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PURPOSE The US Food and Drug Administration–expanded access program (EAP) uses a single patient use (SPU) mechanism to provide patient access to investigational agents in situations where no satisfactory or comparable therapy is available. Genomic profiling of de novo and relapsed or refractory childhood cancer has led to increased identification of new drug targets in the last decade. The aim of this study is to examine the SPU experience for genomically targeted therapies in patients with pediatric cancer. PATIENTS AND METHODS All genomically targeted therapeutic SPUs obtained over a 5-year period were evaluated at four large pediatric cancer programs. Data were collected on the type of neoplasm, agents requested, corresponding molecularly informed targets, and clinical outcomes. RESULTS A total of 45 SPUs in 44 patients were identified. Requests were predominantly made for CNS and solid tumors (84.4%) compared with hematologic malignancies (15.6%). Lack of an available clinical trial was the main reason for SPU initiation (64.4%). The median time from US Food and Drug Administration submission to approval was 3 days (range, 0-12 days) and from Institutional Review Board submission to approval was 5 days (range, 0-50 days). Objective tumor response was seen in 39.5% (15 of 38) of all evaluable SPUs. Disease progression was the primary reason for discontinuation of drug (66.7%) followed by toxicity (13.3%). CONCLUSION SPU requests remain an important mechanism for pediatric access to genomically targeted agents given the limited availability of targeted clinical trials for children with high-risk neoplasms. Furthermore, this subset of SPUs resulted in a substantial number of objective tumor responses. The development of a multi-institutional data registry of SPUs may enable systematic review of toxicity and clinical outcomes and provide evidence-based access to new drugs in rare pediatric cancers.

Background: The novel coronavirus disease 2019 (COVID-19), emerged in Wuhan, China in December 2019 and then spread worldwide rapidly. The records from World Health Organisation (WHO), Centres of Disease Control and Prevention (CDC) and Food and Drug Administration (FDA) backup the fact that no medications have proven to be completely effective for prevention or treatment of SARS-CoV-2. The clinical trials are underway for many repurposed, investigational drugs and vaccine candidates. BioNTech and Pfizer Inc, Moderna, Gamaleya institute and University of Oxford (collaboration with AstraZeneca) announced positive results in the Phase 3 interim analyses of vaccine trials in November 2020. Twelve countries have approved Pfizer- BioNTech COVID-19 vaccine for emergency use, as of December 2020. Objectives: The objective was to summarize the repurposed/investigational drugs, their mechanism of action, and rationale for their use in COVID-19 treatment. The article also aimed to summarize the vaccine trials that are currently undergoing across the globe. Methods: In order to find the content for review, studies defining COVID-19 chronology, repurposed drugs along with their mode of action and potential vaccine trials were studied and summarized. Results and Conclusion: The article summarizes potential therapeutic candidates (repurposed and investigational agents) for SARS-CoV-2, their possible mechanism of action and discussion related to their involvement in recent clinical trials. Innovative vaccine platform technologies are also highlighted that are recently being used in the vaccine production pipeline.

Statins remain the drugs of choice in patients at risk of or with atherosclerotic cardiovascular disease (ASCVD). Statins have limitations that drive the development of investigational agents to manage dyslipidemias and/or reduce ASCVD risk. There are a few small-molecule drugs that have the potential to mitigate ASCVD risk either alone or in combination with statins. Most lipid-modifying drugs in clinical development are biologic agents that target specific enzymes or genetic-based protein synthesis. Limitations of the biologic agents include complex mechanisms of action and manufacturing processes with indications in select patients with genetic dyslipidemia or who have failed traditional therapies. The ultimate clinical utility of the new and investigational agents will become established over the next several years.Lay abstract The most common medications that reduce fat (cholesterol) in the blood are called ‘statins.’ Statins reduce the chance of having a heart attack, stroke or cardiac death. Statins do not completely eliminate these risks and some patients cannot tolerate them. New medications are being tested to find out if they reduce the risk of heart problems. Many of the new drugs are called ‘biologics.’ Biologics work through complex mechanisms to reduce the amount of fat produced or by limiting the toxicity of the fat. Many of the new medications are difficult to manufacture and must be given as injections. They are expensive but possibly effective for patients unable to take statins or patients with rare cholesterol disorders.

Introduction The field of myeloproliferative neoplasms (MPN) has entered a new, exciting era since the clinical development and FDA-approval of the JAK1/2 inhibitor ruxolitinib in 2011 and the JAK2 inhibitor fedratinib in 2019 for treatment of myelofibrosis (MF), the most aggressive MPN. Notwithstanding the unprecedented clinical benefits, including transformative improvement in quality-of-life that the approved JAK inhibitors have elicited in MF patients and their widespread use, a tenacious quest for novel MF treatment strategies has been pursued. Research endeavors have focused on developing new monotherapies and rational combination treatments that exhibit complementary activity or act synergistically with ruxolitinib.1,2 The new regimens in clinical development are aimed at addressing major unmet medical needs, such as anemia and thrombocytopenia, progression of MF to acute myeloid leukemia, suboptimal response or resistance to ruxolitinib,3 and the short overall survivals associated with the former settings.4,5 The novel investigational agents may target alternate biological pathways besides JAK/STAT and/or enhance the efficacy of ruxolitinib. In this abstract, we have highlighted select, promising investigational agents that are currently evaluated in pivotal phase 3 clinical trials for MF (Table 1).

Purpose of Review This review summarizes the investigational antifungals in clinical development with the potential to address rising drug resistance patterns. The relevant pharmacodynamics, spectrum of activity, preclinical studies, and latest clinical trial data are described. Recent Findings Agricultural and medicinal antifungal use has been selected for inherently drug-resistant fungi and acquired resistance mechanisms. The rates of fungal infections and immunocompromised populations continue to grow as few new antifungals have hit the market. Several agents with the potential to address the emergence of multidrug-resistant (MDR) molds and yeasts are in clinical development. Summary Evolved formulations of echinocandins, polyenes, and triazoles offer less toxicity, convenient dosing, and greater potency, potentially expanding these classes’ indications. Ibrexafungerp, olorofim, oteseconazole, and fosmanogepix possess novel mechanisms of actions with potent activity against MDR fungi. Successful clinical development is neither easy nor guaranteed; thus, perpetual efforts to discover new antifungals are needed.

