Phase I Study of a Combination of Fluvastatin and Celecoxib in Children with Relapsing/Refractory Low-Grade or High-Grade Glioma (FLUVABREX).

Preclinical data support the activity of celecoxib and fluvastatin in high-grade (HGG) and low-grade gliomas (LGG). A phase I trial (NCT02115074) was designed to evaluate the safety of this combination in children with refractory/relapsed HGG and LGG using four dose levels of fluvastatin with a fixed daily dose of celecoxib. A Continual Reassessment Method was used for fluvastatin dose escalation. Dose-limiting toxicities (DLT) were determined on the first treatment cycle. Twenty patients were included. Ten LGG and ten HGG patients received a median of 3.5 treatment cycles. Two DLTs were reported: one grade 3 maculopapular rash (4 mg/kg dose level) and one grade 4 increase of Creatine Phospho-Kinase (6 mg/kg dose level). We identified the dose of 6 mg/kg/day as the recommended phase II dose (RP2D) of fluvastatin with celecoxib. Four patients with LGG continued treatment beyond 12 cycles because of stable disease, including one patient who received 23 treatment cycles. In children with refractory/relapsed glioma, the RP2D of fluvastatin with celecoxib is 6 mg/kg/day. The long-term stable diseases observed in LGG suggest a possible role of the combination in a maintenance setting, given its good tolerance and low cost for children living in low- and middle-income countries.

Impact of pharmacogenetics on variability in exposure to oral vinorelbine among pediatric patients: a model-based population pharmacokinetic analysis.

PURPOSE: Better understanding of pharmacokinetics of oral vinorelbine (VNR) in children would help predicting drug exposure and, beyond, clinical outcome. Here, we have characterized the population pharmacokinetics of oral VNR and studied the factors likely to explain the variability observed in VNR exposure among young patients. DESIGN/METHODS: We collected blood samples from 36 patients (mean age 11.6 years) of the OVIMA multicentric phase II study in children with recurrent/progressive low-grade glioma. Patients received 60 mg/m2 of oral VNR on days 1, 8, and 15 during the first 28-day treatment cycle and 80 mg/m2, unless contraindicated, from cycle 2-12. Population pharmacokinetic analysis was performed using nonlinear mixed-effects modeling within the Monolix® software. Fifty SNPs of pharmacokinetic-related genes were genotyped. The influence of demographic, biological, and pharmacogenetic covariates on pharmacokinetic parameters was investigated using a stepwise multivariate procedure. RESULTS: A three-compartment model, with a delayed double zero-order absorption and a first-order elimination, best described VNR pharmacokinetics in children. Typical population estimates for the apparent central volume of distribution (Vc/F) and elimination rate constant were 803 L and 0.60 h-1, respectively. Following covariate analysis, BSA, leukocytes count, and drug transport ABCB1-rs2032582 SNP showed a dramatic impact on Vc/F. Conversely, age and sex had no significant effect on VNR pharmacokinetics. CONCLUSION: Beyond canonical BSA and leukocytes, ABCB1-rs2032582 polymorphism showed a meaningful impact on VNR systemic exposure. Simulations showed that the identified covariates could have an impact on both efficacy and toxicity outcomes. Thus, a personalized dosing strategy, using those covariates, could help to optimize the efficacy/toxicity balance of VNR in children.

Pharmacokinetics of oral vinorelbine in French children with recurrent or progressive primary low-grade glioma.

AIMS: There is a crucial need for pharmacokinetic (PK) data on oral vinorelbine (VNR) in the paediatric population. The aim of this work was to assess the PK profile of orally administered VNR in children with recurrent/progressive primary low-grade glioma (LGG). METHODS: A multicentre, open-label, single-arm intervention phase II study was conducted. Patients, aged between 6 and 18 years, with histologically confirmed recurrent or progressive primary LGG or non-documented typical optic pathway tumours, were included. PK parameters were estimated by non-compartmental analysis using Phoenix WinNonlin® software (version 8.0, Certara, Inc.). The influence of demographic and biological covariates on VNR PK parameters was investigated using a multivariate linear regression analysis. RESULTS: PK analysis included 36 patients with a median age (range) of 11 (6-17) years. Estimates of apparent oral clearance (CL/F), apparent volume of distribution (V/F), half-life (t1/2 ) and their between-subject variability (CV%) at 60 mg m-2 dose level, were 472 L h-1 (51.8%), 7002 L (57.9%) and 10 h (21.0%), respectively. Negligible accumulation of VNR between C1 and C2 was observed. CL/F and V/F were found to increase with body surface area (BSA) (P = .004). Lower area under the concentration-time curve (AUC) levels were observed among children in comparison to adults. CONCLUSION: Higher doses may be necessary for children with LGG. BSA showed a significant impact on VNR systemic exposure. We believe that our findings will serve as a basis for further studies to better characterize the concentration-response relationships of VNR among paediatric patients.

