Investigator-initiated Protocols Research Articles

Abstract OT2-05-01: FLEX: 30K Full Transcriptome, Real-World Evidence Database for Early-Stage Breast Cancer, and Investigator-Initiated Protocols

Abstract FLEX: 30K Full Transcriptome, Real-World Evidence Database for Early-Stage Breast Cancer, and Investigator-Initiated Protocols BACKGROUND: Genomic signatures, such as the 70-gene MammaPrint, provide additional prognostic information for early-stage breast cancer (EBC), such as tumor metastatic potential, and expand the available information clinicians and patients require for shared treatment decision making beyond the standard clinicopathologic factors. EBC tumors are further stratified into clinically actionable subtypes by molecular assays such as the 80-gene molecular profiling assay BluePrint, improving pathological complete response rates (pCR) and outcomes as evidenced by a number of recent trials. The ongoing FLEX Study (NCT03053193) is designed to expand the genomic information available for EBC cases, and to increase the speed of data generation for rare and underserved research areas. To date, FLEX is the largest international multicenter real-world evidence (RWE) EBC registry, with more than 10,000 patients enrolled in fewer than five years since opening. FLEX pairs full genome data with more than 800 clinical data points collected over 10 years of follow up to provide the most comprehensive big data database available for early-stage breast cancer. The FLEX enrollment has a goal of a minimum of 30,000 patients within 10 years. METHODS: The FLEX study is a multicenter, prospective, observational trial for patients ≥18 years old with histologically proven stage I-III invasive breast cancer that is node negative or positive (up to three nodes) who receive MammaPrint, with or without BluePrint as standard of care management. Patients consent to the collection of clinically annotated full transcriptome data. Additionally, this study protocol allows physicians to investigate targeted populations or clinical trial investigator-initiated studies (IIS) upon approval by a peer-driven Scientific Review Committee. As patients enrolled in the FLEX study meet all eligibility criteria for inclusion no additional consent is required. The FLEX enrollment has already surpassed 1/3 of set target goal. As of April 2022, the trial has surpassed 10,000 patients enrolled at nearly 100 trial sites across the US and Europe, Middle East and Africa (EMEA). To date, there have been 36 publications in international scientific congresses with 39 FLEX IIS and in progress. With over 250 active and collaborating physicians leveraging the shared infrastructure, the IIS have enabled the ability to address disparities in treatment to underrepresented populations, rare subtypes, age, and patient centered specific topics. Current and future questions investigated via this platform will continue to strive to improve outcomes for early-stage breast cancer patients. Citation Format: Alejandra Perez, Hannah Linden, Nathalie Johnson, Sami Diab, Chirag Jani, Chelsea D. Gawryletz, Richard Fine, Laura Lawson, Megan Baker, Victoria Poillucci, Lisa E. Blumencranz, William Audeh. FLEX: 30K Full Transcriptome, Real-World Evidence Database for Early-Stage Breast Cancer, and Investigator-Initiated Protocols [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr OT2-05-01.

Abstract OT2-07-01: The FLEX real-world data platform explores new gene expression profiles and investigator-initiated protocols in early-stage breast cancer

Abstract Background: Genomic signatures provide prognostic information such as tumor metastatic potential, outperforming information gained from clinicopathologic factors alone, which has transformed personalized treatment of early breast cancer. Together, whole genome expression data can accurately stratify tumors into clinically actionable molecular subtypes. The FLEX study (NCT03053193) is a large, real-world dataset, combining whole genome expression with clinically annotated data, to accelerate research and discovery of subgroups in breast cancer. The goal of FLEX is to discover and develop novel genomic profiles that bring precision oncology to the clinic, and ultimately improve treatment and outcomes of patients with breast cancer. Study Design: The FLEX study is a multicenter, prospective observational trial of patients aged ≥ 18 years with stage I-III breast cancer who receive MammaPrint, with or without BluePrint. Patients consent to the acquisition of clinical data and clinically annotated full transcriptome tumor analysis. The FLEX study creates a unique infrastructure to develop and investigate hypotheses for targeted subset analyses and/or clinical trials. In doing so, the adaptive protocol allows submission of investigator-initiated sub-studies. Upon approval by a Scientific Review Committee, FLEX investigators can query the clinical and genomic data in FLEX to investigate hypotheses for targeted subset analysis. Patients enrolled in the original study who meet all eligibility criteria may be enrolled in sub-studies without additional consent. All necessary clinical data will be collected from patients, starting from diagnosis through 10-year follow-up. Sub-study research categories include: breast cancer and age, optimization of therapeutic strategies, breast cancer tumor types, biomarker identification and quality of care. The FLEX enrollment goal is a minimum of 30,000 patients within 10 years; since April 2017, more than 7,500 patients were enrolled at more than 90 sites. Participating sites include community hospitals and nine National Cancer Institute-designated comprehensive cancer centers to ensure inclusion of diverse populations, particularly patient populations that are underrepresented in traditional clinical trials. Most recently, the FLEX network was expanded globally with additional sites in Greece and Israel. To date, 38 investigator-initiated sub-studies have been approved, resulting in 23 published abstracts at national congresses. Trial contact information: NCT03053193, FLEX@agendia.com Citation Format: Cynthia X. Ma, Robert Maganini, Pat Whitworth, Jennifer A. Crozier, Joyce O'Shaughnessy, Sami Diab, Beth-Ann Lesnikoski, June Lee, Nina D'Abreo, Blanche H. Mavromatis, Pond Kelemen, Darina Pronin, Hiwot Abebe, Michelle L. Bolner, Christine Finn, Lisa Blumencranz, William Audeh, FLEX Investigators Group. The FLEX real-world data platform explores new gene expression profiles and investigator-initiated protocols in early-stage breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr OT2-07-01.

