On January 24, 2023 Deciphera Pharmaceuticals, Inc. (NASDAQ: DCPH), a biopharmaceutical company focused on discovering, developing, and commercializing important new medicines to improve the lives of people with cancer, reported the presentation of additional data from the planned exploratory analysis from the INTRIGUE Phase 3 clinical study of QINLOCK using circulating tumor DNA (ctDNA) from patients with gastrointestinal stromal tumor (GIST) previously treated with imatinib (Press release, Deciphera Pharmaceuticals, JAN 24, 2023, View Source [SID1234626490]).

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The presentation titled "Mutational heterogeneity of imatinib resistance and efficacy of ripretinib vs sunitinib in patients with gastrointestinal stromal tumor: ctDNA analysis from INTRIGUE" was presented by Sebastian Bauer, M.D., University Hospital Essen, University Duisburg-Essen and German Cancer Consortium at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Plenary Series Session and is available on the Company’s website at www.deciphera.com/presentations-publications.

"We are pleased with the exploratory analysis, which showed that QINLOCK provided clinically meaningful benefit for second-line GIST patients based on the mutational drivers of their disease. QINLOCK’s impressive median progression free survival of 14.2 months compared to 1.5 months for sunitinib underscores the potential of QINLOCK to become the standard-of-care for second-line GIST patients with mutations in KIT exon 11 and 17/18 only," said Dr. Bauer. "I look forward to the upcoming INSIGHT pivotal Phase 3 study, which aims to provide more evidence of the potential benefit QINLOCK can offer to these post-imatinib patients."

Results of ctDNA Analysis

An exploratory objective in the INTRIGUE Phase 3 study in GIST patients previously treated with imatinib was to evaluate anti-tumor efficacy of QINLOCK according to baseline KIT primary and secondary mutational status. Baseline peripheral whole blood was analyzed by Guardant360, a 74-gene ctDNA next-generation sequencing liquid biopsy assay. Key highlights from the analysis presented today include the following:

Mutational Subgroups

Of the 453 patients in the overall intent-to-treat population (ITT), baseline ctDNA was analyzed in 362 patients for whom evaluable samples were available. ctDNA was detected in 280 samples and KIT mutations were detected in 213 patients.
In patients with a KIT exon 11 primary mutation:
52 patients had additional mutations in KIT exon 17/18 only.
41 patients had additional mutations in KIT exon 13/14 only.
22 patients had additional mutations in both KIT exon 13/14 and exon 17/18.
Efficacy Results of ctDNA Analysis

Patients with mutations in KIT exon 11 and exon 17/18 only derived substantially improved clinical benefit with QINLOCK versus sunitinib.
QINLOCK demonstrated a median PFS (mPFS) of 14.2 months compared to 1.5 months for the sunitinib arm (Hazard Ratio [HR] 0.22, nominal p value <0.0001).
QINLOCK demonstrated a confirmed objective response rate (ORR) of 44.4% (n=12 of 27) compared to 0% for sunitinib (nominal p value 0.0001).
OS for the QINLOCK arm has not reached a median, while patients randomized to the sunitinib arm had a median OS (mOS) of 17.5 months (HR 0.34, nominal p value 0.0061).
Patients with mutations in KIT exon 11 and 13/14 only derived substantially improved clinical benefit with sunitinib versus QINLOCK.
QINLOCK demonstrated a mPFS of 4 months compared to 15 months for the sunitinib arm (HR 3.94, nominal p value 0.0005).
QINLOCK demonstrated a confirmed ORR of 9.5% (n=2 of 21) compared to 15% (n=3 of 20) for sunitinib (nominal p value 0.5922).
QINLOCK demonstrated a mOS of 24.5 months, while patients randomized to the sunitinib arm has not reached a median (HR 1.75, nominal p value 0.2085).
Safety and Tolerability

QINLOCK was generally well-tolerated and the safety profiles were consistent with the primary analysis of the INTRIGUE study.
For patients with mutations in KIT exon 11 and exon 17/18 only, fewer patients in the QINLOCK arm experienced Grade 3-4 treatment-related adverse events compared to sunitinib (33% vs 50%).
Based on the results of the ctDNA analysis and discussions with the U.S. Food and Drug Administration (FDA), the Company plans to initiate the INSIGHT pivotal Phase 3 clinical study of QINLOCK versus sunitinib in second-line GIST patients with mutations in KIT exon 11 and 17/18 only. In the planned study, approximately 54 patients will be randomized 2:1 to either QINLOCK 150 mg once daily or sunitinib 50 mg once daily for four weeks followed by two weeks without sunitinib. The primary endpoint will be PFS as determined by independent radiologic review using modified Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria. The Company expects to initiate the INSIGHT study in the second half of 2023.

