Advanced Recurrent Ovarian Cancer Research Articles

Infiltration of tumor by T cells following treatment with DPX-Survivac and intermittent low dose cyclophosphamide (CPA) leads to clinical responses in advanced recurrent ovarian cancer (OvCa).

6075 Background: DPX-Survivac is a novel T-cell activating therapy designed to elicit an effective immune response against survivin expressing tumors. Its unique mechanism of action (MOA) facilitates active and sustained uptake of target peptides by APC at the injection site. APCs subsequently present the antigen in local lymph nodes generating survivin-specific T cells that traffic to distant tumor sites and elicit effective tumor cell death. DPX-Survivac is used in combination with intermittent low dose CPA which acts as an immunomodulator of T-cell responses. Methods: The study enrolled 22 patients with recurrent, advanced platinum-sensitive and -resistant ovarian cancer. Patients received 2 subcutaneous injections of DPX-Survivac 3 weeks apart and every 8 weeks thereafter, and intermittent low dose CPA for up to 1 year. Paired tumor biopsies were performed prior to treatment and on treatment. Primary endpoints were ORR, DCR and safety. Secondary endpoints include cell mediated immunity, immune cell infiltration in paired biopsy samples, DOR, TTP, OS and biomarker analyses. Results: Twenty-two patients were enrolled in the study. Three patients were discontinued prematurely due to early progression leaving 19 patients for response evaluation. The population is heavily pre-treated with a median of 3 lines of prior treatment [range 1 to 8]; 77.3% of patients are platinum-resistant. At the time of data cut-off, 3/19 patients (15.8%) achieved PR and one additional patient met PR on target lesions but had a newly detected lesion; 10/19 patients (52.6%) showed tumor regression on target lesions at > 1 scan. The median time on study (N=19) is 131 days [63 to ˃295]. Six patients are still on trial. The clinical responses and benefits observed with treatment are associated with an increase in systemic survivin-specific T cells and tumor immune-infiltration. Moreover, RNAseq analysis on paired tumor tissue revealed an enrichment in cytolytic T-cell signature. The most common AEs were grade 1-2 injection site reactions; 4 treatment-related SAEs were reported. Conclusions: DPX-Survivac and intermittent low dose CPA shows promising clinical activity in heavily pre-treated patients with recurrent OvCa. The preliminary results, supported by strong translational data, link the observed clinical benefits with the unique MOA of DPX-Survivac. These clinical results suggest that DPX-Survivac/CPA is an active regimen in OvCa and warrant testing in an expanded cohort of patients. Clinical trial information: NCT02785250.

Final results from the KEYNOTE-100 trial of pembrolizumab in patients with advanced recurrent ovarian cancer.

6005 Background: Pembrolizumab (pembro) showed modest clinical activity in patients (pts) with recurrent advanced ovarian cancer (AOC) after a median follow-up of 16.9 mo in an interim analysis of KEYNOTE-100 (NCT02674061). We present the protocol-specified final analysis based on a data cutoff of 18-SEP-2019. Methods: Key eligibility criteria included epithelial ovarian, fallopian tube, or primary peritoneal cancer, confirmed recurrence following front-line platinum-based therapy, ECOG PS 0-1, and provision of a tumor sample for biomarker analysis. Pts in cohort A received ≤2 prior chemotherapy lines for recurrent AOC and had a platinum-free or treatment-free interval (PFI/TFI) of ≥3 to 12 mo. Pts in cohort B received 3-5 prior chemotherapy lines and had a PFI/TFI of ≥3 mo. Pts received pembro 200 mg Q3W for 2 yr or until progression, death, or unacceptable toxicity. Tumor imaging was performed every 9 wk for 1 yr and every 12 wk thereafter. Primary study endpoint was ORR per RECIST v1.1 by independent central review in both cohorts and by tumor PD-L1 expression using the combined positive score (CPS). Secondary endpoints included DOR, DCR (CR+PR+SD≥24 wk), PFS, OS, and safety. Results: 376 pts were enrolled and treated, 285 in cohort A and 91 in cohort B. Median age (range) was 61 (25 to 89) yr, 64.4% had ECOG PS 0, and 75.3% had high grade serous disease. In cohorts A and B, ORR (95% CI) was 8.1% (5.2, 11.9) and 9.9% (4.6, 17.9) in the total population, 6.9% (2.8, 13.8) and 10.2% (3.4, 22.2) in pts with CPS ≥1, and 11.6% (3.9, 25.1) and 18.2% (5.2, 40.3) in pts with CPS ≥10. Median DOR (range) was 8.3 (3.9 to 35.4+) mo in cohort A and 23.6 (3.3+ to 32.8+) mo in cohort B. DCR (95% CI) was 22.1% (17.4, 27.4) and 22.0% (14.0, 31.9). Median PFS was 2.1 mo in both cohorts. In cohorts A and B, median OS was 18.7 mo (17.0, 22.5) and 17.6 mo (13.3, 24.4) in the total population, 20.6 mo (15.2, 23.2) and 20.7 mo (13.6, 27.4) in pts with CPS ≥1, and 21.9 mo (12.9, 26.8) and 24.0 mo (14.5, NR) in pts with CPS ≥10. 73.7% of pts had treatment-related AEs and 20.2% were grades 3-4. There were 2 treatment-related deaths (Stevens-Johnson syndrome and hypoaldosteronism). Immune-mediated AEs occurred in 23.7% of pts. Conclusions: Pembro monotherapy was associated with modest antitumor activity in pts with recurrent AOC. There appeared to be a trend toward increased ORR with higher PD-L1 expression in both cohorts. Responses were durable and typically lasted ≥6 months. Median OS was 18.7 months overall, with a trend toward a longer OS with increasing PD-L1 expression in both cohorts. No new safety signals were identified. Clinical trial information: NCT02674061.

