Phase II study of gemcitabine in recurrent platinum-and paclitaxel-resistant ovarian cancer

OBJECTIVE: To determine the activity and tolerability of gemcitabine in the palliative treatment of ovarian cancer. METHODS: Patients affected by ovarian cancer, and with progressive disease after treatment with platinum/paclitaxel-based chemotherapy, were enrolled into this phase II study. Gemcitabine, 1000 mg/m(2), was administered on days 1, 8, and 15, by 30-min intravenous infusion. Cycles were repeated every 28 days. RESULTS: Fifty patients were enrolled. All the patients were platinum and/or paclitaxel resistant (median number of previous regimens, 2; range, 1-5). Median platinum-free interval was 3 (range, 1-11) months and median paclitaxel-free interval was 6 (range, 1-36) months. A total of 210 courses were evaluable for toxicity, with a median number of four cycles administered per patient (range, 1-10). A grade 3 or 4 hematological toxicity was observed in 27 patients (54%) (anemia grade 3, 16%; grade 4, 2%; neutropenia grade 3, 24%; grade 4, 18%; thrombocytopenia grade 3, 8%; grade 4, 0%). A 20-50% dose reduction was required for 36 patients (72%, 55% of cycles). Blood transfusions were necessary for 15 patients (30%), while 2 (4%) were treated with erythropoetin. Granulocyte colony-stimulating factor was necessary in 4 patients (8%). Nonhematological toxicity was mild and manageable. Only 4 patients (8%) experienced a grade 3 hepatic toxicity (elevated liver enzymes). Forty-one patients (82%) are, so far, evaluable for response. Among them, 7 partial responses (17%; 95% confidence interval [CI], 6-29), 15 disease stabilizations (>16 weeks) (36.6%; 95% CI, 21.9-51.3), and 19 progressions (46.3%; 95% CI, 31.0-61.6) have been registered. An overall clinical benefit was observed in 53.7% of patients. Thirteen patients (31.7%) had a time-to-progression exceeding 24 weeks. CONCLUSIONS: This study confirms the activity and safety of gemcitabine in heavily pretreated patients with recurrent ovarian cancer.     

Phase II trial of paclitaxel and nedaplatin in patients with advanced/recurrent uterine cervical cancer: a Kansai Clinical Oncology Group study

Objective

A multicenter phase II trial was conducted to evaluate the activity and toxicity of paclitaxel and nedaplatin (cis-diammineglycolatoplatonum) in patients with advanced/recurrent uterine cervical cancer.

Methods

Patients were required to have measurable disease. Histologic confirmation of the primary diagnosis as uterine cervical cancer was mandatory. The treatment consisted of paclitaxel 175 mg/m² over 3 hours and nedaplatin 80 mg/m² intravenously over 1 hour on day 1 every 28 days until progressive disease or adverse effects prohibited further therapy.

Results

Fifty patients were enrolled into the study protocol from October 2007 to February 2010. 45 patients(90%) were eligible for assessment of response (RECIST version 1.0) to treatment; 31 patients (62%) received prior radiotherapy and 23 patients (46%) received prior chemotherapy. The overall response rate was 44.4% (11 complete responses and 8 partial responses) with 22.2% of patients having stable disease. Grades 3 or 4 adverse events (NCI-CTCAE ver 3) included neutropenia (n = 16, 32.7%), febrile neutropenia (n = 1, 2.0%), anemia (n = 9, 18.4%), but there was no significant thrombocytopenia. Non-hematologic toxicity was generally not serious and without a dominant pattern. The median progression-free survival was 7.5 months (95% C.I., 5.7, 9.4) and overall survival was 15.7 months (95% C.I., 9.4, 21.9).

Conclusions

Paclitaxel 175 mg/m² and nedaplatin 80 mg/m² intravenously on day 1 every 28 days in patients with advanced/recurrence uterine cervical cancer demonstrated easy administration, favorable antitumor activity, and the toxicity profile of this regimen would be decreased compared with cisplatin-containing combinations. Evaluation of this regimen in phase III trials is warranted.     

