A Randomized Phase II Trial of Epigenetic Priming with Guadecitabine and Carboplatin in Platinum-resistant, Recurrent Ovarian Cancer.

PURPOSE: Platinum resistance in ovarian cancer is associated with epigenetic modifications. Hypomethylating agents (HMA) have been studied as carboplatin resensitizing agents in ovarian cancer. This randomized phase II trial compared guadecitabine, a second-generation HMA, and carboplatin (G+C) against second-line chemotherapy in women with measurable or detectable platinum-resistant ovarian cancer. PATIENTS AND METHODS: Patients received either G+C (guadecitabine 30 mg/m2 s.c. once-daily for 5 days and carboplatin) or treatment of choice (TC; topotecan, pegylated liposomal doxorubicin, paclitaxel, or gemcitabine) in 28-day cycles until progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS); secondary endpoints were RECIST v1.1 and CA-125 response rate, 6-month PFS, and overall survival (OS). RESULTS: Of 100 patients treated, 51 received G+C and 49 received TC, of which 27 crossed over to G+C. The study did not meet its primary endpoint as the median PFS was not statistically different between arms (16.3 weeks vs. 9.1 weeks in the G+C and TC groups, respectively; P = 0.07). However, the 6-month PFS rate was significantly higher in the G+C group (37% vs. 11% in TC group; P = 0.003). The incidence of grade 3 or higher toxicity was similar in G+C and TC groups (51% and 49%, respectively), with neutropenia and leukopenia being more frequent in the G+C group. CONCLUSIONS: Although this trial did not show superiority for PFS of G+C versus TC, the 6-month PFS increased in G+C treated patients. Further refinement of this strategy should focus on identification of predictive markers for patient selection.

Comparing glomerular filtration rate equations and the impact of different creatinine assays on the assessment of renal function in cancer patients.

BACKGROUND: Equations to estimate glomerular filtration rate based on serum creatinine are commonly used in cancer patients to assess renal function. However, there is uncertainty regarding which equation is most appropriate for this population and the impact of different creatinine assays. METHODS: Measured isotopic glomerular filtration rate results from 120 oncology patients were used to evaluate and compare all four versions of the Wright equation, Cockcroft and Gault, Modification of Diet in Renal Disease (MDRD), Chronic Kidney Disease Epidemiology Collaboration and the Janowitz and Williams formula; using eight different creatinine assays (five Jaffe, three enzymatic). RESULTS: The enzymatic version of the Wright equation without creatine kinase performed better than the other versions for all eight creatinine assays. However, MDRD and Janowitz and Williams gave the best overall performance in this patient population. Performance was highly dependent on the creatinine assay used, for example, the percentage of results within 30% of the isotopic glomerular filtration rate (P30) ranged from 90.8% to 60.8% for MDRD. CONCLUSION: The performance of any equation to estimate glomerular filtration rate is highly dependent on the creatinine assay used. Oncology units should assess the performance of glomerular filtration rate equations using their laboratory creatinine assay to determine whether they can be used safely and effectively in cancer patients.

Copy number signatures and mutational processes in ovarian carcinoma.

The genomic complexity of profound copy number aberrations has prevented effective molecular stratification of ovarian cancers. Here, to decode this complexity, we derived copy number signatures from shallow whole-genome sequencing of 117 high-grade serous ovarian cancer (HGSOC) cases, which were validated on 527 independent cases. We show that HGSOC comprises a continuum of genomes shaped by multiple mutational processes that result in known patterns of genomic aberration. Copy number signature exposures at diagnosis predict both overall survival and the probability of platinum-resistant relapse. Measurement of signature exposures provides a rational framework to choose combination treatments that target multiple mutational processes.

NuMA overexpression in epithelial ovarian cancer.

Highly aneuploid tumours are common in epithelial ovarian cancers (EOC). We investigated whether NuMA expression was associated with this phenomenon.NuMA protein levels in normal and tumour tissues, ovarian cell lines and primary cultures of malignant cells derived from ovarian ascitic fluids were analysed by Affymetrix microarray analysis, immunoblotting, immunohistochemistry (IHC) and immunofluorescence (IF), with results correlated to associated clinical data. Aneuploidy status in primary cultures was determined by FACS analysis.Affymetrix microarray data indicated that NuMA was overexpressed in tumour tissue, primary cultures and cell lines compared to normal ovarian tissue. IHC revealed low to weak NuMA expression in normal tissues. Expression was upregulated in tumours, with a significant association with disease stage in mucinous EOC subtypes (p = 0.009), lymph node involvement (p = 0.03) and patient age (p = 0.04). Additional discontinuous data analysis revealed that high NuMA levels in tumours decreased with grade (p = 0.02) but increased with disease stage (p = 0.04) in serous EOC. NuMA expression decreased in late disease stage 4 endometrioid EOCs. High NuMA levels decreased with increased tumour invasion in all subtypes (p = 0.03). IF of primary cultures revealed that high NuMA levels at mitotic spindle poles were significantly associated with a decreased proportion of cells in cytokinesis (p = 0.05), increased binucleation (p = 0.021) and multinucleation (p = 0.007), and aneuploidy (p = 0.008).NuMA is highly expressed in EOC tumours and high NuMA levels correlate with increases in mitotic defects and aneuploidy in primary cultures.

