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We show, for the first time, radio measurements of the depth of shower maximum (X_{max}) of air showers induced by cosmic rays that are compared to measurements of the established fluorescence method at the same location. Using measurements at the Pierre Auger Observatory we show full compatibility between our radio and the previously published fluorescence dataset, and between a subset of air showers observed simultaneously with both radio and fluorescence techniques, a measurement setup unique to the Pierre Auger Observatory. Furthermore, we show radio X_{max} resolution as a function of energy and demonstrate the ability to make competitive high-resolution X_{max} measurements with even a sparse radio array. With this, we show that the radio technique is capable of cosmic-ray mass composition studies, both at Auger and at other experiments.

Background: Immune checkpoint blockers (ICBs) in combination with antiangiogenic drugs showed synergistic efficacy in several tumour types. New patterns of progression have recently been defined upon treatment with ICB alone including atypical responses such as pseudoprogression (PsPD), dissociated response and hyperprogressive disease (HPD). This study aimed to describe the patterns of response observed in patients treated with combination ICB with antiangiogenic drugs., Methods: We conducted a monocentric retrospective analysis of patients (pts) enrolled in phase I trials at Gustave Roussy assessing the combination of ICB and antiangiogenic drugs. Radiological CT scans were centrally reviewed by a senior radiologist according to iRECIST criteria including progressive disease (PD), partial response (PR) and stable disease (SD). HPD was defined as a progression at the first evaluation with a delta tumour growth rate exceeding 50%. PsPD was defined as initial progression followed by stabilisation or decrease of tumour size, DisR as a concomitant size decrease in some tumour lesions and size increase in others. Both PsPD and DisR are defined as atypical responses. Overall response rate included PR and complete response (CR) and disease control rate included PR, CR and SD., Results: Between December 2016 and June 2020, 111 pts were included. The median follow up was 12.8 months (11.3-15.1). The most common tumour types were lung and pleura (20%), kidney (18%) and bladder (17%). The overall response rate and disease control rate were 21.6% (n = 24) and 59% (n = 65), respectively. Twenty-one patients (19%) experienced PD as the best response. PsPD, DisR and HPD were observed in 4 (3.6%), 11 (9.9%) and 7 (6.3%) pts, respectively. DisR and PsPD were associated with longer iProgression Free Survival (median: 6.9 and 18.9 months, respectively) and iOverall Survival (median: 28.4 and 31.1 months, respectively) than a median of SD in immune progression-free survival (median: 4.2 months) and immune overall survival (median: 12.7 months)., Conclusion: Patients treated with ICBs and antiangiogenic agents display atypical responses. Survival might be longer in patients with DisR responses and PsPD disease than patients with HPD, PD and SD., Competing Interests: Conflict of interest statement The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: As part of the Drug Development Department (DITEP): Principal/sub-Investigator of Clinical Trials for Abbvie, Adaptimmune, Adlai Nortye USA Inc, Aduro Biotech, Agios Pharmaceuticals, Amgen, Argen-X Bvba, Arno Therapeutics, Astex Pharmaceuticals, Astra Zeneca Ab, Aveo, Basilea Pharmaceutica International Ltd, Bayer Healthcare Ag, Bbb Technologies Bv, Beigene, BicycleTx Ltd, Bioalliance Pharma, Blueprint Medicines, Boehringer Ingelheim, Boston Pharmaceuticals, Bristol Myers Squibb, Ca, Celgene Corporation, Chugai Pharmaceutical Co, Cullinan-Apollo, Curevarc, Daiichi Sankyo, Debiopharm, Eisai, Eisai Limited, Eli Lilly, Exelixis, Faron Pharmaceuticals Ltd, Forma Tharapeutics, Gamamabs, Genentech, Glaxosmithkline, H3 Biomedicine, Hoffmann La Roche Ag, Imcheck Therapeutics, Innate Pharma, Institut De Recherche Pierre Fabre, Iris Servier, Iteos Belgium SA, Janssen Cilag, Janssen Research Foundation, Kura Oncology, Kyowa Kirin Pharm. Dev, Lilly France, Loxo Oncology, Lytix Biopharma As, Medimmune, Menarini Ricerche, Merck Sharp & Dohme Chibret, Merus, Molecular Partners Ag, Nanobiotix, Nektar Therapeutics, Novartis Pharma, Octimet Oncology Nv, Oncoethix, Oncopeptides, Onyx Therapeutics, Orion Pharma, Oryzon Genomics, Ose Pharma, Pfizer, Pharma Mar, Pierre Fabre Medicament, Plexxikon, Roche, Sanofi Aventis, Seattle Genetics, Sotio A.S, Syros Pharmaceuticals, Taiho Pharma, Tesaro, Turning Point Therapeutics, Xencor. Research Grants from Astrazeneca, BMS, Boehringer Ingelheim, GSK, INCA, Janssen Cilag, Merck, Novartis, Pfizer, Roche, Sanofi Non-financial support (drug supplied) from Astrazeneca, Bayer, BMS, Boringher Ingelheim, GSK, Medimmune, Merck, NH TherAGuiX, Pfizer, Roche. T.Assi and S.Ammari have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this article., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Objective: To determine the difference in prevention of chemotherapy-induced fatigue between time-acupoints-space acupuncture (ATAS) administered weekly compared to sham acupuncture and non-acupuncture in patients with early breast cancer receiving adjuvant chemotherapy by epirubicine-cyclophosphamide (EC) followed by paclitaxel, as measured by the multi-dimensional fatigue inventory (MFI) over the previous week and Visual Analogue Scale measuring fatigue (VAS-F), and to evaluate the effects of ATAS on self-reported neuropathy pain, sleep, anxiety and depression., Methods: In this multicenter clinical trial, we have randomized patients into 3 groups: ATAS, Sham and non-acupuncture with an unequal randomization of 2∶1∶1. A cloud related electronical clinical report form and smartphone platform was established for data entry. Patients with a history of stage Ⅰ-Ⅲ breast cancer scheduled to receive adjuvant chemotherapy. Acupuncture will be delivered once a week during chemotherapy with VAS-F evaluation. In order to qualify and quantify the mechanism of fatigue induced by chemotherapy with or without acupuncture, an evaluation of immune profiling was incorporate in this study., Results: The presence and seriousness of chemotherapy-induced fatigue should be considered in therapeutic programs for early breast cancer treatment. Fatigue induced by adjuvant chemotherapy in patients with breast cancer remains a major concern affecting the quality of life significantly. Unfortunately, we do not have effective pharmacological interventions yet. And clinical trials of acupuncture in preventing chemotherapy-induced fatigue in patients with early breast cancer have not been reported., Conclusion: The findings of the trial will allow us to determine the effects of acupuncture treatment approach. We will also be able to confirm whether ATAS is better than sham acupuncture and non-acupuncture treatments.

