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Boundless Bio Presents Data Assessing the Relationship Between Extrachromosomal DNA and Biomarker Signatures Associated with Response to Checkpoint Inhibitors in Gastric Cancer at the 2020 ASCO Virtual Annual Meeting

On May 29, 2020 Boundless Bio, a company interrogating and targeting extrachromosomal DNA (ecDNA) in aggressive cancers, reported that it will present data at the 2020 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Virtual Annual Meeting that highlight ecDNA’s relationship with biomarkers associated with response to immunotherapy in gastric cancer and therefore the importance of identifying ecDNA patient populations (Press release, Boundless Bio, MAY 29, 2020, View Source [SID1234558716]).

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The poster, "Extrachromosomal DNA (ecDNA) carrying amplified oncogenes as a biomarker for insensitivity to checkpoint inhibitor treatment in gastric cancer patients," will be presented on Friday, May 29, in ASCO (Free ASCO Whitepaper)’s Developmental Therapeutics – Immunotherapy session. The presentation can be accessed starting at 8:00 a.m. EDT (Abstract 3123, Presentation 187) as part of ASCO (Free ASCO Whitepaper)’s on-demand content; ASCO (Free ASCO Whitepaper) is being held virtually this year due to COVID-19.

ecDNA are identified with high frequency across many solid tumor types and thought to be one of the key drivers of the most aggressive cancers – specifically, those cancers characterized by high copy number amplifications of oncogenes. Tumors enabled by ecDNA have a distinct fitness advantage of producing multiple oncogene copies, which drives tumor aggressiveness, rapid progression, and resistance to standard treatment options.

"The analysis being presented today demonstrates that the presence of ecDNA in gastric cancer is negatively associated with biomarkers typically associated with response to checkpoint inhibitor therapies. The implication is that the presence of ecDNA in solid tumors potentially renders these cancers unresponsive to immunotherapy and highlights the importance of creating therapies that directly address cancer cells’ ability to employ ecDNA to grow and resist standard of care treatments," said Zachary Hornby, President and Chief Executive Officer of Boundless Bio. "Boundless Bio is committed to continuing to elucidate the role of ecDNA in cancer biology, oncogene amplification, and tumor adaptability and to bringing the first medicines leveraging these insights to patients with intractable cancers."

Study Details

The analysis examined whether patients with gastric tumors that possess ecDNA represent a subset of patients that lack biomarkers associated with clinical response to anti-PD-1 checkpoint inhibitor therapy. Boundless Bio researchers employed computational analysis to determine the ecDNA status of a cohort of gastric cancer patients (N = 108) whose whole genome sequencing data were publicly available in The Cancer Genome Atlas (TCGA). The cohort was grouped into five molecular subtypes:

Microsatellite instability (MSI)
Epstein-Barr virus (EBV)
Genomically stable (GS)
Chromosomal instability (CIN)
ecDNA positive (ecDNA)
Additionally, the relationships among the molecular subtypes above and common biomarker signatures associated with response to checkpoint inhibitors were assessed:

MSI status
PD-L1 levels
Tumor mutational burden (TMB)
Tumor immune signature (TIS)
The analysis found that 32% of gastric cancer patients in the cohort were positive for ecDNA signatures, and those ecDNA+ patients were mutually exclusive from the 23% of patients who showed MSI high (MSI-H), which is associated with response to checkpoint inhibitors, such as pembrolizumab, in gastric cancer. Further, it found that the ecDNA-positive subtype had statistically significantly lower TIS than all of the other molecular subtypes (p-value < 0.05), except for the tumors marked by the CIN subtype (p-value = 0.09). The ecDNA-positive subtype also had lower PD-L1 expression than all the other molecular subtypes but the GS and CIN subtypes.

Overall, the analysis demonstrated that patients whose tumors are ecDNA positive are a unique population that displays a signature that lacks the hallmark biomarkers that predict response to checkpoint inhibitor therapy, implying that ecDNA+ patients may not respond to standard of care immunotherapies. Boundless Bio is developing novel therapeutic strategies directed to mechanisms critical for ecDNA function in cancer.

