Kidney function in patients with ovarian cancer treated with poly (ADP-ribose) polymerase (PARP) inhibitors.

BACKGROUND: Poly (ADP-ribose) polymerase inhibitors (PARPi) have revolutionized the treatment of ovarian cancer; however, real-world data on kidney function among patients treated with PARPi are lacking. METHODS: We identified adults treated with olaparib or niraparib between 2015 and 2021 at a major cancer center in Boston, MA, USA. We determined the incidence of any acute kidney injury (AKI), defined as at least a 1.5-fold rise in serum creatinine from baseline in the first 12 months following PARPi initiation. We calculated the percentage of patients with any AKI and sustained AKI and adjudicated the etiologies by manual chart review. We compared trajectories in estimated glomerular filtration rate (eGFR) among PARPi-treated and carboplatin and paclitaxel-treated patients with ovarian cancer, matched by baseline eGFR. RESULTS: Of 269 patients, 60 (22.3%) developed AKI, including 43 of 194 (22.1%) olaparib-treated patients and 17 of 75 (22.7%) niraparib-treated patients. Only 9 of 269 (3.3%) had AKI attributable to the PARPi. Of the 60 patients with AKI, 21 (35%) had sustained AKI, of whom 6 had AKI attributable to the PARPi (2.2% of the whole cohort). eGFR declined within 30 days post-PARPi initiation by 9.61 (SD = 11.017) mL/min per 1.73 m2 but recovered by 8.39 (SD = 14.05) mL/min per 1.73 m2 within 90 days after therapy cessation. There was no difference in eGFR at 12 months post-therapy initiation in patients receiving PARPi or controls receiving carboplatin and paclitaxel (P = .29). CONCLUSIONS: AKI is common following PARPi initiation as is a transient decline in eGFR; however, sustained AKI directly attributable to the PARPi and long-term eGFR decline are uncommon.

Phase II Trials of Iniparib (BSI-201) in Combination with Gemcitabine and Carboplatin in Patients with Recurrent Ovarian Cancer.

BACKGROUND: Iniparib (BSI-201), a novel anticancer agent thought to have poly(ADP-ribose) polymerase (PARP) inhibitory activity and synergy with both gemcitabine and carboplatin (GC) was evaluated in 2 cohorts with GC. METHODS: Parallel multicenter, single-arm, phase II studies using a Simon two-stage design. Eligible patients had a histological diagnosis of epithelial ovarian carcinoma, fallopian tube cancer, or primary peritoneal carcinoma and demonstration of platinum-sensitive (≥6 months [mo]) or -resistant disease (relapse 2-6 mo post-platinum). Carboplatin (AUC 4 IV day 1), gemcitabine (1000 mg/m2 IV days 1 and 8), and iniparib (5.6 mg/kg IV days 1, 4, 8, and 11) were given on a 21-day cycle. RESULTS: The overall response rate (ORR RECIST 1.0) in platinum sensitive disease was 66% (95% CI, 49-80) with a higher response rate in the 15 pts with germline BRCA mutations (gBRCAmut) (73%). Median PFS was 9.9 (95% CI, 8.2-11.3) months. In the platinum resistant population the ORR was 26% (95% CI, 14-42), however in the 11 pts for whom BRCA mutation was present, the best overall response was PR in 5 (46%). Median PFS was 6.8 months (range, 5.7-7.7 months). Notably, among the 17 CA-125-response-evaluable patients who did not achieve tumor response, 7 (41.2%) patients had a CA125 response, and 93% has clinical benefit (CR + PR + SD). The GCI combination was generally well tolerated despite a high incidence of thrombocytopenia and neutropenia, with no new toxicities. CONCLUSIONS: Given the subsequent lack of efficacy demonstrated for iniparib in breast cancer, these are studies of GC and demonstrate a higher than traditionally appreciated activity in patients with platinum-sensitive and -resistant recurrent ovarian cancer, especially in patients that harbor a BRCA mutation, resetting the benchmark for efficacy in phase II trials. (ClinicalTrials.gov Identifiers: NCT01033292 & NCT01033123).

A phase I study of AZD2171 and Temsirolimus in patients with advanced gynecological malignancies.