P112 - MammaPrint, BluePrint, and full-genome data linked with clinical data to evaluate new gene EXpression profiles (FLEX): a real-world dataset and investigator-initiated protocols in ESBC

P112 - MammaPrint, BluePrint, and full-genome data linked with clinical data to evaluate new gene EXpression profiles (FLEX): a real-world dataset and investigator-initiated protocols in ESBC

Abstract OT-12-01: The FLEX real-world data platform explores new gene expression profiles and investigator-initiated protocols in early stage breast cancer

Abstract Background: Genomic expression profiles have implications for the personalized treatment of breast cancer beyond clinical and pathological features by enabling the classification of breast cancers into molecular subtypes and providing prognostic information about the metastatic potential of tumors. However, full genome expression data should be combined with comprehensive clinical information to precisely stratify tumors into clinically actionable subgroups. The FLEX Registry aims to aggregate a large, real-world dataset, which will enable the discovery of novel genomic profiles to improve precision in the management of breast cancer, particularly in underrepresented patient subsets in traditional clinical trials. Trial Design: The FLEX Registry (NCT03053193) is a multi-center, prospective, observational trial for patients with stage I-III breast cancer whose primary tumor is analyzed by MammaPrint, with or without BluePrint.The primary objective of FLEX is to create a large scale, population-based registry that links comprehensive clinical data with full genome expression data to elucidate new prognostic and/or predictive gene associations in a real-world setting. The FLEX Registry employs a shared study infrastructure to develop and investigate hypotheses for targeted subset analyses and/or clinical trials based on full genome expression data. The adaptable protocol is designed to be amended with the inclusion of additional targeted sub-studies. Patients enrolled in the initial study are eligible for inclusion in sub-studies for which they meet all eligibility criteria and additional consent is not required. Data will be collected on patients from diagnosis through10 years of follow-up and any necessary additional clinical data will be collected as specified in the appendix protocols. The target enrollment of FLEX is a minimum of 10,000 patients; over 5,000 patients have enrolled sinceApril 2017 at more than 85 sites, including eight National Cancer Institute-designated comprehensive cancer centers. The FLEX collaborative platform allows participating investigators the opportunity to author their own sub-study protocols, as approved by the FLEX Review Committee. Sub-study research categories include: Age and Breast Cancer, Optimizing Therapy Strategies, Breast Cancer and MetabolicSyndrome, ctDNA and Liquid Biopsy, Genomics and Subtypes, Social and Ancestry, and Neoadjuvant Therapy and Surgery. To date, twenty-five investigator-initiated sub-studies have been approved.Trial contact information: NCT03053193FLEX@agendia.com Citation Format: Laura Lee, Sami Diab, Julie Barone, Jennifer A Crozier, Margret Chen, Rakshanda L Rahman, Robert Maganini, Douglas Marks, Amy M Truitt, Lisa Blumencranz, Erin Yoder, Sarah Untch, William Audeh, Bastiaan van der Baan, FLEX Investigators Group. The FLEX real-world data platform explores new gene expression profiles and investigator-initiated protocols in early stage breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr OT-12-01.

Ethical Considerations When Using a Mobile Eye Tracker in a Patient-Facing Area: Lessons from an Intensive Care Unit Observational Protocol.

This article describes the process of designing, approving, and conducting an investigator-initiated protocol to use an eye-tracking device in a health care setting. Participants wore the device, which resembles eyeglasses, in a front-facing manner in an intensive care unit for the study of personnel gaze patterns, producing a visual record of workflow. While the data of interest for our study was not specifically the health information protected by the privacy rule of the Health Insurance Portability and Accountability Act (HIPAA), a wide variety of such data was captured by the eye-tracking device, and the prospective consent of all people who might have been incidentally videotaped was not feasible. The protocol therefore required attention to unique ethical considerations-including consent, privacy and confidentiality, HIPAA compliance, institutional liability, and the use of secondary data. The richness of eye-tracker data suggests various beneficial applications in health care occupational research and quality improvement. Therefore, sharing our study's successful design and execution, including proactive researcher-institutional review board communication, can inform and encourage similarly valuable, ethical, and innovative audiovisual research techniques.

