GCIG CA125 Criteria Research Articles

Pegylated liposomal doxorubicin and carboplatin versus paclitaxel and carboplatin as first-line treatment for Chinese patients with ovarian cancer: A multi-center, randomized, open-label trial.

5556 Background: Paclitaxel combined with carboplatin is a standard first-line chemotherapy regimen for ovarian cancer. This study was designed to evaluate the efficacy and safety of pegylated liposomal doxorubicin (PLD) plus carboplatin (CD) compared with paclitaxel plus carboplatin (CP) as first-line treatment for epithelial ovarian cancer (EOC). Methods: Patients with stage IC to IV EOC, fallopian tube cancer, or primary peritoneal cancer were eligible for enrolment in this open-label, randomized controlled trial at 20 centers in China. Patients were randomly assigned 1:1 to CD group (carboplatin area under the curve [AUC] 5 plus PLD 30 mg/m2) or CP group (carboplatin AUC 5 plus paclitaxel 175 mg/m2) every 3 weeks for 3-6 cycles. The primary end point was progression free survival (PFS); secondary end points were overall survival (OS), objective response rate (ORR), disease control rate (DCR) and safety. Results: Between March, 2019 to December, 2021, 395 patients were enrolled, of whom 391 patients were analyzed (195 assigned to CD, 196 to CP). Baseline characteristics were balanced between the two treatment groups. The median follow-up was 21.6 months for the CD group and 22.5 months for the CP group. There was no significant difference in PFS between the two arms (P=0.516); the median PFS was 28.1 months and 30.1 months in the CD and CP arms, respectively. OS data were immature at data cutoff, with a total of 26 deaths in the two treatment groups. In patients with at least one measurable lesion at baseline, ORR was 65.5% in the CD arm and 66.2% in the CP arm (P= 0.941); DCR was 74.1% and 73.8% in the CD and CP arms, respectively (P= 0.971). Among patients who were evaluable by GCIG CA125 criteria, CA125 response was obtained in 86.0% and 88.5% of patients in the CD and CP arms, respectively (P=0.560). More frequent grade 1 to 3 alopecia (32.1% vs 12.3%) and neurotoxicity (20.4% vs 0%) were observed in the CP arm; more hand-foot syndrome (grade 1 to 3, 10.8% vs 2.6%), and oral mucositis (grade 1-3, 12.8% vs 5.1%) in the CD arm. Conclusions: The efficacy of CD regimen is comparable to that of CP, with less alopecia and neurotoxicity. CD may be an alternative first-line treatment for EOC. However, survival data are not yet mature, and longer follow-up is needed. Clinical trial information: NCT03794778 .

Results of TRIO-15, a multicenter, open-label, phase II study of the efficacy and safety of ganitumab in patients with recurrent platinum-sensitive ovarian cancer

BackgroundIGF signaling has been implicated in the pathogenesis and progression of ovarian carcinoma (OC). Single agent activity and safety of ganitumab (AMG 479), a fully human monoclonal antibody against IGF1R that blocks binding of IGF1 and IGF2, were evaluated in patients with platinum-sensitive recurrent OC. MethodsPatients with CA125 progression (GCIG criteria) or measurable disease per RECIST following primary platinum-based therapy received 18 mg/kg of ganitumab q3w. The primary endpoint was objective response rate (ORR) assessed per RECIST 1.1 by an independent radiology review committee (IRC) and/or GCIG CA125 criteria. Secondary endpoints included clinical benefit rate (CBR), progression free survival (PFS) and overall survival (OS). Results61 pts. were accrued. Objective responses were seen in 5/61 patients (ORR 8.2%, 95% CI, 3.1–18.8) with 1 partial response (PR) by RECIST and 2 complete responses (CR) as well as 2 PR by CA125 criteria. CBR was 80.3% (95% CI, 67.8–89.0%). The median PFS according to RECIST by IRC was 2.1 months (95% CI, 2.0–3.1). The median PFS per RECIST IRC and/or CA125 was 2.0 months (95% CI, 1.8–2.2). The median OS was 21 months (95% CI, 19.5-NA). The most common overall adverse events were fatigue (36.1%) and hypertension (34.4%). Grade 1/2 hyperglycemia occurred in 30.4% of patients. Hypertension (11.5%) and hypersensitivity (8.2%) were the most frequent grade 3 adverse events. ConclusionsIGF1R inhibition with ganitumab was well-tolerated, however, our results do not support further study of ganitumab as a single agent in unselected OC patients.

Single-arm phase II trial of carboplatin and mirvetuximab soravtansine as neoadjuvant chemotherapy (NACT) for advanced- stage ovarian, fallopian tube or primary peritoneal cancer (EOC) who are folate receptor α positive (NCT04606914) (578)

Objectives: The primary objective is to assess the feasibility and safety of obtaining tissue, assessing alpha-folate receptor status, and initiating treatment based on this data using a 21-day schedule in the advanced-stage ovarian, fallopian tube, or peritoneal cancer patients, without an unacceptable interval debulking surgery (IDS) delay. Secondary objectives include assessing progression-free survival, percentage of disease-free survival at two years, ORR prior to IDS per iRECIST 1.1 and GCIG CA-125 criteria, and percentage of optimal cytoreduction and pathological complete response (pCR) at IDS. Methods: This is a phase II study design with carboplatin and mirvetuximab (FRa receptor monoclonal antibody.) Patients with biopsy-confirmed, newly diagnosed, advanced-stage serous epithelial ovarian cancer appropriate for NACT will have centralized tumor evaluation via immunohistochemistry for FRa receptor overexpression. IHC staining is 2+ in 75% of cells will define eligibility. Patients will receive NACT with one lead-in cycle of single-agent carboplatin AUC 5/6, physician’s choice), followed by AUC 5 carboplatin and Mirvetuximab 6mg/kg adjusted to ideal body weight every 21days for three cycles prior to interval cytoreductive surgery (iCRS.) Patients eligible for surgery will undergo an iCRS no sooner than three weeks but no later than six weeks following the completion of cycle 3. Postoperatively, patients will complete three additional cycles of carboplatin-mirvetuximab for a total of 6 intended cycles. A total of 70 patients will be included. Patients with BRCA mutations are not excluded from this trial and may receive standard of care maintenance therapy, including bevacizumab and/or PARP inhibitors per physician’s choice in the adjuvant setting. After completion of adjuvant treatment, participants will be assessed approximately every 12 weeks by radiologic imaging to monitor disease status using RECIST 1.1 criteria. Objectives: The primary objective is to assess the feasibility and safety of obtaining tissue, assessing alpha-folate receptor status, and initiating treatment based on this data using a 21-day schedule in the advanced-stage ovarian, fallopian tube, or peritoneal cancer patients, without an unacceptable interval debulking surgery (IDS) delay. Secondary objectives include assessing progression-free survival, percentage of disease-free survival at two years, ORR prior to IDS per iRECIST 1.1 and GCIG CA-125 criteria, and percentage of optimal cytoreduction and pathological complete response (pCR) at IDS. Methods: This is a phase II study design with carboplatin and mirvetuximab (FRa receptor monoclonal antibody.) Patients with biopsy-confirmed, newly diagnosed, advanced-stage serous epithelial ovarian cancer appropriate for NACT will have centralized tumor evaluation via immunohistochemistry for FRa receptor overexpression. IHC staining is 2+ in 75% of cells will define eligibility. Patients will receive NACT with one lead-in cycle of single-agent carboplatin AUC 5/6, physician’s choice), followed by AUC 5 carboplatin and Mirvetuximab 6mg/kg adjusted to ideal body weight every 21days for three cycles prior to interval cytoreductive surgery (iCRS.) Patients eligible for surgery will undergo an iCRS no sooner than three weeks but no later than six weeks following the completion of cycle 3. Postoperatively, patients will complete three additional cycles of carboplatin-mirvetuximab for a total of 6 intended cycles. A total of 70 patients will be included. Patients with BRCA mutations are not excluded from this trial and may receive standard of care maintenance therapy, including bevacizumab and/or PARP inhibitors per physician’s choice in the adjuvant setting. After completion of adjuvant treatment, participants will be assessed approximately every 12 weeks by radiologic imaging to monitor disease status using RECIST 1.1 criteria.