PURPOSE: Temsirolimus, a mTOR inhibitor, and AZD2171, a VEGFR inhibitor, have independently shown activity in patients with gynecological malignancies. Understanding the pivotal role of the PI3K/PTEN/AKT/mTOR pathway in regulating angiogenesis, a phase I study utilizing Temsirolimus and AZD2171 was initiated to study the safety of targeting the mTOR and VEGF pathway in patients with recurrent or refractory gynecological malignancies. METHODS: Patients with advanced gynecological cancers were enrolled in this phase 1 study with Temsirolimus and AZD2171. A traditional 3 + 3 design was followed. The primary objective was to determine the MTD of the combination. Secondary objectives included efficacy, progression free survival (PFS) and toxicity profile. An expansion phase was planned after the MTD was determined. RESULTS: The study enrolled 11 patients over 16 months. All patients were enrolled in dose level 1. Due to toxicity, the trial was halted at dose level 1. No MTD was determined. The most common grade 3/4 toxicities included hypertension, thrombocytopenia, thromboembolic events, and hypertriglyceridemia. Five patients were evaluable for best overall clinical response. The best overall clinical response was stable disease. Two patients died without documented progression of disease. The median PFS was 7.2 months. CONCLUSIONS: Despite a conservative dose escalation, the toxicity data demonstrated that the combination of AZD2171 and Temsirolimus was not tolerable. Increased awareness of novel toxicities, pharmacological interactions, coupled with strict patient selection and early mitigation of side effects may enhance phase I clinical trial development.

Sequential Phase II clinical trials evaluating CRLX101 as monotherapy and in combination with bevacizumab in recurrent ovarian cancer.

BACKGROUND: Topoisomerase-1 inhibitors are an important class of cytotoxics associated with toxicity that limits their use. CRLX101 is a novel cyclodextrin-containing polymer conjugate of camptothecin (CPT) that self-assembles into nanoparticles to deliver sustained levels of active CPT into cancer cells while substantially reducing systemic exposure. METHODS: We conducted sequential phase II, open label, single arm clinical trials to evaluate CRLX101 as a single agent (n = 29) and with bevacizumab (Bev) (n = 34). Patients (pts) had measurable recurrent epithelial ovarian, tubal or primary peritoneal cancer, that could be platinum refractory, resistant or sensitive. Cohort A (Single agent CRLX101) allowed up to 3 prior chemotherapy regimens, but no prior topo-1 inhibitors. Pts received CRLX101 15 mg/m2 IV every 14 days Q28 with response evaluation every 2 cycles. Cohort B also received Bev 10 mg/kg D1,15 Q28, and included only platinum resistant disease with up to 2 prior lines, and more rigorous eligibility criteria. RESULTS: CRLX101 was well tolerated other than nausea, fatigue and anemia. 29 pts. received a median of 3 (1-16) cycles with a clinical benefit rate (CBR) of 68% and overall response rate (ORR) of 11%. With the addition of Bev in Cohort B (n = 34), the CBR was increased to 95% and the ORR to 18%. PFS was 4.5 months (0.9 to 15.9 months) in Cohort A and 6.5 months (2.8 to 14.4 months) in Cohort B. Bev increased the incidence of hypertension and qualitatively increased bladder toxicities, but without SAEs. CONCLUSIONS: CRLX101 meets the clinical need for an effective and tolerable topoisomerase I inhibitor and can be safely combined with bevacizumab.

Phase 1 and 2 study of carboplatin and pralatrexate in patients with recurrent, platinum-sensitive ovarian, fallopian tube, or primary peritoneal cancer.

BACKGROUND: The objective of this phase 1 and 2 trial was to identify the appropriate dose of combined carboplatin and pralatrexate for patients with recurrent, platinum-sensitive ovarian, fallopian tube, and primary peritoneal cancer. METHODS: In phase 1, patients received carboplatin (at an area under the curve of 5) and increasing doses of pralatrexate until the maximum-tolerated dose (MTD) of pralatrexate was achieved. The primary endpoint was the response rate. Additional endpoints were safety, response duration, progression-free survival, overall survival, and pharmacokinetics. RESULTS: Thirty patients were enrolled in phase 1, and 20 were enrolled in phase 2. Of all 50 patients, 49 completed the study. The mean patient age was 59 years, and patients completed a median of 6 cycles. The MTD for pralatrexate was 105 mg/m2 . The clinical benefit rate (complete responses plus partial responses plus stable disease) was 86%. Of 26 patients who received the MTD, 12 had a partial response, 11 had stable disease, and 2 had disease progression. The progression-free survival rate at 3 and 6 months was 87% and 79%, respectively; and the overall survival rate was 98% at 6 and 12 months and 66% at 24 months. Of 30 patients, 18 (60%) in phase 1 experienced an adverse event of any grade; and, of those, 4 patients (13%) had a grade 3 or greater adverse event. In phase 2, 12 patients (60%) had an adverse event of any grade, and 4 (20%) had grade 3 or greater toxicity. There was a significant reduction in the total body clearance of pralatrexate when it was received concurrently with carboplatin. CONCLUSIONS: Most patients responded to carboplatin-pralatrexate combination. This regimen is well tolerated and effective in this patient population. Cancer 2016;122:3297-3306. © 2016 American Cancer Society.

