Abstract Objective This phase II, multicenter, single-arm, two-stage study in platinum-resistant, advanced epithelial ovarian or primary peritoneal cancer evaluated the efficacy, safety, and ...tolerability of weekly single-agent volociximab. Pharmacokinetic/pharmacodynamic (PK/PD) studies were also performed. Methods Sixteen patients were enrolled in Stage 1. Volociximab was administered at 15 mg/kg IV qwk until progression of disease or drug intolerability. Tumor response was assessed every 8 weeks. Serum samples for PK or whole blood for the evaluation of circulating tumor cells, endothelial cells, and endothelial progenitor cells were obtained on Days 1, 8, 15, 29, and 50. Ascites from one patient was collected for volociximab concentration analysis. Archived tumor tissue was analyzed by immunohistochemistry (IHC) for α5 integrin expression. Results Safety data are available on all 16 patients; 14 were evaluable for efficacy. One patient had stable disease at 8 weeks. The remaining 13 progressed on treatment. Twelve patients (75%) experienced study-related adverse events (AEs); the most common (≥ 20%) were headache and fatigue. Three patients experienced possible study-related serious AEs (SAEs): reversible posterior leukoencephalopathy syndrome, pulmonary embolism, and hyponatremia. Peak serum concentrations of volociximab increased 2–3 fold from Day 1 to Day 50. Clinically relevant trough levels were achieved (> 150 μg/mL). IHC analysis of archived tumor sections showed low-to-moderate expression of α5 integrin on all ovarian cancer tissue evaluated. Conclusion Despite insufficient clinical activity in this refractory patient population to continue the study, weekly volociximab was well tolerated, and the gained understanding of the mechanism of action of volociximab will inform future development efforts.
Combination cediranib/olaparib has reported activity in relapsed ovarian cancer. This phase 2 trial investigated the activity of cediranib/olaparib in relapsed ovarian cancer and its association with ...homologous recombination deficiency (HRD).
Seventy patients were enrolled to cohorts of either platinum-sensitive or platinum-resistant ovarian cancer and received olaparib tablets 200 mg twice daily and cediranib tablets 30 mg once daily under a continuous dosing schedule. HRD testing was performed on pre-treatment, on-treatment and archival biopsies by sequencing key homologous recombination repair (HRR) genes and by genomic LOH analysis. The primary objective for the platinum-sensitive cohort was the association of HRD, defined as presence of HRR gene mutation, with progression-free survival (PFS). The primary objective for the platinum-resistant cohort was objective response rate (ORR), with a key secondary endpoint evaluating the association of HRD status with activity.
In platinum-sensitive ovarian cancer (N = 35), ORR was 77.1% (95% CI 59.9–89.6%) and median PFS was 16.4 months (95% CI 13.2–18.6). Median PFS in platinum-sensitive HRR-HRD cancers (N = 22) was 16.8 months (95% CI 11.3–18.6), and 16.4 months (95% CI 9.4-NA) in HRR-HR proficient cancers (N = 13; p = 0.57). In platinum-resistant ovarian cancer (N = 35), ORR was 22.9% (95% CI 10.4–40.1%) with median PFS 6.8 months (95% CI 4.2–9.1). Median PFS in platinum-resistant HRR-HRD cancers (N = 7) was 10.5 months (95% CI 3.6-NA) and 5.6 months (95% CI 3.6–7.6) in HRR-HR proficient cancers (N = 18; p = 0.23).
Cediranib/olaparib had clinical activity in both platinum-sensitive and -resistant ovarian cancer. Presence of HRR gene mutations was not associated with cediranib/olaparib activity in either setting.
•Combination cediranib/olaparib has clinical activity in relapsed platinum sensitive and resistant ovarian cancer.•Mutations in homologous recombination repair genes were not associated with clinical activity of cediranib/olaparib.•Exploratory analysis of loss of heterozygosity did not demonstrate association with activity of cediranib/olaparib.