Background: New patterns of progression under immune-oncology (IO) antibodies (mAb) have been described such as pseudoprogression. Except for melanoma, variations between studies reveal difficulties to establish their prevalence., Methods: This retrospective study enrolled patients participating in IO phase I trials at Gustave Roussy cancer center for solid tumors excluding melanoma. Radiological assessment according to iRECIST was correlated with prospectively registered patient characteristics and outcomes. Pseudoprogression (PsPD) was defined as RECIST-defined progression followed by stabilization or decrease at the next imaging, and dissociated response (DisR) as concomitant decrease in some tumor lesions and increase in others at a same timepoint., Results: Among 360 patients included, 74% received IO mAb combination: 45% with another IO mAb, 20% with targeted therapy and 10% with radiotherapy. The overall response rate was 19.7%. PsPD were observed in 10 (2.8%) patients and DisR in 12 (3.3%) patients. Atypical responses (AR), including PsPD and DisR, were not associated with any patient's baseline characteristics. Compare with typical responder patients, patients experiencing AR presented a shorter iPFS (HR 0.34; p < 0.001) and OS (HR 0.27; p = 0.026). Among the 203 patients who progressed in 12 weeks, 80 (39.4%) patients were treated beyond progression. PD was confirmed in 80% of cases, while 10% of patients presented a response., Conclusion: Pseudoprogression and dissociated response are uncommon patterns of progression. Their prevalence should be balanced with the rate of real progressing patients treated beyond progression. Prognosis or on-treatment biomarkers are needed to identify early patients who will benefit from immunotherapy.

Irinotecan is an anticancer drug with a broad spectrum of activity, characterized by multistep and complex pharmacology. Regardless of its schedule of administration, neutropenia and delayed-type diarrhea are the most common side effects. The latter was the dose-limiting toxicity in phase I trials, and its prediction by pharmacogenetic (UGT1A1*28/*28) testing remains sub-optimal. Recent studies have highlighted the important role of the intestinal bacterial β-glucuronidase (BGUS) in the onset of irinotecan-induced diarrhea. Intestinal BGUS hydrolyses glucuronidated metabolites to their toxic form in intestines, resulting in intestinal damage. BGUS selective inhibitors that are currently in development may alleviate irinotecan-induced diarrhea, and may help to reduce its morbidity and enhance its activity. The discussion and description of irinotecan pharmacology may generate ideas that form the basis of clinical trials focusing on a personalized approach to treatment. In addition, we hypothesize that using BGUS activity as a predictive biomarker of irinotecan-induced diarrhea severity will help to select cancer patients for treatment with irinotecan chemotherapy (whether at full or adapted dose)., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Reliable evaluation of treatment benefit in early phase clinical trials is necessary. The time to progression ratio (TTPr), which compares successive TTP in a single patient, is a powerful criteria for determining targeted or immune therapies efficacy., Methods: We evaluated 205 TTPr in a large cohort of 177 advanced cancer patients enrolled in at least two Phase 1/1b trials (out of 2827 phase 1/1b-treated patients) at Gustave Roussy., Results: This first wide description of TTPr showed that, under the hypothesis of overall absence of treatment line effect, the median TTPr was 0.7 and that 25% of patients presented a TTPr above the conventional efficacy threshold of 1.3., Conclusions: A higher median TTPr and a larger proportion of patients above the 1.3 threshold should therefore be achieved to conclude to drug efficacy. New guidelines for TTPr interpretation and calibration are proposed, which warrant independent prospective validation.

