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.

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"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.

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]).

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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.

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.

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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.

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.

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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.

On May 29, 2020 EMD Serono, the biopharmaceutical business of Merck KGaA, Darmstadt, Germany in the US and Canada, reported that updated data from the ongoing, single-arm Phase II VISION study evaluating tepotinib* as a single agent in patients with advanced non-small cell lung cancer (NSCLC) with MET exon 14 (METex14) skipping alterations were published in The New England Journal of Medicine (NEJM) (Press release, EMD Serono, MAY 29, 2020, View Source [SID1234558711]). Results from the primary analysis of data from 99 patients with at least 9 months of follow-up demonstrate consistent response rate and durable anti-tumor activity across lines of treatment in patients assessed by both liquid biopsy (LBx) and tissue biopsy (TBx). Results from the VISION study were also presented at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) ASCO (Free ASCO Whitepaper)20 Virtual Scientific Program on May 29, including data from the primary analysis (Abstract #9556) and including patient-reported outcomes (PROs) of health-related quality of life (HRQoL) (Abstract #9575). Tepotinib is designed to be a highly selective1 oral MET inhibitor that is administered once daily and is designed to inhibit the oncogenic MET receptor signaling caused by MET (gene) alterations.

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"MET exon 14 skipping is a primary oncogenic driver, but until recently there have been no approved treatment options targeting this genetic alteration in NSCLC," said Paul K. Paik, M.D., primary study investigator, lead author and Clinical Director, Thoracic Oncology Service, Memorial Sloan Kettering Cancer Center. "These new findings highlight the importance of routine next-generation sequencing to identify METex14 skipping alterations and demonstrate tepotinib’s durable anti-tumor activity in patients who are typically elderly, and whose cancers are often harder to treat."

This new analysis of data from 99 patients in the fully enrolled Cohort A with at least 9 months of follow-up was published by The New England Journal of Medicine on May 29. Results demonstrate objective response rate (ORR) of 46% (95% CI, 36–57) among patients with METex14 skipping alterations identified by either LBx or TBx as assessed by Independent Review Committee (IRC), and 56% (95% CI, 45–66) as assessed by investigators. The median duration of response (DOR) was 11.1 months (95% CI, 7.2–could not be estimated (NE)) among patients with METex14 skipping alterations identified by either LBx or TBx as assessed by IRC, and 14.0 months (95% CI, 9.7–18.3) as assessed by investigators. Results were consistent across different lines of treatment and in patients assessed by LBx or TBx. Additional endpoints were progression-free survival (PFS) and overall survival (OS).

Patients with brain metastases at baseline (n=11) benefitted similarly from treatment. In these patients, systemic ORR as assessed by independent review was 55% (95% CI, 23–83), with a median DOR of 9.5 months (95% CI, 6.6–NE) and a median PFS of 10.9 months (95% CI, 8.0–NE).

Results also include the first patient-reported quality-of-life outcomes in patients with NSCLC with METex14 skipping alterations. Quality of life was maintained over time of treatment with tepotinib, with symptoms of dyspnea remaining stable and cough symptoms improving. The first longitudinal on-treatment biomarker data from LBx samples were also reported, showing high concordance between molecular circulating free DNA response (defined as METex14 depletion) and clinical response based on measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST).

Out of 152 patients evaluable for safety, treatment-related adverse events (TRAEs) of all grades were reported in 135 patients (89%). Grade 3 TRAEs were reported in 38 patients (25%), and 3 patients (2%) experienced Grade 4 TRAEs. One death was considered by the investigator to be treatment-related and occurred in a 79-year-old patient with respiratory failure and dyspnea, secondary to interstitial lung disease. The most common Grade ≥3 TRAE was peripheral edema, which occurred in 11 patients (7%). Serious TRAEs were reported in 23 patients (15%). Permanent tepotinib discontinuations due to TRAEs were reported in 17 patients (11%), and 50 patients (33%) required a dose reduction due to TRAEs. Peripheral edema was the most common TRAE leading to a dose reduction (25 patients, 16%) or dose interruption (28 patients, 18%); permanent discontinuation was uncommon (7 patients, 5%).

