Project Funding Details

Title: A Phase 1 Safety Study of BXQ-350 Administered as a Single Agent by Intravenous Infusion in Children and Young Adults with Recurrent or Relapsed Solid Tumors or Recurrent Malignant Brain Tumors or Newly Diagnosed Diffuse Intrinsic Pontine Glioma (DIPG)
Alt. Award Code: Setty2018
Funding Organization: CancerFree Kids
Budget Dates: 2018-07-01 to 2019-06-30
Principal Investigator: Setty, Bhuvana
Institution: Nationwide Children's Hospital
Region: North America
Location: Columbus, OH, US

Collaborators

Name	Institution	Region	Location
AbdelBaki, Mohamed	Nationwide Children's Hospital	North America	Columbus, OH, US
Cripe, Timothy	Nationwide Children's Hospital	North America	Columbus, OH, US

Technical Abstract

Scientific Summary: Cancer remains the number one cause of death by disease in children. Over the past few decades, the field of pediatric oncology stalled in improving survival and decreasing toxicities for children with relapsed refractory solid tumors. For example, children with relapsed/refractory Ewing sarcoma had a 68% response rate to the combination of cyclophosphamide, vinorelbine and temsirolimus but only a 27% 2-year overall survival (1). Patients with relapsed/refractory high-risk neuroblastoma treated with chemotherapy alone have a 16% response rate and 2-year event-free survival of only 13% (2) and those with relapsed/refractory rhabdomyosarcoma treated with vinorelbine, cyclophosphamide, and temsirolimus have a 47% response rate and a 6 month survival of about 65% (3). In the central nervous system, recurrent ependymoma remains a therapeutic challenge with extremely poor prognosis. Similarly, diagnoses of diffuse intrapontine gliomas and high grade gliomas comprise up to 14% of tumors diagnosed in children 10-19 years of age, and have a dismal 2-year survival of less than 10% and 20% respectively. (4, 5) Despite the availability of antitumor agents, there remains a dire medical need for novel therapeutic agents that are better tolerated and more effective than currently available options. To achieve this aim, we are investigating the utility of BXQ-350, which is a novel anti-neoplastic therapeutic agent configured from two components: Saposin C (SapC), an expressed (human) lysosomal protein, and the phospholipid dioleoylphosphatidyl-serine (DOPS), a phospholipid located on cell membranes. When both the components are assembled together forming stable SapC-DOPS nanovesicles (clinical formulation BXQ-350), the agent exhibits the propensity to enter the body and brain, target cells in the tumor mass, and induce cell death. BXQ- 350 has a novel mechanism of action by targeted binding to phosphatidylserine (PS) patches that are characteristic of tumor cells and neovasculature. Its mechanism of action is thought to involve catalysis of acid sphingomyelinase and elevation of ceramide resulting in cell death or apoptosis (6). Data from preclinical studies indicate that SapC-DOPS has a broad killing effect on many tested human cancer cells and models, including high grade gliomas (HGG), pancreatic cancers, and neuroblastomas (7). BXQ-350 is currently in Phase 1 safety, efficacy and pharmacokinetic clinic trials in adult patients with advanced solid tumors or recurrent high grade gliomas with some patients on study for more than 14 months with preliminary promising results of efficacy and a favorable adverse event profile. (Bexion, unpublished personal communication) We have drafted a phase I safety study of BXQ-350 in children. The primary objectives of this Phase I study are [1] to characterize the safety profile and determine the maximum tolerated dose (MTD) of BXQ-350, when given as a single agent at escalating doses and [2] to assess preliminary antitumor activity, defined as maximal radiological response during treatment, using Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1 (v1.1) criteria for solid tumors and Revised Assessment in Neuro-Oncology (RANO) criteria for recurrent malignant brain tumors or newly diagnosed DIPG. Secondary objectives include evaluation of progression free survival at 6 months for patients with advanced solid tumor or recurrent brain tumors. We aim to determine the Maximum Tolerated dose (MTD) and/or recommended phase 2 dose of BXQ-350. Study design includes rapid dose escalation with three patient cohorts until the MTD is established or the highest planned dose level is reached. Once complete, patients will receive the MTD as determined with dose escalation. There will be up to 4 institutions participating in this study, one of which we hope will be Cincinnati Children’s Hospital Medical Center, where the technology was developed (pending legal agreements with Bexion). References: 1. Raciborska A, Bilska K, Drabko K, et al. Pediatric Blood and Cancer. 2013;60(10): 1621-1625. 2. Bagatell R, London WB, Wagner LM, et al. J Clin Oncol. 2011; 29:208-213. 3. Mascarenhas L, Meyer WH, Lyden E, et al. J Clin Oncol. 2014; ASCO Annual Meeting Abstracts;32(15): 10003. 4. Lam S, Lin Y, Auffinger B, Melkonian S. Journal of pediatric neurosciences 10(3), 199-206 (2015). 5. Hennika T, Becher OJ. Journal of child neurology doi:10.1177/0883073815601495 6. Qi X, Chu Z, Mahller YY, Stringer KF, Witte DP, Cripe TP. Clin Cancer Res. 2009;15:5840-51. 7. Chu Z, Abu-Baker S, Palascak MB, Ahmad SA, Franco RS, Qi X. PLoS ONE. 2013. 8(10):e75507. doi:10.1371/journal.pone.0075507