Abstract LB-320: The FLEX real world data platform explores new gene expression profiles and investigator-initiated protocols in early stage breast cancer

Abstract Background: Genomic expression profiles have enabled the classification of breast cancers into molecular subtypes and provide prognostic information about the metastatic potential of the tumor, both of which have implications for the personalized treatment of breast cancer beyond clinical and pathological features. However, to precisely stratify tumors into actionable subgroups, full genome expression data should be combined with comprehensive clinical information. The FLEX Registry aims to aggregate a large, real-world dataset, which will enable the discovery of novel genomic profiles, particularly for patient subsets that are poorly represented in traditional clinical trials and will contribute to improved precision in the management of breast cancer. Trial Design: The FLEX Registry (NCT03053193) is a multicenter, prospective, observational trial for patients with Stage I, II, and III breast cancer. Patients with stage I-III breast cancer who receive MammaPrint, with or without BluePrint, on a primary tumor are eligible for enrollment. The primary objective of FLEX is to create a large scale, population-based registry that links complete clinical data with full genome expression data to elucidate new prognostic and/or predictive gene associations in a real-world setting. The FLEX Registry employs a shared study infrastructure to develop and investigate hypotheses for targeted subset analyses and/or clinical trials based on full genome expression data. The adaptable protocol is designed to be amended with the inclusion of targeted sub-studies. Patients enrolled in the initial study are eligible for inclusion in sub-studies for which they meet all eligibility criteria and additional consent is not required. Data will be collected on patients from diagnosis through 10 years of follow-up and any necessary additional clinical data will be collected as specified in the appendix protocols. Target enrollment is a minimum of 10,000 patients; >4,000 patients have enrolled since April 2017 at more than 80 sites, including seven National Cancer Institute-designated comprehensive cancer centers. The FLEX collaborative platform enables participating investigators the opportunity to author their own sub-study protocols, as approved by the FLEX Steering Committee. Fifteen sub-studies have been approved for investigation within the FLEX Registry. Citation Format: Jennifer Crozier, Adam Brufsky, Ian Grady, Sami Diab, Blanche Mavromatis, Nina D'Abreo, Carrie Dul, Rakhshanda Layeequr Rahman, Sarah Untch, Erin Yoder, Heather M. Kling, Amy M. Truitt, William Audeh, Bastiaan van der Baan, FLEX Investigators Group. The FLEX real world data platform explores new gene expression profiles and investigator-initiated protocols in early stage breast cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr LB-320.

The FLEX real-world data platform explores new gene expression profiles and investigator-initiated protocols in early stage breast cancer.

TPS7088 Background: Genomic expression profiles have enabled the classification of breast cancers into molecular sub-types and provide prognostic information about the metastatic potential of the tumor, both of which have implications for the personalized treatment of breast cancer beyond clinical and pathological features. However, to precisely stratify tumors into actionable subgroups, full genome expression data should be combined with comprehensive clinical information. The FLEX Registry aims to aggregate a large, real-world dataset, which will enable discovery of novel genomic profiles, particularly for patient subsets that are underrepresented in traditional clinical trials and will contribute to improved precision in the management of breast cancer. Methods: The FLEX Registry (NCT03053193) is a multi-center, prospective, observational trial for patients with Stage I, II, and III breast cancer. Patients with stage I-III breast cancer who receive the 70-gene signature risk of recurrence test, with or without the 80-gene signature molecular sub-typing test, on a primary tumor are eligible for enrollment. The primary objective of FLEX is to create a large scale, population-based registry that links complete clinical data with full genome expression data to elucidate new prognostic and/or predictive gene associations in a real-world setting. The FLEX Registry employs a shared study infrastructure to develop and investigate hypotheses for targeted subset analyses and/or clinical trials based on full genome expression data. The adaptable protocol is designed to be amended with the inclusion of targeted sub-studies. Patients enrolled in the initial study are eligible for inclusion in sub-studies for which they meet all eligibility criteria and additional consent is not required. Data will be collected on patients from diagnosis through 10 years of follow-up and any necessary additional clinical data will be collected as specified in the appendix protocols. Target enrollment is a minimum of 10,000 patients; >4,000 patients have enrolled since April 2017 at more than 80 sites, including seven National Cancer Institute-designated comprehensive cancer centers. The FLEX collaborative platform enables participating investigators the opportunity to author their own sub-study protocols, as approved by the FLEX Steering Committee. Fifteen sub-studies have been approved for investigation within the FLEX Registry. Clinical trial information: NCT03053193 .

Abstract OT3-17-02: The FLEX real world data platform explores new gene expression profiles and investigator-initiated protocols in early stage breast cancer

