Long-term safety in patients with recurrent ovarian cancer treated with niraparib versus placebo: Results from the phase III ENGOT-OV16/NOVA trial.

OBJECTIVE: Niraparib is a poly(ADP-ribose) polymerase (PARP) inhibitor approved for use in heavily pretreated patients and as maintenance treatment in patients with newly-diagnosed or recurrent ovarian cancer following a response to platinum-based chemotherapy. We present long-term safety data for niraparib from the ENGOT-OV16/NOVA trial. METHODS: This multicenter, double-blind, randomized, controlled phase III trial evaluated the efficacy and safety of niraparib for the treatment of recurrent ovarian cancer. Patients were randomly assigned 2:1 to receive either once-daily niraparib 300 mg or placebo. Two independent cohorts were enrolled based on germline BRCA mutation status. The primary endpoint was progression-free survival, reported previously. Long-term safety data were from the most recent data cutoff (September 2017). RESULTS: Overall, 367 patients received niraparib 300 mg once daily. Dose reductions due to TEAEs were highest in month 1 (34%) and declined every month thereafter. Incidence of any-grade and grade ≥ 3 hematologic and symptomatic TEAEs was also highest in month 1 and subsequently declined. Incidence of grade ≥ 3 thrombocytopenia decreased from 28% (month 1) to 9% and 5% (months 2 and 3, respectively), with protocol-directed dose interruptions and/or reductions. Acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) were reported in 2 and 6 niraparib-treated patients, respectively, and in 1 placebo patient each. Treatment discontinuations due to TEAEs were <5% in each month and time interval measured. CONCLUSION: These data demonstrate the importance of appropriate dose reduction according to toxicity criteria and support the safe long-term use of niraparib for maintenance treatment in patients with recurrent ovarian cancer. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01847274.

Antitumor activity and safety of pembrolizumab in patients with advanced recurrent ovarian cancer: results from the phase II KEYNOTE-100 study.

BACKGROUND: Advanced recurrent ovarian cancer (ROC) is the leading cause of gynecologic cancer-related death in developed countries and new treatments are needed. Previous studies of immune checkpoint blockade showed low objective response rates (ORR) in ROC with no identified predictive biomarker. PATIENTS AND METHODS: This phase II study of pembrolizumab (NCT02674061) examined two patient cohorts with ROC: cohort A received one to three prior lines of treatment with a platinum-free interval (PFI) or treatment-free interval (TFI) between 3 and 12 months and cohort B received four to six prior lines with a PFI/TFI of ≥3 months. Pembrolizumab 200 mg was administered intravenously every 3 weeks until cancer progression, toxicity, or completion of 2 years. Primary end points were ORR by Response Evaluation Criteria in Solid Tumors version 1.1 per blinded independent central review by cohort and by PD-L1 expression measured as combined positive score (CPS). Secondary end points included duration of response (DOR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety. RESULTS: Cohort A enrolled 285 patients; the first 100 served as the training set for PD-L1 biomarker analysis. Cohort B enrolled 91 patients. ORR was 7.4% for cohort A and 9.9% for cohort B. Median DOR was 8.2 months for cohort A and not reached for cohort B. DCR was 37.2% and 37.4%, respectively, in cohorts A and B. Based on the training set analysis, CPS 1 and 10 were selected for evaluation in the confirmation set. In the confirmation set, ORR was 4.1% for CPS <1, 5.7% CPS ≥1, and 10.0% for CPS ≥10. PFS was 2.1 months for both cohorts. Median OS was not reached for cohort A and was 17.6 months for cohort B. Toxicities were consistent with other single-agent pembrolizumab trials. CONCLUSIONS: Single-agent pembrolizumab showed modest activity in patients with ROC. Higher PD-L1 expression was correlated with higher response. CLINICAL TRIAL NUMBER: Clinicaltrials.gov, NCT02674061.

Final report on serial phase II trials of all-intraperitoneal chemotherapy with or without bevacizumab for women with newly diagnosed, optimally cytoreduced carcinoma of Müllerian origin.