"Designed to have a highly selective mechanism of action, tepotinib has the potential to make a difference in the treatment and lives of people living with non-small cell lung cancer harboring METex14 skipping alterations," said Luciano Rossetti, Global Head of Research & Development for EMD Serono. "Following on the recent approval of tepotinib in Japan as the first therapy for the treatment of advanced NSCLC harboring MET gene alterations, the publication of these data underscores our commitment to advancing scientific understanding and potential therapeutic options for this challenging cancer."

The ongoing Phase II VISION (NCT02864992) clinical trial is a single-arm, open-label, multi-cohort study investigating the safety and efficacy of tepotinib as a single agent in patients with advanced or metastatic NSCLC with METex14 skipping alterations identified by LBx and/or TBx. The use of both LBx and TBx to identify patients for the VISION study is intended to support improved patient selection and is consistent with the company’s focus on patient-centric drug development.

Lung cancer is the most common type of cancer worldwide, with 2 million cases diagnosed annually.2 Alterations of the MET signaling pathway are found in various cancer types, including 3% to 5% of NSCLC cases, and correlate with aggressive tumor behavior and poor clinical prognosis.3-5 Patients with NSCLC harboring METex14 skipping tend to be older than those with NSCLC harboring other alterations.6 In the Phase II VISION study, the patient population is generally characterized as elderly, with a median age of 74.0 years, and as having poor clinical prognosis typical of NSCLC with METex14 skipping alterations.

In March 2020, the Japanese Ministry of Health, Labour and Welfare (MHLW) approved tepotinib for the treatment of patients with unresectable, advanced or recurrent NSCLC with METex14 skipping alterations. In September 2019, the US Food and Drug Administration (FDA) granted Breakthrough Therapy Designation for tepotinib in patients with metastatic NSCLC harboring METex14 skipping alterations who progressed following platinum-based cancer therapy. EMD Serono plans to file tepotinib for regulatory review with the FDA in 2020. Tepotinib is also being investigated in the INSIGHT 2 study (NCT03940703) in combination with the tyrosine kinase inhibitor (TKI) osimertinib in epidermal growth factor receptor (EGFR)-mutated, MET amplified, locally advanced or metastatic NSCLC that has acquired resistance to prior EGFR TKI.

Discovered in-house at Merck KGaA, Darmstadt, Germany, tepotinib is an oral MET inhibitor that is designed to inhibit the oncogenic MET receptor signaling caused by MET (gene) alterations.

*Tepotinib is currently under clinical investigation and not yet approved in any markets outside of Japan.

Dr. Paik has provided compensated advisory services to EMD Serono.

About Non-Small Cell Lung Cancer
With 2 million cases diagnosed annually, lung cancer (including trachea, bronchus and lung) is the most common type of cancer worldwide and the leading cause of cancer-related death, with 1.7 million mortality cases worldwide.2 Alterations of the MET signaling pathway, including MET exon 14 (METex14) skipping alterations and MET amplifications, occur in 3% to 5% of NSCLC cases.3-5

About Tepotinib
Tepotinib is an oral MET inhibitor that is designed to inhibit the oncogenic MET receptor signaling caused by MET (gene) alterations. Discovered in-house at Merck KGaA, Darmstadt, Germany, it has been designed to have a highly selective mechanism of action, with the potential to improve outcomes in aggressive tumors that have a poor prognosis and harbor these specific alterations. Tepotinib is currently under clinical investigation in NSCLC and not yet approved in any markets outside of Japan. Merck KGaA, Darmstadt, Germany, is actively assessing the potential of investigating tepotinib in combination with novel therapies and in other tumor indications.

References

Bladt F, et al. Clin Cancer Res 2013;19:2941-2951.
Bray F, et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2018;68(6):394-424. View Source View Source.
Reungwetwattana T, et al. Lung Cancer 2017;103:27-37.
Mo HN, et al. Chronic Dis Transl Med 2017;3(3):148-153.
Lutterbach B, et al. Cancer Res 2007;67:2081-8.
Schrock AB et al. J Thorac Oncol 2016;11(9):1493-1502.
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