Background Women with ovarian cancer treated with chemotherapeutic platinum agents frequently develop hypersensitivity reactions (HSRs). How best to risk-stratify patients for desensitization is ...uncertain. Objectives To evaluate skin test (ST) reactivity to carboplatin in patients with recent and remote histories of carboplatin HSR and to review the relationship between skin test reactivity and tolerance of subsequent carboplatin desensitization. Methods Thirty-eight women with carboplatin HSR were evaluated by ST to carboplatin. Thirty women subsequently underwent 106 desensitizations to carboplatin. Results Carboplatin ST was positive in 25 of 38 patients (66%). Of patients with recent HSR (<3 months), 20 of 24 (83%) tested positive, whereas 5 of 14 (36%) with remote HSR (>9 months) tested positive ( P < .01). Nineteen carboplatin ST+ and 11 ST− patients underwent desensitization to carboplatin. Seven ST+ patients (37%) had mild HSR during desensitization but completed the desensitization with additional treatment or protocol modification. ST− patients with a recent history of HSR (n = 3) tolerated a rapid protocol without HSR and remained ST– with repeated testing. Six of 8 ST− patients (75%) with remote HSR reacted during desensitization. The HSRs were more severe and often associated with an elevated tryptase level. Five of 7 patients retested became ST+ before the second desensitization. Carboplatin desensitization was successfully completed in 105 of 106 (99%) treatment courses. Conclusions The timing of carboplatin ST in relation to initial HSR is vital for risk stratification and subsequent desensitization. Initial ST− patients with a remote history of HSR are at high risk for conversion to ST+ and can develop more severe HSR.
Breast Cancer Risk Assessment: Moving Beyond BRCA 1 and 2 Scalia-Wilbur, Jennifer, MS; Colins, Bradley L; Penson, Richard T., MD, MRCP ...
Seminars in radiation oncology,
2016, January 2016, 2016-Jan, 2016-01-00, 20160101, Letnik:
26, Številka:
1
Journal Article
Recenzirano
The National Cancer Institute estimates that 12.3% of all women (about 1 in 8) would be diagnosed with breast cancer throughout their lifetime. In 2015, a projected 231,840 new cases are expected in ...the United States, accompanied by 40,290 deaths. Presently, breast cancer is responsible for 6.8% of all cancer deaths, and roughly 30% of all cancers in women. Since the discovery of the BRCA gene in 1994, efforts have been made to develop effective screening methods for breast cancer detection. Although the BRCA gene certainly opened the door to breast cancer genetics, a wide variety of new genes have recently been linked to breast cancer risk, and the tools to screen for genes beyond just BRCA1 and BRCA2 are available. However, the indications for both screening and prevention of inherited predispositions beyond BRCA1 and BRCA2 are not entirely clear, and as a result, much of the ongoing work is aimed at determining the role of broader genetic screening in women deemed at sufficiently high risk for breast cancer based on family history. On this topic, we provide a brief overview of the genes associated with breast cancer risk as well as the technological platforms available to patients. We conclude by discussing recommendations of expert groups and what they practically mean for patients.
Report the results from a preplanned interim analysis of a phase III, double blind, randomized controlled study of ofranergene obadenovec (VB-111), a targeted anti-cancer gene therapy, in combination ...with paclitaxel in patients with platinum resistant ovarian cancer (PROC).
The OVAL (NCT03398655) study is an on-going study where patients are randomly assigned in a 1:1 ratio to weekly paclitaxel 80 mg/m2 with VB-111 or placebo. The protocol specifies a pre-planned unblinded futility interim analysis of CA-125 response per GCIG criteria in the first 60 evaluable patients. The futility rule determined for this analysis was that the response rate of VB-111 must be greater than the response rate of placebo by at least 10% in order to continue the study. Coincident with the interim analysis, the blinded CA-125 response rate was estimated as a proportion of the first 60 evaluable patients with CA-125 response per GCIG criteria. Post-treatment fever is provided as a possible surrogate marker of VB-111 therapy activity.