IGNITE: A phase II signal-seeking trial of adavosertib targeting recurrent high-grade, serous ovarian cancer with cyclin E1 overexpression with and without gene amplification.

5515 Background: Cyclin E1 gene amplification and protein over-expression is a marker of platinum resistance in high grade serous ovarian, fallopian tube or primary peritoneal cancer (HGSC), and may predict response to WEE1 inhibition. Adavosertib, a WEE1 inhibitor, has demonstrated activity in unselected women with recurrent ovarian and serous endometrial cancer. We aimed to evaluate the efficacy of adavosertib in women with recurrent platinum resistant HGSC with cyclin E1 over-expression, with and without gene amplification. Methods: IGNITE is a multicentre, phase 2 trial with 2 cohorts of women with recurrent platinum resistant HGSC. Tumors were assessed for cyclin E1 protein expression by IHC and CCNE1 copy number by FISH. Patients were assigned to Cohort 1 if tumors were cyclin E1 over-expressed (H-score>50) and amplified (≥8 copies), and Cohort 2 if tumors were overexpressed and nonamplified. Patients with evaluable disease by RECIST v1.1 or GCIG CA-125 criteria were included. Adavosertib 300mg PO was given daily on days 1-5 and 8-12 of a 21-day cycle. The primary endpoint was investigator assessed clinical benefit (CB) defined as absence of progression for ≥ 18 weeks. Here we present the 18-week response data for the first 32 patients treated from Cohort 2, with a data cut-off of August 2021. Results: Between Jan-2020 and May-2021, 32 patients were accrued to Cohort 2. Median age was 62 years (range 42-77) and 84% had received ≥2 prior lines of chemotherapy. Median cyclin E1 IHC H-score was 120 and 28 patients (88%) had measurable disease by RECIST. Median number of cycles commenced was 8 (range 1-19). Overall response rate (ORR) was 53% and CB rate was 61% for all evaluable patients. Seventeen patients (53%) required a dose reduction, most commonly for neutropenia or fatigue. Seventeen patients experienced ≥Grade 3 treatment related adverse event, and 4 patients (15%) discontinued due to toxicity. Conclusions: The efficacy results in a biomarker-selected cohort of patients are promising with a higher response rate than reported in previous studies of adavosertib in unselected women with recurrent HGSC. Duration of response and progression free survival data will be presented as data matures. Clinical trial information: ACTRN12619001185156P. [Table: see text]

Abstract GMM-048: CTDNA RESPONSE TO THE PARP INHIBITOR RUCAPARIB PREDICTS PROGRESSION-FREE SURVIVAL AND BEST OVERALL RESPONSE ON THE ARIEL2 TRIAL

Abstract BACKGROUND: High grade serous ovarian carcinoma (HGSOC) is characterized by ubiquitous TP53 mutation and has the highest genomic complexity of all epithelial neoplasms. Sensitivity to PARP inhibitor therapy is strongly associated with homologous recombination deficiency (HRD). Genomic biomarkers of HRD such as genome-wide loss of heterozygosity (LOH) scores predict HRD and response to rucaparib. We hypothesized that functional testing of response during PARP inhibitor treatment using changes in circulating tumour DNA (ctDNA) could improve prediction of patient outcome. We tested whether the change in ctDNA TP53 mutant allele fraction (MAF) after one cycle of rucaparib treatment was predictive of progression free survival (PFS) and response in patients from the phase 2 ARIEL2 trial in women with platinum-sensitive recurrent high grade ovarian cancer (NCT01891344). METHODS: We analyzed serial plasma samples (n = 636) from 142 HGSOC patients during screening, on day 1 of each treatment cycle, and at the end of rucaparib treatment. Targeted amplicon deep sequencing (TADS) of TP53 was performed on DNA extracted from plasma (median depth 6916×). Somatic TP53 mutation and loss of heterozygosity score (LOH) were available from archival and biopsy specimens. Statistical analyses were pre-specified and ctDNA analysis was carried out blinded to visit and response data. TP53 MAF changes after one cycle of treatment were compared with PFS and best overall response assessed by RECIST v1.1 and GCIG CA-125 criteria. Optimal cut points for ctDNA response were determined using a cross-validation analysis. In cases with >1 TP53 mutation, response assessment was performed using the mutation with highest MAF. RESULTS: We detected TP53 mutations in plasma from 134 patients; all cases were concordant between tumour and plasma except for one patient (present in plasma but not tumour). In 18 patients (13%), 2 or more TP53 mutations were detected in ctDNA. The median TP53 MAF prior to cycle 1 was 2.6% (IQR 0.3–8.6). Reduction of >70% of TP53 MAF in ctDNA between cycle 1 and 2 was significantly predictive of improved PFS (n = 97; HR = 0.53, 95% CI 0.34-0.85, p = 0.008, median 273 vs 158 days, sensitivity 76%, specificity 62%) and best overall response (n = 97; OR = 7.04, 95% CI 2.69–21.06, p < 0.001). Combining ctDNA and LOH scores did not improve prediction of response. CONCLUSIONS Response measured by >70% fall in TP53 ctDNA between pre-cycle 1 and pre-cycle 2 of rucaparib therapy was significantly associated with best overall response and improved PFS. Similar findings were observed in a retrospective study of recurrent HGSOC treated with standard of care chemotherapy. The pathological or genomic factors causing multiple TP53 mutations in ctDNA are unknown. The association between early fall in ctDNA and validated RECIST and CA-125 response markers provides strong evidence that ctDNA may have utility for detecting early response to targeted therapy. Further analyses in randomized studies should be performed to confirm that ctDNA response has strong predictive value. Citation Format: Anna Piskorz, David Robertson, Kevin K. Lin, James Morris, Elaina Mann, Amit Oza, Robert L. Coleman, David M. O'Malley, Michael Friedlander, Janiel M. Cragun, Ling Ma, Heidi Giordano, Iain A. McNeish, Elizabeth Swisher, James Wason, James D. Brenton. CTDNA RESPONSE TO THE PARP INHIBITOR RUCAPARIB PREDICTS PROGRESSION-FREE SURVIVAL AND BEST OVERALL RESPONSE ON THE ARIEL2 TRIAL [abstract]. In: Proceedings of the 12th Biennial Ovarian Cancer Research Symposium; Sep 13-15, 2018; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2019;25(22 Suppl):Abstract nr GMM-048.