Background: Long-term responders have been observed with anti-programmed death 1 and anti-programmed death ligand 1 (anti-PD(L)1). Optimal duration of therapy in responding and stable disease (SD) patients is unclear with various attitudes encompassing treatment until progression disease, stopping therapy after a defined timeframe., Patients and Methods: We report the experience of 13 patients who discontinued immune checkpoint inhibitor in phase I trials as per protocol while experiencing a tumour-controlled disease. According to protocols, patients could restart the same immunotherapy if radiological or clinical progression occurred., Results: Patients were treated for colorectal microsatellite instability-high genotype (n = 5), urothelial carcinoma (n = 3), melanoma (n = 2), non-small-cell lung cancer (n = 2) and triple-negative breast cancer (n = 1) for a median time of 12 months (range 10.6-12). Patients achieved 1 (8%) complete response, 10 (77%) partial response (PR) and 2 (15%) SD. The median progression-free survival 1 (PFS1) defined as the time from the first infusion until progression was 24.4 months (range 15.8-49). The median time free-treatment after discontinuation was 12.6 months (range 4-39.7). Eight patients experienced disease progression and were retreated. Best responses observed after rechallenging were 2 PR (25%) and 6 SD (75%). Median PFS2 defined from the first day of retreatment until disease progression or the last news was 12.9 months (range 5-35.4). No grade 3/4 events occurred during the study period., Conclusion: Our data suggest that anti-PD(L)1 therapy should be resumed if progression occurs after a planned anti-PD(L)1 interruption. Further prospective studies are needed to confirm these results., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Purpose: Enrolment process influences the likelihood of patients' inclusion in early clinical trials (ECT) through social, medical and organisational factors., Patients and Methods: All patients referred from 2008 to 2016 to the Drug Development Department (DITEP) of Gustave Roussy (GR) were reviewed. Referring physician, organisational factors, medical and socioeconomic characteristics for patients were analysed. Multivariate analysis was performed with regard to those factors. A telephone survey was conducted on a sample of referring physicians located outside GR (N = 142)., Results: Between 2008 and 2016, 8694 requests were received with 49% from external physicians. Here, 4517 were male patients with a median age of 58 [49-66] years (range 18-85). Tumour types were gastrointestinal (28%), lung (19%), breast (9%) and gynaecologic (8%). Mean enrolment rate was 37% (ranging from 24 to 45%). From 2008 to 2016, the enrolment rate decreases from 39% to 24%. In the meantime, DITEP trials portfolio evolves with the part of precision medicine trials increase from 12% to 40%. Factors that were significantly associated with a lower likelihood of being enrolled were referral from an external physician (OR 0.15 s.16-0.21]) compared to a physician from DITEP and year of the request (2.74 [1.8-2.9] 2008 versus 2016). The enrolment rate and the number of patients addressed have a high variability regarding referring physicians, which is little explained by characteristics as training, previous experience or attitude regarding ECT., Conclusion: Beyond patients' individual characteristics, we show that organisational and professional factors have a major impact on likelihood of enrolment in ECT., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

The 'Therapeutics discovery: From bench to first in-human trials' conference, held at the King Abdullah International Medical Research Center (KAIMRC), Ministry of National Guard Health Affairs (MNGHA), Kingdom of Saudi Arabia (KSA) from October 10-12, 2017, provided a unique opportunity for experts worldwide to discuss advances in drug discovery and development, focusing on phase I clinical trials. It was the first event of its kind to be hosted at the new research center, which was constructed to boost drug discovery and development in the KSA in collaboration with institutions, such as the Academic Drug Discovery Consortium in the United States of America (USA), Structural Genomics Consortium of the University of Oxford in the United Kingdom (UK), and Institute of Materia Medica of the Chinese Academy of Medical Sciences in China. The program was divided into two parts. A pre-symposium day took place on October 10, during which courses were conducted on clinical trials, preclinical drug discovery, molecular biology and nanofiber research. The attendees had the opportunity for one-to-one meetings with international experts to exchange information and foster collaborations. In the second part of the conference, which took place on October 11 and 12, the clinical trials pipeline, design and recruitment of volunteers, and economic impact of clinical trials were discussed. The Saudi Food and Drug Administration presented the regulations governing clinical trials in the KSA. The process of preclinical drug discovery from small molecules, cellular and immunologic therapies, and approaches to identifying new targets were also presented. The recommendation of the conference was that researchers in the KSA must invest more fund, talents and infrastructure to lead the region in phase I clinical trials and preclinical drug discovery. Diseases affecting the local population, such as Middle East Respiratory Syndrome and resistant bacterial infections, represent the optimal starting point.

Introduction: Therapeutic inhibition of the human epidermal receptor 3 (ERBB3, HER3) has been challenged by the low frequency of ERBB3 somatic alterations across cancer types. We have evaluated the clinical utility to use available inhibitors of the HER family in the context of ERBB3 mutations., Patients and Methods: In this study, we have selected patients with somatic ERBB3 alterations detected in their tumours from the molecular screening programs running at our institution. Techniques used for molecular screening were targeted next generation sequencing, comparative genomic hybridisation and/or whole exome sequencing on fresh frozen tumour biopsies., Results: On the 844 patients with a molecular portrait of their tumours, 31 (3.7%) had a somatic mutation of ERBB3. Overall, 9 patients received available inhibitors of HER family, including trastuzumab and/or lapatinib or afatinib. Sixteen patients received other molecularly targeted agents, including the Mammalian Target Of Rapamycin (mTOR), the Phosphatidylinositol-4,5-Bisphosphate 3-Kinase (PI3K) or NOTCH inhibitors or chemotherapy, and 4 patients failed being treated. Thirteen different histological subtypes were affected by ERBB3 mutations; top ones were colorectal carcinomas (6 patients), non-small cell lung cancers (4 patients, including a squamous cell carcinoma), head and neck squamous cell carcinomas (3 patients) and breast carcinomas (3 patients). The presence of a mutation in the tyrosine kinase domain of the ERBB3/HER3 protein detected in four patients' tumours was significantly related to good progression-free survival (hazard ratio [HR] = 0.18, p value = 0.022) and overall survival (HR = 0.19, p value = 0.03) in univariate analysis. Treatment of these four patients included at least a tyrosine kinase inhibitor lapatinib or afatinib., Conclusion: Our exploratory analysis suggests that mutations in the tyrosine kinase domain of the HER3 protein are related to a favourable outcome under HER family inhibitors., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

