Editores da série MOC: Antonio Carlos Buzaid - Fernando Cotait Maluf - Carlos H. Barrios

Editor-convidado: Caio Max S. Rocha Lima

ASCO 2014

[ASCO 2014] Câncer Ginecológico

Apoio:

astellas_marca-onco_150x60     Roche_azul_80x45

A equipe do MOC selecionou os abstracts de maior impacto da ASCO 2014. Veja abaixo os destaques em Câncer de ginecológico:

Câncer de Ovário

Câncer de Útero

Câncer de Colo do Útero

 

Câncer de Ovário

A phase 3 randomized double-blind trial of maintenance with niraparib versus placebo in patients with platinum-sensitive ovarian cancer (ENGOT-OV16/NOVA trial)

Abstract No: TPS5625
Author(s): Ursula Matulonis, Sven Mahner, Robert Michael Wenham, et al.
The ENGOT-OV16/NOVA study is a double-blind, 2:1 randomized, placebo controlled international ph III study of oral niraparib versus placebo in patients (pts) with platinum (plat) sensitive recurrent OvCa. Primary objective is to evaluate efficacy of niraparib as maintenance therapy in pts who have plat sensitive OvCa as assessed by the prolongation of progression free survival (PFS). PFS will be independently evaluated in a cohort of gBRCAmut pts and in pts who have HGSC histology and are nongBRCAmut. As of 04 February 2014, 37 pts have been enrolled and randomized in the study. The trial will be open at >100 sites in 15 countries in collaboration with ENGOT (NSGO, AGO, NCRI, GEICO, BGOG, GINECO, MaNGO, AGO Austria, MITO).

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A phase II randomized open-label study of MM-121, a fully human monoclonal antibody targeting ErbB3, in combination with weekly paclitaxel versus weekly paclitaxel in patients with platinum-resistant/refractory ovarian cancers

Abstract No: 5519
Author(s): Joyce Liu, Isabelle Laure Ray-Coquard, et al.
This was a global, open-label, randomized Phase II study of MM-121 in patients with platinum resistant ovarian cancer. Patients were randomized (Ratio 2:1) to receive MM-121 plus paclitaxel (M+P) or paclitaxel alone (P). The primary objective was to compare progression-free survival (PFS) between the groups. Pretreatment fresh biopsies obtained from all patients were analyzed to assess a pre-specified set of mechanistically-linked biomarkers (BM): heregulin (HRG), betacellulin, EGFR, ErbB2, and ErbB3. Results: 223 patients (140 (M+P), 83 (P)) were included in the efficacy analyses. Baseline demographics and disease characteristics were balanced. Most patients (80.3%) had received 2 or more prior platinum-based regimens. Median PFS was analyzed after 171 events (115 (M+P), 56 (P)) and was 3.75 months (M+P) and 3.68 months (P) with a stratified hazard ratio (HR) of 1.027 [95% CI 0.741 – 1.425]. Conclusions: A signal of benefit was observed in a biomarker positive subpopulation, althoughthe study regimen was not effective at prolonging PFS in the overall study population.

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A randomized phase 2 trial comparing efficacy of the combination of the PARP inhibitor olaparib and the antiangiogenic cediranib against olaparib alone in recurrent platinum-sensitive ovarian cancer

Abstract No: LBA5500
Author(s): Joyce Liu, William Thomas Barry, Michael J. Birrer, et al.
The full, final text of this abstract will be posted online at 7:30 AM (EDT) on Saturday, May 31.

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Comparison of treatment invasiveness between upfront debulking surgery versus interval debulking surgery following neoadjuvant chemotherapy for stage III/IV ovarian, tubal, and peritoneal cancers in phase III randomized trial: JCOG0602

Abstract No: 5508
Author(s): TAKASHI ONDA, Hiroyuki Yoshikawa, Taro Shibata, et al.
Background: We conducted a phase III trial comparing upfront primary debulking surgery (PDS) and NAC for stage III/IV ovarian, tubal and peritoneal cancers (JCOG0602). Two preceding studies, EORTC55971 and CHORUS, successfully demonstrated non-inferior survival of patients treated with NAC. However, invasiveness of treatment (Tx) has not yet fully been analyzed. To prove efficacy of NAC compared to standard Tx, it is necessary to demonstrate apparently reduced invasiveness of Tx. Conclusions: Tx with NAC is less invasive than standard Tx. When non-inferior survival will be confirmed in this trial and new staging system is established, Tx with NAC can become a new standard Tx for advanced ovarian cancer.

