Randomized phase II trial of sorafenib alone or in combination with carboplatin/paclitaxel in women with recurrent platinum sensitive epithelial ovarian, peritoneal, or fallopian tube cancer.

BACKGROUND/PURPOSE: This study was designed to evaluate the response and toxicity of sorafenib alone or when combined with carboplatin and paclitaxel in patients with platinum-sensitive, recurrent ovarian cancer, fallopian tube cancer, or primary peritoneal cancer (EOC). METHODS: Patients with recurrent platinum-sensitive EOC with no more than 2 prior courses of chemotherapy were randomized to single-agent sorafenib 400 mg twice daily or combination sorafenib 400 mg bid (days 2-19) with IV carboplatin (AUC 6) and IV paclitaxel 175 mg/m(2) (S+C/T) every 3 weeks. Single agent sorafenib could cross over to combination upon progression. RESULTS: Patients were initially randomized to either arm, however, due to poor accrual, sorafenib arm was prematurely closed. A total of 13 patients were evaluable for response to sorafenib and 23 patients were evaluable for response to S+C/T. Objective response rate (RR) was 15 % for patients on sorafenib vs. 61 % for patients on S+C/T (p = 0.014); stable disease was seen in 62 % and 35 %, respectively. Clinical benefit rate (CBR) at 4 months (mos.) was 69 % for S and 65 % for S+C/T. The median progression free survival was 5.6 months on sorafenib vs. 16.8 months on S+C/T (p = 0.012) and there was no significant difference of overall survival between two arms (p = 0.974) with median overall survival 25.6 months under sorafenib vs. 25.9 months on S+C/T. Patients remained on trial for a median of 7.8 cycles on sorafenib and 5.4 cycles on S+C/T. CONCLUSION: Sorafenib, alone or in combination with carboplatin and paclitaxel, has activity in patients with platinum-sensitive EOC. Sorafenib in combination with carboplatin and paclitaxel improved RR and PFS; however, there were increased grade and frequencies of toxicities.

Radiochemotherapy plus 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP, NSC #663249) in advanced-stage cervical and vaginal cancers.

OBJECTIVE: Cervical and vaginal cancers have virally-mediated or mutated defects in DNA damage repair responses, making these cancers sensible targets for ribonucleotide reductase inhibition during radiochemotherapy. METHODS: We conducted a phase II study evaluating 3× weekly 2-hour intravenous 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP, 25 mg/m(2)) co-administered with 1× weekly intravenous cisplatin (40 mg/m(2)) and daily pelvic radiation (45 Gy) in women with stage I(B2)-IV(B) cervical (n=22) or stage II-IV vaginal (n=3) cancers. Brachytherapy followed (40 Gy). Toxicity was monitored by common terminology criteria for adverse events (version 3.0). The primary end point of response was assessed by 3-month posttherapy 2-[(18)F] fluoro-2-deoxy-d-glucose positron emission tomography (PET/CT) and clinical examination. RESULTS: 3-AP radiochemotherapy achieved clinical responses in 24 (96% [95% confidence interval: 80-99%]) of 25 patients (median follow-up 20 months, range 2-35 months). 23 (96% [95% confidence interval: 80-99%]) of 24 patients had 3-month posttherapy PET/CT scans that recorded metabolic activity in the cervix or vagina equal or less than that of the cardiac blood pool, suggesting complete metabolic responses. The most frequent 3-AP radiochemotherapy-related adverse events included fatigue, nausea, diarrhea, and reversible hematological and electrolyte abnormalities. CONCLUSIONS: The addition of 3-AP to cisplatin radiochemotherapy was tolerable and produced high rates of clinical and metabolic responses in women with cervical and vaginal cancers. Future randomized phase II and III clinical trials of 3-AP radiochemotherapy are warranted.

Phase II Clinical Trial of Robotic Stereotactic Body Radiosurgery for Metastatic Gynecologic Malignancies.

