CA-125 Response Rate Research Articles

Acupuncture and Related Therapies for Endometriosis: A Network Meta-Analysis of Randomized Controlled Trials.

Acupuncture and related therapies are effective and safe ways to relieve the pain, and improve the health and quality of life in women with endometriosis-related pain. However, it is still unclear which treatment is the most effective. Our study aims to summarize the evidence and determine the most effective and safe method to treat the endometriosis. We searched PubMed, EMBASE, Cochrane Library, and Web of science, China Biology Medicine, China National Knowledge Infrastructure, Wan fang Data, Chinese Scientific Journal Database and conducted manual searches of relevant papers, summarized randomized clinical trials of acupuncture-related therapies for endometriosis from database inception to 21 April 2024. After independent literature screening and data extraction that pain VAS was selected as the primary outcome measure. The quality evaluation was conducted by Review Manager 5.4. Perform network meta-analysis (NMA) used Stata 15.0 software. Forty-two eligible trials involving six acupuncture-related interventions and 3,635 participants were included in this NMA. Pairwise meta-analyses show that combination therapy was more efficacious than western medicine and Chinese herb medicine for pain VAS scores, serum CA125 level and response rate results. The NMA estimates indicated that: for pain VAS scores, acupuncture (SMD: -2.33; 95% CI: -4.37, -0.29) and combination therapy (SMD: 1.79 95% CI: 1.21, 2.41) were superior to western medicine. For serum CA125 level, acupoint application (SMD: -11.33 95% CI: -20.28, -2.97) and combination therapy (SMD: 6.20; 95% CI: 1.60, 10.75) were associated with better efficacy when considered alongside western medicine. For response rate, combination therapy (SMD: 0.20; 95% CI: 0.14, 0.29) and auricular therapy (SMD: 8.01; 95% CI: 2.08, 45.37) were more efficacious than western medicine. The comprehensive ranking results show that acupoint catgut embedding was the best performing at lowering pain VAS scores, acupoint application was identified as the most effective in reducing serum CA125 level, and auricular therapy was ranked first in improving the response rate. Acupoint catgut embedding, auricular therapy, acupoint application and combination therapy may be the best solutions for the treatment of endometriosis. Additional trials are needed to develop higher-quality evidence and optimal regimens.

Study on the efficacy and toxicity of pamiparib combined with tamoxifen in the treatment of patients with epithelial ovarian cancer with biochemical recurrence during first-line PARPi maintenance therapy.

TPS5621 Background: A high proportion of ovarian cancer patients tend to have elevated CA-125 1-6 months before imaging recurrence. The time between biochemical recurrence (i.e., only elevated CA-125 without imaging finding or clinical symptoms) to imaging recurrence can be considered a "window period", and if the “window period” can be extended, it may convert platinum-resistant relapsed patients to platinum-sensitive patients, and ultimately improving patient outcomes. The timing of treatment for the biochemical recurrent patients has been controversial. Tamoxifen, an anti-estrogenic drug, is considered an effective option for these patients. Pamiparib (BGB-290) is an investigational small molecule inhibitor of PARP1 and PARP2. According to OReO study(NCT03106987), the "PARPi after PARPi" strategy is effective in recurrent ovarian cancer patients previously treated with a PARP inhibitor. Therefore, we aim to further explore the use of PARP inhibitors in maintenance therapy for patients with ovarian cancer. Methods: This study (NCT05669768) will evaluate the efficacy and toxicity of pamiparib and tamoxifen in ovarian cancer patients with biochemical recurrence during first-line PARPi maintenance therapy. The included ovarian cancer patients are required to achieve No Evidence of Disease (NED) or demonstrated a response following platinum-based chemotherapy, with normalized CA-125 levels. First-line maintenance treatment with a PARP inhibitor is mandatory, with a minimum interval of ≥6 months to biochemical recurrence. The trial design is interventional, employing a Simon two-stage design to estimate sample size. The primary outcome of the study is the CA-125 response rate, which was assessed according to the GCIG criteria.1 The secondary outcome was Time to First Subsequent Therapy (TFST). Patients undergo regular assessments for tumor markers and imaging throughout treatment. If persistent elevation of tumor markers or the detection of recurrent lesions or distant metastases is observed, the patient is promptly removed from the study group. Standardized antitumor therapy is then initiated based on the patient's condition. The total planned enrollment is 46 participants, utilizing a single-group assignment and an open-label design. 1 of planned 12 patients for the first stage of accrual have been enrolled. Reference: 1. Rustin GJ, Vergote I, Eisenhauer E, et al. Definitions for response and progression in ovarian cancer clinical trials incorporating RECIST 1.1 and CA 125 agreed by the Gynecological Cancer Intergroup (GCIG). Int J Gynecol Cancer. 2011;21(2):419-423. Clinical trial information: NCT05669768 .

