bluuebunny/crossref_metadata_2025 huggingface dataset:
FDA’s Oncology Center for Excellence Pilots Project Orbis: A framework for concurrent submission and review of oncology products among international partners.
Authors: Spillman Dianne , Arora Shaily , Venugopal Rajesh , Scott Bradley , Golding Sarah , Richardson Nicholas , Kasamon Yvette L. , Ethier Jean-Francois , Gurd Kate , Singh Harpreet , DeClaro R. Angelo , Beaver Julia A. , Kim Tamy , Goldberg Kirsten B. , Kluetz Paul Gustav , Theoret Marc Robert , Pazdur Richard
Published: May 2020

e14125

Background: Cancer therapeutics often receive FDA approval months to years before regulatory submission to other countries. [i] Registrational trials in oncology are increasingly international, with many patients enrolled outside of the United States. Harmonizing access to new global standards of treatment may facilitate optimal design and conduct of global clinical trials. Methods: In May 2019, the Oncology Center for Excellence launched Project Orbis in collaboration with the Australian Therapeutic Good Administration (TGA) and Health Canada. The aim of this initiative is to provide a framework for concurrent submission and review of oncology products among international partners to facilitate global access. Results: The first Project Orbis was a collaborative review of a supplemental application for lenvatinib and pembrolizumab for patients with advanced endometrial cancer. This review also deployed other OCE regulatory review tools including the Real-Time Oncology Review (RTOR) pilot program, which can streamline the submission of data prior to the completion and submission of the entire application, and its accompanying Assessment Aid, to facilitate discussions among regulatory agencies. Lenvatinib and pembrolizumab was approved on September 17, 2019, in conjunction with the TGA and Health Canada, three months prior to the FDA goal date. FDA, TGA, and Health Canada issued a second action under Project Orbis on November 21, 2019, with the approval of acalabrutinib for patients with chronic lymphocytic leukemia or small lymphocytic lymphoma. Several other products are under international review as part of this pilot program and a summary of timelines and outcomes will be described. Conclusions: Project Orbis is an innovative OCE initiative that leverages the Center’s longstanding communication and collaboration with international regulators. This pilot program facilitates concurrent submission and review of oncology products among global regulatory health agencies. Continued efforts under Project Orbis will build on the initial success to incorporate additional global partners including Swissmedic and Singapore’s Health Science Authority. [i] The Centre for Innovation in Regulatory Science (CIRS). R&D Briefing 70 New drug approvals in six major authorities 2009-2018: Focus on Facilitated Regulatory Pathways and Orphan Status
Responding to narrowing discrimination protections: Can hospital policies protect transgender and gender diverse patients with cancer?
Authors: Alpert Ash , Tarras Elizabeth Stieglitz , Sampson Amani , Strawderman Myla S. , Sutter Megan , Quinn Gwendolyn P.
Published: May 2020

e14126

Background: The U.S. Department of Health and Human Services recently proposed to eliminate federal protections against discrimination in healthcare on the basis of gender identity. This proposal seeks to alter the Patient Protection and Affordable Care Act Section 1557 Rule, which currently prohibits sex discrimination in any health program receiving federal financial assistance. The provisional change poses imminent threats to transgender and gender diverse (TGD) communities who face discrimination in healthcare, and in cancer care specifically. If current federal protections are eliminated, enacting local non-discrimination policies may safeguard TGD individuals’ rights to access safe equitable cancer care. To determine the need for local policy change, we sought to assess the current protections based on gender identity and expression for patients at National Cancer Institute (NCI)-Designated Cancer Centers. Methods: Publicly available hospital non-discrimination policies and Patients’ Bill of Rights were examined from the main affiliated hospitals of each of the 62 NCI-Designated Cancer Centers, excluding laboratories. The policies were classified as clearly including gender identity and expression or not. McNemar’s Test calculated differences between non-discrimination policies and Patient’ Bill of Rights. Results: Of 62 institutions, 30 (48.4%) clearly included gender identity and expression in their hospital non-discrimination policies, whereas 45 (72.6%) included gender identity and expression in their Patients’ Bill of Rights ( p= 0.014). Thirty-seven (59.7%) institutions included gender identity and expression in only one of the documents (Table). Conclusions: NCI-Designated Cancer Centers do not consistently include gender identity and expression in publicly available non-discrimination documents. The discrepancy between Patients’ Bill of Rights documents and hospital non-discrimination policies suggests a difference between what institutions outwardly convey to patients and what they operationalize in their legal documents. Paired outcomes from 62 independent NCI-Designated Cancer Centers. [Table: see text]
QT assessments in oncology drug development and related labels.
Authors: Zheng Nan , Zhao Hong , Li Mike , Adeojo Lilian Wanjiku , Uppoor Visesh , Garnett Christine
Published: May 2020

