bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase II trial of the oral PARP inhibitor olaparib (AZD2281) in BRCA-deficient advanced ovarian cancer
Authors: Audeh M. W. , Penson R. T. , Friedlander M. , Powell B. , Bell-McGuinn K. M. , Scott C. , Weitzel J. N. , Carmichael J. , Tutt A. 
Published: August 2020

5500 Background: Olaparib (AZD2281; KU-0059436) is a novel, orally active PARP inhibitor that induces synthetic lethality in homozygous BRCA-deficient cells. A phase I trial identified 400 mg bd as the maximum tolerated dose (MTD) with an initial signal of efficacy in BRCA-deficient cancers (ASCO 2008; abst 5510). The primary aim of this study was to test the efficacy of olaparib in confirmed BRCA1/BRCA2 carriers with advanced chemotherapy-refractory ovarian cancer. The secondary aim was to assess the safety and tolerability profile in ovarian cancer patients with BRCA1/2 deficiency. Methods: In an international, multicenter, proof-of-concept, single-arm, phase II study, two patient (pt) sequential cohorts received continuous oral olaparib in 28-day cycles, initially at the MTD, 400 mg bd (33 pts), and subsequently at 100 mg bd (24 pts), a previously shown clinically active and PARP inhibitory dose. Eligibility criteria included confirmed genetic BRCA1/2 mutation and recurrent, measurable, incurable disease (previous chemotherapy, median 3 lines). The primary efficacy endpoint was best objective response rate (ORR; RECIST) post baseline. Change in CA125 was a secondary efficacy endpoint. All adverse events were reported using CTCAE v3. Results: At this interim analysis dated October 31, 2008, of 57 enrolled pts (39 BRCA1 deficient and 18 BRCA2 deficient), 33 were evaluable at 400 mg bd and 24 at 100 mg bd. The confirmed RECIST ORR was 33% at 400 mg bd and 12.5% at 100 mg bd. Clinical benefit rate (ORR and/or confirmed >50% decline in CA125) was 57.6% at 400 mg bd and 16.7% at 100 mg bd. Toxicity was mainly mild in severity, reflecting grade 1/2 nausea (44%); fatigue (35%); and anemia (14%). Grade 3 toxicity occurred infrequently, and comprised primarily nausea (7%) and leukopenia (5%). Conclusions: Oral olaparib is well tolerated and highly active in advanced, chemotherapy-refractory BRCA-deficient ovarian cancer, with greater activity seen at the higher dose. Toxicity in BRCA1/2 carriers was similar to that seen in non-carriers. This study provides positive proof of the concept of the activity and tolerability of genetically defined targeted therapy with olaparib in BRCA-deficient ovarian cancers. [Table: see text]
A randomized phase II placebo-controlled trial using maintenance therapy to evaluate the vascular targeting agent BIBF 1120 following treatment of relapsed ovarian cancer (OC)
Authors: Ledermann J. A. , Rustin G. J. , Hackshaw A. , Kaye S. B. , Jayson G. , Gabra H. , James L. E. , Bell S. , Temple G. 
