On June 7, 2022 Daiichi Sankyo (TSE: 4568) and Sarah Cannon Research Institute (Sarah Cannon) reported that initial results from the first-in-human phase 1 study of DS-6000, a CDH6 directed DXd antibody drug conjugate (ADC), suggest early clinical activity in patients with advanced ovarian cancer or renal cell carcinoma with disease progression following standard of care treatment (Press release, Daiichi Sankyo, JUN 7, 2022, View Source [SID1234615720]). The data were presented today in an oral session (Abstract #3002) at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) (#ASCO22) Annual Meeting.

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Patients with advanced ovarian cancer or renal cell carcinoma may have disease progression after initial treatments and there is a need for new therapeutic approaches for recurrent disease, as five-year survival rates in the U.S. are low at 30% and 15%, respectively.1,2,3,4 The CDH6 protein is significantly overexpressed in ovarian cancer and renal cell carcinoma and has been identified as a promising therapeutic target.5,6

Preliminary safety and efficacy results of DS-6000 were reported from the dose escalation part of the phase 1 trial in 30 heavily pretreated patients, including 21 patients with advanced ovarian cancer, one of which was missing a primary diagnosis of ovarian cancer, and nine patients with renal cell carcinoma.

The safety and tolerability of DS-6000 was evaluated at increasing dose levels from 1.6 mg/kg to 9.6 mg/kg with two dose-limiting toxicities observed at the 9.6 mg/kg dose (grade 3 febrile neutropenia and grade 4 thrombocytopenia). The most common treatment-related emergent adverse events (TEAEs) (≥ 10% of patients) reported were nausea (60.0%), fatigue (56.7%), vomiting (30.0%), neutrophil count decrease (23.3%), decreased appetite (20.0%), and diarrhea (13.3%). Grade ≥ 3 TEAEs occurred in seven patients (23.3%), the most common of which were neutrophil count decrease (16.7%), anemia (6.7%) and febrile neutropenia (6.7%). One patient experienced grade 2 pneumonitis at the 9.6 mg/kg dose that led to treatment discontinuation.

Preliminary efficacy results in 20 evaluable patients included six partial responses (PRs) in patients with ovarian cancer (n=5) and renal cell carcinoma (n=1). Four PRs were confirmed and two are awaiting confirmation. Stable disease was reported in 12 patients with platinum-resistant ovarian cancer. Eight CA-125 responses were observed in 17 evaluable patients with ovarian cancer, based on the Gynecologic Cancer Intergroup (GCIG) criteria.

"These initial results from the first-in-human trial of DS-6000 suggest early signals of safety and efficacy in patients with advanced renal cell or ovarian cancer with disease progression following multiple standard treatments," said Erika Hamilton, MD, Director, Breast Cancer and Gynecologic Cancer Research, Sarah Cannon Research Institute at Tennessee Oncology, Nashville, Tennessee. "Based on these data, enrollment is underway in the dose expansion phase of the trial to further evaluate safety and efficacy of DS-6000 in patients with platinum-resistant ovarian cancer or clear cell renal cell carcinoma."

All patients enrolled in the study (n=30) had received a median of three prior lines of systemic therapies (range, 1-12), including four (range, 1-12) for patients with ovarian cancer and two (range, 1-6) for patients with renal cell carcinoma. Seventeen of the 20 patients with ovarian cancer had platinum-resistant disease. As of the data cut-off on February 25, 2022, 17 patients (56.7%) were still being treated with DS-6000 including 12 patients with ovarian cancer and five patients with renal cell carcinoma.

"Despite recent additions to the treatment landscapes for recurrent ovarian and renal cell cancer, continued innovation is needed to improve outcomes for these patients. We have combined our DXd ADC technology with a promising therapeutic target, CDH6, with the aim to develop a new class of therapy for patients with cancer," said Gilles Gallant, BPharm, PhD, FOPQ, Senior Vice President, Global Head, Oncology Development, Oncology R&D, Daiichi Sankyo. "We are encouraged by these preliminary data, which suggest that DS-6000 may have the potential to serve as a new type of targeted therapy option for patients with advanced renal cell or ovarian tumors, including platinum-resistant ovarian cancer, and further evaluation is ongoing in the dose expansion part of the trial."