Regorafenib or Tamoxifen for platinum-sensitive recurrent ovarian cancer with rising CA125 and no evidence of clinical or RECIST progression: A GINECO randomized phase II trial (REGOVAR)

ObjectiveTo evaluate the efficacy and safety of regorafenib versus tamoxifen in platinum-sensitive ovarian cancer biological recurrence, defined by CA-125 increase without radiological (RECIST criteria) or symptomatic evidence of progression. Patients and methods116 patients with platinum-sensitive ovarian cancer presenting an isolated increase of CA-125 were planned to be randomized. Regorafenib was administered orally at 160 or 120 mg daily, 3 weeks on/1 week off or tamoxifen at 40 mg daily, until disease progression or development of unacceptable toxicity. The primary endpoint was Progression-Free Survival, assessed by progression according to RECIST 1.1 or death (by any cause). Secondary endpoints included Overall Survival, Best Response and CA-125 response rate. Results68 patients were randomized. Median age was 67 years (range: 30–87). Primary site of cancer was ovarian for most patients (92.6%). Tumors were predominantly serous / (89.7%), high grade (83.6%) and initial FIGO staging was III for 69.6% of the patients. Most (79.4%) patients were included after the first line of platinum-based treatment. After a median follow-up of 32 months, there was no difference of progression-free survival (PFS) between regorafenib and tamoxifen groups (p = 0.72), with median PFS of 5.6 months (CI 90%: 3.84–7.52) for the tamoxifen arm and 4.6 months (CI 90%: 3.65–7.33) for the regorafenib arm. There was also no difference in term of overall survival, best response or CA-125 response, delay to next therapy. Regorafenib presented a less favorable safety profile than tamoxifen, with grade 3/4 events occurring for 90.9% of the patients compared to 54.3% for tamoxifen. The most frequent were cutaneous, digestive, and biological events. Notably, hand-foot syndrome occurred in 36.4% of these patients. ConclusionRegorafenib presented an unfavorable toxicity profile compared to tamoxifen, with no superior efficacy in this population of patients.

Utilizing an interim futility analysis of the OVAL study (VB-111-701/GOG 3018) for potential reduction of risk: A phase III, double blind, randomized controlled trial of ofranergene obadenovec (VB-111) and weekly paclitaxel in patients with platinum resistant ovarian cancer

ObjectiveReport the results from a preplanned interim analysis of a phase III, double blind, randomized controlled study of ofranergene obadenovec (VB-111), a targeted anti-cancer gene therapy, in combination with paclitaxel in patients with platinum resistant ovarian cancer (PROC). MethodsThe OVAL (NCT03398655) study is an on-going study where patients are randomly assigned in a 1:1 ratio to weekly paclitaxel 80 mg/m2 with VB-111 or placebo. The protocol specifies a pre-planned unblinded futility interim analysis of CA-125 response per GCIG criteria in the first 60 evaluable patients. The futility rule determined for this analysis was that the response rate of VB-111 must be greater than the response rate of placebo by at least 10% in order to continue the study. Coincident with the interim analysis, the blinded CA-125 response rate was estimated as a proportion of the first 60 evaluable patients with CA-125 response per GCIG criteria. Post-treatment fever is provided as a possible surrogate marker of VB-111 therapy activity. ResultsThe median age of the evaluable patients was 62 years (range 41–82); 97% had high-grade serous cancer; 58% had been treated with 3 or more previous lines of therapy, 70% received prior anti-angiogenic treatment, 43% received prior PARP inhibitors. CA-125 response in the VB-111 and weekly paclitaxel treated arm met the pre-specified interim criterion of an absolute advantage of 10% or higher compared to the control. Blinded results show a 53% CA-125 response rate (32/60) with 15% complete response (n=9). Assuming balanced randomization and an absolute advantage of 10% or higher to the VB-111 arm, it may be deducted that the response in the VB-111 treatment arm is 58% or higher. Among patients with post-treatment fever, the CA-125 response rate was 69%. ConclusionsAt the time of the interim analysis, response rate findings are comparable to the responses seen in a similar patient population in the phase I/II study. The independent data and safety monitoring committee (iDSMC) recommended continuing the OVAL trial as planned. No new safety signals were identified.

A phase I trial a FR alpha targeted thymidylate synthase inhibitor CT900 exploring four schedules of treatment in expansion cohorts of patients with high-grade serous ovarian cancer.

