Adaption of neurosurgical resection patterns for pediatric low-grade glioma spanning two decades-Report from the German LGG-studies 1996-2018.

INTRODUCTION: Neurosurgery is considered the mainstay of treatment for pediatric low-grade glioma (LGG); the extent of resection determines subsequent stratification in current treatment protocols. Yet, surgical radicality must be balanced against the risks of complications that may affect long-term quality of life. We investigated whether this consideration impacted surgical resection patterns over time for patients of the German LGG studies. PATIENTS AND METHODS: Four thousand two hundred and seventy pediatric patients from three successive LGG studies (median age at diagnosis 7.6 years, neurofibromatosis (NF1) 14.7%) were grouped into 5 consecutive time intervals (TI1-5) for date of diagnosis and analyzed for timing and extent of first surgery with respect to tumor site, histology, NF1-status, sex, and age. RESULTS: The fraction of radiological LGG diagnoses increased over time (TI1 12.6%; TI5 21.7%), while the extent of the first neurosurgical intervention (3440/4270) showed a reduced fraction of complete/subtotal and an increase of partial resections from TI1 to TI5. Binary logistic regression analysis for the first intervention within the first year following diagnosis confirmed the temporal trends (p < 0.001) and the link with tumor site for each extent of resection (p < 0.001). Higher age is related to more complete resections in the cerebellum and cerebral hemispheres. CONCLUSIONS: The declining extent of surgical resections over time was unrelated to patient characteristics. It paralleled the evolution of comprehensive treatment algorithms; thus, it may reflect alignment of surgical practice to recommendations in respect to age, tumor site, and NF1-status integrated as such into current treatment guidelines. Further investigations are needed to understand how planning, performance, or tumor characteristics impact achieving surgical goals.

Electronic health intervention to manage symptoms of immunotherapy in patients with cancer (SOFIA): Results from a randomized controlled pilot trial.

BACKGROUND: For patients receiving immune checkpoint inhibitors, early detection of immune-related adverse events (irAEs) is critical for one's safety. To this end, a smartphone app (SOFIA) was developed that featured the assessment of electronic patient-reported outcomes (ePROs) focusing on irAEs as well as a set of comprehensive supportive information. Its feasibility and preliminary efficacy were evaluated in a randomized controlled trial (RCT). METHODS: Patients who received immune checkpoint inhibition therapy were randomly assigned to an intervention group (IG) or a control group (CG; care as usual). During the 12-week intervention period, IG patients used SOFIA to report twice weekly ePROs and receive cancer- and immunotherapy-relevant contents. Before a patient's next clinical visit, the physician in charge was given the ePRO reports. The primary objective was to test the feasibility of SOFIA. Furthermore, the preliminary efficacy of SOFIA for health-related quality of life (HRQOL), psychosocial outcomes, and medical data was examined. Clinical outcomes were assessed at baseline (T0), post-intervention (T1), and a 3-month follow-up (T2). RESULTS: Seventy-one patients were randomized to the IG (n = 34) or the CG (n = 37). SOFIA showed high feasibility and acceptance. At T1, patients in the IG reported significantly better HRQOL and role functioning and less depression, distress, and appetite loss. No significant differences were revealed regarding medical data, the utilization of supportive care services, or survival. CONCLUSIONS: SOFIA showed high feasibility and acceptance and improved HRQOL and psychosocial outcomes. These results suggest further evaluation of efficacy in a large-scale confirmatory multicenter RCT.

[18F]FET-PET in children and adolescents with central nervous system tumors: does it support difficult clinical decision-making?