e14127

Background: A thorough QT (TQT) study, designed to evaluate whether a new drug excludes a small mean increase in the QTc interval (i.e., > 10 ms) which is considered to have low proarrhythmic risk, is often not feasible for oncology drugs. Alternative designs that assess the QTc changes in cancer patients are used to exclude large mean increases (i.e., > 20 ms) for drugs where the expected benefit outweighs the small proarrhythmic risk. A retrospective analysis was conducted to evaluate QT study designs and the consistency of QT labeling for oncology drugs. Methods: This analysis included FDA approved oncology drugs with QT studies reviewed by CDER’s Interdisciplinary Review Team as of 10/01/2019. Information collected included the clinical study design (i.e., TQT, alternative designs such as a sub-study in a Phase 2/3 trial), primary analysis (i.e., central tendency or concentration-QTc [CQT] analysis), QT findings at the therapeutic dose (i.e., the mean [M] and the upper bound of 90% confidence interval [UCI] of QTc changes), supportive data (i.e., nonclinical cardiac safety data, if applicable), conclusion of the QT assessment, and labeling statements in Section 12.2 (Pharmacodynamics) and Section 5 (Warnings & Precautions) of the product labels. Baseline QTc values in these alternative studies were compared to those in TQT studies across different therapeutic areas. Results: The analysis included 72 oncology drugs. The mean baseline QTc value is 411.2 ms in male patients (n = 6951) and 394.6 ms in male healthy volunteers (n = 22288), and 414.3 ms in female patients (n = 6412) and 408.8 ms in female healthy volunteers (n = 15682). Alternative study designs were used for 63 (87.5%) drugs while TQT study was only used for 9 (12.5%) drugs. CQT was used as the primary analysis for 11 (15.3%) drugs. Among the 72 product labels, 8 labels do not have QT information in Section 12.2 and 9 labels inconsistently describe the results of an alternative study. Warnings and Precautions for QT Prolongation in Section 5 of the labels were triggered by positive signals in the QT assessment or clinical trial safety monitoring experience. Conclusions: Cancer patients had higher QTc and less sex difference at baseline than healthy volunteers. QT labeling consistency in Section 12.2 could be improved by standardizing the description of study results based on QT study designs. Disclaimer: The contents reflect the views of the authors and should not be construed to represent the FDA's views or policies.
Achieving national cancer governance reform: Lessons from a successful academic, clinical, and community advocacy approach in New Zealand.
Authors: Jackson Christopher G. C. A. , Sarfati Diana
Published: May 2020

e14131

Background: Cancer survival in New Zealand (NZ) is high in global terms but gains in outcome are less than in comparable countries over recent time cohorts. Outcomes of indigenous Māori New Zealanders are significantly worse for most major cancers. This is potentially due to decentralisation of cancer provision and lack of emphasis on national governance. Methods: In 2017, academics, clinicians and patient advocates embarked on a planned and sustained programme of advocacy with the goal of establishing a national cancer plan, centralised cancer governance, and publicly reportable cancer outcomes and quality indicators by region and ethnicity. Elements central to success were partnerships with politicians and opposition parties, building credible media voices, establishing international academic collaborations, clear problem identification, positive evidence-based policy solutions, sustained and consistent yet varied media messaging, and strong relatable patient stories with direct citizen engagement. Results: As a direct result, in 2019 the Government established a National Cancer Agency, updated the national cancer plan for the first time in 16 years, moved to dissolve regional cancer networks, and appointed a national director of cancer control. New funding specifically for cancer investment was also announced and commitments to additional funding have been made. We review the strategies that were most successful, challenges encountered, and outcomes achieved. Conclusions: Advocacy and collaboration between patients, academics and clinicians remains a powerful stimulus for meaningful policy change. Our approach can be instructive for other countries where national cancer control and governmental leadership are faltering.
ACT for prevention and prophylaxis of cancer-associated thrombosis (CAT).
Authors: Tsoukalas Nikolaos , Christopoulou Athina , Papandreou Christos N , Kapodistrias Nikolaos , Koumarianou Anna , Peroukidis Stavros , Kalofonos Haralabos , Samelis Georgios , Andreadis Charalampos , Ardavanis Alexandros , Samantas Epaminontas , Bokas Alexandros , Ligdas Athanasios , Athanasiadis Ilias , Barbounis Vasileios , Kentepozidis Nikolaos K. , Mavroudis Dimitrios , Athanasiadis Athanasios , Papakotoulas Pavlos , Boukovinas Ioannis
Published: May 2020

e14135

Background: CAT is the 2nd leading cause of death in oncology patients and there is need for thrombosis management across the natural history of cancer because of its dynamic nature. Anticoagulant therapy is the cornerstone of prevention and treatment, since thrombosis interferes with cancer treatment, increases health care resource utilization, imposes emotional and economic burden. Methods: A prospective observational study conducted by HeSMO across Greece, aiming to record the clinical practice of CAT prophylaxis in patients with solid tumors. Ambulatory, high risk for thrombosis, active cancer patients who received thromboprophylaxis are enrolled after signing informed consent. Results: Preliminary results are collected from 17 oncology departments. From the 272 enrolled patients, 176 (64.7%) have completed second visit (3-4 cycles of anticancer treatment). Primary cancers included: lung 31.3%, pancreas 26.1%, colorectal 13.6%, gynecological cancers 10.2%, stomach 7.8%, bladder 6.3%, and others.75.6% of the patients had metastatic disease. 1/3 of the patients were smokers or ex-smokers, and 33% underwent surgery. Most of patients (65.9%) were at 1st line treatment and 17.6% at 2nd line. The vast majority (90.3%) were treated with High-Risk for Thrombosis Chemotherapy Agents (HRTCAs) such as cisplatin etc. Regarding Khorana score, 65.1% had ≥2. In particular, 86.7% of patients with Khorana score ≤1 received HRTCAs while 95.4% of patients with score = 2.All patients received thromboprophylaxis, specifically: 93.0% tinzaparin, 5.2% fondaparinux and 1.8% other (enoxaparin, bemiparin) with average duration 5.3±3.1 months. 67.1% of the patients received higher than standard prophylactic doses. 3 patients (1.7%) experienced thrombotic events (2 DVT and 1 PE). These 3 patients had metastases and were treated with HRTCAs. Five grade 1 bleeding events were reported (2.8%). Conclusions: Thromboprophylaxis of CAT is both safe and effective. Oncologists are alerted about CAT negative influences in cancer patients’ prognosis. Apart from Khorana score, factors such as metastases, use of HRTCAs along with drug-drug interactions, increase the LMWHs usage often in higher than prophylactic doses in CAT management. Clinical trial information: NCT03909399.
To scan or not to scan: An evaluation of preoperative MRI use in primary breast cancer assessments.
Authors: McKenzie Tesia , Matinho Davina , Scott Olivia , Khan Arbaz , Lachica Mila , Topilow Arthur A. , Johnson Miller Denise , Secic Michelle
Published: May 2020