Ac 225 quinoline theragnosis in recurrent advanced ovarian cancer

Ac 225 quinoline theragnosis in recurrent advanced ovarian cancer

KN100: Results from Japanese patients with advanced recurrent ovarian cancer treated with pembrolizumab monotherapy

Abstract Background Interim results from the ongoing, 2-cohort, phase 2 KEYNOTE-100 study (NCT02674061) have suggested clinical efficacy of pembrolizumab (pembro) monotherapy in some patients (pts) with advanced ovarian cancer (AOC). Here, we present efficacy and safety results from Japanese pts in KEYNOTE-100. Methods Pts with epithelial AOC, fallopian tube cancer, or primary peritoneal cancer with prior treatment with debulking surgery followed by front-line platinum-based chemotherapy (CT) and documented disease recurrence were eligible for this study. Cohort A received ≤2 prior CT lines and had a platinum- or treatment-free interval (PFI; TFI) of 3-12 months. Cohort B received 3-5 prior CT lines and had a PFI/TFI of ≥ 3 months. All pts received pembro 200 mg every 3 weeks as monotherapy for 2 years or until progression, death, unacceptable toxicity, or consent withdrawal. The primary objectives were ORR per RECIST v1.1 by blinded independent central review for each cohort and by tumor PD-L1 expression. The relationship between PD-L1 expression (defined as combined positive score [CPS]) and ORR was assessed. Results In the second interim analysis (Matalounis, ASCO 2018) of the overall study population (N = 376), the ORR in Cohort A and B were 7% (95% CI, 5-11; n = 285) and 10% (95% CI, 5-18; n = 91), respectively. 21 Japanese pts were treated (19 in Cohort A; 2 in Cohort B). Mean (SD) age was 57 (10) years; 91% had ECOG PS 0, and 76% had stage 3-4 disease. The ORR in all pts was 19% (95% CI, 5-42). ORR increased with increasing PD-L1 expression: 25% (2/8) with CPS ≥1 and 50% (1/2) with CPS ≥10. 62% of pts had treatment-related adverse events (TRAEs), and 24% had grade 3-5 TRAEs. There were no treatment-related deaths in this subpopulation. Conclusion Pembro monotherapy was associated with antitumor activity in Japanese pts with recurrent AOC, with no new safety signals identified in this subpopulation. There was a potential trend associated with ORR and PD-L1 expression.

Bioengineered adipose-derived stem cells for targeted enzyme-prodrug therapy of ovarian cancer intraperitoneal metastasis