Published: August 2020

5501 Background: BIBF 1120 is a new targeted therapeutic agent for maintenance therapy in OC. It is a unique triple angiokinase inhibitor, targeting 3 receptor classes involved in the formation of blood vessels (VEGFR, PDGFR, and FGFR). Methods: Continuous BIBF 1120 (250 mg, oral, twice daily) for up to 9 months (mo) was compared with placebo in a novel application of a randomized double-blind trial in pts who responded to their last (at least second line) chemotherapy. The primary endpoint, progression-free survival at 36 weeks, was confirmed by CT assessment, performed at 12-week intervals. Results: 84 pts were randomized (44 BIBF 1120; 40 placebo), mean age 60y (range 27–76). All had responded according to GCIG criteria. Treatment-free interval before prior chemotherapy was <6 mo for 41% and 6–12 mo for 59% of pts. Median treatment duration was 116 days (d), range, 2–281d (BIBF 1120) and 101 d, 2–239d (placebo). Five BIBF 1120 pts completed 9 mo of treatment vs 0 placebo pts. The 36-wk PFS rates (95% confidence interval [CI]) were 15.6% (3.8, 27.3) for BIBF 1120 and 2.9% (0.0, 8.4) for placebo. Although the trial was not powered for a direct comparison, the PFS hazard ratio was 0.68 (95% CI: 0.42, 1.09). Median time to RECIST progression (mo) was 4.8 for BIBF 1120, and 2.8 for placebo. There were no deaths during treatment. Grade 3 and 4 adverse events (AE) were seen in 54 and 7% (BIBF 1120) and 25 and 3% (placebo) of pts. Expected gastrointestinal toxicities occurred slightly more frequently in the BIBF 1120 arm (16 vs 10%, all gd 3; no gd 4 events). Elevated liver enzymes occurred in 43% (BIBF 1120) vs. 6.3% (placebo). Conclusions: Our trial suggests that maintenance BIBF 1120 could delay disease progression in OC pts who had previously responded to chemotherapy. A large phase III trial is needed to confirm the efficacy of this drug. [Table: see text]
Prognostic impact of the time interval between primary surgery and start of first-line chemotherapy in patients with advanced ovarian cancer: Analysis of prospective randomized phase III trials
Authors: Mahner S. , Staehle A. , zu Eulenburg C. , Wegscheider K. , Reuss A. , Pujade-Lauraine E. , Harter P. , Ray-Coquard I. , Pfisterer J. , du Bois A. 
Published: August 2020

5514 Background: Primary surgery followed by platinum-taxane chemotherapy is the standard therapy of advanced ovarian cancer. It is not clear, whether the time interval between surgery and start of first line chemotherapy (time to chemo - TTC) has an impact on the clinical outcome. Methods: Individual patient data meta-analysis of three prospective randomized AGO-OVAR/GINECO trials (AGO OVAR 3, 5, and 7) conducted between 1995 and 2002 to investigate platinum-taxane based chemotherapy regimens in advanced ovarian cancer. Cox proportional hazard models were applied to evaluate the prognostic impact of different variables on survival; TTC was introduced as a continuous variable. Results: A total of 3,326 patients were analyzed. Chemotherapy was started within 8 weeks after surgery. Median progression-free survival (PFS) was 17.91 months (95% CI: 17.15–18.73 months) and median overall survival (OS) 37.83 months (95% CI: 36.57–38.90 months). The median TTC was 19 days (95% CI: 18–19 days, range 1–56 days). By multivariate analysis of the total cohort, there was no significant association between TTC and PFS (p = 0.131) or OS (p = 0.372). In the subgroup of patients with no residual tumor after debulking surgery (n = 1.101), a significant and independent correlation between early start of chemotherapy and improved overall survival was observed (p = 0.022). Conclusions: Our analysis represents the largest study investigating treatment delivery and outcome in ovarian cancer. The time interval between primary surgery and start of first line chemotherapy seems to have no general impact in all patients. However, it could be demonstrated for the first time that a delayed start of chemotherapy was independently associated with decreased overall survival in patients with complete surgical debulking. As previously shown for other biological factors in ovarian cancer, the presence of residual tumor after surgery seems to prevail over the prognostic impact of therapy initiation. No significant financial relationships to disclose.
Expression of the epidermal growth factor receptor (EGFR) pathway in cervical cancer (CC) patients (pts)
Authors: Movva S. , Arias-Pulido H. , Chavez A. , Joste N. , Lomo L. , Lee S. J. , Verschraegen C. F. 