Abstract Background discussion: Genomic signatures are revolutionizing the definition, identification, and treatment of breast cancer. To precisely stratify breast cancers into actionable subgroups, full genome (FG) expression data and matching clinical data must be aggregated into a large, real-world dataset. Such a dataset will accelerate research and discovery, especially for smaller patient subsets that are not as widely represented within the current body of literature. Trial design and aims: FLEX is a multicenter, prospective, population-based, observational trial for patients with Stage I, II, and III breast cancer. All patients with stage I to III breast cancer who receive MammaPrint (MP), with or without BluePrint (BP) on a primary breast tumor are eligible for enrollment. The study’s primary aim is to create a large scale, population-based registry of full genome expression data matched with clinical data to investigate new gene associations with prognostic and/or predictive value in a real-world setting. Secondary objectives include utilizing the shared study infrastructure to examine and generate hypotheses for targeted subset analyses and/or trials based on full genome expression data. The design of FLEX allows targeted sub-studies and sub-analyses to be added as appendices after the initial baseline study is opened. Data collection follows patients from diagnosis through 10 years of follow-up. Patients enrolled in the initial study are also eligible for inclusion in sub-studies for which they meet all criteria and additional consent is not required. Additional clinical data will be collected as specified in the appendix protocols. The FLEX collaborative platform allows participating investigators the opportunity to author their own sub-study protocols, as approved by the FLEX Steering Committee of their peers. 14 sub-studies have already been identified and approved (Table 1). Eligibility and accrual: The study will enroll a minimum of 10000 patients aged ≥18 years with histologically proven invasive stage I, II, or III breast cancer. Since April 2017 over 2362 patients have been enrolled. Trial contact information: NCT03053193 FLEX@agendia.com TABLE 1PIINSTITUTIONTYPEADDITIONAL CONSENTARM(S)DESCRIPTIONMehran HabibiJohns HopkinsLocal SubstudyYesNeoadjuvantComprehensive gene expression profiling of breast cancer in patients receiving short-course endocrine therapy prior to surgeryMehran HabibiJohns HopkinsLocal SubstudyYesAllCorrelation of the microbiome with breast cancer gene expressionThomas LomisValley Breast ClinicCollaborative group substudyYesNeoadjuvantComplementary data collection for patients participating in the ODM-201 trial. FLEX will provide gene expression profiling for exploratory and signature discovery purposesIan GradyNorth Valley Breast CareSubstudyNoAllImpact of genomic risk classification on travel time to receive breast cancer care: a QOL studyPat WhitworthNashville Breast CenterSubstudyNoNeoadjuvantGenomic reclassification of large tumors in patients eligible to receive neoadjuvant therapyAdam BrufskyUniversity of Pittsburgh Medical CenterSubstudyNoNeoadjuvant, adjuvantResponse to standard chemotherapy regimens in clinically ER+/PR+/HER2+ (triple positive) patients according to BluePrint molecular subtypesAdam BrufskyUniversity of Pittsburgh Medical CenterSubstudyNoAllExpression signatures by response to bisphosphonates in ER+ patients receiving adjuvant therapy (SOC option), or for osteoporosis after primary treatmentAdam BrufskyUniversity of Pittsburgh Medical CenterSubstudyNoAllGene expression in breast cancer patients with obesityJennifer A. CrozierBaptist MD Anderson Cancer CenterSubstudyNoAllMP and BP in male breast cancerJennifer A. CrozierBaptist MD Anderson Cancer CenterSubstudyNoAllMP and BP evaluation in breast cancer patients ≥70Jennifer A. CrozierBaptist MD Anderson Cancer CenterSubstudyNoAllFG evaluation in invasive lobular carcinomaJennifer A. CrozierBaptist MD Anderson Cancer CenterSubstudyNoAllMP and BP relation to clinical PR positivityJennifer A. CrozierBaptist MD Anderson Cancer CenterSubstudyNoAllMP and BP relation to clinical Ki67 scoreJennifer A. CrozierBaptist MD Anderson Cancer CenterSubstudyNoAllMP and BP in metaplastic breast cancer Citation Format: Jennifer A Crozier, Gordan Srkalovic, Adam Brufsky, Mehran Habibi, Pat Whitworth, Charles Cox, Ian Grady, Thomas Lomis, Nina D'Abreo, Erin B Yoder, Sarah Untch, Heather Kling, William Audeh, Bastiaan Van der Baan, FLEX Investigators Group. The FLEX real world data platform explores new gene expression profiles and investigator-initiated protocols in early stage breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr OT3-17-02.

Clinical Trial in Progress: The FLEX Big Data Platform explores new gene expression profiles and investigator-initiated protocols in early-stage breast cancer.

TPS3155 Background: Genomic signatures are revolutionizing the definition, identification, and treatment of breast cancer. To precisely stratify breast cancers into actionable subgroups, full genome expression data and matching clinical data must be aggregated into a large data set. Such a data set will accelerate research and discovery, especially for smaller patient subsets who are not as widely represented within the current body of literature. Methods: FLEX is a multicenter, prospective, population-based, observational trial for patients with Stage I, II, and III breast cancer. All patients with stage I to III breast cancer who receive MammaPrint, with or without BluePrint on a primary breast tumor are eligible for enrollment. The study’s primary aim is to create a large scale, population-based registry of full genome expression data matched with clinical data to investigate new gene associations with prognostic and/or predictive value. Secondary objectives include utilizing the shared study infrastructure to examine and generate hypotheses for targeted subset analyses and/or trials based on full genome expression data. The design of FLEX allows targeted sub-studies and sub-analyses to be added as appendices after the initial baseline study is opened. Patients enrolled in the initial study are also eligible for inclusion in sub-studies where they meet all criteria and additional consent is not required. Additional clinical data will be collected as specified in the appendix protocols. The FLEX collaborative platform allows participating investigators the opportunity to author their own sub-study protocols, as approved by the FLEX Steering Committee of their peers. 13 sub-studies have already been identified and are under development. Eligibility: The study will enroll a minimum of 10000 patients aged ≥18 years with histologically proven invasive stage I-III breast cancer who signed informed consent. Enrollment began April 2017 and 1506 patients have been enrolled. Clinical trial information: NCT03053193.