Midazolam sedation in palliative medicine: retrospective study in a French center for cancer control.

BACKGROUND: French legislation about sedation in palliative medicine evolved in 2016 with the introduction of a right to deep and continuous sedation, maintained until death. The objective was to describe midazolam sedation at the COL (Centre Oscar Lambret [Oscar Lambret Center], French regional center for cancer control), in order to establish a current overview before the final legislative changes. METHODS: Descriptive, retrospective and single-center study, concerning major patients in palliative care hospitalized from 01/01/2014 to 12/31/2015, who had been sedated by midazolam. The proven sedations (explicitly named) and the probable sedations were distinguished. RESULTS: A total of 54 sedations were identified (48 proven, 6 probable). Refractory symptoms accounted for 48.1% of indications, complications with immediate risk of death 46.3%, existential suffering 5.6%. Titration was performed in 44.4% of cases. Sedation was continuous until death for 98.1% of the cases. Probable sedation had a higher failure rate than proven sedation. Significant differences existed for the palliative care unit compared to other units regarding information to the patient, their consent, anticipation, mention by correspondence and carrying out titrations. When patients had already been treated with midazolam, the induction doses, initial maintenance doses, and doses at the time of death were significantly higher. For those receiving opioids, the maintenance dose at the time of death was higher. No comparison found a difference in overall survival. CONCLUSIONS: After a sufficient follow-up has enabled teams to familiarize with this new legislation, reflection on sedation should be conducted to adapt to final recommendations.

Prognostic and predictive factors for angiosarcoma patients receiving paclitaxel once weekly plus or minus bevacizumab: an ancillary study derived from a randomized clinical trial.

BACKGROUND: We report here a correlation analysis conducted along with a phase II trial assessing bevacizumab in combination with weekly paclitaxel. METHODS: Circulating pro/anti-angiogenic factors were assessed on day 1 (D1) and day 8 (D8). The prognostic value for progression-free survival (PFS) was evaluated using a Cox model with biomarkers as continuous variables. RESULTS: Among the 51 patients enrolled and treated in this trial, biomarker analysis was performed for 42: 18 in Arm A (single-agent) and 24 in Arm B (combination). With a median follow-up of 46 months, PFS was 5.5 versus 5.7 months, respectively (p = 0.75). According to univariate analysis, factors associated with a poor PFS were as follows: visceral angiosarcoma, de novo angiosarcoma, and high PlGF and low VEGF-C baseline values. In multivariate analysis, de novo angiosarcoma (HR = 2.5; p = 0.024) and baseline VEGF-C value (HR = 0.7; p = 0.003) were significant prognostic factors. We observed a significant increase in circulating PlGF (< 0.001) and a decrease in VEGF (< 0.001) during bevacizumab treatment. An increase in FGF was associated with a poor outcome. CONCLUSIONS: De novo angiosarcoma and a low baseline level of VEGF-C were found to be associated with a poor prognosis. Addition of bevacizumab induces major changes in circulating biomarkers (VEGF and PlGF) in a short timeframe without impacting PFS. TRIAL REGISTRATION: Retrospectively registered on EudraCT N° 2009-017020-59 and NCT01303497 (February 24, 2011).

Impact of Trabectedin Interruption and Subsequent Rechallenge on Progression in Patients With Advanced Soft Tissue Sarcoma: Long-term Follow-up of the T-DIS trial.

OBJECTIVE: To assess the impact of trabectedin rechallenge. PATIENTS AND METHODS: In the T-DIS trial (NCT0130309), after the 6 initial cycles of trabectedin, patients who were free from progressive disease (PD) were randomly assigned either to continuous treatment with trabectedin (C arm) or therapy interruption (I arm). Patients randomized in the interruption arm were allowed to restart trabectedin in case of PD. Herein we report an update of the impact of trabectedin discontinuation after subsequent rechallenge. RESULTS: From February 2011 to March 2013, 27 and 26 nonprogressive patients were randomized to C and I arm, respectively. Twenty-two of 26 patients in I arm and 25 of 27 patients in C arm received 7 cycles and more. After randomization, the median number of cycles was similar in both arms (C arm: 5 cycles [range, 1 to 34]; I arm: 6 cycles [range, 1 to 48], P=0.96). After a median follow-up from randomization of 35.3 months, continuous treatment with trabectedin was associated with a significant improvement in progression-free survival compared with the rechallenge arm (5.3 vs. 3.5 mo, P=0.019). The observed difference in median overall survival from the seventh cycle did not meet the level of significance (26.0 vs. 14.9 mo, P=0.14). The safety profile was similar in both arms. Mean time spent without symptoms and toxicity (Q-TWIST) was higher in the C arm, but the difference did not reach the level of significance. CONCLUSIONS: We have demonstrated that trabectedin retains its activity when patients are rechallenged on progression after a treatment break.