BACKGROUND: Intraperitoneal (IP) chemotherapy can improve outcomes for women with optimally cytoreduced epithelial ovarian cancer but toxicities are a concern. We conducted 2 phase 2 trials of an IV/IP regimen using carboplatin and paclitaxel without (Trial A) and with bevacizumab (Trial B). METHODS: Both trials consisted of carboplatin AUC 6 day 1, and paclitaxel 60 mg/m2 on days 1,8, 15 of a 21-day cycle; in Trial B, patients received IV bevacizumab 15 mg/kg every cycle starting cycle 2. Chemotherapy was administered IV for cycle 1 and then IP for all subsequent cycles. Primary objectives included safety and tolerability, pathologic CR rate (Trial A), and the rate of completion of IP cycles of therapy (Trial B). Progression-free (PFS), overall survival (OS), and pharmacokinetic analysis were secondary endpoints. RESULTS: 81 patients were treated on both trials (n = 40 and 41 in trials A and B, respectively). Median age for trials A and B was 59 (range, 36-76) and 55 (range, 19-69) years, respectively. 68% and 85% of patients, respectively for A and B, completed at least 4 cycles of treatment in both trials. Treatment with bevacizumab resulted in higher rates of grade 3 fatigue (37 versus 33%) and grade 3-4 diarrhea (22 versus 8%). Median PFS was 23.5 (95%CI 16.2-35.3) and 25 (95%CI 16.4-42.7) months, respectively; median OS was 68 (95%CI 49.5-NR) and 79.7 (95%CI 59.0-79.7) months, respectively for Trial A and B. CONCLUSIONS: Weekly administered IP carboplatin and IP paclitaxel is tolerable and safe with similar activity with and without concommittant bevacizumab in these 2 trials.

Overall survival and updated progression-free survival outcomes in a randomized phase II study of combination cediranib and olaparib versus olaparib in relapsed platinum-sensitive ovarian cancer.

BACKGROUND: Olaparib is a poly(ADP-ribose) polymerase inhibitor and cediranib is an oral anti-angiogenic. In the primary analysis of this phase II study, combination cediranib/olaparib improved progression-free survival (PFS) compared with olaparib alone in relapsed platinum-sensitive ovarian cancer. This updated analysis was conducted to characterize overall survival (OS) and update PFS outcomes. PATIENTS AND METHODS: Ninety patients were enrolled to this randomized, open-label, phase II study between October 2011 and June 2013 across nine United States-based academic centers. Data cut-off was 21 December 2016, with a median follow-up of 46 months. Participants had relapsed platinum-sensitive ovarian cancer of high-grade serous or endometrioid histology or had a deleterious germline BRCA1/2 mutation (gBRCAm). Participants were randomized to receive olaparib capsules 400 mg twice daily or cediranib 30 mg daily and olaparib capsules 200 mg twice daily until disease progression. RESULTS: In this updated analysis, median PFS remained significantly longer with cediranib/olaparib compared with olaparib alone (16.5 versus 8.2 months, hazard ratio 0.50; P = 0.007). Subset analyses within stratum defined by BRCA status demonstrated statistically significant improvement in PFS (23.7 versus 5.7 months, P = 0.002) and OS (37.8 versus 23.0 months, P = 0.047) in gBRCA wild-type/unknown patients, although OS was not statistically different in the overall study population (44.2 versus 33.3 months, hazard ratio 0.64; P = 0.11). PFS and OS appeared similar between the two arms in gBRCAm patients. The most common CTCAE grade 3/4 adverse events with cediranib/olaparib remained fatigue, diarrhea, and hypertension. CONCLUSIONS: Combination cediranib/olaparib significantly extends PFS compared with olaparib alone in relapsed platinum-sensitive ovarian cancer. Subset analyses suggest this margin of benefit is driven by PFS prolongation in patients without gBRCAm. OS was also significantly increased by the cediranib/olaparib combination in this subset of patients. Additional studies of this combination are ongoing and should incorporate analyses based upon BRCA status. TRIAL REGISTRATION: Clinicaltrials.gov Identifier NCT0111648.

Safety and dose modification for patients receiving niraparib.