The objective of this study was to develop a stem cell-based system for targeted suicide gene therapy of recurrent, metastatic, and unresectable ovarian cancer. Malignant cells were obtained from the ascites of a patient with advanced recurrent epithelial ovarian cancer (named OVASC-1). Cancer cells were characterized to determine the percentages of drug-resistant ALDH+ cells, MDR-1/ABCG2 overexpressing cells, and cancer stem-like cells. The sensitivity and resistance of the OVASC-1 cells and spheroids to the metabolites of three different enzyme/prodrug systems were assessed, and the most effective one was selected. Adipose-derived stem cells (ASCs) were genetically engineered to express recombinant secretory human carboxylesterase-2 and nanoluciferase genes for simultaneous disease therapy and quantitative imaging. Bioluminescent imaging, magnetic resonance imaging and immuno/histochemistry results show that the engineered ASCs actively targeted and localized at both tumor stroma and necrotic regions. This created the unique opportunity to deliver drugs to not only tumor supporting cells in the stroma, but also to cancer stem-like cells in necrotic/hypoxic regions. The statistical analysis of intraperitoneal OVASC-1 tumor burden and survival rates in mice shows that the administration of the bioengineered ASCs in combination with irinotecan prodrug in the designed sequence and timeline eradicated all intraperitoneal tumors and provided survival benefits. In contrast, treatment of the drug-resistant OVASC-1 tumors with cisplatin/paclitaxel (standard-of-care) did not have any statistically significant benefit. The histopathology and hematology results do not show any toxicity to major peritoneal organs. Our toxicity data in combination with efficacy outcomes delineate a nonsurgical and targeted stem cell-based approach to overcoming drug resistance in recurrent metastatic ovarian cancer.

Pembrolizumab with low dose carboplatin for recurrent platinum resistant ovarian, fallopian tube, and primary peritoneal cancer-interim results.

5519 Background: Pembrolizumab has shown activity in advanced recurrent ovarian cancer (AOC) with an 8% response rate and median progression-free survival (PFS) of 2.1 months reported in KEYNOTE-100. Because platinum chemotherapies also induce T cell proliferation and enhance tumor cell recognition through PD-1/PD-L, we assessed the safety and activity of pembrolizumab with carboplatin in platinum resistant AOC. Methods: Key eligibility criteria for this Phase 1/2 single arm trial were platinum resistant AOC, fallopian tube, or peritoneal cancer, progression after subsequent systemic therapy, and ECOG PS 0-1. Pembrolizumab 200mg was given on Day 1 and carboplatin AUC 2 on Day 8 and 15 of a 3 week cycle until progression, unacceptable toxicity, or consent withdrawal. Imaging was done before cycles 4 and 8, then every 3 months and unconfirmed objective response assessed by blinded independent review per RECIST 1.1. Adverse events (AEs) were reported per Common Terminology for Adverse Events v5.0. PD-L1 expression was assessed by immunohistochemistry. Results: 27 patients (median age: 64) had received a median of 5 (range: 2-9) prior lines of systemic therapy, which included bevacizumab in 74% of patients. The most common treatment related (TR) AEs were lymphopenia (18%) and anemia (9%). The majority of TR AEs were grade 1 or 2 (93%). 6% of AEs were grade 3 with lymphopenia the most common. Two grade 4 AEs were neutropenia and lymphopenia. Of 23 patients evaluable for best objective response, 13.0% (95% CI, 2.7-33.6) had partial response (PR), 65.2% (95% CI, 42.7-83.6) had stable disease (SD), and 21.7% (95% CI, 7.4-43.7) had progression. 7 of the 23 evaluable patients (30.4%) had archival tumor with modified percent scoring ≥5 for PD-L1 and all achieved PR (3/7, 42.8%) or SD (4/7, 57.2%). Overall median PFS was 4.6 months (95% CI, 2.7-6.2). Rate of PFS at 6 months was 40.4% (95% CI, 25.5-65.5). Median follow-up is 6.2 months and PFS is based on current data, but 8 patients remain on study and estimates will be updated. Conclusions: Pembrolizumab with low dose carboplatin was well tolerated and showed activity in heavily pretreated platinum resistant AOC. Survival and biomarker analyses are ongoing. Clinical trial information: NCT03029598.

Meta-analysis of toxicity data in thoracic and abdominal malignancies from: Clinical trials in tumor treating fields.