PURPOSE: Positron emission tomography (PET) with O-(2-[18F]fluoroethyl)-L-tyrosine ([18F]FET) is a well-established tool for non-invasive assessment of adult central nervous system (CNS) tumors. However, data on its diagnostic utility and impact on clinical management in children and adolescents are limited. METHODS: Twenty-one children and young adults (13 males; mean age, 8.6 ± 5.2 years; range, 1-19 at initial diagnosis) with either newly diagnosed (n = 5) or pretreated (n = 16) CNS tumors were retrospectively analyzed. All patients had previously undergone neuro-oncological work-up including cranial magnetic resonance imaging. In all cases, [18F]FET-PET was indicated in a multidisciplinary team conference. The impact of PET imaging on clinical decision-making was assessed. Histopathology (n = 12) and/or clinical and imaging follow-up (n = 9) served as the standard of reference. RESULTS: The addition of [18F]FET-PET to the available information had an impact on further patient management in 14 out of 21 subjects, with avoidance of invasive surgery or biopsy in four patients, biopsy guidance in four patients, change of further treatment in another five patients, and confirmation of diagnosis in one patient. CONCLUSION: [18F]FET-PET may provide important additional information for treatment guidance in pediatric and adolescent patients with CNS tumors.

Cytokine release syndrome-like serum responses after COVID-19 vaccination are frequent and clinically inapparent under cancer immunotherapy.

Patients with cancer frequently receive immune-checkpoint inhibitors (ICIs), which may modulate immune responses to COVID-19 vaccines. Recently, cytokine release syndrome (CRS) was observed in a patient with cancer who received BTN162b2 vaccination under ICI treatment. Here, we analyzed adverse events and serum cytokines in patients with 23 different tumors undergoing (n = 64) or not undergoing (n = 26) COVID-19 vaccination under ICI therapy in a prospectively planned German single-center cohort study (n = 220). We did not observe clinically relevant CRS (≥grade 2) after vaccination (95% CI 0-5.6%; Common Terminology of Adverse Events v.5.0) in this small cohort. Within 4 weeks after vaccination, serious adverse events occurred in eight patients (12.5% 95% CI 5.6-23%): six patients were hospitalized due to events common under cancer therapy including immune related adverse events and two patients died due to conditions present before vaccination. Despite absence of CRS symptoms, a set of pairwise-correlated CRS-associated cytokines, including CXCL8 and interleukin-6 was >1.5-fold upregulated in 40% (95% CI 23.9-57.9%) of patients after vaccination. Hence, elevated cytokine levels are common and not sufficient to establish CRS diagnosis.

Phase I/II study of the LAG-3 inhibitor ieramilimab (LAG525) ± anti-PD-1 spartalizumab (PDR001) in patients with advanced malignancies.

BACKGROUND: Lymphocyte-activation gene 3 (LAG-3) is an inhibitory immunoreceptor that negatively regulates T-cell activation. This paper presents preclinical characterization of the LAG-3 inhibitor, ieramilimab (LAG525), and phase I data for the treatment of patients with advanced/metastatic solid tumors with ieramilimab ±the anti-programmed cell death-1 antibody, spartalizumab. METHODS: Eligible patients had advanced/metastatic solid tumors and progressed after, or were unsuitable for, standard-of-care therapy, including checkpoint inhibitors in some cases. Patients received ieramilimab ±spartalizumab across various dose-escalation schedules. The primary objective was to assess the maximum tolerated dose (MTD) or recommended phase II dose (RP2D). RESULTS: In total, 255 patients were allocated to single-agent ieramilimab (n=134) and combination (n=121) treatment arms. The majority (98%) had received prior antineoplastic therapy (median, 3). Four patients experienced dose-limiting toxicities in each treatment arm across various dosing cohorts. No MTD was reached. The RP2D on a 3-week schedule was declared as 400 mg ieramilimab plus 300 mg spartalizumab and, on a 4-week schedule (once every 4 weeks; Q4W), as 800 mg ieramilimab plus 400 mg spartalizumab; tumor target (LAG-3) suppression with 600 mg ieramilimab Q4W was predicted to be similar to the Q4W, RP2D schedule. Treatment-related adverse events (TRAEs) occurred in 75 (56%) and 84 (69%) patients in the single-agent and combination arms, respectively. Most common TRAEs were fatigue, gastrointestinal, and skin disorders, and were of mild severity; seven patients experienced at least one treatment-related serious adverse event in the single-agent (5%) and combination group (5.8%). Antitumor activity was observed in the combination arm, with 3 (2%) complete responses and 10 (8%) partial responses in a mixed population of tumor types. In the combination arm, eight patients (6.6%) experienced stable disease for 6 months or longer versus six patients (4.5%) in the single-agent arm. Responding patients trended towards having higher levels of immune gene expression, including CD8 and LAG3, in tumor tissue at baseline. CONCLUSIONS: Ieramilimab was well tolerated as monotherapy and in combination with spartalizumab. The toxicity profile of ieramilimab in combination with spartalizumab was comparable to that of spartalizumab alone. Modest antitumor activity was seen with combination treatment. TRIAL REGISTRATION NUMBER: NCT02460224.

