Publications by authors named "Stéphanie Henry"

11 Publications

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A phase II study of monalizumab in patients with recurrent/metastatic squamous cell carcinoma of the head and neck: The I1 cohort of the EORTC-HNCG-1559 UPSTREAM trial.

Eur J Cancer 2021 Oct 9;158:17-26. Epub 2021 Oct 9.

Service d'Oncologie Médicale, Institut Roi Albert II, Cliniques Universitaires Saint-Luc and Institut de Recherche Clinique et Expérimentale, Université Catholique de Louvain (UCLouvain), Avenue Hippocrate 10, 1200 Brussels, Belgium. Electronic address:

Purpose: Monalizumab is a monoclonal antibody targeting the inhibitory natural killer group 2A (NKG2A) receptor localised on natural killer (NK) and T cells. Its ligand, the human leukocyte antigen E (HLA-E), is overexpressed in squamous cell carcinoma of the head and neck (SCCHN). By targeting the HLA-E-NKG2A pathway, monalizumab may enhance NK and T cell activity.

Experimental Design: The UPSTREAM trial is a biomarker-driven umbrella trial studying targeted therapies and immunotherapies in patients with recurrent/metastatic (R/M) SCCHN progressing after platinum therapy. The immunotherapy 1 (I1) cohort was a phase II, single-arm substudy evaluating monalizumab (10 mg/kg intravenously on day 1 of a 14-day cycle). The primary end-point was the objective response (OR) rate (Response Evaluation Criteria in Solid Tumours 1.1) over the first 16 weeks. A two-stage Simon design was used (H1 15%, H0 3%, α 8%, power 90%) with pre-planned interruption of accrual if no OR was observed after the first 25 patients.

Results: Twenty-six eligible patients were enrolled. Seventeen (65%) patients had received ≥2 previous lines of systemic treatment, and 15 (58%) patients were PD(-L)1 inhibitor pretreated. No OR was observed. Stable disease was observed in 6 patients (23%) with a median duration of 3.8 months (95% confidence interval [CI]: 2.7-NE). The median progression-free survival and overall survival were 1.7 months (95% CI: 1.5-1.8) and 6.7 months (95% CI: 3.0-9.6), respectively. The most frequent treatment-related adverse event was grade I/II fatigue (19%).

Conclusions: Monalizumab monotherapy has limited activity in R/M SCCHN. The I1 cohort did not meet its primary objective. Monalizumab combined with durvalumab is under investigation within UPSTREAM.
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http://dx.doi.org/10.1016/j.ejca.2021.09.003DOI Listing
October 2021

A randomized, placebo-controlled phase 2 study of paclitaxel in combination with reparixin compared to paclitaxel alone as front-line therapy for metastatic triple-negative breast cancer (fRida).

Breast Cancer Res Treat 2021 Sep 3. Epub 2021 Sep 3.

Rogel Cancer Center, University of Michigan, Ann Arbor, MI, 48109, USA.

Purpose: CXCR1, one of the receptors for CXCL8, has been identified as a druggable target on breast cancer cancer stem cells (CSC). Reparixin (R), an investigational oral inhibitor of CXCR1, was safely administered to metastatic breast cancer patients in combination with paclitaxel (P) and appeared to reduce CSC in a window-of-opportunity trial in operable breast cancer. The fRida trial (NCT02370238) evaluated the addition of R to weekly as first-line therapy for metastatic (m) TNBC.

Subjects And Methods: Subjects with untreated mTNBC were randomized 1:1 to R or placebo days 1-21 in combination with weekly P 80 mg/m on days 1, 8, 15 of 28-day cycles. The primary endpoint was PFS by central review.

Results: 123 subjects were randomized (62 to R + P and 61 to placebo + P). PFS was not different between the 2 groups (median 5.5 and 5.6 months for R + P and placebo + P, respectively; HR 1.13, p = 0.5996). ALDH and CD24/CD44 CSC centrally evaluated by IHC were found in 16 and 34 of the 54 subjects who provided a metastatic tissue biopsy at study entry. Serious adverse events (21.3 and 20% of subjects) and grade ≥ 3 adverse reactions (ADR) (9.1 and 6.3% of all ADRs) occurred at similar frequency in both groups.

Conclusion: fRida is the first randomized, double-blind clinical trial of a CSC-targeting agent in combination with chemotherapy in breast cancer. The primary endpoint of prolonged PFS was not met.

Clinical Trial Registration/date Of Registration: NCT01861054/February 24, 2015.
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http://dx.doi.org/10.1007/s10549-021-06367-5DOI Listing
September 2021

The Alternative Sigma Factor SigB Is Required for the Pathogenicity of Bacillus thuringiensis.