A targeted therapy is recommended in case of ERBB2 alteration for breast and gastric carcinomas, but miscellaneous other tumor types are ERBB2- altered at low prevalence. Broadening the administration of HER2 inhibitors across tumor types and genomic alterations could benefit to patients with refractory metastatic tumors. Targeted next-generation-sequencing (tNGS) and comparative genomic hybridization array (CGH) have been performed on fresh tumor biopsies of patients included in the MOSCATO-01 and ongoing MOSCATO-02 trials to administrate HER2 inhibitors in case of ERBB2 pathogenic mutation of amplification. Between December 2011 and January 2017 a molecular analysis was performed for 934 patients (759 CGH and 912 tNGS). A novel ERBB2 alteration has been found in 4.7% ( n = 44/934), including 1.5% ( n = 14/912) ERBB2 mutations, and 4% ( n = 30/759) ERBB2 amplifications. A matched HER2 inhibitor was administrated to 70% (31/44) of patients and consisted in trastuzumab plus chemotherapy for 90% of them (28/31). On the 31 evaluable patients, 1 complete response (CR), 10 partial response (PR) and 2 stable disease (SD) >24 weeks were observed accounting for a clinical benefit rate (CBR) of 42% ( n = 13/31, 95% CI 25-61%). Besides breast and oesogastric carcinomas, 19 patients affected by 8 different tumor types had a CBR of 25% for ERBB2 mutations ( n = 2/8, 95% CI 3%-65%, with 2 PR) and 64% for ERBB2 amplifications ( n = 7/11, 95% CI 31%-89%; with 1 CR, 4 PR, 2 SD). ERBB2 genomic alterations were diffuse across metastatic tumor types and signs of efficacy emerged for HER2 targeted treatments, especially in case of ERBB2 amplifications or a p.S310Y ERBB2 mutation., Competing Interests: CONFLICTS OF INTEREST The authors declare no potential conflicts of interest related to the study.

Introduction: Life expectancy evaluation is crucial when selecting patients who may benefit from phase I studies. The Royal Marsden Hospital (RMH) prognostic score, based on three objective variables (number of metastatic sites, lactate dehydrogenase (LDH) and serum albumin) was validated in patients treated with cytotoxics and targeted therapies. We aimed to determine if those factors were applicable to immune-checkpoint therapies (ICTs) in phase I trials and to evaluate new variables that may preclude a better prognosis in patients receiving ICT., Patients and Methods: We conducted a retrospective analysis of survival risk factors in a discovery cohort of 155 patients enrolled into ICT phase I trials at our institution. We computed univariate analysis and multivariate analysis (MVA) of demographics, clinical and biological data to assess their prognostic value for overall survival (OS). MVA results were used to build a prognostic score for OS. A validation cohort of 113 patients enrolled in phase I ICT trials was used to prospectively validate this score., Results: A total of 155 patients (M/F: 83/72; median age 59) receiving an experimental ICT between March 2012 and January 2016 were included in the discovery cohort. An MVA assessing the RMH score variables showed that low albumin (hazard ratio [HR] 1.73, 95% confidence interval [CI] 1.05-2.86) and LDH > upper limit normal (ULN) (HR 1.88, 95% CI 1.12-3.15) were independent negative prognostic factors for OS. Interestingly, neutrophil-to-lymphocyte ratio (NLR) > 6 (HR 1.75, 95% CI 1.04-2.95) was associated with a decrease in OS. The number of metastases was not associated with a poorer outcome for this ICT cohort (HR 0.83, 95% CI 0.51-1.35). A risk score based on the results of the MVA (NLR > 6 = 1; LDH > ULN = 1; albumin < 35 g/l = 1) showed that patients presenting a high score (>1) had a significantly shorter OS (20.4 weeks; 95% CI 5.7-35.2) compared to those with a low score (0 or 1) (68.9 weeks; 95% CI 50-83.7) (HR 2.9, 95% CI 1.87-4.64). In the validation cohort of 113 patients, again the patients presenting a high score showed an inferior OS (HR 6.3, 95% CI 2.7-14.8)., Conclusion: In ICT phase I trials, traditional prognostic variables included in the RMH score may be suboptimal to determine patient's prognosis. In this context, the NLR is a significant prognostic variable. The Gustave Roussy Immune Score, based on albumin, LDH and NLR, allows a better selection of patients for ICT phase I trials., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

In this implementation phase of the European Cancer Patient's Bill of Rights (BoR), we confirm the following three patient-centred principles that underpin this initiative:The right of every European citizen to receive the most accurate information and to be proactively involved in his/her care.The right of every European citizen to optimal and timely access to a diagnosis and to appropriate specialised care, underpinned by research and innovation.The right of every European citizen to receive care in health systems that ensure the best possible cancer prevention, the earliest possible diagnosis of their cancer, improved outcomes, patient rehabilitation, best quality of life and affordable health care. The key aspects of working towards implementing the BoR are:Agree our high-level goal. The vision of 70% long-term survival for patients with cancer in 2035, promoting cancer prevention and cancer control and the associated progress in ensuring good patient experience and quality of life.Establish the major mechanisms to underpin its delivery. (1) The systematic and rigorous sharing of best practice between and across European cancer healthcare systems and (2) the active promotion of Research and Innovation focused on improving outcomes; (3) Improving access to new and established cancer care by sharing best practice in the development, approval, procurement and reimbursement of cancer diagnostic tests and treatments.Work with other organisations to bring into being a Europe based centre that will (1) systematically identify, evaluate and validate and disseminate best practice in cancer management for the different countries and regions and (2) promote Research and Innovation and its translation to maximise its impact to improve outcomes., Competing Interests: Competing interests: None declared.