Combined inhibition of CXCL12 and PD-1 in MSS colorectal and pancreatic cancer: modulation of the microenvironment and clinical effects.

BACKGROUND: Immunotherapy in microsatellite stable colorectal or pancreatic cancer has not shown promising results. It has been hypothesized that targeting immunosuppressive molecules like SDF1-alpha/CXCL12 could contribute to immunotherapy and animal models showed promising results on T cell activation and migration in combination with immune checkpoint inhibition. METHODS: Here, we describe the successful application of anti-CXCL12 (NOX-A12) in patients with advanced stage pretreated metastatic colorectal and pancreatic cancer (OPERA trial). The treatment consisted of 2 weeks of anti-CXCL12 monotherapy with NOX-A12 followed by combination therapy with pembrolizumab (n=20 patients) until progression or intolerable toxicity had occurred. RESULTS: The treatment was safe and well tolerated with 83.8% grade I/II, 15.5% grade III and 0.7% grade V adverse events. Of note, for a majority of patients, time on trial treatment was prolonged compared with their last standard treatment preceding trial participation. Systematic serial biopsies revealed distinct patterns of modulation. Tissue and clinical responses were associated with Th1-like tissue reactivity upon CXCL12 inhibition. A downregulation of a cytokine cassette of interleukin (IL)-2/IL-16/CXCL-10 was associated with tumor resistance and furthermore linked to a rare, CXCL12-associated CD14+CD15+promonocytic population. T cells showed aggregation and directed movement towards the tumor cells in responding tissues. Serum analyses detected homogeneous immunomodulatory patterns in all patients, regardless of tissue responses. CONCLUSIONS: We demonstrate that the combination of CXCL12 inhibition and checkpoint inhibition is safe and grants further exploration of synergistic combinatorial strategies.

Natural and cryptic peptides dominate the immunopeptidome of atypical teratoid rhabdoid tumors.

BACKGROUND: Atypical teratoid/rhabdoid tumors (AT/RT) are highly aggressive CNS tumors of infancy and early childhood. Hallmark is the surprisingly simple genome with inactivating mutations or deletions in the SMARCB1 gene as the oncogenic driver. Nevertheless, AT/RTs are infiltrated by immune cells and even clonally expanded T cells. However, it is unclear which epitopes T cells might recognize on AT/RT cells. METHODS: Here, we report a comprehensive mass spectrometry (MS)-based analysis of naturally presented human leukocyte antigen (HLA) class I and class II ligands on 23 AT/RTs. MS data were validated by matching with a human proteome dataset and exclusion of peptides that are part of the human benignome. Cryptic peptide ligands were identified using Peptide-PRISM. RESULTS: Comparative HLA ligandome analysis of the HLA ligandome revealed 55 class I and 139 class II tumor-exclusive peptides. No peptide originated from the SMARCB1 region. In addition, 61 HLA class I tumor-exclusive peptide sequences derived from non-canonically translated proteins. Combination of peptides from natural and cryptic class I and class II origin gave optimal representation of tumor cell compartments. Substantial overlap existed with the cryptic immunopeptidome of glioblastomas, but no concordance was found with extracranial tumors. More than 80% of AT/RT exclusive peptides were able to successfully prime CD8+ T cells, whereas naturally occurring memory responses in AT/RT patients could only be detected for class II epitopes. Interestingly, >50% of AT/RT exclusive class II ligands were also recognized by T cells from glioblastoma patients but not from healthy donors. CONCLUSIONS: These findings highlight that AT/RTs, potentially paradigmatic for other pediatric tumors with a low mutational load, present a variety of highly immunogenic HLA class I and class II peptides from canonical as well as non-canonical protein sources. Inclusion of such cryptic peptides into therapeutic vaccines would enable an optimized mapping of the tumor cell surface, thereby reducing the likelihood of immune evasion.