6043 Background: CT900 (BTG945/ONX-0801) is a novel small molecule that binds to folate receptor alpha (FRα), is internalized and causes cytotoxicity by thymidylate synthase inhibition. Methods: The aims of the expansion cohorts were to determine toxicity, response rates and correlation of the response to FRα expression in patients with HGSOC (NCT02360345). Four expansion cohorts were studied which included: schedule A (6 mg/m2/q every 2 weeks), schedule B (12 mg/m2/q every 2 weeks), schedule C (12 mg/m2/q every 2 weeks with 12 mg dexamethasone IV and 8 mg of dexamethasone for 2 days) and schedule D (12 mg/m2/q every 3 weeks). Response rates were assessed by RECIST V1.1 and GCIG CA125 response criteria. Patients who were withdrawn for reasons other than toxicity within 8 weeks (cohorts A, B, C) and 12 weeks (cohort D) were not assessable for efficacy. FRα expression was quantified using immunohistochemistry. Results: A total of 67 patients were treated in the 4 cohorts (14, 25, 15 and 13 for cohorts A, B, C and D). The median age was 62 (IQR 57 - 68) and the median lines of previous treatment was 5 (range 1 to 13). A majority of patients were platinum resistant. The most common toxicities across all expansion cohorts were: fatigue (51%), nausea (36%), anemia (27%), fever (25%), AST elevation (21%), most of which were grade 1 - 2. Toxicity of special interest included radiological changes of pneumonitis and was 15% in all cohorts (7%, 16%, 27% and 8% in cohorts A, B, C and D, respectively). These changes were grade 1 - 2 in all but one case. RECIST response rates in evaluable patients across the different cohorts were: A 1/8 (13%), B 6/21 (29%), C 5/12 (42%) and D 2/12 (17%). FRα expression in archival tumor tissue was measured in 59/67 patients. Expression was found to be high/medium in 43/59 (73%), low in 7/59 (12%) and negative/very low in 9/59 (15%). In patients with high/medium FRα expression, the RECIST response rates in different cohorts were: A 0/9 (0%), B 6/16 (38%), C 4/12 (33%) and D 1/6 (17%). The CA125 response rate in all patients within cohort B was 13/25 (52%) and 10/16 (63%) in patients with high/medium FRα expression. Conclusions: CT900 has shown clinical activity in patients with heavily pre-treated platinum-resistant, high/medium FRα expressing HGSOC. Based on toxicity and efficacy, the schedule of 12 mg/m2/q2 weekly (schedule B) is the recommended phase II dose for further evaluation in patients with relapsed high/medium FRα expressing HGSOC. Clinical trial information: NCT02360345.

Clinical trial in progress: Pivotal study of VB-111 combined with paclitaxel versus paclitaxel for treatment of platinum-resistant ovarian cancer (OVAL, VB-111-701/GOG-3018).

TPS6097 Background: Ofranergene obadenovec (VB-111) is a targeted anti-cancer gene therapy with a dual mechanism: a broad antiangiogenic effect and induction of a tumor directed viral immune response. In a phase II trial in platinum resistant ovarian cancer VB-111 in combination with weekly paclitaxel showed a CA-125 response rate (RR) of 58% and median overall survival (OS) of 498 days compared to 172.5 days in the sub-therapeutic dose (p = 0.028). The combination treatment was well tolerated. Favorable outcomes were associated with induction of an immunotherapeutic effect of tumor infiltration with CD-8 T cells. Based on these observations, a phase III randomized controlled trial, VB-111-701/GOG-3018 (OVAL) was initiated in collaboration with the GOG Foundation, Inc. Methods: The OVAL study, NCT03398655, is an international, randomized, double-blind, placebo-controlled, phase III study. Patients with recurrent platinum-resistant epithelial ovarian cancer, who have measurable disease (RECIST 1.1) and were previously treated with up to 5 lines are randomized 1:1 to receive VB-111 (1x1013 VPs) with weekly paclitaxel (80mg/m2), or weekly paclitaxel with placebo. Randomization is stratified by number of prior treatment lines, prior antiangiogenic therapy and platinum refractory disease status. Treatment beyond asymptomatic RECIST progression may continue until progression is confirmed by follow up imaging. The primary endpoints are OS, safety and tolerability. Secondary endpoints include progression free survival, and objective RR by CA-125 (per GCIG criteria) and RECIST 1.1. The sample size calculation of 400 patients (event driven) provides 92% power to detect a difference in survival at the two-sided 5% significance level using the logrank test. A pre-planned interim analysis will take place in Q1 2020 to assess whether the CA-125 RR per GCIG criteria in the treatment arm is sufficiently larger than in the control arm and is comparable to the positive results of the phase II study. Study enrolment is ongoing and over 80 patients were enrolled in the US and Israel. Enrollment expansion to Europe is planned in 2020. Clinical trial information: NCT03398655.

Phase 2 trial of tisotumab vedotin in platinum-resistant ovarian cancer (innovaTV 208).

TPS5602 Background: Ovarian cancer (OC) is the most lethal gynecologic cancer, accounting for ≈185,000 deaths worldwide in 2018. Most patients (pts) initially respond to platinum-based chemotherapy (chemo), but more than 50% of pts recur. Pts who recur in ≤6 months have platinum-resistant OC (PROC), which is associated with poor prognosis. Standard therapy for PROC includes chemo ± bevacizumab (bev). However, many pts receive single-agent chemo, which demonstrates limited response and survival (≈12% ORR, 3-4 mo PFS, ≈12 mo OS). Therefore, there is an urgent need for novel therapeutic strategies. Tissue factor (TF) is a novel oncogenic target expressed in OC. Tisotumab vedotin (TV) is a first-in-class antibody drug conjugate comprising a TF-targeted fully human monoclonal antibody conjugated to the microtubule-disrupting agent monomethyl auristatin E. TV has shown encouraging antitumor activity and a manageable safety profile in PROC in the multicohort phase 1/2 innovaTV 201 study. innovaTV 208 is a multicenter, open-label, phase 2 trial with a safety run-in phase for a dose-dense regimen (DDR) evaluating the efficacy and safety of TV in pts with PROC. Methods: innovaTV 208 will enroll ≈142 adult pts with platinum-resistant epithelial ovarian, primary peritoneal, or fallopian tube cancer; measurable disease by RECIST v1.1; and ECOG score 0-1. Eligible pts must have received bev-containing treatment for OC. Pts with platinum-refractory disease, increased risk of bleeding, active ocular surface disease, or grade > 1 peripheral neuropathy will be excluded. A safety run-in phase for the DDR will be performed in up to 12 pts who received ≤5 prior treatment regimens for PROC. In the DDR, TV will be given at previously decided lower doses IV 3Q4W for the same dose intensity as the standard 1Q3W dose; the primary endpoint is incidence of DLTs. In phase 2, pts who received ≤1 prior cytotoxic chemo regimen for PROC will be randomized to receive TV administered as IV 1Q3W or as IV 3Q4W, if shown to be tolerable. The primary endpoint for phase 2 is confirmed ORR by RECIST v1.1. Secondary endpoints include DOR, time to response, DCR, CA-125 response rate by GCIG criteria, PFS, OS, pharmacokinetics, and safety. Clinical trial information: NCT03657043.

