On March 11, 2024 Calidi Biotherapeutics Inc. (NYSE American: CLDI) ("Calidi"), a clinical-stage biotechnology company developing a new generation of targeted oncolytic virotherapies, and City of Hope, one of the largest cancer research and treatment organizations in the United States, today jointly reported that the California Institute for Regenerative Medicine (CIRM) has awarded Karen Aboody, M.D., City of Hope professor in the Department of Stem Cell Biology and Regenerative Medicine and Division of Neurosurgery, a $5.3 million grant to fund preclinical translational studies, product manufacturing, and clinical trial design using Calidi’s licensed oncolytic virotherapy product, CLD-101, in patients with chemo-resistant, metastatic ovarian cancer (Press release, Calidi Biotherapeutics, MAR 11, 2024, View Source [SID1234641041]). CLD-101 is the lead therapeutic candidate in Calidi’s NeuroNova program, comprising tumor-tropic neural stem cells (NSCs) that deliver an oncolytic adenovirus (NSC-CRAd-S-pk7) selectively to tumor sites.

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Aboody and her team have been key collaborators with Calidi over the past four years, and Calidi’s knowledge and expertise has enhanced key attributes of the CLD-101 program, in particular Calidi’s next generation manufacturing process and potency optimization, leading to higher yields and improved oncolytic activity of the CLD-101 product for use in high-grade glioma, and now ovarian cancer. This proposed CLD-101 treatment utilizes a neural stem cell line to deliver an oncolytic adenovirus directly to abdominal ovarian tumor sites. The virus infects and kills the tumor cells, even if they are chemo-resistant, which then stimulates the patient’s immune system to infiltrate, recognize, and fight the tumor. In collaboration with Calidi, Aboody will lead the groundbreaking work.

"We are delighted to receive this financial support from CIRM, which enables us to complete the preclinical translational studies, product manufacturing, and clinical trial design needed for FDA approval to move this novel treatment to ovarian cancer patients within two to three years. This CIRM grant will allow us to further utilize Calidi’s manufacturing processes, which we believe will optimize the potency of the CLD-101 oncolytic virotherapy treatment product, and improve clinical outcomes for women with stage III ovarian cancer," said Aboody.

"This is the third grant from CIRM supporting the development of Calidi’s assets, further validating our novel cell therapy platforms and their versatility for multiple cancer indications," said Allan Camaisa, CEO and Chairman of the Board of Calidi Biotherapeutics. "We have been focused on enhanced cell manufacturing processes and providing novel options to patients with a variety of serious cancers, and we are grateful for the continued support from CIRM, as we advance our clinical programs."

In July 2023, Calidi announced the dosing of the first patient in a City of Hope Phase 1 clinical trial evaluating CLD-101 in recurrent high-grade glioma patients. The company expects to provide a clinical update in the first half of 2024. Additionally, a previously completed Phase 1 dose escalation trial assessed the safety of a single dose of CLD-101 administered into the walls of the surgical resection cavity, in newly diagnosed high-grade glioma patients. In this trial, CLD-101 demonstrated safety and the stimulation of an anti-tumor response, with results published in Lancet Oncology.

For more information about this trial, click here or contact [email protected] or (626) 218-4062.

Aboody has financial interest in and is a paid advisory board member for Calidi Biotherapeutics.

About CLD-101

The CLD-101 platform, which includes NSC-CRAd-S-pk7, is an allogeneic, "off-the-shelf" therapy comprised of an immortalized NSC line loaded with an engineered oncolytic adenovirus. In High Grade Glioma brain cancer patients, upon surgical resection of tumor, NSC-CRAd-S-pk7 is injected into the walls of the resection cavity. The anti-cancer virus it releases is expected to infect and kill any remaining tumor cells, which is also postulated to stimulate a tumor-specific immune response from the patient. Calidi holds an exclusive worldwide licensing agreement covering the NSC-CRAd-S-pk7 technology.

On March 11, 2024 Novocure (NASDAQ: NVCR) reported a late breaking abstract which reviews the results of an exploratory subgroup analysis of the phase 3 ENGOT-ov50 / GOG-3029 / INNOVATE-3 (INNOVATE-3) clinical trial has been selected for presentation at the "Best Oral Session – Late Breaking Abstracts" on Sunday, March 10, 2024 at the European Society on Gynaecological Oncology (ESGO) 2024 Congress in Barcelona (Press release, NovoCure, MAR 11, 2024, View Source [SID1234641040]).