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A phase III trial of adjuvant chemotherapy following chemoradiation as primary treatment for locally advanced cervical cancer compared to chemoradiation alone: Outback (ANZGOG0902/GOG0274/RTOG1174)

Abstract No: TPS5632
Author(s): Linda R. Mileshkin, Kailash Narayan, Kathleen N. Moore, et al.OUTBACK is a randomised phase III Gynecologic Cancer InterGroup (GCIG) trial designed and led by the Australia New Zealand Gynaecological Oncology Group (ANZGOG) in collaboration with the NHMRC Clinical Trials Centre. OUTBACK is suitable for women with locally advanced cervical cancer (FIGO stage IB1 & node positive, IB2, II, IIIB or IVA). The primary objective is to determine if the addition of adjuvant chemotherapy to standard cisplatin-based chemo-radiation improves OS. Women are randomized to either (A) standard cisplatin-based chemo-radiation or (B) standard cisplatin-based chemo-radiation followed by 4 cycles of carboplatin and paclitaxel chemotherapy. The IDMC last reviewed the trial in September 2013 and recommended that the trial continue as planned.

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Current practice and use of neoadjuvant therapy in ovarian cancer in the National Cancer Database

Abstract No: 5586
Author(s): Angela Jain, Elizabeth Handorf; et al.
We identified women with advanced stage OC diagnosed between 1998 and 2011 and treated with chemotherapy and surgery using the NCDB. Using Chi-squared tests and multivariate logistic regression, we analyzed rates of NAC by age, facility type, race, payor status, income, location, Charlson score, year of diagnosis and facility location. Due to data availability, survival analysis was restricted to patients diagnosed between 2003 and 2005. We used Kaplan-Meier curves and proportional hazards regression to assess overall survival in patients treated with neoadjuvant vs adjuvant chemotherapy. Conclusions: The use of neo-adjuvant chemotherapy in OC has increased over time. Although we found significantly lower survival among patients given neoadjuvant therapy, this result is limited by potential selection bias. We found that patients treated with neoadjuvant therapy also had risk factors such as increased co-morbidities, coverage by Medicaid, and older age.

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ICON8: An international randomized trial comparing two dose-dense regimens, 3-weekly carboplatin plus weekly paclitaxel (CwT), and weekly carboplatin-paclitaxel (wCwT), to standard 3-weekly treatment in women with newly diagnosed ovarian, fallopian tube, and primary peritoneal cancer

Abstract No: TPS5611
Author(s): Jane Hook, Sally Patricia Stenning, James Brenton, et al.
ICON8 (NCT01654146) is a Gynecologic Cancer Intergroup, 3-stage phase III trial open at 111 centres. ICON8 is the first trial designed to permit variation in timing of surgery; randomization is stratified by IPS/DPS. Pts are randomized (1:1:1) to receive 6 21-d cycles of (1) carboplatin AUC5 + paclitaxel 175mg/m2 q3w, (2) carboplatin AUC5 q3w + paclitaxel 80mg/m2 q1w or (3) carboplatin AUC2 + paclitaxel 80mg/m2 q1w. Stage 1 (safety and feasibility) is complete (Hook, 18th ESGO Meeting 2013). The IDMC reviewed stage 2 (activity) in January 2014 and recommended that recruitment continue to all arms. Stage 3 (efficacy) is powered for dual primary outcome measures: progression free and overall survival. Secondary outcomes are toxicity, quality of life and cost effectiveness. 1,000 of 1,485 women have been recruited. Accrual is expected to complete in Q4 2014. Collection of tumor tissue, germline DNA and serial plasma is ongoing in parallel (TRICON8) with 90% pts participating. ICON8B, an extension in high risk pts comparing CwT with or without bevacizumab and CT + bevacizumab is planned.