e14146

Background: Breast cancer (BC) is the most common invasive cancer in adult females.The role of preoperative MRI in assessing the extent of primary breast cancer remains controversial. This study’s objective is to determine if MRIs performed after the diagnosis of invasive/non-invasive-breast cancer will identify additional breast cancers. We hypothesize that preoperative MRIs will result in the discovery of additional significant lesions, leading to changes in surgical treatment. Methods: A retrospective study of 389 BC patient charts were reviewed, dated from January 2000- July 2019. Files were collected from an office in the Breast Cancer Surgery Department. Information on each patient’s imaging studies, treatment, demographics, surgery, and pathology were collected and stored in anonline cloud system. Summary statistics, including proportions, percentages, and difference of proportion hypothesis tests were utilized to interpret the data. All statistical tests were conducted at a 95% confidence interval. Results: We reviewed the charts of 335 patients that met eligibility criteria. In 221 newly diagnosed cancers, a preoperative MRI was taken before treatment. 127 cancers (57.5%)showed additional finding.In BC patients with additional preoperative MRI findings, we observed 61.4%true positive and 38.6%false positive results. These values are comparable to prior studies.We determined that the treatment plan was altered in 17.6%of all patients who received an MRI and in 30.7%of patients with a true positive MRI finding, which is also consistent with previous literature.A majority of the treatment changes were from Lumpectomy to Mastectomy. Conclusions: Literature on MRI use in BC diagnosis exists; our study differs by focusing on newly diagnosed breast cancers.We discovered 35.3% of preoperative MRIs identified a true additional finding in known breast cancer. In addition, our true positive rate (61.4%) and false positive rate (22.2%) of MRI findings is comparable to those of previous studies. Plans were changed in 30.7% of additional findings supporting the idea that preoperative MRI studies are useful when organizing surgical treatment. Further studies to demonstrate the impact on local recurrence rates and overall survival, may clarify the true role of pre-operative MRI in these cases.
Safe handling system construction for hazardous drugs (HDs) through the HD exposure surveillance by National Hospital Organization Network in Japan.
Authors: Aogi Kenjiro , Watanabe Kenichi , Watanabe Takanori , Matsui Akira , Sato Yasuyuki , Yasojima Hiroyuki , Yamashita Yoshinori , Ootsuka Shinya , Tokunaga Eriko , Anami Setsuko ,   NHO Network Study Group for Constructing the Safe Handling System of Hazardous Drugs in Japan
Published: May 2020

e14147

Background: In Japan, much labor has been devoted to handle occupational exposure to hazardous drugs (HDs) after the publication of a guideline for preventing HD exposure on cancer treatments in 2015. However, the safe HD handling systems have not yet constructed in Japanese hospitals. To find out the current HD exposure and construct the safe HD handling system, a multi-institutional surveillance of HD exposure in the National Hospital Organization (NHO) cancer hospitals was commenced from Feb 2016 to Mar 2018. Methods: Thirty-two NHO institutes joined in this survey. HD surveys were performed 3 times in each institute, evaluating cyclophosphamide and fluorouracil exposures using wipe and sampling sheet methods at 18 places in outpatient chemotherapy and pharmacology units. To share information and discuss about HD exposure handling procedures, the study group meeting was held several times. Furthermore, HD handling system in each hospital was evaluated using handling system scoring established by Yoshida in Osaka Institute of Public Health. As an additional study, factors affecting commitment wills of staffs were also evaluated during the safe HD handling system construction using a multiple regression model. Results: As HD control systems constructed, HD exposure in each hospital was improved gradually with construction of the handling system. Staffs’ commitment to their institutes was shown as the result of safety awareness improvement induced by the HD safe handling system construction (standardization coefficient β: 0.346). Conclusions: HD exposures were improved in NHO cancer hospitals through the HD exposure evaluation with constructions of the safe HD handling system.
The incidence of treatment related acute kidney injury in cancer patients: A retrospective analysis.
Authors: Baralo Bohdan , Hossain Samia , Hanif Muhammad , Khokhar Suhail , Mulla Sana , Keshava Vinay E. , Krupadev Archen , Gudipally Sindusha , Modi Simple , Thirumaran Rajesh
Published: May 2020