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The randomized, phase 3 INNOVATE-3 clinical trial evaluated the use of Tumor Treating Fields (TTFields) therapy together with paclitaxel in platinum-resistant ovarian cancer (PROC) in patients with a maximum of five total prior lines of systemic therapy. While the INNOVATE-3 study did not meet its primary endpoint of overall survival in the intent-to-treat population, an exploratory analysis of a subgroup from the trial concluded that PLD-naïve patients treated with TTFields therapy and paclitaxel saw a significant improvement in overall survival compared to PLD-naïve patients treated with paclitaxel alone. Of the 558 total patients enrolled in the INNOVATE-3 clinical trial, 201 patients (36%) were PLD-naïve. Overall survival in PLD-naïve patients randomized to receive TTFields therapy and paclitaxel was 16.0 months (n=113), compared to 11.7 months in PLD-naïve patients randomized to receive paclitaxel alone (n=88). In the PLD-naïve subgroup, baseline demographics were similar across both cohorts. Novocure is further exploring the effect of doxorubicin on tumor tissue alteration and the potential consequences for TTFields dose. The findings from this post-hoc analysis may help explain the potential survival benefit observed in INNOVATE-3 patients who received only one prior line of therapy, as previously reported. TTFields therapy was well-tolerated, and no additive systemic toxicity or safety signals were observed.

"We are extremely pleased to share these data with our colleagues at ESGO and humbled by the selection for a best oral presentation session," said primary investigator Professor Ignace Vergote, MD, PhD, Professor at the Catholic University of Leuven, Belgium. "There is an immense clinical need for safe, effective and less toxic therapies for PROC patients and I look forward to continued exploration of TTFields therapy in gynecological cancers."

"The presentation of these data is an exciting achievement for the INNOVATE-3 investigators, as well as the Novocure team, reflecting exceptional work, collaboration and dedication," said Nicolas Leupin, MD, PhD, Novocure’s Chief Medical Officer. "I would like to thank our collaborators, ENGOT and The GOG Foundation, for their partnership designing and conducting the INNOVATE-3 trial. These findings provide valuable new insights, and we are eager to continue exploring the capabilities of TTFields therapy in the treatment of solid tumors."

The exploratory analysis from the INNOVATE-3 data will be presented on Sunday, March 10, 2024 at 11:50 a.m. UTC+1 by Professor Vergote, and has been selected for inclusion in the "Best Oral Session – Late Breaking Abstracts" as part of the European Society on Gynaecological Oncology (ESGO) annual congress.

About ENGOT-ov50 / GOG-3029 / INNOVATE-3
The ENGOT-ov50 / GOG-3029 / INNOVATE-3 clinical trial was designed to evaluate the safety and effectiveness of TTFields together with paclitaxel in patients with platinum-resistant ovarian cancer and a maximum of five total prior lines of systemic therapy. The primary endpoint of INNOVATE-3 was overall survival. Secondary endpoints include progression-free survival, objective response rate, severity and frequency of adverse events, time to undisputable deterioration in health-related quality of life or death, and quality of life. Enrollment in the trial closed in October 2021 with 558 patients enrolled, beginning the minimum 18-month follow-up period. In 2023, Novocure announced the trial did not meet its primary endpoint. Together with investigators, the company will continue to analyze the data from the INNOVATE-3 trial.

The European Network for Gynaecological Oncological Trial groups ("ENGOT") and The GOG Foundation, Inc. ("GOG"), third-party clinical trial networks, collaborated with Novocure on the trial. Both ENGOT and GOG were involved in the development and facilitation of the trial at leading cancer centers in Europe and the United States.

About Ovarian Cancer
In the U.S., ovarian cancer ranks fifth in cancer deaths among women, with approximately 24,000 women diagnosed each year. Ovarian cancer incidence increases with age, and the median age at time of diagnosis is 63 years old.

Physicians use different combinations of surgery and pharmacological therapies to treat ovarian cancer, depending on the stage of the disease. Surgery is usually used in early stages of the disease and is usually combined with chemotherapy, including paclitaxel and platinum-based chemotherapy. Unfortunately, the majority of patients are diagnosed at an advanced stage when the cancer has spread outside of the ovaries to include regional tissue involvement and/or metastases. Platinum-based chemotherapy remains part of the standard of care in advanced ovarian cancer, but most patients with advanced ovarian cancer will have tumor progression or, more commonly, recurrence. Almost all patients with recurrent disease ultimately develop platinum resistance, and the prognosis for this population remains poor.

