On July 1, 2021 Celsion Corporation (NASDAQ: CLSN), Celsion GmbH, a wholly owned subsidiary of Celsion Corporation, a clinical-stage biotechnology company, reported commencement of enrollment in Oxford University’s Phase I PanDox study with ThermoDox in conjunction with Focused Ultrasound in patients with pancreatic cancer (Press release, Celsion, JUL 1, 2021, View Source [SID1234584552]). ThermoDox is Celsion’s proprietary heat-activated liposomal encapsulation of doxorubicin.

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This investigator-led study sponsored by the University of Oxford and supported by the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre has now received ethics, MHRA and institutional R&D approval to commence (ClinicalTrials.gov Identifier: NCT04852367). PanDox is being carried out as a multi-disciplinary collaboration between Celsion, the Oxford University Institute of Biomedical Engineering, the Oncology Clinical Trials Office (OCTO) and the Oxford University Hospitals NHS Foundation Trust. Prof. Mark Middleton, MD, Head of the Department of Oncology at the University of Oxford is the chief clinical investigator and Prof. Constantin Coussios, FREng, PhD, Director of the Institute of Biomedical Engineering, is the lead scientific investigator.

The primary endpoint of the two-arm 18-subject PanDox study is enhanced uptake of doxorubicin in pancreatic tumors using ThermoDox and Focused Ultrasound (FUS), compared to systemic delivery of free doxorubicin. ThermoDox, a heat activated liposomal doxorubicin, will be administered intravenously in 12 patients with non-resectable pancreatic ductal adenocarcinoma (PDAC) and locally activated by focused ultrasound-mediated hyperthermia. This will be compared to conventional systemic delivery of doxorubicin without FUS in 6 patients.

Secondary endpoints include:

Comparing radiologically assessed tumor activity and response with ThermoDox and FUS to free drug alone.
Examining the impact on patient symptoms of ThermoDox plus FUS.
Assessing the safety profile of both FUS and ThermoDox.
The PanDox study is expected to be completed by December 2022 and is similar in design to Oxford’s 10-patient TARDOX study, which demonstrated that ThermoDox plus focused ultrasound increased doxorubicin tumor concentrations by up to 10-fold and enhanced nuclear drug uptake in patients with liver tumors. The findings of the TARDOX study are published in Lancet Oncology (Lyon et al., 2018) and Radiology (Gray et al., 2019).

Preclinical studies conducted at the University of Washington and published in the International Journal of Hyperthermia describe similarly compelling results from experiments performed in a murine model of pancreatic cancer. Those studies demonstrated that ThermoDox plus focused ultrasound increased localized concentration and nuclear uptake of doxorubicin 23-fold compared with a 2-fold increase for hyperthermia and free doxorubicin.

Commenting on the PanDox clinical study, Dr. Laura Spiers, lead oncology clinical research fellow on the PanDox study, said, "Pancreatic cancer has a low five-year survival rate of approximately 10% and drug-based treatments remain less effective than in other cancers, in part due to the unique challenges presented by the stroma surrounding pancreatic tumors. Therefore, finding innovative and effective means of delivering high concentrations of anti-cancer agents such as doxorubicin may lead to a breakthrough for this difficult-to-treat cancer."

Dr. Michael Gray, lead biomedical engineering research fellow, added, "Based on the patient-specific treatment planning approaches developed and validated during the TARDOX trial, PanDox will deliver focused ultrasound mild hyperthermia without either MR-based or invasive thermometry. The ultimate goal is to develop a cost-effective and scalable approach that can be rapidly deployed for the benefit of pancreatic cancer patients".

"This Phase 1 study at Oxford University is the first new trial to be performed under the auspices of Celsion’s wholly owned subsidiary Celsion GmbH, which was recently established to manage all current and future investigator-sponsored trials with ThermoDox," said Andreas Voss, M.D., managing director of Celsion GmbH. "We look forward to providing ThermoDox and other support to Professor Coussios as he and his colleagues strive to provide options to pancreatic cancer patients, as well as to other investigators pursuing compelling possibilities with ThermoDox."