e14150

Background: Development of the Acute kidney injury (AKI) in the patients receiving chemotherapy and immunotherapy is a factor associated with higher admission to the hospital, prolonged hospitalization, increased morbidity and mortality, dose reduction, moving to less effective regimens, inability to enroll in clinical trials. Methods: A retrospective cohort of the 95 patients, who received chemo immunotherapy in the infusion center of Mercy Fitzgerald Hospital in 2018-2020 were analysed. The pool of the patients had multiple oncological pathologies and were on different chemo immunotherapeutic regimens. All creatinine levels before starting chemotherapy, before and after each cycle were assessed. We used a Kidney Disease: Improving Global Outcomes criteria to define AKI (at least 1.5 increase in creatinine within 7 days of cycle or 0.3 creatinine increase in 48 hours) and grades of AKI. We considered AKI related to chemotherapy, if it developed in specified timeframe after chemotherapy defined above. The cases when patient did not meet criteria for AKI, but had a patterns suggestive of it (no repeat test within 7 days, but repeat test within 3 weeks, with increase in creatinine > 37.5%) were defined as potentially missed AKI. Results: 12 patients developed chemoimmunotherapy related AKI (12.63%). 1 patient had 3 episodes of the AKI related to chemotherapy. 4 patients received platinum-based chemotherapy. On average every patient received 12cycles of chemotherapy. After the first two cycles of chemotherapy AKI developed in 7 Patients (58.33%). 10patients had AKI after 7 cycles (83.33%). It worth mentioning that only 42% of the chemotherapeutic cycles had follow-up creatinine within 7 days. 7 patients (7.37%) had fallen under a potentially missed AKI criteria. 2 more patients were diagnosed with AKI that was not related to the chemotherapy. Conclusions: In our study there was a significant incidence of AKI in the patients receiving chemoimmunotherapy. Current guidelines do not advocate close monitoring(weekly) of renal function in patients receiving chemoimmunotherapy unless the patient receives an chemotherapeutic agent known to cause nephrotoxicity. Repeat creatinine within 7 days after chemotherapy may be necessary to allow early detection of AKI, that can potentially to improved outcomes. Large prospective studies may be necessary to confirm our findings that very close monitoring of renal function can improve detection of the AKI and outcomes due to possibility of early intervention.
Upfront or delayed radiation with next generation tyrosine kinase inhibitor therapy in driver mutation positive NACLC brain metastasis.
Authors: Yang Mike , Palmer Joshua David , Mo Xiaokui , Carbone David Paul , Welliver Meng XU
Published: May 2020

e14503

Background: NSCLC with driver mutations may be managed with SRS, WBRT, and TKIs. Prior studies have demonstrated a worse survival with a delay in brain radiotherapy. We sought to determine if there is a difference in CNS PFS, OS, and cumulative incidence of intracranial brain failure (CI IBF) with next generation TKIs. Methods: A total of 69 patients with driver mutation NSCLC patients with brain metastasis were included. CNS PFS was measured from brain metastasis diagnosis. CI ICF was measured as any new or progressive disease on MRI Brain imaging. Results: The 1 year OS was 65.7% vs 60% (p = 0.9) for the RT and TKI arms. The CNS PFS was 82% vs 72% and CI ICF 13.5% vs 22% in the RT vs TKI arms, respectively. Conclusions: There was no difference in overall survival in our cohort when giving TKI therapy upfront or delayed with radiation. There was a clinically meaningful improvement in CNS PFS at 1 year but was not significant. There findings warrant further study.
Assessment of patient-reported outcomes in patients treated with radiation therapy to brain malignant tumors.
Authors: Yang Li , Xu Zhiyuan , Zhang Hang , Kong Feng-Ming Spring
Published: May 2020

e14521

Background: Patient reported outcome is limited in patients with radiation therapy (RT) to brain tumors. The purpose of this study is to exam Patient Reported Outcome Measures (PROM) at baseline and end for RT in patients receiving RT to brain malignant tumors. Methods: This is a prospective study of quality of life. Patients ≥ 18-year old requiring RT to brain primary or metastatic malignant tumors were eligible. The PROM was assessed by self-administrated questionnaire PROMIS-29 Profile v2.1 and was completed prior to and at end of RT. Raw scores directly got from the PROMIS questionnaire were translated to T-scores according to the recommendation by the PROMIS INSTRUMENTS. A T-score of 50 is the average for general population and a higher PROMIS T-score represents more of the concept being measured. Results: Between July 2019 and December 2019, a total of 23 patients enrolled and completed PROMIS questionnaire and 19 completed questionnaire at end of RT. The median age was 55 (range 21-67), fifteen were men. The median doses of local brain RT and WBRT were 60Gy (range 40.05-60Gy) and 25Gy (range 20-36Gy), respectively. For the seven domain teams, physical function, anxiety, depression, fatigue, sleep disturbance, ability to participate in social roles and activities and pain interference, the number of patients with each T-score greater than 50 was 8 (34.8%), 13 (56.5%), 8 (34.8%), 6 (26.1%), 6 (26.1%), 13 (56.5%) and 9 (39.1%) at baseline and 7 (36.8%), 9 (47.4%), 7 (36.8%), 6 (31.6%), 6 (31.6%), 9 (47.4%) and 5 (26.3%) at end of RT, respectively. Physical function and sleep disturbance at end of RT was correlated with the corresponding value at baseline (Fisher’s exact test P = 0.045 and 0.017, respectively). None of the 7 domain teams’ T-scores changed significantly at end of RT. Pain intensity evaluated by NRS decreased significantly (mean 0.89 vs 1.53, P = 0.048). There is no difference in the mean T-score for all the 7 domain teams and NRS pain intensity between the local or whole brain RT patients at baseline and end of RT. Conclusions: This preliminary study demonstrated that brain RT did not alter PROM significantly in patients with primary or metastatic malignant brain tumors but decreased pain intensity in those patients.
Venous thromboembolic events in glioblastoma patients: Common complication but not a major reason for death.
Authors: Gramatzki Dorothee , Eisele Amanda , Seystahl Katharina , Le Rhun Emilie , Rushing Elisabeth Jane , Roth Patrick , Stahel Rolf A. , Weller Michael
Published: May 2020