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Independent radiologic review of AURELIA, a phase 3 trial of bevacizumab (BV) plus chemotherapy (CT) for platinum (PT)-resistant recurrent ovarian cancer (OC)

Abstract No: 5540^
Author(s): Amreen Husain, Yan V. Wang, Rikke Frederiksen, David T. Bollag, et al.
Background: AURELIA is a phase 3, randomized, open-label trial in patients (pts) with PT-resistant, recurrent OC (NCT00976911). Based on investigator (INV) assessment of radiographic data, CT + BV showed significant improvement vs CT alone in the primary end point of progression-free survival (PFS) (Pujade-Lauraine, JCO in press). Median PFS was 3.4 months for CT vs 6.8 months for CT + BV (stratified hazard ratio [HR], 0.38; 95% confidence interval [CI], 0.30–0.49; P<.001). As this was an open-label trial, an independent review committee (IRC) assessment of radiologic data was conducted retrospectively to confirm these results. Methods: Radiologic images were provided to the IRC for 92.2% of randomized pts; 82.5% of pts were IRC-evaluable. Data were reviewed in a blinded manner according to a prespecified charter following modified RECIST v.1.0. PFS analysis was based on the intent-to-treat population. Conclusions: The PFS analysis results from the IRC assessment were consistent with those from the primary INV-led PFS analysis, despite a trend for INV assessment of PD at a later date in the CT + BV arm in this trial. The results provided further evidence that INV-determined PFS based on RECIST is reliable and reproducible in OC clinical trials.

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Independent review of AGO-OVAR 12, a GCIG/ENGOT-Intergroup phase III trial of nintedanib (N) in first-line therapy for ovarian cancer (OC)

Abstract No: 5556^
Author(s): Gunnar Kristensen, Philipp Harter, Olivier Trédan, et al.
Background: N is an oral inhibitor of VEGFR, PDGFR, and FGFR. As reported earlier, in the AGO-OVAR12 trial, N compared to placebo (Pl), added to standard chemotherapy, significantly prolonged investigator (inv)-determined PFS (1° endpoint [EP]) in first-line OC. Here we report independent review committee (IRC)-determined PFS. Methods: IRC-PFS was predefined as sensitivity analysis to the 1° EP (database lock triggered by inv-PFS events). IRC-PFS was analyzed in the intent-to-treat population (n=1366), based on RECIST 1.1 and restrictive predefined clinical (clin) criteria. Debulking surgery details were provided to the IRC radiologist to support assessment of baseline (BL) tumor burden, and additional clin data to the IRC oncologist for a final integrative review. Results: Adherence to prescheduled imaging within 4 weeks of the prescribed date was high (>75%); independent review was completed for 94% of patients (pts). The IRC identified 4.3% of pts without tumor lesions at BL compared to 31.5% in on-site imaging; and 50.7% were stratified as free of residual tumor (integrating also surgery information) at randomization. Event concordance between IRC- and inv-PFS was very high (85.8%). Low discordance overall was primarily due to 19.5% (N) and 16.5% (Pl) of inv-determined PFS events (n=752 events) not detected by IRC, IRC detected an event in 9.2% (N) and 8.5% (Pl) of patients without inv-determined event (IRC total n=668 events). Concordance for event date was high, 75% of dates differed by <4 weeks. IRC-PFS was similar to inv-PFS (IRC: HR 0.86 [0.74-1.01], mPFS N=19.5 mo vs Pl=16.8 mo; inv: HR 0.84 [0.72-0.98], mPFS N=17.2 mo vs Pl=16.6 mo). Outcome of post hoc defined subgroup analysis (risk groups by stage and tumor burden) were also similar (‘low-risk’, IRC: HR 0.77 [0.62-0.96], mPFS N=27.8 mo vs Pl=21.9 mo; inv: HR 0.74 [0.61-0.91], mPFS N=27.1 mo vs Pl=20.8 mo). Conclusions: IRC-PFS (sensitivity analysis of 1° was highly concordant with inv-PFS regarding PFS events, event dates, and overall outcome. Consistency of BL tumor assessment by the IRC, site-radiologists and clinical inv was low, possibly affecting individual PFS assessment but not overall HR.