e14658 Background: Tumor Treating Fields (TTFields) are a non-invasive, loco-regional, antimitotic treatment modality, which has been approved for the treatment of glioblastoma (GBM) by the FDA. Mild-moderate localized dermatitis was reported in 52% of newly diagnosed GBM patients treated in the EF-14 [NCT0091640] phase 3 trial (with only 2% having Grade 3 skin toxicity). The toxicity of TTFields has been investigated in a number of pilot studies for malignancies located outside of the brain, and here we present a meta-analysis of toxicities reported in them. Methods: A total of 192 patients from four pilot clinical studies in the following malignancies were included: Advanced lung cancer, advanced pancreatic cancer, pleural mesothelioma and recurrent ovarian cancer. All patients received chemotherapy in addition to TTFields. Adverse events (AEs) and their association with the treatment were evaluated using CTCAE Criteria. Toxicities were reported as incidence by body system and MedDRA term out of the number of patients who received any amount of TTFields treatment. Results: The median age of patients was 63 (range: 44-78), 73 (49-81), 67 (27-78) and 60 (45-77) for EF-15 [NCT00749346], PANOVA [NCT01971281], STELLAR [NCT02397928] and INNOVATE [NCT02244502], respectively. The incidence of several low grade gastrointestinal (GI) toxicities was ≥5%: constipation (16%), diarrhea (14%), nausea (27%), vomiting (13%). None of the GI toxicities was associated with TTFields. Low grade general disorders such as asthenia (12%) and fatigue (18%) were common but not associated with TTFields. The incidence of arrhythmias was ≤2%. 58% of the patients had dermatological AEs, but only 6% had grade 3 dermatitis. 9% of patients had low grade pruritus. Conclusions: No new safety signals associated with TTFields were identified in this meta-analysis. The incidence of TTFields-related skin toxicity was similar to that reported in glioblastoma patients. The application of TTFields to the torso is safe. Clinical trial information: [NCT00749346], [NCT01971281], [NCT02397928], [NCT02244502].

DPX-Survivac and intermittent low-dose cyclophosphamide (CPA) with or without epacadostat (E) in the treatment of subjects with advanced recurrent epithelial ovarian cancer (DeCidE1 trial): T cell responses and tumor infiltration correlate with tumor regression.

5576 Background: DPX-Survivac is a novel T cell activating therapy designed to elicit an effective immune response against recurrent ovarian cancers that express the survivin protein. The survivin specific T cells induced by DPX-Survivac can infiltrate the tumors and are associated with clinical responses. It is likely that achieving an anti-tumor effect requires a favorable ratio of T cells to tumor cells. Epacadostat (E) is an IDO1 enzyme inhibitor that may enhance effector T cell proliferation, shifting the tumor microenvironment (TME) away from an immunosuppressive state toward one supporting productive immune response. Methods: Recurrent ovarian cancer patients with advanced and metastatic progressive disease were treated with DPX-Survivac, intermittent low dose CPA with or without E. In the Phase 1b, 53 subjects were enrolled to receive DPX-Survivac, low dose CPA and E BID. In the Phase 2, 12 subjects were randomized to receive DPX-Survivac and low dose CPA with or without E. The data on immunological responses, biomarkers, and clinical responses were analyzed in relation to the baseline sum of target lesions per RECIST 1.1. Results: The study showed that DPX-Survivac and intermittent low dose CPA with or without E can generate strong T cell responses. The infiltration of tumors with survivin-specific T cells correlates with the observed tumor regression. The sum of target tumor measurements at baseline by RECIST 1.1 correlated with observed clinical benefits. In the group of 15 patients with the baseline sum of target lesions less than 5 cm, all subjects have shown clinical benefits. Four of these subjects reached partial response and remained without progression over a prolonged period. Conclusions: The treatment studied leads to strong survivin-specific T cell responses. Infiltration of tumors by survivin-specific T cells correlated with clinical benefit in treated subjects. A predictive model based on tumor size to improve response to DPX-Survivac in recurrent ovarian cancer is being prospectively explored. Clinical trial information: NCT02785250.

87P - New clinical data from the DeCidE1 trial: Results on DPX-Survivac, low dose cyclophosphamide (CPA), and epacadostat (INCB024360) in subjects with advanced recurrent epithelial ovarian cancer

87P - New clinical data from the DeCidE1 trial: Results on DPX-Survivac, low dose cyclophosphamide (CPA), and epacadostat (INCB024360) in subjects with advanced recurrent epithelial ovarian cancer

Alisertib in Combination With Weekly Paclitaxel in Patients With Advanced Breast Cancer or Recurrent Ovarian Cancer