Digital Pathology Scoring of Immunohistochemical Staining Reliably Identifies Prognostic Markers and Anatomical Associations in a Large Cohort of Oral Cancers.

Utilizing digital pathology algorithms for the objective quantification of immunohistochemical staining, this study aimed to identify robust prognostic biomarkers for oral cancer. Tissue microarrays with specimens of a large cohort of oral squamous cell carcinoma (n=222) were immunohistochemically stained to determine the expression of PD-L1, EGFR, and COX-2 and the amount of infiltrating NK cells and CD8-positive T cells. Immunoreactivity scores were assessed using both a classical manual scoring procedure and a digital semi-automatic approach using QuPath. Digital scoring was successful in quantifying the expression levels of different prognostic biomarkers (CD8: p<0.001; NK cells: p=0.002, PD-L1: p=0.026) and high levels of concordance with manual scoring results were observed. A combined score integrating EGFR expression, neck node status and immune cell signatures with a significant impact on overall and progression-free survival was identified (p<0.001). These data may contribute to the ongoing research on the identification of reliable and clinically relevant biomarkers for the individualization of primary and adjuvant treatment in oral cancer.

eHealth intervention to manage symptoms for patients with cancer on immunotherapy (SOFIA): a study protocol for a randomised controlled external pilot trial.

INTRODUCTION: Immune checkpoint therapy (ICT) is associated with a distinct pattern of immune-related adverse events (irAEs) caused by inadvertently redirecting immune responses to healthy tissues. IrAEs can occur at any time; however, in most cases, they arise during the first 14 weeks of the beginning of immune checkpoint blockade. In many cases, immunotherapy must be discontinued due to irAEs. Early detection of irAEs triggers the temporary withholding of ICT or initiation of short-term immunosuppressive treatment, is crucial in preventing further aggravation of irAEs and enables safe re-exposure to ICT. This prospective study aims to evaluate the feasibility of an eHealth intervention for patients under immunotherapy (managing symptoms of immunotherapy, SOFIA). The SOFIA-App consists of two components: SOFIA-Monitoring, a tool to rate patient-reported outcomes (PROs) including irAEs, and SOFIA-Coaching, which provides important information about cancer-specific and immunotherapy-specific topics and the counselling services of the National Centre for Tumour Diseases (NCT) Heidelberg. METHODS AND ANALYSIS: We outlined a patient-level two-arm randomised controlled pilot trial of the intervention (SOFIA) versus no-SOFIA for patients with cancer beginning an immunotherapy, aged ≥18 years, recruited from the NCT, Heidelberg. Feasibility outcomes include: recruitment rate; drop-out rate; reasons for refusal and drop-out; willingness to be randomised, utilisation rate of SOFIA-Monitoring and utilisation time of SOFIA-Coaching, physicians utilisation rate of the PROs; feasibility of the proposed outcome measures and optimal sample size estimation. The clinical outcomes are measures of quality of life, psychosocial symptoms, self-efficacy, physician-patient communication and medical process data, which are assessed at the beginning of the intervention, postintervention and at 6-month follow-up. ETHICS AND DISSEMINATION: This trial protocol was approved by the Ethical Committee of Heidelberg University, Germany (Reference, S-581/2018). TRIAL REGISTRATION NUMBER: We registered the study in the German Clinical Trial Register (Reference: DRKS00021064). Findings will be disseminated broadly via peer-reviewed empirical journals, articles and conference presentations.

EGFR and PI3K Pathway Activities Might Guide Drug Repurposing in HPV-Negative Head and Neck Cancers.

