Safety and efficacy of the tumor-selective adenovirus enadenotucirev with or without paclitaxel in platinum-resistant ovarian cancer: a phase 1 clinical trial.

BACKGROUND: Treatment outcomes remain poor in recurrent platinum-resistant ovarian cancer. Enadenotucirev, a tumor-selective and blood stable adenoviral vector, has demonstrated a manageable safety profile in phase 1 studies in epithelial solid tumors. METHODS: We conducted a multicenter, open-label, phase 1 dose-escalation and dose-expansion study (OCTAVE) to assess enadenotucirev plus paclitaxel in patients with platinum-resistant epithelial ovarian cancer. During phase 1a, the maximum tolerated dose of intraperitoneally administered enadenotucirev monotherapy (three doses; days 1, 8 and 15) was assessed using a 3+3 dose-escalation model. Phase 1b included a dose-escalation and an intravenous dosing dose-expansion phase assessing enadenotucirev plus paclitaxel. For phase 1a/b, the primary objective was to determine the maximum tolerated dose of enadenotucirev (with paclitaxel in phase 1b). In the dose-expansion phase, the primary endpoint was progression-free survival (PFS). Additional endpoints included response rate and T-cell infiltration. RESULTS: Overall, 38 heavily pretreated patients were enrolled and treated. No dose-limiting toxicities were observed at any doses. However, frequent catheter complications led to the discontinuation of intraperitoneal dosing during phase 1b. Intravenous enadenotucirev (1×1012 viral particles; days 1, 3 and 5 every 28-days for two cycles) plus paclitaxel (80 mg/m2; days 9, 16 and 23 of each cycle) was thus selected for dose-expansion. Overall, 24/38 (63%) patients experienced at least 1 Grade ≥3 treatment-emergent adverse event (TEAE); most frequently neutropenia (21%). Six patients discontinued treatment due to TEAEs, including one patient due to a grade 2 treatment-emergent serious AE of catheter site infection (intraperitoneal enadenotucirev monotherapy). Among the 20 patients who received intravenous enadenotucirev plus paclitaxel, 4-month PFS rate was 64% (median 6.2 months), objective response rate was 10%, 35% of patients achieved stable disease and 65% of patients had a reduction in target lesion burden at ≥1 time point. Five out of six patients with matched pre-treatment and post-treatment biopsies treated with intravenous enadenotucirev plus paclitaxel had increased (mean 3.1-fold) infiltration of CD8 +T cells in post-treatment biopsies. CONCLUSIONS: Intravenously dosed enadenotucirev plus paclitaxel demonstrated manageable tolerability, an encouraging median PFS and increased tumor immune-cell infiltration in platinum-resistant ovarian cancer. TRIAL REGISTRATION NUMBER: NCT02028117.

Effect of oxaliplatin plus 5-fluorouracil or capecitabine on circulating and imaging biomarkers in patients with metastatic colorectal cancer: a prospective biomarker study.

BACKGROUND: Patients with metastatic colorectal cancer are treated with cytotoxic chemotherapy supplemented by molecularly targeted therapies. There is a critical need to define biomarkers that can optimise the use of these therapies to maximise efficacy and avoid unnecessary toxicity. However, it is important to first define the changes in potential biomarkers following cytotoxic chemotherapy alone. This study reports the impact of standard cytotoxic chemotherapy across a range of circulating and imaging biomarkers. METHODS: A single-centre, prospective, biomarker-driven study. Eligible patients included those diagnosed with colorectal cancer with liver metastases that were planned to receive first line oxaliplatin plus 5-fluorouracil or capecitabine. Patients underwent paired blood sampling and magnetic resonance imaging (MRI), and biomarkers were associated with progression-free survival (PFS) and overall survival (OS). RESULTS: Twenty patients were recruited to the study. Data showed that chemotherapy significantly reduced the number of circulating tumour cells as well as the circulating concentrations of Ang1, Ang2, VEGF-A, VEGF-C and VEGF-D from pre-treatment to cycle 2 day 2. The changes in circulating concentrations were not associated with PFS or OS. On average, the MRI perfusion/permeability parameter, Ktrans, increased in response to cytotoxic chemotherapy from pre-treatment to cycle 2 day 2 and this increase was associated with worse OS (HR 1.099, 95%CI 1.01-1.20, p = 0.025). CONCLUSIONS: In patients diagnosed with colorectal cancer with liver metastases, treatment with standard chemotherapy changes cell- and protein-based biomarkers, although these changes are not associated with survival outcomes. In contrast, the imaging biomarker, Ktrans, offers promise to direct molecularly targeted therapies such as anti-angiogenic agents.