BACKGROUND: Recurrent gynecologic cancers are often difficult to manage without significant morbidity. We conducted a phase II study to assess the safety and the efficacy of ablative robotic stereotactic body radiosurgery (SBRT) in women with metastatic gynecologic cancers. METHODS: A total of 50 patients with recurrent gynecologic cancer who had single or multiple (≤4) metastases underwent robotic-armed Cyberknife SBRT (24Gy/3 daily doses). Toxicities were graded prospectively by common toxicity criteria for adverse events (version 4.0). SBRT target responses were recorded following RECIST criteria (version 1.0). Rates of clinical benefit for SBRT and non-radiosurgical disease relapse were calculated. Disease-free and overall survivals were estimated by the Kaplan-Meier method and the Cox proportional hazards model was used to control for prognostic variables. FINDINGS: SBRT was safely delivered, with 49 (98%) of 50 patients completing three prescribed fractions. The most frequent grade 2 or higher adverse events attributed to SBRT included fatigue (16%), nausea (8%), and diarrhea (4%). One (2%) grade four hyperbilirubinemia occurred. SBRT target response was 96% (48 of 50 patients). A 6-month clinical benefit was recorded in 34 [68% (95% CI, 53.2, 80.1)] patients. No SBRT targeted disease progressed. Non-radiosurgical disease relapse occurred in 31 (62%) patients. Median disease-free survival was 7.8 months (95% CI, 4.0, 11.6). Median overall survival was 20.2 months (95% CI, 10.9, 29.5). INTERPRETATION: SBRT safely controlled metastatic gynecologic cancer targets. Given an observed high rate of non-radiosurgical disease relapse, a phase I trial assessing co-administration of SBRT and cytotoxic chemotherapy is underway. FUNDING: Case Comprehensive Cancer Center.

Toxicity of weekly oral topotecan in relation to dosage for gynecologic malignancies: a phase I study.

The aim of this study was to determine the dose of weekly oral topotecan that allows safe administration and to evaluate the pharmacokinetics of this dose in patients with recurrent gynecologic malignancies. The first cohort of patients received oral topotecan 6 mg/week administered orally on days 1, 8, and 15 of a 28-day regimen. A standard 3+3 dose-escalating phase design was used for dose levels II-V (8, 10, 12 and 14 mg/week). Toxicity was scored according to the Common Terminology Criteria for Adverse Events. Cumulative toxicity was summarized in the 6-12 mg/week combined cohort and 14 mg/week cohort separately. Pharmacokinetic samples were obtained for day 1, cycle 1 only in the expansion cohort (dose level V). Twenty-five patients received a total of 88 cycles of therapy. Hematologic toxicities of grade 3 (6-12 mg dose) were neutropenia (25%) and anemia (8.3%). Gastrointestinal toxicities of grade 3 were diarrhea (16.7%) and obstruction (8.3%, disease-related). Grade 3 or 4 (14 mg/week) hematologic toxicities consisted of neutropenia (38.5%), platelets (15.4%), anemia (15.4%), infection with neutropenia (7.7%), and thrombosis (7.7%). Gastrointestinal toxicities of grade 3 were diarrhea (7.7%), obstruction (7.7%), and vomiting (7.7%). One patient died secondary to neutropenic sepsis. One patient (4%; 95% confidence interval: 2.1, 22.3) showed a partial response and five patients (20%; 95% confidence interval: 7.6, 41.3) had stable disease. An oral topotecan dose of 14 mg/week for 3 consecutive weeks out of 4 is mostly associated with acceptable toxicities and may be considered for use in future single-agent phase II trials.

A phase I study of concurrent weekly topotecan and cisplatin chemotherapy with whole pelvic radiation therapy in locally advanced cervical cancer: a gynecologic oncology group study.