There is an unmet medical need for the treatment of recurrent ovarian cancer, and new approaches are needed to improve progression-free survival (PFS) and overall survival. This phase 1/2 study evaluated the activity of alisertib in combination with weekly paclitaxel in patients with breast (phase 1) and ovarian cancer (phase 1 and phase 2). An open-label phase 1 and randomized phase 2 clinical trial conducted from April 16, 2010, for phase 1 and March 28, 2012, to August 12, 2013, for phase 2 was conducted at 33 sites (United States, France, and Poland). Data are reported from a cutoff date of August 12, 2014, with a median duration of follow-up of 7.2 months in the alisertib plus paclitaxel arm and 4.6 months in the paclitaxel arm. A total of 191 women with advanced breast (phase 1 only) or recurrent ovarian cancer were enrolled, including 142 patients randomized to alisertib plus paclitaxel (n = 73) or paclitaxel alone (n = 69) in the phase 2 study. Patients were randomized 1:1 stratified by platinum-free interval (refractory, 0-6 months, 6-12 months) and prior weekly taxane treatment (yes, no) to receive alisertib 40 mg twice per day orally and 3 days on and 4 days off for 3 weeks, plus paclitaxel (60 mg/m2 intravenously, days 1, 8, and 15), or weekly paclitaxel 80 mg/m2 intravenously in 28-day cycles. Primary endpoint was PFS; primary efficacy analysis and safety analysis used modified intention to treat (mITT) population (all randomized patients who received ≥1 dose of study drug). The median age for the 191 patients enrolled in phase 1 was 59 (range, 29-75) years. The median age for the 142 patients enrolled in phase 2 was 63 (range, 30-81) years for patients receiving alisertib plus paclitaxel and 61 (range, 41-81) years for patients receiving paclitaxel. At data cutoff, 107 (75%) patients had a documented PFS event; 52 (71%) in the alisertib plus paclitaxel arm, and 55 (80%) in the paclitaxel arm. Median PFS was 6.7 months with alisertib plus paclitaxel vs 4.7 months with paclitaxel (HR, 0.75; 80% CI, 0.58-0.96; P = .14; 2-sided P value cutoff = .20 to be considered worthy of further investigation). Drug-related grade 3 or higher adverse events were reported in 63 (86%) vs 14 (20%) patients in the alisertib plus paclitaxel and paclitaxel arms, including 56 (77%) vs 7 (10%) neutropenia, 18 (25%) vs 0 stomatitis, and 10 (14%) vs 2 (3%) anemia; 54 (74%) vs 17 (25%) had adverse events leading to dose reductions. Two patients died during the study (1 in each arm); neither death was considered related to study drug. The primary endpoint, PFS, significantly favored alisertib plus paclitaxel over paclitaxel alone. Further investigation is warranted. ClinicalTrials.gov identifier: NCT01091428.

LBA36 - Association of PD-L1 expression and gene expression profiling with clinical response to pembrolizumab in patients with advanced recurrent ovarian cancer: Results from the phase II KEYNOTE-100 study

LBA36 - Association of PD-L1 expression and gene expression profiling with clinical response to pembrolizumab in patients with advanced recurrent ovarian cancer: Results from the phase II KEYNOTE-100 study

956P - A phase Ib and randomised phase II trial of pazopanib with or without fosbretabulin in advanced recurrent ovarian cancer

Background: Prospective trials have validated angiogenesis as a treatment target in ovarian cancer although improvements in PFS have been modest. One potential strategy to improve efficacy is to combine anti-vascular agents. Fosbretabulin (F) is an intravenous vascular disrupting agent and pazopanib (P) is an oral VEGFR tyrosine kinase inhibitor. Methods: A multi-centre Phase 1b(P1b)/randomised phase 2 (RP2) trial that recruited women with recurrent epithelial ovarian cancer and a platinum-free interval of 3-12 months. Any Bevacizumab had been received ≥6 months prior to recruitment. Phase 1b dose levels ranged from F = 54mg/m2 d1,8,15q28d + P = 600mg/day (F54+P600) up to F = 60mg/m2 d1,8,15q28d + P = 800mg/day. In RP2 participants received either RP2D or P = 800mg/day (P800). Primary outcome in P1b was safety plus RP2D and in RP2 was RECIST PFS. Results: 12 and 21 patients were recruited to P1b & RP2 respectively. The RP2D was F54+P600. In the RP2 median PFS was 7.6 months (95%CI 4.1-not estimated) in F54+P600 group vs. 3.7 months (95%CI 1.0-8.1) in P800 group (HR 0.30, 95%CI 0.08-1.03, P = 0.06). Four patients who received F+P (2 in P1b and 2 in RP2) developed acute hypertension plus reversible secondary cardiac toxicity. The occurrence of cardiac toxicity resulted in premature discontinuation of the trial. Data on circulating biomarkers of angiogenesis collected in in P1b & RP2 will also be presented. Conclusions: F54+P600 appeared effective but was associated with reversible secondary cardiac toxicity that with better hypertension control might have been avoided. Clinical trial identification: EudraCT: 2013-005471-40. Legal entity responsible for the study: The Christie NHS Foundation Trust. Funding: Novartis & Mateon Therapeutics. Disclosure: G.J.S. Rustin: Advisory board: Mateon, Roche, AstraZeneca in past 3 years, only Roche in past year. All other authors have declared no conflicts of interest.