Antiangiogenic therapy in oncology: current status and future directions.

Angiogenesis, the formation of new blood vessels from pre-existing vessels, has been validated as a target in several tumour types through randomised trials, incorporating vascular endothelial growth factor (VEGF) pathway inhibitors into the therapeutic armoury. Although some tumours such as renal cell carcinoma, ovarian and cervical cancers, and pancreatic neuroendocrine tumours are sensitive to these drugs, others such as prostate cancer, pancreatic adenocarcinoma, and melanoma are resistant. Even when drugs have yielded significant results, improvements in progression-free survival, and, in some cases, overall survival, are modest. Thus, a crucial issue in development of these drugs is the search for predictive biomarkers-tests that predict which patients will, and will not, benefit before initiation of therapy. Development of biomarkers is important because of the need to balance efficacy, toxicity, and cost. Novel combinations of these drugs with other antiangiogenics or other classes of drugs are being developed, and the appreciation that these drugs have immunomodulatory and other modes of action will lead to combination regimens that capitalise on these newly understood mechanisms.

Preclinical evaluation of the pharmacodynamic properties of 2,5-diaziridinyl-3-hydroxymethyl-6-methyl-1,4-benzoquinone.

PURPOSE: The purpose of our study was to investigate the cellular accumulation, DNA cross-linking ability, and cellular toxicity of RH1 (2,5-diaziridinyl-3-[hydroxymethyl[-6-methyl-1,4-benzoquinone), a novel DNA alkylating agent currently in clinical trials. In addition, the in vivo efficacy of RH1 formulated in different vehicles was also compared. EXPERIMENTAL DESIGN: RH1 is activated by the two-electron reducing enzyme NQO1 [NADPH:quinone oxidoreductase] forming a potent cytotoxic agent that cross-links DNA. We have used whole blood, cell lines, and primary explanted tumor cultures to measure both the cellular accumulation, DNA cross-linking, and cytotoxicity of RH1. Furthermore, the pharmacokinetic and pharmacodynamic characteristics of RH1 formulated in different vehicles were measured in vivo using the validated comet-X assay in mice bearing human tumor xenografts. RESULTS: Accumulation of RH1 was shown to be both time and concentration dependent, reaching a maximum after 2 hours and correlated well with DNA cross-linking measurements. DNA cross-linking in vitro could be detected at low (1-10 nmol/L) concentrations after as little as 2 hours exposure. In primary tumor cultures, RH1 induces much higher levels of DNA cross-links at lower doses than either mitomycin C or cisplatin. In vivo efficacy testing using polyvinyl pyrrolidone, saline, or cyclodextrin as vehicles showed DNA cross-links readily detectable in all tissues examined and was enhanced when given in cyclodextrin compared with polyvinyl pyrrolidone or saline. CONCLUSIONS: RH1 represents a potent bioreductive anticancer drug, which may prove effective in the treatment of cancers, particularly those that overexpress NQO1. DNA cross-linking can be reliably measured in tissue using the validated comet-X assay.

Phase III randomized trial of docetaxel-carboplatin versus paclitaxel-carboplatin as first-line chemotherapy for ovarian carcinoma.