Catumaxomab for the treatment of malignant ascites in patients with chemotherapy-refractory ovarian cancer: a phase II study.

OBJECTIVE: The aim of this study was to investigate the efficacy and safety of intraperitoneal catumaxomab in heavily pretreated patients with chemotherapy-refractory ovarian cancer and recurrent symptomatic malignant ascites. METHODS: The study is a single-arm open-label multicenter US phase II study. Patients received 4 three-hour intraperitoneal catumaxomab infusions (10, 20, 50, and 150 µg within 10 days). The primary end point was the percentage of patients with at least a 4-fold increase in the puncture-free interval (PuFI) relative to the pretreatment interval. The main secondary end points were puncture-free survival, overall survival, ascites symptoms, and safety. Time to first therapeutic puncture (TTPu) was analyzed post hoc. RESULTS: Forty patients were screened, and 32 patients (80%) were treated. Seven patients (23%) achieved the primary end point. The median PuFI was prolonged 2-fold from 12 to 27.5 days. The median TTPu was prolonged 4-fold from 12 to 52 days. The median puncture-free survival and overall survival were 29.5 and 111 days, respectively. Nineteen patients (59%) required puncture after catumaxomab treatment. Ascites symptoms improved in most of the 13 predefined categories. At study end, most symptoms were still improved compared with screening. The most frequent treatment-related adverse events were related to cytokine release (vomiting, nausea, pyrexia, fatigue, and chills) or intraperitoneal administration (abdominal pain). Transient increases in liver parameters and transient decreases in blood lymphocytes were regularly observed but were generally without clinical relevance. CONCLUSIONS: Catumaxomab prolonged PuFI and TTPu had a beneficial effect on quality of life, as shown by the improvement in ascites symptoms, and had an acceptable safety profile, which is consistent with its mode of action.

Patterns of recurrence in patients treated with bevacizumab in the primary treatment of advanced epithelial ovarian cancer.

OBJECTIVE: The purpose of this study was to compare the distribution of the first site of recurrence in patients with epithelial ovarian cancer (EOC) who received first-line treatment with bevacizumab compared with patients who did not receive bevacizumab. METHODS: From the Cancer Registry database at our institutions, we identified a group of patients with recurrent EOC who underwent treatment from January 1, 2005, to December 31, 2010. Each patient record was evaluated to classify the site of first recurrence. Correlation between categorical variables was assessed with χ² test. RESULTS: Two hundred ninety-two patients with advanced EOC (stage III or IV) who originally responded to chemotherapy and had a recurrence were identified. Of these, 37 (12.5%) had received postoperative chemotherapy bevacizumab, and 255 (87.5%) did not. Compared with those not treated with bevacizumab, there was a lower incidence of liver recurrence (0% vs 9%; P = 0.05) and a higher rate of lung and/or pleural recurrence (22% vs 5%; P = 0.001) and recurrence at distant sites (22% vs 9%; P = 0.03) in patients who received bevacizumab. There was no difference in the incidence of ascites at the time of recurrence between these groups. CONCLUSIONS: Patients who received bevacizumab as part of primary treatment for EOC had a higher rate of lung and/or pleural recurrence and a lower rate of liver recurrence. There was no difference in the rate of ascites at the time of recurrence.

Trabectedin as single agent in relapsed advanced ovarian cancer: results from a retrospective pooled analysis of three phase II trials.