PURPOSE: To determine the maximum tolerated dose (MTD) and acute dose-limiting toxicities (DLT) of intravenous topotecan administered with weekly cisplatin during pelvic radiation therapy in patients with locally advanced cervical cancer. METHODS: Patients were treated at one of two dose levels receiving intravenous topotecan at 0.5mg/m(2) and cisplatin at either 30 or 40 mg/m(2) given weekly for 6 weeks concurrently with pelvic radiation and intracavitary brachytherapy. The primary endpoint for the escalation study was acute dose-limiting toxicities occurring within 30 days of completing radiation therapy. RESULTS: Eleven patients were enrolled. Dose-limiting toxicity consisting of Grade 3 nausea and vomiting lasting >24h in one patient and grade 3 febrile neutropenia in another patient occurred at the first dose level of weekly topotecan 0.5mg/m(2) and cisplatin 40 mg/m(2). This necessitated de-escalation to weekly cisplatin 30 mg/m(2) in combination with topotecan 0.5mg/m(2) and pelvic radiation. This dose level was tolerable in 6 evaluable patients with only one DLT consisting of grade 4 thrombocytopenia, grade 3 abdominal pain and grade 3 elevated gamma glutamyl transpeptidase (GGT). CONCLUSIONS: In women with locally advanced cervical cancer, intravenous topotecan 0.5mg/m(2) and cisplatin 30 mg/m(2) given weekly for 6 weeks with concurrent pelvic radiation and intracavitary brachytherapy were tolerable. Further expansion of the feasibility cohort of this study was suspended based on the results of a phase 3 trial comparing the efficacy of platinum combinations in advanced and recurrent cervical cancer.

A double-blind, randomized trial of pyridoxine versus placebo for the prevention of pegylated liposomal doxorubicin-related hand-foot syndrome in gynecologic oncology patients.

BACKGROUND: The objective of this study was to compare the incidence of hand-foot syndrome (HFS) in patients who received pyridoxine versus placebo during pegylated liposomal doxorubicin (PLD) chemotherapy for recurrent ovarian, breast, or endometrial cancer. METHODS: Patients received PLD 40 mg/m(2) for a maximum of 6 cycles. Patients were assigned randomly to receive pyridoxine 100 mg twice daily (Group A) or placebo (Group B) and received standard HFS education. Patients completed the Functional Assessment of Cancer Therapy quality-of-life (QOL) questionnaire. The incidence of HFS as measured by common toxicity criteria was compared between groups. Analyses were conducted according to an intent-to-treat basis. Chi-square tests or Fisher exact tests were used. RESULTS: Thirty-four patients were enrolled (18 in Group A and 16 in Group B), and 5 patients were unevaluable for HFS assessment. Overall, 15 of 29 patients (52%) had HFS (all grades), and 10 of 29 patients (35%) had grade 2/3 events. Eight of 15 patients in Group A (53%) and 7 of 14 patients in Group B (50%) had HFS (P = .857). For grade 2/3 events, there was no difference between groups: Six of 15 events (40%) occurred in Group A, and 4 of 14 events (29%) occurred in Group B (P = .70). There was no difference in QOL scores between patients who had grade 2/3 HFS and patients who had grade 0/1 HFS. QOL analysis revealed that all patients had elevated social well being. CONCLUSIONS: Pyridoxine as administered in the current study did not prevent HFS in patients who received PLD. It is possible that QOL is not compromised in patients with HFS because they may have increased social well being while coping with their disease.

A phase I study of oral topotecan and pegylated liposomal doxorubicin (doxil) in platinum-resistant ovarian and peritoneal cancer.

