scholarly journals Integrating data from the Investigational Medicinal Product Dossier/investigator's brochure. A new tool for translational integration of preclinical effects

2018 ◽  
Vol 84 (7) ◽  
pp. 1457-1466 ◽  
Author(s):  
Joop van Gerven ◽  
Adam Cohen
Keyword(s):  
Medicinal Product ◽  
Investigational Medicinal Product

scholarly journals Commentary: considerations for using the ‘Trials within Cohorts’ design in a clinical trial of an investigational medicinal product

Trials ◽  
2018 ◽  
Vol 19 (1) ◽  
Author(s):  
Anna C. Bibby ◽  
David J. Torgerson ◽  
Samantha Leach ◽  
Helen Lewis-White ◽  
Nick A. Maskell
Keyword(s):  
Clinical Trial ◽  
Medicinal Product ◽  
Investigational Medicinal Product ◽  
Trials Within Cohorts

EANM guideline for the preparation of an Investigational Medicinal Product Dossier (IMPD)

2014 ◽  
Vol 41 (11) ◽  
pp. 2175-2185 ◽  
Author(s):  
Sergio Todde ◽  
Albert D. Windhorst ◽  
Martin Behe ◽  
Guy Bormans ◽  
Clemens Decristoforo ◽  
...  
Keyword(s):  
Medicinal Product ◽  
Investigational Medicinal Product

scholarly journals The Spatial Heterogeneity in Newly Diagnosed Multiple Myeloma Patients - from Sub-Clonal Architecture to the Immune Microenvironment

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 729-729
Author(s):  
Lukas John ◽  
Alexandra Poos ◽  
Stephan M Tirier ◽  
Jan-Philipp Mallm ◽  
Nina Prokoph ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Medicinal Product ◽  
Board Of Directors ◽  
Research Funding ◽  
Tumor Heterogeneity ◽  
Investigational Medicinal Product ◽  
Mutational Signatures ◽  
Advisory Committees ◽  
Cell Clones