About the INSIGHT Study

The planned INSIGHT Phase 3 clinical study is a randomized, global, multicenter, open-label study to evaluate the efficacy and safety of QINLOCK compared to sunitinib in patients with GIST previously treated with imatinib with mutations in KIT exon 11 and 17/18 only (excluding patients with mutations in KIT exons 9, 13, or 14). In the study, 54 patients will be randomized 2:1 to either QINLOCK 150 mg once daily or sunitinib 50 mg once daily for four weeks followed by two weeks without sunitinib. The primary endpoint is PFS as determined by independent radiologic review using modified RECIST 1.1 criteria. Secondary endpoints include ORR as determined by independent radiologic review using modified RECIST 1.1 criteria and OS.

About the INTRIGUE Study

The INTRIGUE Phase 3 clinical study is a randomized, global, multicenter, open-label study to evaluate the efficacy and safety of QINLOCK compared to sunitinib in patients with GIST previously treated with imatinib. In the study, 453 patients were randomized 1:1 to either QINLOCK 150 mg once daily or sunitinib 50 mg once daily for four weeks followed by two weeks without sunitinib. As previously reported, the study did not achieve the primary efficacy endpoint of PFS as determined by independent radiologic review using modified RECIST 1.1 criteria. The statistical analysis plan included a hierarchical testing sequence that included testing patients with a KIT exon 11 primary mutation and then in the all patient intent-to-treat (AP) population. In patients with a KIT exon 11 primary mutation (n=327), QINLOCK demonstrated an mPFS of 8.3 months compared to 7.0 months for the sunitinib arm (HR 0.88, p=0.360). Although not formally tested due to the rules of the hierarchical testing sequence, in the AP population QINLOCK demonstrated a mPFS of 8.0 months compared to 8.3 months for the sunitinib arm (HR 1.05, nominal p=0.715). QINLOCK was generally well tolerated. Fewer patients in the QINLOCK arm experienced Grade 3-4 treatment-emergent adverse events compared to sunitinib (41.3% vs 65.6%).

On January 24, 2023 Carina Biotech Pty Ltd ("Carina," "the Company"), a cell therapy immuno-oncology company developing CAR-T and other adoptive cell therapies for the treatment of solid cancers, reported that it has received the "safe to proceed" letter from the U.S (Press release, Carina Biotech, JAN 24, 2023, View Source [SID1234626489]). FDA for its Investigational New Drug (NDA) application to conduct a first-in-human Phase 1/2a clinical trial of CNA3103, its LGR5-targeted chimeric antigen receptor T cell (CAR-T) therapy candidate, in patients with advanced colorectal cancer (CRC).

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The Phase 1/2a clinical trial will enroll a total of 44 patients with metastatic disease failing prior lines of chemotherapy and who express LGR5 on their cancer cells. Twenty-four patients in the Phase 1 segment will be enrolled in select Australian centers. Following a BOIN (Bayesian Optimal Interval) design, ascending CAR-T cell doses will be administered to cohorts of three patients each, to assess the safety and tolerability of CNA3103, and to determine its optimal dose. The subsequent Phase 2 segment will enroll 20 patients at the optimal dose, in both Australia and the U.S., to characterize the activity of CNA3103, in terms of antitumor response, duration of response and time to disease progression.

"Our positive engagement with the FDA marks a major step forward for Carina and our continued efforts to develop CNA3103 as a potential treatment for the third most common cancer in the U.S. and worldwide, colorectal cancer," said Deborah Rathjen, Carina’s Chief Executive Officer. "The FDA’s letter provides the pathway for this clinical trial and further validates that a significant unmet need exists for more effective treatment options for colorectal cancer. Preparations, including site selection, are underway as we aim to commence enrolling patients during the first half of 2023."

"This interaction with the FDA corroborates our ability to gain the agency’s support for our proposed trial of CNA3103 in metastatic colorectal cancer patients," said José Iglesias, MD, Carina’s Chief Medical Officer. "Our approach is doubly innovative, in being one of the of emergent CAR-T treatment protocols in solid tumors and in utilizing a novel, and to our knowledge, unique CAR-T construct against LGR5 – an important cancer stem cell-associated antigen linked to the pathogenesis, dissemination, and treatment resistance of colorectal cancer."

About CNA3103

Carina’s proprietary CNA3103 CAR-T cell targets LGR5, a cancer stem cell marker that is highly expressed on advanced colorectal cancer and some other cancers. In colorectal cancer patients, LGR5 expression has been correlated with poor prognosis. Cancer stem cells are a small sub-population of cells within a tumor with the ability to self-renew, differentiate into the many cell types of a tumor, initiate new tumors, and resist chemotherapy and radiotherapy (leading to relapses). By targeting cancer stem cells, it is hoped that this therapy will reduce the tumor’s ability to generate new cancer cells, resulting in durable tumor suppression and preventing the relapses that are very common in patients with colorectal cancer. Carina’s pre-clinical studies of CNA3103 have shown promising results with complete tumor regression and no tumor recurrence following a single administration. CNA3103 has also demonstrated impressive tumor access and prolonged survival, enabling rejection of new tumors.