About ecDNA

Extrachromosomal DNA, or ecDNA, are large circles of DNA containing genes that are outside the cells’ chromosomes and can make many copies of themselves. ecDNA can be rapidly replicated within the cell, causing high numbers of oncogene copies, a trait that can be passed to daughter cells in asymmetric ways during cell division. Cells have the ability to upregulate or downregulate ecDNA and resulting oncogenes to ensure survival under selective pressures, including chemotherapy, targeted therapy, immunotherapy, or radiation, making ecDNA one of cancer cells’ primary mechanisms of recurrence and treatment evasion. ecDNA are rarely seen in healthy cells but are found in many solid tumor cancers. They are a key driver of the most aggressive and difficult-to-treat cancers, specifically those characterized by high copy number amplification of oncogenes.

MiNA Therapeutics Presents Top Line Results from Phase Ib Study of MTL‑CEBPA in Combination with Sorafenib in Liver Cancer at 2020 ASCO Annual Meeting

On May 29, 2020 MiNA Therapeutics, the pioneer in RNA activation therapeutics, reported top line results from the Phase Ib dose escalation and cohort expansion study, OUTREACH, of lead candidate MTL-CEBPA in combination with sorafenib standard of care in patients with advanced hepatocellular carcinoma (HCC or liver cancer) (Press release, MiNA Therapeutics, MAY 29, 2020, View Source [SID1234558715]). The study met its primary endpoints of safety and tolerability for MTL‑CEBPA administered either concomitantly or sequentially with sorafenib. In addition, five patients experienced objective tumour responses, including two complete responses during the combination treatment. The data will be presented during a poster session at the 2020 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting, held virtually from May 29 – May 31, 2020.

"We are delighted to have confirmed objective tumour responses in a Phase Ib study in advanced liver cancer patients who are poorly served by existing treatments," commented Robert Habib, CEO of MiNA Therapeutics. "Combined with previous positive results, these data suggest that by reducing immune suppression in the tumour microenvironment, MTL‑CEBPA may increase the effectiveness of sorafenib standard of care."

At the data cut-off of February 1, 2020, 36 patients with advanced HCC had been treated with MTL‑CEBPA in combination with sorafenib in the Phase Ib study. 22 patients received MTL‑CEBPA and sorafenib concomitantly, and 14 patients received the two agents sequentially. Both concomitant and sequential treatment regimens were generally very well tolerated, and no maximum tolerated dose was determined. The profile of adverse events was consistent with the known safety profile of each agent and the underlying disease. In addition, concomitant sorafenib treatment did not alter the pharmacokinetics of MTL‑CEBPA. Five patients who were naïve to prior tyrosine kinase inhibitor (TKI) treatment experienced objective tumour responses, including two patients who experienced complete remission. Tumour responses were most pronounced in those TKI naïve patients with viral aetiology, where four out of nine evaluable patients experienced objective responses.

Treatment was associated with a reduction in both the number of immature immune suppressor cells as well as genetic markers of immune suppression in patient samples. These biomarker data validate the mechanism of action of MTL‑CEBPA in reducing immune suppression, which has been identified as a resistance mechanism of solid tumours to cancer treatment, including sorafenib.

These encouraging Phase Ib data add to the previously published positive Phase I results in which four out of five patients experienced a durable, objective response to off-study sorafenib treatment after discontinuation of MTL‑CEBPA. As a single agent treatment, sorafenib is associated with a very low objective response rate. In a recent Phase III study, complete responses were observed in 1% of patients and partial responses were observed in 6% of patients based on RECIST 1.1 criteria in 372 patients1.

The poster will be made available on the "Publications" page of MiNA’s website.