993O - OCTOPUS: A randomised, multi-centre phase II umbrella trial of weekly paclitaxel+/- novel agents in platinum-resistant ovarian cancer: Vistusertib

BackgroundOCTOPUS, an NCRI investigator-initiated umbrella phase II trial, tests the addition of targeted agents to weekly paclitaxel (wP) in recurrent platinum-resistant/refractory ovarian cancer. The first agent tested is the dual mTORC1/mTORC2 inhibitor vistusertib (V). Preclinical studies support targeting PI3K/AKT/mTOR signalling. The combination of V and wP showed activity in ovarian high grade serous carcinoma (HGSC) in phase I. This is the first randomised trial of wP and dual mTORC1/2 inhibition in ovarian cancer. MethodsIn this double-blind trial, patients with platinum-resistant/refractory HGSC were randomised 1:1 to wP (80mg/m2 D1, D8, D15 of 28day cycle) + oral V (50mg BD) or placebo (P) (D1-3, D8-10, D15-17). The primary endpoint is progression-free survival (PFS) (RECIST v1.1/GCIG CA125 criteria) and response is a key secondary end-point. A mandatory pre-treatment biopsy (if technically feasible), archival tumour tissue and serial blood samples were collected. The study uses a 3-outcome approach: significance at 10% (1-sided) for PFS indicates activity, significance at 20% also requires evidence of an improvement in response. The study has 90% power to detect a hazard ratio (HR) of 0.67. Results140 patients were randomised; median age 63 (range: 36-86); 18% platinum-refractory; 54% had ≥3 prior therapy; 7% had prior taxane in previous 6 months (m); 66% had an image-guided biopsy at study entry. Median PFS was 4.5 vs 4.2m (HR 0.84; 80% CI 0.67 to 1.07; 1-sided p=0.18); median OS was 9.7 vs 11.1m (HR 1.21, 80% CI 0.91 to 1.60; p=0.80); RR (RECIST/GCIG CA125: CR+PR) was 53% vs 56% for wP+V vs wP+P respectively. Grade 3/4 adverse events were 24 vs 25%. There was significantly more gastro-oesophageal reflux (grd 1/2 10 v 0%), rash (grd 2/3 9 v 0%) and lymphopenia (grd 2/3/4 47 v 31%) on wP+V. Ongoing translational research exploring the influence of PI3K/mTOR signalling on platinum resistance and response to wP will be presented. ConclusionsThere was modest evidence of improvement in PFS with the addition of V, but this was not supported by response or OS. Translational research and subgroup analyses are ongoing. Clinical trial identificationISRCTN16426935. Legal entity responsible for the studyNHS Greater Glasgow and Clyde/University of Glasgow. FundingAstraZeneca. DisclosureS. Banerjee: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Honoraria (self), Advisory / Consultancy: Tesaro; Honoraria (self), Advisory / Consultancy: Clovis; Honoraria (self): Roche; Honoraria (self): Merck; Travel / Accommodation / Expenses: Nucana; Honoraria (self): Immunogen; Honoraria (self), Advisory / Consultancy: Seattle Genetics; Honoraria (self), Advisory / Consultancy: Gamamabs. A.R. Clamp: Honoraria (self), Research grant / Funding (institution), Travel / Accommodation / Expenses: AstraZeneca; Honoraria (self), Travel / Accommodation / Expenses: Clovis. J. krell: Honoraria (self), Advisory / Consultancy: AstraZeneca; Research grant / Funding (institution): Takeda. R.M. Glasspool: Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: AstraZeneca; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Tesaro; Honoraria (self), Advisory / Consultancy: Clovis; Honoraria (self), Advisory / Consultancy: Immunogen; Honoraria (self), Advisory / Consultancy: Sotio; Research grant / Funding (institution): Boehringer Ingelheim; Research grant / Funding (institution): Lilly/Ignyta; Travel / Accommodation / Expenses: Roche. C. Orbegoso: Full / Part-time employment: AstraZeneca. C. Gourley: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Honoraria (self), Advisory / Consultancy: Roche; Honoraria (self), Advisory / Consultancy: Clovis; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Tesaro; Honoraria (self), Advisory / Consultancy: Foundation One; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Nucana; Honoraria (self), Advisory / Consultancy: Chugai; Research grant / Funding (institution): Aprea; Research grant / Funding (institution): Novartis. U. Banerji: Honoraria (self), Advisory / Consultancy: Astellas; Honoraria (self), Advisory / Consultancy: Novartis; Honoraria (self), Advisory / Consultancy: Karas Therapeutics; Honoraria (self), Advisory / Consultancy: Novartis; Honoraria (self), Advisory / Consultancy: Astex; Honoraria (self), Advisory / Consultancy: Eli Lilly; Honoraria (self), Advisory / Consultancy: Phoenix ACT; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): ONX; Research grant / Funding (institution): BTG; Research grant / Funding (institution): Chugai; Research grant / Funding (institution): Verastem. C. Shepherd: Full / Part-time employment: AstraZeneca. W. Brugger: Full / Part-time employment: AstraZeneca. I.A. McNeish: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: AstraZeneca; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Clovis; Honoraria (self), Advisory / Consultancy: Tesaro; Honoraria (self), Advisory / Consultancy: Takeda. All other authors have declared no conflicts of interest.