J Bacteriol 2020 10 8;202(21). Epub 2020 Oct 8.

Université Paris-Saclay, INRAE, AgroParisTech, Micalis Institute, Jouy-en-Josas, France

To adapt to changing and potentially hostile environments, bacteria can activate the transcription of genes under the control of alternative sigma factors, such as SigB, a master regulator of the general stress response in several Gram-positive species. is a Gram-positive spore-forming invertebrate pathogen whose life cycle includes a variety of environments, including plants and the insect hemocoel or gut. Here, we assessed the role of SigB during the infectious cycle of in a insect model. We used a fluorescent reporter coupled to flow cytometry and showed that SigB was activated We also showed that the pathogenicity of the Δ mutant was severely affected when inoculated via the oral route, suggesting that SigB is critical for adaptation to the gut environment of the insect. We could not detect an effect of the deletion on the survival of the bacteria or on their sporulation efficiency in the cadavers. However, the gene encoding the pleiotropic regulator Spo0A was upregulated in the Δ mutant cells during the infectious process. Pathogenic bacteria often need to transition between different ecosystems, and their ability to cope with such variations is critical for their survival. Several Gram-positive species have developed an adaptive response mediated by the general stress response alternative sigma factor SigB. In order to understand the ecophysiological role of this regulator in , an entomopathogenic bacterium widely used as a biopesticide, we sought to examine the fate of a Δ mutant during its life cycle in the natural setting of an insect larva. This allowed us, in particular, to show that SigB was activated during infection and that it was required for the pathogenicity of via the oral route of infection.
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http://dx.doi.org/10.1128/JB.00265-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7549364PMC
October 2020

Phase 1 Study Evaluating the Association of the Cyclin-Dependent Kinase 4/6 Inhibitor Ribociclib and Cetuximab in Recurrent/Metastatic p16-Negative Squamous Cell Carcinoma of the Head and Neck.

Front Oncol 2019 19;9:155. Epub 2019 Mar 19.

Departments of Medical Oncology and Head and Neck Surgery, Institut Roi Albert II, Institut de Recherche Clinique et Expérimentale (Pole MIRO), Cliniques Universitaires Saint-Luc, Catholic University of Louvain, Woluwe-Saint-Lambert, Belgium.

The majority of human papillomavirus (HPV)-negative squamous cell carcinoma of the head and neck (SCCHN) present upregulation of the epidermal growth factor receptor (EGFR) and frequent alterations in the cyclin D1-cyclin dependent kinase (CDK) 4/6 (CDK 4/6)-retinoblastoma protein (pRb) pathway, resulting in cell cycle progression and tumor proliferation. This study investigated the combination of ribociclib, an orally highly selective inhibitor of CDK 4/6, and cetuximab in recurrent and/or metastatic (R/M) SCCHN. A phase I trial using a 3 + 3 design was performed to determine the dose limiting toxicity (DLT) and maximum tolerated dose (MTD) of ribociclib with standard dose of weekly cetuximab in HPV-negative patients with R/M SCCHN. Ribociclib was administered orally (3 weeks on/1 week off) at dose level 1 of 400 mg daily and dose level 2 of 600 mg daily. The MTD of ribocilib was then further evaluated in an expansion cohort. 10 patients were enrolled in the escalation trial. No DLTs were observed at dose level 1 ( = 3); at dose level 2, one patient was replaced due to rapid disease progression, and one patient out of six evaluable patients experienced a DLT (grade 4 thrombocytopenia >7 days). Ribociclib 600 mg daily was thus determined to be the MTD. Eleven additional patients were enrolled in the expansion cohort. Diarrhea (52%), rash (52%), fatigue (43%), nausea (33%), and mucositis (28%) were the most frequent grade 1-2 adverse events (AE). Neutropenia was the most frequent grade 3-4 AE (20%). Median progression-free survival (PFS) was 3.5 months (range 0.4-17.3 months) and median overall survival (OS) was 8.3 months (range 0.4-24.1 months). Among the 19 radiologically evaluable patients, two (10.5%) achieved a partial response and 11 (58%) had stable disease. The MTD of ribociclib is 600 mg daily when administered in combination with standard dose cetuximab for 3 weeks on and 1 week off. This combination was safe and showed efficacy. Further clinical trials should be conducted to evaluate the antitumor effects of this combination. ClinicalTrials.gov: NCT02429089; Eudract number 2014-005371-83.
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http://dx.doi.org/10.3389/fonc.2019.00155DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6433958PMC
March 2019

Durvalumab for recurrent or metastatic head and neck squamous cell carcinoma: Results from a single-arm, phase II study in patients with ≥25% tumour cell PD-L1 expression who have progressed on platinum-based chemotherapy.