The median age of the evaluable patients was 62 years (range 41–82); 97% had high-grade serous cancer; 58% had been treated with 3 or more previous lines of therapy, 70% received prior anti-angiogenic treatment, 43% received prior PARP inhibitors. CA-125 response in the VB-111 and weekly paclitaxel treated arm met the pre-specified interim criterion of an absolute advantage of 10% or higher compared to the control. Blinded results show a 53% CA-125 response rate (32/60) with 15% complete response (n=9). Assuming balanced randomization and an absolute advantage of 10% or higher to the VB-111 arm, it may be deducted that the response in the VB-111 treatment arm is 58% or higher. Among patients with post-treatment fever, the CA-125 response rate was 69%.
At the time of the interim analysis, response rate findings are comparable to the responses seen in a similar patient population in the phase I/II study. The independent data and safety monitoring committee (iDSMC) recommended continuing the OVAL trial as planned. No new safety signals were identified.
•OVAL is a Phase III trial using paclitaxel and VB-111 in recurrent ovarian cancer•VB-111 has a dual mechanism targeting tumor vasculature and anti-tumor immunity•CA-125 response in the VB-111 treated arm met the pre-specified interim criterion•Assuming balanced randomization, the response in the VB-111 arm was at least 58%•The OVAL study has been recommended to continue enrollment as planned
PURPOSE New strategies are needed to improve outcomes for patients with advanced ovarian cancer. Bevacizumab is a recombinant humanized monoclonal antibody that neutralizes vascular endothelial ...growth factor but is associated with GI perforations (GIPs) in patients with recurrent disease. PATIENTS AND METHODS An open-label, phase II clinical trial was conducted in newly diagnosed patients with stage > or = IC epithelial müllerian tumors. Patients received intravenous (IV) carboplatin (area under the curve = 5), paclitaxel (175 mg/m(2) IV), and bevacizumab (15 mg/kg IV) for six to eight cycles on day 1 every 21 days. Bevacizumab was omitted in the first cycle and continued as a single agent for 1 year. Results Sixty-two women participated in this study. Fifty-one patients (82%) were optimally surgically cytoreduced before treatment. The median age was 58 years (range, 18 to 77 years). Forty-five women (73%) had ovarian cancer, 10 (16%) had peritoneal cancer, four (6%) had fallopian tube cancers, and three (5%) had uterine papillary serous tumors. The majority of patients (90%) had stage III or IV disease. A median of 17 maintenance cycles (range, 0 to 25+ cycles) of bevacizumab (556 cycles) were administered with mild toxicity. Treatment was associated with two pulmonary embolisms and two GIPs, all occurring during the chemotherapy phase of treatment (364 total cycles). No grade 4 toxicities were seen during maintenance bevacizumab treatment. Radiographic responses were documented in 21 (75%) of 28 women with measurable disease (11 complete responses and 10 partial responses), with CA-125 responses in 76% of patients (11 complete responses, 21%; and 35 partial responses, 55%). The progression-free survival rate at 36 months was 58%. CONCLUSION The regimen of carboplatin, paclitaxel, and bevacizumab with maintenance bevacizumab is feasible, safe, and worthy of future study in advanced ovarian cancer.
MEK inhibitors (MEKi) lack monotherapy efficacy in most RAS-mutant cancers. BCL-xL is an anti-apoptotic protein identified by a synthetic lethal shRNA screen as a key suppressor of apoptotic response ...to MEKi.
We conducted a dose escalation study (NCT02079740) of the BCL-xL inhibitor navitoclax and MEKi trametinib in patients with RAS-mutant tumors with expansion cohorts for: pancreatic, gynecologic (GYN), non-small cell lung cancer (NSCLC), and other cancers harboring KRAS/NRAS mutations. Paired pretreatment and day 15 tumor biopsies and serial cell-free (cf)DNA were analyzed.