1031P - OCTAVE: A phase I study of enadenotucirev, an oncolytic group B adenovirus, in combination with weekly paclitaxel in platinum-resistant epithelial ovarian cancer

BackgroundEnadenotucirev (EnAd) is a tumor selective Ad11/Ad3 group B adenovirus that has demonstrated pre-clinical activity in a model of platinum-resistant ovarian cancer. Synergy has also been reported between oncolytic adenoviruses and microtubule manipulating drugs such as paclitaxel (Pxl). This study aims to establish the tolerability and preliminary efficacy of EnAd delivered in combination with Pxl. Here we present data from the intravenous (IV) dose expansion group. MethodsPatients with platinum-resistant or refractory ovarian cancer received a minimum of two 28-days cycles of IV infusional EnAd (1x1012 viral particles) on days 1, 3 and 5, and IV Pxl (80mg/m2) on days 9, 16 and 23. Baseline and on-treatment biopsies were taken. Primary endpoint was safety and tolerability; additional endpoints included, response rate (RECISTv1.1/GCIG CA125 criteria) and duration of response. ResultsTwenty patients, median age 60.5 years (range 37-78) who had received a median of 4 prior lines of therapy (range 1-12) were enrolled. Adverse events reported from the combination of EnAd and Pxl were as previously described (for both agents individually), with ‘flu-like symptoms reported in the majority of patients following EnAd administration. Hematological changes including neutropenia, previously identified at higher doses of EnAd IV monotherapy, were reported at the dose level tested in this study population. Virus kinetics, cytokine and anti-virus antibody responses were consistent with previous results with EnAd. As of 03May19, Investigator-assessed ORR is 37.5% (6/16), with median DoR of 16 weeks (range 8-32). Reductions in CA125 broadly follow the pattern of tumor regression, with 36% (4/11) achieving response according to GCIG CA125 criteria. Disease control rate (RECIST CR, PR, SD) is 75% (12/16). To date, matched biopsies (N=2) have been analysed for pharmacodynamic markers, providing preliminary evidence of increased CD8 T cell infiltration in on-treatment tumour biopsies. ConclusionsThe combination of EnAd and Pxl has manageable tolerability. Favorable disease control is noted in this recurrent platinum-resistant population, which is worthy of further investigation. Clinical trial identification2013-001276-38. Legal entity responsible for the studyPsiOxus Therapeutics Ltd. FundingPsiOxus Therapeutics Ltd. DisclosureR. Brown: Shareholder / Stockholder / Stock options, Full / Part-time employment: PsiOxus Therapeutics Ltds. D. Krige: Full / Part-time employment: PsiOxus Therapeutics Ltds. J. Bendall: Full / Part-time employment: PsiOxus Therapeutics Ltds. G. Di Genova: Full / Part-time employment: PsiOxus Therapeutics Ltds. H. McElwaine-Johnn: Leadership role, Shareholder / Stockholder / Stock options, Full / Part-time employment: PsiOxus Therapeutics Ltds. All other authors have declared no conflicts of interest.

1027P - Early prediction of the platinum-resistant relapse risk using the CA125 modeled kinetic parameter KELIM: A pooled analysis of AGO-OVAR 7 & 9; ICON 7 (AGO/GINECO/ MRC CTU/GCIG trials)

BackgroundPlatinum-resistant relapse after 1st line treatment (platinum-free interval < 6 months) is a very detrimental event for patient survival. The modeled CA125 elimination parameter KELIM calculated during the first 100 chemotherapy days is a predictive factor of PFS/OS in 1st line treatment (Colomban et al. Clin Cancer Res 2019). KELIM was associated with the risk of subsequent platinum-resistant relapse (PtRR) in neoadjuvant setting (Robelin et al. Proc ASCO 2019). The objective was to validate the predictive value of KELIM in 1st line treatment (with primary debulking surgery) on the data of 3 large phase III trials, and to integrate it in a Platinum-Resistant Recurrence Score. MethodsData from AGO-OVAR 9 (carboplatin-paclitaxel (CP) +/- gemcitabine); AGO-OVAR 7 (CP +/- topotecan); and ICON 7 trials (CP +/- bevacizumab) were analyzed. The predictive value of individual modeled KELIM regarding the risk of subsequent PtRR was assessed with other prognostic factors (stages; histological subtypes; grades; arms; GCIG CA125 criteria; Oza groups in ICON 7) using multivariate ROC curve & logistic models. ResultsAmong assessable 2868 patients, 208 patients experienced subsequent PtRR (7.2%). Median KELIM (days-1) gradually increased with the subsequent PFIs: <6 months, 0.043; 6-12 months, 0.052; > 12 months, 0.065 (P<0.05). Using multivariate logistic models, 3 covariates were significantly associated with PtRR risk: continuous KELIM (OR, 0.17 95% CI [0.11-0.25]; disease stage III (OR, 7.51 [3.70-18.02]); or stage IV (OR, 19.28 [9.06-47.80]); or Oza high risk group in ICON7 (OR 2.35 [1.79-3.10]). They were integrated in a Platinum-Resistant Recurrence Score meant to predict the individual risk of subsequent PtRR (i.e. risk calculated at 60% if KELIM = 0.2 and stage III). ConclusionsModeled KELIM, easily calculable online with three CA125 values observed during the first 100 adjuvant chemotherapy days (http://www.biomarker-kinetics.org/), is related to primary chemoresistance and survival. It has been integrated in a Platinum Resistant Recurrence Score that predicts the individual risk of PtRR in 1st line setting. Legal entity responsible for the studyARCAGY-GINECO. FundingHas not received any funding. DisclosureAll authors have declared no conflicts of interest.

PARAGON: A Phase II study of anastrozole in patients with estrogen receptor-positive recurrent/metastatic low-grade ovarian cancers and serous borderline ovarian tumors

ObjectiveTreatment options are limited for patients with recurrent/metastatic low-grade ovarian cancers (LGOCs) and serous borderline ovarian tumors (SBOTs) as response rates to chemotherapy are low. A subset of patients appears to derive clinical benefit from antiestrogens, but most studies have been retrospective and clinical benefit rates (CBR) remain uncertain. The primary aim of PARAGON was to prospectively investigate the CBR of anastrozole, an aromatase inhibitor, in patients with estrogen receptor (ER) and/or progesterone receptor (PR) positive LGOC and SBOT. MethodsPost-menopausal women with ER-positive and/or PR-positive recurrent/metastatic LGOCs and SBOTs and evaluable disease by RECIST v1.1 or GCIG CA125 criteria were treated with anastrozole 1 mg daily until progression or unacceptable toxicity. ResultsThirty-six patients were enrolled. Clinical benefit at 3 months (primary endpoint) was observed in 23 patients (64%, 95% CI 48%–78%) and was similar at 6 months (61%, 95% CI 43%–75%). The median duration of clinical benefit was 9.5 months (95% CI 8.3–25.8). Best study response was partial response by RECIST in 5 patients (14%), stable disease in 18 patients (50%) with progressive disease in 13 patients (36%). Median PFS was 11.1 months (95% CI 3.2–11.9). Anastrozole was well-tolerated. Patients with evidence of clinical benefit at 3 months reported less pain, fatigue, and improved physical and role functioning as early as 1 month of commencing treatment. ConclusionsAnastrozole was associated with a CBR of 61% of patients with recurrent ER-positive and/or PR-positive LGOC or SBOT for at least 6 months with acceptable toxicity.