Eur J Cancer 2019 01 18;107:142-152. Epub 2018 Dec 18.

Medical Oncology Department, Catalan Institute of Oncology, University of Barcelona, IDIBELL, Barcelona, Spain.

Background: Patients with recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC) progressing on platinum-based chemotherapy have poor prognoses and limited therapeutic options. Programmed cell death-1 (PD-1) and its ligand 1 (PD-L1) are frequently upregulated in HNSCC. The international, multi-institutional, single-arm, phase II HAWK study (NCT02207530) evaluated durvalumab monotherapy, an anti-PD-L1 monoclonal antibody, in PD-L1-high patients with platinum-refractory R/M HNSCC.

Patients And Methods: Immunotherapy-naïve patients with confirmed PD-L1-high tumour cell expression (defined as patients with ≥25% of tumour cells expressing PD-L1 [TC ≥ 25%] using the VENTANA PD-L1 [SP263] Assay) received durvalumab 10 mg/kg intravenously every 2 weeks for up to 12 months. The primary end-point was objective response rate; secondary end-points included progression-free survival (PFS) and overall survival (OS).

Results: Among evaluable patients (n = 111), objective response rate was 16.2% (95% confidence interval [CI], 9.9-24.4); 29.4% (95% CI, 15.1-47.5) for human papillomavirus (HPV)-positive patients and 10.9% (95% CI, 4.5-21.3) for HPV-negative patients. Median PFS and OS for treated patients (n = 112) was 2.1 months (95% CI, 1.9-3.7) and 7.1 months (95% CI, 4.9-9.9); PFS and OS at 12 months were 14.6% (95% CI, 8.5-22.1) and 33.6% (95% CI, 24.8-42.7). Treatment-related adverse events were 57.1% (any grade) and 8.0% (grade ≥3); none led to death. At data cut-off, 24.1% of patients remained on treatment or in follow-up.

Conclusion: Durvalumab demonstrated antitumour activity with acceptable safety in PD-L1-high patients with R/M HNSCC, supporting its ongoing evaluation in phase III trials in first- and second-line settings. In an ad hoc analysis, HPV-positive patients had a numerically higher response rate and survival than HPV-negative patients.
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http://dx.doi.org/10.1016/j.ejca.2018.11.015DOI Listing
January 2019

Randomized Phase II Study of Cabazitaxel Versus Methotrexate in Patients With Recurrent and/or Metastatic Squamous Cell Carcinoma of the Head and Neck Previously Treated With Platinum-Based Therapy.

Oncologist 2016 12 30;21(12):1416-e17. Epub 2016 Nov 30.

Department of Medical Oncology, University Hospital Ghent, Ghent, Belgium.

Lessons Learned: Cabazitaxel has activity in squamous cell carcinoma of the head and neck (SCCHN) and taxane-resistant cell lines. For the first time, cabazitaxel was investigated in incurable patients with recurrent SCCHN. Patients were randomly assigned to cabazitaxel every 3 weeks or weekly methotrexate.This phase II study did not meet its primary endpoint.Cabazitaxel has low activity in SCCHN.The toxicity profile in this population also was not favorable owing to the high rate of febrile neutropenia observed (17%).

Background: Cabazitaxel is a second-generation taxane that improves the survival of patients with metastatic castrate-resistant prostate cancer following docetaxel therapy. Cabazitaxel has activity in squamous cell carcinoma of the head and neck (SCCHN) and taxane-resistant cell lines. In this randomized phase II trial, we investigated cabazitaxel in patients with recurrent SCCHN.

Methods: Patients with incurable SCCHN with progression after platinum-based therapy were randomly assigned to cabazitaxel every 3 weeks (cycle 1, 20 mg/m, increased to 25 mg/m for subsequent cycles in the absence of nonhematological adverse events [AEs] greater than grade 2 and hematological AEs greater than grade 3) or methotrexate (40 mg/m/week). The patients were stratified according to their performance status and previous platinum-based chemotherapy for palliation versus curative intent. The primary endpoint was the progression-free survival rate (PFSR) at 18 weeks.