Published: August 2020

5519 Background: EGFR, a membrane tyrosine kinase receptor that regulates multiple functions such as cell growth, differentiation, gene expression and development through at least 3 pathways, is overexpressed in a wide variety of solid tumors, including CC. The downstream activation of the EGFR pathways has not been studied extensively. The aim of this study is to assess the correlation between EGFR-HER-2-HER-3-HER-4 status, downstream pathways (STAT 3, survivin, RAS) with pt characteristics, overall survival and recurrence free survival in pts diagnosed with invasive CC. Methods: Receptor expressions were assessed by immunohistochemistry on 80 pts from our clinic. Tumors were scored by percentage of cells stained multiplied by intensity for a score range of 0–300 by two pathologists. Median EGFR score was 140. Pts were categorized as low expressor (EGFR score lower than 140) or as high expressor (EGFR score greater than 140). Differences in receptor expression were compared using the Log-rank test for overall (OS) and recurrence-free survivals (RFS) and by Chi-square analyses for the clinical parameters (age, stage, histology, and grade). Results: A total of 80 pts data was analyzed. Mean age of the sample was 48 years. 23% of pts had well differentiated tumors. 80% had squamous histology. 39% had stage IIB or higher. 25% died of cancer. By Log-rank test, standard prognostic factors (age, stage, grade, and histology) showed the expected differences in survival, confirming the validity of the sample. However there were no correlations between the clinical parameters, OS, or RFS with EGFR expression. Data on HER-2–3-4, STAT3, survivin and RAS will be presented at the meeting. Conclusions: Although no correlation has been found between clinical outcome and EGFR expression, EGFR inhibitors of the extracellular domain are expected to be useful for the treatment of CC that overexpress this receptor. These results will serve as baseline data needed to test cetuximab and other EGFR inhibitors in pts with CC. No significant financial relationships to disclose.
BRCA1 protein expression as a predictor of outcome following chemotherapy in sporadic epithelial ovarian cancer (EOC)
Authors: Carser J. E. , Quinn J. E. , Michie C. O. , McCluggage W. G. , Williams A. R. , Mullan P. B. , Gourley C. M. , Harkin D. P. 
Published: August 2020

5527 Background: Reduced expression of BRCA1 is observed in a substantial proportion of sporadic EOC. First line management of EOC involves platinum and taxane based chemotherapy. In vitro studies demonstrate that reduction in BRCA1 protein expression leads to enhanced sensitivity to platinum but relative resistance to taxane chemotherapy. We investigated the relationship between BRCA1 protein expression by immunohistochemistry (IHC) and survival in EOC patients, correlating outcome with type of chemotherapy received. Methods: 97 archival formalin-fixed, paraffin embedded tumour samples were identified from the Edinburgh Cancer Centre ovarian database. All patients received platinum based chemotherapy (platinum only n = 50, platinum/taxane n = 47). Tumour sections were stained for BRCA1 protein and scored by two independent reviewers. Tumours were graded from 0 (no BRCA1 protein) to 4 (>90% cells positive). BRCA1 protein expression was correlated with progression-free (PFS) and overall survival (OS) by Kaplan-Meier analysis. Results: Overall, patients with no detectable BRCA1 protein had a significantly improved PFS compared to those with positive staining (17.4 months vs 12.2 months, p = 0.04). Specifically, patients receiving platinum only regimens had a significantly improved PFS if they had no detectable BRCA1 protein compared to those with positive staining (14.5 months vs 10.8 months, p = 0.035).In contrast, patients positive for BRCA1 protein (grades 1–4) had a significant increase in both OS (43.7 months vs 20.4 months, p = 0.03) and PFS (12.7 months vs 10.9 months p = 0.02) if they received platinum/taxane combination over platinum alone. Patients with no detectable BRCA1 protein (grade 0) had no significant difference in OS or PFS whether they were treated with combination or platinum only chemotherapy. Conclusions: This study provides initial evidence that BRCA1 protein expression may be a predictive marker of chemotherapy response in sporadic EOC. Specifically, patients with positive BRCA1 staining demonstrate a better clinical outcome with platinum/taxane based chemotherapy over platinum alone whereas no such difference was seen in those with no BRCA1. Further prospective clinical studies are required to validate these findings. No significant financial relationships to disclose.