Antitumor activity and safety of pembrolizumab in patients with advanced recurrent ovarian cancer: Interim results from the phase 2 KEYNOTE-100 study.

5511Background: Data from the KEYNOTE-028 study (NCT02054806) suggested that pembrolizumab (pembro) has clinical activity in patients (pts) with PD-L1+ advanced ovarian cancer (AOC). We assessed th...

TOPACIO/Keynote-162 (NCT02657889): A phase 1/2 study of niraparib + pembrolizumab in patients (pts) with advanced triple-negative breast cancer or recurrent ovarian cancer (ROC)—Results from ROC cohort.

106Background: Platinum-resistant OC (PROC) has few treatment options. Niraparib is an oral PARP inhibitor (PARPi) approved for maintenance treatment of ROC. Anti–programmed death (PD)–1 monotherap...

Efficacy and safety of the traditional Japanese herbal medicine kamikihito for bone marrow suppression, particularly thrombocytopenia, during chemotherapy for advanced recurrent ovarian cancer

ABSTRACTAimThe aim of this study was to evaluate the efficacy and safety of the traditional herbal medicine kamikihito for bone marrow suppression, particularly thrombocytopenia, during cancer chemotherapy.MethodsThis retrospective pilot study investigated changes in hemoglobin (Hb) and neutrophil and platelet (Plt) count from before to after kamikihito treatment in nine patients with advanced recurrent ovarian cancer who developed grade ≥3 thrombocytopenia during chemotherapy (13 and 16 cycles before and after kamikihito use, respectively).ResultsAlthough the nadir Hb did not change significantly, the degree of change in Hb (baseline – nadir) during respective chemotherapy cycles (before vs after kamikihito use: 1.8 vs 1.0 g/dL), was significantly mitigated after kamikihito use. The nadir neutrophil count and degree of change in neutrophil count did not differ with kamikihito use. The nadir Plt count was slightly higher after kamikihito use (before, 2.9 × 104/μL; after, 3.4 × 104/μL), and the degree of change in Plt count (before, 12.7 × 104/μL vs after, 10.9 × 104/μL), was significantly mitigated after kamikihito use. Finally, significantly fewer days were required for Plt recovery from the nadir to a ≤grade 2 Plt count decrease after kamikihito use (before, 9.3 days; after, 5.8 days).ConclusionIn patients undergoing chemotherapy for advanced recurrent ovarian cancer, kamikihito could alleviate anemia and thrombocytopenia and reduce the risk of requiring blood transfusion. Future prospective studies with larger sample sizes are warranted to accumulate further data.

Aurora A Functional Single Nucleotide Polymorphism (SNP) Correlates With Clinical Outcome in Patients With Advanced Solid Tumors Treated With Alisertib, an Investigational Aurora A Kinase Inhibitor

BackgroundAlisertib (MLN8237) is an investigational, oral, selective Aurora A kinase inhibitor. Aurora A contains two functional single nucleotide polymorphisms (SNPs; codon 31 [F/I] and codon 57 [V/I]) that lead to functional changes. This study investigated the prognostic and predictive significance of these SNPs. MethodsThis study evaluated associations between Aurora A SNPs and overall survival (OS) in The Cancer Genome Atlas (TCGA) database. The Aurora A SNPs were also evaluated as predictive biomarkers for clinical outcomes to alisertib in two phase 2 studies (NCT01045421 and NCT01091428). Aurora A SNP genotyping was obtained from 85 patients with advanced solid tumors receiving single-agent alisertib and 122 patients with advanced recurrent ovarian cancer treated with alisertib plus weekly paclitaxel (n=62) or paclitaxel alone (n=60). Whole blood was collected prior to treatment and genotypes were analyzed by PCR. FindingsTCGA data suggested prognostic significance for codon 57 SNP; solid tumor patients with VV and VI alleles had significantly reduced OS versus those with II alleles (HR 1.9 [VI] and 1.8 [VV]; p<0.0001). In NCT01045421, patients carrying the VV alleles at codon 57 (n=53, 62%) had significantly longer progression-free survival (PFS) than patients carrying IV or II alleles (n=32, 38%; HR 0.5; p=0.0195). In NCT01091428, patients with the VV alleles at codon 57 who received alisertib plus paclitaxel (n=47, 39%) had a trend towards improved PFS (7.5months) vs paclitaxel alone (n=32, 26%; 3.8months; HR 0.618; p=0.0593). In the paclitaxel alone arm, patients with the VV alleles had reduced PFS vs modified intent-to-treat (mITT) patients (3.8 vs 5.1months), consistent with the TCGA study identifying the VV alleles as a poor prognostic biomarker. No significant associations were identified for codon 31 SNP from the same data set. InterpretationThese findings suggest that Aurora A SNP at codon 57 may predict disease outcome and response to alisertib in patients with solid tumors. Further investigation is warranted.