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MITO-11: A randomized multicenter phase II trial testing the addition of pazopanib to weekly paclitaxel in platinum-resistant or -refractory advanced ovarian cancer (AOC)

Abstract No: 5503^
Author(s): Sandro Pignata, Domenica Lorusso, Giovanni Scambia,et al.Background: few drugs are available for patients (pts) with platinum resistant or refractory AOC; their efficacy is scanty. Evidence on antiangiogenic drugs efficacy in AOC is increasing. Pazopanib is an oral multi-kinase inhibitor of VEGFR-1, -2, -3, PDGFR-α and -β and c-Kit with antiangiogenic properties. Conclusions: The addition of pazopanib to wP in the treatment of pts with platinum-resistant or refractory advanced ovarian cancer might produce a significant prolongation of PFS and OS. A phase 3 trial is strongly supported.

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PENELOPE/AGO-OVAR 2.20: A double-blind placebo (PLA)-controlled randomized phase III ENGOT trial evaluating chemotherapy (CT) with or without pertuzumab (P) for platinum-resistant ovarian cancer

Abstract No: TPS5613
Author(s): Christian Kurzeder, Jose Maria Del Campo, Patricia Pautier, et al.
Recruitment to each CT cohort is capped at 1/3 of the total sample size. Primary PFS analysis will be done after 109 IRC-assessed PFS events, providing 95% power to detect a PFS hazard ratio (HR) of 0.50 (median PFS 1.4→2.8 mo) with 2-sided log-rank at α=0.05. Final OS analysis is planned after 129 deaths in Part 2, providing 80% power to detect an OS HR of 0.61 (median OS 8.4→13.8 mo); 2-sided log-rank at α=0.05. By 27 Jan 2014, 62 pts were randomized.

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Pertuzumab (P) plus chemotherapy (CT) for platinum-resistant ovarian cancer: Safety run-in results of the PENELOPE trial

Abstract No: 5552
Author(s): Antonio Gonzalez-Martin, Patricia Pautier, Sven Mahner, et al.
Background: In platinum-resistant ovarian cancer, the monoclonal antibody P, which inhibits HER2 heterodimerization, improved PFS when added to gemcitabine in the subgroup of pts with low tumor HER3 mRNA expression [Makhija, 2010]. The 2-part PENELOPE trial (NCT01684878) is prospectively investigating P added to single-agent CT in this population. Results: InPart 1, 50 pts were enrolled and treated between Oct 2012 and Jul 2013. At data cut-off (Aug 27, 2013), 8 TOP and 17 PAC pts remained on treatment. Conclusions: Both regimens were tolerable. Based on these results, the IDMC had no objection to the trial proceeding to Part 2 (double-blind randomized comparison of CT [TOP, PAC, or gemcitabine] + P or placebo).

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Phase II trial of oxaliplatin and 5-FU in patients (pts) with platinum-resistant recurrent (PRR) ovarian carcinoma (OVCA)

Abstract No: 5580
Author(s): Joseph N. Kerger, Fabienne Lebrun, Thierry Gil, et al. Conclusions: In this heavily pretreated patient population with PRR OVCA, this modified FOLFOX6 regimen exhibited a promising activity with an expected, but acceptable safety profile and might deserve further exploration, maybe in combination with biological or targeted agents.

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Primary versus interval debulking surgery and the risk to induce platinum resitance

Abstract No: 5588
Author(s): Alexandre Andre Balieiro Anastacio da Costa, Camila Vieira Valadares, Augusto Saito, et al.
We did a retroscpective review of medical records from 213 patients with stage IIIC and IV ovarian carcinoma treated at a single institution from 2000 to 2013. We analysed the association of baseline clinical and pathological characteristics with time to first platinum resistant relapse (TTPR), platinum resitant disease at first relapse, defined as a platinum free interval (PFI) after first line chemotherapy less than 6 months, and overall response rate (ORR) to chemotherapy at first platinum sensitive relapse. Conclusions: IDS may be associated to a greater risk of platinum resistance induction. Some of the bias in choosing PDS or IDS may not have been accounted in this analysis due to its the retrospective nature, but it supports the hypotesis of other papers and suggests that it would be interesting to see this analysis done in patients from PDS vs IDS clincal trials already published.