e14530

Background: Venous thromboembolic events (VTE) are a major complication in cancer patients. Anticoagulant use is the appropriate treatment for acute VTE in cancer patients, although associated with increased risk for bleeding, especially in brain tumor patients. In glioblastoma patients it remains unclear whether occurrence of VTE is associated with survival and to what extent thromboprophylaxis is necessary and efficient. Methods: Frequency, risk factors, and treatment of VTE as well as its complications were assessed in an epidemiological glioblastoma cohort in the Canton of Zurich, Switzerland, in the years 2005 to 2014. Association of clinical data with survival were retrospectively analyzed using the log rank test. Results: Four-hundred-nineteen patients diagnosed with isocitrate dehydrogenase wildtype glioblastoma were identified in the 10-year time-frame. Median overall survival (OS) was 12.4 months (95% CI 11.4-13.4) with a median follow up of 64.5 months (95% CI 46.6-82.4).VTE were seen in 65 patients (15.7%; 5 patients with missing information on VTE).Median time from diagnosis of glioblastoma to occurrence of VTE was 2.0 months (95% CI 0.8-3.1). A history of VTE was found in 6 patients (9.2%). Thirty-nine patients were on steroids (62.5%; 1 patient with missing data) at time of diagnosis of VTE, and 35 patients (56%; 3 patients with missing data) had a Karnofsky Performance Score of less than 70%. At the time patients were diagnosed with VTE the majority of patients (93.8%) were treated with therapeutic anticoagulation. Complications resulting in stop of anticoagulation occurred in 11 patients (18.0%; 4 patients had no anticoagulation) mainly because of intracranial bleedings (9 patients). OS was not different (p = 0.355) between patients who were diagnosed with VTE and those who were not. Tumor progression (283 patients, 77.3%) was the major reason for death (366 patients with confirmed death) in this patient cohort, only 3 patients (0.8%) died because of confirmed VTE and another 5 patients (1.4%) had an unexpected sudden death. Conclusions: Although VTE was identified in 65 patients (16%) diagnosed with glioblastoma, VTE was no major reason for death. On a population-based level these data do not support the implementation of primary thromboprophylaxis in this cohort of patients.
Differential expression of KDM1A and SMAD7 genes in gliomas depending on the tumor grade.
Authors: Pushkin Anton A. , Alliluev Ilya A. , Rostorguev Eduard E. , Kavitskiy Sergey E. , Kuznetsova Natalya S. , Timoshkina Natalya N. , Kit Oleg I.
Published: May 2020

e14549

Background: Gliomas are the most common type of primary brain tumors characterized by pronounced proliferation and aggressive infiltration. The purpose of the study was to analyze the expression of genes participating in the EGFR, TGF-B, HH/GLI, NOTCH and HIF1-alpha signaling pathways, transcription factors HBP1, MSI1/2 and demethylating agents in samples of various glioma types. Methods: The study included paired samples (tumor and physiologically unchanged neural tissue) obtained from 75 patients with histologically verified glial tumors of various grades (G2 - 21, G3 - 11, G4 - 43 patients). Relative expression of 15 genetic loci (EGFR, SMAD4, SMAD7, SMO, NOTCH1, NOTCH2, HBP1, HIF1A, EGLN1, EGLIN3, KDM1B, KDM1A, MSI1, MSI2, TET1) was measured by RT-qPCR. The PSMC, TBP and RPLO genes were used as the reference sequences. The 2−ΔΔ Сt method was used to analyze the qPCR data. Statisical processing of the results was performed with the Statistica 10 program (StatSoft Inc., USA). Results: G2 gliomas showed a significant change in the relative expression of the KDM1A gene (p = 0.00572); G3 - a significant change in the relative expression of the HIF1A gene (p = 0.012726); G4 - significant changes in the relative expression of the EGFR (p = 0.021324), SMAD4 (p = 0.016534), SMAD7 (p = 0.000003), HBP1 (p = 0.003264), HIF1A (p = 0.007612), EGLN1 (p = 0.001623), EGLN3 (p = 0.004231) genes. Registered changes in the expression of the KDM1A and SMAD7 genes in the studied sample significantly differentiated the G2 and G4 glial tumors (p = 0.013 and p = 0.049, respectively). G2 tumors were characterized with increased expression of the KDM1A gene and decreased by more than 1.1 times in 95% of patients. 88% of patients with G4 tumors demonstrated no changes or a decrease in the KDM1A gene expression and decreased SMAD7 expression by more than 1.5 times. Conclusions: The established significant change in the expression of the KDM1A and SMAD7 genes depending on the tumor grade can be used for the differential diagnosis of gliomas.
Phase I trial characterizing the pharmacokinetic profile and NK and CD8+ t cell expansion with n-803, a chimeric IL-15 superagonist, in healthy volunteers.
Authors: Wrangle John M. , Rubinstein Mark P , Mart Caroline , Azar Joseph H. , Williams Cameron , Swiderska-Syn Marzena , Macpherson Linda , Beall Jonathan , Hill Elizabeth Goodwin , Lee John H. , Rock Amy , Soon-Shiong Patrick
Published: May 2020