On July 1, 2021 Novocure (NASDAQ: NVCR) reported final results from its phase 2 pilot HEPANOVA trial in liver cancer testing the safety and efficacy of Tumor Treating Fields (TTFields) together with sorafenib for the treatment of advanced hepatocellular cancer (Press release, NovoCure, JUL 1, 2021, View Source [SID1234584553]). In 21 evaluable patients, the disease control rate was 76% in a patient population with poor prognosis and limited exposure to study treatments. The objective response rate for the intent-to-treat population was 9.5%. In patients who completed at least 12 weeks of TTFields treatment, the disease control rate was 91% with an objective response rate of 18%. The final HEPANOVA results will be presented at the virtual ESMO (Free ESMO Whitepaper) World Congress on Gastrointestinal Cancer on July 1.

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The HEPANOVA trial enrolled 27 patients with unresectable hepatocellular cancer. Fourteen of the 27 patients, or 52%, had a Child-Turcotte-Pugh (CTP) score of 7 or 8, representing significant liver dysfunction. Six patients, or 22% of the study population, survived less than 12 weeks. The median sorafenib treatment duration was only nine weeks, a much shorter treatment duration than the referenced historical controls1. The median treatment duration of TTFields was 10 weeks.

"We are very encouraged by the HEPANOVA results, especially in light of the poor prognosis of the study population and low treatment exposure," said Dr. Uri Weinberg, Novocure’s Chief Science Officer. "We intend to initiate a randomized controlled trial as soon as possible and are working with key opinion leaders to finalize a protocol incorporating the evolving treatment landscape in advanced liver cancer. We are particularly interested in the potential to use TTFields together with immunotherapy in this aggressive disease given in vivo data which suggest that using TTFields together with anti-PD-1 therapy results in increased tumor response versus either therapy alone."

The objective response rate reached 9.5% in the 21 evaluable patients, more than double the historical controls. The disease control rate was 76%, a much higher rate than the historical controls of 43% to 52%. For the 11 patients who completed at least 12 weeks of TTFields therapy, the objective response rate was 18%. The disease control rate for patients who completed at least 12 weeks of TTFields therapy was 91%. The objective response rate is defined as the percentage of patients who achieved complete or partial response. The disease control rate includes the percentage of responders plus the patients who achieved stable disease. In the intent-to-treat population, median progression free survival was 5.8 months and median time-to-progression was 8.9 months, higher than the historical, sorafenib alone control for both endpoints. No increase in the toxicity of sorafenib and no device-related serious adverse events were reported.

"Hepatocellular cancer is a particularly aggressive disease," said Professor Anca-Ligia Grosu, Medical Director at the University of Freiburg, and the principal investigator of the HEPANOVA trial. "A clear unmet need remains for safe and effective combination treatments. These data show that Tumor Treating Fields have the potential to extend survival in advanced liver cancer without increasing side effects. I look forward to further exploration of efficacy in a randomized, controlled trial."

About Liver Cancer
Liver cancer is a leading cause of cancer deaths worldwide and is the sixth leading cause of cancer deaths annually in the U.S. The incidence of liver cancer is approximately 42,000 new cases annually in the U.S. The five-year survival rate with existing standards of care is less than 20%.

Hepatocellular carcinoma is the most widespread type of cancer that originates from the liver. Advanced liver cancer has spread either to the lymph nodes or to other organs and because these cancers are widespread, they cannot be treated with surgery. The current common standard treatment for patients with advanced disease and those who progressed on loco-regional therapy is systemic therapy with sorafenib, lenvatinib, or atezolizumab plus bevacizumab.

Use of Tumor Treating Fields for the treatment of liver cancer is investigational only.

About Tumor Treating Fields
Tumor Treating Fields, or TTFields, are electric fields that disrupt cancer cell division.

When cancer develops, rapid and uncontrolled division of unhealthy cells occurs. Electrically charged proteins within the cell are critical for cell division, making the rapidly dividing cancer cells vulnerable to electrical interference. All cells are surrounded by a bilipid membrane, which separates the interior of the cell, or cytoplasm, from the space around it. This membrane prevents low frequency electric fields from entering the cell. TTFields, however, have a unique frequency range, between 100 to 500 kHz, enabling the electric fields to penetrate the cancer cell membrane. As healthy cells differ from cancer cells in their division rate, geometry and electric properties, the frequency of TTFields can be tuned to specifically affect the cancer cells while leaving healthy cells mostly unaffected.