Introduction: Glioblastoma (GBM) is associated with a poor prognosis. This review will discuss different directions of treatment, mostly regarding immunotherapies and combinatorial approaches., Development: Standard treatment for newly diagnosed GBM is maximal and safe surgical resection followed by concurrent radiochemotherapy (RCT) based on temozolomide, allowing 14.6 months median survival. Nowadays, no combination with molecular-targeted therapy had significantly improved prognosis. Phases I and II data are emerging, highlighting the potential efficacy of associations with other therapies. Studies have suggested the potential of targeting tumor stem cells, at less partially responsible for resistance to RCT. There is now some evidence that immunotherapy is also relevant for brain tumors. Treatment strategies have mainly explored vaccines strategies, such as the dendritic cell, heat shock protein or EGFRvIII vaccines. Of the work initiated in melanoma, immune checkpoints inhibitors have exhibited stimulating results. Others trials have demonstrated potential of autologous stimulated lymphocytes. Moreover, strong data indicates that radiation therapy has the potential to promote immunogenicity and create a sort of in situ personalized vaccine., Conclusion: These data provide strong evidence to support the potential of associating combinatorial targeted and/or immunotherapeutic regimens in patients with GBM that may change patient outcome., (Copyright © 2016 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.)

Cancer immunotherapy is coming of age; it has prompted a paradigm shift in oncology, in which therapeutic agents are used to target immune cells rather than cancer cells. The first generation of new immunotherapies corresponds to antagonistic antibodies that block specific immune checkpoint molecules cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), programmed cell death protein (PD-1) and its ligand PD-L1. Targeting these checkpoints in patients living with cancer had led to long-lasting tumour responses. By unbalancing the immune system, these new immunotherapies also generate dysimmune toxicities, called immune-related adverse events (IRAEs) that mainly involve the gut, skin, endocrine glands, liver, and lung but can potentially affect any tissue. In view of their undisputed clinical efficacy, anti-CTLA-4 and anti-PD-1 antibodies are entering in the routine oncological practice, and the number of patients exposed to these drugs will increase dramatically in the near future. Although steroids can be used to treat these IRAEs, the associated immunosuppression may compromise the antitumour response. Oncologists must be ready to detect and manage these new types of adverse events. This review focuses on the mechanisms of IRAE generation, putative relationship between dysimmune toxicity and antitumour efficacy, as a basis for management guidelines., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

For decades, immunotherapy strategies have failed to succeed in lung cancer. However, the recent success of immune checkpoint inhibitors and the progress in the understanding of the immunobiology of lung cancer have changed this paradigm. Here we review ongoing clinical trials and recent results obtained with these novel lung cancer immunotherapies.

The US Chinese Anti-Cancer Association (USCACA) teamed up with Chinese Society of Clinical Oncology (CSCO) to host a joint session at the17th CSCO Annual Meeting on September 20th, 2014 in Xiamen, China. With a focus on breakthrough cancer medicines, the session featured innovative approaches to evaluate breakthrough agents and established a platform to interactively share successful experiences from case studies of 6 novel agents from both the United States and China. The goal of the session is to inspire scientific and practical considerations for clinical trial design and strategy to expedite cancer drug development in China. A panel discussion further provided in-depth advice on advancing both early and full development of novel cancer medicines in China.

Purpose: Improved prognostic accuracy for treatment response and a wider understanding of drug effects in humans are crucial for enhancing the utility of sorafenib and other promising targeted therapies. We developed a strategy of global genomic investigation of sequential tumor biopsy samples at baseline and 21 days post treatment, and applied this approach in a phase I study of sorafenib plus dacarbazine in patients with solid tumors. The objective of this study was also to validate functional parameters of DCE-US as surrogate markers to predict earlier response., Experimental Design: Patients received 21-day cycles of oral sorafenib, 400 mg twice daily and dacarbazine, 1,000 mg/m(2) in a 1-h intravenous infusion on day 1. Efficacy was assessed using response evaluation criteria in solid tumors. Sequential biopsy samples (baseline and day 21) were obtained from the same tumor. Changes from baseline in global gene expression (GE) measured by genomic microarrays and in tumor vascularity at baseline, D8, D21, D 42 and every 2 cycles using dynamic contrast-enhanced ultrasonography (DCE-US) were analyzed for patients with and without a clinical response to treatment at 3 months., Results: Among 23 patients evaluable for treatment efficacy, 17 were eligible for gene expression and DCE-US analyses. One patient achieved a partial response; 14 exhibited stable disease. Ten patients were defined as exhibiting stable disease (SD) and 7, progressive disease (PD) at 3 months. Genomic analyses identified a 237-gene signature that distinguished SD from PD at 3 months. Of note, CDK4 overexpression and PDGFR downregulation were associated with PD. Functional parameters of DCE-US representing the blood volume at baseline, day 8, and day 21 were correlated with disease progression at 3 months., Conclusions: This novel approach of sequential investigations in a phase I trial was feasible, detecting early changes in gene expression and tumor vascularity evaluated using DCE-US that may be predictive of clinical outcome.