About Tumor Treating Fields Therapy
Tumor Treating Fields (TTFields) are electric fields that exert physical forces to kill cancer cells via a variety of mechanisms. TTFields do not significantly affect healthy cells because they have different properties (including division rate, morphology, and electrical properties) than cancer cells. The multiple, distinct mechanisms of TTFields therapy work together to selectively target and kill cancer cells. Due to its multimechanistic actions, TTFields therapy can be added to cancer treatment modalities in approved indications and demonstrates enhanced effects across solid tumor types when used with chemotherapy, radiotherapy, immune checkpoint inhibition, or PARP inhibition in preclinical models. TTFields therapy provides clinical versatility that has the potential to help address treatment challenges across a range of solid tumors. To learn more about Tumor Treating Fields therapy and its multifaceted effect on cancer cells, visit tumortreatingfields.com.

On March 11, 2024 Delta-Fly Pharma reported that Following to the previous information on Jan. 30th. in 2024, we are excited to share our latest development status (Press release, Delta-Fly Pharma, MAR 11, 2024, https://www.businesswire.com/news/home/20240311048389/en/Delta-Fly-Pharma-Inc.-FDA-submission-of-the-protocol-of-the-Phase-III-study-of-DFP-10917-combined-with-Venetoclax-VTX-in-the-AML-patients-pretreated-by-VTX-involved-one-regimen [SID1234641039]).

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FDA submission of the protocol of the Phase I/II study of DFP-10917 combined with Venetoclax (VTX) in the AML patients pretreated by VTX involved one regimen have been done on March 8th, 2024.

The Phase I/II study of DFP-10917 with VTX in the above AML patients shall be started at Wake Forest and the other hospitals soon after FDA approval.

The interim analysis of the Phase III study of DFP-10917 in patients with recurrent or refractory acute myeloid leukemia (R/R AML) at multicenter in the US is undergoing for the reason there are patients with a long-term survival may effect on OS analysis.

The invention with the combination of DFP-14927 with VTX in AML was granted in Japan, US, and Taiwan.

Please take notice of our own innovative approach for miserable cancer patients and contact with us.

On March 11, 2024 Verastem Oncology (Nasdaq: VSTM), a biopharmaceutical company committed to advancing new medicines for patients with cancer, reported multiple oral and poster presentations, including a late-breaking oral presentation of avutometinib and defactinib combination from the RAMP 201 Part A trial in heavily pretreated patients with low-grade serous ovarian cancer (LGSOC), at the Society of Gynecologic Oncology (SGO) 2024 Annual Meeting on Women’s Cancer, to be held on March 16-18 in San Diego, California (Press release, Verastem, MAR 11, 2024, View Source [SID1234641038]). Verastem will have an exhibition booth (#420) at the meeting to provide an overview of its ongoing cancer research.

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"Important subgroup analyses from Part A of the Phase 2 RAMP 201 clinical trial evaluating avutometinib and defactinib demonstrate how our research in low-grade serous ovarian cancer continues to elucidate the potential use of this combination in a heavily pretreated patient population, including patients who received a prior MEK-only inhibitor," said Dan Paterson, president and chief executive officer of Verastem Oncology. "In addition, the plenary oral presentation highlighting preclinical efficacy of avutometinib in combination with a FAK inhibitor reinforces the potential of this combination in low-grade serous ovarian cancer regardless of KRAS status. Furthermore, the oral presentation from the LGSOC Patient Impact Survey, that is supported by Verastem Oncology, highlights the negative social and emotional impact patients experience living with this rare ovarian cancer."

Key Data Presentations:

Late-Breaking Oral Presentation

Title: Avutometinib plus defactinib in recurrent, low-grade serous ovarian cancer: A subgroup analysis of ENGOT-ov60/GOG-3052/RAMP 201 Part A
Session: Scientific Plenary IV: Late Breaking Abstract Session 1
Date/Time: Sunday, March 17, 2024, 4:15 – 5:30 p.m. PDT
Presenter: Dr. Susanna Banerjee, BBS, MA, PhD, FRCP
Focused Plenary Oral Presentation

Title: Preclinical efficacy of RAF/MEK clamp avutometinib in combination with FAK inhibition for low grade serous ovarian cancer
Session: Focused Plenary V: Rare Cancer: Updates in Uncommon Cancers
Date/Time: Sunday, March 17, 2024, 1:45 – 2:45 p.m. PDT
Presenter: Michelle Greenman, MD, MPH
Oral Poster Presentation