Flipping the Switch: Initial Results of Genetic Targeting of the Fetal to Adult Globin Switch in Sickle Cell Patients

▪Autologous gene therapy (GT) for beta-hemoglobinopathies has demonstrated encouraging early safety and efficacy using addition of a sickling-resistant globin gene to stem cells. Another therapeutic strategy for sickle cell disease (SCD) is erythroid-specific inactivation of BCL11A, which is a validated repressor of gamma globin expression (Sankaran et al. Science 2011). This approach has the distinct advantage of simultaneously inducing fetal hemoglobin (HbF) while coordinately decreasing sickle hemoglobin (HbS). Since hemoglobin (Hb) polymerization in sickle red cells is highly dependent on the intracellular concentration of HbS and is strongly inhibited by HbF, effective BCL11A repression should prevent the sickling phenotype within red cells. We have shown that erythroid-specific expression of microRNA-adapted shRNAs (shRNAmiR) targeting BCL11A effectively induces HbF in human erythroid cells derived from transduced HSCs, largely attenuating the hematologic effects of SCD in a murine model while avoiding negative effects in HSCs and B lymphocytes (Brendel et al. JCI 2016). Here we report the initial results of a pilot clinical study utilizing a shRNAmiR lentiviral vector (LVV) targeting BCL11A for autologous GT in SCD patients.Transduction of hematopoietic cells with GMP lentiviral vector (BCH_BB-LCRshRNA(miR)) expressing the shRNAmiR for BCL11A in an erythroid-specific fashion showed no toxicity in engraftment and genotoxicity assays, efficient transduction rates of 80-95% of CD34+-derived erythroid colony forming cells from healthy donors and SCD patients, and >95% of transduced erythroid colonies demonstrating HbF levels of 50-95% of total Hb. Transduction at clinical scale with plerixafor mobilized CD34+ cells from three SCD donors yielded vector copies of 3.7 - 5.2/cell.Patients with severe SCD were screened for eligibility according to an IND enabled, IRB-approved investigator-initiated protocol. The first cohort included patients ≥ 18 years old. After at least 3 months of protocol-required transfusions, autologous CD34+ cells were collected by plerixafor mobilization and apheresis, and then transduced under GMP conditions with the BCH_BB-LCRshRNA(miR) vector. As of July 28, 2018, 3 patients representing the adult cohort had undergone a total of 3 (n=2) or 4 (n=1) days of mobilization. Mean single-day apheresis yields were 3.2 (range 1.5 - 6.8) x 106 CD34+ cells/kg. No Grade 3 or 4 AEs were attributed to mobilization and collection, although one subject developed an incidentally-discovered line-associated atrial clot and pulmonary embolism. Transduced cell products for these 3 patients have cell doses of 3.3 - 6.7 x 106 CD34+ cells/kg, VCN of 3.3 - 5.1 copies per cell and >95% vector-positive CD34+-derived colonies. One subject (BCL002), who had been regularly transfused for 17 years, has undergone infusion of gene-modified cells after myeloablative busulfan conditioning and achieved neutrophil engraftment after 22 days. Post-infusion follow-up is 78 days. At the time of the last analysis 76 days after GT and 64 days after last RBC transfusion (Table 1) subject BCL002 had a sustained Hb of >10 g/dL and, compared to pre-GT, there was a notable absence of irreversibly sickled cells on peripheral smear and a persistently low absolute reticulocyte count consistent with markedly reduced hemolysis. Hb electrophoresis showed 23.3% HbF, 51.8% HbS and 22.3% HbA (from residual transfused cells) with a HbF/(HbF+HbS) ratio of 29.7%. At day 76, the number of F cells had risen to 59.7% with 12pg HbF/F cell. In flow-sorted immature erythroid cells γ-globin mRNA was >80% of total β-like globins in the graft-derived population and BCL11A protein was reduced by ~90%. Adverse events observed from the start of conditioning until latest follow-up were consistent with myeloablative conditioning, and there have been no product-related adverse events and no SCD-related complications.These early results show: (1) feasibility of enrollment, cell procurement, and GMP manufacturing of gene modified CD34+ cells in 3 adult SCD patients; (2) the first proof of principle demonstrating shRNAmiR-based gene knockdown in humans, and (3) successful rapid induction of HbF in the first patient infused, with marked attenuation of hemolysis in the early phase of autologous reconstitution. Based on the trajectory of increasing HbF/(HbF+HbS), near full suppression of the SCD phenotype is expected. [Display omitted] DisclosuresEsrick:Bluebird Bio: Honoraria. Negre:bluebird bio: Other: Spouse employed by bluebird Bio. Dansereau:Bluebird Bio: Consultancy. Braunewell:Bluebird Bio: Employment, Equity Ownership. Christiansen:Bluebird Bio: Employment, Equity Ownership, Other: Salary. Nikiforow:Kite Pharma: Consultancy. Achebe:Luitpold Pharmaceutical: Consultancy; AMAG Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees; Syros pharmaceuticals: Consultancy. Negre:Bluebird Bio: Employment, Equity Ownership, Other: Salary. Heeney:Sancilio Pharmaceuticals: Consultancy, Research Funding; Ironwood: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees; Vertex/Crisper: Other: Data Monitoring Committee; Pfizer: Research Funding; Astra Zeneca: Consultancy, Research Funding. Williams:Bluebird Bio: Research Funding.