A phase II evaluation of bevacizumab in the treatment of recurrent or persistent endometrial cancer: A Gynecologic Oncology Group (GOG) Study
Authors: Aghajanian C. , Sill M. W. , Darcy K. , Greer B. , McMeekin D. S. , Rose P. G. , Rotmensch J. , Barnes M. N. , Hanjani P. , Leslie K. 
Published: August 2020

5531 Background: Bevacizumab (BV) is a recombinant, humanized monoclonal antibody directed against vascular endothelial growth factor, has demonstrated clinical benefit in multiple tumor types. This is the first report of the activity of bevacizumab in patients with recurrent or persistent endometrial cancer (EMC). Methods: Eligible patients had persistent or recurrent EMC after receiving 1–2 prior cytotoxic regimens, measurable disease, and GOG performance status < 2. Treatment consisted of BV 15 mg/kg IV q 3 weeks until disease progression or prohibitive toxicity. Primary endpoints were progression-free survival (PFS) at 6 months, objective response rate, and toxicity by NCI CTCAE v3.0. The clinical trial was carried out in a flexible 2-stage group sequential design intended to detect either cytostatic or cytotoxic activity. Sample sizes were targeted to limit the probability of designating ineffective regimens as being active 10% with at least 90% statistical power. Clinically significant improvements were 20% increases in the proportion responding or surviving progression-free at 6 months over historical controls. Results: From March 2006 to January 2008, 56 patients were enrolled. Two were excluded due to a second primary and one due to inadequate pathology; thus, the sample included 53 patients. Median age was 62 (range 44–84) years, and prior treatment consisted of 1 or 2 regimens in 33 and 20 patients, respectively. Twenty-eight patients (52.8%) had prior radiation. Early results showed 8/53 (15.1%) response rate, with 1 complete response and 7 partial responses; and 19/53 (35.8%) of patients progression free at 6 months with 2 patients pending at the time of data analysis. Median PFS was 4.2 months. Median Overall survival (OS) was 10.5 months. The following grade 3 or 4 toxicities were observed: anemia (1 grade 3), cardiovascular (4 grade 3), constitutional (2 grade 3), hemorrhage (1 grade 3), hepatic (1 grade 3), musculoskeletal (2 grade 3), metabolic (1 grade 3, 1 grade 4), neurologic (1 grade 3), pain (4 grade 3), and vascular (1 grade 3, 1 grade 4). Conclusions: BV appears to have single agent activity in women with recurrent or persistent EMC and warrants further investigation. No significant financial relationships to disclose.
Phase I and pharmacokinetic study of the novel VEGF-directed fusion protein, aflibercept, in combination with docetaxel in women with recurrent ovarian, fallopian tube, and primary peritoneal cancer
Authors: Coleman R. L. , Kamat A. , Iyer R. , Kundra V. , Garcia M. , Jaffe R. B. , Sood A. K. 