Endocrine treatment of high grade serous ovarian carcinoma; quantification of efficacy and identification of response predictors

ObjectivesThe role of endocrine therapy (ET) in high grade serous ovarian carcinoma (HGSOC) is poorly defined due to the lack of phase III data and significant heterogeneity of clinical trials performed. In this study, we sought to identify predictive factors of endocrine sensitivity in HGSOC. MethodsHGSOC patients who received at least four weeks of ET for relapsed disease following one line of chemotherapy at the Edinburgh Cancer Centre were identified. Exclusion criteria were use of endocrine therapy as maintenance therapy or of unknown duration. Duration of therapy and best CA125 response as per modified GCIG criteria were recorded. Oestrogen receptor (ER) histoscore, treatment free interval, prior lines of chemotherapy, and type of ET were evaluated as predictive factors. ResultsOf 431 patients identified, 269 were eligible (77.0% letrozole, 18.6% tamoxifen, 2.2% megesterol acetate, 2.2% other). The median duration of therapy was 126 days (range 28–1427 days). 32.7% remained on ET for ≥180 days and 14.1% for ≥365 days. The CA125 response and clinical benefit rates (response or stable disease) were 8.1% and 40.1% respectively. ER histoscore >200 (P = 0.0016) and a treatment free interval of ≥180 days (P < 0.0001) were independent predictive factors upon multivariable analysis. ConclusionsET should be considered as a viable strategy to defer subsequent chemotherapy for relapsed HGSOC. Patients with an ER histoscore >200 and a treatment free interval of ≥180 days are most likely to derive benefit.

Vistusertib (dual m-TORC1/2 inhibitor) in combination with paclitaxel in patients with high-grade serous ovarian and squamous non-small-cell lung cancer

BackgroundWe have previously shown that raised p-S6K levels correlate with resistance to chemotherapy in ovarian cancer. We hypothesised that inhibiting p-S6K signalling with the dual m-TORC1/2 inhibitor in patients receiving weekly paclitaxel could improve outcomes in such patients. Patients and methodsIn dose escalation, weekly paclitaxel (80mg/m2) was given 6/7weeks in combination with two intermittent schedules of vistusertib (dosing starting on the day of paclitaxel): schedule A, vistusertib dosed bd for 3 consecutive days per week (3/7days) and schedule B, vistusertib dosed bd for 2 consecutive days per week (2/7days). After establishing a recommended phase II dose (RP2D), expansion cohorts in high-grade serous ovarian cancer (HGSOC) and squamous non-small-cell lung cancer (sqNSCLC) were explored in 25 and 40 patients, respectively. ResultsThe dose-escalation arms comprised 22 patients with advanced solid tumours. The dose-limiting toxicities were fatigue and mucositis in schedule A and rash in schedule B. On the basis of toxicity and pharmacokinetic (PK) and pharmacodynamic (PD) evaluations, the RP2D was established as 80mg/m2 paclitaxel with 50mg vistusertib bd 3/7days for 6/7weeks. In the HGSOC expansion, RECIST and GCIG CA125 response rates were 13/25 (52%) and 16/25 (64%), respectively, with median progression-free survival (mPFS) of 5.8months (95% CI: 3.28–18.54). The RP2D was not well tolerated in the SqNSCLC expansion, but toxicities were manageable after the daily vistusertib dose was reduced to 25mg bd for the following 23 patients. The RECIST response rate in this group was 8/23 (35%), and the mPFS was 5.8months (95% CI: 2.76–21.25). DiscussionIn this phase I trial, we report a highly active and well-tolerated combination of vistusertib, administered as an intermittent schedule with weekly paclitaxel, in patients with HGSOC and SqNSCLC. Clinical trial registrationClinicialTrials.gov identifier: CNCT02193633

Response rates to second-line platinum-based therapy in ovarian cancer patients challenge the clinical definition of platinum resistance