Efficacy and safety of 153Sm-EDTMP as treatment of painful bone metastasis: a large single-center study.

PURPOSE: The purpose of this study is to assess the efficacy of 153Sm-EDTMP (Quadramet®) in a clinical setting. METHODS: We have conducted a retrospective study of all consecutive patients (pts) treated with 153Sm-EDTMP for painful bone metastases. At each visit (before and after treatment), four parameters were collected: (i) pain assessment according to the 10-step visual analogue scale (VAS), (ii) sleep disturbance related to pain, (iii) dose of analgesic medication, and (iv) answer to the following closed question "Do you think you obtained a benefit from treatment?" Success of treatment was defined by the combination of these four parameters. RESULTS: Three hundred seventy consecutive 153Sm-EDTMP treatments for painful bone metastases were given. Patients had the following primary tumors: breast carcinoma (153), prostate carcinoma (155), lung carcinoma (27), or other cancers (35). Fifty-eight percent of the patients had received previous external osseous radiotherapy. Ninety-seven percent of the patients were treated with concomitant analgesics and 61% were treated with diphosphonates. A clinical benefit was described in 55.0% of cases at D30. Treatment was more effective in cases of breast and prostate cancers compared with other types of primary cancers. Patients described a benefit at D30 in 62, 58, 6, and 38% of cases of breast, prostate, lung, and other cancers. The subjective efficacy was accompanied by a decrease in analgesic intake in 35.0% of cases. CONCLUSION: 153Sm-EDTMP therapy is an effective supportive treatment in patients who suffer from bone metastases, especially in patients with breast or prostate cancer.

Pretherapeutic staging of locally advanced cervical cancer: Inframesenteric paraaortic lymphadenectomy accuracy to detect paraaortic metastases in comparison with infrarenal paraaortic lymphadenectomy.

BACKGROUND: Extended-field chemoradiation therapy is usually performed in patients with locally advanced cervical cancer (LACC) and paraaortic (PA) node metastases. Considering the very low rate of skip metastases above inferior mesenteric artery, ilio-inframesenteric paraaortic lymph node dissection (IM-PALND) seems to be an adequate pattern of PALND. Our objective was to assess the accuracy of this management to determine PA nodal status in comparison with infrarenal paraaortic lymphadenectomy (IR-PALND) in case of squamous or glandular cervical cancer. METHODS: All patients with LACC and negative MRI and PET/CT imaging at paraaortic level had laparoscopic staging (followed, if negative, by extraperitoneal paraaortic lymphadenectomy). From January 2011 to September 2015, patients who had IM-PALND were included and were compared to a previous historical series of IR-PALND patients. The two groups differed only at the upper level of dissection. Characteristics of nodal involvement at paraaortic level depending on level of dissection, PET/CT imaging and histology were studied. RESULTS: 119 women were included in our study, with 56 patients in the IM-PALND group and 63 in the IR-PALND group. In the IM-PALND group, fewer nodes were resected (p<0.001). There was no difference between the two groups regarding nodal status at paraaortic level (p=0.77). Patterns of nodal involvement were similar whichever the histological subtype of cervical cancer (squamous or glandular). CONCLUSION: IM-PALND appears to be equally effective to assess paraaortic nodal involvement in LACC for both histological subtypes - glandular and squamous carcinomas - and to select patients for extended-field chemoradiation therapy.

REGOSARC: Regorafenib versus placebo in doxorubicin-refractory soft-tissue sarcoma-A quality-adjusted time without symptoms of progression or toxicity analysis.