Optimized sequence of drug administration and schedule leads to improved dose delivery for gemcitabine and paclitaxel in combination: a phase I trial in patients with recurrent ovarian cancer

We examined appropriate sequence, schedule, and doses of gemcitabine (G) and paclitaxel (T) in patients with persistent or recurrent epithelial ovarian cancer. Patients received a maximum of six cycles of gemcitabine on days 1 and 8 (starting 1000 mg/m(2)), and paclitaxel (starting 135 mg/m(2)) on day 8 (groups A and B) or day 1 (group C). Drug sequences (G-->T and T-->G) were tested in group A. In group A, changing sequences of gemcitabine and paclitaxel infusion were evaluated. Sequence G-->T raised grade 3 alanine transaminase in two of three patients leading to use of T-->G sequence for remainder of study. In group B, maximum tolerable dose was reached at gemcitabine 1000 mg/m(2) and paclitaxel 175 mg/m(2). Reducing paclitaxel to 150 mg/m(2) allowed escalation of gemcitabine to 1250 mg/m(2), but neutropenia-related treatment delays occurred. Giving paclitaxel on day 1 (group C) enabled administration of paclitaxel 175 mg/m(2) and gemcitabine 1250 mg/m(2) with minimal dose adjustments. The overall response rate was 41.0%, with 2 complete responses and 14 partial responses in 39 eligible patients. The schedule of paclitaxel 175 mg/m(2) (day 1) and gemcitabine 1250 mg/m(2) (days 1 and 8), with sequence of T-->G, appears most suitable with tolerable toxicity and promising activity.     

Phase II study of irinotecan plus doxorubicin for early recurrent or platinum-refractory ovarian cancer: interim analysis

The aim of this study was to evaluate the efficacy and toxicity of irinotecan and doxorubicin in the treatment of patients with early recurrent or platinum-refractory ovarian cancer. Nineteen woman from five different institutions were treated. Two patients had platinum-refractory cancer, 11 had platinum-resistant disease, and 6 had platinum-sensitive tumors. An intravenous infusion of Irinotecan (50 mg/m(2)) was given on days 1, 8, and 15, while doxorubicin (40 mg/m(2)) was administered as an intravenous bolus on day 3. This treatment schedule was repeated every 4 weeks. Among the 13 patients defined as having platinum-refractory/platinum-resistant disease, 4 patients achieved a clinical response (30.8%, 95% CI: 9.1-61.4), while only one of 6 patients defined as having platinum-sensitive disease achieved a clinical response (16.7%, 95% CI: 0.4-64.1). Leukopenia and neutropenia were the major dose-limiting toxicities. Grade 3 or 4 leukopenia and neutropenia were noted in 24 (48%) and 33 (66%) of the courses, while febrile neutropenia occurred in 2 courses. Five patients (26%) had grade 2 or worse diarrhea during 7 courses. Our data demonstrated that this regimen might be comparable to standard approved agents in patients with early recurrent or platinum refractory ovarian cancer.     

Phase II study of carboplatin followed by sequential gemcitabine and paclitaxel as first-line treatment for advanced ovarian cancer

The aim of this exploratory phase II study was to evaluate sequential chemotherapy with carboplatin followed by gemcitabine-paclitaxel combination in chemonaive patients with advanced ovarian cancer. The primary objective was to evaluate time to progressive disease (TTPD); secondary objectives included the evaluation of 1- and 3-year survival, response rates, and toxicity. Following initial debulking surgery or biopsy, patients with FIGO stage IIC-IV disease received four cycles of carboplatin area under the curve (AUC) 6 (day 1) every 21 days, followed by four cycles of gemcitabine 1000 mg/m(2) (days 1 and 8) and paclitaxel 175 mg/m(2) (day 8) every 21 days. A total of 47 patients enrolled, 44 (93.6%) completed the initial four cycles, and 39 patients (82.9%) completed the planned eight cycles. The median and maximum lengths of follow-up were 31.2 and 43.7 months, respectively. Median TTPD was 13.8 months (95% CI, 11.6-21.0 months), and median survival time was 31.2 months (95% CI, 25.2-39.6 months). Survival at 1 and 3 years was 95.7% and 44.2%, respectively. Of the 43 evaluable patients, most (95.3%) of them achieved a CA-125 marker response based on Gynecologic Cancer Intergroup (GCIG) definition. The partial response rate in the seven patients with measurable disease was 46.4%. Myelosuppression was the major toxicity, with grade 3 and 4 neutropenia observed in 76.6% patients and thrombocytopenia in 12.8% patients. The sequential approach of carboplatin followed by gemcitabine-paclitaxel as first-line treatment for patients with ovarian cancer is feasible and well tolerated, and depending upon the findings from other major trials, it may merit further evaluation.     