Presentation information
Title: Phase Ib dose escalation and cohort expansion study of the novel myeloid differentiating agent MTL-CEBPA in combination with sorafenib in patients with advanced hepatocellular carcinoma (HCC)
Abstract no: 4601
Session: Gastrointestinal Cancer—Gastroesophageal, Pancreatic, and Hepatobiliary
Date / time: Friday, May 29, 2020 / 8:00 am Eastern Time

About MTL-CEBPA

MTL-CEBPA is the first therapy to specifically up-regulate CCAAT/enhancer binding protein alpha (C/EBP-α), a transcription factor that acts as a master regulator of myeloid cell lineage determination and differentiation. Dysregulated myeloid cells have been implicated in several diseases and identified as a critical barrier for many therapies to induce clinical responses in solid tumour cancers. In pre-clinical studies MTL-CEBPA has been shown to improve the anti-tumour activity of cancer therapies by targeting dysregulated myeloid cells and reducing their suppression in the tumour microenvironment.

Sangamo Therapeutics Announces Participation at the Jefferies Virtual Healthcare Conference

On May 29, 2020 Sangamo Therapeutics, Inc. (Nasdaq: SGMO), a genomic medicine company, reported that management will present at the Jefferies Virtual Healthcare Conference on Tuesday, June 2 at 4:00 p.m. ET (Press release, Sangamo Therapeutics, MAY 29, 2020, View Source [SID1234558714]).

The presentation will be webcast live and may be accessed via a link on the Sangamo Therapeutics website in the Investors and Media section under Events and Presentations.

Celsion Reports Data Safety Monitoring Board Recommendation to Proceed to Phase II of the OVATION 2 Study in Advanced Ovarian Cancer

On May 29, 2020 Celsion Corporation (NASDAQ: CLSN), a leading oncology drug development company, reported the final recommendations of the Data Safety Monitoring Board (DSMB) following completion of the Phase I dose-finding and tolerance portion of the Phase I/II OVATION 2 Study with GEN-1 in advanced (Stage III/IV) ovarian cancer (Press release, Celsion, MAY 29, 2020, View Source [SID1234558713]). Based on favorable safety data from 15 randomized patients, the DSMB has recommended that the Phase II portion of the OVATION Study proceed with the dose of 100 mg/m2. The DSMB also determined that safety is satisfactory with an acceptable risk/benefit, and that patients tolerate up to 17 doses of GEN-1 during a course of treatment that lasts up to six months. No dose limiting toxicities were reported.

The OVATION 2 Study combines GEN-1, the Company’s IL-12 gene-mediated immunotherapy, with standard-of-care neoadjuvant chemotherapy (NACT) in patients newly diagnosed with Stage III/IV ovarian cancer. NACT is designed to shrink the cancer as much as possible for optimal surgical removal after three cycles of chemotherapy. Following NACT, patients undergo interval debulking surgery (IDS), followed by three additional cycles of chemotherapy in order to treat any remaining tumor after the surgery.

The OVATION 2 Study is an open-label, 1-to-1 randomized trial, 80% powered to show the equivalent of a 33% improvement in progression-free survival (PFS) (HR=0.75), the primary endpoint, when comparing the treatment arm (NACT + GEN-1) with the control arm (NACT alone). GEN-1 is a formulation of Celsion’s proprietary, synthetic, non-viral cell transfection platform TheraPlas, which incorporates DNA plasmids coded for the inflammatory protein interleukin-12 (IL-12). Cell transfection is followed by persistent, local secretion of the IL-12 protein at therapeutic levels.

In March 2020, the Company announced the following clinical data from these first 15 patients enrolled in the OVATION 2 Study:

Of the 15 patients treated in the Phase I portion of the OVATION 2 Study:
Nine were treated with GEN-1 at a dose of 100 mg/m² plus NACT,
Six were treated with NACT only,
All 15 had successful resections of their tumors, with seven out of nine patients (78%) in the GEN-1 treatment arm having a complete tumor resection (R0), which indicates a microscopically margin-negative resection in which no gross or microscopic tumor remains in the tumor bed, and
Only three out of six patients (50%) in the NACT only treatment arm had an R0 resection.
When combining these results with the surgical resection rates observed in the Company’s prior Phase Ib dose-escalation trial (the OVATION 1 Study), a population of patients with inclusion criteria identical to the OVATION 2 Study, the data reflect the strong dose-dependent efficacy of adding GEN-1 to the current standard of care NACT:
% Patients with R0 Resections
0, 36, 47 mg/m² of GEN-1 plus NACT n=12 42%
61, 79, 100 mg/m² of GEN-1 plus NACT n=17 82%
The objective response rate (ORR) as measured by Response Evaluation Criteria in Solid Tumors (RECIST) criteria for the 0, 36, 47 mg/m² dose GEN-1 patients were comparable, as expected, to the 61, 79, 100 mg/m² higher dose GEN-1 patients, with both groups demonstrating an approximate 80% ORR.
The Company also engaged Medidata, a Dassault Systèmes company, to examine matched patient data provided by Medidata in a synthetic control arm (SCA) with results from the Company’s completed Phase Ib dose-escalation OVATION 1 Study. The results were announced in March 2020, and showed positive data in PFS as follows:

GEN-1 Population PFS Hazard Ratio (Confidence Interval)
Intent-to-treat, n=15 0.53 (95% CI 0.16, 1.73); log-rank p=0.29
Per-protocol, n=14 0.33 (95% CI 0.08, 1.37); log-rank p=0.11
Patients in the GEN-1 arm virtually demonstrated a doubling of control of their cancer compared with the SCA. Findings are not statistically significant due to the small number of patients.

"These findings show a consistent dose dependent clinical response in both surgical outcome and tumor response. This is further supported by a series of translational data of the tumor microenvironment," noted Dr. Nicholas Borys, Celsion’s executive vice president and chief medical officer. "Continuing our clinical research program at the higher, 100mg/m2 dose, in this advance stage ovarian cancer population, holds promise and is strongly encouraged by our study investigators and medical advisors. We look forward to initiating enrollment as quickly as possible."

"We are excited to be moving into the Phase II portion of the OVATION 2 Study, and thank the DSMB for their work and advice," said Michael H. Tardugno, Celsion’s chairman, president and chief executive officer. "The recommendation to proceed at the highest dose and the fact patients were able to tolerate 17 doses bode well for study success, particularly in light of the body of positive data we have generated for GEN-1 in the advanced ovarian cancer indication. With no good treatment options available, we are hopeful GEN-1 will make a meaningful difference in the lives of these women. As previously announced, we plan to begin the Phase II study in the fourth quarter of this year."

In March 2020, the Company announced that GEN-1 has received Orphan Drug Designation from the European Medicines Agency. Celsion plans to consult with the U.S. Food and Drug to request Fast Track review and potential Breakthrough Therapy designation for GEN-1 based on this encouraging clinical data.

About GEN-1 Immunotherapy

GEN-1, designed using Celsion’s proprietary TheraPlas platform technology, is an IL-12 DNA plasmid vector encased in a nanoparticle delivery system, which enables cell transfection followed by persistent, local secretion of the IL-12 protein. IL-12 is one of the most active cytokines for the induction of potent anti-cancer immunity acting through the induction of T-lymphocyte and natural killer (NK) cell proliferation. The Company has previously reported positive safety and encouraging Phase I results with GEN-1 given as monotherapy in patients with peritoneally metastasized ovarian cancer, and recently completed a Phase Ib trial of GEN-1 in combination with PEGylated doxorubicin in patients with platinum-resistant ovarian cancer.

TRACON Pharmaceuticals Highlights Updated Envafolimab Results In MSI-H/DMMR Colorectal Cancer And Results From Clinical Trial Of Opdivo And Yervoy Combination Therapy In Undifferentiated Pleomorphic Sarcoma Conducted By Alliance For Clinical Trials In Onc