Cancer Types

Brain Tumor

Common Scientific Outline (CSO) Research Areas

5.4 Treatment Systemic Therapies - Clinical Applications

Single-funder organizations
Partner	Caveat
ACS	Dollar amounts found in the ICRP database are different than what is reported in the American Cancer Society's Annual Report. The dollar amounts spent on research reported in audited reports include operating expenses of the Research Department. Additionally, the dollar amounts also exclude all grants that were cancelled after being awarded, but include money that was returned from grants cancelled in the current year that were awarded in previous years. The dollar amounts reported in the database are unaudited and include grants awarded each fiscal year, exclusive of grants that cancelled before activation.
CBCRP	The California Breast Cancer Research Program grants are awarded only to individuals or institutions in California. Grants to the University of California receive only direct funds, while grants to other institutions also receive indirect costs (overhead) at 25% or the federally negotiated rate. Collaborative awards are counted in graphs and tables by the number of co-Principal Investigators rather than the number of projects.
Komen	Dollar amounts found in the ICRP database are different than what is reported on Komen\'s website or in Komen\'s Annual Report for the following reasons: Komen commits all funds necessary to support a research grant in the year it is awarded. Therefore, Komen\'s website reports on the full amount of each grant in the year it is initiated, while the ICRP data is annualized, as described. Komen funds research grants to our Scientific Advisors (Scientific Advisory Board members and Komen Scholars) and also provides discretionary funding of research-related projects that are not traditional research grants (e.g. support of the Komen Tissue Bank, ASCO and AACR meeting support). These are included in the overall Research Program spending, as reported in our Annual Report and on our website, but are not included in the ICRP database.
NIH	NIH projects in NIH Reporter assigned to the Spend Category ‘cancer’ are included in the ICRP database from FY2005 onwards. A small number of projects are excluded if essential information is missing (primarily Project title, Institution). Previous years’ data were drawn from the NFRP and may be incomplete. Starting in FY2007 NCI reports funding supplements, etc., for each grant separately instead of including them in the main project, therefore the number of projects may differ significantly from those of previous years. Projects with a cost of $0 include those that were a no-cost extension of the grant or when funding was provided by another NIH institute or center for that FY. NCI dollars in the ICRP database are drawn from NIH reporter and may not match dollars from other NCI-only databases.
Worldwide Cancer Research	Worldwide Cancer Research is unique in that the majority of our funding is awarded to researchers in countries outside the UK. Like many UK research charities, Worldwide Cancer Research only funds the direct costs of research. This creates significant problems in making quantitative comparisons between our funding and that provided by some of the other agencies in the ICRP, which fund both the direct and indirect costs (often called overheads) of research.

