On October 8, 2021 The Childhood Cancer STAR Act and Childhood Cancer Data Initiative (CCDI) reported that are major federal government-led initiatives that exist in part because of years of advocacy work by members of the brain tumor and childhood cancer communities (Press release, National Brain Tumor Society, OCT 8, 2021, View Source [SID1234591041]). As we reflect back on Childhood Cancer Awareness Month (CCAM) this past September, we want to share updates on these initiatives as a reminder of the ongoing impact that advocacy makes possible.

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"The progress of the STAR Act and CCDI illustrate the commitment and increase in focus on research in childhood cancer," says Danielle Leach, chief of government and community relations at NBTS. "Cancer is the number one cause of death by disease among children, and pediatric brain tumors are the leading cause of cancer-related death in this population. Therefore, seeing this increased collaboration and commitment is promising. Now is the time for advocates to continue to work together to support increases in federal research funding so this critical work can create the change we so desperately need to find cures and quality of life."

Childhood Cancer Data Initiative

In late 2020, following extensive input from NBTS and advocates, Congress approved funding for CCDI at $50 million per year for 10 years. Once that funding was secured, the CCDI steering committee, which includes NBTS CEO David Arons, delivered a report to the National Cancer Institute on the goals of the initiative:

Gather data from every child, adolescent, and young adult diagnosed with pediatric cancer, regardless of where they receive their care.
Create a national strategy of appropriate clinical and molecular characterization to speed diagnosis and inform treatment for all types of pediatric cancers.
Develop a platform and tools to bring together clinical care and research data that will improve preventive measures, treatment, quality of life, and survivorship for pediatric cancers.
Based on these goals, the National Cancer Institute (NCI) is currently building the National Childhood Cancer Registry, which will centralize all existing data on cancer patients from birth to 39 years old and include information on their treatments, tumor types, outcomes, and post-care experiences. This registry will make it easier for researchers to collaborate and build on each others’ work, and hopefully, increase the pace of progress.

Danielle Leach

Also leveraging funding from the STAR Act, the NCI is working with Children’s Oncology Group (COG) to build a "biobank" of tumor tissue samples— a national "Molecular Characterization Protocol"— that will make it easier for researchers leading studies to acquire samples of tissue for their work. According to the NCI, this biobank will focus on cancers for which existing treatments are limited or ineffective and tissue for research is lacking and therefore will help fill a gap in the current research landscape.

As NCI Director Dr. Ned Sharpless wrote in a recent blog, these initiatives will "provide unprecedented insights into the drivers of childhood cancers and how they become resistant to treatment, as well as factors that influence the risk of treatment-related side effects…Collecting comprehensive data from as many children as possible will give researchers a more thorough understanding of how well treatments work…[and] make it easier for researchers to monitor the health of survivors of childhood cancer throughout their lives, providing further insights into the impact of cancer and its treatments."

STAR ACT

The STAR Act is the most comprehensive childhood cancer bill in history. It expands opportunities for childhood cancer research, improves efforts to identify and track childhood cancer incidences, and enhances the quality of life for childhood cancer survivors.

Since the bill was signed into law in 2018, NBTS advocates have played an active role in ensuring that the STAR Act has been fully funded at $30 million every year by asking for funding through activities like Head to the Hill and our online action alerts. Additionally, Danielle Leach sits on the Centers for Disease Control and Prevention Childhood Cancer STAR Act advisory group.

To date, funding from the STAR Act has led to:

Seven new research grants for "Improving Outcomes for Pediatric, Adolescent, and Young Adult Cancer Survivors."
Ten new research grants for "Research to Reduce Morbidity and Improve Care for Pediatric, and Adolescent and Young Adult (AYA) Cancer Survivors."
Additional funding for the CDC to expand the capacity of state cancer registries and their abilities to collect data on childhood cancer cases and trends.
More details related to these and other updates were included in a comprehensive overview put together by the Alliance for Childhood Cancer, for which NBTS serves as the co-chair of the policy committee.

On October 8, 2021 Precision BioSciences, Inc. (Nasdaq: DTIL), a clinical stage biotechnology company using its ARCUS genome editing platform to develop allogeneic CAR T and in vivo gene editing therapies, reported that issued the following statement about the safety of its allogeneic CAR T cell therapies (Press release, Precision Biosciences, OCT 8, 2021, View Source [SID1234591036]).

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1) Precision BioSciences’ allogeneic CAR T cells are made using its proprietary ARCUS genome editing platform designed for precision, specificity, and safety.

2) Precision BioSciences’ CAR T cells are the only allogeneic CAR T cells in human clinical trials made with a single gene editing step to specifically avoid the potentially deleterious effects of making multiple edits to T cells.