Published: August 2020

5549 Background: VEGF blockade has proved to be a promising therapeutic strategy in solid tumors, including ovarian. Aflibercept, a novel fusion protein consisting of the extracellular domains of VEGFR1/2 binds VEGF A, B and PlGF. Aflibercept has been studied as a single agent in heavily pretreated ovarian cancer patients. We hypothesized that the combination of aflibercept and docetaxel could be safely administered to women with recurrent ovarian cancer. Correlative biomarker and imaging studies of anti-angiogenesis targeting, pharmacokinetics (PK) and preliminary efficacy were additional objectives. Methods: Eligible patients had measurable, recurrent disease with no more than 3 prior chemotherapeutic regimens. Study design was a “lead-in” phase I trial; cycle 0, administered aflibercept IV as a single agent in 1 of 3 dose levels (2, 4, or 6 mg/kg) in a 3+3 design. Aflibercept was given in subsequent cycles with docetaxel (75 mg/m2); each cycle was 21 days. Correlative studies in cycle 0 were: PK (single agent), circulating endothelial cells and precursors (CEC, CEP), and imaging FDG-PET, DCE-MRI (baseline, day 2 and day 21). Efficacy evaluation (RECIST) was conducted q2 cycles of combination therapy. Results: Nine patients were recruited, 3 at each dose level. All are evaluable. No DLTs were observed in cycles 0 and 1; The most common hematological toxicities were myelosuppression (1 Grade 4 ANC) and anemia (Grade 2). Non-hematological toxicities (Gr 3) included headache, hypertension, fatigue and ulceration. One patient each with hypertension and ulceration lead to treatment discontinuation after 4 and 13 cycles, respectively. FDG-PET defined SUVmax in target lesions within 25% of baseline in 7 patients; 2 others had >25% increase at 48 hours post treatment. CECs, CEPs, DCE-MRI and PK are being analyzed. Confirmed PR was observed in 2 (22%) with 1 additional near PR. Median number of cycles: 5 (range 3–15). All have now progressed, median time to progression: 15 weeks. Conclusions: Aflibercept can be safely administered at 6 mg/kg with docetaxel repeatedly in this population of recurrent ovarian cancer patients. Preliminary efficacy supports phase II study, which is ongoing. No significant financial relationships to disclose.
Topotecan weekly versus routine 5-day schedule in patients with platinum-resistant ovarian cancer (TOWER): A randomized, multicenter trial of the North-Eastern German Society of Gynecological Oncology (NOGGO)
Authors: Sehouli J. , Oskay-Oezcelik G. , Stengel D. , Harter P. , Kurzeder C. , Belau A. , Belau A. , Markmann S. , Lorenz R. , Mueller L. , Lichtenegger W. 
Published: August 2020

5553 Background: In women with platinum-resistant recurrent ovarian cancer, weekly administration of topotecan (Tw) may be equally effective, but better tolerated than conventional 5-day dosing (Tc). We conducted a randomized multicenter trial to validate this assumption. Methods: The trial was pre-registered at clinicaltrials.gov ( NCT00170677 ). Women with platinum-resistant ovarian and fallopian tube cancers or primary peritoneal carcinoma, and measurable or assessable disease (GCIG criteria) were randomized to receive either Tw (d1,8,15/q28d, 4 mg/m2) or Tc (d1–5/q21d, 1.25 mg/m2). The predefined stopping rule, based on the primary endpoint of best CA-125 or tumor response, was not reached (presented at ASCO 2007, Abstract 5526). This permitted the accrual of 194 patients, 154 of whom could be assessed for CA-125 or tumor response (SD + CR + PR). We also compared progression-free (PFS) and overall survival (OS), as well as toxicity between trial groups. Results: Mean age was 61.8 (SD 9.8) years, and 59 women were on third-line treatment. Patients received a total of 809 cycles of chemotherapy. Demographic baseline characteristics, tumor stages and grades, and previous lines of chemotherapy were well balanced between treatment groups. There were 35 / 75 (47%) and 45 / 79 (57%) responses in the Tw and Tc groups, respectively (risk ratio [RR] 1.22, 95% CI 0.89–1.66). Median PFS and OS did not differ markedly between both regimens (3.2 versus 4.4 months, hazard ratio [HR] 1.30, 95% CI 0.96–1.77 and 9.8 versus 10.0 months, HR 1.08, 95% CI 0.77–1.52). The risk of grade III/IV hematological toxicity was significantly lower in the Tw group (anemia: RR 0.35, p = 0.007, neutropenia: RR 0.38, p = 0.0001, thrombopenia: RR 0.23, p = 0.0004). Conclusions: Weekly administration of topotecan shows no substantial difference in endpoints of effectiveness compared to conventional dosing, but is associated with a significantly lower likelihood of severe hematological toxicity. Weekly topotecan should be considered as a possible treatment alternative in women with platinum-resistant ovarian cancer because of its favourable benefit-risk-profile. No significant financial relationships to disclose.
