ◽

J S Abrams ◽

D Hiponia ◽

M Eisenberger ◽

...

Keyword(s):

Combination Chemotherapy ◽

Overall Response Rate ◽

Response Rate ◽

Complete Response ◽

Small Cell ◽

Small Cell Lung ◽

Individualized Dosing ◽

Initial Cohort ◽

Calculated Dose ◽

Dose Limiting Toxicity

Thrombocytopenia, the dose-limiting toxicity of carboplatin, is manageable and predictable with the dosing equation: Dose (mg/m2) = (0.091) (creatinine clearance)/(body surface area) (desired percentage change in platelet count) + 86. We used this equation to dose patients receiving carboplatin (day 1) and etoposide (80 mg/m2 days 1 to 3). An initial cohort of 14 patients with non-small-cell lung cancer (NSCLC) were treated with 75% of the calculated dose of carboplatin (29 evaluable courses) as a precaution against added myelosuppression from combination chemotherapy. The observed reduction in platelets was essentially equal to the reduction in platelets predicted if patients had received carboplatin alone. Subsequently, a second cohort of 20 evaluable patients with NSCLC received the full calculated dose of carboplatin and etoposide (51 evaluable courses). There was a linear relationship between observed (o) and predicted (p) reductions in platelets. With full-dose carboplatin in combination with etoposide, there was a significantly greater carboplatin dosage administered, greater reduction in platelets, and lower platelet nadir. Among 34 evaluable patients (80 courses) there was one complete response (CR) and four partial responses (PRs) for an overall response rate of 15% (90% confidence +/- 9%). The median duration of survival for responders was 336+ days and for nonresponders was 204+ days. Therapy was well tolerated. This study, in addition, supports our concept of individualized dosing of carboplatin and the underlying pharmacokinetic/pharmacodynamic relationships and represents an interesting pharmacodynamic and quantitative approach to studying potential drug-drug interactions and defining appropriate dosages for combination chemotherapy.

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Randomized Phase II Evaluation of Bevacizumab Versus Bevacizumab Plus Fosbretabulin in Recurrent Ovarian, Tubal, or Peritoneal Carcinoma: An NRG Oncology/Gynecologic Oncology Group Study

Journal of Clinical Oncology ◽

10.1200/jco.2015.65.8153 ◽

2016 ◽

Vol 34 (19) ◽

pp. 2279-2286 ◽

Cited By ~ 33

Author(s):

Bradley J. Monk ◽

Michael W. Sill ◽

Joan L. Walker ◽

Christopher J. Darus ◽

Gregory Sutton ◽

...

Keyword(s):

Overall Response Rate ◽

Response Rate ◽

Gynecologic Oncology ◽

Combination Regimen ◽

Gynecologic Oncology Group ◽

Peritoneal Carcinoma ◽

Vascular Disrupting Agent ◽

Overall Response ◽

Grade 3 ◽

Vascular Disrupting

Purpose The vascular disrupting agent fosbretabulin tromethamine selectively targets pre-existing tumor vasculature, which causes vascular shutdown and leads to cancer cell death and necrosis. Antiangiogenesis agents such as bevacizumab, a humanized antivascular endothelial growth factor monoclonal antibody, might prevent revascularization during and after treatment with a vascular disrupting agent. Patients and Methods Patients with recurrent or persistent epithelial ovarian, tubal, or peritoneal carcinoma, measurable or detectable disease, and three or fewer prior regimens were randomly assigned to bevacizumab (15 mg/kg intravenously once every 3 weeks) or the combination of bevacizumab (15 mg/kg) plus fosbretabulin (60 mg/m2) intravenously once every 3 weeks until disease progression or toxicity. Randomization was stratified by disease status (measurable v nonmeasurable), prior bevacizumab, and platinum-free interval. The primary end point was progression-free survival (PFS). The study was designed with 80% power for a one-sided alternative at a 10% level of significance to detect a reduction in the hazard by 37.5%. Results The study enrolled 107 patients. Median PFS was 4.8 months for bevacizumab and 7.3 months for bevacizumab plus fosbretabulin (hazard ratio, 0.69; 90% two-sided CI, 0.47 to 1.00; one-sided P = .05). The proportion responding (overall response rate) to bevacizumab was 28.2% among 39 patients with measurable disease and 35.7% among 42 patients treated with the combination. The relative probability of responding was 1.27 (90% CI, 0.74 to 2.17; one-sided P = .24). Adverse events greater than grade 3 were more common in the combination regimen than in bevacizumab only for hypertension (35% v 20%). There was one grade 3 thromboembolic event in the combination arm and one intestinal fistula in the bevacizumab only arm. Conclusion On the basis of the PFS, overall response rate, and tolerability of these two antivascular therapies, further evaluation is warranted for this chemotherapy-free regimen. Fosbretabulin in combination with bevacizumab increases the risk of hypertension.

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Paclitaxel has moderate activity in squamous cervix cancer. A Gynecologic Oncology Group study.

Journal of Clinical Oncology ◽

10.1200/jco.1996.14.3.792 ◽

1996 ◽

Vol 14 (3) ◽

pp. 792-795 ◽

Cited By ~ 159

Author(s):

W P McGuire ◽

J A Blessing ◽

D Moore ◽

S S Lentz ◽

G Photopulos

Keyword(s):

Response Rate ◽

Gynecologic Oncology ◽

Cervix Cancer ◽

Moderate Activity ◽

Gynecologic Oncology Group ◽

Preclinical Research ◽

Cancer Breast ◽

Starting Dose ◽

Spectrum Activity ◽

Final Response

PURPOSE Taxol (paclitaxel; Bristol-Myers Squibb, Princeton, NJ) is a new antineoplastic drug with broad-spectrum activity in solid tumors, including epithelial ovarian cancer, head and neck cancer, esophageal cancer, breast cancer, bladder cancer, and lung cancer. Its unique mechanism of action, polymerization of tubulin monomers, has stimulated both clinical and preclinical research on this agent. As limited drug supplies became more plentiful, a phase II trial of Taxol was initiated in patients with advanced squamous cervix cancer who had received no prior chemotherapy. PATIENTS AND METHODS In this trial, 30 assessable patients were initially entered onto the study and four partial responses were seen. Further accrual of 22 assessable patients was then accomplished to define better the response rate with smaller confidence intervals. The starting dose of Taxol was 170 mg/m2 (135 mg/m2 for patients with prior pelvic radiation) given as a 24-hour continuous intravenous infusion with courses repeated every 3 weeks. Dose escalations to 200 mg/m2 and deescalations to 110 mg/m2 were allowed based on adverse effects. RESULTS The final response rate was 17% (two complete responses and seven partial responses). The primary and dose-limiting toxicity was neutropenia. CONCLUSION The response rate makes Taxol a drug with sufficient activity to explore it in combination with other agents with similar activity.

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