ObjectiveThe aim of this study was to compare response rates and survival in women with “platinum resistant” epithelial ovarian cancer (EOC) who received further platinum-based or non‑platinum chemotherapy for treatment at first relapse. MethodsPatients with high-grade EOC (including fallopian tube and peritoneal cancer) of all histologies recruited to the Australian Ovarian Cancer Study (AOCS) and treated with platinum-based primary chemotherapy were included. Response to second-line chemotherapy, overall survival (OS) and survival after treatment for first progression (OS2) were determined in all histologies and separately in women with high-grade serous tumors. ResultsOf the 341 patients classified as platinum-resistant by the 6-month threshold, 243 (71%) were treated with chemotherapy at relapse. CA-125 response rates to platinum-based chemotherapy were significantly higher compared to non‑platinum chemotherapy (51% vs 21%, P < 0.001). Among patients with a platinum-free interval (PFI) of 3–6 months, OS2 in patients treated with platinum was significantly longer compared to individuals receiving non‑platinum-based treatment (median 17.67 months, 95% CI: 14.79–20.75 vs. 10.62 months, 95% CI: 8.02–12.72, P = 0.022). The patterns were similar when restricted to patients with high-grade serous histology. In patients with PFI <3 months, there was no significant difference in response or survival according to type of second-line treatment. ConclusionsOur findings further question the use of a 6-month PFI as an arbitrary threshold for subsequent treatment decision-making. Some patients considered “platinum resistant” still derive clinical benefit from platinum-based chemotherapy. Biomarkers of platinum sensitivity are needed in clinical practice to identify potential responders who should be offered re-treatment with platinum.

TAX-TORC: A phase I trial of vistusertib (AZD2014) in combination with weekly paclitaxel with integrated pharmacodynamic (PD) and molecular characterization (MC) studies.

2571 Background: In ovarian cells isolated from ascites, p-S6K levels were found to correlate with resistance to chemotherapy. We hypothesised that inhibiting p-S6K signalling with dual m-TORC1/2 inhibitor vistusertib (V) in addition to paclitaxel (P) would improve outcomes of patients with high-grade serous ovarian cancer (HGSOC). Methods: In the dose escalation part, weekly P 80mg/m2IV (6/7 weeks) was evaluated in combination with two schedules of V; Schedule A: V (25, 50 or 75mg) BID PO on day(D) 1-3/week and Schedule B: V (75 or 100mg) BID PO D1-2/week. This was followed by an expansion cohort in 25 HGSOC patients. Results: Dose limiting toxicities in Schedule A were fatigue and mucositis and in Schedule B were diarrhoea, rash and fatigue. The AUC, Cmax and half-life of V in the 50mg-cohort were 2821ng.hr/ml, 926ng/ml and 3hrs, comparable to single agent studies. PD analysis (from six 50mg-cohort patients) in platelet-rich plasma showed increased phosphorylation of Ser473 AKT following P induction (1.4 fold, p = 0.1378). Following addition of V to P, phosphorylation levels 4hrs post-treatment with V fell significantly to 53% of pre-dose levels (p = 0.0495). This was 61% lower than the corresponding time point following P alone. Based on toxicity, pharmacokinetic and PD evaluation, recommended phase 2 dose was established as P 80mg/m2 D1 and V 50mg BID D1-3 for 6/7 weeks. In the HGSOC expansion, 96% of patients had relapsed within 12 months of last platinum therapy and 100% had received previous paclitaxel, with a median of 3 previous lines of treatments. RECIST and GCIG CA125 response rates were 13/25 (52%) and 15/25 (60%) respectively, with median progression free survival of 5.5 months. MC was performed on archival tumor tissue of 24/25 HGSOC expansion cohort patients, with the most common mutations occurring in p53 (100%), BRCA (17%), and MUC16 (17%). ATM mutations occurred in 17% (n = 4), 3 of whom had a response. Conclusions: We report a highly active combination of paclitaxel with an intermittent schedule of vistusertib in patients with HGSOC. This combination is now being evaluated in a randomised controlled trial for this indication. Clinical trial information: NCT02193633.

Phase I study of olaparib (O), in combination with oral cyclophosphamide (C), in patients (pts) with metastatic triple negative breast cancer (TNBC) and recurrent high grade serous ovarian cancer (OVCA).