Chimeric antigen receptor (CAR) T-cell therapy has quickly emerged as a highly promising treatment for patients with relapsed and refractory multiple myeloma. There are numerous candidates under development, each with their unique characteristics and points of differentiation. The most recent US Food and Drug Administration approval of the first B-cell maturation antigen-targeted CAR-T cell therapy on March 26, 2021, has paved a path forward for the eventual evaluation of more of these investigational agents undergoing clinical trials. Herein, we highlight, from a clinical development perspective, the CAR-T cell therapies farthest along in development with updated data from the American Society of Hematology 2020 annual meeting. We also discuss potential paths of overcoming resistance to these therapies and the future direction for CAR-T cell therapeutics in multiple myeloma.

Improving interpretation of existing guidelines and management of protocol deviation processes could increase process efficiencies and help reduce noise to support rapid identification of important protocol deviations. Towards this end, TransCelerate identified key principles to build upon and clarify the definition of a protocol deviation and developed a holistic approach to protocol deviation management. The approaches are flexible to suit a variety of indications, study designs, and investigational agents while also supporting consistent application within a study, program or organization.

Coronavirus disease 2019 (COVID-19) has resulted in an unprecedented pandemic, challenging practitioners to identify safe and effective therapeutic options in a limited amount of time. The rapid genomic sequencing of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) provided a significant number of therapeutic targets. Repurposed and investigational agents are being studied for use in COVID-19. Although knowledge is rapidly expanding in regard to COVID-19 and there is promise with a few agents, there are no definitely proven effective therapies at this time. Supportive care remains the mainstay of therapy while ongoing clinical trials are being conducted.

New clinical trials for diabetic macular oedema (DMO) are being designed to prove superiority over aflibercept when this agent is already very effective in improving visual acuity (VA) and DMO. The aim of this study was to determine the optimal inclusion–exclusion criteria for trials to aim for superiority in visual outcomes with newer agents. As Phase 1 studies are short duration, we aimed to evaluate the early response of aflibercept in a real-world cohort initiated on monthly aflibercept for 3 consecutive injections and observed the effects at 4 months. The sub-optimal responders were pre-defined based on different cut-offs for VA and central sub-field thickness (CST). 200 patients with treatment naïve DMO treated with 3 loading doses of aflibercept were included in the study. We found that those presenting with baseline VA of 35–54 ETDRS letters (n = 43) had higher proportion of sub-optimal responders compared to other categories (p

Introduction: Systemic sclerosis (SSc) is an autoimmune connective tissue disease that is characterized by excessive collagen deposition, vascular dysfunction, and fibrosis of cutaneous and visceral organs. Current therapeutic options are limited and provide only modest benefit.Areas covered: This review summarizes investigational agents in recent Phase I and II clinical trials evaluated for the treatment of SSc with a focus on skin in patients with early diffuse disease and interstitial lung disease. We performed a search on Pubmed and https://clinicaltrials.gov with keywords systemic sclerosis, Phase I clinical trial, and Phase II clinical trial to identify relevant studies from 2015 to 2019.Expert opinion: Therapeutic interventions in SSc should be guided by the level of disease activity and the degree of organ involvement. While most novel agents have failed to meet the primary endpoints of reducing skin thickening as measured by the modified Rodnan skin score, some have shown promise in improving the Composite Response Index for Clinical Trials in Early Diffuse Cutaneous Systemic Sclerosis (CRISS), reducing lung function decline, or improving patient-reported outcomes. However, most of the current evidence is based on small or open-label clinical trials. Well-designed, large, randomized, Phase III clinical trials are necessary to define the roles of investigational agents in treating SSc.

Patients with cancer who have exhausted standard treatments often seek access to investigational drugs. Often, however, such access is unavailable, due to either the unavailability of a trial, lack of an open recruiting spot on the trial, even when the trial itself is open, or the inability of the patient to meet one or more trial eligibility criteria. In such settings patients often seek access to investigational agents outside of a trial. The federal “Right to Try” legislation was passed to create an additional avenue, different from the FDA's Expanded Access, or “Compassionate Use” Program, through which patients might obtain access to investigational drugs. A year after this legislation was signed into law, there remains both a limited awareness of it and a substantial degree of misunderstanding on the part of those who are aware of it. The law creates an avenue to greatly facilitate off-study administration when patient, physician, and the manufacturer are all in agreement regarding the off study use of an eligible investigational agent. The law does not, however, empower a patient to impose a demand on either a provider or a drug manufacturer, nor does it require any entity to provide financial coverage for the drug. Eligible drugs are those which are not approved by the FDA for any indication, have completed a phase I trial, have an ongoing pivotal trial, and have an active registration plan. We review the specific law with commentary on its implications for improved access to investigational drugs outside of clinical trials.

Remdesivir is a nucleoside monophosphoramidate prodrug that has been FDA approved for coronavirus disease 2019 (COVID-19). However, the clinical efficacy of remdesivir for COVID-19 remains contentious, as several trials have not found statistically significant differences in either time to clinical improvement or mortality between remdesivir-treated and control groups. Similarly, the inability of remdesivir to provide a clinically significant benefit above other investigational agents in patients with Ebola contrasts with strong, curative preclinical data generated in rhesus macaque models. For both COVID-19 and Ebola, significant discordance between the robust preclinical data and remdesivir’s lackluster clinical performance have left many puzzled. Here, we critically evaluate the assumptions of the models underlying remdesivir’s promising preclinical data and show that such assumptions overpredict efficacy and minimize toxicity of remdesivir in humans. Had the limitations of in vitro drug efficacy testing and species differences in drug metabolism been considered, the underwhelming clinical performance of remdesivir for both COVID-19 and Ebola would have been fully anticipated.