Title: Voices of women with low-grade serous ovarian cancer: Results from a multinational survey
Session: Poster Session II
Date/Time: Monday, March 18, 2024, 11:45 a.m. – 12:45 p.m. PDT
Presenter: Charlotte C. Sun, DrPH, MPH
Trials in Progress Poster Presentation

Title: A phase III, randomized trial evaluating avutometinib plus defactinib compared with investigator’s choice of therapy in patients with recurrent low-grade serous ovarian cancer: GOG-3097/ENGOT-ov81/NCRI/RAMP 301
Session: Poster Session II
Date/Time: Monday, March 18, 2024, 11:45 a.m. – 12:45 p.m. PDT
Presenter: Rachel N. Grisham, MD
Drs. Banerjee and Grisham are paid consultants for Verastem Oncology. The multinational survey is supported by Verastem Oncology.

About the Avutometinib and Defactinib Combination

Avutometinib is a RAF/MEK clamp that induces inactive complexes of MEK with ARAF, BRAF and CRAF potentially creating a more complete and durable anti-tumor response through maximal RAS/MAPK pathway inhibition. In contrast to currently available MEK-only inhibitors, avutometinib blocks both MEK kinase activity and the ability of RAF to phosphorylate MEK. This unique mechanism allows avutometinib to block MEK signaling without the compensatory activation of MEK that appears to limit the efficacy of other MEK-only inhibitors. The U.S. Food and Drug Administration (FDA) granted Breakthrough Therapy designation for the combination of Verastem Oncology’s investigational RAF/MEK clamp avutometinib, with defactinib, a selective FAK inhibitor, for the treatment of all patients with recurrent LGSOC regardless of KRAS status after one or more prior lines of therapy, including platinum-based chemotherapy. Avutometinib alone or in combination with defactinib was also granted Orphan Drug Designation by the FDA for the treatment of LGSOC.

Verastem Oncology is currently conducting clinical trials with its RAF/MEK clamp avutometinib in RAS pathway-driven tumors as part of its (Raf And Mek Program). RAMP 301 (NCT06072781) is a Phase 3 confirmatory trial evaluating the combination of avutometinib and defactinib versus standard chemotherapy or hormonal therapy for the treatment of recurrent LGSOC. RAMP 201 (NCT04625270) is a Phase 2 registration-directed trial of avutometinib in combination with defactinib in patients with recurrent LGSOC and has completed enrollment in the dose optimization and expansion phases and is enrolling for low-dose evaluation.

Verastem Oncology has established clinical collaborations with Amgen and Mirati to evaluate LUMAKRAS (sotorasib) and KRAZATI (adagrasib) in combination with avutometinib in KRAS G12C mutant NSCLC as part of the RAMP 203 (NCT05074810) and RAMP 204 (NCT05375994) trials, respectively. Supported by the "Therapeutic Accelerator Award" Verastem Oncology received from PanCAN, Verastem Oncology is conducting RAMP 205 (NCT05669482), a Phase 1b/2 clinical trial evaluating avutometinib and defactinib with gemcitabine/nab-paclitaxel in patients with front-line metastatic pancreatic cancer.

On March 11, 2024 Cellworks Group Inc., a leader in Personalized Therapy Decision Support and Precision Drug Development, reported the results from a real-world study of gastroesophageal cancer which found that Therapy Response Index (TRI) scores generated using the Cellworks Biosimulation Platform predicted overall survival (OS) above and beyond standard clinical factors, including patient age, sex, and tumor-node-metastasis (TNM) staging (Press release, Cellworks, MAR 11, 2024, View Source [SID1234641037]). The study also showed a significant association between a patient’s TRI score and disease-free survival (DFS) and tumor regression grade (TRG).

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The peer-reviewed paper, ‘Integration of genomic aberrations to predict clinical outcomes for patients with gastroesophageal adenocarcinoma receiving neoadjuvant chemotherapy,’ is available at ESMO (Free ESMO Whitepaper) Gastrointestinal Oncology.

Despite progress in gastroesophageal cancer therapy, only a small proportion of patients attain long-term survival. Previous precision-based strategies have been constrained by focusing on single biomarker–drug associations. This oversimplified approach to the disease has resulted in a wide spectrum of patient outcomes, with long-term survival rates spanning from 25% to 75% using multi-modality therapy — a combination of chemotherapy, radiation, surgical resection, and adjuvant nivolumab, which has become the standard of care.