UK Organizations that are part of NCRI
Partner	Caveat
NCRI (GENERIC)	NCRI submits data to ICRP on behalf of all UK NCRI members from its Cancer Research Database (CaRD). The database only includes entries where funding can be directly attributed to a set of clearly defined research objectives. This means that the CaRD only contains information on all direct research funding (project, programme, fellowship, unit and institute) financed by NCRI Member organizations, for which an abstract has been submitted and where the project is active in any given financial year (April - March). Examples of funding that are currently outside the scope of CaRD are infrastructure, meeting grants and research management support."
Breakthrough (UK)	The ICRP database includes all Breakthrough Breast Cancer\'s research spend reported through its Annual Reports & Accounts. There is some variance due to different reporting periods (1 April snapshot versus full financial year) meaning that some research spend that is already committed may not be included in the ICRP figures. Expenditure on non-research charitable activities and management support costs are excluded from the NCRI, and by extension, the ICRP dataset. For further information on Breakthrough\'s research please visit www.breakthroughresearch.org.uk or email research@breakthrough.org.uk
CR-UK (UK)	The ICRP database includes around 70% of Cancer Research UK\'s direct research spend per financial year as reported through its Annual Reports & Accounts. There is some variance due to different reporting periods meaning that some direct research spend that is planned for allocation will not be included in the ICRP figures. Expenditure on vital research services, technology transfer, meeting grants, research management support and infrastructure to support Cancer Research UK\'s activities is excluded from the NCRI, and by extension, the ICRP dataset.
Department of Health (UK)	There will always be some variance between the figures available on ICRP and the figures reported publicly by DH. There are two reasons for this. Firstly, there is variance due to different reporting periods (1 April snapshot of ICRP versus full financial year reporting by DH). Secondly, the Department\'s National Institute for Health Research (NIHR) encompasses various expenditure on NHS infrastructure for research relevant to cancer that is not in a format that it is possible to capture for ICRP.
Macmillan (UK)	The ICRP database represents about 90% of Macmillan Cancer Support\'s direct research spend per financial year. There is some variance due to different reporting periods meaning that some direct research spend that is planned for allocation will not be included in the ICRP figures. Expenditure on research management support and infrastructure to support Macmillan Cancer Support\'s activities is excluded from the NCRI, and by extension, the ICRP dataset.
Scottish Government Health Directorates (UK)	Scottish Government is committed to improve the health of the Scottish population and the Chief Scientist\'s Office (CSO) funds across a broad range of relevant disease areas. Overall, 75% of the CSO spend is committed to research infrastructure in NHS Scotland. This and much other research expenditure is therefore outside the NCRI remit and, by extension, the ICRP dataset.

Canadian organizations who are part of the CCRA
Partner	Caveat
CCRA	Caveats/limitations specific to Canadian Cancer Research Alliance organizations can be accessed here.

Difference	Detail	Impact on investment figures
Not all CCRS participating organizations are included in the ICRP.	For the period 2005–2021, CCRA submitted data to the ICRP for 35 organizations and three now defunct multi-funded initiatives (CBCRA, CPCRI, and CTCRI). Note that the Canadian Breast Cancer Research Foundation merged operations with the Canadian Cancer Society in February 2017 and Prostate Cancer Canada merged in 2020. Importantly, Alberta Innovates did not report any research projects for 2020 and 2021 due to staffing constraints. Projects within the CCRS total 30,218, of which 24,129 were reported to ICRP.	Moderate for years 2020 and 2021
Not all CCRS projects are included in the ICRP.	“Related support” grants (i.e., travel awards, workshops/symposia, LOIs, etc.) are not submitted to ICRP, but are included in reports released by CCRA. In addition, equipment/infrastructure grants through the Canada Foundation for Innovation and for other funders where the cancer relevance weighting is less than 80% are not reported to the ICRP, but are included in CCRA reports. Any project with cancer relevance of less than 20% is also not reported to the ICRP.	Moderate
Co-funded projects are listed by the administering organization.	Projects that are co-funded appear under the administering organization and are not duplicated per funder. Within CCRA reports, however, investments are reported by the actual funders.	Minor
ICRP uses a different approach to calculating annual project investment.	CCRA provides ICRP with the project budget (adjusted for cancer relevance) and start and end dates. A pro-rated calculation is used to derive annual investment. Within the CCRS, prorated calculations on the basis of annual project amounts (where those data are available) are used to calculate the annual investment.	Minor
ICRP uses different site coding conventions.	The cancer site/type codes used within the CCRS are different from ICRP site codes so results by site will vary in some instances.	Minor
ICRP has technical limitations.	ICRP has a technical limit of 12 site codes and 8 CSO codes and this requires truncation for a couple of large-scale projects within the CCRS.	Very minor
CCRA provides less descriptive information about its projects to ICRP.	Lay abstracts are submitted by CCRA to the ICRP in lieu of technical abstracts and in their language of origin. For projects without lay abstracts (and there are a significant number of these), only titles are provided. An English translation is provided alongside all French project titles to facilitate use of the search engine.	No impact on investment figures, but limits full functionality of search engine especially for organizations that do not collect/report lay abstracts.