1stOncology™: Cancer Intelligence Service – Page 11738 – 1stOncology is recognized as a Top 10 Global Pharma Analytic Provider

AVEO Oncology Announces TIVO-3 Final Overall Survival Results Featured at ASCO 2020 Virtual Scientific Program and Submitted to U.S. FDA as Part of NDA Filing

On May 29, 2020 AVEO Oncology (NASDAQ: AVEO) reported the presentation of results from the final analysis of overall survival (OS) in its pivotal Phase 3 TIVO-3 trial comparing tivozanib, the Company’s next-generation vascular endothelial growth factor (VEGF) receptor tyrosine kinase inhibitor (TKI), to sorafenib in 3rd and 4th line renal cell carcinoma (RCC) (Press release, AVEO, MAY 29, 2020, View Source [SID1234558717]). The results, which have been submitted to the U.S. Food and Drug Administration (FDA) as part of the Company’s New Drug Application (NDA) submitted in March, are being featured today at the ASCO (Free ASCO Whitepaper) 2020 Virtual Scientific Program in a poster titled, "TIVO-3: Final OS analysis of a phase III, randomized, controlled, multicenter, open-label study to compare tivozanib to sorafenib in subjects with metastatic renal cell carcinoma (RCC)" (abstract 5062). A copy of the poster will be available at the ASCO (Free ASCO Whitepaper) virtual meeting beginning today, May 29, 2020, at 8:00 AM ET. The poster and accompanying oral presentation by Sumanta (Monty) Pal, MD, Associate Clinical Professor, Department of Medical Oncology and Therapeutics Research, and Co-director, Kidney Cancer Program, at City of Hope Comprehensive Cancer Center, can be viewed at www.aveooncology.com.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

Schedule Your 30 min Free Demo!

As previously announced, the TIVO-3 trial met the primary endpoint of progression free survival (PFS) (HR=0.73; p=0.02) and the secondary endpoint of overall response rate (ORR) (18% vs. 8%; p=0.02). The final OS hazard ratio (HR), which assesses the overall relative risk of death, was 0.97 (95% CI: 0.75-1.25; p=0.82), favoring tivozanib and improving from the previously reported interim HR of 0.99. Updated median OS, representing a single point in time in the OS curve, was 16.4 months for tivozanib (95% CI: 13.4-22.2) and 19.2 months for sorafenib (95% CI: 15.0-24.2). These OS HR results are similar to those of prior VEGFR TKI vs. VEGFR TKI studies in RCC.1-4

Tivozanib was found to be generally well-tolerated, with grade 3 or higher adverse events (AEs) consistent with those observed in previous tivozanib trials. The most common AE in patients receiving tivozanib was hypertension (38% vs. 25% for sorafenib, of treated patients), an AE known to reflect effective VEGF pathway inhibition. Infrequent but severe AEs reported in greater number in the tivozanib arm were thrombotic events (5% vs. 4% for sorafenib, of treated patients) similar to those observed in previous tivozanib studies. Dose reductions and interruptions due to AEs were significantly lower for tivozanib vs. sorafenib, despite nearly double the average number of cycles initiated for the tivozanib arm (11.9 months vs. 6.7 months for sorafenib), treatment related AEs leading to permanent discontinuation were 8% for tivozanib vs. 15% for sorafenib.

"We believe the TIVO-3 data demonstrate a favorable risk/benefit profile for tivozanib in the growing population of patients who have relapsed or become refractory to multiple lines of therapy, including checkpoint inhibitors," said Dr. Pal. "The lack of clinical data to guide treatment decisions in a robust, evidence-based manner in this setting is a serious and growing unmet medical need, particularly as this population continues to grow thanks to improved treatment in earlier lines. TIVO-3 provides the first positive superiority study to help guide this important treatment decision and, furthermore, offers this highly refractory patient population a favorable tolerability profile as indicated by fewer dose reductions, interruptions and discontinuations over a less selective VEGFR TKI in sorafenib."

"This outcome marks a significant milestone in a long journey to see tivozanib fulfill its potential, and is a critical step forward in our goal to improve both efficacy outcomes and patient experience for individuals living with cancer," said Michael Bailey, president and chief executive officer of AVEO. "Tivozanib has the potential to define highly refractory kidney cancer treatment, an area with no current evidence-based standard of care. We look forward to continuing our dialogue with the FDA as we work toward a marketing authorization decision, and we will continue to build on our foundation for commercial readiness. We owe our deepest gratitude to the patients and their families for participating in the tivozanib clinical program, and to the healthcare professionals who have continued to believe in the potential of tivozanib."

Conference Call and Webcast

In connection with this announcement, AVEO will host a conference call and audio webcast today, May 29, 2020, at 8:30 am Eastern Time. Dr. Pal will join the AVEO management team to review the data announced today. The call can be accessed by dialing (844) 882-7841 (U.S. and Canada) or (574) 990-9828 (international). The passcode for the conference call is 7967605. To access the live audio webcast, or the subsequent archived recording, please visit the Investors section of the AVEO website at www.aveooncology.com. The webcast will be recorded and available for replay on AVEO’s website for two weeks.

About Tivozanib (FOTIVDA)

Tivozanib (FOTIVDA) is an oral, once-daily, next-generation vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor (TKI) discovered by Kyowa Kirin and approved for the treatment of adult patients with advanced renal cell carcinoma (RCC) in the European Union, the United Kingdom, Norway, New Zealand and Iceland. It is a potent, selective and long half-life inhibitor of all three VEGF receptors and is designed to optimize VEGF blockade while minimizing off-target toxicities, potentially resulting in improved efficacy and minimal dose modifications.5,6 Tivozanib is being studied in the TIVO-3 trial, which is supporting a regulatory submission of tivozanib in the U.S. seeking marketing approval as a treatment for relapsed or refractory RCC. Tivozanib has been shown to significantly reduce regulatory T-cell production in preclinical models7 and has demonstrated synergy in combination with nivolumab (anti PD-1) in a Phase 2 study in RCC8. Tivozanib has been investigated in several tumor types, including renal cell, hepatocellular, colorectal, ovarian and breast cancers.

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]).

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.