Whether cells are healthy or cancerous, cell division, or mitosis, is the same. When mitosis starts, charged proteins within the cell, or microtubules, form the mitotic spindle. The spindle is built on electric interaction between its building blocks. During division, the mitotic spindle segregates the chromosomes, pulling them in opposite directions. As the daughter cells begin to form, electrically polarized molecules migrate towards the midline to make up the mitotic cleavage furrow. The furrow contracts and the two daughter cells separate. TTFields can interfere with these conditions. When TTFields are present in a dividing cancer cell, they cause the electrically charged proteins to align with the directional forces applied by the field, thus preventing the mitotic spindle from forming. Electrical forces also interrupt the migration of key proteins to the cell midline, disrupting the formation of the mitotic cleavage furrow. Interfering with these key processes disrupts mitosis and can lead to cell death.

TTFields is intended principally for use together with other standard-of-care cancer treatments. There is a growing body of evidence that supports TTFields’ broad applicability with certain other cancer therapies, including radiation therapy, certain chemotherapies and certain immunotherapies. In clinical research and commercial experience to date, TTFields has exhibited no systemic toxicity, with mild to moderate skin irritation being the most common side effect.

Fundamental scientific research extends across two decades and, in all preclinical research to date, TTFields has demonstrated a consistent anti-mitotic effect. The TTFields global development program includes a broad range of clinical trials across all phases, including four phase 3 pivotal trials in a variety of tumor types. To date, more than 18,000 patients have been treated with TTFields.

On July 1, 2021 Puma Biotechnology, Inc. (NASDAQ: PBYI), a biopharmaceutical company, reported that the U.S. Food and Drug Administration (FDA) approved a labeling supplement to the U.S. Prescribing Information for NERLYNX that incorporates the use of NERLYNX dose escalation as evaluated in the Phase II CONTROL Trial and the new 133 count commercial NERLYNX SKU (Press release, Puma Biotechnology, JUL 1, 2021, View Source [SID1234584554]). The new 133 count SKU, i.e., a bottle containing a four-week supply of 133 tablets, is aligned with the use of NERLYNX dose escalation and designed to better support patient needs.

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The CONTROL study was a multicenter, open-label, multi-cohort trial evaluating patients with early stage HER2-positive breast cancer treated with NERLYNX 240 mg daily for up to one year who received loperamide prophylaxis with additional anti-diarrheal treatment as needed (PRN) or NERLYNX dose escalation with loperamide as needed. Patients in the dose escalation cohort received NERLYNX 120 mg daily for Week 1, followed by NERLYNX 160 mg daily for Week 2, followed by NERLYNX 240 mg daily for Week 3 and thereafter for the duration of treatment.

Data from this study showed that dose escalation in the extended adjuvant setting, coupled with PRN Loperamide, led to a greater than 60% reduction in the percentage of patients who experienced Grade 3 diarrhea (40% vs. 13%), a 50% reduction in median cumulative days of Grade 3 diarrhea (5 days vs. 2.5 days) and an approximate 80% reduction in discontinuation rates (17% vs. 3%) when compared to ExteNET, where no dose escalation or antidiarrheal prophylaxis was mandated.

Hope S. Rugo, MD, Professor of Medicine at the University of California San Francisco Comprehensive Cancer Center, said, "The inclusion of dose escalation in the prescribing information is a critical road-map for health care providers and patients as they seek to optimize treatment and reduce therapy-related toxicity in the early breast cancer and metastatic settings."

Alan H. Auerbach, Chief Executive Officer and President of Puma, said, "We believe that utilizing dose escalation has the potential to improve the overall tolerability of NERLYNX and increase the average length of therapy, with the end result benefiting more patients battling breast cancer."

About HER2-Positive Breast Cancer

Up to 20% of patients with breast cancer tumors over-express the HER2 protein (HER2-positive disease) and in the ExteNET study, 57% of patients were found to have tumors that were hormone-receptor positive. HER2-positive breast cancer is often more aggressive than other types of breast cancer, increasing the risk of disease progression and death. Although research has shown that trastuzumab can reduce the risk of early stage HER2-positive breast cancer recurring, up to 25% of patients treated with trastuzumab experience recurrence within 10 years, the majority of which are metastatic recurrences.

