Hemophilia gene therapy: ushering in a new treatment paradigm?

After 3 decades of clinical trials, repeated proof-of-concept success has now been demonstrated in hemophilia A and B gene therapy. Current clinical hemophilia gene therapy efforts are largely focused on the use of systemically administered recombinant adeno-associated viral (rAAV) vectors for F8 or F9 gene addition. With multiple ongoing trials, including licensing studies in hemophilia A and B, many are cautiously optimistic that the first AAV vectors will obtain regulatory approval within approximately 1 year. While supported optimism suggests that the goal of gene therapy to alter the paradigm of hemophilia care may soon be realized, a number of outstanding questions have emerged from clinical trial that are in need of answers to harness the full potential of gene therapy for hemophilia patients. This article reviews the use of AAV vector gene addition approaches for hemophilia A and B, focusing specifically on information to review in the process of obtaining informed consent for hemophilia patients prior to clinical trial enrollment or administering a licensed AAV vector.

Clinical utility of targeted next generation sequencing assay in IDH-wildtype glioblastoma for therapy decision-making

BACKGROUND Targeted gene NGS testing is available through many academic institutions and commercial entities and is increasingly incorporated in practice guidelines for glioblastoma (GBM). This single-center retrospective study aimed to evaluate the clinical utility of incorporating NGS results in the management of GBM patients at a clinical trials-focused academic center. METHODS We identified 1,011 consecutive adult patients with pathologically confirmed GBM (IDHwt or IDHmut) who had somatic tumor sequencing (Oncopanel, ~500 cancer gene panel) at DFCI from 2013-2019. Clinical records of all IDHwt GBM patients were reviewed to capture clinical trial enrollment and off-label targeted therapy use based on NGS results. RESULTS Of the 557 IDHwt GBM patients with sequencing, 182 entered clinical trials at diagnosis (32.7%) and 213 (38.2%) entered after recurrence. Sequencing results for 130 patients (23.3%) were utilized for clinical trial enrollment for either targeted therapy indications (6.9 % upfront and 27.7% at recurrent clinical trials and 3.1% for off-label targeted therapy) or exploratory studies (55.4% upfront and 6.9% recurrent clinical trials). Median overall survival was 20.1 months with no survival difference seen between patients enrolled in clinical trials compared to those who were not, in a post hoc analysis. CONCLUSIONS While NGS testing has become essential for improved molecular diagnostics, our study illustrates that targeted gene panels remain underutilized for selecting therapy in GBM-IDHwt. Targeted therapy and clinical trial design remain to be improved to help leverage the potential of NGS in clinical care.

Identifying and Overcoming Barriers in Clinical Trial Enrollment for Veterans with Blood Cancers