A Comparison of Patients with Acute Myeloid Leukemia and High-Risk Myelodysplastic Syndrome Treated On versus Off Study

Abstract Introduction: Despite decades of research, acute myeloid leukemia (AML) remains difficult to treat, and clinical trials are recommended as first line therapy by the NCCN. Although many new drugs show promise in early trials, further experience often does not confirm these results. One possible explanation is that patients on trials are not broadly representative. Here, we retrospectively compared characteristics, response, and survival in patients given the same investigational regimens according to whether treatment was given on versus off study. Methods: Patients treated for AML or high-risk MDS at FHCRC/UW between 2008 and 2015 were included. Investigator-initiated protocols for newly diagnosed (ND) and relapsed / refractory (RR) disease were included if ≥15 patients were treated off study. Analyses used Fisher’s exact test, Wilcoxon rank sum test, the Kaplan-Meier method, and Cox multivariate models. Results: 165 ND patients received either escalating doses of G-CLAM or idarubicin, cytarabine, and pravastatin while 243 RR patients received G-CLAM, decitabine-primed MEC or G-CLAC. Overall, 216 were treated on study and 192 were treated off study; reasons for the latter were: protocol not open (n=64), high treatment-related mortality score (n=21), poor health / organ function (n=26), physician or patient preference (n=25), lack of insurance (n=6), and not identified (n=50). No significant differences were found in age, gender, cytogenetic risk, or primary vs. secondary leukemia, but those treated on study in dose escalation protocols were more likely to receive higher doses. RR patients treated off study had typically received more salvage regimens. The 86 ND patients treated on study had higher rates of CR/CRi (90% vs. 64%, P Despite having higher remission rates, ND patients treated on vs. off study had comparable OS, and, among patients achieving remission, RFS (Figure 1a and 1b). After multivariate adjustment, there remained no association with OS (HR 0.87 [0.52-1.47]) or RFS (HR 0.96 [0.53-1.75]). Survival outcomes were also similar regardless of study assignment among RR patients (Figure 1c and 1d), in both univariate and multivariate analysis (OS, HR 0.82 [0.58-1.17]; RFS HR 0.72 [0.39-1.34]). Patients treated on or off dose escalation protocols at the maximum tolerated dose were no more likely to achieve remission or have longer survival, and incorporating subsequent allogeneic transplant as a time-varying covariate did not significantly affect outcomes. Conclusions: The higher response rates in ND patients treated on vs. off study suggests a measure of selection bias unrelated to readily assessable covariates, while the fundamental determinant of response in RR patients and survival in all patients appears to be unfavorable disease features (adverse cytogenetics, number of prior salvages, duration of CR1). Routine reporting of off study data for investigator-initiated studies could provide a clearer picture of regimen response rates and would grant further insight into the effects of selection bias. Download : Download high-res image (94KB) Download : Download full-size image Disclosures Othus: Glycomimetics: Consultancy; Celgene: Consultancy. Shadman: Gilead: Honoraria, Research Funding; Pharmacyclics: Honoraria, Research Funding; Emergent: Research Funding; Acerta: Research Funding.

Agents to reduce cytokine storm

The increasing insight into pathomechanisms of dysregulated host response in several inflammatory diseases led to the implementation of the term “cytokine storm” in the literature more than 20 years ago. Direct toxic effects as well as indirect immunomodulatory mechanisms during cytokine storm have been described and were the basis for the rationale to use several substances and devices in life-threatening infections and hyperinflammatory states. Clinical trials have been performed, most of them in the form of minor, investigator-initiated protocols; major clinical trials focused mostly on sepsis and septic shock. The following review tries to summarize the background, pathophysiology, and results of clinical investigations that had implications for the development of therapeutic strategies and international guidelines for the management of hyperinflammation during syndromes of cytokine storm in adult patients, predominantly in septic shock.