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Randomized phase III trial of paclitaxel/carboplatin (PC) versus cisplatin/irinotecan (CPT-P) as first-line chemotherapy in patients with clear cell carcinoma (CCC) of the ovary: A Japanese Gynecologic Oncology Group (JGOG)/GCIG study

Abstract No: 5507
Author(s): Aikou Okamoto, Toru Sugiyama, Tetsutaro Hamano, et al.
Patients (pts) with Stage I-IV CCC were randomized to receive paclitaxel 175mg/m2 plus carboplatin AUC6 IV q3wk or irinotecan 60mg/m2 IV (days 1, 8, 15) plus cisplatin 60mg/m2 IV (day 1) q4wk for 6 cycles. International central pathologic review was performed for all cases. The primary endpoint was progression-free survival (PFS). Secondary endpoints were overall survival (OS), response rate per RECIST, and adverse events. Adverse events were graded according to NCI-CTCAE, version 3.0. Conclusions: In this first CCC-specific international clinical trial, survival benefit was not observed by CPT-P. Since both regimens were well tolerated and the toxicity profiles were different, CPT-P can be an alternative regimen for CCC.

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SOLO1 and SOLO2: Randomized phase III trials of olaparib in patients (pts) with ovarian cancer and a BRCA1/2 mutation (BRCAm)

Abstract No: TPS5616
Author(s): Kathleen N. Moore, Paul DiSilvestro, Elizabeth S. Lowe, et al.
SOLO1 and SOLO2 are double-blind multicenter studies in which pts are being randomized (2:1) to receive olaparib (300 mg [2 x 150 mg tablets] bid) or placebo. Both trials are recruiting pts with high-grade serous or endometrioid ovarian cancer, including primary peritoneal and/or fallopian tube cancer, who have a known deleterious (or suspected deleterious) BRCAm and who are in complete or partial response following the completion of platinum-based chemotherapy. To be eligible for SOLO1, pts must have newly diagnosed, advanced (FIGO stage III–IV) disease and have responded to first-line platinum therapy, whereas pts in SOLO2 must have completed ≥2 lines of platinum therapy. All eligible pts will have a BRCAm and will undergo germline BRCA testing (Myriad Integrated BRACAnalysis) as part of the trials. For both trials, the primary objective is PFS by blinded independent central review using RECIST v1.1. Radiologic scans will be performed at baseline and every 12 weeks for 120 (SOLO1) or 72 (SOLO2) weeks, and every 24 weeks thereafter. Blinded treatment will continue until objective disease progression. Primary analyses will be performed at ≈60% maturity using log-rank tests. Other objectives for both trials include: overall survival; time to earliest progression (RECIST or CA-125); time from randomization to second progression (PFS2); HRQoL; tolerability. Enrollment began in Sep 2013. As of Jan 2014, both trials have recruited approximately 10% of the target patient population. Target recruitment: SOLO1, n≈344 randomized pts (≈110 sites worldwide); SOLO2, n≈264 randomized pts (≈80 sites worldwide).

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Temsirolimus in women with platinum-resistant ovarian cancer or advanced/recurrent endometrial cancer: A multicenter phase II trial of the AGO Study Group (AGO-GYN 8)

Abstract No: 5565
Author(s): Guenter Emons, Christian Kurzeder, Barbara Schmalfeldt, et al. Patients (pts) with platinum and taxane resistant OC (n = 22) or with advanced/recurrent EC, who had not received previous chemotherapy (n = 22) were treated with weekly IV infusions of T (25 mg). Primary endpoint was progression free survival after 4 months (OC) or 6 months (EC). A two stage design was used with second stage of accrual if < 10 of the first 22 pts (OC) or < 7 of the first 22 pts (EC) had progressive disease after the first 8 weeks of T-treatment. Conclusions: T-treatment was well tolerated in our patients. It did, however, not meet the predefined efficacy criteria with 10 of 22 pts (OC) and 7 of 22 pts (EC) having progressive disease after 8 weeks of treatment.