"The focus for guiding treatment decisions for gastroesophageal patients has centered on specific biomarkers such as HER2, MSI, PD-L1 and CLD18.2," said Dr. Elizabeth Smyth, Oxford University Hospitals NHS Foundation Trust; and Co-Principal Investigator of the study. "However, further refinement of treatment selection using computational biomarkers might be possible. This study highlights the unique value that Cellworks computational biosimulation can bring to the treatment decision process by utilizing a patient’s comprehensive genomic profile and biosimulating all possible therapy combinations. This approach could offer a promising avenue for recommending a treatment strategy at an individual level, thereby improving patient outcomes."

"The size and complexity of comprehensive genomic panels pose a formidable challenge, making it difficult for oncologists to translate the intricate biology into actionable clinical decisions," said Dr. Rebecca Fitzgerald, MD, Professor of Cancer Prevention at the University of Cambridge; Director of the Early Cancer Institute; and Co-Principal Investigator of the study. "This study demonstrates that utilizing whole genome sequencing of a patient’s gastroesophageal cancer along with Cellworks personalized biosimulation approach has the potential to highlight when alternative treatment strategies such as fluoropyrimidines, taxanes, anthracyclines or platinum compounds may yield superior outcomes for a specific patient."

"The transition from small panel NGS to whole exome and whole genome sequencing brings new insights about each cancer’s complex proteogenomic network," said Dr. Michael Castro M.D., Oncologist at Beverly Hills Cancer Center; and Chief Medical Officer at Cellworks, Group Inc. "These insights reveal the basis for drug sensitivity and resistance that allows oncologists to select the optimal combination therapy for individual patients and creates the possibility of targeting the sources of therapeutic resistance. The view that genomic information is ‘unactionable’ is transformed by artificial intelligence (AI)-level molecular diagnosis provided by Cellworks’ biosimulation. Most genomic information that can be measured is highly relevant to tumor biology and treatment response but is beyond the grasp of busy clinicians. With Cellworks biosimulation, the oncogene-only approach to precision medicine is already obsolete."

Clinical Study

Methods
The performance of Cellworks in silico biosimulation and Therapy Response Index (TRI) scores were studied in patients with gastroesophageal adenocarcinoma (OGA) with operable cancers from the UK Oesophageal Cancer Clinical and Molecular Stratification (OCCAMS) International Cancer Genome Consortium study. A total of 270 patients with OGA were selected who had 50x whole genome sequencing carried out on tissue derived from either biopsy or resection within 12 months of treatment. Patients were treated with chemotherapy drugs or regimes according to UK clinical guidelines.

Biosimulation was carried out utilizing the Cellworks computational biology model (CBM), which uses both mechanistic and statistical approaches to integrate a patient’s genomic aberrations, revealing signaling pathway dysregulation and variable drug response. Using patient-specific predictions derived from the CBM, a TRI score was used to predict therapeutic overall survival (OS), disease-free survival (DFS) and tumor regression grade (TRG).

Results
The results of the study revealed that the association of TRI value with overall survival (OS) for gastroesophageal adenocarcinoma patients was significant (P = 0.0012) above and beyond standard clinical factors including patient age, sex, tumor-node-metastasis (TNM) stage and neoadjuvant therapy. The association between TRI values and disease-free survival (DFS) was also significant (P = 0.0288). In addition, the TRI values optimized for tumor regression grade (TRG) displayed a significant association (P = 0.0011).

Conclusions
This study concluded that TRI scores for gastroesophageal adenocarcinoma patients predict OS and DFS beyond clinical factors. These results highlight the clinical value of employing Cellworks biosimulation for personalized therapy selection and warrant additional clinical evaluation.

Cellworks Platform and Therapy Response Index (TRI)

The Cellworks Platform biosimulates the impact of specific drug compounds on an individual patient or class of patients using their genomic profile. Multi-omic data from an individual patient or cohort is used as input to the in silico Cellworks Computational Biology Model (CBM) to generate a personalized or cohort-specific disease model. The CBM is a highly curated mechanistic network of 6,000+ human genes, 30,000 molecular species and 600,000 molecular interactions. This model along with associated drug models are used to biosimulate the impact of specific compounds or combinations of drugs on the patient or cohort and produce therapy response predictions, which are statistically modeled to produce a qualitative Therapy Response Index (TRI) score, scaled from 0 (unfavorable outcome) to 100 (favorable outcome) for a specific therapy. The Cellworks CBM has been tested and applied against various clinical datasets with results provided in over 125 presentations and publications with global collaborators.