Phase II trial of vinorelbine for relapsed ovarian cancer: a Southwest Oncology Group study

OBJECTIVES: To assess the activity of vinorelbine in women with recurrent or resistant epithelial ovarian cancer following treatment with platinum and paclitaxel in terms of survival rate at 6 months, objective response rate (in the subset of patients with bidimensionally measurable disease), and health-related quality of life. METHODS: Seventy-nine evaluable patients with progressive ovarian cancer following platinum and taxane therapy received vinorelbine 30 mg/m(2) days 1 and 8 of a 21-day treatment cycle. RESULTS: Six-month survival rate for the entire group was 65% (95% CI: 54-75%) and median survival was 10.1 months (95% CI: 7.7-13.6 months). In the 71 women with measurable disease, 0 complete and 2 partial responses were observed (RR = 3%) (95% CI: 0.3-10%). Patients reported substantial symptom-related distress at baseline, which persisted, but did not worsen, during treatment. Patients also had impaired physical functioning at baseline and this continued to decline during treatment. CONCLUSIONS: The 6-month survival rate achieved with salvage vinorelbine is comparable to the results obtained with other salvage therapies in patients with relapsed ovarian cancer. During the initial 10 weeks of treatment, vinorelbine did not appear to be effective in alleviating the symptom-related distress or progressive impairment of physical functioning associated with this disease.     

Phase II study of gemcitabine and weekly paclitaxel in recurrent platinum-resistant ovarian cancer

OBJECTIVE: The purpose of this study is to evaluate the activity of gemcitabine and weekly paclitaxel in patients with platinum-resistant ovarian cancer. METHODS: Thirty-five patients with platinum-resistant disease and prior treatment with paclitaxel received treatment with paclitaxel 80 mg/m(2) IV over 60 min, followed by gemcitabine 1000 mg/m(2) IV administered on days 1, 8, and 15. Cycles were repeated every 4 weeks. RESULTS: All patients had platinum-resistant disease and all had received prior treatment with paclitaxel. Patients were heavily pretreated as the median number of chemotherapy regimens for recurrent disease was 2 (0-3). The overall response rate was 40% (95% confidence intervals (24%, 58%) and 37% of patients achieved stable disease. The median time to progression was 5.7 months (95% CI, 4.6, 8.5) and median overall survival 13.1 months (95% CI, 10.6, 15.9). More than 50% of patients were alive at 12 months, including six patients (17%) who were alive at 24 months. Treatment was well tolerated. Grades 3-4 neutropenia occurred in 17 patients (48.5%), grade 3 thrombocytopenia in 7 (20%), grade 3 anemia in 3 (8.5%). The most common serious non-hematological toxicities were nausea (14%), vomiting (14%), and fatigue (34%). CONCLUSIONS: The regimen of weekly paclitaxel and gemcitabine exhibits significant activity in heavily pretreated patients, is well tolerated, and is associated with encouraging survival. This regimen should be considered as a treatment option in patients with chemotherapy-resistant ovarian cancer.     

Phase II trial of carboplatin and infusional cyclosporine with alpha-interferon in recurrent ovarian cancer: a California Cancer Consortium Trial

The purpose of this study was to estimate the response rate of 26-h continuous infusion cyclosporine A (CSA) combined with carboplatin (CBDCA) and subcutaneous alpha-interferon (IFN), in recurrent ovarian cancer (OC), and to measure their effects on CBDCA pharmacokinetics. OC patients relapsing following platinum-based chemotherapy received CBDCA area under the curve (AUC 3) with CSA and IFN, every 3 weeks. The pharmacokinetics of CSA and CBDCA were determined in a subset of patients. Thirty patients received 84 courses of therapy. Three partial responses were observed. Nine patients were stable for >4 months. Toxicity was similar to that observed in our previously reported phase I study and consisted of myelosuppression, nausea, vomiting, and headache. The mean end of infusion CSA level (high-performance liquid chromatographic assay [HPLC]) was 1109 +/- 291 microg/mL (mean +/- SD). CBDCA pharmacokinetics revealed a measured AUC of 3.61 versus a targeted AUC of 3, suggesting a possible effect of IFN on CBDCA levels versus errors in the estimation of CBDCA clearance using measured creatinine clearance. Steady-state levels of >1 microg/mL CSA (HPLC assay) are achievable in vivo. Insufficient clinical resistance reversal was observed in this study to warrant further investigation of this combination.     