Background: Niraparib is a poly(ADP-ribose) polymerase inhibitor approved in the USA and Europe for maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in complete or partial response to platinum-based chemotherapy. In the pivotal ENGOT-OV16/NOVA trial, the dose reduction rate due to treatment-emergent adverse event (TEAE) was 68.9%, and the discontinuation rate due to TEAE was 14.7%, including 3.3% due to thrombocytopenia. A retrospective analysis was carried out to identify clinical parameters that predict dose reductions. Patients and methods: All analyses were carried out on the safety population, comprising all patients who received at least one dose of study drug. Patients were analyzed according to the study drug consumed (i.e., as treated). A predictive modeling method (decision trees) was used to identify important variables for predicting the likelihood of developing grade ≥3 thrombocytopenia within 30 days after the first dose of niraparib and determine cut-off points for chosen variables. Results: Following dose modification, 200 mg was the most commonly administered dose in the ENGOT-OV16/NOVA trial. Baseline platelet count and baseline body weight were identified as risk factors for increased incidence of grade ≥3 thrombocytopenia. Patients with a baseline body weight <77 kg or a baseline platelet count <150 000/µl in effect received an average daily dose ∼200 mg (median = 207 mg) due to dose interruption and reduction. Progression-free survival in patients who were dose reduced to either 200 or 100 mg was consistent with that of patients who remained at the 300 mg starting dose. Conclusions: The analysis presented suggests that patients with baseline body weight of <77 kg or baseline platelets of <150 000/µl may benefit from a starting dose of 200 mg/day. ClinicalTrials.gov ID: NCT01847274.

Phase I dose escalation study of the PI3kinase pathway inhibitor BKM120 and the oral poly (ADP ribose) polymerase (PARP) inhibitor olaparib for the treatment of high-grade serous ovarian and breast cancer.

Background: Based upon preclinical synergy in murine models, we carried out a phase I trial to determine the maximum tolerated dose (MTD), toxicities, pharmacokinetics, and biomarkers of response for the combination of BKM120, a PI3K inhibitor, and olaparib, a PARP inhibitor. Patients and methods: Olaparib was administered twice daily (tablet formulation) and BKM120 daily on a 28-day cycle, both orally. A 3 + 3 dose-escalation design was employed with the primary objective of defining the combination MTD, and secondary objectives were to define toxicities, activity, and pharmacokinetic profiles. Eligibility included recurrent breast (BC) or ovarian cancer (OC); dose-expansion cohorts at the MTD were enrolled for each cancer. Results: In total, 69 of 70 patients enrolled received study treatment; one patient never received study treatment because of ineligibility. Twenty-four patients had BC; 46 patients had OC. Thirty-five patients had a germline BRCA mutation (gBRCAm). Two DLTs (grade 3 transaminitis and hyperglycemia) were observed at DL0 (BKM120 60 mg/olaparib and 100 mg b.i.d.). The MTD was determined to be BKM120 50 mg q.d. and olaparib 300 mg b.i.d. (DL8). Additional DLTs included grade 3 depression and transaminitis, occurring early in cycle 2 (DL7). Anticancer activity was observed in BC and OC and in gBRCAm and gBRCA wild-type (gBRCAwt) patients. Conclusions: BKM120 and olaparib can be co-administered, but the combination requires attenuation of the BKM120 dose. Clinical benefit was observed in both gBRCAm and gBRCAwt pts. Randomized phase II studies will be needed to further define the efficacy of PI3K/PARP-inhibitor combinations as compared with a PARP inhibitor alone.

Phase I study of safety and pharmacokinetics of the anti-MUC16 antibody-drug conjugate DMUC5754A in patients with platinum-resistant ovarian cancer or unresectable pancreatic cancer.