OBJECTIVES: The feasibility, safety, and preliminary efficacy of a second-line combination therapy for oral topotecan and pegylated liposomal doxorubicin in patients with platinum-resistant or refractory epithelial ovarian, peritoneal, or tubal carcinoma were investigated in this phase I trial. METHODS: A fixed dose of oral topotecan 2.3 or 1.53 mg/m(2) on days 1 through 5 and escalating doses of pegylated liposomal doxorubicin on day 1 of a 28-day cycle were administered. Dose-limiting toxicities and maximum tolerated doses were recorded. Safety was assessed by adverse event monitoring, and complete and partial responses were recorded. RESULTS: Twenty-two patients received a total of 61 courses of therapy. The maximum tolerated dose of combination therapy was 1.53 mg/m(2) of topotecan on days 1 through 5 and 40 mg/m(2) of pegylated liposomal doxorubicin on day 1 of a 28-day cycle. Because of cumulative thrombocytopenia, the dose of topotecan was decreased by one-third from 2.3 to 1.53 mg/m(2) in an effort to increase the dose of pegylated liposomal doxorubicin. Only 5 patients completed >4 cycles of therapy. The most common grade 4 adverse events at dose level 4 were neutropenia (5/9 patients) and leukopenia (2/9 patients). Overall responses were observed in 2 of 22 patients. CONCLUSIONS: Oral topotecan and pegylated liposomal doxorubicin can be combined at doses that are active as monotherapies. However, the overall response rates after monotherapy in patients with platinum-resistant ovarian cancer are comparable to or higher than those observed in this phase I study of combination therapy.

A phase I study of gemcitabine followed by cisplatin concurrent with whole pelvic radiation therapy in locally advanced cervical cancer: a Gynecologic Oncology Group study.

PURPOSE: To determine the maximum tolerated dose (MTD) of gemcitabine followed by cisplatin that can be administered weekly during pelvic radiation therapy in patients with locally advanced cervical cancer. METHODS: A phase I and feasibility study with dose escalation of gemcitabine in cohorts of three to six patients to determine the MTD (the dose level at which no more than one of six patients experienced a acute dose-limiting toxicity) was conducted. RESULTS: Thirteen patients were entered on the phase I trial. Acute dose-limiting toxicity occurred with weekly cisplatin at a dose of 40 mg/m(2) and gemcitabine at a dose of 100 mg/m(2). The study was modified, decreasing the dose of cisplatin to 30 mg/m(2) in an effort to dose escalate gemcitabine. Acute dose-limiting toxicity occurred again with weekly cisplatin at a dose of 30 mg/m(2) and gemcitabine at a dose of 75 mg/m(2) (dose level 3). In addition to acute hematologic and acute and late non-hematologic toxicities, late grade 3 and 4 GI and GU toxicities have occurred in two of six patients at dose level 3. Twelve of thirteen patients remained disease-free following treatment. CONCLUSION: The MTD found in this chemoradiation study was weekly gemcitabine 50 mg/m(2) followed by cisplatin 40 mg/m(2). The alternative drug sequence has been reported by others to allow higher doses of gemcitabine. However, at this dose level chronic toxicity was observed. Further expansion of the feasibility cohort of this study was suspended pending the efficacy and toxicity results of a large trial which has recently been completed.

Paclitaxel, carboplatin and pegylated liposomal doxorubicin in ovarian and peritoneal carcinoma: a phase I study of the Gynecologic Oncology Group.

PURPOSE: Based on the activity and tolerability of liposomal doxorubicin in platinum- and paclitaxel-resistant ovarian carcinoma, we conducted a phase I trial of pegylated liposomal doxorubicin with paclitaxel and carboplatin to determine the maximum tolerated dose (MTD) in chemotherapy naive ovarian, peritoneal and tubal carcinoma patients. METHODS: Three schedules were studied: paclitaxel, carboplatin and pegylated liposomal doxorubicin every 28 days; paclitaxel and carboplatin every 21 days with liposomal doxorubicin every 42 days; and weekly paclitaxel, carboplatin (AUC=5) every 21 days and liposomal doxorubicin every 42 days. The paclitaxel dose was 175 mg/m(2) over 3 h on an every 3-4 week schedule and 60 mg/m(2) when administered weekly. Based on the frequency of neutropenic sepsis, grade 4 thrombocytopenia and > or =grade 3 non-hematologic toxicity, the starting dose of liposomal doxorubicin of 20 mg/m(2) was escalated to determine the MTD. RESULTS: A total of 210 (21-day) cycles were administered to 37 patients. Dose-limiting toxicity (DLT) occurred when liposomal doxorubicin was administered at 40 mg/m(2). Because of treatment-related delays resulting in decreased paclitaxel/carboplatin dose intensity, administration was modified to be given every 21 days, with liposomal doxorubicin given every 42 days. Since neutropenia was the DLT of this schedule, the schema was further modified to administer paclitaxel weekly; however, weekly administration was inconsistent because of toxicity. CONCLUSION: Paclitaxel 175 mg/m(2), carboplatin (AUC=5) and pegylated liposomal doxorubicin 30 mg/m(2) are tolerable without supportive therapy. The usual dose intensity of paclitaxel/carboplatin was maintained by administering liposomal doxorubicin every other cycle.