About the Phase 1 Study

The two-part, multicenter, open-label, first-in-human phase 1 trial is evaluating the safety and efficacy of DS-6000 in adult patients with advanced ovarian cancer and renal cell carcinoma resistant or refractory to standard of care therapy. Patients with ovarian cancer need to be previously treated with platinum-based chemotherapy and a taxane.

The first part of the study (dose escalation) is assessing the safety and tolerability of increasing doses of DS-6000 to determine the maximum tolerated dose (MTD) and/or recommended dose for expansion (RDE). The second part of the study (dose expansion) will further evaluate the safety and efficacy of DS-6000 at the RDE of 8.0 mg/kg in patients with advanced ovarian cancer and in patients with advanced renal cell carcinoma.

The primary objective of the dose escalation part of the study is to assess the safety and tolerability of increasing doses of DS-6000 to determine the maximum tolerated dose (MTD) and/or recommended dose for expansion (RDE) in patients with advanced ovarian tumors or renal cell carcinoma. The primary objective of the second part of the study (dose expansion) is to further evaluate the safety and efficacy of DS-6000 at the RDE in two cohorts including patients with advanced renal cell carcinoma in Cohort 1 and patients with advanced ovarian cancer in Cohort 2. The study will evaluate safety endpoints including dose-limiting toxicities and adverse events and efficacy endpoints including objective response rate, duration of response, disease control rate, clinical benefit rate, time to response and progression-free survival. Pharmacokinetic and exploratory biomarker endpoints also will be assessed.

A total of approximately 102 patients are expected to be enrolled in this study at multiple sites in the U.S. For more information, please visit Clinicaltrials.gov.

About CDH6

CDH6 (human cadherin-6) is a cadherin family protein overexpressed in several cancers, particularly ovarian tumors and renal cell carcinoma.5 Overexpression of CDH6 is associated with tumor growth and proliferation and is correlated with poor prognosis in patients with renal cell carcinoma.5 No CDH6 directed cancer therapies are currently approved for treatment of any cancer.

About Ovarian Cancer and Renal Cell Carcinoma

Approximately 314,000 women were diagnosed with ovarian cancer worldwide in 2020 and more than 207,000 died from the disease.7 The five-year survival rate for patients in the U.S. with advanced ovarian cancer is 30%.3 More than 70% of patients diagnosed with stage III or IV ovarian cancer will have a recurrence of their disease within the first five years following standard treatment with platinum chemotherapy-based regimens.8 For patients who develop resistance to platinum-based chemotherapy, treatment options are especially limited.8

Renal cell carcinoma accounts for approximately 90% of all kidney cancer.9 Approximately 431,000 people were diagnosed with kidney cancer worldwide in 2020 and more than 179,000 people died from the disease.7 The five-year survival rate for patients in the U.S. with advanced renal cell carcinoma is 15%.4 Patients with advanced or metastatic renal cell cancer may progress after first-line treatment with immune checkpoint inhibitor-based regimens and have limited treatment options as disease progression continues.10

The introduction of targeted treatments and immunotherapies in recent years has increased options and improved survival outcomes for some patients with ovarian cancer or renal cell carcinoma, but new therapeutic approaches and options are needed for tumors that progress on available medicines.10,11

About DS-6000

DS-6000 is an investigational potential first-in-class CDH6 directed ADC and one of five ADCs in clinical development in the oncology pipeline of Daiichi Sankyo. Designed using Daiichi Sankyo’s proprietary DXd ADC technology, DS-6000 is comprised of a humanized anti-CDH6 IgG1 monoclonal antibody attached to a number of topoisomerase I inhibitor payloads (an exatecan derivative, DXd) via tetrapeptide-based cleavable linkers.

Daiichi Sankyo is developing DS-6000 through a strategic collaboration with Sarah Cannon Research Institute with study operational oversight and delivery provided through Sarah Cannon’s early phase oncology clinical research organization, Sarah Cannon Development Innovations in Nashville, TN.

DS-6000 is an investigational medicine that has not been approved for any indication in any country. Safety and efficacy have not been established.