While genetic alterations in Epidermal growth factor receptor (EGFR) and PI3K are common in head and neck squamous cell carcinomas (HNSCC), their impact on oncogenic signaling and cancer drug sensitivities remains elusive. To determine their consequences on the transcriptional network, pathway activities of EGFR, PI3K, and 12 additional oncogenic pathways were inferred in 498 HNSCC samples of The Cancer Genome Atlas using PROGENy. More than half of HPV-negative HNSCC showed a pathway activation in EGFR or PI3K. An amplification in EGFR and a mutation in PI3KCA resulted in a significantly higher activity of the respective pathway (p = 0.017 and p = 0.007). Interestingly, both pathway activations could only be explained by genetic alterations in less than 25% of cases indicating additional molecular events involved in the downstream signaling. Suitable in vitro pathway models could be identified in a published drug screen of 45 HPV-negative HNSCC cell lines. An active EGFR pathway was predictive for the response to the PI3K inhibitor buparlisib (p = 6.36E-03) and an inactive EGFR and PI3K pathway was associated with efficacy of the B-cell lymphoma (BCL) inhibitor navitoclax (p = 9.26E-03). In addition, an inactive PI3K pathway correlated with a response to multiple Histone deacetylase inhibitor (HDAC) inhibitors. These findings require validation in preclinical models and clinical studies.

High frequency of disease progression in pediatric spinal cord low-grade glioma (LGG): management strategies and results from the German LGG study group.

BACKGROUND: Knowledge on management of pediatric spinal cord low-grade glioma (LGG) is scarce. METHODS: We analyzed clinical datasets of 128 pediatric patients with spinal LGG followed within the prospective multicenter trials HIT-LGG 1996 (n = 36), SIOP-LGG 2004 (n = 56), and the subsequent LGG-Interim registry (n = 36). RESULTS: Spinal LGG, predominantly pilocytic astrocytomas (76%), harbored KIAA1549-BRAF fusion in 14/35 patients (40%) and FGFR1-TACC1 fusion in 3/26 patients (12%), as well as BRAFV600E mutation in 2/66 patients (3%). 10-year overall survival (OS) and event-free survival (EFS) was 93% ± 2% and 38% ± 5%, respectively. Disseminated disease (n = 16) was associated with inferior OS and EFS, while age ≥11 years and total resection were favorable factors for EFS. We observed 117 patients following total (n = 24) or subtotal/partial resection (n = 74), biopsy (n = 16), or radiologic diagnosis only (n = 3). Eleven patients were treated first with chemotherapy (n = 9) or irradiation (n = 2). Up to 20.8 years after diagnosis/initial intervention, 73/128 patients experienced one (n = 43) or up to six (n = 30) radiological/clinical disease progressions. Tumor resections were repeated in 36 patients (range, 2-6) and 47 patients required nonsurgical treatment (chemotherapy, n = 20; radiotherapy, n = 10; multiple treatment lines, n = 17). Long-term disease control for a median of 6.5 (range, 0.02-20) years was achieved in 73/77 patients following one (n = 57) or repeated (n = 16) resections, and in 35/47 patients after nonsurgical treatment. CONCLUSIONS: The majority of patients experienced disease progression, even after years. Multiple interventions were required for more than a third, yet multimodal treatment enabled long-term disease control. Molecular testing may reveal therapeutic targets.

Local and systemic therapy of recurrent ependymoma in children and adolescents: short- and long-term results of the E-HIT-REZ 2005 study.

BACKGROUND: Survival in recurrent ependymomas in children and adolescents mainly depends on the extent of resection. Studies on repeated radiotherapy and chemotherapy at relapse have shown conflicting results. METHODS: Using data from the German multi-center E-HIT-REZ-2005 study, we examined the role of local therapy and the efficacy of chemotherapy with blockwise temozolomide (TMZ) in children and adolescents with recurrent ependymomas. RESULTS: Fifty-three patients with a median age of 6.9 years (1.25-25.4) at first recurrence and a median follow-up time of 36 months (2-115) were recruited. Gross- and near-total resection (GTR/NTR) were achieved in 34 (64.2%) patients and associated with a markedly improved 5-year overall survival (OS) of 48.7% vs. 5.3% in less than GTR/NTR. Radiotherapy showed no improvement in OS following complete resection (OS: 70 (CI: 19.9-120.1) vs. 95 (CI: 20.7-169.4) months), but an advantage was found in less than GTR/NTR (OS: 22 (CI: 12.7-31.3) vs. 7 (CI: 0-15.8) months). Following the application of TMZ, disease progression was observed in most evaluable cases (18/21). A subsequent change to oral etoposide and trofosfamide showed no improved response. PF-A EPN were most abundant in relapses (n = 27). RELA-positive EPN (n = 5) had a 5-year OS of 0%. CONCLUSION: The extent of resection is the most important predictor of survival at relapse. Focal re-irradiation is a useful approach if complete resection cannot be achieved, but no additional benefit was seen after GTR/NTR. Longer-term disease stabilization (>6 months) mediated by TMZ occurred in a small number of cases (14.3%).