Antibody-drug conjugates (ADCs) are complex engineered therapeutics consisting of monoclonal antibodies, directed toward tumor-associated antigens, to which highly potent cytotoxic agents are attached using chemical linkers. This targeted drug delivery strategy couples the precision of the antibody targeting moiety with the cytocidal activity of the payload, which is generally too toxic on its own to be systemically administered. In this manner, ADCs confer a means to reduce off-target toxicities in patients by limiting the exposure of normal tissues to the payload, thus broadening the potential therapeutic window compared with traditional chemotherapy. The pace of ADC development is accelerating, with the number of investigational agents in human trials having more than tripled over the past 5 years, underscoring the enthusiasm for this transformative approach to cancer treatment. Here, we review the key structural elements of ADC design (antibody, linker, and payload), highlighting critical aspects and technological advances that have affected the clinical effectiveness of this class of biopharmaceuticals. The ADC field continues to evolve, including ongoing efforts aimed at improving target selection, developing payloads with varied mechanisms of action and increased potency, designing innovative bioconjugation strategies, as well as maximizing efficacy and tolerability in patients. An overview of the current clinical trial landscape is provided, with emphasis on the clinical experience of the four ADCs to have received regulatory approval to date, as well as additional promising candidates currently in late-stage clinical development in both solid tumor and hematological malignancies.

Purpose/Objective(s) Despite the promise of improving the therapeutic ratio of radiation with novel pharmaceuticals, the last drug to receive FDA approval for use in combination with radiation was over 15 years ago. We sought to examine the oral abstracts presented at the ASTRO annual meetings over the past 9 years that involved drugs or biologics used concurrently with radiation, with the goal of reporting trends and identifying opportunities to accelerate drug development in this area. Materials/Methods All published abstracts selected for an oral scientific session at the ASTRO annual meeting from years 2011-2019 were manually reviewed. Abstracts pertaining to drug-radiotherapy combinations aimed at improving anti-tumor efficacy or minimizing radiation toxicities were included in our analysis and categorized by type of study (preclinical, retrospective, phase 1, 2, or 3), disease site, category of drug (radiosensitizer, radioprotector, supportive care), specific drug class (immunotherapy, cytotoxic, etc.), and FDA approval status of drug/biologic at time of presentation. Descriptive statistics were used to identify trends over time. Results A total of 3,089 abstracts were reviewed and 258 (8.4%) met our pre-specified criteria for a study investigating drug-radiotherapy combinations. The relative number of abstracts discussing radiation-drug combinations ranged from 6.2% (2015) to 10.9% (2011) of the total number of abstracts selected for oral presentation. Of the prospective trials presented, 25% were phase 1, 51.5% phase 2, and 23.5% phase 3. The most common drug class studied in clinical trials was cytotoxic chemotherapy. Of the investigational agents explored in phase 3 trials (N = 39), all but 2 had previously received marketing approval for use in other indications. The only exceptions to this were avasopasem manganese (a novel radioprotector), and an unspecified oral mucosa protectant that may or may not require marketing approval prior to use. None of the clinical data presented has been used as primary efficacy data to support an FDA indication. Expected trends were observed, such as the use of anti-angiogenic and anti-EGFR agents decreasing over time and the use of immune modulatory agents increasing over time. Conclusion Despite an explosion of targeted therapies in oncology, the majority of clinical trials of drug-radiotherapy combinations presented at ASTRO Annual Meetings investigated cytotoxic chemotherapeutics that had already received marketing approval. The pharmaceuticals investigated in phase 3 trials during this time period had been FDA approved for a median of 25 years at the time of oral presentation and none of the data has been used to support FDA approval. This suggests a lack of support from Industry and Cooperative Groups for late phase combination trials with novel agents as well as a lack of incentives for Sponsors to seek supplemental indications with radiation.

Radiation oncologists and nuclear medicine physicians have seen a resurgence in the clinical use of radiopharmaceuticals for the curative or palliative treatment of cancer. To enable the discovery and the development of new targeted radiopharmaceutical treatments, the United States National Cancer Institute has adapted its clinical trial enterprise to accommodate the requirements of a development program with investigational agents that have a radioactive isotope as part of the studied drug product. One change in perspective has been the consideration of investigational radiopharmaceuticals as drugs, with maximum tolerable doses determined by normal organ toxicity frequency like in drug clinical trials. Other changes include new clinical trial enterprise elements for biospecimen handling, adverse event reporting, regulatory conduct, writing services, drug master files, and reporting of patient outcomes. Arising from this enterprise, the study and clinical use of alpha-particle and beta-particle emitters have emerged as an important approach to cancer treatment. Resources allocated to this enterprise have brought forward biomarkers of molecular pathophysiology now used to select treatment or to evaluate clinical performance of radiopharmaceuticals. The clinical use of diagnostic and therapeutic radionuclide pairs is anticipated to accelerate radiopharmaceutical clinical development.

Treatment of blast crisis (BC) is one of the remaining challenges in the management of CML. Tyrosine kinase inhibitors (TKI) have moderately improved survival in BC, but a median survival of less than 1 year is still unsatisfactory. Earlier recognition of end-phase CML and early treatment intensification might improve outcome. High-risk additional chromosomal abnormalities and somatic mutations have been proposed for risk assessment and better recognition of patients at risk for progression to end-phase CML. In this article we review features of BC, tests required for diagnosis of BC, options of prevention, and the various treatment modalities of BC (intensive chemotherapy alone or in combination with TKI, allo-SCT, investigational agents). The best prognosis is observed in patients that achieve a second chronic phase (CP2). Allo-SCT probably further improves prognosis in CP2. The choice of TKI should be directed by the mutation profile of the patient. Also, a better pathophysiologic understanding of BC is addressed. Current treatment options are combined in a concluding strategy for the management of CML end phase and BC.