Phase I (safety assessment) of durvalumab (MEDI4736) with focal sensitizing radiotherapy in platinum resistant ovarian, primary peritoneal or fallopian tube epithelial carcinoma.

TPS5604 Background: Radiation (RT) of malignant neoplasms can induce immunogenic tumor cell death, alter the tumor micro-environment and enhance recruitment of anti-tumor T cells. Co-administration of focal RT and an immune checkpoint-inhibiting agent may overcome immune-suppressive signals and potentiate systemic responses. A phase I study is underway to assess the safety of RT combined with PD-L1 inhibition in patients with recurrent epithelial ovarian/fallopian tube/peritoneal carcinomas (OV). Methods: Women with platinum resistant epithelial OV, ECOG PS 0/1 and ≤ 2 lines of treatment in the platinum-resistant setting are eligible. 1 lesion evaluable by RECIST criteria (v 1.1) and 2 additional lesions suitable for RT (minimal treatment volume 4cc) are required. Pre- and on-treatment biopsies for correlative studies are mandatory. The primary objectives are to assess the safety and tolerability of the focal RT combined with the immune checkpoint inhibitor, durvalumab (D), as defined by dose-limiting toxicities (DLTs), and to define the maximum tolerated RT dose and treatment schedule. The secondary objectives are to evaluate the clinical activity of focal RT and D [RECIST (v 1.1), GCIG CA-125, and immune-related response criteria], progression free survival and overall survival. D 1500 mg delivered intravenously every 28 days = one cycle. RT to the 2 selected target lesions is delivered 24-36 hours prior to the infusion of D. The RT starting dose-level is 24Gy (in 4 fractions) per lesion (given Days -1, 1 and 28 of Cycle 1 and Day 1 of Cycle 2). A 3+3+3 design will permit more extensive exploration of toxicity if DLTs are observed (Table). Investigator assessed DLTs are defined by CTCAE v. 4.03 and include the following: any grade ≥3 adverse event suspected to be related to D or RT (necrosis or recall reactions at previously irradiated sites, RT induced bowel perforation, any unexpected grade 3 or greater toxicity at the site of RT), any grade ≥2 allergic or autoimmune event that involves vital organ function, and any other grade 3 allergic or autoimmune events that do not resolve to grade 1 before the next scheduled dose of D. Treatment may continue up to 12 months. Enrollment began August 2018. To date, no DLTs have been observed at dose level 1 (n= 3) and enrollment is ongoing. Clinical trial information: NCT03283943. [Table: see text]

Abstract AP27: FEASIBILITY OF MONITORING RESPONSE TO THE PARP INHIBITOR RUCAPARIB WITH TARGETED DEEP SEQUENCING OF CIRCULATING TUMOR DNA (CTDNA) IN WOMEN WITH HIGH GRADE OVARIAN CARCINOMA ON THE ARIEL2 TRIAL

Abstract BACKGROUND: TP53 mutations are present in &amp;gt;97% cases of high-grade serous ovarian cancer (HGSOC). Detection of TP53 mutations in ctDNA extracted from plasma has the potential to monitor disease course and treatment response. We have developed targeted amplicon deep sequencing (TADS) to detect low frequency mutations throughout the TP53 gene in ctDNA. Rucaparib is a PARP inhibitor in development for treatment of tumors with HR pathway deficiency. We used TADS to assess TP53 mutant allele fraction (MAF) in ctDNA from patients in ARIEL2, a phase 2 study of rucaparib for treatment of relapsed high-grade ovarian cancer (NCT01891344). MATERIAL AND METHODS: Plasma samples (n=65) from 18 patients were collected during screening, on day 1 of each cycle, and at the end of rucaparib treatment. DNA extracted from plasma underwent TADS of TP53 (median depth 6916×). FFPE tumor specimens were profiled using an NGS-based assay with a targeted gene panel including TP53. Investigator-assessed clinical response rates were evaluated by RECIST v1.1 and GCIG CA-125 criteria. RESULTS: Concordant TP53 mutations were detected in tumor and ctDNA from plasma for all 18 patients. Median TP53 MAF at screening and cycle 1 day 1 was 5.1% (interquartile range: 1.1–17.5, n=16) and 3.8% (IQR: 0.68–10.3, n=16), respectively. Fourteen patients were evaluable for response measured by quantification of TP53 MAF between cycle 1 and 2 (missing sample: n=2; TP53 MAF &amp;lt;0.5%; n=2). 7/9 patients with &amp;gt;50% reduction of TP53 MAF in ctDNA at cycle 2 achieved a RECIST confirmed PR (see Table); this included 5/6 patients with either a germline or somatic mutation in BRCA1/BRCA2. No patients with &amp;lt;50% reduction at cycle 2 (n=5) achieved a RECIST response. CONCLUSIONS: Noninvasive detection of TP53 mutations by TADS is feasible, using plasma samples collected from women with relapsed platinum-sensitive high-grade ovarian cancer participating in an international multicenter trial. Circulating tumor DNA is a promising biomarker for monitoring response to the PARP inhibitor rucaparib. We are now testing the pre-specified hypothesis that a &amp;gt;50% reduction in TP53 MAF between baseline and cycle 2 is predictive of response to rucaparib using 560 plasma samples from 139 ARIEL2 subjects. Updated results will be presented at the meeting. Citation Format: Anna Piskorz, Kevin K. Lin, James Morris, Elaina Mann, Amit Oza, Robert L. Coleman, David M. O'Malley, Michael Friedlander, Janiel M. Cragun, Ling Ma, Heidi Giordano, Nitzan Rosenfeld, Mitch Raponi, Iain A. McNeish, Elizabeth Swisher, James D. Brenton. FEASIBILITY OF MONITORING RESPONSE TO THE PARP INHIBITOR RUCAPARIB WITH TARGETED DEEP SEQUENCING OF CIRCULATING TUMOR DNA (CTDNA) IN WOMEN WITH HIGH GRADE OVARIAN CARCINOMA ON THE ARIEL2 TRIAL [abstract]. In: Proceedings of the 11th Biennial Ovarian Cancer Research Symposium; Sep 12-13, 2016; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(11 Suppl):Abstract nr AP27.