Introduction Equitable and diverse clinical trials participation is essential for practice-changing results to be applicable to all patients. However, patients who identify as minorities, who live in rural areas, and who have low income are typically underrepresented in clinical trials. Increasing clinical trial participation in general and among underrepresented patients in particular is a goal of The Leukemia & Lymphoma Society's (LLS) Clinical Trial Support Center (CTSC), a clinical trial nurse navigation service for patients with blood cancers and their oncologists. The Veterans Health Administration (VA) is a national network of health care facilities. Approximately 3% of cancers in the United States are diagnosed in the VA. The prevalence of certain blood cancers is higher in the VA, in part due to military exposures. Veterans who receive care in the VA are more likely to have lower income, live in rural areas, and have comorbidities than patients who receive care in the private sector. Clinical trial participation among Veterans may be hampered by VA-specific factors (e.g. relatively fewer clinical trial options in the VA, lack of awareness that Veterans may be referred to participate in clinical trials outside of the VA) and patient-specific factors (e.g. income, rurality, comorbidities, and minority status). This study aimed to characterize and overcome barriers to Veteran enrollment in blood cancer clinical trials. Methods The LLS CTSC performs clinical trial searches using a database with information from clinicaltrials.gov and other proprietary data. To assess the impact of geography and rurality on the availability of clinical trials, we performed simulated searches for clinical trials in proximity of 13 VA facilities (6 rural, 7 urban), six blood cancers (AML, CLL, DLBCL, FL, MDS, MM), and two disease statuses (new diagnosis, relapsed/refractory). To further evaluate barriers to CTSC referral and clinical trial enrollment among Veterans who receive care in the VA, we collected data about referral patterns of VA hematologist-oncologists and Veterans' treatment choices at four VA facilities between September 2020 through May 2021. Results When evaluating both 100- and 200-mile radii from the VA facilities in simulated searches, there were significantly more clinical trials available for Veterans who receive care in urban compared to rural areas and on the East or West Coast compared to the Midwest, in aggregate (all cancers) and by disease type or status (p unadj < 0.0001). Forty-eight Veterans with blood cancers at the Durham NC, Salem VA, Sioux Falls SD, and Clarksburg WV VA facilities had consideration of clinical trials as a treatment option by oncology providers over a nine-month period. All Veterans were male, with 33 White/15 African-American, 47 non-Hispanic/1 Hispanic, age 41-93 years (median 71), living 0.2-186 miles from their VA facility (median 33.1), with diverse diseases and stages represented. Of the 48 patients, 14 patients were not asked if they wanted clinical trials information; reasons were need for immediate therapy, co-morbidities, or patient circumstances. Of 34 patients who were asked if they wanted clinical trials information, 14 did not agree to a referral to the CTSC; reasons were preference for immediate therapy, wanting care in the VA, wanting standard therapy, and lack of transportation. Of 20 referred Veterans, two enrolled in clinical trials outside the VA (for CLL and PMF), with investigational therapy provided by the study sponsors. Conclusions Using data from simulated and actual patient referrals to the LLS CTSC, we identified patient, provider, and location specific barriers for Veteran referral and enrollment in blood cancer clinical trials. When offered information about clinical trials, the majority of patients agreed to an LLS CTSC referral, suggesting that patients are generally willing to receive education and information about trial participation if given the opportunity. The LLS CTSC nurse navigators can overcome barriers to enrollment by providing education and identifying potential clinical trials within a desired geographic area. In addition to resources provided by the LLS CTSC, opening additional clinical trials in rural areas and within the VA system could help increase Veteran participation in clinical trials for blood cancers. Disclosures Rodgers: MJH Lifesciences: Consultancy. Weiss: AbbVie Inc.: Research Funding; Amgen Inc.: Research Funding; AstraZeneca Pharmaceuticals: Research Funding; Bristol Myers Squibb: Research Funding.

Stakeholder Perceptions of Barriers to Diverse Acute Myeloid Leukemia Clinical Trial Enrollment at Comprehensive Cancer Centers