For patients with advanced non–small cell lung cancer, genomic profiling of tumors to identify potentially targetable alterations and thereby inform treatment selection is now part of standard care. While molecular analyses are primarily focused on actionable biomarkers associated with regulatory agency-approved therapies, there are a number of emerging biomarkers linked to investigational agents in advanced stages of clinical development will become approved agents. A particularly timely example is the reported data and US Food and Drug Administration approval of highly specific small molecule inhibitors of the proto-oncogene tyrosine-protein kinase receptor RET indicate that testing for tumor RET gene fusions in patients with NSCLC has become clinically important. As the number of biomarkers to be tested in NSCLC grows, it becomes increasingly important to optimize and prioritize the use of biopsy tissue, in order to both continue to allow accurate histopathological diagnosis and also to support concurrent genomic profiling to identify perhaps relatively uncommon genetic events. In order to provide practical expert consensus guidance to optimize processes facilitating genomic testing in NSCLC and to overcome barriers to access and implementation, a multidisciplinary advisory board was held in New York, on January 30, 2019. The panel comprised physicians involved in sample procurement (interventional radiologists and a thoracic surgeon), surgical pathologists specializing in the lung, molecular pathologists, and thoracic oncologists. Particular consideration was given to the key barriers faced by these experts in establishing institutional genomic screening programs for NSCLC. Potential solutions have been devised in the form of consensus opinions that might be used to help resolve such issues.

Acute myeloid leukemia (AML) is classified into four broad categories in the revised World Health Organization classification for myeloid neoplasms; AML with recurrent genetic abnormalities, AML with myelodysplasia-related changes, therapy-related myeloid neoplasms, and AML not otherwise specified. With better understanding of the disease biology, many novel agents have been developed and are now incorporated in the treatment paradigm for AML. We summarize in this chapter the molecular landscape of AML, novel therapies that have received regulatory approval, as well as selected investigational agents that are in early stages of development (first-in human trials) and focus on those in later stages of development. Each section will emphasize selected investigational agents based on their mechanism of action or targeted pathway.

In the current era, the survival of extremely low-birth-weight infants has increased considerably because of new advances in technology; however, these infants often develop chronic dysfunction of the lung, which is called bronchopulmonary dysplasia (BPD). BPD remains an important cause of neonatal mortality and morbidity despite newer and gentler modes of ventilation. BPD results from the exposure of immature lungs to various antenatal and postnatal factors that lead to an impairment in lung development and aberrant growth of lung parenchyma and vasculature. However, we still struggle with a uniform definition for BPD that can help predict various short- and long-term pulmonary outcomes. With new research, our understanding of the pathobiology of this disease has evolved, and many new mechanisms of lung injury and repair are now known. By utilizing the novel ‘omic’ approaches in BPD, we have now identified various factors in the disease process that may act as novel therapeutic targets in the future. New investigational agents being explored for the management and prevention of BPD include mesenchymal stem cell therapy and insulin-like growth factor 1. Despite this, many questions remain unanswered and require further research to improve the outcomes of premature infants with BPD.

The molecular characterization of tumors now informs clinical cancer care for many patients. This advent of molecular oncology has been driven by the expanding number of therapeutic biomarkers that can predict sensitivity to both approved agents and investigational agents. Beyond its role in driving clinical-trial enrollments and guiding therapy in individual patients, large-scale clinical genomics in oncology also represents a rapidly expanding research resource for translational scientific discovery. Here we review the progress, opportunities, and challenges of scientific and translational discovery from prospective clinical genomic screening programs now routinely conducted for patients with cancer. Molecular characterization of tumors informs clinical cancer care. Here, Taylor and colleagues review the progress, opportunities, and challenges of scientific and translational discovery that leverages prospective data from clinical genomic screening.

Hypomethylating agents (HMA) are the standard of care for patients ≥65 years with intermediate-high risk myelodysplastic syndrome (MDS) unsuitable for intensive therapy or stem cell transplant (SCT). However, many patients will develop relapse/refractory disease, at which point limited treatment options remain. There has been a lot of research into investigational agents following HMA failure, especially now into targeted therapy, but there is no final consensus or convincing data to guide clinicians. Low-dose cytarabine (LDAC) has been in the armamentarium for some time, but the value of LDAC is judged differently by various guidelines. Nevertheless, in a subgroup of patients who fail on a HMA and wish to continue treatment, LDAC may still have the potential to improve overall survival (OS). In this case report, we present an 85-year-old gentleman with HMA refractory high-risk/transforming MDS (with a noncomplex karyotype) achieving an ongoing six-year OS with single-agent second-line LDAC. LDAC may therefore still be considered by clinicians as a therapeutic option, but when available, patients should be enrolled on a clinical trial.

The success of targeted and immune therapies in other malignancies has led to an exponential increase in the number of active and pending clinical trials using these therapeutic approaches in patients with gynecologic cancers. These novel investigational agents are associated with unique and potentially life-threatening toxicities and many require special multidisciplinary logistical considerations. The objective of this review is to describe a practical approach for the safe implementation of targeted and immune therapies in academic gynecologic oncology practices based on our experience at M.D. Anderson Cancer Center.

Purpose of Review This review discusses the need for computational modeling in myelodysplastic syndromes (MDS) and early test results. Recent Findings As our evolving understanding of MDS reveals a molecularly complicated disease, the need for sophisticated computer analytics is required to keep track of the number and complex interplay among the molecular abnormalities. Computational modeling and digital drug simulations using whole exome sequencing data input have produced early results showing high accuracy in predicting treatment response to standard of care drugs. Furthermore, the computational MDS models serve as clinically relevant MDS cell lines for pre-clinical assays of investigational agents. Summary MDS is an ideal disease for computational modeling and digital drug simulations. Current research is focused on establishing the prediction value of computational modeling. Future research will test the clinical advantage of computer-informed therapy in MDS.