OCTOPUS: A randomised, multi-centre phase II umbrella trial of weekly paclitaxel+/- novel agents in platinum-resistant ovarian cancer—Vistusertib (AZD2014).

TPS5609 Background: There is an urgent need to improve outcomes for patients with platinum-resistant and refractory ovarian cancer (PROC). OCTOPUS is an umbrella phase II framework for testing whether the addition of novel targeted agents to weekly paclitaxel (wPxl) improves efficacy in PROC. The first agent to be evaluated is the dual mTORC1/mTORC2 inhibitor, vistusertib (AZD2014), as preclinical studies support targeting the PI3kinase/Akt/mTOR pathway in PROC and the combination of vistusertib and wPxl has shown promising preliminary activity in high grade serous ovarian cancer (HGS) patients in a phase I trial (Banerji et al poster discussion ESMO 2016). This is the first randomised trial of wPxl and a dual mTORC1/2 inhibitor in ovarian cancer. Methods: OCTOPUS is an investigator-initiated, randomised, double-blind, placebo-controlled, multicentre, phase II trial. 140 patients with PROC (histologically confirmed HGS) are randomised 1:1 to receive wPxl (80mg/m2 D1, D8, D15 of 28 day cycle) plus oral vistusertib (50mg BD) or placebo (D1-3, D8-10, D15-17). The primary endpoint is progression-free survival (PFS) based on combined RECIST v1.1/GCIG CA125 criteria. The study is designed to detect a 50% improvement in median PFS from 3.7 months on placebo to 5.55 months on the experimental arm with 90% power, at the 20% 1-sided level of statistical significance (or equivalently with 80% power at the 10% level of statistical significance) using a 3-outcome design. Secondary endpoints include response (based on RECIST 1.1 and GCIG CA125 criteria), overall survival, toxicity and quality of life. Patients whom received prior wPxl for PROC are not eligible. A mandatory pre-treatment biopsy (if technically feasible), archival tissue, and serial blood samples will be collected for translational research studies. 49 patients have been recruited. The study is part of the NIHR CRN Cancer/Astrazeneca Alliance, sponsored by NHS Greater Glasgow and Clyde/University of Glasgow and endorsed by Cancer Research UK (CRUKE/14/052). Clinical trial information: ISRCTN16426935.

Two prognostic populations of ovarian cancer patients defined by CA125 modeled kinetic parameter KELIM (AGO-OVAR 7 &amp; 9; ICON 7 AGO/GINECO/ MRC CTU/GCIG trials).

5554 Background: Longitudinal CA125 kinetics during treatment can be assessed by mathematical models. The modeled CA125 elimination parameter KELIM (with 3-4 timepoints) was an early prognostic factor in CALYPSO (Gynecol Oncol 2013). Validating the prognostic value of KELIM in phase 3 trial datasets with different 1st line treatments was warranted. Methods: Data from AGO-OVAR 9 (training set: carboplatin-paclitaxel (CP) +/- gemcitabine; n=1742); AGO-OVAR 7 (validation set: CP +/- topotecan; n=1308); and ICON 7 trials (validation set: CP +/- bevacizumab; n=1528) were analyzed. CA125 profiles were fit to nonlinear mixed effect equations, and KELIM estimated in all patients at 100 days. KELIM prognostic value was tested regarding PFS and OS against other prognostic factors (stage; pathology; grade; arms; GCIG CA125 criteria; Oza groups in ICON 7) using univariate/multivariate tests. Results: KELIM (≤ or &gt; median 0.0598) had reproducible independent prognostic value for PFS (AGO 9: HR = 0.60 [0.53-0.69]; AGO 7: HR = 0.58 [0.40-0.83]; ICON-7: HR=0.65 [0.44-0.96]) and for OS (AGO 9: HR = 0.55 [0.47-0.64]; AGO 7: HR = 0.55 [0.35-0.86]; ICON-7: HR=0.49 [0.41-0.57]) by multivariate tests. Other significant factors for PFS &amp; OS: stage IV in AGO7 &amp; 9 (HR=6.0 to 8.3) and ICON 7 poor progn group (PFS HR=2.24 PFS; OS HR=2.22 [1.9-2.6]). KELIM prognostic value was independent on regimen arms (Table), maintained within ICON7 progn groups (best OS gain with bevac if poor progn &amp; unfav KELIM), and better than GCIG CA125 (inconsistent progn value). Conclusions: The reproducible &amp; independent early prognostic value of KELIM regarding PFS and OS is validated. Easily calculable online, it early discriminates 2 ovarian cancer populations for PFS &amp; OS whatever treatments, and is a new reference prognostic factor. [Table: see text]

Abstract 4670: A novel companion diagnostic predicts response to the PARP inhibitor rucaparib in ovarian cancer

Abstract Background: Genomic studies suggest that ∼50% of high-grade serous ovarian cancers (OC) have homologous recombination deficiency (HRD). Germline BRCA1/2 mutations (gBRCAmut) are expected to account for 1/3 of HRD in OC, and identification of non-gBRCAmut HRD tumors likely to respond to PARP inhibitors (PARPi) remains a challenge. Using comprehensive next generation sequencing (NGS)-based tumor genomic profiling, we developed a companion diagnostic HRD assay to predict sensitivity to the PARP inhibitor rucaparib by combining tumor BRCA1/2 status (germline and somatic) and genomic loss of heterozygosity (LOH). The HRD assay is being validated in a Phase 2 study (ARIEL2) and will be prospectively applied to the primary analysis of the ongoing Phase 3 study (ARIEL3) of rucaparib. Methods: The HRD assay uses 50-200ng of DNA from tumor FFPE specimens, which undergoes sequencing library construction and hybrid-capture of all coding exons from 100s of cancer-related genes. Libraries are sequenced to high, uniform depth (&amp;gt;500× unique coverage, Illumina® HiSeq) and data are processed by a customized pipeline that accurately detects all classes of genomic alterations, including BRCA1/2 base substitutions, indels, and homozygous deletions. Genomic LOH is assessed by a CGH-like analysis of sequencing coverage and &amp;gt;3,500 genome-wide SNPs and a tumor is classified as HRD with either BRCA1/2 alteration or high genomic LOH (LOH+). Somatic/germline status of discovered BRCA1/2 alterations is assessed by a previously-presented computational approach (“SGZ”, AACR 2014 abstract #1893), and verified against medical records where available. ARIEL2 is an ongoing single-arm (n = 180), open-label study of rucaparib in recurrent, platinum-sensitive OC patients. The primary objective is to evaluate clinical activity of rucaparib among 3 prospectively defined subgroups: tumor BRCAmut, BRCAwt/LOH+ (“BRCAness”) and BRCAwt/LOH-. Response is determined by RECIST and/or GCIG-CA125 criteria. Results: The HRD assay was performed on tumors from 121 patients, of whom 25% were found to be BRCA mutant (17 germline/12 somatic), 42% had the BRCAness signature (BRCAwt/LOH+), and 33% were biomarker negative (BRCAwt/LOH-). Efficacy data available for 61 patients revealed objective response rates (combined RECIST/CA125 criteria) at 70%, 40% and 8%, respectively. Responses were observed for all classes of genomic alterations, and in gBRCAmut and non-gBRCAmut tumors. Conclusions: Preliminary clinical data indicates that the HRD assay identifies OC patients likely to respond to rucaparib and highlights the potential for innovative companion diagnostics enabled by comprehensive genomic profiling based on NGS. Citation Format: James Sun, Iain McNeish, Robert L. Coleman, Amit Oza, Clare Scott, David M. O'Malley, Kevin K. Lin, Christine Burns, Christine Vietz, Philip J. Stephens, Murtaza Mehdi, Matthew Hawryluk, Heidi Giordano, Mitch Raponi, Lindsey Rolfe, Jeff Isaacson, Vincent A. Miller, Andrew Allen, Elizabeth Swisher, Roman Yelensky. A novel companion diagnostic predicts response to the PARP inhibitor rucaparib in ovarian cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4670. doi:10.1158/1538-7445.AM2015-4670