On July 1, 2021 Hubro Therapeutics, a clinical stage company advancing a pipeline of proprietary peptide cancer vaccines, reported that successful closing of a private placement that will allow the company to initiate clinical development of its lead product candidate FMPV-1 targeting TGFbR2 neo-antigen present in colorectal-, stomach and endometrial-cancer (Press release, Hubro Therapeutics, JUL 1, 2021, View Source [SID1234584938]).

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Hubro Therapeutics announced today that the company has raised 61,5 million NOK (≈6,5 mill.euro) in a heavily oversubscribed financing round backed by existing investors Jandersen Kapital, Investinor, RADFORSK Investeringsstiftelse, Algot Invest and others. The company is grateful for existing shareholders’ continued belief in the company. The company also welcomed new investors, most notably Canica Holding AG who was offered about fifty percent of the newly issued shares.

On July 1, 2021 QIAGEN (NYSE: QGEN; Frankfurt Prime Standard: QIA) reported a global strategic alliance with Japan’s Sysmex Corporation (Tokyo Stock Exchange, First Section [Ticker Code: 6869]) for the development and commercialization of cancer companion diagnostics, which will leverage both QIAGEN’s leadership in this field and Sysmex’s Plasma-Safe-SeqS technology for next generation sequencing (NGS) (Press release, Qiagen, JUL 1, 2021, View Source [SID1234586595]).

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The alliance aims to foster collaborations with pharmaceutical companies for the development of drug treatments for cancer and promote early clinical adoption of ultra-sensitive liquid biopsy companion diagnostics. QIAGEN and Sysmex have a longstanding partnership, which, for example, provides the ipsogen JAK2 blood-cancer test in Japan. Cancer companion-diagnostics products will be launched by QIAGEN and Sysmex in various regions of the world.

Genetic analysis of tumors makes it possible to identify the genes responsible for the development and spread of a tumor and to target treatment accordingly. But the traditional analysis of solid tumors is constrained by their heterogeneity – varying concentrations of cancer cells, for example – and by sample availability. Liquid biopsy addresses these challenges and, in combination with sensitive NGS, allows the evaluation of patients at different points of their cancer treatment. It enables doctors to spot new anomalies and adjust treatments to make them more precise, and to develop novel targeted therapies.

"Combining QIAGEN’s global reach with Sysmex’s NGS capabilities is an important milestone in advancing the use of NGS technologies in clinical decision-making and is a testament to our shared vision of using this powerful technology to improve outcomes for patients worldwide," said Jean-Pascal Viola, Senior Vice President, Head of the Molecular Diagnostics Business Area and Corporate Business Development at QIAGEN. "This alliance will add strong NGS capabilities to our regulatory and clinical expertise and commercialization, and help our partners in the pharmaceuticals industry by expanding our strong position and product offering in companion diagnostics. We look forward to this alliance creating significant benefits for our pharma partners – and ultimately for treating patients."

"The alliance with QIAGEN promises Sysmex a great application for Sysmex’s Plasma-Safe-SeqS technology, which can detect gene mutations of cancer in blood with ultra-high sensitivity. We believe that QIAGEN is the best for Sysmex to expand this globally," said Hiroshi Kanda, Member of the Managing Board and Senior Executive Officer, Head of Corporate Business Development at Sysmex.

QIAGEN is a pioneer in precision medicine. It is the global leader in collaborating with pharmaceuticals and biotechnology companies to co-develop companion diagnostics that detect genetic abnormalities and guide clinical decision-making. QIAGEN has an unmatched breadth and depth of technologies – from NGS to polymerase chain reaction (PCR) – for companion-diagnostics development. QIAGEN’s portfolio includes ten PCR-based companion-diagnostics products that are approved by the FDA. They include therascreen EGFR for non-small cell lung cancer, therascreen KRAS for colorectal cancer and NSCL (including the G12C mutation), therascreen FGFR for urothelial cancer, therascreen PIK3CA for breast cancer based on tissue or plasma samples, and the therascreen BRAF kit for colorectal cancer.

QIAGEN has master collaboration agreements with more than 25 companies to develop and commercialize companion diagnostics for drugs in development – a pipeline of potential products to advance precision medicine and benefit patients. QIAGEN has partnered with Illumina to broaden the use of NGS-based companion and other in-vitro diagnostics (IVD) kits in patient management.