BACKGROUND: MUC16 is a tumor-specific antigen overexpressed in ovarian (OC) and pancreatic (PC) cancers. The antibody-drug conjugate (ADC), DMUC5754A, contains the humanized anti-MUC16 monoclonal antibody conjugated to the microtubule-disrupting agent, monomethyl auristatin E (MMAE). PATIENTS AND METHODS: This phase I study evaluated safety, pharmacokinetics (PK), and pharmacodynamics of DMUC5754A given every 3 weeks (Q3W, 0.3-3.2 mg/kg) or weekly (Q1W, 0.8-1.6 mg/kg) to patients with advanced recurrent platinum-resistant OC or unresectable PC. Biomarker studies were also undertaken. RESULTS: Patients (66 OC, 11 PC) were treated with DMUC5754A (54 Q3W, 23 Q1W). Common related adverse events (AEs) in >20% of patients (all grades) over all dose levels were fatigue, peripheral neuropathy, nausea, decreased appetite, vomiting, diarrhea, alopecia, and pyrexia in Q3W patents, and nausea, vomiting, anemia, fatigue, neutropenia, alopecia, decreased appetite, diarrhea, and hypomagnesemia in Q1W patients. Grade ≥3-related AE in ≥5% of patients included neutropenia (9%) and fatigue (7%) in Q3W patients, and neutropenia (17%), diarrhea (9%), and hyponatremia (9%) in Q1W patients. Plasma antibody-conjugated MMAE (acMMAE) and serum total antibody exhibited non-linear PK across tested doses. Minimal accumulation of acMMAE, total antibody, or unconjugated MMAE was observed. Confirmed responses (1 CR, 6 PRs) occurred in OC patients whose tumors were MUC16-positive by IHC (2+ or 3+). Two OC patients had unconfirmed PRs; six OC patients had stable disease lasting >6 months. For CA125, a cut-off of ≥70% reduction was more suitable for monitoring treatment response due to the binding and clearance of serum CA125 by MUC16 ADC. We identified circulating HE4 as a potential novel surrogate biomarker for monitoring treatment response of MUC16 ADC and other anti-MUC16 therapies in OC. CONCLUSIONS: DMUC5754A has an acceptable safety profile and evidence of anti-tumor activity in patients with MUC16-expressing tumors. Objective responses were only observed in MUC16-high patients, although prospective validation is required. CLINICAL TRIAL NUMBER: NCT01335958.

Olaparib monotherapy in patients with advanced relapsed ovarian cancer and a germline BRCA1/2 mutation: a multistudy analysis of response rates and safety.

BACKGROUND: The PARP inhibitor olaparib (Lynparza™) demonstrates antitumor activity in women with relapsed ovarian cancer and a germline BRCA1/2 mutation (gBRCAm). Data from olaparib monotherapy trials were used to explore the treatment effect of olaparib in patients with gBRCAm ovarian cancer who had received multiple lines of prior chemotherapy. PATIENTS AND METHODS: This analysis evaluated pooled data from two phase I trials [NCT00516373 (study 2); NCT00777582 (study 24)] and four phase II trials [NCT00494442 (study 9); NCT00628251 (study 12); NCT00679783 (study 20); NCT01078662 (study 42)] that recruited women with relapsed ovarian, fallopian tube or peritoneal cancer. All patients had a documented gBRCAm and were receiving olaparib 400 mg monotherapy twice daily (capsule formulation) at the time of relapse. Objective response rate (ORR) and duration of response (DoR) were evaluated using original patient outcomes data for patients with measurable disease at baseline. RESULTS: Of the 300 patients in the pooled population, 273 had measurable disease at baseline, of whom 205 (75%) had received ≥3 lines of prior chemotherapy. In the pooled population, the ORR was 36% [95% confidence interval (CI) 30-42] and the median DoR was 7.4 months (95% CI 5.7-9.1). The ORR among patients who had received ≥3 lines of prior chemotherapy was 31% (95% CI 25-38), with a DoR of 7.8 months (95% CI 5.6-9.5). The safety profile of olaparib was similar in patients who had received ≥3 lines of prior chemotherapy compared with the pooled population; grade ≥3 adverse events were reported in 54% and 50% of patients, respectively. CONCLUSION: Durable responses to olaparib were observed in patients with relapsed gBRCAm ovarian cancer who had received ≥3 lines of prior chemotherapy. CLINICALTRIALSGOV: NCT00516373; NCT00494442; NCT00628251; NCT00679783; NCT00777582; NCT01078662.

Phase II trial of erlotinib in women with squamous cell carcinoma of the vulva.