Hypomethylating agents (HMA) have played a pivotal role for treating myelodysplastic syndromes (MDS) over the past decade, inducing sustained hematological responses and delaying progression to leukemia. However, a vast majority of patients will experience treatment failure within 2 years, with poor prognoses and limited options, and management of this growing patient population remains unclear. Areas covered: With the introduction of new agents in the MDS field, a better understanding of the biology of MDS, and updated information on standard of care options (including allogeneic transplantation), we re-evaluate the global treatment strategy in MDS via novel agents, focusing in particular on investigational approaches for patients who fail to respond to HMA when applicable. This review aims to address two questions: what are reasonable alternatives to HMA in MDS, and what strategies can be used for patients experiencing HMA failure. Expert opinion/commentary: HMA therapy remains a mainstay of treatment, even if additional research is still warranted to maximize its benefits for the different groups of patients. The outcome of patients experiencing HMA failure remains grim, without standard of care, but several new approaches seem promising, as there is an increasing focus on studying treatments for patients refractory to HMA treatment.

Background Fibrodysplasia ossificans progressiva (FOP) is a catastrophic genetic disorder of progressive heterotopic ossification (HO). Assessment of functional mobility in FOP will be essential to support clinical trials of investigational agents. Results Of necessity, we developed a simple, rapidly-administered, cumulative analogue joint involvement scale (CAJIS) for FOP based on assessments in 144 individuals worldwide with classic FOP. Conclusions CAJIS scores correlated with patient age, activities of daily living, and ambulatory function with excellent inter-rater variability. We show here that the CAJIS score provides an accurate and reproducible snapshot of total body and regional mobility burden in FOP.