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Trabectedin plus pegylated liposomal doxorubicin (PLD) prior to subsequent platinum chemotherapy in patients with platinum-resistant (PR) recurrent ovarian cancer (ROC): Results from OVA-301 follow-up

Abstract No: 5551
Author(s): Nicoletta Colombo, Antonio Casado, Consuelo Fernandez, et al.
Background: OVA-301, a randomized phase III study of trabectedin plus PLD (n=337) vs. PLD alone (n=335) in patients with ROC demonstrated a statistically longer progression-free survival (PFS) in the combination arm (median PFS: 7.3 vs. 5.8 months; HR: 0.79; p=0.0190) (Monk, JCO 2010). However, among PR patients PFS (4.0 vs. 3.7 months) and overall survival (OS; 14.2 vs. 12.4 months) were not statistically different (Monk, EJC 2013). Based on in vitro (D’Incalci, AACR 2013) and clinical (Casado, ASCO 2013) data, trabectedin may lead to an increased sensitivity to subsequent platinum even in PR patients. Methods: An exploratory analysis of OS, counted from the administration of trabectedin/PLD or PLD until death, was performed in PR patients retreated with third-line platinum after OVA-301. Results: Overall, 59 PR patients with a median age of 55 years (range 26-79) were analyzed. Similar proportions of patients in each arm received subsequent platinum (trabectedin/PLD: 27/115, 23.5%; PLD: 32/117, 27.4%). Both in trabectedin/PLD (55.6%) and PLD (68.8%) arm most had serous-papillary histology and a median progression-free interval of 4.5 (range 0.7-6) and 4.2 (range 1.1-5.9) months, respectively. A median of 6 trabectedin/PLD cycles (range 1-20) and 5 PLD cycles (range 1-9) was given. Trabectedin/PLD resulted in a 42% risk reduction of disease progression or death compared with PLD (median PFS: 5.6 vs. 5.0; p=0.062). Patients with PR ROC treated with trabectedin/PLD, followed by the subsequent reintroduction of platinum achieved a 38% decrease in the risk of death compared with PLD (median OS: 22.2 vs. 15.50; p=0.078). Besides, patients pretreated with trabectedin/PLD who received a platinum salt had a 7.8-months longer median OS than those retreated with a non-platinum regimen (median OS: 22.2 vs. 14.4; p=0.055). Conclusions: Our results hypothesize that the intercalation with trabectedin/PLD prior to subsequent platinum retreatment may contribute to prolong PFS with apparent sensitization of the PR patients to allow further platinum retreatment which could ultimately lead to longer survival.

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Weekly administration of bevacizumab, eribulin, and oxalilplatin in patients with platinum-resistant and refractory ovarian carcinomas: A phase II study

Abstract No: 5566
Author(s): Yuji Ikeda, Masashi Takano, Hiroko Kouta, et al.
Background: Eribulin, inhibiting a protein component of tubulin, is a candidate for paclitaxel-refractory breast cancers, and Bevacizumab (B) is known to enhance efficacy of anti-cancer agents in ovarian cancers. A phase II study to evaluate weekly administration of B with eribulin and oxaliplatin (EriOX) in patients with platinum-resistant and refractory ovarian carcinomas (PR-ROC) was performed. Methods: Simon’s two-stage design was used. In the first stage, 15 patients were accrued. If there were no responder in these patients, the study would be stopped. Otherwise, eight additional patients will be accrued for a total of 23. If three or more responder were observed in 23 patients, this design yields a type I error rate of 0.03 and power of 0.80 when the true response rate were 18%. Patients with PR-ROC were treated with weekly-B-EriOX consisting of B (2mg/kg), eribulin (1mg/m2) and oxaliplatin (30mg/m2). Conclusions: Weekly B and EriOX administration had significant activity with mild AE in patients with PR-ROC. These results warrant further prospective study.