Gynecologic oncology patients' satisfaction and symptom severity during palliative chemotherapy.

BACKGROUND: Research on quality and satisfaction with care during palliative chemotherapy in oncology patients has been limited. The objective was to assess the association between patient's satisfaction with care and symptom severity and to evaluate test-retest of a satisfaction survey in this study population. METHODS: A prospective cohort of patients with recurrent gynecologic malignancies receiving chemotherapy were enrolled after a diagnosis of recurrent cancer. Patients completed the Quality of End-of-Life care and satisfaction with treatment scale (QUEST) once upon enrollment in an outpatient setting and again a week later. Patients also completed the Mini-Mental Status Exam, the Hospital Anxiety/Depression Scale, a symptom severity scale and a demographic survey. Student's t-test, correlation statistics and percent agreement were used for analysis. RESULTS: Data from 39 patients were analyzed. Mean (SD) quality of care summary score was 41.95 (2.75) for physicians and 42.23 (5.42) for nurses (maximum score was 45; p = 0.76 for difference in score between providers). Mean (SD) satisfaction of care summary score was 29.03 (1.92) for physicians and 29.28 (1.70) for nurses (maximum score was 30; p = 0.49 for difference between providers). Test-retest for 33 patients who completed both QUEST surveys had high percent agreement (74-100%), with the exception of the question regarding the provider arriving late (45 and 53%). There was no correlation between quality and satisfaction of care and symptom severity. Weakness was the most common symptom reported. Symptom severity correlated with depression (r = 0.577 p < 0.01). There was a trend towards a larger proportion of patients reporting pain who had three or more prior chemotherapy regimens (p = 0.075). Prior number of chemotherapy regimens or time since diagnosis was not correlated with symptom severity score. Anxiety and depression were correlated with each other (r = 0.711, p < 0.01). There was no difference in symptom severity score at enrollment between those patients who have since died (n = 19) versus those who are still alive. CONCLUSION: The QUEST Survey has test-retest reliability when used as a written instrument in an outpatient setting. However, there was no correlation between this measure and symptom severity. Patient evaluation of care may be more closely related to the interpersonal aspects of the health care provider relationship than it is to physical symptoms.

Sequential prolonged oral topotecan and prolonged oral etoposide as second-line therapy in ovarian or peritoneal carcinoma: a phase I Gynecologic Oncology Group study.