Introduction: The outcome of patients (pts) with myelofibrosis (MF) who discontinue ruxolitinib (RUX) is poor with scarce therapeutic possibilities (Palandri et al, 2020). However, some evidences suggest that pts may respond to a rechallenge of RUX after drug stop (Gerds et al, 2018). Aims: To investigate in a real-world context: 1) frequency and reasons for rechallenge; 2) therapeutic effects of rechallenge; 3) impact of rechallenge on overall survival (OS) Methods: After IRB approval, a clinical database was created in 20 European Hematology Centers including now retrospective data of 703 MF pts who started RUX from Jan 2011 to Nov 2019. Only chronic phase (CP) pts who stopped RUX for ≥14 days and survived ≥30 days after discontinuation were included. A specific survey collected clinical/laboratory data at RUX stop and at rechallenge, reasons for discontinuation and treatments before rechallenge. OS was estimated from the date of the first/only RUX discontinuation to last contact (log-rank test). Results: A total of 219 CP pts was evaluable for this study. In 60 (27.4%) pts, RUX was re-challenged for ≥14 days after the first discontinuation (RUX-again), while 159 (72.6%) pts discontinued RUX permanently (RUX-stop). The median time from RUX start to stop was of 16.5 and 12.3 mos for RUX-again and RUX-stop pts, respectively (p=0.41). At RUX start, characteristics of RUX-again were: median age 67y (24-88); males 61.7%; PMF 53.3%; median Hb 10.2 g/dl; median PLT/WBC: 249/12.6 x109/l; median RUX starting dose: 15mg BID. Baseline characteristics of RUX-again and RUX-stop pts were comparable. In the 60 RUX-again pts, reasons for discontinuation included loss of/inadequate response (18 pts, 30%) and toxicity (42 pts, 70%). Toxicity included G3-4 thrombocytopenia (38.1%), anemia (26.2%), infections (21.4%), other (14.3%). Conversely, RUX-stop pts discontinued RUX mainly due to loss of/inadequate response (75 pts, 47.2%), while intolerable toxicity occurred in 69 pts (43.4%) (p=0.004) and other causes in 9.4%. At first RUX discontinuation, 35.7% of RUX-again pts presented with large (>10 cm) splenomegaly; median Total Symptoms Score (TSS) was 10 (TSS>20 in 30.4% of pts). The median duration of temporary RUX discontinuation was 2 mos (range 0.5-71.1). During RUX stop, 65% of RUX-again pts did not receive any therapy, 15% received only palliation (steroids, hydroxyurea), while 11.7% switched to investigational agents, 3.3% underwent splenectomy and 5% allogeneic transplantation. Compared to disease status at first RUX stop, at RUX restart there was a significant increase of pts with large splenomegaly and high TSS, while the PLT count was higher and RUX dose significantly lower (Table 1). The median duration of RUX rechallenge was 7.5 mos (0.5-72.7). During the rechallenge, 44.6% and 48.3% pts improved spleen and symptoms, and there was a significant increase in pts with TSS reduction (p=0.01); 8 pts (13.3%) continued RUX with stable/worsening spleen size and improvement in TSS. Conversely, 26.8% and 20% of pts had increase in spleen size and in symptoms, respectively. While Hb levels remained stable, PLT count significantly decreased during rechallenge (p The reasons for temporary discontinuation had no impact on the reduction of spleen/symptoms during rechallenge and on OS. However, comparing RUX-again and RUX-stop pts, RUX-again pts showed a better OS, with a median survival of 41.1 mos and 23.7, respectively in the 2 cohorts (Fig. 1). Conclusions: This real-world study highlights that RUX rechallenge is quite common in CP-MF pts, involving almost 30% of treated pts, particularly when the discontinuation is due to toxicity. The temporary discontinuation, while improving PLT count, generally caused a significant increase in disease burden. After rechallenge, almost 50% of pts achieved clinical responses regardless of reason of first discontinuation. This residual disease control activity, that correlated with improved OS, should be weighed up also given the new therapeutic possibilities available in these pts. Disclosures Palandri: Novartis: Consultancy, Honoraria. Breccia:Abbvie: Consultancy; Bristol-Myers Squibb/Celgene: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Incyte: Consultancy, Honoraria. Benevolo:Amgen: Honoraria; Celgene: Honoraria; Novartis: Honoraria. Cavazzini:Incyte: Honoraria; Pfize: Honoraria; Novartis: Honoraria. Crugnola:Janssen: Honoraria; BMS: Honoraria; Novartis: Honoraria; Celgene: Honoraria. Heidel:CTI: Consultancy; Celgene: Consultancy; Novartis: Consultancy, Research Funding. Pane:Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Other: travel expenses, Speakers Bureau; Daiichi Sankyo: Consultancy, Other: Travel Expenses; Novartis pharma SAS: Consultancy, Other: Travel Expenses, Research Funding, Speakers Bureau; Janssen: Other: Travel Expenses; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Other: Travel Expenses, Speakers Bureau; AbbVie: Consultancy, Other: Travel Expenses, Speakers Bureau. Cuneo:janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Krampera:Janssen: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Semenzato:Takeda: Honoraria; Roche: Honoraria; Abbvie: Honoraria. Lemoli:AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees; Servier: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; BerGenBio ASA: Research Funding. Cavo:Jannsen, BMS, Celgene, Sanofi, GlaxoSmithKline, Takeda, Amgen, Oncopeptides, AbbVie, Karyopharm, Adaptive: Consultancy, Honoraria. Palumbo:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Introduction: The JAK1/2 inhibitor, ruxolitinib, was approved in the USA in 2011 for the treatment of patients with myelofibrosis (MF) with intermediate and high-risk IPSS score (International Prognostic Scoring System). In the approval phase 3 COMFORT 1 - 2 studies, about 50% patients were taking ruxolitinib for at least 3 years, respectively. Objective: We sought to evaluate the characteristics and outcome of MF patients on long-term ruxolitinib therapy (≥3 years) at our center. Methods: We retrospectively reviewed the charts of patients with MF who were treated with ruxolitinib for ≥3 years. Cytogenetic were classified into risks according to Gangat et all, JCO, 2011. Descriptive statistics were used for nominal and continues variables, captured at the time of ruxolitinib start. Duration of therapy and overall survival (OS) were estimated using the Kaplan-Meier method, from the start of ruxolitinib initiation until the last day of initial ruxolitinib therapy, the date of last follow-up or death, respectively. Response to therapy was according to IWG-MRT 2013 criteria. Results: Among 437 patients who initiated therapy with ruxolitinib at our center, 136 (31%) remained on therapy for ≥3 years and represent current cohort. Ninety-one patients (67%) were newly diagnosed; the remaining patients presented after a median of 28 months (range, 4-228) from MF diagnosis. Median time to initiate ruxolitinib from presentation to our center was 1 month (range, 0.3-123) for all patients. However, the time was longer for patients who presented > 3 months from MF diagnosis (median of 11.5 months; range, 3.5-123). Patient's characteristics (n = 136) at the time of ruxolitinib initiation are summarized in Table 1. Median age was 67 years (range, 32-84), and 76 (56%) of patients were males. Half of the patients had high risk IPSS score, > 80% had systemic symptoms or splenomegaly. Eighty six percent of patients had diploid or favorable karyotype. JAK2 mutation was detected in 87% of tested patients. Median duration of ruxolitinib therapy was 72 months (95% CI: 66-78). Over the median follow-up of 83 months (range, 36-174), 63 patients (46%) died. Currently, 48 (35%) patients are still on ruxolitinib; 88 discontinued therapy after a median time of 55 months (range, 47-63). By 5th and 7th year of therapy, out of 136 patients that were treated for at least 3 years, 35% and 65% percent of patients discontinued treatment. The reasons for discontinuation included allogeneic stem cell transplantation (SCT, n 5), cytopenia (n 6), progression of MF (n 38), progression to accelerate phase (n 2) or acute leukemia (n 7), patient's choice (n 11), and death (n 23: infection 4, cardiac 3, cancer 3, others 16). Overall, 101 patients (74%) achieved IWG-MRT response, represented in majority by clinical improvement (CI) in spleen (n 90, 84%) and CI in TSS (n 51, 71%), respectively. The remaining patients achieved clinical benefit not qualifying for overall IWG-MRT response. Median duration of IWG-MRT response was 55 months (95% CI: 48-63). Responses were ongoing in 29 patients (29% of initial responders) at the time of last follow-up. Median duration of therapy was 75 months (95% CI: 68-82) for responders vs 60 months (95% CI: 39-79) for non-responders, p = 0.74. Median OS from the start of ruxolitinib was 90 months (95% CI: 76-104), Figure 1. Median OS for patients who were on ruxolitinib for ≥5 years (n = 73) was 106 months (95% CI: 80-137). Univariate and multivariate analysis for factors associated with OS is shown in Table 2. After ruxolitinib discontinuation, 25 patients received subsequent treatment at our center: SCT in 6, another JAK inhibitor in 11, other investigational agents in 3, chemotherapy in 5 patients. Median OS from ruxolitinib discontinuation was 20 months (95% CI: 12-28). Conclusion: Our data with the longest follow-up of patients receiving ruxolitinib for ≥3 years confirm the long-term benefit of this therapy with a median OS approaching 8 years since ruxolitinib treatment initiation. Disclosures Bose: Incyte Corporation: Consultancy, Honoraria, Research Funding, Speakers Bureau; Blueprint Medicines Corporation: Honoraria, Research Funding; Promedior, Inc.: Research Funding; Pfizer, Inc.: Research Funding; Kartos Therapeutics: Honoraria, Research Funding; Astellas Pharmaceuticals: Research Funding; Celgene Corporation: Honoraria, Research Funding; Constellation Pharmaceuticals: Research Funding; CTI BioPharma: Honoraria, Research Funding; NS Pharma: Research Funding. Pemmaraju:AbbVie: Honoraria, Research Funding; Incyte Corporation: Honoraria; MustangBio: Honoraria; Affymetrix: Other: Grant Support, Research Funding; Plexxikon: Research Funding; Celgene: Honoraria; Blueprint Medicines: Honoraria; Stemline Therapeutics: Honoraria, Research Funding; Daiichi Sankyo: Research Funding; Novartis: Honoraria, Research Funding; Pacylex Pharmaceuticals: Consultancy; LFB Biotechnologies: Honoraria; Roche Diagnostics: Honoraria; SagerStrong Foundation: Other: Grant Support; DAVA Oncology: Honoraria; Samus Therapeutics: Research Funding; Cellectis: Research Funding. Kantarjian:Daiichi-Sankyo: Research Funding; Ariad: Research Funding; Astex: Research Funding; Agios: Honoraria, Research Funding; Cyclacel: Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Research Funding; Takeda: Honoraria; Jazz Pharma: Research Funding; Immunogen: Research Funding; AbbVie: Honoraria, Research Funding; Novartis: Research Funding; Pfizer: Honoraria, Research Funding; BMS: Research Funding. Verstovsek:Celgene: Consultancy, Research Funding; NS Pharma: Research Funding; AstraZeneca: Research Funding; Roche: Research Funding; Genentech: Research Funding; Novartis: Consultancy, Research Funding; Incyte Corporation: Consultancy, Research Funding; CTI Biopharma Corp: Research Funding; Promedior: Research Funding; Gilead: Research Funding; Blueprint Medicines Corp: Research Funding; PharmaEssentia: Research Funding; Sierra Oncology: Consultancy, Research Funding; Protagonist Therapeutics: Research Funding; ItalPharma: Research Funding.