A phase I/II study of the vascular disrupting agent BNC105P in combination with gemcitabine-carboplatin in partially platinum-sensitive ovarian cancer patients in first or second relapse: An international collaborative group trial of ANZGOG and HOG.

TPS5612 Background: BNC105P is a tubulin polymerization inhibitor and a vascular disrupting agent (VDA). In vivo exposure to BNC105P leads to selective damage of tumor vasculature in both primary and metastatic lesions, causing disruption of blood flow to tumors, hypoxia, and associated tumor necrosis. BNC105P also has a direct anti-proliferative action on cancer cells, including ovarian cancer cell lines. Pre-clinical data has demonstrated synergistic activity of BNC105P when combined with platinum or with gemcitabine, supporting the proposed study design. This study will determine the safety and efficacy of BNC105P in ovarian cancer when used in combination with gemcitabine-carboplatin. The target population is women with ovarian or primary peritoneal cancers who progressed 4 to 9 months after first-line platinum based chemotherapy, or 4 to 12 months after second line platinum based chemotherapy. Methods: A single arm phase I will be used to determine the phase II dose for the triplet combination (3-6 subjects per dose level, maximum of 24 subjects). Four dose levels of BNC105P (12-16 mg/m2) and gemcitabine (800-1000 mg/m2) will be assessed. The dose of carboplatin will be set at AUC 4. Enrolment to cohort 2 started in January 2013. The phase II component will consist of a 2-arm, randomized (1:1) study of BNC105P, gemcitabine and carboplatin versus gemcitabine and carboplatin alone. The primary endpoint for the phase II trial is objective response rate (ORR, according to RECIST 1.1 and/or GCIG CA125 criteria. An ORR of 40% or more with the experimental regimen would be considered worthy of further investigation, assuming an ORR of 20% with the control regimen. 110 phase II participants are planned (N = 55/arm). Treatment allocation will be balanced using minimization for the study site, target lesions according to RECIST (present vs. absent), progression free interval from last platinum based chemotherapy regimen (&lt;6 months vs 6 months or more), and first relapse vs. second relapse. Biomarker (tissue and blood-borne) sampling and PK analysis will also be undertaken. Clinical trial information: NCT01624493.

Panitumumab and Pegylated Liposomal Doxorubicin in Platinum-Resistant Epithelial Ovarian Cancer With KRAS Wild-Type: The PaLiDo Study, a Phase II Nonrandomized Multicenter Study

The increasing number of negative trials for ovarian cancer treatment has prompted an evaluation of new biologic agents, which in combination with chemotherapy may improve survival. The aim of this study was to investigate the response rate in platinum-resistant, KRAS wild-type ovarian cancer patients treated with pegylated liposomal doxorubicin (PLD) supplemented with panitumumab. Major eligibility criteria were relapsed ovarian/fallopian/peritoneal cancer patients with platinum-resistant disease, measurable disease by GCIG CA125 criteria and KRAS wild-type. Patients were treated with panitumumab 6 mg/kg day 1 and day 15 and with PLD 40 mg/m2 day 1, every 4 weeks. Forty-six patients were enrolled by 6 study sites in this multi-institutional phase II trial. The response rate in the intention-to-treat population (n = 43) was 18.6%. Progression-free and overall survival in the intention-to-treat population was 2.7 months (2.5-3.2 months, 95% confidence interval) and 8.1 months (5.6-11.7 months, 95% confidence interval), respectively. The most common treatment-related grade 3 toxicities included skin toxicity (42%), fatigue (19%), and vomiting (12%). The combination of PLD and panitumumab demonstrates efficacy in platinum refractory/resistant patients but the skin toxicity was considerable.

Randomized phase III study of erlotinib versus observation in patients with no evidence of disease progression after first-line platin-based chemotherapy for ovarian carcinoma: A GCIG and EORTC-GCG study.

LBA5000 Background: The epidermal growth factor receptor (EGFR) has been found to be overexpressed in 55-98% of advanced epithelial ovarian cancer. This trial evaluated the efficacy of maintenance erlotinib, an EGFR tyrosine kinase inhibitor, after first-line chemotherapy. Methods: Eligible patients (pts) had high-risk FIGO stage I or stage II-IV epithelial ovarian, peritoneal or fallopian tube cancer and were not selected for EGFR expression. All patients underwent first line therapy (6-9 cycles of 3-weekly platinum-based chemotherapy (CT)) and showed no signs of progression at the end of CT. Patients were randomised to maintenance erlotinib 150 mg daily for 2 years or observation. Primary endpoint was progression-free survival (PFS) by RECIST in combination with GCIG CA125 criteria. The final design provided 80% power to detect a PFS hazard ratio (HR) of 0.80 with 2-sided log-rank test at 5% after 632 events in 830 patients. Stratifications factors were stage, institution, age, response to and type of first-line CT. Immunohistochemistry (IHC) and FISH for EGFR, and EGFR mutation analyses were performed in 330 patients. The study was registered as NCT00263822 and EudraCT number 2004-004333-34. Results: Between Oct 2005 and Feb 2008, 835 pts were randomised by 125 institutions from 10 countries. The most important baseline characteristics, PFS and OS are summarized in the table. Median follow-up was 51 months. 25% of the patients stopped erlotinib due to side effects (of these 67% due to rash). The predictive value of IHC and FISH for EGFR, and EGFR mutations are being evaluated and will be presented at the meeting. Conclusions: In the overall study populationmaintenance erlotinib after first-line treatment in ovarian cancer did not improve progression-free or overall survival. [Table: see text]