Carbon ion reirradiation compared to intensity-modulated re-radiotherapy for recurrent head and neck cancer (CARE): a randomized controlled trial.

BACKGROUND: Intensity-modulated re-radiotherapy (reIMRT) has been established as a standard local treatment option in patients with non-resectable, recurrent head and neck cancer (rHNC). However, the clinical outcome is unfavorable and severe toxicities (≥grade III) occurred in 30-40% of patients. The primary aim of the current trial is to investigate carbon ion reirradiation (reCIRT) compared to reIMRT in patients with rHNC regarding safety/toxicity as well as local control, overall survival (OS), and quality of life (QoL). METHODS: The present trial will be performed as a single center, two-armed, prospective phase II study. A maximum of 72 patients will be treated with either reIMRT or reCIRT to evaluate severe (≥grade III) treatment-related toxicities (randomization ratio 1:1). The primary target value is to generate less than 35% acute/subacute severe toxicity (≥grade III), according to the Common Terminology Criteria for Adverse Events v5.0, within 6 months after study treatment. The total dose of reirradiation will range between 51 and 60 Gy or Gy (RBE), depending primarily on the radiotherapy interval and the cumulative dose to organs at risk. Individual dose prescription will be at the discretion of the treating radiation oncologist. The local and distant progression-free survival 12 months after reirradiation, the OS, and the QoL are the secondary endpoints of the trial. Explorative trial objectives are the longitudinal investigation of clinical patient-related parameters, tumor parameters on radiological imaging, and blood-based tumor analytics. DISCUSSION: Recent retrospective studies suggested that reCIRT could represent a feasible and effective treatment modality for rHNC. This current randomized prospective trial is the first to investigate the toxicity and clinical outcome of reCIRT compared to reIMRT in patients with rHNC. TRIAL REGISTRATION: ClinicalTrials.gov ; NCT04185974 ; December 4th 2019.

Treatment of children under 4 years of age with medulloblastoma and ependymoma in the HIT2000/HIT-REZ 2005 trials: Neuropsychological outcome 5 years after treatment.

Young children with brain tumours are at high risk of developing treatment-related sequelae. We aimed to assess neuropsychological outcomes 5 years after treatment. This cross-sectional study included children under 4 years of age with medulloblastoma (MB) or ependymoma (EP) enrolled in the German brain tumour trials HIT2000 and HIT-REZ2005. Testing was performed using the validated Wuerzburg Intelligence Diagnostics (WUEP-D), which includes Kaufman-Assessment-Battery, Coloured Progressive Matrices, Visual-Motor Integration, finger tapping "Speed", and the Continuous Performance Test. Of 104 patients in 47 centres, 72 were eligible for analyses. We assessed whether IQ was impacted by disease extent, disease location, patient age, gender, age at surgery, and treatment (chemotherapy with our without craniospinal irradiation [CSI] or local radiotherapy [LRT]). Median age at surgery was 2.3 years. Testing was performed at a median of 4.9 years after surgery. Patients with infratentorial EPs (treated with LRT) scored highest in fluid intelligence (CPM 100.9±16.9, mean±SD); second best scores were achieved by patients with MB without metastasis treated with chemotherapy alone (CPM 93.9±13.2), followed by patients with supratentorial EPs treated with LRT. In contrast, lowest scores were achieved by patients that received chemotherapy and CSI, which included children with metastasised MB and those with relapsed MB M0 (CPM 71.7±8.0 and 73.2±21.8, respectively). Fine motor skills were reduced in all groups. Multivariable analysis revealed that type of treatment had an impact on IQ, but essentially not age at surgery, time since surgery or gender. Our results confirm previous reports on the detrimental effects of CSI in a larger cohort of children. Comparable IQ scores in children with MB treated only with chemotherapy and in children with EP suggest that this treatment strategy represents an attractive option for children who have a high chance to avoid application of CSI. Longitudinal follow-up examinations are warranted to assess long-term neuropsychological outcomes.