PM00104 (Zalypsis®) is a new synthetic alkaloid with potent cytotoxic activity against tumor cell lines. This phase I clinical trial determined the maximal tolerated dose (MTD) and recommended dose (RD) for phase II trials of PM00104 administered as a 1-hour intravenous (i.v.) infusion weekly for three consecutive weeks resting every fourth week (d1,8,15 q4wk). Forty-nine patients with advanced solid malignancies received PM00104 following a toxicity-guided, accelerated, dose-escalation design. Doses evaluated ranged from 0.07 to 3.0 mg/m(2). Dose-limiting toxicities (DLTs) appeared at the highest doses tested and comprised grade 3 diarrhea and grade 4 lipase increase at 2.0 mg/m(2); grade 1 thrombocytopenia and grade 2 neutropenia with two infusion omissions, grade 3 fatigue and grade 4 febrile neutropenia at 2.5 mg/m(2); and grade 3/4 fatigue, grade 4 neutropenia lasting >5 days and grade 4 thrombocytopenia at 3.0 mg/m(2). RD was established at 2.0 mg/m(2). PM00104-related adverse events at the RD were mostly grade 1/2, with fatigue, nausea and vomiting as the most common. Transient and manageable myelosuppression and transaminase increases were also reported. Main pharmacokinetic parameters increased linearly with dose. Disease stabilization lasting ≥ 3 months was found in 4 patients with cervical carcinoma, colorectal adenocarcinoma, lachrymal adenoid carcinoma, and bladder carcinoma (n=1 each). In conclusion, PM00104 2.0 mg/m(2) 1-hour, d1,8,15 q4wk showed a positive risk-benefit ratio, which has supported its further evaluation in three ongoing phase II clinical trials.

Purpose: BMS-690514 is a potent, reversible oral inhibitor of epidermal growth factor receptor (EGFR/HER-1), HER-2 and -4, and vascular endothelial growth factor receptors (VEGFRs)-1 to -3 offering targeted inhibition of tumour growth and vascularisation in a single agent. This phase I-IIa study was designed to identify the maximum tolerated dose (MTD) and assess safety, antitumour activity, pharmacokinetics and pharmacodynamics of BMS-690514., Patients and Methods: In phase I, patients with advanced solid tumours received escalating doses of once-daily BMS-690514. In phase IIa, erlotinib-naïve (cohort A) or erlotinib-resistant (cohort B) patients with advanced non-small-cell lung cancer (NSCLC) received BMS-690514 once-daily at the MTD., Results: In phase I (n=28), the MTD was determined to be 200mg daily. BMS-690514 was rapidly absorbed and highly metabolised after repeated oral administration with minimum drug accumulation. In phase IIa (n=62), the most frequent treatment-related adverse events were diarrhoea and acneiform rash. Adverse events that led to >1 discontinuation were diarrhoea (n=4; 4%) and rash (n=2; 2%). Disease control (≥4months) and objective response rates, respectively, were 43.3% and 3.3% (cohort A) and 22.6% and 3.2% (cohort B). Six of 21 (29%) NSCLC patients with wild-type EGFR achieved disease control versus seven of 10 (70%) patients with EGFR mutations (including T790M). At MTD, BMS-690514 modulated pharmacodynamic biomarkers associated with inhibition of VEGFR- and EGFR-signalling pathways., Conclusion: This phase I-IIa study suggests that BMS-690514 has manageable safety profile and antitumour activity in patients with NSCLC at 200mg/d, including those with EGFR mutations conferring resistance to erlotinib., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Background: ES-285 (spisulosine) is a novel compound derived from the marine mollusk Spisula polynoma with evidence of preclinical antitumor activity. This phase I clinical trial was designed to identify the maximum tolerated dose (MTD) and the recommended dose for phase II trials (RD), as well as to evaluate the safety profile, pharmacokinetics and preliminary efficacy data of ES-285 in patients with advanced solid tumors., Patients and Methods: Sixty-one patients at two medical institutions were treated with a 3-h ES-285 intravenous infusion every 3 weeks. Nine dose levels were evaluated., Results: No dose-limiting toxicities (DLTs) were observed during dose escalation from 4 to 128 mg/m(2). Six patients had seven DLTs at the three highest dose levels tested: 256 mg/m(2) (n = 2), 200 mg/m(2) (n = 3) and 160 mg/m(2) (n = 1). Grade 3/4 transaminase increases (n = 3), grade 3/4 central nervous system disorders [confusion (n = 2) and ataxia (n = 1)], and grade 3 pyrexia (n = 1) were the dose-limiting toxicities found with this ES-285 administration schedule. Pharmacokinetic analysis showed ES-285 dose linearity, wide distribution and a long half-life. One non-confirmed partial response was observed in a patient with metastatic melanoma treated with ES-285 128 mg/m(2), and 18 patients showed stable disease at different dose levels, lasting longer than 3 months in six patients., Conclusion: Dose level VIII (200 mg/m(2)) was considered the MTD, and dose level IX (160 mg/m(2)) was defined as the RD. Limited antitumor activity was observed.

Background: Sequential tumour biopsies are of potential interest for the rational development of molecular targeted therapies., Patients and Methods: From June 2004 to July 2009, 186 patients participated in 14 phase I clinical trials in which sequential tumour biopsies (13 trials) and/or sequential normal skin biopsies (6 trials) were optional. All patients had to sign an independent informed consent for the biopsies., Results: Tumour biopsies were proposed to 155 patients and 130 (84%) signed the consent while normal skin biopsies were proposed to 70 patients and 57 (81%) signed the consent. Tumour biopsies could not be carried out in 41 (31%) of the 130 consenting patients. Tumour biopsies were collected at baseline in 33 patients, at baseline and under treatment in 56 patients. Tumour biopsies were obtained using an 18-gauge needle, under ultrasound or computed tomography guidance. Only nine minor complications were recorded. Most tumour biopsy samples collected were intended for ancillary molecular studies including protein or gene expression analysis, comparative genomic hybridization array or DNA sequencing. According to the results available, 70% of the biopsy samples met the quality criteria of each study and were suitable for ancillary studies., Conclusions: In our experience, the majority of the patients accepted skin biopsies as well as tumour biopsies. Sequential tumour and skin biopsies are feasible and safe during early-phase clinical trials, even when patients are exposed to anti-angiogenic agents. The real scientific value of such biopsies for dose selection in phase I trials has yet to be established.