Safety and Efficacy of Panitumumab (pmab) in HPV Positive (+) and HPV Negative (−) Recurrent/metastatic (R/M) Squamous Cell Carcinoma of the Head and Neck (SCCHN): Analysis of the Phase 3 SPECTRUM Trial

and GCIG CA125 criteria. 3 core PTB obtained before and after 4 weeks of GSK795, were analysed by immunohistochemistry (IHC) and Reverse Phase Protein Array (RPPA). Sequenom mutation profiling (SMP) of archival tissue and PTB was also done. Results: The most common drug related AE was G1/2 vomiting (33%); there was only one G3 drug related AE: hepatotoxicity. A PK-PET PD relationship was observed between GSK795 plasma Cmax and Ki for best responding lesions. Although no RECISTv1.1 responses were noted, CA125 GCIG criteria PR rate was 20% (n = 2/10). A direct correlation was observed between best CA125 response, best CT response and disease stabilization (p 52 weeks. IHC and RPPA showed PD evidence of PI3K/AKT pathway inhibition (pAKT/PRAS40) irrespective of response status. SMP demonstrated mutations associated with response (PIK3CA) and resistance (Kras, MET) to GSK795. RPPA identified putative predictive (S6), resistance (CCNE1) and response (Bid) biomarkers suitable for validation for AKT inhibitor therapy.

A phase I trial of the PARP inhibitor olaparib (AZD2281) in combination with the antiangiogenic cediranib (AZD2171) in recurrent ovarian or triple-negative breast cancer.

5028 Background: Olaparib is an orally-bioavailable PARP inhibitor with activity as monotherapy in ovarian and breast cancer; cediranib is a multitargeted kinase inhibitor of VEGFR-1/2/3 and c-kit. PARP-inhibition has anti-angiogenic effects in the preclinical setting; however, the effect of combined therapy against PARP and angiogenesis has not been reported. We investigated the toxicities and recommended phase 2 dosing (RP2D) of the combination of cediranib and olaparib (NCT01116648). Methods: Cediranib tablets daily and olaparib capsules BID were administered PO in cohorts of 3 pts in a standard 3+3 Phase 1 design. Eligibility included pts with recurrent ovarian or metastatic triple-negative breast cancer. Pts had measurable disease by RECIST 1.1 or met GCIG CA125 criteria. No prior anti-angiogenic therapies in the recurrent setting or prior PARP-inhibitors were allowed. Results: 18 pts (13 ovarian, 5 breast) have been accrued thus far to 4 dose levels: DL0: cediranib (C) 20mg daily/olaparib (O) 100mg BID (3 pts); DL1: C 20mg daily/O 200mg BID (3 pts); DL2: C 30mg daily/O 200mg BID (6 pts); DL3: C 30mg daily/O 400mg BID (6 pts). 2 DLTs (1 gr 4 neutropenia ≥ 4d; 1 gr 4 thrombocytopenia) were seen at the highest dose level. Other gr 3/4 toxicities include gr 4 neutropenia (1 pt), hypertension (3 pts), fatigue (3 pts), anorexia (1 pt), nausea (1 pt), and asymptomatic PE (1 pt). The RP2D is anticipated to be cediranib 30mg daily/olaparib 200mg BID. 10 ovarian and 1 breast cancer pt were known BRCA mutation carriers. Ovarian pts had a median of 2 prior lines of therapy (range 1-9); breast pts had 3 (2-5). Best response for 9 evaluable ovarian cancer pts at time of data capture include 1 cCR (DL1), 3 cPR (2 DL0, 1 DL3), 1 uPR (DL2), 3 cSD (1 DL1, 2 DL3), and 1 uSD (DL2). Best response for 5 evaluable breast cancer pts include 1 cSD (DL1), 2 uSD (1 DL0, 1 DL2), and 2 PD (2 DL3). Conclusions: The combination of cediranib and olaparib has hematologic toxicity DLTs and anticipated class toxicities, with preliminary evidence of efficacy in the tested population, including a 56% unconfirmed response rate in ovarian cancer patients.

Predictive value of serum CA125 levels in women with persistent or recurrent epithelial ovarian cancer (EOC) or primary peritoneal cancer (PPC) treated with bevacizumab (Bev) on a Gynecologic Oncology Group (GOG) phase II trial

e16505 Background: The clinical utility of serum CA125 in patients (pts) with EOC/PPC treated with biologic agents is unknown. The primary objective of this study was to determine the proportion of pts treated with bevacizumab on a phase II clinical trial with stable disease by RECIST who demonstrated disease progression (pgrn) as assessed by modified GCIG CA125 criteria. Methods: Sixty-two pts with measurable recurrent or persistent EOC/PPC were treated with bevacizumab 15 mg/kg Q 21 days on a phase II clinical trial. Primary endpoints of the clinical trial were progression-free (PF) survival at 6 months and response assessed by RECIST criteria. Pts were removed from therapy/evaluation for disease prgn by RECIST, toxicity, or by subject request. Serum CA125 was collected at entry and prior to each cycle but levels were only used to define a complete response which required CA125 normalization (≤35). Modified GCIG criteria were retrospectively applied to these CA125 values to determine time to progression from date of entry to either the first time CA125&gt;70 for pts whose CA125 normalized on treatment or was greater than 2X the nadir value for pts whose CA125 did not normalize. Censored cases provided time until the date of last CA125 measurement. Results: The median PFS by RECIST was 4.7 mos. Of those patients who had prgn by CA125, the median residual time to prgn by RECIST was 1.4 mos. In all, twenty-five (40.3%) pts survived PF for 6 mos. by RECIST and 16 (25.8%) by CA125. Ten pts who survived PF for at least 6 mos. by RECIST indicated treatment failure before 6 mos. by CA125, or 40% of the 25 positive outcomes. Eight pts continued to receive treatment for at least 4 mos. after prgn by CA125, with one continuing therapy for more than 3 years. Conclusions: Serum CA125 levels were a useful marker of progression in some pts treated on this trial; however, some pts received clinical benefit from continued therapy in spite of indications of disease prgn by CA125. Consideration should be given before discontinuing bevacizumab therapy based on CA125 progression alone. No significant financial relationships to disclose.