On June 7, 2022 Evaxion Biotech A/S (NASDAQ: EVAX) ("Evaxion" or the "Company"), a clinical-stage biotechnology company specializing in the development of AI-powered immunotherapies, reported that it has entered into a committed equity purchase agreement (the "Agreement") with Lincoln Park Capital Fund, LLC ("LPC"), for the issuance and sale, from time to time, of up to $40 million of its American Depositary Shares (the "ADSs"), each of which represents one ordinary share, DKK 1 nominal value, of the Company (the "Ordinary Shares") (Press release, Evaxion Biotech, JUN 7, 2022, View Source [SID1234615741]).

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Under the terms of the Agreement, Evaxion has the right, at its sole discretion, but not the obligation, to sell to LPC up to $40 million of its ADSs over the 36-month term of the Agreement, subject to certain conditions.

Lars Wegner, CEO of Evaxion, said: "We are pleased to conclude this Agreement with Lincoln Park Capital, securing access to $40 million from a widely respected investor in the biotech industry and further strengthening Evaxion’s financial position during a period of market uncertainty. This equity facility will contribute to the progression of our exciting portfolio of assets, including personalized cancer medicines, developed in programs EVX-01 and EVX-02, both of which are currently in Phase 2 clinical development, according to plan. This gives us momentum to reach our value-creating, upcoming clinical milestones. Importantly, it also maintains Evaxion’s flexibility in deciding if and when to exercise the option to sell, so we can continue to choose the optimum development path for the Company."

Evaxion had cash and cash equivalents of $31.4 million at the end of the first quarter of 2022 and expects its cash position, without proceeds from the Agreement, to be sufficient to fund operating expenses and capital expenditure requirements through at least the next 12 months.

There are no upper limits to the price LPC may pay to purchase the ADSs, and the purchase price will be based on the prevailing market prices of the ADSs at the time of each sale to LPC. Evaxion controls the timing and amount of any future sales of its ADSs to LPC. The Company may terminate the Agreement at any time, in its sole discretion, without any additional cost or penalty. In consideration for entering into the Agreement, LPC received 428,572 Ordinary Shares represented by ADSs from the Company.

On June 6, 2022 Cogent Biosciences, Inc. (Nasdaq: COGT), a biotechnology company focused on developing precision therapies for genetically defined diseases, reported it will host an investor webcast on Friday, June 10, 2022 at 8:00am ET (2:00pm CEST) to discuss initial clinical data from its on-going Phase 2 APEX trial evaluating bezuclastinib in patients with Advanced Systemic Mastocytosis being presented at the European Hematology Association (EHA) (Free EHA Whitepaper) Congress (Press release, Cogent Biosciences, JUN 6, 2022, View Source [SID1234615619]).

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The event will be led by Andrew Robbins, Cogent’s President and CEO, and will include a presentation by Daniel J. DeAngelo, M.D., Ph.D., Chief of the Division of Leukemia at the Dana-Farber Cancer Institute. The speakers and additional members of Cogent leadership will be available during the Question and Answer session.

The webcast will be accessible through the Investors and Media section of Cogent’s website at www.cogentbio.com. Following the live webcast, an archived replay will also be available.

On June 6, 2022 Enlivex Therapeutics Ltd. (Nasdaq: ENLV, the "Company"), a clinical-stage macrophage reprogramming immunotherapy company targeting diseased macrophages in patients with sepsis and solid tumors, reported that the Israeli Ministry of Health (MOH) authorized the initiation of a company-sponsored Phase I/II clinical trial evaluating Allocetra combined with chemotherapy in patients with peritoneal metastases arising from solid cancer (Press release, Enlivex Therapeutics, JUN 6, 2022, View Source [SID1234615635]).

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Peritoneal cancer, whether originating from a primary tumor within the peritoneum or from a metastatic tumor elsewhere in the body, is a terminal disease with a poor prognosis. Patients with peritoneal metastases are in urgent need of novel treatment options, as standard-of-care (SOC) chemotherapy provides only modest survival benefits. The median survival of patients with peritoneal metastases differs based on the location of the primary tumor but is frequently poor, with survival rates of 2.9 months, 6.5 months, and 6.9 months reported for cancers of pancreatic, gastric, and colorectal origins, respectively.