On January 24, 2023 GlycoNet researchers Dr. Chantelle Capicciotti from Queen’s University and Dr. Matthew Macauley from the University of Alberta reported that they are developing technologies to study cancer cells and understand how they evade the immune system (Press release, GlycoNet, JAN 24, 2023, View Source;utm_medium=rss&utm_campaign=glycoengineering-provides-insight-into-new-cancer-immunotherapies [SID1234626488]).

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Normally, the immune system tells abnormal cells apart from healthy ones by the different features on the cells. For example, healthy cells usually display sialic acids, which are a type of sugar, on their cell surfaces. When a family of proteins from the immune system called Siglecs scans these cells, they first bind to sialic acids. The binding triggers a signal telling the body that the encountered cell is safe, helping the immune system distinguish "self" from "non-self." However, cancer cells can trick the immune system by boosting the proportion of sialic acids on their cell surface. When Siglecs meet a cancer cell, a binding interaction occurs, leaving the false impression to the immune system that the cancer cell is safe. The immune system does not attack these cancer cells.

It has been reported that Siglecs are one of the mechanisms cancer cells leverage to evade the immune system, but according to Capicciotti, there is limited understanding of the structures and the identities of biomolecules that Siglecs interact with.

"This is important for developing cancer therapeutics," says Capicciotti, "if we know what is binding to Siglecs, we can block the binding interactions, and the immune system will be able to identify cancer cells and destroy them."

The problem is that there are 15 known Siglecs in humans and a variety of sialic acid-containing sugars as well as sialylated glycoproteins on cell surfaces. Each Siglec binds to different sialic acids and promotes immune responses through distinct mechanisms. Many of these mechanisms and binding interactions are not well-known. To find out which Siglec binds to which type of sialic acid-containing sugars on cell surfaces, Capicciotti and Macauley have joined efforts with Lance Wells and Peng Zhao from the Complex Carbohydrates Research Centre at the University of Georgia, as the teams have complementary tools to solve this puzzle.

In 2020, the Macauley Lab reported the development of a platform that used Velcro-like effects to strengthen the sugar-binding properties of Siglecs, making them easier to study.

In the Capicciotti Lab, researchers have been focusing on glycan editing, where they use enzymes to chew up or install sugar derivatives or glycans on cell surfaces. Traditionally, cell surface remodelling is done by removing the genes that correspond to the enzymes responsible for installing or fragmenting glycans on cell surfaces. However, this method can take weeks, is not always versatile, and requires a comprehensive platform. "By using enzymes to modify cells from the outside, we can remodel the cells within a few hours," says Capicciotti.

For this project, Capicciotti uses the enzymes to selectively install analogues of sialic acids developed from her lab. These analogues have a small chemical functionality that makes them "activatable" by UV light. When the analogue is in proximity with its Siglec binding partner, the UV irradiation cross-links the two molecules. This means they are now linked together chemically and will not fall apart, making the binding interactions easier to detect and isolate. If, however, the Siglec of interest is not the right binding partner of the selectively installed analogue, no cross-linking will occur upon UV irradiation. In this case, the two molecules do not chemically link together, and the researchers can infer that this pair of Siglec and sialic acids likely are not what cancer cells leverage to evade the immune system.

The Capicciotti and Macauley Labs have demonstrated a proof of concept with a panel of enzymes capable of installing UV-activatable sialic acids on cell surfaces that can cross-link with well-studied Siglecs.

"Right now, we’re exploring Siglecs that are less known and less studied," says Capicciotti. "Our next step is to collaborate with proteomics experts at the Complex Carbohydrates Research Centre to uncover which glycoproteins are displaying the sialic acids we installed on the cell surfaces that were involved with binding to the Siglec."

The team’s final goal is to identify targets involved in binding between Siglecs and sialylated glycoproteins on cancer cells. This can facilitate the development of new inhibitors to block off these binding interactions so that the immune system can recognize cancer cells and trigger appropriate immune responses.

This project is funded by GlycoNet, the Complex Carbohydrates Research Centre, Queen’s University and Alzheimer Society of Canada.

On January 24, 2023 Can-Fite BioPharma Ltd. (NYSE American: CANF) (TASE: CANF), a biotechnology company advancing a pipeline of proprietary small molecule drugs that address inflammatory, cancer and liver diseases, reported that its anti-cancer drug Namodenoson significantly inhibits the growth of pancreatic carcinoma as a stand-alone treatment (Press release, Can-Fite BioPharma, JAN 24, 2023, View Source [SID1234626487]). In combination with the leading chemotherapy used in pancreatic cancer, gemcitabine, Namodenoson demonstrated a significant additive effect. These pre-clinical studies were conducted on advanced pancreatic carcinoma patient cells. Namodenoson’s molecular mechanism of action in pancreatic cancer involves the regulation of the NF-κB /IκB /STAT3-mediated pathway.