Purpose: We studied the safety, tolerability, and recommended dose of BMS-599626, an orally bioavailable inhibitor of the human epidermal growth factor receptor (HER) family of receptor tyrosine kinases., Patients and Methods: Patients with advanced solid tumors that expressed epidermal growth factor receptor (EGFR) and/or HER-2 were recruited and enrolled in a phase I, open-label, dose escalation trial of oral BMS-599626 starting at 100 mg/day given once daily for at least 28 days., Results: Forty-five patients received BMS-599626 (100-660 mg/day). Dose-limiting toxic effects were reported at 660 mg/day (grade 3 elevation of hepatic transaminases [two patients] and QTc interval prolongation [one patient]), therefore the recommended maximum tolerated dose was 600 mg/day. The most frequent drug-related toxic effects were diarrhea (30% of patients), anorexia (13%), asthenia (30%), and cutaneous toxic effects, including skin rash (30%). Pharmacokinetic analysis demonstrated C(max) and exposure to BMS-599626 in patients increased with dose. Eleven patients had stable disease and received BMS-599626 for ≥ 4 months. Serial skin and tumor biopsies taken before and after treatment revealed expected changes in pharmacodynamic biomarkers, indicating that the EGFR and HER-2 pathways were affected. Positron emission tomography imaging showed a metabolic response in 2 of 10 patients evaluated., Conclusion: BMS-599626 was generally well tolerated, with disease stabilization across a range of tumor types and doses.

Purpose: Sorafenib, a multikinase inhibitor of Raf and several growth factor receptors, is under investigation in combination with dacarbazine, a commonly used chemotherapeutic agent for the treatment of many cancers. The current phase I study investigates the effects of sorafenib on the pharmacokinetic (PK) profile of dacarbazine and its metabolite 5-amino-imidazole-4-carboxamide (AIC). (AIC is formed in amounts equimolar to the active alkylating moiety, methane diazohydroxide, which is undetectable by known validated assays.), Methods: Patients with advanced solid tumors received intravenous dacarbazine 1,000 mg/m(2) on day 1 of a 21-day cycle to evaluate the PK of dacarbazine alone. Sorafenib 400 mg was administered twice daily continuously starting at day 2 of cycle 1. The PK of dacarbazine in the presence of sorafenib was assessed on day 1 of cycle 2. Sorafenib PK was also assessed at steady state., Results: PK data were available for 15 of 23 patients. With concomitant administration of sorafenib, the mean AUC and C (max) values of dacarbazine were reduced by 23 and 16%, respectively. Mean AUC and C (max) values of AIC were increased by 41 and 45%, respectively, with individual increases of up to 106 and 136%, respectively. The apparent terminal half-lives of the two compounds were not significantly influenced by sorafenib. Based on coefficients of variation, the AUC and C (max) values for sorafenib and its three metabolites were highly variable with dacarbazine coadministration., Conclusions: Concomitant administration of sorafenib and dacarbazine as described above may result in decreased dacarbazine exposure but increased AIC exposure.

Background: PHA-793887 is an inhibitor of multiple cyclin dependent kinases (CDK) with activity against CDK2, CDK1 and CDK4. The primary objectives of this first in man study were to determine the dose limiting toxicities (DLTs), maximum tolerated dose (MTD) and recommended phase II dose of PHA-793887., Results: Although toxicity was acceptable at initial dose levels, PHA-793887 was poorly tolerated at doses ≥44 mg/m2. The most frequent events across all dose levels were gastrointestinal or nervous system events. DLTs were experienced by two of three patients at the dose level of 66 mg/m2, and by three of nine patients at the dose level of 44 mg/m2. In all but one patient the DLT was hepatotoxicity; fatal hepatorenal failure was seen in one patient treated at the 44 mg/ m2 dose level. There were no objective responses, but disease stabilization was observed in five patients. Over the dose range investigated, pharmacokinetic studies showed that systemic exposure to PHA-793887 increased with the dose and was time-independent. The study terminated after the enrolment of 19 patients due to the severe hepatic toxicity., Patients and Methods: Cohorts of three to six patients were treated at doses of 11, 22, 44 and 66 mg/m2 of PHA-793887 administered as 1-hour intravenous infusion on days 1, 8 and 15 in a 4-week cycle. Safety and pharmacokinetics were investigated., Conclusion: PHA-793887 induces severe, dose-related hepatic toxicity, which was not predicted by pre-clinical models and currently precludes its further clinical development.

Background: Sunitinib is a multitargeted, oral tyrosine kinase inhibitor with antitumour and antiangiogenic activity. We investigated the safety and pharmacokinetics of sunitinib in combination with irinotecan in patients with advanced, refractory solid tumours., Methods: Sunitinib was initially administered once daily at 37.5 mg per day on days 1-14 of a 21-day cycle, in which irinotecan 250 mg m(-2) was given on day 1. In a second cohort, the sunitinib dose was reduced to 25 mg per day. Blood samples were collected for pharmacokinetic studies., Results: In the sunitinib 37.5 mg per day cohort, 3 out of 10 evaluable patients had objective responses, but dose-limiting toxicities (DLTs) of neutropenia, pneumococcal sepsis, and fatigue were observed. There were no DLTs in the sunitinib 25 mg per day cohort. Paired observations of pharmacokinetic parameter values of sunitinib and irinotecan alone vs the combination did not reveal significant drug-drug interactions. The maximum tolerated dose was defined as sunitinib 25 mg per day (days 1-14) with irinotecan 250 mg m(-2) (day 1), but no activity was observed at this dose., Conclusion: Although a higher sunitinib dose of 37.5 mg per day (days 1-14) with irinotecan showed preliminary evidence of antitumour activity, this dose was poorly tolerated. Therefore, this particular combination will not be pursued for further studies.