BACKGROUND: In a placebo-controlled, randomized phase 2 trial (ClinicalTrials.gov identifier NCT01900743), regorafenib improved progression-free survival (PFS) for patients with doxorubicin-pretreated advanced nonadipocytic sarcoma. A quality-adjusted time without symptoms of progression or toxicity (Q-TWiST) post hoc exploratory analysis was applied to provide an integrated measure of its clinical benefit. METHODS: In the base-case analysis, each patient's overall survival (OS) was partitioned into 3 mutually exclusive health states: the time with a grade 3 or 4 adverse event (TOX), the time without symptoms of disease or grade 3 or 4 toxicity from treatment, and the time after tumor progression or relapse. The time spent in each state was weighted with a health-state utility associated with that state and was summed to calculate the Q-TWiST. The stability of the base-case analysis was explored with several sensitivity analyses. RESULTS: In nonadipocytic sarcoma, the PFS was (4.0 months [2.6-5.5 months] with regorafenib vs 1.0 month [0.9-1.8 months] with a placebo; hazard ratio, 0.36 [0.25-0.53]; P < .0001); the OS was 13.4 months (8.6-17.3 months) with regorafenib and 9.0 months (6.8-12.5 months) with a placebo (hazard ratio, 0.67 [0.44-1.02]). With the classic definition of TOX (including all grade 3 and 4 clinical adverse events), the Q-TWiSTs were 8.0 months (7.0-9.0 months) with regorafenib and 5.7 months (4.9-6.4 months) with a placebo (P < .001). CONCLUSIONS: For patients with doxorubicin-pretreated soft-tissue sarcoma, regorafenib significantly improved quality-adjusted survival in comparison with a placebo. Cancer 2017;123:2294-2302. © 2017 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society. This is an open access article under the terms of the Creative Commons Attribution NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

Morbidity of Staging Inframesenteric Paraaortic Lymphadenectomy in Locally Advanced Cervical Cancer Compared With Infrarenal Lymphadenectomy.

OBJECTIVE: Extended-field chemoradiation is typically used for the management of patients with locally advanced cervical cancer. Given the low rate of skipped metastases above the inferior mesenteric artery, ilioinframesenteric dissection seems to be an acceptable pattern of paraaortic lymph node dissection (LND). Our objective is to compare the surgical morbidity of inframesenteric LND (IM-LND) with infrarenal LND (IR-LND). METHODS: In our center, all of the patients with locally advanced cervical cancer and negative magnetic resonance imaging and positron emission tomography-computed tomography imaging at the paraaortic level were offered laparoscopic staging including a diagnostic laparoscopy followed, if negative, by an extraperitoneal paraaortic lymphadenectomy. From January 2011 to September 2015, we included patients who had paraaortic LND from both common iliac bifurcations and divided them into 2 groups according to dissection pattern: to the inferior mesenteric artery (IM-LND) level or to the left renal vein (IR-LND) level. The perioperative and postoperative data were retrospectively recorded. RESULTS: A total of 119 women were included in our study: 56 in the IM-LND group and 63 in the IR-LND group. There was no difference in the patients' characteristics between groups. Regarding the surgical procedure, the operating time was shorter in the IM-LND group than the IR-LND group, 174 ± 50 minutes versus 209 ± 61 minutes (P = 0.001), respectively. There was no significant difference in intra- and postoperative complications, overall survival, or progression-free survival. CONCLUSIONS: In our series, exclusive IM-LND surgery is faster than IR-LND and results in similar morbidity and survival rates. These results confirm the feasibility and the applicability of IM-LND to simplify the surgical procedure without impacting survival. More patients should be included in the study to demonstrate the lower rate of morbidity.

Circulating vascular endothelial growth factor (VEGF) as predictive factor of progression-free survival in patients with advanced chordoma receiving sorafenib: an analysis from a phase II trial of the french sarcoma group (GSF/GETO).

BACKGROUND: Patients with advanced chordoma are often treated with tyrosine kinase inhibitors without any predictive factor to guide decision. We report herein an ancillary analysis of the the Angionext phase II trial (NCT 00874874). RESULTS: From May 2011 to January 2014, 26 were sampled. The 9-month PFS rate was 72.9% (95%-CI: 45.9-87.9). During sorafenib treatment, a significant increase in PlGF (18.4 vs 43.8 pg/mL, p<0.001) was noted along with a non-significant increase in VEGF (0.7 vs 1.0 ng/mL, p=0.07). VEGF at D1 >1.04 ng/mL (HR=12.5, 95%-CI: 1.37-114, p=0.025) and VEGF at D7 >1.36 ng/mL (HR=10.7, 95%-CI: 1.16-98, p=0.037) were associated with shorter PFS. The 9-month PFS rate was 92.3% (95%-CI: 56.6-98.9) when VEGF at D1 was ≤1.04 ng/mL versus 23.3% (95%-CI: 1.0-63.2) when >1.04 ng/mL. PATIENTS AND METHODS: Chordoma patients were treated with sorafenib 800 mg/day for 9 months, unless earlier occurrence of progression or toxicities. Six biomarkers (sE-Selectin, VEGF, VEGF-C, placental growth factor (PlGF), Thrombospondin, Stem Cell Factor (SCF)) were measured at baseline (day 1: D1) and day 7 (D7). CONCLUSION: High levels of VEGF was associated with poor outcome.