It is known in the field that making multiple edits in T cells can result in chromosomal abnormalities. Specifically, it has been shown to be an issue in TCR/CD52 edited cells. As published in Cancer Research[1], "Translocation frequencies ranged from 10-4 to 2×10-2 with translocations resulting in acentromeric or dicentromeric chromosomes occurring the least frequently."
Precision’s lymphodepletion strategy does not include an anti-CD52 monoclonal antibody, and therefore does not require editing CD52 in the CAR T cells.
3) In addition, Precision BioSciences believes the oligo-capture method is the most sensitive method available for off-target detection allowing for superior product characterization with respect to gene editing safety. Importantly, this method is used to engineer out off-target editing of the ARCUS nucleases during the research phase of product development.

4) As part of product release testing, Precision BioSciences evaluates chromosomal abnormalities and confirms that the CAR T cells are not transformed.

5) Across four clinical programs in more than 100 patients treated with PBCAR T cells, Precision BioSciences has seen no evidence of chromosomal abnormalities.

Precision BioSciences is actively recruiting patients in ongoing clinical studies of PBCAR0191 (NCT03666000) for patients with relapsed or refractory (R/R) non-Hodgkin lymphoma (NHL) and R/R B-cell acute lymphoblastic leukemia, PBCAR19B (NCT04649112) for patients with R/R NHL, and PBCAR269 (NCT04171843) for patients with R/R multiple myeloma.

On October 8, 2021 Black Diamond Therapeutics, Inc. (Nasdaq: BDTX), a precision oncology medicine company pioneering the discovery and development of MasterKey therapies, reported the presentation of preclinical data for three early-stage pipeline programs in oral and poster sessions at the AACR (Free AACR Whitepaper)-NCI-EORTC Virtual AACR-NCI-EORTC (Free AACR-NCI-EORTC Whitepaper) International Conference on Molecular Targets and Cancer Therapeutics (EORTC-NCI-AACR) (Free ASGCT Whitepaper) (Free EORTC-NCI-AACR Whitepaper) (Press release, Black Diamond Therapeutics, OCT 8, 2021, View Source [SID1234591032]).

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"Despite clinical advances in precision medicines for patients with non-small cell lung cancer (NSCLC) harboring an epidermal growth factor receptor (EGFR) mutation, multiple areas of unmet need persist, which include patients whose tumors have developed resistance to current-generation therapies, express non-canonical (or uncommon) mutations, and have metastasized to the brain," said Elizabeth Buck, Ph.D., Chief Scientific Officer of Black Diamond Therapeutics. "BDTX-1535 has demonstrated a breadth of coverage of oncogenic EGFR mutations expressed in NSCLC, which coupled with a brain-penetrant pharmacokinetic (PK) profile, supports the potential of BDTX-1535 as an optimal therapeutic candidate for these NSCLC patient populations."

Dr. Buck continued: "Additionally, B-Raf (BRAF) and fibroblast growth factor receptor (FGFR) are validated therapeutic targets, yet current standards of care are associated with meaningful limitations, yielding persistent unmet needs for these cancer patients. Our BRAF program compounds are designed to selectively target a full spectrum of Class II/III BRAF oncogenic mutations without inducing paradoxical activation, which can lead to secondary malignancies. Our FGFR compounds are designed to target a full spectrum of oncogenic FGFR2 and FGFR3 mutations, including known resistance mutations, while sparing FGFR1, the inhibition of which is associated with toxicities, including hyperphosphatemia."

The presentations describe the following data:

BDTX-1535 Program:
The presentation describes preclinical data for BDTX-1535, which is designed as a potent, selective, and brain-penetrant inhibitor of a spectrum of EGFR mutations expressed in glioblastoma multiforme (GBM) and NSCLC.

In cell-based assays, BDTX-1535 achieved potent and selective inhibition of EGFR mutations expressed in NSCLC, including the EGFR- C797S mutation that can arise following treatment with osimertinib.
BDTX-1535 demonstrated a favorable brain-penetrant PK profile in mouse, rat, and dog models.
In an EGFR Exon19+C797S mouse allograft efficacy model, BDTX-1535 showed dose-dependent tumor growth inhibition and achieved complete regression without notable impact on body weight.
Black Diamond expects to file an Investigational New Drug (IND) application for BDTX-1535 in the first half of 2022.
BRAF Program:
The presentation describes preclinical data for a lead compound from Black Diamond’s BRAF program, which is designed for potency and selectivity against a spectrum of non-canonical Class II/III (non-V600) mutations, as well as to avoid induction of paradoxical activation.