On May 29, 2020 TRACON Pharmaceuticals (NASDAQ:TCON), a clinical stage biopharmaceutical company focused on the development and commercialization of novel targeted cancer therapeutics and utilizing a cost efficient, CRO-independent product development platform to partner with ex-U.S. companies to develop and commercialize innovative products in the U.S., reported data from poster #11511 at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) 2020 Virtual Scientific Program, entitled, "Multicenter phase II study of nivolumab +/- ipilimumab for patients with metastatic sarcoma (Alliance A091401): Results of expansion cohorts (Press release, Tracon Pharmaceuticals, MAY 29, 2020, View Source [SID1234558712])." Investigators from the Alliance for Clinical Trials in Oncology (Alliance), a broad community of scientists and clinicians who are committed to the prevention and treatment of cancer, reported an impressive 29% confirmed objective response rate (ORR) in patients (n=14) with highly refractory Undifferentiated Pleomorphic Sarcoma (UPS) who received Opdivo in combination with Yervoy in a non-comparative randomized trial.

TRACON recently reported on the results of poster #3021 at ASCO (Free ASCO Whitepaper) 2020, entitled "Envafolimab (KN035) in Advanced Tumors with Mismatch-Repair Deficiency," which was presented by the Company’s corporate partners, 3D Medicines and Alphamab Oncology, and showed that single agent envafolimab demonstrated a 30.0% confirmed ORR in 50 patients with MSI-H/dMMR colorectal cancer (CRC) who failed a fluoropyrimidine, oxaliplatin and irinotecan (n=39) or those with advanced gastric cancer who failed at least one prior systemic treatment (n=11), who had at least two on-study tumor assessments. The confirmed ORR in MSI-H/dMMR CRC patients treated with envafolimab who failed a fluoropyrimidine, oxaliplatin and irinotecan was 28.2%, which was nearly identical to the 28% confirmed ORR reported in the Opdivo package insert in MSI-H/dMMR CRC patients who failed a fluoropyrimidine, oxaliplatin and irinotecan.

"The previously reported non-comparative randomized Alliance clinical data indicated that Opdivo combined with Yervoy tripled the ORR in high grade sarcomas compared to single agent Opdivo (ORR of 16% versus 5%). These new data from expansion cohorts indicate that the combination of Opdivo and Yervoy demonstrated a higher ORR than Opdivo alone in UPS, of 29% in highly refractory disease. It has been shown that UPS is one of the sarcoma subtypes with the highest responses to checkpoint inhibitors to date and, given these encouraging combination therapy data, the upcoming ENVASARC pivotal trial is a potentially promising study for patients," said Sandra D’Angelo, M.D., Associated Attending at Memorial Sloan Kettering Cancer Center and lead investigator for the Alliance clinical trial.

"We believe these data bode well for the ENVASARC trial, which will assess the potential of envafolimab as a single agent and in combination with Yervoy in UPS that has progressed following one or two prior lines of treatment," said James Freddo, M.D., TRACON Chief Medical Officer. "Given the ASCO (Free ASCO Whitepaper) 2020 data indicating that envafolimab’s activity is similar to that of Opdivo in MSI-H/dMMR cancer, but without infusion related reactions, we believe our trial’s objective of targeting a 15% ORR in ENVASARC is achievable. Moreover, given the 4% ORR of Votrient, the only approved therapy for refractory UPS and myxofibrosarcoma (MFS), a sarcoma subtype genetically related to UPS that will also be included in ENVASARC, we believe envafolimab combined with Yervoy could provide a transformative new standard of care for sarcoma patients."

The complete envafolimab clinical trial poster is available at: View Source

The complete Alliance clinical trial poster is available at: View Source

About Envafolimab

Envafolimab is a novel, single-domain antibody against PD-L1 that is administered by subcutaneous injection without the need for an adjuvant. Envafolimab is currently dosing in Phase 1 trials in the U.S. and Japan and is being studied in China in a Phase 2 registration trial as a single agent in patients with MSI-H/dMMR cancer, and in combination with gemcitabine and oxaliplatin in a Phase 3 registration trial in biliary tract cancer. 3D Medicines and Alphamab Oncology plans to submit a BLA in China for envafolimab in 2020 based on overall response rate and duration of response in MSI-H/dMMR patients. The submission would be based on the data from the ongoing pivotal phase 2 trial of envafolimab in MSI-H/dMMR cancer.