A Comparison of Patients with Acute Myeloid Leukemia and High-Risk Myelodysplastic Syndrome Treated on Versus Off Study

Introduction: Despite decades of research, acute myeloid leukemia (AML) remains difficult to treat, and clinical trials are recommended as first line therapy by the NCCN. Although many new drugs show promise in early trials, further experience often does not confirm these results. One possible explanation is that patients on trials are not broadly representative. Here, we retrospectively compared characteristics, response, and survival in patients given the same investigational regimens according to whether treatment was given on versus off study.Methods: Patients treated for AML or high-risk MDS at FHCRC/UW between 2008 and 2015 were included. Investigator-initiated protocols for newly diagnosed (ND) and relapsed / refractory (RR) disease were included if ≥15 patients were treated off study. Analyses used Fisher’s exact test, Wilcoxon rank sum test, the Kaplan-Meier method, and Cox multivariate models.Results: 165 ND patients received either escalating doses of G-CLAM or idarubicin, cytarabine, and pravastatin while 243 RR patients received G-CLAM, decitabine-primed MEC or G-CLAC. Overall, 216 were treated on study and 192 were treated off study; reasons for the latter were: protocol not open (n=64), high treatment-related mortality score (n=21), poor health / organ function (n=26), physician or patient preference (n=25), lack of insurance (n=6), and not identified (n=50). No significant differences were found in age, gender, cytogenetic risk, or primary vs. secondary leukemia, but those treated on study in dose escalation protocols were more likely to receive higher doses. RR patients treated off study had typically received more salvage regimens.The 86 ND patients treated on study had higher rates of CR/CRi (90% vs. 64%, P<0.001) and CR without MRD (67% vs. 36%, P<0.001) than the 79 treated off study. These associations remained after adjusting for treatment date, age, gender, secondary leukemia, adverse cytogenetics, and regimen type (OR 3.99 [95% CI: 1.60-9.97] and OR 2.93 [1.39-6.17] respectively). In contrast, neither CR/CRi nor CR without MRD rates differed for RR patients treated on (n=130) or off (n=113) protocol: 52% vs. 41%, P=0.07 and 28% vs. 19%, P=0.14. The same applied after adjusting for the above factors as well as duration of first remission and salvage number: OR 1.79 [0.95-3.40] and OR 1.73 [0.80-3.71].Despite having higher remission rates, ND patients treated on vs. off study had comparable OS, and, among patients achieving remission, RFS (Figure 1a and 1b). After multivariate adjustment, there remained no association with OS (HR 0.87 [0.52-1.47]) or RFS (HR 0.96 [0.53-1.75]). Survival outcomes were also similar regardless of study assignment among RR patients (Figure 1c and 1d), in both univariate and multivariate analysis (OS, HR 0.82 [0.58-1.17]; RFS HR 0.72 [0.39-1.34]). Patients treated on or off dose escalation protocols at the maximum tolerated dose were no more likely to achieve remission or have longer survival, and incorporating subsequent allogeneic transplant as a time-varying covariate did not significantly affect outcomes.Conclusions: The higher response rates in ND patients treated on vs. off study suggests a measure of selection bias unrelated to readily assessable covariates, while the fundamental determinant of response in RR patients and survival in all patients appears to be unfavorable disease features (adverse cytogenetics, number of prior salvages, duration of CR1). Routine reporting of off study data for investigator-initiated studies could provide a clearer picture of regimen response rates and would grant further insight into the effects of selection bias. [Display omitted] DisclosuresOthus:Glycomimetics: Consultancy; Celgene: Consultancy. Shadman:Gilead: Honoraria, Research Funding; Pharmacyclics: Honoraria, Research Funding; Emergent: Research Funding; Acerta: Research Funding.

Abstract OT2-3-06: A phase II, non-randomized, multicenter, exploratory trial of single agent BKM120 in patients with triple-negative metastatic breast cancer.

Abstract Despite best available therapy, triple-negative breast cancer (TNBC) continues to be associated with poorer outcomes when compared to other breast cancer subtypes and poses a serious therapeutic challenge. Therefore, novel and more efficacious therapies are in great need. It is widely accepted nowadays, that TNBC is not homogeneous, but comprised of a number of subpopulations very different in genetic make-up, oncogene dependence, and response to treatment. Among these, multiple core phosphatidylinositol-3-kinase (PI3K) pathway components are known to be altered in TNBC. The relevance of activating mutations in the PI3KCA gene or PTEN/INPP4B loss of protein expression on the virulence of breast cancer and response to PI3K inhibitors is yet to be elucidated. PI3K hyperactivity due to these alterations suggests that inhibitors of the PI3K pathway may be used to reverse resistance. BKM120 is a potent and highly specific oral pan-class I PI3K inhibitor currently in clinical development. This non-randomized, two-stage, open-label, single-arm exploratory trial is designed to elucidate the preliminary therapeutic value of BKM120 in patients with metastatic TNBC and to identify subpopulations that may mostly benefit. Women 18 years and above with confirmed mTNBC who have received at least two prior chemotherapy regimens in the adjuvant or metastatic setting are eligible to participate. Availability of a tumor block from the primary tumor or accessible metastasis for biopsy is mandatory. The primary objective is to determine the clinical activity of BKM120 defined as the clinical benefit rate (CR, PR or SD for more than 4 months per RECIST 1.1). Secondary objectives are to determine progression-free survival, overall survival, safety profile, pharmacodynamic effects, and to identify biomarkers predictive of response. BKM120 will be administered orally at a 100-mg dose, once daily, in a continuous schedule. Treatment will continue until disease progression, unacceptable toxicity, or decision of the physician or the patient to terminate participation. Stage 1 will include up to 50 patients with an intermediate analysis after the enrollment of the first 29 subjects. If no sufficient activity is observed, the clinical trial will be terminated. If drug activity is observed, enrollment will continue up Stage 1 completion. After 50 patients are enrolled, a comprehensive analysis of molecular markers using technology and knowledge gathered in the Stand Up to Cancer Dream Team will take place. This analysis will be focused in identifying molecular markers predictive of response that would guide patient selection for Stage 2. Two clone investigator-initiated protocols (one for the US, one for Spain) are enrolling in parallel. A total of 110 patients will take part in this study in four sites in Spain and in 2 in the US: 50 patients in Stage 1 and 60 in Stage 2, exploring a maximum of 3 subgroups of 20 patients each. The trial is funded by a Stand Up to Cancer Dream Team Translational Research Grant, a Program of the Entertainment Industry Foundation (SU2C-AACR-DT0209) and supported by Novartis. Patient enrollment started in June 2012. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr OT2-3-06.