Gemcitabine monotherapy in recurrent ovarian cancer: from the bench to the clinic

Abstract.   Bookman MA. Gemcitabine monotherapy in recurrent ovarian cancer: from the bench to the clinic. Int J Gynecol Cancer 2005; 15(Suppl. 1): 12–17.
Gemcitabine (2'2'-difluorodeoxycytidine [dFdC]) is a synthetic analog of deoxycytidine with two fluorine atoms at the 2' position of the carbohydrate. As a hydrophobic molecule, dFdC competes for intracellular access via membrane-associated nucleoside transporter proteins. Following intracellular transport, dFdC is phosphorylated sequentially by deoxycytidine kinase to gemcitabine triphosphate, which inhibits ribonucleotide metabolism, hinders DNA processing, and increases accumulation of intrastrand adducts and interstrand cross-links, thereby leading to a G₁ block in the cell cycle. dFdC monotherapy has been extensively evaluated at doses of 800–1250 mg/m². dFdC is generally well tolerated, with the most frequently occurring dose-limiting toxicities being hematologic, noncumulative, and easily managed by dose alteration. Several studies involving treatment of recurrent ovarian cancer patients with dFdC monotherapy, most of whom had platinum-resistant disease and/or prior exposure to paclitaxel, led to overall response rates of 14–22% and a median duration of response of 4.0–10.6 months. An additional one third of the participants experienced stable disease for an overall clinical benefit in approximately one half of the treated patients. Tumor cells with a multidrug resistance phenotype have increased sensitivity to dFdC (collateral sensitivity). As dFdC is unaffected by platinum resistance, and not susceptible to classic multidrug resistance, it could be particularly beneficial to administer following treatment with agents that induce multidrug resistance. Integration of dFdC with platinum and/or radiation should also be investigated.     

Phase II study of irinotecan in combination with bevacizumab in recurrent ovarian cancer

Objectives

To evaluate the efficacy and safety of irinotecan and bevacizumab in recurrent ovarian cancer. The primary objective was to estimate the progression free survival (PFS) rate at 6 months. Secondary objectives included estimation of overall survival (OS), objective response rate (ORR), duration of response, and an evaluation of toxicity.

Effectiveness of weekly topotecan in patients with recurrent epithelial ovarian cancer

The objective of this study was to investigate the effectiveness and toxicity of weekly topotecan in patients with recurrent epithelial ovarian cancer. Twenty patients were treated with topotecan at a dose of 4 mg/m(2) weekly. Efficacy was determined according to the Response Criteria in Solid Tumors (RECIST) Gynecologic Cancer Inter Group criteria. Median age was 62 years (45-78). Patients had received 1-7 (median 3) prior chemotherapy lines. A total of 203 weekly treatments were administered. In 13 patients (65%) treatment delay was necessary due to bone marrow toxicity. Grade 3/4 neutropenia occurred in 11 patients (55%) and grade 3/4 thrombocytopenia in four patients (20%). Six patients (30%) needed a dose reduction, and 42 cycles (21%) were given with dose reduction. No neutropenia, fever, or sepsis was observed. There was one complete response and one partial response (response rate 10%). All patients with response had platin-sensitive disease (three out of eight). Six patients needed blood transfusion. None of the patients required granulocyte/granulocyte-macrophage colony-stimulating factor. The median duration of response was 13 months. In addition, there were four patients (20%) with a stable disease lasting at least for 4 months. Based on the results of this Phase II study, the toxicity of weekly topotecan seems to be lower than with the 3-weekly topotecan. The response rate of 10% is low but was not expected to be higher as these patients were heavily pretreated.     

Early CA-125 fluctuations in patients with recurrent ovarian cancer receiving chemotherapy