BACKGROUND: Chemotherapy with a platinum agent and a taxane (paclitaxel) is considered the standard of care for treatment of ovarian carcinoma. We compared the combination of docetaxel-carboplatin with the combination of paclitaxel-carboplatin as first-line chemotherapy for stage Ic-IV epithelial ovarian or primary peritoneal cancer. METHODS: We randomly assigned 1077 patients to receive docetaxel at 75 mg/m2 of body surface area (1-hour intravenous infusion) or paclitaxel at 175 mg/m2 (3-hour intravenous infusion). Both treatments then were followed by carboplatin to an area under the plasma concentration-time curve of 5. The treatments were repeated every 3 weeks for six cycles; in responding patients, an additional three cycles of single-agent carboplatin was permitted. Survival curves were calculated by the Kaplan-Meier method, and hazard ratios were estimated with the Cox proportional hazards model. All statistical tests were two-sided. RESULTS: After a median follow-up of 23 months, both groups had similar progression-free survival (medians of 15.0 months for docetaxel-carboplatin and 14.8 months for paclitaxel-carboplatin; hazard ratio [HR] docetaxel-paclitaxel = 0.97, 95% confidence interval [CI] = 0.83 to 1.13; P = .707), overall survival rates at 2 years (64.2% and 68.9%, respectively; HR = 1.13, 95% CI = 0.92 to 1.39; P = .238), and objective tumor (58.7% and 59.5%, respectively; difference between docetaxel and paclitaxel = -0.8%, 95% CI = -8.6% to 7.1%; P = .868) and CA-125 (75.8% and 76.8%, respectively; difference docetaxel-paclitaxel = -1.0%, 95% CI = -7.2% to 5.1%; P = .794) response rates. However, docetaxel-carboplatin was associated with substantially less overall and grade 2 or higher neurotoxicity than paclitaxel-carboplatin (grade > or =2 neurosensory toxicity in 11% versus 30%, difference = 19%, 95% CI = 15% to 24%; P<.001; grade > or =2 neuromotor toxicity in 3% versus 7%, difference = 4%, 95% CI = 1% to 7%; P<.001). Treatment with docetaxel-carboplatin was associated with statistically significantly more grade 3-4 neutropenia (94% versus 84%, difference = 11%, 95% CI = 7% to 14%; P<.001) and neutropenic complications than treatment with paclitaxel-carboplatin, although myelosuppression did not influence dose delivery or patient safety. Global quality of life was similar in both arms, but substantive differences in many symptom scores favored docetaxel. CONCLUSIONS: Docetaxel-carboplatin appears to be similar to paclitaxel-carboplatin in terms of progression-free survival and response, although longer follow-up is required for a definitive statement on survival. Thus, docetaxel-carboplatin represents an alternative first-line chemotherapy regimen for patients with newly diagnosed ovarian cancer.

Molecular imaging and biological evaluation of HuMV833 anti-VEGF antibody: implications for trial design of antiangiogenic antibodies.

BACKGROUND: Vascular endothelial growth factor (VEGF) is a potent angiogenic cytokine, and various inhibitory agents, including specific antibodies, have been developed to block VEGF-stimulated angiogenesis. We developed HuMV833, a humanized version of a mouse monoclonal anti-VEGF antibody (MV833) that has antitumor activity against a number of human tumor xenografts, and investigated the distribution and biologic effects of HuMV833 in patients in a phase I trial. METHODS: Twenty patients with progressive solid tumors were treated with various doses of HuMV833 (0.3, 1, 3, or 10 mg/kg). Positron emission tomography with (124)I-HuMV833 was used to measure the antibody distribution in and clearance from tissues. Magnetic resonance imaging was used to measure the vascular permeability surface area product with a first-pass pharmacokinetic model (k(fp)) to determine tumor vascular permeability. RESULTS: The antibody was generally well tolerated, although the incremental dose, phase I study design, and pharmacodynamic endpoints could not identify the optimum biologically active dose. Antibody distribution and clearance were markedly heterogeneous between and within patients and between and within individual tumors. HuMV833 distribution to normal tissues also varied among patients, but the antibody was cleared from these tissues in a homogeneous fashion. Permeability was strongly heterogeneous between and within patients and between and within individual tumors. All tumors showed a reduction in k(fp) 48 hours after the first treatment (median = 44%; range = 4%-91%). CONCLUSIONS: Because of the heterogeneity in tumor biology with respect to antibody uptake and clearance, we suggest that either intrapatient dose escalation approaches or larger, more precisely defined patient cohorts would be preferable to conventional strategies in the design of phase I studies with antiangiogenic compounds like HuMV833.