Immunoglobulins in Adult Sepsis and Septic Shock

For more than 30years, intravenously administered immunoglobulins (ivIG) have been used to treat primary and secondary syndromes of immune deficiency. Increasing insight into pathomechanisms of severe sepsis and septic shock have led to the implementation of ivIG therapy in the strategies for adjunctive therapy in sepsis in both adults and children. Direct antitoxic effects, as well as indirect immunomodulatory mechanisms of ivIG have been described in the literature and were the basis for the rationale to use these substances in life-threatening infections and hyperinflammatory states. Several clinical trials have been performed, most of them as minor, investigator-initiated protocols. This review summarizes the results of clinical investigations and systematic meta-analyses that have implications for the development of therapeutic strategies, and international guidelines for the management of severe sepsis and septic shock in adult patients.

Impact of standard of care for psychosis in Parkinson disease

Neuropsychiatric symptoms are frequently found in patients with advanced Parkinson disease (PD).1 Psychotic symptoms, defined as disturbances of perception and thought, including visual or auditory hallucinations, paranoid delusions and delirium,...

Transgastric Peritoneoscopy Versus Laparoscopy for the Detection and Biopsy of Peritoneal Metastases

875 Transgastric Peritoneoscopy Versus Laparoscopy for the Detection and Biopsy of Peritoneal Metastases Douglas O. Faigel, Rogier P. Voermans, Mark I. Van Berge Henegouwen, Sean Conlon, James T. Spivey, Renee L. Rowe, Brett C. Sheppard, Paul Fockens The presence of peritoneal metastases is a frequent cause of unresectability for GI malignancies such as pancreatic cancer. Preoperative detection is difficult and laparoscopy (LAP) is frequently required to exclude metastatic disease prior to resection. Transgastric peritoneoscopy (TGP) may be an alternative to LAP, which could be performed at the time of a staging EUS. Aims: Create a model of peritoneal metastases for use in the development of TGP. Employ this model to compare TGP to LAP.Methods: This investigator-initiated protocol was performed in the live anesthetized acute porcine model. 2.5 mm color-coded beads were stapled via LAP to the peritoneum to simulate metastases. Three to 7 beads were placed in each of 12 animals (total 64 beads). Locations and number of beads were randomized and assigned using opaque envelopes. A pre-assessed list of essential locations was used: abdominal peritoneum (14 beads), diaphragm (11), surface of liver (32), and miscellaneous sites (7): duodenal curve, visceral peritoneum, omentum, anterior stomach and pelvis. 3-port LAP was performed by one of 2 surgeons blinded as to the location and number of beads. TGP was then performed with a 2 channel therapeutic upper endoscope using either standard accessories (forceps, cap)(TGP-S) or with a specially designed toolkit (bendable overtube, articulating retractors and graspers)(TGP-T) in randomized order by one of 2 endoscopists also blinded to bead placement. Primary endpoint was visualization and touching the bead with a biopsy forceps within a 30 min time limit. A noninferiority design comparing LAP to TGP was used to calculate the sample size. Fisher’s exact test with Bonferroni’s correction for multiple testing was used to calculate p-values. Results: A total of 64 beads were placed into 12 pigs. LAP found 61 beads (yield Z 95%, 95% CI: 89-100%), TGP-S 39 beads (61%, CI: 49-73%, p ! 0.0002 vs. LAP), TGP-T 40 beads (63%, CI: 51-74%, p ! 0.0002 vs. LAP). TGP-S and TGP-Twere similar in the number, distribution and time to detect beads. Both TGPS and TGP-T were each superior for detecting beads on the abdominal and diaphragmatic peritoneum (n Z 25) than for the other sites (n Z 49): TGP-S 92% vs. 35% (p ! 0.0002), TGP-T 100% vs. 31% (p ! 0.0002). Conclusions: In this first prospective, blinded, comparative trial TGP was inferior to LAP for the detection of simulated metastases. We successfully created a model for peritoneal metastases and established the benchmark for LAP detection. This model will be useful for future device development, which should focus on improved access to the region of the liver and enhanced endoscope optics and performance.

Current Issues in Clinical Trial Design

Current Issues in Clinical Trial Design