e15008

Background: The oncotherapeutic promise of IL-15, a potent immune stimulant, is limited by short serum half-life. The fusion protein N-803 is an IL-15 superagonist complex that has > 20-fold longer half-life in vivo vs IL-15. This study characterized the pharmacokinetic (PK) profile, biological activity, and safety of N-803 after subcutaneous administration to healthy human volunteers. Methods: Volunteers were randomized 1:1 to receive 1 mg/mL or 2 mg/mL N-803. Each subject received 2 doses of N-803: 10 µg/kg followed 24 days later by 20 µg/kg. After each dose, PK and safety measures were assayed for 9 successive days. Primary endpoint was the PK profile of N-803; secondary was safety; and exploratory endpoints were cytokine levels, immune cell characterization, and immunogenicity. Results: N-803 resulted in no grade ≥3 or serious adverse events (AEs). Mild injection site reactions, chills, and pyrexia were the most common AEs. Serum N-803 concentrations peaked 10.3-15.4 hours after administration and declined with a half-life of 20.0-20.7 hours. Peak N-803 serum concentrations were dose-dependent, with a 1.5-fold increase in Cmax after administration of 20 µg/kg vs 10 µg/kg. In the peripheral blood, N-803 induced a transient decline, followed by a significant increase (3-fold) in NK cell number that persisted for ≥24 days. N-803 also caused a significant proliferation of NK (22-fold increase in Ki-67+ cells), CD8+ (27-fold) and CD4+ T (11-fold) cells; however, increased cell number occurred only in NK cells. N-803 administration also increased serum levels of interferon gamma, IL-10, and IL-6. One of 14 evaluable subjects had measureable anti-N-803 antibodies at the end-of-study visit. Conclusions: N-803 results in prolonged elevation of drug serum concentrations, contrasting with rapid clearance of recombinant human IL-15 (ie, half-life of ~20 vs < 1 hour). N-803 administration was well-tolerated in healthy volunteers, without evidence of adverse systemic inflammatory responses, and resulted in proliferation of NK cells and CD8+ T cells, as well as sustained increases in NK cell number. Findings in this study are consistent with published results from N-803 administration in treating liquid tumors and lung cancer. Our results demonstrate N-803 administration potentiates the proliferation and activity of lymphocytes with antitumor and antivirus properties, and suggest this investigational product holds promise in treatment of cancer as well as infectious disease such as HIV. Clinical trial information: NCT03381586 .
Phase I study of SNK01 (autologous non-genetically modified natural killer cells with enhanced cytotoxicity) in refractory metastatic solid tumors.
Authors: Chawla Sant P. , Kim Katherine M , Chua Victoria S. , Jafari Omid , Song Paul Y.
Published: May 2020

e15024

Background: Natural Killer (NK) cells possess the innate ability to detect transformed cancer cells and kill them, thus playing a key role in cancer immunosurveillance and antitumor immunity. In general, prior NK cell therapies have not shown efficacy in solid tumors and the expansion of NK cells in cancer patients to clinically therapeutic doses is quite challenging, making allogenic preferable to autologous treatment. SNK01 is a first-in-kind, autologous non-genetically modified NK cell therapy with enhanced cytotoxicity which can be consistently produced even from heavily pretreated cancer patients, and has been shown to have efficacy against numerous solid tumor types in preclinical studies. Methods: In this single-arm Phase I study (NCT03941262) to investigate the safety and efficacy of SNK01, patients with refractory metastatic solid tumors were treated in a 3 + 3 dose escalation study with five weekly infusions of SNK01 at 1, 2, or 4 x 109 cells per infusion. Primary endpoint is safety and quality of life (QoL), and secondary endpoint is objective response rate (ORR). Results: Seven of nine planned patients have been enrolled up to date and five have completed treatment. All patients have rapidly progressive metastatic disease and have received an average of five lines of prior therapy. Tumor types include one non-small lung cancer, one colorectal cancer, and five sarcomas. Median age is 52 (32-62). All patients have had successful expansion and cytotoxic enhancement of their NK cells. Three patients have completed 1 x 109 SNK01 and two patients have completed 2 x 109 SNK01. There have been no adverse events according to NCI-CTCAE v 5.0 or any cytokine release syndrome, and all patients have reported an overall improvement in QoL. At week 9, three of three patients at the 1 x 109 dose and one of two at the 2 x 109 achieved a best overall response of stable disease as per RECIST 1.1. Conclusions: Expanding and increasing the cytotoxicity of NK cells in our heavily pretreated patients has been consistently reliable. SNK01 monotherapy has been very safe and well tolerated in patients with rapidly progressive solid tumors. MTD has not been reached and dose escalation is ongoing. Evaluation of anti-tumor activity is ongoing, but at a minimum, SNK01 appears to slow and possibly halt progression in very aggressive disease and improve quality of life while improving the overall quality of life. The remaining two planned patients are currently being enrolled and a full update will be presented. Clinical trial information: NCT03941262 .
Results from Melanoma Antigen Redirected Vaccine Stimulated Autologous Lymphocytes (MARVSmALo): A pilot study.
Authors: Fulbright Joy M. , Doolittle Gary C. , Rooney Cliona M. , Ganguly Siddhartha , Abhyankar Sunil H. , Gilbert Margaret , Dakhova Olga , Al-Sabbagh Mina , Zhang Huimin , Myers G. Douglas , Lapteva Natalia
Published: May 2020