1104 Background: Poly (ADP-ribose) polymerase (PARP) inhibitors can potentiate chemotherapy induced DNA damage, through synthetic lethality, leading to increased tumor death. We hypothesized that O+C would increase antitumor activity of O through increased DNA damage induced by C. This study ( ANZCTR N12613000924752) evaluated the safety and activity of O+C. Methods: Eligible patient (pts) had performance status 0-2, with ≤3 lines of therapy (including platinum for OVCA and anthracycline and taxane for BC). Pts received O+C with a dose escalations strategy using a 3+3 design with cohort expansions once maximal tolerated dose (MTD) was determined. Dose level 1 (DL1); O, 300 mg bid continuously, C, 50mg on days 1,3 and 5 weekly, 21 day cycle. Dose level 2 (DL2); O, 300 mg bid continuously, C, 50mg days 1-5 weekly 21 day cycle. Dose limiting toxicity was evaluated during 1st two cycles. Safety was assessed by CTCAEv4.0 and efficacy with RECISTv1.1 and GCIC criteria. Results: Of the 32 pts (median age 56, 9 had BC ( BRCA1 22%, BRCA2 44%) and 23 had HGSOC ( BRCA1 39%, BRCA2 26%). 4 pts were treated at DL1 and 28 pts at DL2. DL2 was the MTD. At the time of analysis, 16 of 29 pts had 8 cycles of O+C, with 14 of 16 pts continued with O beyond the 8th cycle. One pt stopped because of adverse events (AEs) and the remaining 12 stopped due to disease progression. The median treatment duration of O+C was 4.3 months (0.7-23.5). Common AEs were nausea (Grade (Gr) 1/2: 88%, Gr 3: 3%), fatigue (Gr 1/2: 81%), constipation (Gr 1/2: 38%, Gr 3: 3%), and vomiting (Gr 1/2: 38%, Gr 3: 3 %). There were no grade (Gr) 4 or 5 AE. 50% required blood transfusion for anemia. Unconfirmed disease control rate (DCR) was 73% (N = 30; CR = 1, PR = 9, SD = 12). DCR for BC and HGSOC were 56% and 81% respectively. In the BRCA cohort (N = 19), DCR was 79%. GCIG CA125 response rates were 70% and 92% for all HGSOC and BRCA cohort respectively. Conclusions: In HGSOC and BC pts, the recommended phase II dose (O 300 mg bid continuously, C 50mg on days 1-5 weekly) is tolerable and active, particularly in those with germline BRCA mutation, supporting our hypothesis. A randomised phase II study in BRCA mutant HGSOC is planned. Clinical trial information: ACTRN12613000924752.

Gamma Knife Surgery for Metastatic Brain Tumors from Gynecologic Cancer: Time for What Saves Time, Grants Time, and Is Tested By Time?

To determine the safety and efficacy of the novel combination of docetaxel, oxaliplatin, and bevacizumab as first-line treatment of advanced cancer of the ovary, peritoneum or fallopian tube after initial debulking surgery.Eligible patients (stage IB-IV) were treated with 6 cycles of oxaliplatin (85 mg/m2), docetaxel (75 mg/m2), and bevacizumab (15 mg/kg) every 3 weeks, followed by single-agent bevacizumab 15 mg/kg every 3 weeks to complete one year of therapy. The primary endpoint was 12-month progression-free survival (PFS).A total of 132 patients (80 with measurable disease at baseline; 52 with non-measurable, evaluable disease at baseline) enrolled and received study treatment. At diagnosis, 76.5% of patients had stage III disease and 20% had stage IV. 62.9% were optimally cytoreduced. The most common grade 3/4 adverse events were neutropenia (42.4%), leukopenia (13.6%), hypertension (8.3%), fatigue (6.1%), and nausea (6.1%). One patient (0.8%) had a fatal gastrointestinal perforation. The best overall confirmed response rate (complete response + partial response [measurable disease subgroup]) was 58.6% (95% CI 49%, 67%). CA-125 response rates for the measurable and non-measurable disease subgroups were 83.0% and 81.5%, respectively. The 12-month PFS rate for the measurable disease subgroup was 65.7% (95% CI 53.4%, 76.7%); median PFS was 16.3 (95% CI 12.6, 19.6) months. Median overall survival was 47.3 (95% CI 34.1, upper limit not applicable) months.This novel treatment regimen may provide a promising therapeutic approach for women with ovarian, primary peritoneal, or fallopian tube carcinoma. No unanticipated safety concerns were identified.

A phase II trial of oxaliplatin, docetaxel, and bevacizumab as first-line therapy of advanced cancer of the ovary, peritoneum, and fallopian tube

ObjectiveTo determine the safety and efficacy of the novel combination of docetaxel, oxaliplatin, and bevacizumab as first-line treatment of advanced cancer of the ovary, peritoneum or fallopian tube after initial debulking surgery. MethodsEligible patients (stage IB-IV) were treated with 6cycles of oxaliplatin (85mg/m2), docetaxel (75mg/m2), and bevacizumab (15mg/kg) every 3weeks, followed by single-agent bevacizumab 15mg/kg every 3weeks to complete one year of therapy. The primary endpoint was 12-month progression-free survival (PFS). ResultsA total of 132 patients (80 with measurable disease at baseline; 52 with non-measurable, evaluable disease at baseline) enrolled and received study treatment. At diagnosis, 76.5% of patients had stage III disease and 20% had stage IV. 62.9% were optimally cytoreduced. The most common grade 3/4 adverse events were neutropenia (42.4%), leukopenia (13.6%), hypertension (8.3%), fatigue (6.1%), and nausea (6.1%). One patient (0.8%) had a fatal gastrointestinal perforation. The best overall confirmed response rate (complete response+partial response [measurable disease subgroup]) was 58.6% (95% CI 49%, 67%). CA-125 response rates for the measurable and non-measurable disease subgroups were 83.0% and 81.5%, respectively. The 12-month PFS rate for the measurable disease subgroup was 65.7% (95% CI 53.4%, 76.7%); median PFS was 16.3 (95% CI 12.6, 19.6) months. Median overall survival was 47.3 (95% CI 34.1, upper limit not applicable) months. ConclusionsThis novel treatment regimen may provide a promising therapeutic approach for women with ovarian, primary peritoneal, or fallopian tube carcinoma. No unanticipated safety concerns were identified.