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Câncer de Útero

A phase III trial of postoperative chemotherapy or no further treatment for patients with node-negative stage I-II intermediate- or high-risk endometrial cancer. ENGOT-EN2-DGCG/EORTC 55102

Abstract No: TPS5628
Author(s): Mansoor Raza Mirza, Caroline Lundgren, Frederic Kridelka, et al.
This multicenter, open-label, 1:1 randomized, phase 3 investigator-initiated study is evaluating postoperative chemotherapy compared with no further treatment in patients with medium- or high-risk, node negative stage I, or stage II endometrial cancer (stage 1: grade 3 endometrioid or any type 2 histology; stage 2: all patients). Patients have undergone hysterectomy and bilateral salpingo-oopherectomy and pelvic lymphadenectomy (minimum 12 pelvic nodes. Para-aortic LNE is optional). Adjuvant brachytherapy is permitted in both arms, though external beam radiotherapy is not allowed. Primary endpoint is overall survival, and secondary endpoints include disease specific survival, progression-free survival, rates of isolated pelvic, distant and mix relapses, quality of life, compliance and toxicity. Carboplatin (AUC5) and paclitaxel (175mg/m2) is given iv every 3 weeks, total 6 courses. This trial will enrol 678 patients. This trial is enrolling patients. Interested institutions are welcome to join the study.

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Phase II study of XL184 (cabozantinib) in recurrent or metastatic endometrial cancer: A trial of the PMH, Chicago, and California Phase II Consortia

Abstract No: TPS5629
Author(s): Michelle Wilson, Neesha C. Dhani, Hal W. Hirte, et al.
This phase II, multicenter single arm trial has a planned enrollment of 36 pts utilizing a Simon 2-stage design to evaluate co-primary endpoints of response rate and 12 week progression-free-survival (PFS) in pts with serous, endometrioid or mixed histology EC (experimental cohort). Eligible pts must have radiographic progression after 1 line of chemotherapy for metastatic disease, or progression within 12 months of adjuvant chemotherapy; prior radio- and hormonal therapy is allowed. Stage I has a planned accrual of 18 pts, study will proceed to stage II with observation of > 2 partial responses (PR) and > 6 12-wk PFS. Pts are also accrued to an exploratory cohort (maximum 30 pts) of rare histology EC (clear cell, carcinosarcoma). XL-184 is administered at a starting dose of 60mg orally once daily on a continuous 28 day cycle. Adverse event (AE) reporting is as per CTCAE v4.0. Pts undergo first CT evaluation after 1 cycle, those with SD or PD and ≤ grade 1 toxicity are eligible for dose escalation. Response assessment is completed every 2 cycles (starting with cycle 3) and per RECIST 1.1. Correlative studies will explore associations between tumour response and baseline mutational and met amplification status. To date 14 (experimental) and 6 (exploratory) pts have been enrolled. Median age is 64 (range 51-80). All pts have received chemotherapy and 70% prior radiation. 44 cycles have been completed (median 2 range 1-5). Once the final pts have been accrued to the experimental arm, a decision to proceed to stage II will be made.

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Phase II trial of GDC-0980 (dual PI3K/mTOR inhibitor) in patients with advanced endometrial carcinoma: Final study results