Introduction Disparities in clinical trial enrollment have the potential to bias findings, limit generalizability, misdirect drug development, and reduce equitable access to novel therapy. Given the unique care delivery and clinical trial patterns of acute leukemia (AML), barriers to trial enrollment for underrepresented groups at the Comprehensive Cancer Centers (CCCs), where patients are often treated, may be distinct. Characterization of these barriers has been limited, preventing the development of interventions to overcome this disparity for AML. Methods We conducted an exploratory qualitative project to characterize barriers to trial enrollment and facilitators to overcome them through a series of focus groups and individual interviews. Participants were persons with AML who identified from one or more underrepresented groups and AML physicians, nurse practitioners, and physician assistants at three Dana-Farber/Harvard Cancer Center hospitals. A moderator guide was developed based on literature review and iteratively revised by study investigators. The questions enabled an open-ended multi-level (patient, provider, trial, institution, societal) exploration of five main domains, including familiarity and experience with clinical trials, factors influencing participation, participant concerns and enrollment supports, and facilitators to address enrollment barriers and disparities. Focus groups and interviews occurred through video conference or phone and were audio recorded and professionally transcribed. The interdisciplinary research team conducted a multi-step thematic analysis guided by framework analysis, and included prefigured and emergent codes. The team-based analysis synthesized data within and across participant types and focused on the identification of key patterns and prevalent themes related to barriers to clinical trial enrollment. Coding and analysis were assisted by NVivo 12 software. Results presented below highlight barriers that were considered relevant to the unique care delivery patterns of AML and clinically significant. Results 37 participants (19 patients; 18 providers) were recruited to focus groups (30) or interviews (7) between 5/6-6/28/2021. Participant characteristics are shown in Table 1. Patient participants were generally familiar with clinical trials. Despite limited explicit expression of enrollment hesitancy, both patients and providers noted multiple potential barriers to clinical trial enrollment specific to AML, including the rapidity from diagnosis to treatment; the inpatient setting of therapy; a lack of knowledge regarding incidence and enrollment demographics and their differences; restrictive trial design factors (e.g., hospital stays, mutation specificity); and concerns over the appropriateness and efficacy of a given trial relative to individual disease risk. Key enrollment barriers reported by participants are shown in Figure 1. Participant-identified facilitators to address these barriers are shown in Figure 2. Facilitators to overcome barriers specific to AML that were considered potentially impactful included: peri-enrollment peer support for patients, continuance of telehealth visits during trial participation, feedback and training to increase provider awareness and understanding of disparities and diverse communities, trial design augmentation to minimize restrictive barriers (centralized laboratory draws, multiple hospitalizations, white blood cell count and organ function criteria) and increase inclusivity (multiple language and culturally competent consent), and bolstering inter-institutional AML program partnerships to increase diverse patient referral. Conclusions Stakeholder-reported barriers to diverse AML clinical trial enrollment at CCCs include multiple disease-specific characteristics that reflect the unique care pattern of AML, such as concerns about restrictive trial design characteristics, the need to be inpatient, and the requirement to make decisions quickly after diagnosis. Several barriers and potential interventions at each level were considered impactful by both providers and patients. These formative data suggest a novel multi-level approach for overcoming AML enrollment disparities at CCCs is needed. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Racial disparities in comprehensive biomarker testing and clinical trial enrollment among patients with metastatic colorectal cancer (mCRC).

125 Background: Racial disparities may exist at many levels in the health care system; in oncology, yet little is known about racial disparities in biomarker testing and clinical trial enrollment among patients with mCRC. This study was designed to explore racial differences in comprehensive biomarker testing and clinical trial enrollment in the US using a large real-world database. Methods: This retrospective observational study utilized the Flatiron Health electronic health records database, which includes longitudinal data from patients diagnosed with mCRC. Patients with mCRC were eligible for this study if they had evidence of systemic therapy from 1/1/2017 through 10/30/2020 and were alive for at least 120 days after metastatic diagnosis. Unadjusted analyses summarized differences in biomarker testing and clinical trial enrollment between White and Black race, adjusted regression analyses were conducted using all baseline variables as covariates. These data are de-identified and are not considered human subjects research in accordance with the US Code of Federal Regulations (45 CFR Part 46). Results: A total of 7,879 patients were eligible: 4,803 (61.0%) were White and 838 (10.6%) were Black. Comprehensive testing by next-generation sequencing (NGS) was received by 51.6% and 41.8% of patients who were White and Black, respectively (p < 0.0001). There was no significant difference in clinical trial participation across all lines of therapy (2.9%, White and 2.9% Black). There was a statistically significant relationship between NGS-based testing and clinical trial enrollment (p < 0.0001), however, race was not identified a moderating factor in this relationship in adjusted regression analyses. The receipt of molecularly-targeted therapy was comparable between both races (11.9% and 9.7% for White and Black, respectively; p = 0.06). Patients received FOLFOX+bevacizumab most commonly in the first line (34.3% White; 40.5% Black), all other regimens were within 2 percentage points between racial groups. Targeted agents were each used by less than 7.4% of the study population. Conclusions: The use of NGS-based testing is significantly different by race in this database. The significant relationship between NGS testing and clinical trial enrollment at any time in the database did not appear to be moderated by race; however, descriptive analyses suggest that the ongoing analyses by line of therapy and considering timing of testing may better quantify these relationships. These data may not be generalizable to the entire US population as they are obtained from a single database that is limited to practices using this EHR system.