Phase II study of CKD602, a camptothecin analog, in combination with carboplatin for the treatment of recurrent ovarian cancer
Authors: Choi C. , Lee Y. , Kim C. , Kang H. , Kim T. , Lee J. , Lee J. , Bae D. , Kim B. 
Published: August 2020

5554 Background: Belotecan (Camtobell, Chong Keun Dang Corp, Seoul, Korea; CKD602) is a camptothecin derivative with anti-tumor properties recently developed. This phase II study was designed to evaluate the toxicity and efficacy of belotecan combined with carboplatin in patients with recurrent epithelial ovarian cancer (EOC). Methods: Belotecan 0.3 mg/m2/day (days 1–5) and carboplatin AUC 5 (day 5) were administered every 3 weeks for 6 cycles. Eligible patients had 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 and CA-125 response; other end points included toxicities and progression free survival (PFS). Results: Until this preliminary analysis, sixteen patients had received the treatment and 13 patients were evaluable for response. Eight patients had platinum-sensitive disease (minimum treatment free interval≥6 months) and 6 had platinum-resistant disease (minimum treatment free interval <6 months). Overall response rate was 53.9%; there were 3 complete responses (23.1%), 4 partial responses (30.8%), 4 patients with stable disease (30.8%), and two patients with progressive disease (15.4%). Grade 3 and 4 hematologic toxicities included neutropenia (38%), thrombocytopenia (25%), and anemia (15%); there was one episode of febrile neutropenia. None of the patients experienced grades 3 and 4 gastrointestinal toxicities, including nausea, vomiting, and anorexia. Conclusions: The newly developed topoisomerase I inhibitor, belotecan (CKD-602), combined with carboplatin is a well-tolerated regimen with activity in recurrent EOC; further testing of this regimen is warranted. No significant financial relationships to disclose.
Phase II study comparing volociximab (an antiangiogenic antibody) and pegylated liposomal doxorubicin (PLD) with PLD alone in recurrent ovarian or primary peritoneal cancer
Authors: Vergote I. B. , Colombo N. , Kutarska E. , Del Campo J. , Pippitt C. , Casado A. , Lengyel E. , Gilder K. , Ho S. , Schilder R. J. 
Published: August 2020

5560 Background: Volociximab (V), a chimeric monoclonal antibody with direct antitumor effects, blocks α5β1 binding to fibronectin and induces apoptosis in proliferating endothelial cells. A Phase I/II study was performed to evaluate PLD with/without V in patients (pts) with recurrent ovarian or primary peritoneal cancer that relapsed after platinum/taxane-based chemotherapy (maximum 2 prior lines). Methods: A 3-arm adaptive randomization design compared efficacy and safety of PLD (40 mg/m2 q4wk) + V (15 mg/kg q2wk or qwk) vs. PLD alone. Pts were stratified by platinum sensitivity and received treatment until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS). Pharmacokinetic (PK) and pharmacodynamic effects were also evaluated. Results: There were 6 iterations of adaptive randomization based on accumulating PFS data. 127 pts were randomized: 66 in Group A (PLD), 34 in Group B (PLD+V [q2wk]), and 27 in Group C (PLD+V [qwk]). The incidence of AEs was balanced across treatment groups. The most common Grade 3/4 AEs (≥5% in any group) were abdominal pain, intestinal obstruction, ascites, fatigue, hypoalbuminemia, and cytopenias. Based on preclinical data, therapeutic levels of V were maintained during treatment, and V did not appear to alter the PK of PLD. Response rates were comparable across groups. There were no CRs; PRs were 16%, 18%, and 19%. The median PFS estimates were 193, 164, and 221 days. Conclusions: The safety profile of V+PLD appeared similar to PLD alone. Preliminary analysis of PFS suggested that there was a low probability of detecting a statistically significant difference in favor of V+PLD, so the study was closed to enrollment. Analyses correlating PFS with platinum sensitivity and α5β1 tumor expression are ongoing. [Table: see text]