OBJECTIVE: To evaluate the efficacy and toxicity of erlotinib in the management of squamous cell carcinoma (SCC) of the vulva. METHODS: Patients with vulvar lesions amenable to surgery or chemoradiation (cohort 1) or those with metastatic measurable disease (cohort 2) received erlotinib 150 mg daily. Patients were monitored for toxicity. Responses were determined by digital photography or RECIST 1.1. Cohort 1 underwent pre and post treatment biopsies. EGFR immunohistochemistry (IHC), fluorescence in-situ hybridization (FISH), and mutational analysis were performed. RESULTS: 41 patients were enrolled: 17 in cohort 1 and 24 in cohort 2. Notable grade 3 or 4 toxicities included allergic reaction (1), diarrhea/electrolyte abnormalities (3), ischemic colitis (1), and renal failure (3) and electrolyte abnormalities (n=2). Mean number of cycles for cohort 2 was 3.3. Overall clinical benefit rate was 67.5% with 11 (27.5%) partial responses (PR), 16 (40.0%) stable disease (SD), and 7 (17.5%) progressive disease. Responses were of short duration. All pre and post treatment biopsies exhibited 2-3+ EGFR staining. 5 of 14 patients (35%) were found to have EGFR amplification (n=3) or high polysomy/trisomy (n=2). These five patients had either a PR (n=3) or SD (n=2). Gain of function mutations were not been identified. CONCLUSIONS: This is the first reported controlled trial evaluating erlotinib for the management of vulvar carcinoma. Toxicities were acceptable given the lack of treatment options for these patients. Given the observed clinical benefits erlotinib may represent one of the most active agents available to treat vulvar SCC.

Long-term adjustment of early-stage ovarian cancer survivors.

The objectives of this study were to describe the quality of life (QOL), consequences of treatment, complementary therapy use, and factors correlating with psychologic state in 58 survivors of early-stage ovarian cancer since little is known about the QOL of early-stage ovarian cancer survivors. Survivors were interviewed using standardized measures to assess physical, psychologic, social, and sexual functioning; impact of cancer on socioeconomic status; and complementary therapy use. Survivors reported good physical QOL scores and few unmet needs. However, menopausal symptoms and negative impact on sexuality were reported. Less than 10% of survivors reported either an interest in sex or were sexually active. Psychologic assessment yielded a subset of 26% of patients with scores suggestive of posttraumatic stress disorder (PTSD) and 40% of survivors scored below the norm on the Mental Health Inventory-17 Survey. One third of patients required treatment for family/personal problems and took antianxiety medications. About 56% of survivors reported fear of cancer recurrence and 59% reported anxiety when their CA125 is tested. Better mental health was significantly related to less fatigue (Functional Assessment of Cancer Therapy [FACT]-fatigue, r = 0.61, P < 0.0001), less pain (European Organisation for Research and Treatment of Cancer [EORTC], r =-0.54, P < 0.0001), fewer stressful life events (Life Event Scale, r =-0.44, P > 0.001), and greater social support (MOS Social Support Survey, r = 0.41, P < 0.01). Early-stage ovarian cancer survivors had few physical complaints and unmet needs, but psychologic distress was evident in a subset of survivors; the majority of survivors reported sexual dysfunction. These results indicate the need for intervention and improved distress screening in the early-stage ovarian cancer population.

Three sequential chemotherapy doublets for the treatment of newly diagnosed advanced müllerian malignancies: the modified triple doublet regimen.

OBJECTIVE: Previously, we reported the use of three sequential doublets (Triple Doublets) in the treatment of women with newly diagnosed and advanced stage müllerian malignancies. The surgically defined negative second look operation (SLO) rate to Triple Doublets was 38%. Modifications were made to this treatment regimen that were predicted to reduce toxicity and possibly increase efficacy. METHODS: Open label two-cohort study. Patients with a new diagnosis of Stages II-IV müllerian malignancy were eligible. After cytoreductive surgery, patients were treated with three sequential doublets including 3 cycles of carboplatin and gemcitabine, and 3 cycles of carboplatin and paclitaxel, and 3 cycles of doxorubicin and topotecan. After therapy, all women were clinically staged and evaluated at SLO if clinical staging was negative for residual disease. Primary endpoints were toxicity and negative SLO rate with rates of 60% and 40% defined a priori in optimally cytoreduced (cohort 1) and suboptimally cytoreduced or Stage IV (cohort 2), respectively. RESULTS: Eighty-five eligible patients were enrolled with a median age of 52 years. Forty-seven and thirty-eight women were in cohorts 1 and 2, respectively. 723 cycles of chemotherapy were delivered with no toxic deaths. Grades 3 and 4 toxicities included neutropenia in 75% of patients and thrombocytopenia in 65% of patients during at least one cycle of therapy. Fever and neutropenia were seen in 3.5% of patients. All Grades 3 and 4 non-hematologic toxicities were seen at a frequency of <10%. Seventy women underwent SLO with a negative SLO rate of 53% with an additional 9% having microscopically positive procedures. Negative SLO rate was 74% in cohort 1 and 36% in cohort 2. CONCLUSIONS: Treatment with the modified triple doublet regimen is tolerable with an encouraging pathologic CR rate.