OBJECTIVE: Preclinical models suggest synergy when topoisomerase I and II inhibitors are given sequentially, but not simultaneously. A phase I study was conducted in previously treated ovarian or peritoneal carcinoma to determine the tolerability (maximum number of days) of sequential oral topotecan and oral etoposide. METHODS: Topotecan (0.8 mg/m(2)) was administered daily (days 1-5) followed by etoposide (50 mg/m(2)) administered daily for up to 5 days (days 8-12). Patients on dose levels 3 and 4 repeated topotecan for up to 5 days starting on day 15 after the initial topotecan and etoposide sequence. Cycles were repeated every 28 days. Dose-limiting toxicities (DLT) were defined as: neutrophils <1000/microl or platelets <50,000/microl before completing administration of etoposide or topotecan; neutropenic fever; platelets <20,000/microl; or a delay greater than 2 weeks in starting cycle 2 due to hematologic toxicity (ANC <1500/microl or platelets <100,000/microl on scheduled day of treatment). RESULTS: Nineteen patients were entered into this trial, and a total of 54 cycles (range 1-10) of therapy were administered. Dose-limiting toxicities, principally neutropenia, occurred when therapy was administered for 3 of 4 weeks. CONCLUSION: Oral topotecan and oral etoposide administered at these doses daily for 5 days sequentially for a maximum of three (out of every four) weeks of therapy are tolerable. In some cases, it may be necessary to hold therapy the third week. Based on the activity seen in this patient population, it is planned to take this regimen into a phase II setting.

A phase II trial of weekly paclitaxel and every 3 weeks of carboplatin in potentially platinum-sensitive ovarian and peritoneal carcinoma.

OBJECTIVE: Paclitaxel administered weekly in equal cumulative doses is associated with less hematologic and non-hematologic toxicity than an every 3-week administration. We studied weekly paclitaxel and 3-week carboplatin in potentially platinum-sensitive recurrent ovarian and peritoneal carcinoma. METHODS: Paclitaxel at a dose of 80 mg/m(2) over 1 h in combination with carboplatin at an AUC of 5 was administered on day 1. Subsequent paclitaxel doses, modified based on the day of treatment ANC, were administered on days 8 and 15. Paclitaxel dose reductions to 75% of prior dose were performed for chemotherapy delays or toxicity. RESULTS: Twenty-eight patients were studied. The median age was 59 (range 42-80). The median platinum-free interval was 12 months (range 7-129 months). A median of six courses (range 1-13) was administered. Paclitaxel dose reductions to 60 mg/m(2) were required in 85% of the patients. Grades 3 and 4 thrombocytopenia were seen in 5 and 0 patients, respectively. Grades 3 and 4 neutropenia were seen in 14 and 1 patients, respectively. One patient was hospitalized for neutropenic fever. Twenty of 26 (77%) evaluable patients have responded with 15 patients (58%) achieving a complete response. CONCLUSIONS: Weekly paclitaxel at a dose of 60 mg/m(2) in combination with carboplatin at an AUC of 5 is well tolerated and active in potentially platinum-sensitive recurrent ovarian and peritoneal carcinoma.

Successful administration of carboplatin in patients with clinically documented carboplatin hypersensitivity.

OBJECTIVE: The goal of this study was to evaluate the tolerance and effectiveness of carboplatin rechallenge using a prolonged desensitizing carboplatin infusion regimen in patients with clinically documented moderate-severe carboplatin hypersensitivity. METHOD: Patients admitted for carboplatin infusion were identified by computerized pharmacy records and retrospectively analyzed. RESULT: Thirty-three patients with recurrent ovarian (N = 27), peritoneal (N = 4), tubal (N = 1), and cervical (N = 1) cancer treated with a prolonged desensitizing carboplatin infusion regimen were identified. The patients had received a median of 10 courses of carboplatin (range 3-33) before developing the moderate-severe hypersensitivity reaction. Two hundred and fifteen courses (median 5, range 1-52) were administered. Twenty-nine patients (88%) were successfully rechallenged while four had a recurrent moderate-severe carboplatin hypersensitivity precluding further administration. Despite initial tolerance of the infusion schedule moderate-severe carboplatin hypersensitivity recurred in 3 additional patients (9%) after two, three, and six subsequent courses. Objective responses to therapy were seen in 22 of 28 evaluable patients (79%). CONCLUSIONS: A prolonged desensitizing carboplatin infusion regimen is tolerated in the majority of patients with clinically documented moderate-severe carboplatin hypersensitivity. Objective response rates seem acceptable with this schedule.