Three phase II studies evaluated trabectedin monotherapy as second-/third-line therapy in patients with refractory/recurrent ovarian cancer (ROC). Three different schedules were investigated: 3-h infusion every 3 weeks (3-h_q3w), 24-h infusion q3w (24-h_q3w), and 3-h weekly infusion for 3 weeks of a 4-week cycle. This retrospective pooled analysis evaluated the efficacy and the safety profile of trabectedin according to each administered regimen. Data from 295 patients were used to compare weekly versus q3w schedules, and 3-h versus 24-h infusion given q3w. Both q3w regimens showed higher overall response rate (36 vs. 16 %; p = 0.0001), disease control rate (66 vs. 46 %; p = 0.0007), and longer median progression-free survival (5.6 vs. 2.8 months; p < 0.0001) than the weekly schedule. Comparable activity was observed for the 3- and 24-h infusions q3w. Common adverse events were nausea, fatigue, vomiting, transient neutropenia, and transaminase increases. A better safety profile regarding neutropenia, fatigue, and vomiting was seen for the 3-h_q3w regimen as compared to the 24-h_q3w one. Trabectedin given as a single agent q3w as 3-h infusion is the schedule of choice for the treatment of ROC, and its efficacy and safety profile favorably compares with other active salvage treatments.

Patient-reported outcomes in relapsed ovarian cancer: results from a randomized Phase III study of trabectedin with pegylated liposomal doxorubicin (PLD) versus PLD alone.

OBJECTIVE: Trabectedin in combination with PLD improves progression-free survival (PFS) and overall response rate (ORR) in comparison to PLD alone in patients with relapsed ovarian cancer (J Clin Oncol; 2010 28:3107-14). Here we report the impact of the treatment combination on patient-reported functional status and symptoms. METHODS: Patient-reported outcome (PRO) questionnaires, EORTC-QLQ C30, OV28, and EQ-5D were completed by patients at screening and on Day 1 of every other treatment cycle starting with Cycle 1, and at the end-of-treatment visit. RESULTS: Of the 672 patients randomized in this study, 663 treated patients completed at least one of the baseline questionnaires. Median cycles of treatment was 6 (131 days) for the combination arm and 5 (143 days) for the monotherapy arm. Longitudinal data analyses showed no significant differences between the treatment arms for any of the pre-specified scales. Similar analyses of other scales, including Health Index scores and Health State on the Visual Analog Scale, support these findings. Start of subsequent therapy was significantly delayed in the combination arm compared with the monotherapy arm (p=0.0032). CONCLUSIONS: The addition of trabectedin to PLD led to little or no decrement in patient-reported functional status and symptoms in patients with relapsed ovarian cancer, as compared to treatment with PLD alone. The combination led to manageable and non-cumulative overall toxicity with a fewer PLD-associated adverse events, and a significant improvement in PFS and ORR compared to single agent.

Trabectedin plus pegylated liposomal doxorubicin (PLD) versus PLD in recurrent ovarian cancer: overall survival analysis.

AIM: Trabectedin in combination with pegylated liposomal doxorubicin (PLD) improves progression-free survival (PFS) compared to PLD alone in recurrent ovarian cancer (J Clin Oncol 2010;28:3107-14). METHODS: Women, stratified by performance status (0-1 versus 2) and platinum sensitivity (platinum-free interval [PFI]<6 versus ≥ 6 months), were randomly assigned to receive PLD 30 mg/m(2) IV followed by a 3-h infusion of trabectedin 1.1mg/m(2) every 3 weeks or PLD 50mg/m(2) every 4 weeks. The study was powered to show a 33% increase in overall survival (OS) after 520 deaths had occurred. RESULTS: After a median follow-up of 47.4 months, there were 522 deaths among 672 subjects. The median OS for trabectedin+PLD and PLD arms was 22.2 and 18.9 months, respectively (hazard ratio [HR]=0.86; 95% confidence interval [CI]: 0.72-1.02; p=0.0835). An unexpected but significant imbalance in the PFI favouring the PLD arm (mean PFI: PLD=13.3 months, trabectedin+PLD=10.6 months) was identified. On the basis of this finding, an unplanned hypothesis generating analysis adjusting for the PFI imbalance and other prognostic factors suggested an improvement in OS associated with the trabectedin+PLD arm (HR=0.82; 95%CI: 0.69-0.98; p=0.0285). In another unplanned exploratory analysis, the subset of patients with a PFI of 6-12 months had the largest difference in OS (HR=0.64; 95%CI: 0.47-0.86; p=0.0027). CONCLUSIONS: The final OS analysis did not meet the protocol-defined criterion for statistical significance. Despite stratification on platinum sensitivity, there was an imbalance in mean platinum free interval that had an effect on OS.