Phase I/II dose finding study of combination cisplatin and gemcitabine in patients with recurrent cervix cancer.

OBJECTIVES: To evaluate the toxicity and efficacy of cisplatin and gemcitabine in women with recurrent cervical cancer. METHODS: A multi-institutional phase I/II dose finding study of cisplatin and gemcitabine delivered to women with recurrent previously radiated cervical carcinoma. RESULTS: Twenty eight patients were enrolled. The mean and median age of patients was 51 years (age range 35 to 70 years). Chemotherapy was given on a 28-day cycle; cisplatin was administered at a fixed dose of 50 mg/m(2), day 1 and gemcitabine, days 1, 8, and 15. Gemcitabine doses started at 600 mg/m(2) (dose level 1) and were escalated by 100 mg/m(2)/dose level until 1000 mg/m(2) (dose level 5). Twenty seven patients were evaluable for toxicity and disease response, and 75 cycles of chemotherapy were administered. Toxicities were predominantly hematological; 18% of patients experienced grade 3 anemia, 37% grade 3 and 11% grade 4 leukopenia, 41% grade 3 neutropenia, and 26% grade 3 thrombocytopenia. The maximally tolerated dose (MTD) was not reached. One patient experienced a dose-limiting toxicity on dose level 2 (febrile neutropenia). One patient had a CR and 3 patients had a PR to therapy (15% response rate), 41% of patients had SD, and 44% had progression of cancer. Median survival was 11.9 months. CONCLUSION: Although this 28-day gemcitabine and cisplatin regimen in recurrent cervix cancer has tolerable toxicity, 21-day regimens are recommended because of improved practicality, higher dose intensity, and higher response rates.

A phase II study of fixed dose rate gemcitabine in patients with relapsed müllerian tumors.

Gemcitabine (2',2'-difluorodeoxycytidine) is a novel purine analog with clinical activity against ovarian cancer. Accumulation of gemcitabine triphosphate (dFdCTP) increases in a linear fashion with prolonged infusions of gemcitabine, and there is a strong relationship between intracellular accumulation of dFdCTP and DNA damage. Women with ovarian, fallopian tube, or primary peritoneal carcinoma and documented recurrent disease were eligible for the study. Patients could not have received more than four prior lines of chemotherapy and had to have measurable or evaluable disease. Gemcitabine 800 mg/m2 administered by intravenous infusion at 10 mg/m2/min (fixed dose rate [FDR]) on days 1 and 8 of a 21-day schedule. Twenty-eight patients with a median age 60 (range, 40-77) years were treated. Although 43% were Eastern Cooperative Oncology Group 0, 50% had liver metastases. Eighty-eight cycles of therapy were delivered (median 2 [range, 1-6]). Five of the first ten patients treated at 800 mg/m2 could not receive day 8 FDR-gemcitabine because of neutropenia, and the starting dose was reduced to 700 mg/m2. Even at this dose there was cumulative hematologic toxicity resulting in dose reductions. Vomiting, mucositis, diarrhea, allergy, rash, fever, and alopecia were mild. In 28 patients, there was only one partial response (4%, 95% CI 0-18%) and median time to progression was 1.7 (interquartile range, 1.2-3.9) months. FDR-gemcitabine 700 mg/m2 administered by intravenous infusion at an FDR of 10 mg/m2/min had minimal activity against heavily pretreated recurrent tumors of müllerian origin. The optimal dose and schedule of gemcitabine is yet to be defined in this population.

A phase I clinical trial of continual alternating etoposide and topotecan in refractory solid tumours.