Farletuzumab (a monoclonal antibody against folate receptor alpha) in relapsed platinum-sensitive ovarian cancer

ObjectiveFarletuzumab is a humanized monoclonal antibody to folate receptor-α, which is over-expressed in most epithelial ovarian cancers but largely absent on normal tissue. We evaluated clinical activity of farletuzumab, alone and combined with chemotherapy, in women with first-relapse, platinum-sensitive ovarian, fallopian tube and primary peritoneal cancers. MethodsFifty-four eligible subjects received open-label farletuzumab weekly, single agent or combined with carboplatin (AUC5–6) and taxane (paclitaxel 175mg/m2 or docetaxel 75mg/m2), every 21days for 6cycles, followed by farletuzumab maintenance until progression. Twenty-eight subjects with asymptomatic CA125 relapse received single-agent farletuzumab and could receive platinum/taxane chemotherapy plus farletuzumab after single-agent progression. Twenty-six subjects with symptomatic relapse entered the combination arm directly; 21 subjects entered after single agent. Primary endpoints included normalized CA125 and Overall Response Rate (ORR). Duration of each subject's second progression-free interval (PFI2) was compared with her own first response interval (PFI1). ResultsFarletuzumab was well-tolerated as single agent, without additive toxicity when administered with chemotherapy. Of 47 subjects who received farletuzumab with chemotherapy, 38 (80.9%) normalized CA125. In 9/42 (21%) evaluable subjects, PFI2 was≥PFI1, better than the historical rate (3%). There was a high response rate among subjects with PFI1 <12months (75%), comparable to that in subjects with PFI1 ≥12months (84%). Complete or partial ORR was 75% with combination therapy. ConclusionBased on this study, farletuzumab with carboplatin and taxane may enhance the response rate and duration of response in platinum-sensitive ovarian cancer patients with first relapse after remission of 6–18months.

CA125, CA199 combined with exfoliative cytometer detection for the diagnosis of Ovarian Cancer of malignant seroperitoneum

Objective To investigate the role of CA125, CA199 combined with exfoliative cytometer detection for the diagnosis of Ovarian Cancer. Methods 32 patients Ovarian Cancer with malignant seroperitoneum was detected. CA125 ,CA199 was detected with ELISA one-step method, and seroperitoneum exfoliative cytometer was detected for light microscope detection, the results were compared. Results Blood serum and seroperitoneum overall masculine response rate was 87.5%; CA199 detection overall masculine response rate was 28. 13%; seroperitoneum exfoliative cytometer detection overall masculine response rate was 53.13%;CA125, CA199 and exfoliative cytometer joint detection overall masculine response rate was 96.88%. There was significant difference about the overall response rate (P＜ 0. 05) between three groups, respectively. Conclusion Seroperitoneum tumor marker CA125, CA199 sensitivity is more height than simple seroperitoneum exfoliative cytometer detection, but Joint detection improve clinical diagnosis of ovarian cancer sensitivity. Key words: CA125; CA199; Exfoliative cytometer detection; Ovarian cancer; Malignant seroperitoneum

Efficacy and safety of farletuzumab, a humanized monoclonal antibody to folate receptor alpha, in platinum-sensitive relapsed ovarian cancer subjects: Final data from a multicenter phase II study.

5001 Background: Farletuzumab (MORAb-003) is a humanized monoclonal antibody to folate receptor alpha, which is overexpressed in most epithelial ovarian cancers (EOC), but largely absent on normal tissue. The phase I study showed signs of activity and did not reach an MTD. Methods: 54 subjects with platinum-sensitive EOC in first relapse received weekly farletuzumab either as single agent (SA) or in combination with carboplatin (AUC 5-6) and taxane (P/T) q 21 days for 6 cycles, followed by farletuzumab maintenance. 28 subjects with asymptomatic CA125 relapse received SA farletuzumab. Subjects could receive P/T plus farletuzumab after SA. 26 subjects with symptomatic relapse entered the combination arm directly and 21 subjects entered after SA. Primary endpoints were normalization of CA125 and Objective Response Rate. Duration of each subject's second response was compared to the duration of their own first response. Results: Farletuzumab was well-tolerated as SA as well as without additive toxicity to P/T. Preliminary data show that of the 44 evaluable subjects who received farletuzumab with P/T, 89% normalized CA-125. In 9/44 (21%) treated subjects, the second remission has been equal to, or longer, than the first remission. There was an unexpectedly high response rate among subjects with a first progression-free interval of <12 months, comparable to that in subjects with a first progression-free interval of >12 months (Table). Conclusions: Preliminary data for this study indicated that farletuzumab with P/T significantly increases objective response rate compared to historic data for P/T alone in platinum-sensitive first-relapsed ovarian cancer subjects and increases the duration of second remission compared to first remission. Combination therapy: Response by length of first progression-free interval First progression-free interval <12 months (n=12) ≥12 months (n=32) CA125 normalization 92% 84% RECIST responder (CR + PR) 64% 71% RECIST patient benefit (CR + PR + SD) 100% 90% Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Morphotek Morphotek Morphotek Morphotek

Prediction of response to chemotherapy by ERCC1 immunohistochemistry and ERCC1 polymorphism in ovarian cancer