Safety, Efficacy, and Biomarker Exploration in a Phase II Study of Bevacizumab, Oxaliplatin, and Gemcitabine in Recurrent Müllerian Carcinoma.

OBJECTIVE: To explore the safety, efficacy, and biomarkers of bevacizumab with gemcitabine and oxaliplatin in women with recurrent platinum-sensitive ovarian carcinoma. METHODS: The patients received bevacizumab (10 mg/kg), gemcitabine (1000 mg/m(2)), and oxaliplatin (65 mg/m(2)) on days 1 and 15 in 28-day cycles. The patients with safely accessible tumor underwent intratumoral fluid pressure (IFP) measurements and positron-emission tomographies immediately and 2 weeks after treatment. Blood biomarkers were evaluated at 5 time points. RESULTS: The trial was closed after enrolling 19 of the 53 projected patient accrual. Thirteen (68.5%) of 19 patients showed a response (1 complete response, 12 partial responses), and 6 patients showed stable disease (31.6%). Median progressive-free survival was 36.9 weeks (258.3 days), and the median overall survival was 112.3 weeks (633 days, not reached). Toxicity was acceptable, and there were no arterial thromboses, serious bleeding, gastrointestinal perforations, or complications from the invasive procedures. Bevacizumab with chemotherapy induced a substantial drop in tumor IFP after treatment. The regimen induced sustained elevation in circulating plasma vascular endothelial growth factor (VEGF), placental growth factor (PlGF), basic fibroblast growth factor (bFGF), soluable vascular endothelial growth factor receptor 2 (sVEGFR2), and circulating progenitor cells. Plasma PlGF, VEGFR2(+) monocytes, and urinary matrix metalloproteinase 2 activity showed differential associations with treatment outcome when evaluated at baseline and after 14 days of treatment. CONCLUSIONS: Despite early termination of the study, the results indicate that the regimen was well tolerated and demonstrated activity in platinum-sensitive ovarian cancer. Biomarker evaluations showed that bevacizumab with chemotherapy significantly changed the levels of several circulating cellular and molecular biomarkers. The increases in plasma PlGF and VEGFR2(+) monocytes showed correlations with outcome. These exploratory data should be further evaluated in future studies of bevacizumab in ovarian cancer.

Trabectedin plus pegylated liposomal Doxorubicin in recurrent ovarian cancer.

PURPOSE: The objective of this study was to compare the efficacy and safety of trabectedin plus pegylated liposomal doxorubicin (PLD) with that of PLD alone in women with recurrent ovarian cancer after failure of first-line, platinum-based chemotherapy. PATIENTS AND METHODS: Women > or = 18 years, stratified by performance status (0 to 1 v 2) and platinum sensitivity, were randomly assigned to receive an intravenous infusion of PLD 30 mg/m(2) followed by a 3-hour infusion of trabectedin 1.1 mg/m(2) every 3 weeks or PLD 50 mg/m(2) every 4 weeks. The primary end point was progression-free survival (PFS) by independent radiology assessment. RESULTS: Patients (N = 672) were randomly assigned to trabectedin/PLD (n = 337) or PLD (n = 335). Median PFS was 7.3 months with trabectedin/PLD v 5.8 months with PLD (hazard ratio, 0.79; 95% CI, 0.65 to 0.96; P = .0190). For platinum-sensitive patients, median PFS was 9.2 months v 7.5 months, respectively (hazard ratio, 0.73; 95% CI, 0.56 to 0.95; P = .0170). Overall response rate (ORR) was 27.6% for trabectedin/PLD v 18.8% for PLD (P = .0080); for platinum-sensitive patients, it was 35.3% v 22.6% (P = .0042), respectively. ORR, PFS, and overall survival among platinum-resistant patients were not statistically different. Neutropenia was more common with trabectedin/PLD. Grade 3 to 4 transaminase elevations were also more common with the combination but were transient and noncumulative. Hand-foot syndrome and mucositis were less frequent with trabectedin/PLD than with PLD alone. CONCLUSION: When combined with PLD, trabectedin improves PFS and ORR over PLD alone with acceptable tolerance in the second-line treatment of recurrent ovarian cancer.

Phase I trial of liposomal doxorubicin and ZD1839 in patients with refractory gynecological malignancies or metastatic breast cancer.