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Namodenoson is currently being evaluated in a pivotal Phase III study in advanced liver cancer and has completely cleared cancer in an advanced liver cancer patient who remains cancer-free 6 years after starting treatment.

"Following Namodenoson’s successful results in advanced liver cancer, we continue to develop our oncology drug for the treatment of additional aggressive tumors including pancreatic cancer. There is a dire need for a safe and effective treatment for patients with pancreatic carcinoma where Namodenoson has an advantage due to its protective effects on the cardiovascular system, liver, and bone marrow," stated Can-Fite CEO Dr. Pnina Fishman "Our pre-clinical Namodenoson studies in pancreatic cancer, combined with the clinical data from liver cancer, may open the door for an effective and safe treatment in this devastating disease which accounts for nearly a half-million diagnoses and deaths each year."

Based on these findings, Can-Fite has filed a patent application that covers the use of Namodenoson for the treatment of pancreatic cancer.

The highest incidence rates for pancreatic cancer are in Asia, Europe, and North America. According to the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper), in 2020, an estimated 496,000 people were diagnosed with pancreatic cancer globally and an estimated 466,000 died from the disease. The 5-year survival rate for people with pancreatic cancer in the U.S. is 11%. Acumen Research estimates the global pancreatic cancer therapeutics market was valued at approximately $3.6 billion in 2021 and is projected to grow to approximately $6.6 billion by 2030.

About Namodenoson

Namodenoson is a small orally bioavailable drug that binds with high affinity and selectivity to the A3 adenosine receptor (A3AR). Namodenoson was evaluated in Phase II trials for two indications, as a second line treatment for hepatocellular carcinoma, and as a treatment for non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH). A3AR is highly expressed in diseased cells whereas low expression is found in normal cells. This differential effect accounts for the excellent safety profile of the drug.

On January 24, 2023 BioAffinity Technologies, Inc. (NASDAQ: BIAF; BIAFW) reported publication of "Detection of early-stage lung cancer in sputum using automated flow cytometry and machine learning" detailing results of the Company’s clinical trial for its non-invasive diagnostic CyPath Lung in Respiratory Research, one of the leading peer-reviewed open access journals in the field of respiratory medicine (Press release, BioAffinity Technologies, JAN 24, 2023, View Source [SID1234626486]).

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CyPath Lung showed 92% sensitivity and 87% specificity in high-risk patients who had nodules smaller than 20 millimeters or no nodules in the lung, with an area under the ROC curve of 94%. Overall, the test resulted in specificity of 88% and sensitivity of 82%, similar to far more invasive procedures currently used to diagnose lung cancer. More than half of those in the cancer cohort had early Stage I or II lung cancer. CyPath Lung detected multiple forms of cancer including adenocarcinoma, squamous cell carcinoma and small cell lung cancer.

"The fact that CyPath Lung can accurately predict lung cancer at an early stage in patients with small nodules is particularly important. Findings of lesions between six and 20 millimeters as a result of lung cancer screening can lead to unnecessary invasive procedures or a ‘watchful waiting’ period for patients," said Vivienne Rebel, MD, PhD, bioAffinity Chief Medical and Science Officer and Executive Vice President. "Our test is intended for use with patients who display these indeterminant nodules to increase the accuracy of lung cancer screening and provide certainty for patients and their physicians."

"CyPath Lung uses an automated flow-based approach combined with machine learning that can be put into routine lab use without requiring expert evaluation of samples or being subject to operator bias," said Madeleine Lemieux, PhD, who is first author and led development of the automated analysis used in CyPath Lung. "The entire sample is rapidly analyzed which ensures maximal sensitivity. The automated, numerical analysis captures complex interactions between lung cancer and the micro-environment to reliably predict the presence of lung cancer that would not be possible for even expert individuals to do from visual flow data."

Before working with bioAffinity Technologies, Dr. Lemieux was a computational biologist at the Dana Farber Institute and Harvard Medical School. She has contributed to more than 40 publications leveraging data from high-throughput platforms. Dr. Lemieux and Dr. Rebel began their successful collaboration during their doctoral studies.

CyPath Lung uses flow cytometry, a method able to interrogate individual cells in a fraction of a second, and automated analysis to identify parameters in sputum that are indicative of cancer. Unlike genomic or other molecular markers used in liquid biopsies, bioAffinity’s CyPath technology does not collect genetic material for evaluation. Instead, CyPath Lung analyzes the lung micro-environment and identifies whole cell populations that indicate cancer is present in the lung.