In cell-based assays, the lead compound demonstrated potent inhibition of a spectrum of Class II/III BRAF mutations.
In contrast to current-generation BRAF inhibitors, such as encorafenib and vemurafenib, treatment of cells harboring wild type BRAF (WT-BRAF) with the Black Diamond compound was not observed to lead to an increase in protein kinase RNA-like endoplasmic reticulum kinase (pERK), a signal of paradoxical activation.
In a BRAF-KIAA1549 fusion allograft tumor model, the lead compound exhibited dose-dependent inhibition of pERK and anti-tumor efficacy.
Black Diamond anticipates an IND filing in 2022.
FGFR Program:
The presentation illustrates the Black Diamond approach, which centers on a four-pronged optimization strategy designed to deliver an inhibitor with broad coverage of FGFR2 and FGFR3 oncogenes, while sparing inhibition of FGFR1 and retaining activity against resistance mutations.

In cell-based assays, FGFR program compounds demonstrated potent and selective inhibition of a spectrum of FGFR2/3 oncogenic mutations, while sparing FGFR1.
Additionally, in cell-based assays, FGFR program compounds demonstrated improved potency against resistance mutations.
In an in vivo study conducted in a UM-UC-14 (FGFR3-S249C) mouse model, FGFR program compounds demonstrated anti-tumor activity. Additionally, in mouse and rat models, FGFR program compounds did not promote hyperphosphatemia.
Black Diamond anticipates an IND filing in 2022.
"Our BDTX-1535, BRAF, and FGFR programs exemplify Black Diamond’s MasterKey approach to drug discovery in which we are able to harness the power of our proprietary MAP drug discovery engine to design spectrum-selective candidates engineered to overcome the limitations of current therapies in each target area," said David M. Epstein, Ph.D., President and Chief Executive Officer of Black Diamond Therapeutics. "These programs underscore the productivity of our MAP engine, and we look forward to providing updates across our pipeline as we advance toward our goal of delivering product candidates that can expand the reach of precision medicine and, in turn, address areas of true unmet need."

The presentations from the AACR (Free AACR Whitepaper)-NCI-EORTC meeting are available on the "Scientific Presentations and Publications" section of the Black Diamond Therapeutics website.

On October 8, 2021 Pacific Cancer Care and Deep Lens reported that they are collaborating to optimize clinical trial matching and accelerate enrollment at the Monterey-based practice through the use of Deep Lens’ artificial-intelligence (AI) based solutions and other services (Press release, Pacific Cancer Care, OCT 8, 2021, View Source [SID1234591026]). Pacific Cancer Care is the largest hematology and oncology practice on the California Central Coast. Deep Lens is a digital healthcare company that helps community oncology practices improve and expand clinical research programs through the use of their proprietary AI solution, VIPER. This partnership will expand Pacific Cancer Care’s existing clinical trial offering to patients by more accurately and effectively identifying eligible patients for trials, improving communications between patient care teams and bringing more trials to the practice.

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"Clinicals trials are not only critical to the advancement of new therapeutic options for cancer, but they present a unique opportunity for patients to access novel treatments well in advance of their commercialization, some of which may help positively impact the state of their disease," said Zach Koontz, M.D., oncologist at Pacific Cancer Care. "We are excited to partner with Deep Lens to broaden our clinical research program through an increased number of trials that we can offer onsite and by expediting the time we can get patients into these trials. We have a very busy practice and we look forward to leveraging other Deep Lens services to help alleviate some of the administrative tasks associated with clinical trial recruitment, so that our staff can focus more exclusively on patient care."

It is estimated that more than 15,000 oncology clinical trials are actively recruiting patients; however, fewer than 1 in 30 patients participate in a clinical trial. Limited trial site resources make it time-consuming to identify eligible patients, especially as trial protocols increase in complexity. VIPER supports care teams by automating the identification of potentially eligible patients at the time of diagnosis and easily matching them to relevant trials.

"Pacific Cancer Care already has an extremely comprehensive clinical research program – they’ve been the first site to offer access to certain therapies via clinical trials and they place great importance on the role that clinical research plays in the overall acceleration of our knowledge and treatment of cancer," said Simon Arkell, president and co-founder at Deep Lens. "We are thrilled to align with such a prominent, reputable practice that is just as passionate as Deep Lens about innovation and the potential of precision therapies for the treatment of cancer. We look forward to helping this practice better serve the Central Coast oncology community."

Deep Lens’ VIPER will pre-screen all patients from Pacific Cancer Care’s EMR (OncoEMR) and integrate molecular data feeds from Caris Life Sciences, Foundation Medicine and Guardant Health as well as all pathology feeds to automatically identify qualified patients for clinical trials. Deep Lens pre-screening and clinical trial matching solution is provided at no cost to oncology practices.

Deep Lens is working with a significant number of community oncology practices representing every region in the U.S. It is estimated that approximately 85 percent of cancer patients are diagnosed and treated at local, community-based oncology practices. Deep Lens is committed to expanding important oncology research by making trials more accessible to a larger and more diverse population within these local community settings.