Abstract No: 5513
Author(s): Vicky Makker, Fernando O. Recio, Ling Ma, et al.
Patients with recurrent or persistent EC treated with 1 or 2 prior lines of chemotherapy but no prior PI3K/mTOR inhibitor received oral GDC-0980 40 mg daily on a 28-day cycle until progression or intolerable toxicity. Type I/II diabetics requiring insulin were excluded. The primary endpoints were progression-free survival (PFS) at 6 months and objective response rate (ORR). Archival tissue samples were collected for PI3K pathway biomarker analysis. Results: A total of 56 women were enrolled including 13 (23%) with well-controlled diabetes at study entry. Discontinuation reasons were disease progression, 24 (43%); adverse events, 13 (23%); withdrawal by subject, 12 (21%). Frequency of Grade 3/4 related adverse events in all patients were hyperglycemia (46%), rash (30%), colitis (5%), and pneumonitis (4%). At 6 months, 20% of patients were progression free (K-M estimate 95% CI: 7%-33%). ORR was 9% (unconfirmed). Median PFS was 3.5 months (95% CI: 2.7-3.7 months). Median time on study was 69 (12-226) days for non-diabetic and 27(4-84) days for diabetic patients. Discontinuation prior to first tumor assessment occurred in 19 patients, with 8/13 diabetics discontinued prior to Cycle 2, due to hyperglycemia. Dose reductions were required for 4 (31%) diabetics and 18 (42%) non-diabetics. Evaluable archival tumor samples were obtained from 44 (85%) patients, and 52% of patients had at least one alteration in PIK3CA, PTEN or AKT1. All 3 patients with a confirmed response had at least one alteration in a PI3K pathway gene. Conclusions: Evaluation of the anti-tumor activity of 40mg GDC-0980 daily was limited by tolerability, especially in diabetic patients. The trial provides data about the PI3K pathway mutation frequency in patients with recurrent EC and suggests that patients with a PI3K pathway mutation may have derived enhanced benefit from GDC-0980.

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Systemic chemotherapy compared with radiation therapy as adjuvant therapy after radical surgery in high-risk stage IB-IIB cervical adenocarcinomas

Abstract No: 5598
Author(s): Toshiyuki Seki, Hiroshi Tanabe, Chie Nagata, et al.
The medical records of the patients with IB-IIB cervical cancer who underwent primary surgery at our 4 institutes from January 2001 to December 2010 were retrospectively reviewed, and the patients with pathologically confirmed bulky tumor (≥4cm), nodal metastasis, and/or parametrium invasion were included. The patients were classified into 3 groups; group 1: patients with SCC who received RT/CCRT, group 2: patients with AC who received RT/CCRT, and group 3: patients with AC who received CT. At first, to determine the efficacy of RT/CCRT to AC patients compared to SCC patients, the progression-free survival (PFS) of group 1 and 2 was compared. Secondly, to investigate the efficacy of CT compared to RT/CCRT for AC patients, the PFS of group 2 and 3 was compared. Results: A total of 135 patients were enrolled (group 1: 90, 2: 23, and 3: 22). The median follow up period was 48 (range: 1-132) months. There was no statistical difference in the proportion of patients with nodal metastasis, parametrial involvement, and bulky tumor between each group. A significant difference in PFS curves was detected between group 1 and 2; AC patients treated with RT/CCRT had poorer prognosis than SCC patients treated with RT/CCRT (RR: 2.504 (95%CI: 1.284-8.871), p=0.014). A significant difference in PFS curves was also detected between group 2 and 3; AC patients had more favorable prognosis when treated with CT compared to RT/CCRT (RR: 0.288 (95%CI: 0.109-0.965), p=0.043). Conclusions: Adjuvant RT/CCRT may be less effective for AC patients, and CT has a potential benefit greater than that of RT/CCRT for AC patients.

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Câncer de Colo do Útero

Cisplatin with dose-dense paclitaxel before and after radical hysterectomy for locally advanced cervical cancer: Final results of a multicenter phase II study (Sankai Gynecology Study Group 013)

Abstract No: 5526
Author(s): Satoshi Yamaguchi, Kiyoshi Fujiwara, Shinya Sato, et al.
Patients with stage IB2, IIA2, or IIB cervical cancer received 3 cycles of cisplatin (75 mg/m2, day 1) with paclitaxel (80 mg/m2, days 1, 8, and 15) every 21 days, RH, and another 2 cycles of the same regimen. Primary endpoint was 2-year recurrence-free survival (RFS). Secondary endpoints were 2-year overall survival (OS), safety, response, and pathologic complete response (pCR), defined as no evidence of malignancy in all surgical specimens. Conclusions: Administering with ddTP before and after RH for locally advanced cervical cancer achieves good survival and is feasible, evidenced by the acceptable toxicity. Phase III studies should compare this with concurrent chemoradiation.

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