The objective of this study was to analyze retrospective populations with recurrent ovarian cancer to assess differences in CA-125 patterns during chemotherapy. The populations included all patients treated between January 1994 and January 2004, who received liposomal doxorubicin and topotecan, and all patients treated between July 1997 and June 2001, who received carboplatin. Prognostic variables were abstracted from the medical records. Eighty-nine patients received liposomal doxorubicin and topotecan therapy and 21 received carboplatin; of these, 59 (liposomal doxorubicin), 60 (topotecan), and 17 (carboplatin) patients had evaluable CA-125 patterns. Patients given liposomal doxorubicin were more likely to have received only one or two cycles of therapy (37/89 [42%]) than patients receiving either carboplatin (5/21 [24%]) or topotecan (20/89[22%]). In cycle 1, CA-125 increases in patients were carboplatin, 4/17 (24%); liposomal doxorubicin, 41/59 (69%); and topotecan, 11/60 (18%). In cycle 2, CA-125 increases were carboplatin, 2/16 (13%); liposomal doxorubicin, 19/37 (51%); and topotecan, 9/50 (18%). In cycle 3, CA-125 increases were carboplatin, 0/12 (0%); liposomal doxorubicin, 7/23 (30%); and topotecan, 6/38 (16%). Of patients having any CA-125 decrease and given two or more cycles, fewer declines were seen in those given liposomal doxorubicin precycle 2 (18/35[51%]) than in those given carboplatin (13/16[81%]) or topotecan (49/56[88%]). The most prominent delay in CA-125 decline was in patients given liposomal doxorubicin compared with those given topotecan or carboplatin. In the entire population, only 3 of 107 (2.8%) patients demonstrated first CA-125 decline precycle 4. Discontinuation of therapy solely on the basis of early CA-125 increase (precycle 3), particularly with liposomal doxorubicin chemotherapy, may exclude some patients who will benefit from continued therapy.     

Developmental chemotherapy in advanced ovarian cancer: Incorporation of topoisomerase-I inhibitors and perspective of the Gynecologic Oncology Group

Abstract. Bookman MA. Developmental chemotherapy in advanced ovarian cancer: Incorporation of topisomerase-I inhibitors and perspective of the Gynecologic Oncology Group.
Despite improvements in median and overall survival using a combination of platinum and paclitaxel, long-term survival rates for patients with advanced epithelial ovarian carcinoma (EOC) remain disappointing, and the development of more effective primary therapy remains a priority. In particular, several interesting chemotherapy agents have demonstrated activity individually in patients with recurrent EOC. Among these are gemcitabine, topotecan, liposomal doxorubicin, and prolonged oral etoposide. Preclinical models have suggested an advantage for combinations of these agents with platinum, which has been attributed to inhibition of DNA synthetic pathways involved in the repair of platinum-DNA adducts. However, efforts to develop multidrug combinations with platinum and paclitaxel have encountered substantial bone marrow toxicity, prompting exploration of alternative schedules and sequences of drug administration. In this regard, the Gynecologic Oncology Group (GOG) has conducted a series of phase I pilot studies in previously untreated patients to define combinations that are suitable for group-wide phase III trials. With international collaboration, GOG has launched a five-arm trial (GOG-0182) that will compare these combinations against carboplatin-paclitaxel. The selection of candidate regimens for this trial illustrate the challenges of drug development in EOC.     

Phase II study of bevacizumab and pemetrexed for recurrent or persistent epithelial ovarian,fallopian tube or primary peritoneal cancer

Objective

We aimed to evaluate the efficacy and safety of combination bevacizumab/pemetrexed for the treatment of recurrent epithelial ovarian cancer (EOC).

Methods

Platinum-sensitive or -resistant patients with recurrent or persistent EOC were eligible if they had received up to 2 prior chemotherapy regimens, including a platinum/taxane regimen without prior bevacizumab. Pemetrexed 500 mg/m² IV and bevacizumab 15 mg/kg IV were administered every 3 weeks. The primary endpoint was 6-month progression-free survival (PFS); other endpoints included toxicities, PFS and overall survival (OS).

Results

Thirty-four patients received a median of 7 treatment cycles (range, 2–26). Median follow-up was 25.7 months (range, 3.0–47.2). Six month progression-free survival (PFS) was 56% (95% CI: 38–71). The following response rates were documented (%; 95% CI): 0 complete response, 14 partial responses (41%; 25–59), 18 stable disease (53%; 35–70) and 2 progressive disease (6%; 1–20). Median PFS was 7.9 months (95% CI, 4.6–10.9), with a median OS of 25.7 months (95% CI, 15.4–29.8). Twenty-two patients (64.7%) had a platinum-free interval (PFI) of > 6 months prior to enrollment. Grade 3–4 hematologic toxicities included neutropenia (50%), leukopenia (26%), thrombocytopenia (12%) and anemia (9%). Non-hematologic grade 3–4 toxicities included metabolic (29%), constitutional (18%), pain (18%) and gastrointestinal (15%). Two patients developed hematologic malignancies within one year of treatment.

Conclusions

Combination bevacizumab/pemetrexed is an active option for both platinum-sensitive and -resistant recurrent EOC. Further investigation of cost and novel toxicities associated with this regimen may be warranted.