Phase I/II trial of carboplatin and paclitaxel chemotherapy in combination with intravenous oncolytic reovirus in patients with advanced malignancies.

PURPOSE: Reovirus type 3 Dearing (RT3D) replicates preferentially in Ras-activated cancers. RT3D shows synergistic in vitro cytotoxicity in combination with platins and taxanes. The purpose of this phase I/II study was to assess RT3D combined with carboplatin/paclitaxel in patients with advanced cancers. EXPERIMENTAL DESIGN: Patients were initially treated in a dose-escalating, phase I trial with intravenous RT3D days 1 to 5, carboplatin [area under curve (AUC) 5, day 1] and paclitaxel (175 mg/m(2), day 1) 3-weekly. RT3D was escalated through three dose levels: 3 × 10(9), 1 × 10(10), and 3 × 10(10) TCID(50) in cohorts of three. Primary endpoints were to define the maximum tolerated dose and dose-limiting toxicity and to recommend a dose for phase II studies. Secondary endpoints included pharmacokinetics, immune response, and antitumor activity. A subsequent phase II study using the 3 × 10(10) TCID(50) dose characterized the response rate in patients with head and neck cancer. RESULTS: Thirty-one heavily pretreated patients received study therapy. There were no dose-limiting toxicities during dose-escalation and most toxicities were grade I/II. Overall effectiveness rates were as follows: one patient had a complete response (3.8%), six patients (23.1%) had partial response, two patients (7.6%) had major clinical responses clinically evaluated in radiation pretreated lesions which are not evaluable by Response Evaluation Criteria in Solid Tumors (RECIST), nine patients (34.6%) had stable disease, and eight patients (30.8%) had disease progression. Viral shedding was minimal and antiviral immune responses were attenuated compared with previous single-agent data for RT3D. CONCLUSIONS: The combination of RT3D plus carboplatin/paclitaxel is well tolerated with evidence of activity in cancer of the head and neck. A randomized phase III study is currently open for recruitment.

The prognostic and predictive value of CA-125 regression during neoadjuvant chemotherapy for advanced ovarian or primary peritoneal carcinoma.

PURPOSE: To assess the significance of CA-125 regression as a prognostic indicator and predictor of optimal cytoreduction at interval debulking surgery (IDS) in women with ovarian or primary peritoneal carcinoma receiving neoadjuvant chemotherapy (NAC). METHODS: 63 women treated between 2004 and 2007 with neoadjuvant platinum-based chemotherapy followed by IDS were studied retrospectively. Pre-operative CA-125 values were used to calculate a regression coefficient (CA-125r) using exponential regression analysis. Outcome endpoints were overall survival (OS), time to CA-125 progression (TTC) by Rustin criteria and time to second-line treatment (TTS). RESULTS: Women with a CA-125 half-life greater than 18 days had a significantly worse OS compared to those with a half-life less than 12 days on univariate testing (HR 3.34, 95% CI 1.25-8.94, p = 0.017). On multivariable analysis, CA-125r was an independent predictor of OS [HR 1.18 (per 0.01 increase in CA-125r), 95% CI 1.01-1.40, p = 0.043]. CA-125r was independently predictive of TTC and TTS (HR 1.17, p ≈ 0.03 for each). CA-125r was also predictive of achieving optimal cytoreduction at IDS (AUC 0.756, p < 0.001). CONCLUSIONS: CA-125 regression rate during pre-operative NAC is of independent prognostic value. CA-125 regression rate strongly predicts for optimal cytoreduction.

Development of antiangiogenic agents for ovarian cancer.

Epithelial ovarian cancer (EOC) remains a major source of cancer morbidity and mortality, despite advances in surgical and chemotherapeutic management. The molecular pathways that control angiogenesis have been demonstrated to be key to the pathogenesis of EOC, and have been shown to have prognostic significance. Increased understanding of the pathways and molecules involved in angiogenesis has allowed the identification of a number of targets for antiangiogenic therapies and the development of a variety of antiangiogenic drugs. There is now significant preclinical evidence, and a growing body of clinical data, demonstrating promising results with antiangiogenic drugs in the treatment of EOC. Single-agent VEGF inhibitor response rates in pretreated patients of between 15 and 20% have been reported, with much higher response rates when used in combination with chemotherapeutic agents. These benefits, however, must be balanced with the toxicities associated with these drugs, particularly the more serious ones, such as gastrointestinal perforation. The results of ongoing and future randomized clinical trials will confirm if, and how, antiangiogenic therapies should be integrated into the routine management of EOC. However, critical issues, such as the relative importance of combination remission induction regimens and maintenance therapy, remain poorly defined.