First-in-human study to assess safety, tolerability, pharmacokinetics, and pharmacodynamics of the anti-CD27L antibody-drug conjugate AMG 172 in patients with relapsed/refractory renal cell carcinoma.

PURPOSE: This study evaluated safety, tolerability, pharmacokinetics, and pharmacodynamics of the anti-CD27L antibody-drug conjugate AMG 172 in patients with relapsed/refractory clear cell renal cell carcinoma (ccRCC). METHODS: This was an open-label, adaptive dose-exploration study in patients with relapsed/refractory ccRCC. The study was conducted in two parts for dose exploration and dose expansion on a biweekly dosing schedule. AMG 172 doses of 0.15, 0.3, 0.6, 1.2, 1.6, 1.8, and 2.4 mg/kg were studied in the dose-exploration phase. RESULTS: The 1.6 mg/kg dose of AMG 172 was identified as the maximum tolerated dose (MTD). The most common adverse events were thrombocytopenia (59%), nausea (54%), decreased appetite (49%), vomiting (46%), and fatigue (35%). The most common dose-limiting toxicity (DLT) was thrombocytopenia. Thrombocytopenia and liver injury constituted DLTs that required discontinuation of treatment. Of the 10 patients treated at the MTD in part 2 of the study, 2 patients had grade 3 hepatocellular injury with aspartate aminotransferase or alanine aminotransferase elevation. Pharmacokinetic profiles indicated low levels of circulating unconjugated antibody and unconjugated cytotoxin. Dose-proportional increases in plasma exposure were observed over the dose range of 0.3-2.4 mg/kg. Following multiple biweekly doses, plasma accumulation was less than two-fold. Two patients (5.4%) had a partial response, 6 patients (16.2%) had stable disease, and 13 patients (35.1%) had progressive disease. CONCLUSION: AMG 172 exhibited a favorable pharmacokinetic profile in patients with relapsed/refractory ccRCC and showed evidence suggestive of limited antitumor activity. Safety and tolerability were as expected for a maytansinoid antibody-drug conjugate.

Idelalisib for optimized CD19-specific chimeric antigen receptor T cells in chronic lymphocytic leukemia patients.

Despite encouraging results with chimeric antigen receptor T (CART) cells, outcome can still be improved by optimization of the CART cell generation process. The proportion of less-differentiated T cells within the transfused product is linked to enhanced in vivo CART cell expansion and long-term persistence. The clinically approved PI3Kδ inhibitor idelalisib is well established in the treatment of B cell malignancies. Besides B cell receptor pathway inhibition, idelalisib can modulate T cell differentiation and function. Here, detailed longitudinal analysis of idelalisib-induced effects on T cell phenotype and function was performed during CART cell production. A third generation CD19.CAR.CD28.CD137zeta CAR vector system was used. CART cells were generated from peripheral blood mononuclear cells of healthy donors (HDs) and chronic lymphocytic leukemia (CLL) patients. Idelalisib-based CART cell generation resulted in an enrichment of less-differentiated naïve-like T cells (CD45RA+CCR7+), decreased expression of the exhaustion markers PD-1 and Tim-3, as well as upregulation of the lymph node homing marker CD62L. Idelalisib increased transduction efficiency, but did not impair viability and cell expansion. Strikingly, CD4:CD8 ratios that were altered in CART cells from CLL patients were approximated to ratios in HDs by idelalisib. Furthermore, in vivo efficacy of idelalisib-treated CART cells was validated in a xenograft mouse model. Intracellular TNF-α and IFN-γ production decreased in presence of idelalisib. This effect was reversible after resting CART cells without idelalisib. In summary, PI3Kδ inhibition with idelalisib can improve CART cell products, particularly when derived from CLL patients. Further studies with idelalisib-based CART cell generation protocols are warranted.