Gemcitabine reverses cisplatin resistance: demonstration of activity in platinum- and multidrug-resistant ovarian and peritoneal carcinoma.

OBJECTIVE: Preclinical models in an ovarian cancer cell line (A2780) demonstrate synergistic activity with the combination of gemcitabine and cisplatin compared to either single agent alone. Platinum resistance is related to expression of excision repair proteins, one of which (ERCC-1) has been identified as playing a critical role in the synergy of gemcitabine and cisplatin. We evaluated the cisplatin and gemcitabine regimen in patients with platinum refractory and multidrug refractory ovarian and peritoneal carcinoma. METHODS: Gemcitabine (750 mg/m(2)) was administered intravenously over 30 min followed by cisplatin (30 mg/m(2)) on Days 1 and 8 every 21 days. Day 8 therapy was canceled for an absolute neutrophil count <1000/mm(3) or platelet count <75,000/mm(3). Sequential dose reductions of gemcitabine to 600, 400, and 300 mg/m(2) were prescribed in the event of canceled therapy, neutropenic sepsis, or severe thrombocytopenia (platelets <20,000/m(3)). RESULTS: Thirty-six platinum- and paclitaxel-resistant patients were studied. Thirty-five were evaluable for response, of which 6 had progressed on gemcitabine as a single agent. Fifteen of the patients responded (42.9%, 95% CI 28.0-59.1%). Eleven were partial clinical responses and 4 were complete clinical responses, with 4 of the 6 patients who had failed gemcitabine as a single agent responding. Among the responding patients the median response duration was 11 months (range 4-14 months). For all patients the progression-free interval was 6 months (range 1-14 months). The median survival was 12 months. CONCLUSION: The combination of gemcitabine and cisplatin is active in patients who are platinum resistant. Additionally, activity is demonstrated even in patients who have previously been resistant to gemcitabine.

A phase I trial of prolonged oral etoposide and liposomal doxorubicin in ovarian, peritoneal, and tubal carcinoma: a gynecologic oncology group study.

OBJECTIVES: In an effort to explore second-line therapy in ovarian, peritoneal, and tubal carcinoma, a phase I trial combining prolonged oral etoposide and liposomal doxorubicin was conducted by the Gynecologic Oncology Group. METHODS: Liposomal doxorubicin (20 mg/m(2)) was administered intravenously over 1 h followed by oral etoposide at 50 mg/m(2)/day beginning on day 2. In the first phase of accrual, the number of days of oral etoposide was increased until its maximum tolerated dose (MTD) was determined based on hematologic toxicity. In the second phase, etoposide was given at the MTD while the dose of liposomal doxorubicin was escalated until its maximum tolerated dose was reached based on hematologic or nonhematologic toxicity. Cycles were repeated every 28 days for a maximum of 12 courses. Dose-limiting toxicity was defined as neutropenic sepsis, grade 4 thrombocytopenia, absolute neutrophil count <1000/microl or platelets <50,000 during treatment with etoposide, or > or =grade 3 mucositis/stomatitis, palmar-plantar erythrodyesthesia, or rash. RESULTS: Fifteen patients were accrued to the study's first phase, and 3 were accrued to the second phase. Dose-limiting hematologic toxicity occurred with 14 days of oral etoposide in combination with liposomal doxorubicin at 20 mg/m(2). Efforts to escalate the dose of liposomal doxorubicin to 30 mg/m(2) in combination with 12 days of oral etoposide at 50 mg/m(2) resulted in dose-limiting hematologic toxicity. Five of 17 (29%; 95% CI: 13-53%) evaluable patients experienced a response. CONCLUSION: The regimen of oral etoposide at 50 mg/m(2)/day for 12 days in combination with liposomal doxorubicin at a dose of 20 mg/m(2) is tolerable without supportive therapy. While this dose of oral etoposide has demonstrated activity as a single agent in ovarian cancer, liposomal doxorubicin has only been effective in ovarian cancer at higher doses. There are no immediate plans to study this combination further.