The planned Phase I/II trial is an open-label dose escalation and expansion trial that is expected to enroll a total of approximately 12 patients across four cohorts. It is designed to evaluate the safety and potential preliminary efficacy of Allocetra combined with SOC chemotherapy in patients with peritoneal metastases arising from solid cancer. The study will begin with two cohorts of intra-patient and intra-cohort dose escalation to determine the maximum feasible dose (MFD) of Allocetra in this population, followed by two additional cohorts comparing administration of Allocetra at the selected dose either before or after administration of SOC via a pressurized intraperitoneal aerosol chemotherapy procedure (PIPAC; a technique applied when patients are not eligible to receive the standard treatment due to a considerable tumor load, or large quantities of persistent ascites and other circumstances).

Intraperitoneally delivered Allocetra and SOC chemotherapy administered via PIPAC will be given to patients every six weeks. Systemic chemotherapy will also be administered per the treating oncologist’s plan. The primary endpoint is the number and severity of Allocetra-related adverse events and serious adverse events during the 16-week period, starting from the first administration of study treatment. Secondary endpoints include efficacy assessments, such as best overall response rate (ORR), progression-free survival, and overall survival. Changes from baseline in macrophage and immune cell characteristics in peritoneal fluid and tissues will also be assessed as an exploratory endpoint.

Currently, the efficacy of many anti-cancer agents is hampered by the body’s tumor defense mechanisms that facilitate the recruitment of macrophages which become "pro-tumor" tumor associated macrophages (TAMs) rather than "anti-tumor" macrophages. The TAMs typically form a physical layer on top of the solid tumor and induce immunosuppression in the solid tumor microenvironment. This in-turn promotes tumor growth and metastasis and contributes to poor clinical outcomes and response to therapy. Previously reported preclinical data from solid tumor models suggest that Allocetra has the potential to reprogram pro-tumor macrophages back to their homeostatic state and may thereby promote disease resolution and provide patients that do not respond well to existing FDA-approved therapies with an effective treatment option.

Einat Galamidi, M.D., Vice President, Medical of Enlivex, stated: "Receiving this authorization from the MOH is an important step toward expanding Allocetra’s potential therapeutic impact into oncology. Our preclinical studies suggest Allocetra may enhance the efficacy of a broad range of therapeutic agents by weakening tumor defense mechanisms through a novel mechanism of action that drives macrophage populations towards a more anti-cancer state. We look forward to beginning the clinical evaluation of this hypothesis through both this chemotherapy combination study and an additional planned solid tumor study that will evaluate Allocetra combined with a checkpoint inhibitor."

Enlivex plans to initiate the Phase I/II trial evaluating Allocetra in combination with chemotherapy in patients with peritoneal metastases arising from solid cancer in Q3 2022. The Company also expects to initiate a Phase I/II trial evaluating Allocetra in combination with an immune checkpoint inhibitor in late 2022.

ABOUT ALLOCETRATM

Allocetra is being developed as a universal, off-the-shelf cell therapy designed to reprogram macrophages into their homeostatic state. Diseases such as solid cancers, sepsis, and many others reprogram macrophages out of their homeostatic state. These non-homeostatic macrophages contribute significantly to the severity of the respective diseases. By restoring macrophage homeostasis, Allocetra has the potential to provide a novel immunotherapeutic mechanism of action for life-threatening clinical indications that are defined as "unmet medical needs", as a stand-alone therapy or in combination with leading therapeutic agents.

On June 6, 2022 Cellworks Group, Inc., a world leader in Personalized Medicine in the key therapeutic areas of Oncology and Immunology, reported results from the myCare-004 study, which demonstrate that the Cellworks Singula Therapy Response Index (TRI) is highly predictive of Overall Survival (OS), Disease-Free Survival (DFS) and Mandard-tumor regression grade (TRG) for gastroesophageal adenocarcinoma (GEA) patients (Press release, Cellworks, JUN 6, 2022, View Source [SID1234615652]). In this retrospective study, Singula TRI provided additional predictive information for OS and DFS beyond patient age, patient gender and physician-prescribed treatment.