Results: Of the 101 patients, 53 and 48, with a median age of 58.0 years (range, 41-80), were randomly assigned to cabazitaxel or methotrexate, respectively. The PFSR at 18 weeks was 13.2% (95% confidence interval [CI], 5%-25%) for cabazitaxel and 8.3% (95% CI, 2%-20%) for methotrexate. The median progression-free survival was 1.9 months in both arms. The median overall survival was 5.0 and 3.6 months for cabazitaxel and methotrexate, respectively. More patients experienced serious adverse events with cabazitaxel than with methotrexate (54% vs. 36%). The most common drug-related grade 3-4 AE in the cabazitaxel arm was febrile neutropenia (17.3%).

Conclusion: This study did not meet its primary endpoint. Cabazitaxel has low activity in recurrent SCCHN.
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http://dx.doi.org/10.1634/theoncologist.2016-0296DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5153346PMC
December 2016

Combined PDGFR and HDAC Inhibition Overcomes PTEN Disruption in Chordoma.

PLoS One 2015 6;10(8):e0134426. Epub 2015 Aug 6.

Department of Neurological Surgery, University of Virginia, PO BOX 800212, Charlottesville, VA 22908, United States of America; Neuro-Oncology Branch, National Cancer Institute, NIH, 9030 Old Georgetown Rd, B82/Rm225, Bethesda, MD 20892, United States of America.

Background: The majority of chordomas show activation of the platelet-derived growth factor receptor (PDGFR). Based on in vitro intertumoral variation in response to recombinant PDGF protein and PDGFR inhibition, and variable tumor response to imatinib, we hypothesized that chordomas resistant to PDGFR inhibition may possess downstream activation of the pathway.

Methods: Molecular profiling was performed on 23 consecutive chordoma primary tissue specimens. Primary cultures established from 20 of the 23 specimens, and chordoma cell lines, UCH-1 and UCH-2, were used for in vitro experiments.

Results: Loss of heterozygosity (LOH) at the phosphatase and tensin homolog (PTEN) locus was observed in 6 specimens (26%). PTEN disruption statistically correlated with increased Ki-67 proliferation index, an established marker of poor outcome for chordoma. Compared to wild type, PTEN deficient chordomas displayed increased proliferative rate, and responded less favorably to PDGFR inhibition. PTEN gene restoration abrogated this growth advantage. Chordomas are characterized by intratumoral hypoxia and local invasion, and histone deacetylase (HDAC) inhibitors are capable of attenuating both hypoxic signaling and cell migration. The combination of PDGFR and HDAC inhibition effectively disrupted growth and invasion of PTEN deficient chordoma cells.

Conclusions: Loss of heterozygosity of the PTEN gene seen in a subset of chordomas is associated with aggressive in vitro behavior and strongly correlates with increased Ki-67 proliferative index. Combined inhibition of PDGFR and HDAC attenuates proliferation and invasion in chordoma cells deficient for PTEN.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0134426PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4527706PMC
May 2016

Endoscopic endonasal approach for resection of cranial base chordomas: outcomes and learning curve.

Neurosurgery 2012 Sep;71(3):614-24; discussion 624-5

Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213, USA.

Background: Gross total resection (GTR) of cranial base chordomas represents a surgical challenge because of the location, invasiveness, and tumor extension. In the past decade, the endoscopic endonasal approach (EEA) has been used with notable outcomes.

Objective: To present the endoscopic endonasal experience in the treatment of cranial base chordomas at our institution.

Methods: From April 2003 to March 2011, 60 patients underwent an EEA for primary (n = 35) or previously treated (n = 25) cranial base chordomas. We evaluated the degree of GTR and complications. We studied the factors that influenced outcomes and compared our surgical results in the early and late years of our experience.

Results: The overall rate of GTR of cranial base chordomas was 66.7% (82.9% in primary and 44% in previously treated patients). The most important limitations for GTR were tumor volume greater than 20 cm (P = .042), tumor location in the lower clivus with lateral extension (P = .022), and previously treated disease (P = .002). The learning curve had a significant impact on GTR, increasing the success rate to 88.9% (92.6% in primary patients and 63.6% in previously treated patients) during recent years (P < .0001). The most frequent complication was cerebrospinal fluid leak (20%) resulting in meningitis in 3.3%. Carotid injuries occurred in 2 patients without any resulting deficit. Neurological complications included new cranial neuropathies (6.7%) and long tract deficits (1.7%). There was no operative mortality in our series.

Conclusion: For the treatment of cranial base chordomas, the EEA is a competitive alternative to transcranial approaches with minimal morbidity and high success rates of GTR when performed by experienced cranial base surgeons.
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http://dx.doi.org/10.1227/NEU.0b013e31825ea3e0DOI Listing
September 2012

The use of chemotherapy regimens carrying a moderate or high risk of febrile neutropenia and the corresponding management of febrile neutropenia: an expert survey in breast cancer and non-Hodgkin's lymphoma.