BACKGROUND: Pegylated liposomal doxorubicin has activity in both breast and ovarian cancer. Preclinical data noted that ZD1839 acts synergistically with chemotherapy. Given the lack of cross-resistance between these two agents, a phase I trial was initiated examining the safety and efficacy of the combination of liposomal doxorubicin and ZD1839 in patients with recurrent gynecologic or metastatic breast cancer. METHODS: Dose-limiting toxicity (DLT) was defined within the first two cycles of treatment. Escalating doses of liposomal doxorubicin were administered every 4 weeks with ZD1839. Pharmacokinetic analysis and correlative studies were performed. RESULTS: Thirty-five patients were enrolled in this study: six in each cohort. One DLT (febrile neutropenia) was observed in cohort 2. Dose level 3 was determined to be the maximum tolerated dose (MTD), and an additional ten patients were accrued. Serious adverse events (SAEs) included one patient with mental status changes believed secondary to disease progression and two central nervous system (CNS) bleeds believed to be unrelated to the combination of study agents. Toxicities were generally mild except for skin and gastrointestinal toxicity. No cardiac toxicity was observed. The best response to therapy included four partial responses and 20 patients with stable disease. CONCLUSIONS: Liposomal doxorubicin with ZD1839 is an active regimen but is associated with increased skin toxicity in patients with advanced breast and gynecologic cancer.

Phase II study of carboplatin, paclitaxel, and bevacizumab with maintenance bevacizumab as first-line chemotherapy for advanced mullerian tumors.

PURPOSE New strategies are needed to improve outcomes for patients with advanced ovarian cancer. Bevacizumab is a recombinant humanized monoclonal antibody that neutralizes vascular endothelial growth factor but is associated with GI perforations (GIPs) in patients with recurrent disease. PATIENTS AND METHODS An open-label, phase II clinical trial was conducted in newly diagnosed patients with stage > or = IC epithelial müllerian tumors. Patients received intravenous (IV) carboplatin (area under the curve = 5), paclitaxel (175 mg/m(2) IV), and bevacizumab (15 mg/kg IV) for six to eight cycles on day 1 every 21 days. Bevacizumab was omitted in the first cycle and continued as a single agent for 1 year. Results Sixty-two women participated in this study. Fifty-one patients (82%) were optimally surgically cytoreduced before treatment. The median age was 58 years (range, 18 to 77 years). Forty-five women (73%) had ovarian cancer, 10 (16%) had peritoneal cancer, four (6%) had fallopian tube cancers, and three (5%) had uterine papillary serous tumors. The majority of patients (90%) had stage III or IV disease. A median of 17 maintenance cycles (range, 0 to 25+ cycles) of bevacizumab (556 cycles) were administered with mild toxicity. Treatment was associated with two pulmonary embolisms and two GIPs, all occurring during the chemotherapy phase of treatment (364 total cycles). No grade 4 toxicities were seen during maintenance bevacizumab treatment. Radiographic responses were documented in 21 (75%) of 28 women with measurable disease (11 complete responses and 10 partial responses), with CA-125 responses in 76% of patients (11 complete responses, 21%; and 35 partial responses, 55%). The progression-free survival rate at 36 months was 58%. CONCLUSION The regimen of carboplatin, paclitaxel, and bevacizumab with maintenance bevacizumab is feasible, safe, and worthy of future study in advanced ovarian cancer.

Phase II trial of GM-CSF in women with asymptomatic recurrent müllerian tumors.

OBJECTIVE: GM-CSF is a recombinant human cytokine, which promotes the proliferation and differentiation of granulocytes and monocytes, and is associated with anti-tumor activity. The primary objective was to define the median time to treatment termination (TTT) with women with relapsed ovarian cancer treated with single agent GM-CSF delivered subcutaneously (SC). PATIENTS AND METHODS: Open label phase II study in asymptomatic patients with recurrent müllerian malignancy without an indication for immediate systemic chemotherapy. In the first cohort of 35 women, GM-CSF 250 microg/m(2) was administered SC on days 1-14 of a 28-day cycle, the second cohort received continuous GM-CSF 150 microg/m(2) given with dose escalation. RESULTS: Seventy-two women were enrolled. Best overall response included one complete response, and 20 patients with stable disease (23%), 4 of whom had stable disease for >6 months. Median TTT was 78 days. Toxicity in both cohorts was generally mild; however, four patients experienced excessive toxicity and withdrew consent. In the first cohort, CA-125 dropped in 70% of women from their baseline on study value (median change -23%, range -48 to +116%) after 14 days of GM-CSF. The magnitude of CA-125 drop during the first 2 weeks of therapy also showed a positive inverse correlation with day 15 white cell count for the whole group (p=0.038). CONCLUSION: GM-CSF is well tolerated and frequently associated with a decline in CA-125 that is correlated with leukocytosis. Although median TTT is modest, a subset of women had prolonged stable disease.