e15026

Background: Despite improvements in treatment with targeted agents and immunotherapeutics metastatic melanoma still has a guarded prognosis. Many melanoma cells upregulate the disialoganglioside GD2. Early GD2 chimeric antigen receptor (CAR) T-cell studies in neuroblastoma demonstrated no toxicity but limited ability to expand in vivo. Strategies to expand these GD2.CAR T cells might improve efficacy while retaining safety. This pilot study aimed to evaluate the safety and efficacy of first generation 14g2a.zeta chimeric antigen receptor ( GD2.CAR ) transduced, activated T cells enriched for vaccine specific cytotoxic T-Lymphocytes (tvs-CTL). Methods: Patients with metastatic melanoma in which standard therapy had failed were eligible if they had recovered from effects of prior therapy, did not have rapidly progressive disease, were free of melanoma involving the CNS and did not have a contraindication to receiving Hepatitis B, Polio or DTAP vaccine. Patients received each of these vaccines prior to cell harvest, 4 days before and 28 days after autologous T cell infusion. Patient 1 was treated with 2 x 108 cell dose and patients 2 and 3 were treated with 4x108 cell dose. We used QPCR to measure transgene copy number in patients before and after infusion. Interferon-gamma enzyme linked immunospot (ELISPOT) assay was used to measure the frequencies of tetanus, pertussis, diphtheria, poliovirus and tumor antigens-specific T cells in peripheral blood. Results: GD2.CAR-tvs-CTL were manufactured and infused in 3 patients. Overall the infusions were safe. Seven low grade adverse events possibly related to study participation were reported. The first 2 patients did not demonstrate robust in vivo expansion of GD2.CAR-tvs-CTLs by QPCR and had rapid disease progression. In patient 3 a significant expansion of GD2.CAR-tvs-CTLs, i.e. 18,250 copies/ug genomic DNA was observed on day 7 and cells persisted at 159 copies/ug DNA for up to 12 months (latest measured time point). High pertussis-specific responses were also observed by INF-gamma ELISPOT in this patient starting from day 14 after the vaccination through month 12. Conclusions: We have demonstrated that GD2.CAR T cells expanded and persisted in melanoma patient for up to 12 months. The use of vaccination before blood procurement for T cell manufacture and boosting virus-specific T cell after CAR T cell infusion is a safe strategy and may have helped induced higher transgene levels in one of three patients. Clinical trial information: NCT02482532 .
Device for the enumeration and continuous removal of circulating tumor cells in improving overall survival of epithelial cancer patients.
Authors: Khandare Jayant , Arora Smriti , Singh Balram , D'Souza Alain , Singh Nitin , Kale Narendra , Bhide Shubham , Ashturkar Amrut , Vasudevan Aravindan , Aland Gourishankar
Published: May 2020

e15043

Background: The presence of circulating tumor cells (CTC) in the vascular system is a tell-tale signature of metastasis in epithelial origin cancers including lung, breast, colorectal and head and neck cancers. Noteworthy, about 90% of cancer deaths are due to the progression of metastasis. Yet, cancer therapy is focussed on inhibiting tumour growth and there is a paucity of options that target metastasis. We demonstrate the POP ‘device’ that removes circulating tumour cells (CTC) from a patient’s blood to reduce the metastatic progression and improve overall survival. Methods: We designed, multi-component glass beads enriched antibody EpCAM conjugate substrates as POP blood fluidic device. We characterized the substrate and accounted for the biocompatibility using whole blood of healthy volunteers. We evaluated, the acute toxicity of substrates using rat (Wistar Albino) whole blood (CPCSEA registration number: 941/PO/Re/S/06/CPCSEA; 31/07/2019) and further studied major histopathological tissues for any toxicity. Finally, we evaluated 06 cancer patients whole blood (1.5 mL) for capturing and for the elimination of CTCs. The captured cells were immuno-stained, and the optimal fluorescence acquisition intensity was critically quantified in accounting CK18 protein over-expression. Results: The multi-component antibody EpCAM based substrate exhibited efficient CTC capture ability with a mean capture efficiency ranging from 40% to 100 % when compared to the OncoDiscover CTC test approved by CDSCO/ drug controller general of India (DCGI). Furthermore, the substrate indicated high biocompatibility primarily exhibited by the absence of haemolysis on whole human blood. Additionally, the preliminary animal experiments in rats showed a 100% survival rate and negligible toxicity to major organs. Conclusions: Removal of circulating tumor cells as a therapeutics is highly implicated in improving the overall survival of epithelial cancer patients.
DNA damage and repair gene panel as a biomarker of immune checkpoint inhibitor response.
Authors: Chen Ming Huang , Pan Yi-Ru , Wu Chiao-En , Yeh Yi Chen , Hung Yi-Ping , Chao Yee , Wang Yu-Chao , Lin Chien-Hsing , Hsieh Jason Chia-Hsun , Yeh Chun-Nan
Published: May 2020

e15052

Background: Immune checkpoint inhibitors (ICIs) have become the standard of care in various cancers, although predictive biomarkers for efficacy still remain largely unknown. Methods: This study aims to develop a novel gene panel by selecting DNA damage and repair (DDR) genes from the Catalogue of Somatic Mutations in Cancer (COSMIC) database and perform validation using publicly available cohorts. Association between the DDR gene panel and tumor mutation burden or microsatellite status were analyzed from The Cancer Genome Atlas (TCGA) database. To further improve the clinical accessibility of the DDR gene panel, we analyzed the feasibility of its predictive value using cell free DNA in from 64 patients receiving ICIs. Results: The 193 mutated DDR genes in various cancers were chosen from the COSMIC databank, and the DDR genes found to individually predict a response rate > 50% in publicly melanoma cohort (Van Allen, et al) were selected. Eighteen DDR genes were selected as the DDR gene panel. The prevalence of the DDR gene mutations and predicted response rate of ICIs were validated in other three publicly available cohorts (Hugo et al, Synder et al, and Rizvi et al.). Tumor mutational burden and high microsatellite instability were positively associated with mutations of the 18 DDR genes for most cancers. Further validation was performed using cell-free DNA from cancer patients receiving ICIs. This DDR gene panel was detected in approximately 30% of various cancers, achieving a predicted response rate of approximately 60% in patients receiving ICIs. Conclusions: Our developed DDR gene panel can serve as a novel and reliable biomarker that can provide critical information for predicting the response to ICIs in cancer patients and guide the appropriate administration of ICIs in clinical practice.
Treatment-related adverse events of combination immune checkpoint inhibitors: Systematic review and meta-analysis.
Authors: Park Robin , Lopes da Silva Laércio , Riano Ivy , Cristancho Cagney , Saeed Anwaar
Published: May 2020