BMC Cancer 2010 Nov 23;10:642. Epub 2010 Nov 23.

Health Economics and Outcomes Research Department, IMS Health Consulting, Medialaan 38, 1800 Vilvoorde, Belgium.

Background: The use of chemotherapy regimens with moderate or high risk of febrile neutropenia (defined as having a FN incidence of 10% or more) and the respective incidence and clinical management of FN in breast cancer and NHL has not been studied in Belgium. The existence of a medical need for G-CSF primary and secondary prophylaxis with these regimens was investigated in a real-life setting.

Methods: Nine oncologists and six hematologists from different Belgian general hospitals and university centers were surveyed to collect expert opinion and real-life data (year 2007) on the use of chemotherapy regimens with moderate or high risk of febrile neutropenia and the clinical management of FN in patients aged <65 years with breast cancer or NHL. Data were retrospectively obtained, over a 6-month observation period.

Results: The most frequently used regimens in breast cancer patients (n = 161) were FEC (45%), FEC-T (37%) and docetaxel alone (6%). In NHL patients (n = 39), R-CHOP-21 (33%) and R-ACVBP-14 (15%) were mainly used. Without G-CSF primary prophylaxis (PP), FN occurred in 31% of breast cancer patients, and 13% had PSN. After G-CSF secondary prophylaxis (SP), 4% experienced further FN events. Only 1 breast cancer patient received PP, and did not experience a severe neutropenic event. Overall, 30% of chemotherapy cycles observed in breast cancer patients were protected by PP/SP. In 10 NHL patients receiving PP, 2 (20%) developed FN, whereas 13 (45%) of the 29 patients without PP developed FN and 3 (10%) PSN. Overall, 55% of chemotherapy cycles observed in NHL patients were protected by PP/SP. Impaired chemotherapy delivery (timing and/or dose) was reported in 40% (breast cancer) and 38% (NHL) of patients developing FN. Based on oncologist expert opinion, hospitalization rates for FN (average length of stay) without and with PP were, respectively, 48% (4.2 days) and 19% (1.5 days). Similar rates were obtained from hematologists.

Conclusions: Despite the studied chemotherapy regimens being known to be associated with a moderate or high risk of FN, upfront G-CSF prophylaxis was rarely used. The observed incidence of severe neutropenic events without G-CSF prophylaxis was higher than generally reported in the literature. The impact on medical resources used is sizeable.
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http://dx.doi.org/10.1186/1471-2407-10-642DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3006392PMC
November 2010

Phase II study of sunitinib in recurrent or metastatic squamous cell carcinoma of the head and neck: GORTEC 2006-01.

J Clin Oncol 2010 Jan 16;28(1):21-8. Epub 2009 Nov 16.

Medical Oncology Unit, Université Catholique de Louvain, Cliniques Universitaires Saint-Luc, 10 Avenue Hippocrate, 1200 Brussels, Belgium.

PURPOSE To assess the efficacy and toxicity of sunitinib monotherapy in palliative squamous cell carcinoma of the head and neck (SCCHN). PATIENTS AND METHODS Thirty-eight patients with SCCHN having evidence of progressive disease (PD) were treated with sunitinib 37.5 mg/d given continuously until PD or unacceptable toxicity. The primary end point was the rate of disease control, defined as stable disease (SD) or partial response (PR) at 6 to 8 weeks after treatment initiation (two-stage design, Simon). Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) was performed in a subset of patients before and 6 to 8 weeks after treatment. The volume transfer constant of the contrast agent (K(trans)) was used to measure changes in the microcirculation blood flow and endothelial permeability of the tumor. Results A PR was observed in one patient, SD in 18, and PD in 19 (Response Evaluation Criteria in Solid Tumors [RECIST]), resulting in a disease control rate of 50%. Among the 18 patients with SD, there were five unconfirmed PRs and six additional minor responses. A significant decrease in K(trans) was seen in three of the four patients who received DCE-MRI monitoring. Grade 5 head and neck bleeds occurred in four patients. Local complications, including the appearance or worsening of tumor skin ulceration or tumor fistula, were recorded in 15 patients. CONCLUSION Sunitinib demonstrated modest activity in palliative SSCHN. The severity of some of the complications highlights the importance of improved patient selection for future studies with sunitinib in head and neck cancer. Sunitinib should not be used outside clinical trials in SSCHN.
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http://dx.doi.org/10.1200/JCO.2009.23.8584DOI Listing
January 2010
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