A phase II evaluation of pemetrexed (Alimta, LY231514, IND #40061) in the treatment of recurrent or persistent endometrial carcinoma: a phase II study of the Gynecologic Oncology.

OBJECTIVE: To estimate the anti-tumor activity of pemetrexed in patients with advanced or recurrent carcinoma of the endometrium and to determine the nature and degree of toxicity. METHODS: A multicenter phase II trial was conducted by the Gynecologic Oncology Group (GOG). Patients must have had advanced or recurrent measurable carcinoma of the endometrium and failed one prior chemotherapy regimen. Pemetrexed at a dose of 900 mg/m(2) was administered as an IV infusion over 10 min every 21 days. RESULTS: From May 1, 2006 to July 31, 2007, 27 patients were entered by 10 member institutions of the GOG with two patients being deemed ineligible. A total of 101 cycles were administered with 28% of patients receiving five or more cycles. Overall, the treatment was well tolerated. More serious toxicities (grade 3 and 4) included anemia in 20%, leukopenia in 40%, neutropenia in 48%, and constitutional in 16%. No treatment-related deaths were reported. One patient (4%) had a partial response. Eleven patients (44%) had stable disease and eleven (44%) patients had increasing disease. Response could not be assessed in two patients (7%). Median progression-free survival was 2.7 months and overall survival was 9.4 months. CONCLUSION: Pemetrexed has minimal activity in the treatment of recurrent or persistent endometrial carcinoma at the dose and schedule tested.

Risk stratification for desensitization of patients with carboplatin hypersensitivity: clinical presentation and management.

BACKGROUND: Women with ovarian cancer treated with chemotherapeutic platinum agents frequently develop hypersensitivity reactions (HSRs). How best to risk-stratify patients for desensitization is uncertain. OBJECTIVES: To evaluate skin test (ST) reactivity to carboplatin in patients with recent and remote histories of carboplatin HSR and to review the relationship between skin test reactivity and tolerance of subsequent carboplatin desensitization. METHODS: Thirty-eight women with carboplatin HSR were evaluated by ST to carboplatin. Thirty women subsequently underwent 106 desensitizations to carboplatin. RESULTS: Carboplatin ST was positive in 25 of 38 patients (66%). Of patients with recent HSR (<3 months), 20 of 24 (83%) tested positive, whereas 5 of 14 (36%) with remote HSR (>9 months) tested positive (P < .01). Nineteen carboplatin ST+ and 11 ST- patients underwent desensitization to carboplatin. Seven ST+ patients (37%) had mild HSR during desensitization but completed the desensitization with additional treatment or protocol modification. ST- patients with a recent history of HSR (n = 3) tolerated a rapid protocol without HSR and remained ST- with repeated testing. Six of 8 ST- patients (75%) with remote HSR reacted during desensitization. The HSRs were more severe and often associated with an elevated tryptase level. Five of 7 patients retested became ST+ before the second desensitization. Carboplatin desensitization was successfully completed in 105 of 106 (99%) treatment courses. CONCLUSIONS: The timing of carboplatin ST in relation to initial HSR is vital for risk stratification and subsequent desensitization. Initial ST- patients with a remote history of HSR are at high risk for conversion to ST+ and can develop more severe HSR.

Phase II evaluation of pemetrexed in the treatment of recurrent or persistent platinum-resistant ovarian or primary peritoneal carcinoma: a study of the Gynecologic Oncology Group.