A total of 91 patients initiated treatment, with 38 in dose escalation. Fifty-eight percent had ≥3 prior therapies. A total of 15 patients (17%) had colorectal cancer, 19 (11%) pancreatic, 15 (17%) NSCLC, and 32 (35%) GYN cancers. The recommended phase II dose (RP2D) was established as trametinib 2 mg daily days 1 to 14 and navitoclax 250 mg daily days 1 to 28 of each cycle. Most common adverse events included diarrhea, thrombocytopenia, increased AST/ALT, and acneiform rash. At RP2D, 8 of 49 (16%) evaluable patients achieved partial response (PR). Disease-specific differences in efficacy were noted. In patients with GYN at the RP2D, 7 of 21 (33%) achieved a PR and median duration of response 8.2 months. No PRs occurred in patients with colorectal cancer, NSCLC, or pancreatic cancer. MAPK pathway inhibition was observed in on-treatment tumor biopsies. Reductions in KRAS/NRAS mutation levels in cfDNA correlated with clinical benefit.
Navitoclax in combination with trametinib was tolerable. Durable clinical responses were observed in patients with RAS-mutant GYN cancers, warranting further evaluation in this population.
In non-gynecologic cancers, clinical trial participation has been associated with aggressive care at the end of life. The objective of this investigation was to examine how trial participation ...affects end of life outcomes in patients with ovarian cancer.
In a retrospective review of women diagnosed with ovarian cancer at our institution between January 2010 and December 2015, we collected variables identified by the National Quality Forum as measures of aggressive end of life care including chemotherapy in the last 14 days of life, intensive care unit (ICU) admission in the last 30 days of life, or death in the acute care setting. Trials investigating medications but not surgical interventions were included. The primary outcome of this study was the association between trial participation and the National Quality Forum measures of aggressive end of life care in ovarian cancer decedents. Data were analyzed with univariable and multivariable parametric and non-parametric testing, and time to event outcomes were analyzed using the Kaplan-Meier method and Cox's proportional hazard models.
Among 391 women treated for ovarian cancer, 62 patients (16%) participated in a clinical trial. Patients enrolled in clinical trials were more likely to have chemotherapy administered within 14 days of death; however, no association was found with other metrics of aggressive care at the end of life including the initiation of a new chemotherapy regimen in the last 30 days of life, ICU admissions, and death in an acute care setting. Among patients with recurrent ovarian cancer, median overall survival for trial participants was 57 months compared with only 31 months in non-trial participants (p<0.001).
In patients with ovarian cancer, clinical trial enrollment is associated with chemotherapy administration within 14 days of death, but not other measures of aggressive care at the end of life. Given the importance of clinical trial participation in improving care for women with ovarian cancer, this study suggests that concerns regarding aggressive care prior to death should not limit clinical trial participation.
Hypertension and proteinuria are common but poorly understood renal toxicities of vascular endothelial growth factor (VEGF) receptor signaling pathway inhibitors. In this phase II study of cediranib ...(AZD2171) for recurrent epithelial ovarian cancer, the time course and severity of BP changes and proteinuria were characterized.
46 women ages 41 to 77 years were treated with cediranib. 26% had baseline hypertension. Twice-daily BP was recorded. Urinalyses were performed every 2 weeks, and in some patients proteinuria was further quantified.
31 women (67%) developed hypertension by day 3; 87% by the end of the study. 43% developed grade > or =3 hypertension. Mean systolic BP increase over 3 days was 18 mmHg. Women above the mean age (> or =57 years) had a larger rise in systolic BP by day 3 (15.9 versus 7.0 mmHg). 14 women developed proteinuria. There was a dose response (45 versus 30 mg daily). Proteinuria also developed rapidly, with 7 of 14 women developing proteinuria within 2 weeks. Only 7 of 20 women who developed grade 3 hypertension developed proteinuria.
Cediranib induced a rapid but variable rise in BP within 3 days of initiation in most patients. Proteinuria was common and also developed rapidly. The rapid development of hypertension suggests that acute inhibition of VEGF-dependent vasodilation might explain the BP rise with VEGF inhibitors. Clinicians must be vigilant in early detection and management of toxicities of this expanding drug class, especially in older patients.
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