Paclitaxel Given Once Per Week With or Without Bevacizumab in Patients With Advanced Angiosarcoma: A Randomized Phase II Trial.

PURPOSE: The aim of this randomized, phase II trial was to explore the activity and safety of adding bevacizumab to paclitaxel once per week in treatment of angiosarcomas (AS). METHODS: Patients were treated with paclitaxel alone (90 mg/m(2) per week for six cycles of 28 days each; arm A) or with paclitaxel combined with bevacizumab (10 mg/kg once every 2 weeks; arm B). In the combination treatment arm, bevacizumab was administered after the six cycles of chemotherapy as maintenance therapy (15 mg/kg once every 3 weeks) until intolerance or progression occurred. Stratification factors were superficial versus visceral AS and de novo versus radiation-induced AS. The primary end point was the 6-month progression-free survival (PFS) rate, which was based on RECIST, version 1.1. Statistical assumptions were P0 = 20%, P1 = 40%, a = 10%, and b = 20%. P0 was the PFS rate at 6 months defining inactive drug, and P1 was the PFS rate at 6 months defining promising drug. RESULTS: A total of 52 patients were enrolled, and 50 were randomly assigned in 14 centers. The most common primary sites were the breast (49%) and skin (12%). There were 17 (34%) visceral and 24 (49%) radiation-induced AS. The performance status was 0 in 24 patients (49%) and 1 in the remaining 25 patients (51%). The median follow-up time was 14.5 months. Both treatment regimens were considered active, with 6-month PFS rates of 54% (14 of 26) in arm A and 57% (14 of 24) in arm B. The median overall survival rates were 19.5 months in arm A and 15.9 months in arm B. Toxicity was higher with the combination arm and included one fatal drug-related toxicity (intestinal occlusion). CONCLUSION: The primary objective was met in both treatment arms. However, the present data do not support additional clinical investigation of combined paclitaxel/bevacizumab for the treatment of advanced AS.

Interruption versus continuation of trabectedin in patients with soft-tissue sarcoma (T-DIS): a randomised phase 2 trial.

BACKGROUND: The benefit or harm of trabectedin discontinuation in patients with non-progressive soft-tissue sarcoma remains unclear. We report the final analysis of a phase 2 trial investigating the clinical benefit of continuation of trabectedin treatment until progression versus interruption of therapy after six treatment cycles in patients with advanced soft-tissue sarcoma. METHODS: For this open-label, non-comparative, multicentre, phase 2 study, eligible adult patients with advanced soft-tissue sarcomas, who had previously received doxorubicin-based chemotherapy and were able to receive trabectedin, were enrolled from 14 centres of the French Sarcoma Group. Trabectedin was administered at a dose of 1·5 mg/m(2) through a central venous line as a 24-h continuous infusion every 3 weeks. After the initial six cycles of trabectedin, patients who were free from progressive disease were randomly assigned in a 1:1 ratio either to continuous treatment or therapy interruption. Randomisation was done centrally by a computer-generated system using permuted blocks of four patients, stratified by tumour grade and performance status. Patients allocated to the interruption group were allowed to restart trabectedin in case of progressive disease. The primary endpoint was progression-free survival at 6 months after randomisation, analysed by intention to treat. This study is registered with ClinicalTrials.gov, number NCT01303094. RESULTS: In 178 evaluable patients, 91 (51%) patients had not progressed after six cycles. Of these patients, 53 patients were randomly assigned to the two treatment groups: 27 to the continuation group and 26 to the interruption group. Overall, patients in the two groups received a similar median number of trabectedin cycles (continuation group: 11 cycles [range 6-31+] vs interruption group: 11 [range 6-23+]). After randomisation, progression-free survival at 6 months was 51·9% (95% CI 31·9-68·6) in the continuation group versus 23·1% (9·4-40·3) in the interruption group (p=0·0200). The occurrence of treatment-related grade 3 adverse events (four [16%] of 25 patients in the continuation group vs three [14%] of 21 in the interruption group) and grade 4 adverse events (one [4%] vs none) was similar in both groups. The most common grade 3 and 4 toxicities were alanine aminotransferase or aspartate aminotransferase increases (one [4%] in the interruption group vs three [14%] in the continuation group), neutropenia (two [8%] vs two [10%]), and intestinal occlusion (one [4%] vs one [5%]). INTERPRETATION: We do not recommend trabectedin discontinuation in patients with advanced, doxorubicin-refractory soft-tissue sarcoma who have not progressed after six cycles of treatment. FUNDING: The French National Cancer Institute (INCa) and PharmaMar SA.