An inherited, chronic progressive, neurodegenerative disorder is Huntington's disease, characterized by motor, cognitive, and psychiatric symptoms. Predictive genetic testing allows earlier diagnosis and identification of gene carriers for Huntington's disease. These individuals are ideal candidates for testing of therapeutic interventions for disease modification. Areas covered: According to queries in Pubmed, Embase and clinical register databases, research and clinical studies emerge on symptomatic and neuroprotective therapies in Huntington's disease. This review discusses novel agents for symptomatic therapy and disease modification. They are currently in phase I and II of drug development Expert opinion: There are promising, safe and well tolerated compounds for amelioration of motor and neuropsychiatric symptoms, but their efficacy still needs to be proven in clinical trials. Deterioration of mutant huntingtin expression, antiapoptotic or cell death inhibition as disease modifying concepts was efficacious in models of Huntington's disease. However, the risk for clinical trial failures is high not only due to ineffectiveness of the tested agent. Negative study outcomes may also result from design misconceptions, underestimation of the heterogeneity of Huntington's disease, too short study durations and too small study cohorts.

Background In recent years, the number of agents for treatment of plaque psoriasis has increased rapidly. Objective To compare available and investigational agents for treatment of psoriasis. Methods Pivotal clinical trials for infliximab, etanercept, adalimumab, ustekinumab, secukinumab, ixekizumab, brodalumab, guselkumab, tildrakizumab, methotrexate, tofacitinib, and apremilast in plaque psoriasis were identified. Percentages of patients achieving PASI 75, 90, and 100 were extracted. Results Seventeen publications, including data from 21 trials, were reviewed. All medications were more efficacious in achieving PASI 75 compared to placebo. Ixekizumab exhibited the greatest difference in PASI 75 and PASI 90, while brodalumab showed the greatest difference in PASI 100. Limitations Heterogeneity existed in patient demographics and study design including primary endpoint weeks between trials. Data included were only from the primary endpoint week. Conclusions All biologics exhibited greater PASI improvement than placebo, with newer agents more capable of achieving PASI 90 and PASI 100. Head-to-head comparator trials are needed for more accurate comparison.

Histology is a treatment target for investigational agents. Histologic activity predicts relapses and increased risk of colorectal neoplasia. Recent studies demonstrated that the proportion of patients achieving histologic improvement is low. Research is needed before providers treat to histologic remission.

Phase I clinical trials have traditionally been focused on populations of normal healthy volunteers with the goal of determining the safety, tolerability, and pharmacokinetic profile of new investigational agents. As CNS drug development shifts its focus to the development of novel molecular entities, this approach will undergo an evolution. In this chapter the authors describe the traditional Phase I approach and challenges facing CNS drug development. The chapter will propose modifications to the traditional Phase I design, including the incorporation of different populations, biomarker surrogates, and adaptive designs.

e13563 Background: Risks and benefits of investigational agents that have not been tested in humans are, at best, incompletely characterized in nonclinical investigations. Despite the growing emphasis to include patient voices in clinical trial design, no published research has explored patient preferences on how best to convey the information that the agent has not been tested in humans. This study established that First in Human (FIH) consent forms present this information in different locations and queried participants for their input on the preferable FIH consent form structure. Methods: Consent forms for FIH oncology trials open to accrual at Winship Cancer Institute in 2019-2020 were analyzed for (1) the location of the mention that the study drug has not been used in humans before (FIH information), (2) the location of animal and other nonclinical data, and (3) placement of the risks section. Patients offered enrollment in a FIH trial were eligible for this study. Participants were interviewed during a clinic visit after consent was obtained. An ethics researcher asked questions about the participant’s opinions on the wording and placement of the FIH, nonclinical, and risk information in the specific trial consent form. All interviews were audio-recorded and double coded by two independent coders. The location of FIH and nonclinical data in the consent forms was compared to the patient’s suggested location for this information. Results: Saturation of themes was reached after interviewing 17 (17/19, 89% accrual) participants who were enrolled in 9 different FIH trials. Twenty FIH consents were qualitatively analyzed. Preferred placement compared to actual consent placement is listed in the table. 82% (14/17) of participants thought that nonclinical data on risks and efficacy was important to mention. 95% (19/20) of consents listed nonclinical data and most participants thought the placement in the consent was appropriate but 18% (3/17) of participants wanted the information earlier in the consent. No consent forms that were analyzed had the risks section before the study schedule; however, 47% (8/17) of participants wanted to move the risks sections before the study schedule. Conclusions: There is considerable variation in the layout of FIH consent forms that does not align with patient preferences. Standardization of FIH consent forms to better reflect patient input is essential in order to promote understandability of these important yet sometimes misunderstood clinical trials and to ensure ethical informed consent.[Table: see text]