e15060

Background: Despite increasing clinical experience with immune checkpoint inhibitors and the recent publication of clinical practice guidelines for managing treatment-related adverse events, precise and nuanced checkpoint inhibitor data in the setting of combination therapy is lacking. Herein we have conducted a systematic review and meta-analysis of treatment-related adverse event data from clinical trials evaluating combination immune checkpoint inhibitors. Methods: Studies published in PubMed, Embase, and Cochrane Database from conception to September 28, 2019 were included in the meta-analysis. Studies were eligible for inclusion if combination immune checkpoint inhibitor therapy was evaluated in advanced unresectable cancer and treatment-related adverse event data were available. For comparison of severity of adverse events in combination versus monotherapy, only the studies containing monotherapy arms as a control population were included, while all were included for calculation of pooled incidence of selected adverse events. Pooled risk ratio (RR) was used for the comparison of combination versus monotherapy and the logit transformed proportion for calculation of pooled incidence. Between-study risk of bias was evaluated using the Begg's funnel plot and Egger's regression test. Subgroup analysis was conducted by combination regimen, cancer type, and dosing regimen. Results: A total of 18 studies comprising 2767 patients across 10 cancer types were included in the final analysis. Combination ICI was associated with a slightly higher risk of all-grade adverse events (RR 1.07 [95% CI 1.03-1.11]) and markedly greater risk of grade 3 or higher adverse events (RR 2.21 [95% CI 1.57-3.10]) compared to monotherapy ICI. Subgroup analyses showed significant differences in risk of grade 3 or higher adverse events between treatment type (PD-1+CTLA-4 and PD-L1+CTLA-4), among cancer types, and among dosing regimens (N1I3, N3I1 and D20T1). Incidence of all-grade adverse events was 0.905 [95% CI 0.842-0.945] and grade 3 or higher events/all-grade adverse events was 0.396 [95% CI 0.315-0.483]. The most common all-grade TRAEs were diarrhea/colitis, fatigue/asthenia, nausea/vomiting, rash, and pruritis. Conclusions: Combination ICI therapy has a significantly different treatment-related adverse event profile compared to monotherapy.
Assessing long-term survival improvement of immune-checkpoint inhibitors (ICI) anticancer agents approved by the Food and Drug Administration: A meta-analysis of randomized controlled trials (RCTs).
Authors: Everest Louis , Chan Kelvin K. , Saluja Ronak , Shah Monica , Nguyen Vivian
Published: May 2020

e15062

Background: Conventional anticancer drugs have been developed to improve overall survival (OS) and/or progression-free survival (PFS) in the palliative intent setting. However, long-term survival is often limited by acquired biologic resistance. In contrast to conventional anticancer drugs, ICIs putatively preserve long-term survival in a small subset of patients. However, in the absence of a gold-standard definition, long-term survival improvement has not been adequately quantified. Long-term survival rate difference has been proposed as a method of quantifying long-term survival. However, there a paucity of literature demonstrating statistical improvements in survival rate. Therefore, the objective of the study was to quantify the improvement in long-term survival rate in OS and PFS improvement in ICIs compared with non-ICIs. Methods: The FDA Hematology/Oncology Approvals & Safety Notification web page was searched for RCTs cited in oncology drug approvals between 01-2011 and 06-2019. The most recent OS and PFS updates were used when available. OS and PFS curves were digitized to reconstruct pseudo individual patient data as per established methods. Survival rate improvement at 1, 2 and 3 years were calculated as differences between the experimental arm and control arm. Survival rate improvements across RCTs at 1, 2 and 3 years were pooled using a random-effects model and the results were compared between ICI and non-ICIs. Subgroup analyses were conducted for melanoma and non-small cell lung cancer. Results: We identified 130 RCTs (22 ICIs, 108 non-ICIs) for analysis. The absolute OS rate improvement was 9.5% in ICIs and 4.9% in non-ICIs at 1-year (difference = 4.6%, p < 0.001), 10.3% in ICIs and 4.9% in non-ICIs at 2-years (difference = 5.3%, p < 0.001), and 10.2% in ICIs and 5.1% in non-ICIs at 3-years (difference = 4.6% p 0.006). The absolute PFS rate improvement was 10.3% in ICIs and 17.7% in non-ICIs at 1-year (difference = -7.3% p < 0.001), and 8.9% in ICIs and 15.5% in non-ICIs at 2-years (difference = -6.6% p < 0.001). Conclusions: Long-term OS survival rate improvements, while statistically significant were only modestly higher in ICIs compared to non-ICIs. PFS survival rate differences were statistically lower in ICIs compared to non-ICIs. While ICIs represent an important shift towards long-term survival, greater emphasis should be placed on rigorously evaluating long-term survival rate improvement and reporting of future novel therapies.