On October 8, 2021 Compass Therapeutics, Inc. (OTC:CMPX) and ABL Bio (KOSDAQ: 298380) reported that clinical trial data for CTX-009 (ABL001/ES104), a dual anti-angiogenic bispecific antibody targeting DLL4 and VEGF-A, at an oral plenary session during the AACR (Free AACR Whitepaper)-NCI-EORTC AACR-NCI-EORTC (Free AACR-NCI-EORTC Whitepaper) International Conference on Molecular Targets and Cancer Therapeutics (EORTC-NCI-AACR) (Free ASGCT Whitepaper) (Free EORTC-NCI-AACR Whitepaper) (Abstract Number: 4749; Session Title: Plenary Session 2: New Drugs on the Horizon I) (Press release, Compass Therapeutics, OCT 8, 2021, View Source [SID1234591025]).

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The first in human Phase 1 single agent dose escalation and expansion study evaluated CTX-009 across nine dose levels. The study enrolled 45 heavily pre-treated patients with cancers primarily of colorectal and gastric origin. CTX-009 was well tolerated across all doses evaluated, with no dose-limiting toxicities reported. The most frequent treatment related adverse event was hypertension, observed in 17 patients of the 45 patients enrolled. Among those, 7 patients reported Grade 3 hypertension and the rest had Grade 1 or Grade 2 (16%). Only 4 mild cases of pulmonary hypertension were reported that were all reversible, and CTX-009 demonstrated significant clinical activity as a stand-alone therapy. The majority (87%) of the patients enrolled in the study had ECOG performance status of 1; 42% (n=19) were patients with gastric cancer and 40% (n=18) were patients with colorectal cancer with a median of three prior lines of systemic anticancer therapies. Importantly, 62% of the patients enrolled were previously treated with anti-VEGF antibodies containing regimens. There were 4 partial responses (including three partial responses confirmed by RECIST 1.1 and one partial response which was unconfirmed) and 20 stable diseases among 39 evaluable patients. The confirmed overall response rate (ORR) across all dose levels tested (0.3 – 17.5mg/kg) was 8%, not including 1 unconfirmed partial response, and the disease control rate (DCR) across all dose levels was 62%. The ORR at the recommended phase 2 doses (RP2D) of 10.0-12.5 mg/kg was 19% (n=3/16) not including one unconfirmed partial response, and the DCR at the RP2D was 69% (n=11/16).

"This is a significant clinical result because current approved anti-angiogenic drugs have little efficacy as a monotherapy. Furthermore, 94% of the colorectal patients and 58% of the gastric patients in this study were previously treated with Avastin (bevacizumab) or Cyramza (ramucirumab), respectively; the response rate is almost three times that seen for current 3rd and 4th line therapies in patients with colorectal and gastric cancers." said Jeeyun Lee, MD, a Professor at the Samsung Medical Center, Seoul, South Korea and the principal investigator of the study.

"The responses to CTX-009 as a monotherapy in this refractory patient population combined with the excellent tolerability profile suggests that CTX-009 can become an important drug for a broad range of solid tumors" said Thomas Schuetz, MD, PhD, CEO and scientific Founder of Compass Therapeutics. "We look forward to developing CTX-009 in the United States and other geographies and to unlocking its full potential". Compass Therapeutics of Boston, Massachusetts holds the global rights to CTX-009 with the exception of S. Korea (rights held by Handok) and China (rights were out-licensed to Elpiscience Biopharma).

"We are pleased to present the clinical data of CTX-009 (ABL001) for the first time at a prominent international conference," said Sang Hoon Lee, PhD, CEO of ABL Bio. "CTX-009 has demonstrated its potential to benefit cancer patients, especially those that have been unable to experience improvements with standard treatments. We expect to further validate the therapeutic value of CTX-009 as it progresses through clinical trials in the U.S., China and South Korea."

"We are happy to see the next frontier of anti-angiogenic therapies, CTX-009 (ES104) showing promising anti-tumor activity in a Phase 1 study as monotherapy," said Steve Chin, MD, CMO of Elpiscience Biopharma, "We look forward to initiating the clinical trials in China to explore its therapeutic potential in the heavily pre-treated digestive tract cancer patients."

About CTX-009

CTX-009 (ABL001/ES104) is a bispecific antibody that simultaneously blocks Delta-like ligand 4/Notch (DLL4) and vascular endothelial growth factor A (VEGF-A) signaling pathways, which are critical to angiogenesis and tumor vascularization. Pre-clinical and early clinical data of CTX-009 suggests that blockade of both pathways provides robust anti-tumor activity across several solid tumors, including colorectal, gastric, cholangiocarcinoma, pancreatic and non-small cell lung cancer. Partial responses to CTX-009 as a monotherapy have been observed in heavily pre-treated cancer patients, who were resistant to currently approved anti-VEGF therapies. CTX-009 has completed a Phase 1 monotherapy dose escalation and expansion study. Phase 1b and Phase 2 combination studies are ongoing.