The goal of this phase I study was to develop a novel schedule using oral etoposide and infusional topotecan as a continually alternating schedule with potentially optimal reciprocal induction of the nontarget topoisomerase. The initial etoposide dose was 15 mg m(-2) b.i.d. days (D)1-5 weeks 1,3,5,7,9 and 11, escalated 5 mg per dose per dose level (DL). Topotecan in weeks 2,4,6,8,10 and 12 was administered by 96 h infusion at an initial dose of 0.2 mg m(-2) day(-1) with a dose escalation of 0.1, then at 0.05 mg m(-2) day(-1). Eligibility criteria required no organ dysfunction. Two dose reductions or delays were allowed. A total of 36 patients with a median age of 57 (22-78) years, received a median 8 (2-19) weeks of chemotherapy. At DL 6, dose-limiting toxicities consisted of grade 3 nausea, vomiting and intolerable fatigue. Three patients developed a line-related thrombosis or infection and one subsequently developed AML. There was no febrile neutropenia. There were six radiologically confirmed responses (18%) and 56% of patients demonstrated a response or stable disease, typically with only modest toxicity. Oral etoposide 35 mg m(-2) b.i.d. D1-5 and 1.8 mg m(-2) 96 h (total dose) infusional topotecan D8-11 can be administered on an alternating continual weekly schedule for at least 12 weeks, with promising clinical activity.

Attitudes to chemotherapy in patients with ovarian cancer.

BACKGROUND: Recurrent ovarian cancer (OVCA) has become the model for cancer as a chronic disease, yet little is known about what motivates patients and physicians in treatment choices. METHODS: We investigated the attitudes of patients with epithelial OVCA and staff towards palliative chemotherapy for recurrent OVCA with a cross-sectional questionnaire study. RESULTS: Instruments were developed and piloted in 15 patients. This exploratory study reflects substantial bias in the sample populations. One hundred twenty-two patients and 37 staff were enrolled in the US and 39 patients and 25 staff were enrolled in the UK. UK patients had a lower educational status (P = 0.001), lower stage disease (P = 0.025), and less prior lines of chemotherapy (P < 0.001). 61% of patients had recurrent OVCA and 67% of staff were physicians. Seventy-three percent of patients recalled a discussion about prognosis and 74% wanted to know details of the prognosis for a typical patient (US = UK). Most patients (48%) thought that their physician was realistic, and 57% of staff felt that they were optimistic. The vast majority of both staff and patients thought that patients positively reinterpreted what they were told. Five percent of staff thought that palliative care was "incompatible" when considering chemotherapy as an option for their second recurrence of OVCA, compared with 36% of US patients, significantly more than the 12% of UK patients (P = 0.007). Patients thought that standard chemotherapy for a second recurrence of OVCA produced remission in 50% and cure in 15% of patients. Staff reported 20% and 0%, respectively. Fifty percent of patients and 57% of staff would want chemotherapy as an asymptomatic patient with a normal CT and a rising CA-125. Patients generally appear to be very tolerant of grade II chemotherapy-induced toxicity with staff being less tolerant than patients of nausea, anorexia, diarrhea, and rash. Staff rated life prolongation by 3 months to 1 year very much less acceptable than patients (P < 0.001). Although possibly allowing comprehensive collection of sensitive data, the questionnaire was too distressing for some patients and made 11% of patients feel uncomfortably anxious. CONCLUSIONS: Patients are optimistic and in the US, may be more reluctant than staff to see the Palliative Care Team. These data challenge the assertion that the use of palliative chemotherapy is physician-driven.

A Phase I-II study of 96-hour infusional topotecan and paclitaxel for patients with recurrent Müllerian tumors.

BACKGROUND: Topotecan and paclitaxel are schedule dependent chemotherapeutic agents with activity against ovarian carcinoma. A Phase I-II study in which both drugs were administered concurrently by 96-hour, continuous, intravenous infusion was performed to determine the maximum tolerated dose (MTD), toxicities, pharmacokinetics, and efficacy of the combination. METHODS: Women with ovarian or primary peritoneal carcinoma and documented recurrent disease were eligible for the study. The dose of topotecan was escalated from 1.6 mg/m(2) while maintaining the paclitaxel dose constant at 100 mg/m(2). Plasma concentrations of both drugs were monitored daily during the first cycle of therapy. RESULTS: Forty-five patients with a median age of 54 years (range, 42-70 years) received 181 cycles of therapy. Five patients were recruited to each of four dose levels (topotecan 1.6 mg/m(2), 2.0 mg/m(2), 2.8 mg/m(2), and 3.6 mg/m(2)), and an additional 25 patients were treated at the MTD (Phase II). Neutropenia and thrombocytopenia became dose limiting toxicities (DLT) at the fourth dose level. Emesis, mucositis, peripheral neuropathy, diarrhea, and alopecia were mild. Twenty patients (44%) had line-related occlusion, thrombosis, or infection. The mean values (+/- standard deviation) of the apparent steady-state plasma concentrations at the Phase II doses were 2.3 nM +/- 0.5 nM for topotecan lactone, 5.6 nM +/- 2.1 nM for total topotecan, and 40.1 nM +/- 16.8 nM for paclitaxel. There were seven partial responses (Phase II) contributing to an objective response rate of 28% and a median survival time of 11.7 months (range, 0.6-20.1 months). CONCLUSIONS: Topotecan at a dose of 2.8 mg/m(2) and paclitaxel at a dose of 100 mg/m(2) administered by concurrent, 96-hour, continuous intravenous infusions shows activity against tumors of Müllerian origin.