Abstract Tumor heterogeneity plays a significant role in the development of therapy resistance in multiple myeloma (MM). Focal lesions (FLs), which are nodular accumulations of MM cells, have been shown to be hotspots of genetic spatial tumor heterogeneity, which is characterized by unique tumor sub-clones at different sites in the bone marrow (BM). However, little is known about the mechanisms leading to mutations in FLs, the architecture of the tumor microenvironment (ME) at these sites, and the link between FL sub-clones and relapse. We applied whole genome sequencing (WGS) to CD138 + MM cells from paired FL and iliac crest random BM aspirates (RBMA) of 15 newly diagnosed MM (NDMM) patients. For 7 of these patients, single cell (sc) analyses were performed, including sc gene expression (scRNA) and T-cell receptor (TCR)-sequencing and sc assay for transposase-accessible chromatin (ATAC)-sequencing for paired BM CD138 + MM and CD138 - ME, as well as peripheral blood mononuclear cells (PBMC). WGS data was analyzed using inhouse pipelines. Mutations, copy-number-variations and mutational signatures were called using mpileup, ACESeq and mmsig. Neoantigen epitopes were predicted using NeoPredPipe. Sc data was generated using the 10X Genomics platform. Pre-processing and analysis of the sc data was performed with CellRanger and the R-packages Seurat, ArchR and inferCNV. In 13/15 patients we found significant differences in chromosomal and mutational profiles between FLs and paired RBMAs, with major unshared mutations (mutation seen in > 60% cells) being enriched at the FL site (mean 310 vs. 123, p<0.05). Mutations in driver genes, such as KRAS, CYLD, CDKN2C and TP53, were site-unique or strongly enriched in FLs in 6/15 patients. To identify the mechanisms underlying heterogeneous mutations, we analyzed mutational signatures and found COSMIC signature SBS18 in these mutations, suggesting a role of reactive oxygen species. Combining WGS and sc sequencing, we observed between 3 and 6 sub-clones per patient. Sub-clones, which dominated in FLs, showed increased regulatory accessibility and expression of genes associated with disease aggressiveness and drug resistance such as CXCR4 and members of the NFKB- and interferon pathways, implying that FLs could play a significant role in the development of treatment resistance. Indeed, comparing sub-clones at baseline and at relapse after high-dose melphalan and autologous stem cell transplantation in one patient, we observed expansions of tumor cells at relapse, which were closely related to the main FL sub-clone at baseline. On average, 23 (range 0-83) site-unique baseline mutations were predicted to be neoantigens. Thus, we hypothesized that spatial tumor heterogeneity could be associated with heterogeneity in the tumor ME. We did not observe expansion of site-unique T cell clones, but some of the clones were enriched up to 10-fold at one of the two sites. These clones were typically seen in the PB at low frequency. Expanded T-cells clones were almost exclusively found in the CD8 +-compartment, with 65% and 27% of expanded T-cell clones being CD45RO +/CD57 +-memory- and CD69 +-effector-T-cells, respectively. Besides differences in the T-cell clonality, we observed changes in proportions of other cell types, including a depletion of CD14+- and CD16+-macrophages in FLs (p<0.05). Furthermore, we observed gene expression differences between FL and RBMA macrophages, especially for genes involved in TNFα, IL-6 and JAK/STAT3 signaling. While CCL2, CD44, CXCL2/3, KLF2/4 and CCR1 were significantly higher expressed in FLs compared to RBMAs, BTG2, DUSP1 and HIF1A were down-regulated. In conclusion, our results strengthen the concept of MM as a spatially heterogeneous disease, suggest that reactive oxygen species result in site-specific mutagenesis, and support the hypothesis that FLs are the origin of aggressive disease. We demonstrate spatial heterogeneity at single-cell level in the BM immune ME for the first time, which implies that understanding the complex biology of FLs could be important in the context of novel immune therapies such as bispecific antibodies and CAR-T-cells. Disclosures John: Janssen: Consultancy. Müller-Tidow: Janssen Cilag: Consultancy, Research Funding; Bioline: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding. Goldschmidt: Takeda: Consultancy, Research Funding; Sanofi: Consultancy, Honoraria, Other: Grants and/or Provision of Investigational Medicinal Product, Research Funding; Dietmar-Hopp-Foundation: Other: Grant; Novartis: Honoraria, Research Funding; Mundipharma: Research Funding; MSD: Research Funding; Molecular Partners: Research Funding; Johns Hopkins University: Other: Grant; Janssen: Consultancy, Honoraria, Other: Grants and/or Provision of Investigational Medicinal Product, Research Funding; Incyte: Research Funding; GSK: Honoraria; Chugai: Honoraria, Other: Grants and/or Provision of Investigational Medicinal Product, Research Funding; BMS: Consultancy, Honoraria, Other: Grants and/or Provision of Investigational Medicinal Product, Research Funding; Celgene: Consultancy, Honoraria, Other: Grants and/or Provision of Investigational Medicinal Product, Research Funding; Adaptive Biotechnology: Consultancy; Amgen: Consultancy, Honoraria, Other: Grants and/or Provision of Investigational Medicinal Product, Research Funding. Raab: Janssen: Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy; GSK: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Honoraria; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees. Weinhold: Sanofi: Honoraria.

scholarly journals CPC-070 Importance of Residual Investigational Medicinal Product Count

2013 ◽  
Vol 20 (Suppl 1) ◽  
pp. A190.2-A190
Author(s):  
N Gastaut ◽  
M Naud ◽  
C Breuker ◽  
E Ripolles ◽  
N Terrail ◽  
...  
Keyword(s):  
Medicinal Product ◽  
Investigational Medicinal Product

scholarly journals Impact of Novel Therapies on CD4-T-Cell-Numbers and Infectious Complications in Patients with Relapsed/Refractory Multiple Myeloma

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 14-14
Author(s):  
Lukas John ◽  
Kaya Miah ◽  
Axel Benner ◽  
Elias K Mai ◽  
Katharina Kriegsmann ◽  
...  
Keyword(s):  
Cell Count ◽  
Medicinal Product ◽  
Board Of Directors ◽  
Research Funding ◽  
Infectious Complications ◽  
Investigational Medicinal Product ◽  
Advisory Committees ◽  
Cd4 Cell Count ◽  
Cd4 Cell ◽  
Relapse Therapy