PURPOSE: To estimate the antitumor activity of pemetrexed in patients with persistent or recurrent platinum-resistant epithelial ovarian or primary peritoneal cancer and to determine the nature and degree of toxicities. PATIENTS AND METHODS: A phase II trial was conducted by the Gynecologic Oncology Group. Patients must have had cancer that had progressed on platinum-based primary chemotherapy or recurred within 6 months. Pemetrexed at a dose of 900 mg/m(2) was to be administered as an intravenous infusion over 10 minutes every 21 days. Dose delay and adjustment was permitted for toxicity. Treatment was continued until disease progression or unacceptable adverse effects. RESULTS: From July 6, 2004, to August 23, 2006, 51 patients were entered. A total of 259 cycles (median, four; range one to 19 cycles) of pemetrexed were administered, with 40% of patients receiving six or more cycles. Overall, the treatment was well tolerated. More serious toxicities (grade 3 and 4) included neutropenia in 42%, leukopenia in 25%, anemia in 15%, and constitutional in 15% of patients. No treatment-related deaths were reported. One patient (2%) had a complete and nine patients (19%) had partial responses, with a median duration response of 8.4 months. Seventeen patients (35%) had stable disease for a median of 4.1 months. Eighteen patients (38%) had increasing disease. Three patients (6%) were not assessable. Median progression-free survival was 2.9 months, and overall survival was 11.4 months. CONCLUSION: Pemetrexed has sufficient activity in the treatment of recurrent platinum-resistant ovarian cancer at the dose and schedule tested to warrant further investigation.

Phase II prospective study of paclitaxel and carboplatin in older patients with newly diagnosed Müllerian tumors.

OBJECTIVES: The primary objective was to determine the completion rate of 6 cycles of paclitaxel and carboplatin chemotherapy with no dose reductions in patients > or =70 years of age. METHODS: Phase II study of intravenous (IV) carboplatin Area Under the Curve (AUC) of 5 and paclitaxel 175 mg/m(2) given to patients > or =70 years of age, had any stage Müllerian cancer, and an ECOG performance status (PS) of 0-2. RESULTS: Twelve patients were enrolled (median age of 82 years, range 75 to 86 years). Six of 12 completed 6 cycles of chemotherapy with no dose reductions. Three patients died on study precipitating study closure; one with refractory cancer following cycle 1, one of aspiration pneumonia after cycle 1, and one with sudden death on day 5 of cycle 6. Patients undergoing upfront debulking surgery tolerated chemotherapy better compared to patients receiving neoadjuvant chemotherapy. Grade 3 or higher hematologic toxicities included 2 patients with febile neutropenia (17%). > or =Grade 3 non-hematologic toxicities included fatigue (8%), nausea (8%), constipation (8%), obstipation (8%), vomiting (8%), and hypoxia (8%). CONCLUSIONS: In this prospective trial of standard carboplatin and paclitaxel chemotherapy in a heterogeneous population of elderly patients, chemotherapy was well tolerated by patients who underwent upfront debulking surgery, had a PS of 0-1, and had few comorbidities. Patients not undergoing upfront debulking surgery because of either advanced cancer or poor surgical risk had excess morbidity/mortality. Prospective studies to identify risk factors for toxicity prediction are needed.

Phase II study of carboplatin and pemetrexed for the treatment of platinum-sensitive recurrent ovarian cancer.

PURPOSE: More efficacious, less toxic combinations are needed to treat platinum-sensitive recurrent epithelial ovarian cancer (EOC). Pemetrexed is a multitargeted antifolate with manageable toxicity and has been combined with carboplatin to treat other cancers. PATIENTS AND METHODS: This is a phase II study of carboplatin area under the curve 5 with pemetrexed 500 mg/m(2) administered intravenously on day 1 every 21 days for six cycles or for up to eight cycles if clinical benefit occurred. Eligible patients had platinum-sensitive recurrent EOC, peritoneal serous cancer, or fallopian tube cancer. The primary objective was to determine response rate defined by Response Evaluation Criteria in Solid Tumors; other end points included toxicities, progression-free survival (PFS), and overall survival (OS). RESULTS: Forty-five patients were accrued; 44 patients received treatment. Overall response rate was 51.1%; there were no complete responses (0%), 23 confirmed partial responses (51.1%), two unconfirmed partial responses (4.4%), 14 patients with stable disease (31.1%), and two patients with progressive disease after two cycles (4.4%). Grade 3 and 4 hematologic toxicities included neutropenia (41%), thrombocytopenia (23%), and anemia (9%); there were no episodes of febrile neutropenia. Grade 3 and 4 nonhematologic toxicities included fatigue (11%), nausea (5%), vomiting (5%), diarrhea (5%), syncope (5%), and pulmonary embolism (5%). Median PFS time was 7.57 months (95% CI, 6.44 to 10.18 months), mean OS time was 20.3 months, and median OS has not yet been reached with a mean follow-up time of 15.3 months. CONCLUSION: Carboplatin/pemetrexed is a well-tolerated regimen with activity in platinum-sensitive recurrent EOC; further testing of this regimen in platinum-sensitive EOC patients is warranted.