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The results from the myCare-004 clinical study were featured in a poster session as part of the 2022 ASCO (Free ASCO Whitepaper) Annual Meeting during the Gastrointestinal Cancer – Gastroesophageal Pancreatic and Hepatobiliary Track and available online as Abstract 4064.

"This study confirmed that there are many dysregulated signaling pathways responsible for hallmark behaviors of cancer and variable drug response in gastroesophageal adenocarcinoma patients," said Dr. Elizabeth Smyth, Cambridge University Hospitals NHS Foundation Trust and Co-Principal Investigator of the myCare-004 clinical study. "Cellworks personalized therapy biosimulation enables us to utilize a patient’s comprehensive next generation sequencing (NGS) results and understand the downstream molecular effects of specific drugs on cell signaling to predict how each patient will respond to therapies prior to treatment. The next step is to evaluate whether biosimulation-informed therapy selection can be used prospectively to improve the survival of GEA patients."

"Gaining a better understanding of the molecular determinants of gastroesophageal adenocarcinoma is key to improving therapy response rates for GEA patients," said Dr. Rebecca Fitzgerald, MD, Professor of Cancer Prevention at the University of Cambridge; Director of the CRUK Cambridge Centre Early Detection Institute; and Co-Principal Investigator of the myCare-004 clinical study. "There are limited treatment options for this cancer type and we look forward to testing the Cellworks personalized therapy predictions in a prospective trial."

The Cellworks Biosimulation Platform simulates how a patient’s personalized genomic disease model will respond to therapies prior to treatment and identifies novel drug combinations for treatment-refractory patients. The platform is powered by the groundbreaking Cellworks Computational Omics Biology Model (CBM), a network of 7,000+ human genes, 30,000+ molecular species and 100+ signaling pathways. As part of the biosimulation process, personalized disease models are created for each patient using their cytogenetic and molecular data as input to the Cellworks CBM. The Cellworks platform analyzes the impact of specific therapies on the patient’s personalized disease model and generates a Singula biosimulation report with Therapy Response Index (TRI) scores from 0 to 100 that predict the efficacy of specific chemotherapies.

myCare-004 Clinical Study

Background

In this study, the Cellworks Singula Therapy Response Index (TRI) was used to prospectively predict the Overall Survival (OS), Disease Free Survival (DFS) and Mandard-tumor regression grade (TRG) in a retrospective cohort of gastroesophageal adenocarcinoma patients from the UK OCCAMS consortium. 271 GEA patients were selected who had pre-chemo treated biopsies with 50x whole genome sequencing. 234 patients were male and 30 female with a median age of 65.6 years. Within the study population, there were 35 T2, 215 T3, 70 N0, 126 N1, 62 N2 and 266 M0. Patients were prescribed chemotherapy treatments according to UK clinical guidelines.

Methods

A mechanistic model created for each patient using comprehensive genomic inputs biosimulated downstream molecular effects of cell signaling and drugs for a patient’s personalized in silico disease model. Random sampling stratified by clinical factors was used to split the data into independent training (N=140) and validation (N=131) subsets. Multivariant Cox Proportional Hazard (PH) and Proportional Odds models were used to predict survival and pathological response as a function of the pre-defined Therapy Response Index (TRI) and clinical thresholds compared with standard clinical factors.

Results

Cellworks Personalized Therapy Biosimulation found that 99% of the patients’ tumors had deficiency in DNA repair genes. Other pathways included amplification of multi-drug resistance pumps, TP53 mutations and aberrations of the PI3K/AKT pathway genes. Cellworks Singula Therapy Response Index (TRI) provided additional predictive information for OS and DFS beyond physician prescribed treatment and standard clinical factors. TRI was also predictive of TRG in univariate analysis. TRI scores were generated for 82 alternate therapies for each patient, enabling selection of optimal therapies with estimates of improvements in median OS and DFS compared to standard care (SC).

Conclusions

The study found that Cellworks Singula TRI was predictive of Overall Survival (OS), Disease-Free Survival (DFS) and Mandard-tumor regression grade (TRG) beyond clinical factors in this cohort of gastroesophageal adenocarcinoma (GEA) patients. These positive results suggest the utility of biosimulation-informed therapy selection to improve survival of GEA patients.