Introduction: Despite improvements in the prognosis of multiple myeloma (MM), most patients ultimately relapse and undergo multiple lines of therapy. Due to the immunocompromising effects of virtually all anti-myeloma agents as well as the disease itself, infections are a frequent complication during therapy and the most important cause of mortality in patients with MM. Establishment of clear predictors of infectious complications, especially under therapy with novel agents, is therefore of major clinical importance to identify patients at risk and to guide anti-infective prophylaxis. Methods: In this prospective, observational cohort study we examined the development of CD4+ T-cell numbers during anti-myeloma therapies which were based on the novel agents daratumumab, carfilzomib, elotuzumab, or pomalidomide and their impact on infectious complications in 96 patients with relapsed/refractory MM (median prior lines of therapy: 2 [1-13], median age: 70 years of age [42-90]). Data on infectious events including CTC-AE severity grading, antimicrobial prophylaxis strategies and vaccination status was collected before start of therapy, after 3 months and after 6 months of therapy. Flow cytometry was used to identify T-cell subsets at all three timepoints. Results: Before start of therapy, 25 patients (26%) had CD4+ cell counts < 200/µl, 75 patients (78%) had CD4+ cell counts < 500/µl. In a multivariate linear regression model the number of previous lines of therapy had a significant negative impact on CD4+-cell numbers at start of relapse therapy (p=0.03), whereas age and active therapy within in the last 6 months did not. With regard to relapse therapy, both pomalidomide and carfilzomib led to a significant reduction in CD4+ cell count after 3 months of therapy (p=0.03 and p= 0.04, resp.) in a multivariate linear regression model. This effect was not noticeable in treatments based on daratumumab. In a multivariate logistic regression analysis with regard to the occurrence of infections ≥ CTC II° within the first 3 cycles of therapy, CD4+ cell count at start of relapse therapy was the only predictor with borderline statistical significance (p=0.06). Conclusions: A significant proportion of patients with relapsed refractory MM show a severe reduction of CD4+ T-cells already at start of relapse therapy, especially after multiple lines of therapy. CD4+ cell count at start of relapse therapy might indicate an increased risk of infectious complications. Additional studies with a larger number of patients are warranted to further elucidate the impact of CD4+ cell count at start of relapse therapy as a predictor of infectious complications in MM and whether it might serve to better identify patients at risk of infectious complications and steer antimicrobial prophylaxis strategies. Disclosures John: Proteona: Research Funding. Mueller-Tidow:Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Daiichi Sankyo: Research Funding; Jose-Carreras-Siftung: Research Funding; Bayer AG: Research Funding; BiolineRx: Research Funding; Wilhelm-Sander-Stiftung: Research Funding; BMBF: Research Funding; Deutsche Krebshilfe: Research Funding; Janssen-Cilag Gmbh: Membership on an entity's Board of Directors or advisory committees; Deutsche Forschungsgemeinschaft: Research Funding. Jordan:priME Oncology: Speakers Bureau; Shire: Membership on an entity's Board of Directors or advisory committees; G1 Therapeutics: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Voluntis: Membership on an entity's Board of Directors or advisory committees; Pomme-med: Speakers Bureau; Hexal: Speakers Bureau; Merck: Membership on an entity's Board of Directors or advisory committees; Merck Sharp & Dome: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; medupdate: Speakers Bureau; Helsinn: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Tesaro: Membership on an entity's Board of Directors or advisory committees; ClinSolResearch: Membership on an entity's Board of Directors or advisory committees; Riemser: Research Funding, Speakers Bureau; Amgen: Speakers Bureau; Kreussler: Membership on an entity's Board of Directors or advisory committees; art-tempi: Speakers Bureau. Goldschmidt:Dietmar-Hopp-Foundation: Other: Grants and/or provision of Investigational Medicinal Product:; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants and/or provision of Investigational Medicinal Product:, Research Funding; Incyte: Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants and/or provision of Investigational Medicinal Product:, Research Funding; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; Johns Hopkins University: Other: Grants and/or provision of Investigational Medicinal Product; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants and/or provision of Investigational Medicinal Product:, Research Funding; Novartis: Honoraria, Research Funding; Mundipharma GmbH: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Molecular Partners: Research Funding; Merck Sharp and Dohme (MSD): Research Funding; University Hospital Heidelberg, Internal Medicine V and National Center for Tumor Diseases (NCT), Heidelberg, Germany: Current Employment; GlaxoSmithKline (GSK): Honoraria; Adaptive Biotechnology: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants and/or provision of Investigational Medicinal Product, Research Funding; Chugai: Honoraria, Other: Grants and/or provision of Investigational Medicinal Product:, Research Funding. Raab:Heidelberg Pharma: Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding.

scholarly journals Characterization of Rare Germline Variants in Familial Multiple Myeloma