Tolerance and toxicity of the PARP inhibitor olaparib in older women with epithelial ovarian cancer

The objective of this study was to determine the overall tolerability and toxicity of olaparib capsules among older (≥65years) patients with recurrent ovarian cancer treated on 8 completed prospective trials of olaparib. An ancillary data analysis of 398 patients with recurrent ovarian cancer enrolled on eight prospective trials of olaparib capsules was performed. Patients aged 65years and older were stratified into age groups by 5year increments (ages 65-69, 70-74, ≥75years) and compared to those <65. Analysis was restricted to those patients receiving the recommended treatment dose of 400mg PO b.i.d. Of the 398 patients included, 78 were ≥65 (age 65-69 n=38, age 70-74 n=23, age≥75 n=17). The majority of elderly patients were Caucasian (n=2 Asian) and had received ≥5 prior lines of chemotherapy. In patients <65, 46.9% required dose reduction as compared to 44.7% of patients 65-69years, 47.8% of patients 70-74years, and 64.7% of patients ≥75years (p=0.62). In patients <65years 41.2% required dose interruption, as compared to 50%, 43.5%, and 64.7% of patients aged 65-69, 70-74, and ≥75, respectively (p=0.11). There were no occurrences of myelodysplastic syndrome or acute myeloid leukemia in any of the older cohorts. Toxicities, including grade 3/4 nausea, were similar across age groups. Tolerability and toxicity of olaparib capsules is similar between women ≥65years and <65years of age treated for advanced recurrent ovarian cancer. Use of olaparib should be considered in this patient population.

Targeted therapy for ovarian cancer: the rapidly evolving landscape of PARP inhibitor use.

Poly(ADP-ribose) polymerase (PARP) inhibitors are a targeted therapy option for ovarian cancer. The goal of this review was to organize and summarize the clinical trials evaluating PARP inhibitor therapy in ovarian cancer as monotherapy, maintenance therapy after partial or complete remission to therapy or as a part of a combination regimen. PubMed, ClinicalTrials.gov, data from the United States Food and Drug Administration (US FDA) and proceedings from scientific conferences were searched for published and unpublished data pertaining to clinical trials and approvals of PARP inhibitor use in ovarian cancer. There have been 36 published phase 1, 2 and 3 studies evaluating the use of olaparib, niraparib, veliparib and rucaparib in ovarian cancer. Olaparib and rucaparib have been approved by the US FDA as monotherapy for advanced recurrent ovarian cancer. Niraparib and olaparib have been approved by the US FDA for maintenance therapy after partial or complete remission in recurrent ovarian cancer. There are currently ten phase 3 trials evaluating PARP inhibitors at various timepoints in ovarian cancer therapy including at the time of primary adjuvant therapy, as maintenance therapy after primary chemotherapy, as monotherapy for recurrent cancer and as maintenance therapy after chemotherapy for recurrence. The landscape of PARP inhibitor use for ovarian cancer is rapidly evolving and PARP inhibitors have become more available as a targeted therapy option for ovarian cancer treatment.