Safety and Efficacy of Durvalumab With or Without Tremelimumab in Patients With PD-L1-Low/Negative Recurrent or Metastatic HNSCC: The Phase 2 CONDOR Randomized Clinical Trial.

Importance: Dual blockade of programmed death ligand 1 (PD-L1) and cytotoxic T-lymphocyte associated protein 4 (CTLA-4) may overcome immune checkpoint inhibition. It is unknown whether dual blockade can potentiate antitumor activity without compromising safety in patients with recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC) and low or no PD-L1 tumor cell expression. Objective: To assess safety and objective response rate of durvalumab combined with tremelimumab. Design, Setting, and Participants: The CONDOR study was a phase 2, randomized, open-label study of Durvalumab, Tremelimumab, and Durvalumab in Combination With Tremelimumab in Patients With R/M HNSCC. Eligibility criteria included PD-L1-low/negative disease that had progressed after 1 platinum-containing regimen in the R/M setting. Patients were randomized (N = 267) from April 15, 2015, to March 16, 2016, at 127 sites in North America, Europe, and Asia Pacific. Interventions: Durvalumab (20 mg/kg every 4 weeks) + tremelimumab (1 mg/kg every 4 weeks) for 4 cycles, followed by durvalumab (10 mg/kg every 2 weeks), or durvalumab (10 mg/kg every 2 weeks) monotherapy, or tremelimumab (10 mg/kg every 4 weeks for 7 doses then every 12 weeks for 2 doses) monotherapy. Main Outcomes and Measures: Safety and tolerability and efficacy measured by objective response rate. Results: Among the 267 patients (220 men [82.4%]), median age (range) of patients was 61.0 (23-82) years. Grade 3/4 treatment-related adverse events occurred in 21 patients (15.8%) treated with durvalumab + tremelimumab, 8 (12.3%) treated with durvalumab, and 11 (16.9%) treated with tremelimumab. Grade 3/4 immune-mediated adverse events occurred in 8 patients (6.0%) in the combination arm only. Objective response rate (95% CI) was 7.8% (3.78%-13.79%) in the combination arm (n = 129), 9.2% (3.46%-19.02%) for durvalumab monotherapy (n = 65), and 1.6% (0.04%-8.53%) for tremelimumab monotherapy (n = 63); median overall survival (95% CI) for all patients treated was 7.6 (4.9-10.6), 6.0 (4.0-11.3), and 5.5 (3.9-7.0) months, respectively. Conclusions and Relevance: In patients with R/M HNSCC and low or no PD-L1 tumor cell expression, all 3 regimens exhibited a manageable toxicity profile. Durvalumab and durvalumab + tremelimumab resulted in clinical benefit, with minimal observed difference between the two. A phase 3 study is under way. Trial Registration: clinicaltrials.gov Identifier: NCT02319044.

Pharmacokinetic Enhancers (Boosters)-Escort for Drugs against Degrading Enzymes and Beyond.

Pharmacokinetic enhancers (boosters) are compounds used in combination with a primary therapeutic agent (drug) and are not used for their direct effects on the disease but because they enhance or restore the activity of the primary agent. Hence, in certain cases, they represent an indispensable escort for enzyme-labile drugs. Pharmacokinetic enhancers can exert their activity on different ways. In the most common case, they inhibit enzymes such as human cytochrome P450 enzymes in the liver or other organs and, thereby, block or reduce undesired metabolism and inactivation of the primary drug. In this review, an overview will be given on the therapeutically most important classes of pharmacokinetic enhancers like ß-lactamase inhibitors, inhibitors of CYP (cytochrome P450) enzymes in HIV therapy and hepatitis C, boosters for fluoropyrimidine-type anticancer agents, compounds utilized for enabling therapy of Parkinson's disease with levodopa, and others. Inhibitors of efflux pumps in both pathogenic bacteria and tumor cells will be addresses shortly.