Background: Masitinib is a tyrosine kinase inhibitor with a pre-clinical profile suggesting greater affinity and selectivity in vitro for the wild-type c-Kit receptor and its juxtamembrane mutation than imatinib., Methods: This dose-escalation study was conducted in patients with advanced and/or metastatic cancer to determine the maximum tolerated dose (MTD) for orally administered masitinib over a 12-week period. Secondary objectives were a clinical assessment of masitinib's activity in cancer patients and establishment of a pharmacokinetic profile., Results: Forty patients with various solid tumours (predominantly GIST, 19 patients) were treated with masitinib at doses ranging between 0.7 and 17.2mg/kg/day. Although the MTD was not formally reached, an acceptable dose for chronic use was identified at 12 mg/kg/day. Treatment-related AEs were frequent (38/40 patients), however, the majority were grade 1 or 2 and demonstrated dose dependency at higher concentrations. Pharmacokinetic results showed a linear, dose-dependent increase of C(max) and AUC. One of two GIST patients with imatinib intolerance had a partial response at 11.1mg/kg/day. About 29% of the imatinib-resistant GIST population and 38% of the overall population had stable disease., Conclusions: The safety profile of masitinib at 12 mg/kg/day b.i.d. for the treatment of solid cancers appears favourable and compatible with a long-term regimen. Tumour control rate in imatinib-resistant patients was encouraging, hence, the activity of masitinib in c-Kit expressing tumours, such as GIST, warrants further exploration as first-line anticancer therapy as well as for imatinib-resistant patients.

Recent advances in the understanding of molecular mechanisms of cancer have led to the development of novel compounds that target specific cancer pathways. These drugs encompass monoclonal antibodies and tyrosine and non-tyrosine kinase inhibitors, and have been approved by the FDA and the European Medicines Agency, among others, for cancer treatment. These agents are associated with several toxic effects including potentially unacceptable gastrointestinal adverse effects. Diarrhea and hepatotoxicity, the most common adverse events experienced with these treatments, can frequently lead to treatment discontinuation and consequently decreased cancer control. We review the incidence and clinical patterns of the gastrointestinal and hepatic toxic effects induced by the main molecular-targeted therapies and propose some hypotheses for the causes of each adverse event.

Background: The oncology community usually perceives phase I oncology trials as associated with poor or limited benefits and substantial risks. There is scarce data concerning outcome and survival of patients enrolled in current phase I oncology trials., Patients and Methods: We reviewed all phase I oncology trials conducted by investigators from the Adult Phase I Unit at Institut Gustave Roussy from 2003 to 2006. We report data concerning patient demographics, treatment outcome, toxicity, survival and type of care after trial exit., Results: We analyzed 10 trials involving 180 participants. The overall response rate was 7.2%. Disease control (objective response plus stable disease) was achieved in 48.2% of patients. The rate of toxic death was 0.5%. In all, 38% of patients had at least one episode of grade 3 or 4 toxic events. The median progression-free survival and the median overall survival (OS) were 2.3 and 8.7 months, respectively. On multivariate analysis, a time between diagnosis of disease and inclusion in the phase I trial > or =24 months and evidence of disease control were statistically significant predictors of improved OS., Conclusion: Current phase I oncology trials are safe and are associated with clinical benefit in a substantial proportion of patients.

Non-small cell lung cancer (NSCLC) with activating mutations in the epidermal growth factor receptor (EGFR) responds to EGFR tyrosine kinase inhibitors such as erlotinib. However, secondary somatic EGFR mutations (e.g., T790M) confer resistance to erlotinib. BMS-690514, a novel panHER/vascular endothelial growth factor receptor (VEGFR) inhibitor described here, exerted antiproliferative and proapoptotic effects on NSCLC cell lines, with prominent efficacy on H1975 cells expressing the T790M mutation. In this model, BMS-690514 induced a G(1) cell cycle arrest, as well as ultrastructural hallmarks of apoptosis, mitochondrial release of cytochrome c, and activation of caspases involved in the intrinsic (e.g., caspase-2, caspase-3, caspase-7, and caspase-9), but not in the extrinsic (e.g., caspase-8), pathway. Caspase inhibition conferred partial protection against BMS-690514 cytotoxicity, pointing to the involvement of both caspase-dependent and caspase-independent effector mechanisms. Transcriptome analyses revealed the up-regulation of proapoptotic (e.g., Bim, Puma) and cell cycle inhibitory (e.g., p27(Kip1), p57(Kip2)) factors, as well as the down-regulation of antiapoptotic (e.g., Mcl1), heat shock (e.g., HSP40, HSP70, HSP90), and cell cycle promoting [e.g., cyclins B1, D1, and D3; cyclin-dependent kinase 1 (CDK1); MCM family proteins; proliferating cell nuclear antigen (PCNA)] proteins. BMS-690514-induced death of H1975 cells was modified in a unique fashion by a panel of small interfering RNAs targeting apoptosis modulators. Down-regulation of components of the nuclear factor-kappaB survival pathway (e.g., p65, Nemo/IKK gamma, TAB2) sensitized cells to BMS-690514, whereas knockdown of proapoptotic factors (e.g., Puma, Bax, Bak, caspase-2, etc.) and DNA damage-related proteins (e.g., ERCC1, hTERT) exerted cytoprotective effects. BMS-690514 is a new pan-HER/VEGFR inhibitor that may become an alternative to erlotinib for the treatment of NSCLC.