Progress in the management of primary and recurrent ovarian carcinomatosis with peritonectomy procedure and HIPEC in a high volume centre

Introduction: The treatment of advanced primary or recurrent ephitelial ovarian cancer still remains an open and a critical question. The addition of HIPEC to cytoreductive surgery has shown improving overall survival rates. The aim of our study is to describe the progress in its management in our Unit and what we have learned after more than 350 HIPEC procedures.Methods: From 1997 to 2016 we conducted a retrospective analysis from a prospective database. We described and analyzed 4 cut-points, 1997–2004, 2009, 2012 and 2016.Results: From 1997 to September 2016, 358 patients have been operated in our Unit by CRS with peritonectomy procedures plus HIPEC for stage IIIc and IV ovarian cancer. The HIPEC procedures rate was 4,7 HIPEC per years in the first years up to 35 HIPEC/year in last era. Mean age was 56,7 years (28–78). Median PCI was 15,8. (range 3–36). R0-cytoreduction was 95%. Severe morbidity and mortality were observed in 15 % and 2%, respectively. The 3 y OS was 77% in primary and 79% in recurrent ovarian cancer. The stage IV was not a risk factor for survival. R1 cytoreduction and positive lymph nodes were risk factors in multivariate analysis.Conclusion: The addition of HIPEC to CRS improves overall survival rates for primary and recurrent ovarian cancer. This therapeutic strategy was incorporated twenty years ago for a few teams in the world and today there is an emerging and strong evidence that could consider it as an standard treatment for the ovarian carcinomatosis.

Abstract NTOC-097: VACCINATION TARGETING INSULIN–LIKE GROWTH FACTOR BINDING PROTEIN–2 (IGFBP–2) IN ADVANCED OVARIAN CANCER: SAFETY, IMMUNOGENICITY, AND SURVEILLANCE, EPIDEMIOLOGY, AND END RESULTS (SEER) COMPARISON

Abstract BACKGROUND: Immunization against self-antigens can induce regulatory responses that inhibit desirable Type 1 antitumor immune responses. Deletion of epitopes that favor a regulatory phenotype may improve the efficacy of therapeutic vaccines. We have developed a novel IGFBP-2 targeting DNA plasmid vaccine that selectively induces Type 1 immunity. IGFBP-2 regulates invasiveness and metastases in ovarian cancer. Eradication of ovarian cancer cells expressing IGFBP-2 through effective immunization could prevent disease relapse or metastasis. METHODS: Twenty-five patients with advanced stage or recurrent ovarian cancer treated to complete remission after primary or salvage therapy received 3 monthly doses of an IGFBP-2 DNA vaccine in a single-arm, non-randomized study. ELISPOT and flow cytometry were used to characterize antigen specific T-cell responses. Serum antibodies were measured using ELISA and Western blot. The SEER database was reviewed to identify women diagnosed between 2006 and 2012 matched for age, year of diagnosis and stage of diagnosis. The difference between dates of diagnosis and enrollment (lead time) was calculated for each patient receiving vaccine. Only SEER patients who survived at least as long as the lead time of their matches plus an additional 6 months were kept for analysis. In cases where this resulted in no SEER matched patients, unmatched vaccine patients were excluded. Overall survival (OS) was analyzed using Cox models and the Kaplan-Meier method. RESULTS: 206 adverse events (AE) were recorded. Fatigue (12%) and injection site reactions (12%) were the most common. 97% of AE were grades 1-2, 3% grade 3, and no grades 4 or 5. In preliminary immune analysis (16 patients), IGFBP-2 specific T-cell precursor frequencies are significantly elevated over baseline levels at 4 (p&amp;lt;0.01) and 6 (p&amp;lt;0.001) months. T-regulatory cells were not increased over the levels measured in a control reference population. No patients developed new IGFBP-2 specific antibody responses after immunization suggesting a lack of Th2 augmentation. Median OS for the matched SEER group (n=754) was 11 months. Matched IGFBP-2 vaccinated patients (n=20) have yet to reach median OS, but the lower 95% confidence limit is 27.3 months (p&amp;lt;0.0001). CONCLUSIONS: IGFBP-2 Th1 selective immunization is well tolerated, generates significant Type I immunity, and may demonstrate clinical efficacy. Citation Format: John B. Liao, Denise L. Cecil, Yushe Dang, Kelsey K. Baker, Kelsie J. Ovenell, Jessica Reichow, Stephanie Parker, Doreen M. Higgins, Jennifer S. Childs, Elizabeth K. Broussard, Andrew L. Coveler, Lupe G. Salazar, Barbara A. Goff, Mary W. Redman, Mary L. Disis. VACCINATION TARGETING INSULIN–LIKE GROWTH FACTOR BINDING PROTEIN–2 (IGFBP–2) IN ADVANCED OVARIAN CANCER: SAFETY, IMMUNOGENICITY, AND SURVEILLANCE, EPIDEMIOLOGY, AND END RESULTS (SEER) COMPARISON [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 NTOC-097.