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 45-46
Author(s):  
Calogerina Catalano ◽  
Joanna Blocka ◽  
Stefanie Huhn ◽  
Nagarajan Paramasivam ◽  
Matthias Schlesner ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Medicinal Product ◽  
Board Of Directors ◽  
Research Funding ◽  
High Impact ◽  
Investigational Medicinal Product ◽  
Genome Wide Association Studies ◽  
Whole Genome ◽  
Advisory Committees ◽  
The Impact

Introduction: The risk of developing Multiple Myeloma (MM) is 2-4 fold higher in first-degree relatives of patients with MM compared to the general population, suggesting genetic predisposition to this cancer. Indeed, recent genome-wide association studies have identified common risk alleles that predispose for MM. Yet, the impact of these variants on MM risk is too low to explain familial aggregation of MM. High-impact alleles have been identified for other cancers such as ovarian and breast cancer (BRCA1,-2) and melanoma (CDKN2A) but the search for such alleles in MM is still in its infancy. In order to identify high-impact alleles in MM we have performed whole genome/exon sequencing (WGS/WES) in members of MM high risk families. Methods: We included 21 families with multiple cases of MM/MGUS. Whole genome/exome sequencing was performed on a total of 46 affected and 20 unaffected family members. Filtering and prioritization of the variants were performed in accordance with the criteria of our in-house familial cancer variant prioritization pipeline version 2 (FCVPPv2). Loss-of-function variants were further screened using MutPred-LOF, Translate tool and IntOGen/c-BioPortal in order to discriminate pathogenic and neutral variants, to translate a nucleotide sequence to a protein sequence and to visualize the domain affected by the variant and the portion of the protein lost after the newly formed stop codon. Variants were analyzed for predicted effects on splicing by using Human Splicing Finder. Results: We found a total of 148 potentially pathogenic variants, 109 non-synonymous and 39 LOF, in 18 out of 21 MM families. Among our genes, many affect protein metabolism, immune system, and other have known links to carcinogenesis. Additionally, some of them are known to interact with key signaling pathways in MM, including PI3K/Akt/mTOR, Ras/Raf/MEK/MAPK, JAK/STAT, NF-κB, Wnt/β-catenin, and RANK/RANKL/OPG, showing congruency with previously reported literature. Interestingly, we also found different missense variants in the same two genes in two unrelated families. Conclusions: We have identified potentially pathogenic gene variants in 85% of MM/MGUS families. Our results can offer a useful reference to gene finding efforts by others in order to improve screening, early diagnosis and personalized therapy of individuals at risk of developing MM. Disclosures Durie: Amgen, Celgene, Johnson & Johnson, and Takeda: Consultancy. Goldschmidt:Merck Sharp and Dohme (MSD): Research Funding; Molecular Partners: Research Funding; Incyte: Research Funding; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; Johns Hopkins University: Other: Grants and/or provision of Investigational Medicinal Product; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants and/or provision of Investigational Medicinal Product:, Research Funding; Dietmar-Hopp-Foundation: Other: Grants and/or provision of Investigational Medicinal Product:; Chugai: Honoraria, Other: Grants and/or provision of Investigational Medicinal Product:, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants and/or provision of Investigational Medicinal Product:, Research Funding; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants and/or provision of Investigational Medicinal Product:, Research Funding; University Hospital Heidelberg, Internal Medicine V and National Center for Tumor Diseases (NCT), Heidelberg, Germany: Current Employment; GlaxoSmithKline (GSK): Honoraria; Adaptive Biotechnology: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants and/or provision of Investigational Medicinal Product, Research Funding; Novartis: Honoraria, Research Funding; Mundipharma GmbH: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding.

The Bone Marrow Microenvironment of Multiple Myeloma Long-Term Survivors at Single Cell Resolution

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 32-33
Author(s):  
Raphael Lutz ◽  
Abdelrahman Mahmoud ◽  
Mohamed H.S. Awwad ◽  
Charles D. Imbusch ◽  
Tobias Boch ◽  
...  
Keyword(s):  
T Cell ◽  
Disease Activity ◽  
Medicinal Product ◽  
Board Of Directors ◽  
Research Funding ◽  
Investigational Medicinal Product ◽  
Initial Diagnosis ◽  
Cell Compartment ◽  
Advisory Committees ◽  
Early Relapse