The clinical utility of liposomal doxorubicin in recurrent ovarian cancer.

OBJECTIVES: The aim of this study was to determine the efficacy and toxicity of single agent off-protocol, liposomal doxorubicin (Doxil Alza), in consecutive patients with recurrent ovarian cancer and to investigate the influence of HER-2/neu expression on response to liposomal doxorubicin. PATIENTS AND METHODS: Retrospective analysis of 72 consecutive patients treated, typically with liposomal doxorubicin 40 mg/m(2) q28 days between January 1997 and December 1998. Results. Twenty-nine patients (40%) had platinum- and taxane-resistant tumors. Nineteen patients (27%) responded with clinical or radiological evidence of response with reduction in CA-125 of >50%. One complete response (CR) and 7 partial responses (PRs) occurred in platinum- and taxane-resistant patients (radiological response (RR) 29%) and 8 PRs occurred in patients with visceral metastases (RR 28%). Time to progression was 5.3 (2.1-12.1) months. Only 7 dose delays (3%) and 20 dose reductions (8%) were necessary in 265 cycles of treatment. Hematological toxicity was generally mild with grade (Gr) > or =III neutropenia in 1 (2%), Gr > or =III thrombocytopenia in 1 (1%), and Gr > or =III anemia in 8 patients (11%). One patient (1%) was admitted with fever and neutropenia. Other toxicity was minimal with Gr > or =III mucositis occurring in 3 patients (4%). Gr > or =III cutaneous toxicity was seen in 6 patients (8%). Three patients (4%) had a >10% fall in ejection fraction but there was no unequivocal clinical heart failure. CONCLUSIONS: The data suggest that liposomal doxorubicin is an active drug in both taxane- and platinum-sensitive and resistant recurrent ovarian cancer. Liposomal doxorubicin is associated with tolerable toxicity and is particularly well tolerated in patients with multiple prior lines of treatment.

Docetaxel administered on a weekly basis for metastatic breast cancer.

PURPOSE: To evaluate the safety and efficacy of weekly docetaxel in women with metastatic breast cancer. PATIENTS AND METHODS: Twenty-nine women were enrolled onto a study of weekly docetaxel given at 40 mg/m(2)/wk. Each cycle consisted of 6 weeks of therapy followed by a 2-week treatment break, repeated until disease progression or removal from study for toxicity or patient preference. Fifty-two percent of patients had been previously treated with adjuvant chemotherapy; 21% had received prior chemotherapy for metastatic breast cancer, and 31% had previously received anthracyclines. All patients were assessable for toxicity; two patients were not assessable for response but are included in an intent-to-treat analysis. RESULTS: Patients received a median of 18 infusions, with a median cumulative docetaxel dose of 720 mg/m(2). There were no complete responses. Twelve patients had partial responses (overall response rate, 41%; 95% confidence interval, 24% to 61%), all occurring within the first two cycles. Similar response rates were observed among subgroups of patients previously treated either with any prior chemotherapy or with anthracyclines. An additional 17% of patients had stable disease for at least 6 months. The regimen was generally well tolerated. There was no grade 4 toxicity. Only 28% of patients had any grade 3 toxicity, most commonly neutropenia and fatigue. Acute toxicity, including myelosuppression, was mild. Fatigue, fluid retention, and eye tearing/conjunctivitis became more common with repetitive dosing, although these side effects rarely exceeded grade 2. Dose reductions were made for eight of 29 patients, most often because of fatigue (n = 5). CONCLUSION: Weekly docetaxel is active in treating patients with metastatic breast cancer, with a side effect profile that differs from every-3-weeks therapy.