The response of tumor cells to platinum-based chemotherapy involves DNA repair mechanisms. Excision repair cross-complementation group 1 (ercc1) is one of the leading genes involved in DNA repair, and several studies have linked ercc1 to platinum resistance in cell lines and in human cancers. A common single nucleotide polymorphism (SNP) of ercc1 at codon 118 has been proposed to impair ercc1 translation and reduce ERCC1 protein expression and consequently influence the response to platinum-based chemotherapy. The primary aim of the present study was to evaluate ERCC1 expression and ercc1 codon 118 polymorphism in epithelial ovarian cancer (EOC) and their possible predictive value in patients treated with platinum-based chemotherapy. Formalin-fixed, paraffin-embedded tissue sections from 159 patients with advanced EOC were used for immunohistochemistry. Ercc1 codon 118 SNP genotyping was performed by real-time polymerase chain reaction. ERCC1 protein overexpression was found in 37.7% of the tumors. The CA-125 response rate was 94.5% (52/55) in patients with ERCC1-negative tumors compared to 80% (36/45) in patients with ERCC1-positive tumors (P= 0.026, χ2). The T/T genotype (44%) signalized a better response to chemotherapy than C/C (15%) + C/T (41%) variants (P= 0.045, trend test). Patients with ERCC1-negative tumors appear to have significantly better response to platinum-based chemotherapy compared to patients with ERCC1-positive tumors, but the differences in response rates did not translate into differences in survival. In addition, the TT genotype seems to be favorable toward better response to platinum-based chemotherapy.

The safety and efficacy of bevacizumab therapy in recurrent ovarian carcinoma

16528 Background: To evaluate the safety and efficacy of bevacizumab alone or in combination therapy in heavily pretreated patients with ovarian cancer. Methods: We identified patients not participating in an ongoing clinical trial who received bevacizumab. Response was retrospectively assessed by CA125 criteria. Complete response (CR) was defined as normalization of serum levels to ≤ 35 U/mL. Partial response (PR) was defined as a ≥50% decrease after initiation of treatment confirmed 28 days apart. Adverse events were prospectively categorized using the common terminology criteria version 3.0. Progression-free and overall survival (PFS and OS) was estimated using Kaplan-Meier method with log-rank test where indicated. Results: Forty-nine patients were identified. The patients were pretreated with a median of 6 (range 1–15) prior chemotherapy regimens including a median of 2 (range 1–6) platinum based regimens. Twenty-two (45%) patients received bevacizumab alone and 27 (55%) received varied combination cytotoxic chemotherapy. Patients received bevacizumab therapy for a median 4.6 months (range 0–27 months). Twenty-two (45%) patients received 10 mg/kg every 2 weeks, while 16 (33%) patients received 15 mg/kg every 3 weeks. Eleven (22%) received both dosing schedules. CTC grade 3 and 4 toxicities occurred in 7 (14.3%) different patients. Toxicities included: 2 (4%) gastrointestinal (GI) perforation, 3 (6%) grade 3 HTN, 1 (2%) transient ischemic attack, and 1 (2%) subarachnoid hemorrhage, Thirty-four patients were evaluable for overall CA-125 response rate (ORR), which included both CR and PR. The ORR for this cohort was 47.1%. The ORR for those who received bevacizumab alone was 30% compared to 65% for those treated with bevacizumab in combination with cytotoxic chemotherapy (P = 0.04). The median PFS for the entire group was 4.6 months (95% CI: 1.1, 8.2 months). The median OS was 11.0 months (95% CI: 3.9, 18.0 months). Conclusions: Bevacizumab alone or in combination therapy is well tolerated and demonstrates activity in heavily pretreated patients with recurrent ovarian cancer. The GI perforation rate in our study is similar to previously reported. Further study of bev alone or in combination therapy is warranted. No significant financial relationships to disclose.

Weekly cisplatin with oral etoposide: a well-tolerated and highly effective regimen in relapsed ovarian cancer

The optimal treatment of progressive ovarian cancer after first-line platinum-based therapy remains a challenge. We collected prospectively data on patients with relapsed or progressive ovarian cancer treated with weekly cisplatin and oral etoposide in our institution to evaluate the feasibility, efficacy, and toxicity of this regimen. Patients (n = 34) had stage IIIC/IV ovarian cancer, which was recurrent or progressive following previous treatment with carboplatin and a taxane. Cisplatin (50 mg/m(2)) was given days 1, 8, 15, 29, 36, and 43, with oral etoposide (50 mg daily) on days 1-15 and 29-43. Responders and those with stable disease then received oral etoposide (50 mg daily for 21 days of a 28-day cycle) until disease progression. The overall CA125 response rate was 88%. The overall radiological response rate was 57%: 78% in the platinum-sensitive group, 50% in the intermediate-sensitive group, and 46% in the platinum-resistant group. Treatment was well tolerated. Median survival in the overall group was 14 months: in the platinum-sensitive group 16.5 months, in the intermediate-sensitive group 11 months, and 10.5 months in the platinum-resistant group. We conclude that weekly cisplatin/etoposide, followed by maintenance oral etoposide, is an active and well-tolerated regimen in relapsed or progressive ovarian cancer, even in platinum-resistant patients.