To date, multiple myeloma (MM) remains an incurable disease with only a minor fraction of patients experiencing long-term remission (LTR) over 7 years after a single therapy line. Myeloma cells strongly depend on the interaction with their bone marrow microenvironment (BMME), but the molecular and cellular adaptations of the BMME to active MM disease and the role of the immune system in patients experiencing LTR remain poorly understood. In order to gain a global and detailed understanding of the BMME, we profiled over 290.000 BM resident cells from 11 MM patients in LTR 7 to 17 years after first-line therapy and 3 healthy donors using droplet-based single-cell RNA sequencing. Paired BM samples collected at initial diagnosis enabled us to analyze the changes from first diagnosis to the state of LTR in individual patients. At initial diagnosis, we observed significant remodeling of the T cell, NK cell and myeloid compartments which was only partially reversible upon LTR. In- depth analysis of the CD8+ T- cell compartment revealed an unknown immunophenotype of myeloma-associated CD8+ T (MAT) cells expressing key mediators of T cell dysfunction such as NR4A2. The amino acid transporter LAT1 (SLC7A5), which is known to be critical to maintain the activation state of T cells, and the surface marker CD6 were specifically expressed by MAT cells. We validated the existence of this novel T cell immunophenotype in an independent group of 30 MM patients using FACS. The number of MAT cells was associated with myeloma cell burden indicating that MAT-cells might be an indirect marker for tumor load within the BM. The clinical and prognostic meaning of this population is currently under investigation. Within the myeloid compartment, we detected myeloma associated myeloid (MAM) cells at initial diagnosis that were only present in case of active disease. These MAM cells shared features of immunosuppression, inflammation and migration as well as chemotaxis hinting towards a phenomenon of immune cell recruitment to the site of disease. At the LTR stage, 6 of 11 patients were still in complete remission (CR), while 5 patients presented with detectable disease activity after having achieved a CR. In the CR-group we observed a healthy-like state in the BMME but still detected a myeloma associated imprint even in minimal residual disease negative patients. Within the CD8+ T cell compartment, this imprint included a higher metabolic activity in the naïve T cell compartment as well as a higher grade of cytotoxicity within the effector T cell and NK cell compartment. These observations might reflect a state of active immunosurveillance in MM patients to maintain CR at the LTR state. In contrast, 5 LTR patients with detectable disease activity lost the CR associated immune signature approaching a BMME remodeling similar to initial diagnosis. Increasing disease activity over the next 2 years within this patient population showed that we captured a state of early relapse. This enabled us to describe programs specific to early relapse in comparison to the full- blown disease state. In this context, an increase in plasmacytoid dendritic cells (pDCs), key players in the production of interferons, was observed at the stage of early relapse hinting towards a role for pDCs in establishing the inflammatory changes in the BMME upon resurgence of disease. Together, this study provides a comprehensive overview of the molecular and cellular patterns within the BMME that underlie active myeloma disease as well as LTR in MM. We describe novel immunophenotypes of T cells and myeloid cells associated with myeloma cell burden within the BM. At the stage of LTR, our results reveal how patients in CR approach a healthy-like state but still preserve an imprint of MM potentially associated with active immunosurveillance. Finally, this study deepens the understanding how BMME remodeling evolves from an early phase of relapse to a full-blown disease. Disclosures Durie: Amgen, Celgene, Johnson & Johnson, and Takeda: Consultancy. Raab:Novartis: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees; Heidelberg Pharma: Research Funding. Müller-Tidow:Pfizer: Research Funding, Speakers Bureau; Daiichi Sankyo: Research Funding; BiolineRx: Research Funding; Janssen-Cilag GmbH: Speakers Bureau. Goldschmidt:BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants and/or provision of Investigational Medicinal Product:, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Research Funding; Merck Sharp and Dohme (MSD): Research Funding; Johns Hopkins University: Other: Grants and/or provision of Investigational Medicinal Product; Dietmar-Hopp-Foundation: Other: Grants and/or provision of Investigational Medicinal Product:; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants and/or provision of Investigational Medicinal Product, Research Funding; Incyte: Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants and/or provision of Investigational Medicinal Product:, Research Funding; Adaptive Biotechnology: Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline (GSK): Honoraria; University Hospital Heidelberg, Internal Medicine V and National Center for Tumor Diseases (NCT), Heidelberg, Germany: Current Employment; Chugai: Honoraria, Other: Grants and/or provision of Investigational Medicinal Product:, Research Funding; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; Molecular Partners: Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants and/or provision of Investigational Medicinal Product:, Research Funding; Mundipharma GmbH: Research Funding.

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