Significant advances have been made toward understanding the biology of neuroendocrine tumors (NET) in terms of defining prognosis and improving clinical management; however, many unmet needs remain. The treatment landscape for NET has evolved, with the approval of the targeted agents everolimus and sunitinib for the treatment of advanced pancreatic NET in 2011 followed by the approval of everolimus for the treatment of advanced nonfunctional gastrointestinal and lung NET in 2016. Mammalian target of rapamycin (mTOR) and components of the mTOR pathway play pivotal roles in NET pathogenesis. Effects of the mTOR inhibitor everolimus have been well documented in preclinical and clinical studies, both as monotherapy and combination therapy. mTOR inhibition as backbone therapy within the NET treatment landscape is a focus of continuing research, which includes evaluation of the growing armamentarium of approved and investigational agents as potential combination partners. Data evaluating the clinical benefits of agents targeting mTOR and related pathways (alone and in combination) in the treatment of patients with NET continue to increase. Many of the findings to date are encouraging.

Robust pharmacodynamic assay results are valuable for informing go/no-go decisions about continued development of new anti-cancer agents and for identifying combinations of targeted agents, but often pharmacodynamic results are too incomplete or variable to fulfill this role. Our experience suggests that variable reagent and specimen quality are two major contributors to this problem. Minimizing all potential sources of variability in procedures for specimen collection, processing, and assay measurements is essential for meaningful comparison of pharmacodynamic biomarkers across sample time points. This is especially true in the evaluation of pre- and post-dose tumor biopsies, which suffer from high levels of tumor insufficiency due to variations in biopsy collection techniques and significant specimen heterogeneity within and across patients. Developing methods to assess heterogeneous biopsies is necessary in order to evaluate a majority of tumor biopsies collected for pharmacodynamic biomarker studies. Improved collection devices and standardization of methods are being sought in order to improve the tumor content and quality of tumor biopsies. In terms of reagent variability, we have found that stringent initial reagent qualification and quality control of R&D-grade reagents is critical to minimize lot-to-lot variability and prevent assay failures, especially for clinical pharmacodynamic questions, which often demand assay performance that meets or exceeds clinical diagnostic assay standards. Rigorous reagent specifications and use of appropriate assay quality control methodologies help to ensure consistency between assay runs, laboratories and trials to provide much needed pharmacodynamic insights into the activity of investigational agents.

INTRODUCTION: The past 10 years have seen dramatic advances in the understanding of the molecular pathogenesis of BCR-ABL negative myeloproliferative neoplasms (MPNs). With this knowledge has come novel, molecularly targeted therapies such as JAK inhibitors that may decrease symptoms and improve quality of life for patients with MPNs. Despite these advances, progression of the disease to an acute leukemic (blast) phase remains difficult to predict and even more difficult to treat, with high rates of disease relapse and mortality. AREAS COVERED: We performed a literature review of known risk factors for progression of MPNs towards blast phase and treatment options for transformed disease, including approved and investigational agents. Herein, we review the current literature and suggest strategies for improving outcomes in the future. EXPERT COMMENTARY: Further understanding of the biologic basis for transformation of MPNs from the chronic to blast phase is needed in order to predict, prevent, and treat these cases. Patients with MPNs in blast phase should be encouraged to participate in clinical trials whenever possible.

A novel coronavirus disease 2019 (COVID-19) infection caused by severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2) first emerged in December 2019 in Wuhan, China, has become a global pandemic. Currently, the management of COVID-19 infection is mainly supportive. Several clinical trials worldwide are evaluating several drugs approved for other indications, as well as multiple investigational agents for the treatment and prevention of COVID-19. Here, we give a brief overview of pharmacological agents and other therapies which are under investigation as treatment options or adjunctive agents for patients infected with COVID-19 and for chemoprophylaxis for the prevention of COVID-19 infection. At the time of writing this commentary, there is no peer-reviewed published evidence from randomized clinical trials of any pharmacological agents improving outcomes in COVID-19 patients. However, it was reported that remdesivir an investigational antiviral agent hastens clinical recovery, but a study is yet to be published in peer-reviewed medical journal.

The 2018 Accelerating Anticancer Agent Development (AAADV) Workshop assembled a panel of experts for an in-depth discussion session to present “Challenges with Novel Clinical Trial Designs.” This panel offered assessments of the challenges faced by industry, the FDA, investigators, institutional review boards, and patients. The panel focused on master protocols, which include umbrella trials, platform trials, and basket trials. Umbrella trials and platform trials share many commonalities, whereas basket trials are more distinct. Umbrella and platform trials are generally designed with multiple arms where patients of the same histology or other unifying characteristics are enrolled into different arms and multiple investigational agents are evaluated in a single protocol. In contrast, basket studies generally enroll patients with different tumor types based on the presence of a specific mutation or biomarker regardless of histology; these trials may include expansion cohorts. These novel designs offer the promise of expedited drug assessment and approval, but they also place new challenges on all the stakeholders involved in the drug development process. Only by identifying the challenges of these complex, innovative clinical trial designs and highlighting challenges from each perspective can we begin to address these challenges. The 2018 AAADV Workshop convened a panel of experts from relevant disciplines to highlight the challenges that are created by master protocols, and, where appropriate, offer strategies to address these challenges.

New Tools in the Ebola Arsenal In an ongoing outbreak of Ebola virus disease in the Democratic Republic of Congo, some patients have received investigational agents that are approved for compassionate use. Efforts are under way to develop a clinical trial that can provide generalizable results.