Fostroxacitabine bralpamide (fostrox)

Clinical development of fostrox in patients with liver cancer

The first-in-human study of fostrox is an open label, multi-center dose escalation/expansion study in 3 parts. The purpose of the study is to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, and signs of antitumor effect of fostrox in patients with advanced liver cancer. In phase 1a individual patients received escalating doses of fostrox and in phase 1b monotherapy the dose was escalated in cohorts of three patients in a 3+3 design to identify the recommended phase 2 dose (RP2D) for monotherapy. In the phase 1b combination part of the study fostrox is administered in combination with Lenvima®, a tyrosine kinase inhibitor or Keytruda®, an anti-PD-1 check-point inhibitor.

Phases 1a and 1b monotherapy enrolled patients with hepatocellular carcinoma (HCC), as well as patients with intrahepatic cholangiocarcinoma and patients with liver metastases from solid tumors and have been completed. Evaluated doses were generally well-tolerated. Liver biopsies showed selective DNA damage in liver tumor tissue while normal liver tissue was minimally or not affected by the treatment. From the patient biopsies we also observed DNA damage in oxygen-poor cancer tissue, which are generally difficult to treat. The tumor selective DNA damage effect was observed at low plasma concentrations of fostrox and acceptable exposure to troxacitabine.

The combination part of the study includes patients diagnosed with HCC who have progressed on, or are intolerant of, first or second line standard therapy. It comprises two arms with inter-patient dose escalations of fostrox in combination with either Lenvima® or Keytruda® using a 3+3 dose escalation design. The study is currently conducted at 15 clinics in the UK, Spain and South Korea.

In February 2023, the initial dose escalation part (phase 1b) of the 1b/2a study with fostrox in HCC, in combination with Lenvima®, was successfully completed. The preliminary results from the dose cohorts are positive with a good safety and tolerability profile and no dose-limiting toxicity has been observed. The recommended dose for phase 2a with fostrox in combination with Lenvima® has been determined to 30 mg for fostrox. In March 2023, the first patient started treatment in phase 2a with fostrox in combination with Lenvima®. In August 2023 the 15th patient was included in the phase 2a study.

In April 2023, Medivir presented new data at the AACR showing significantly improved anti-tumor efficacy in non-clinical tumor models with fostrox in triple combination. The results indicate a potential for triple-combining anti-PD1 and kinase inhibitors with fostrox in the treatment of HCC.

In September promising interim safety and efficacy data from the ongoing phase 1b/2a study of fostrox in combination with Lenvima® in advanced HCC was published. Central review of the 6 patients in phase 1b dose escalation part was performed. In these 6 patients, complete response was recorded in 1 patient, partial response in 2 patients, and stable disease in 2 patients read by an independent radiologist using mRECIST. The interim data from phase 1b further strengthens the previously reported promising safety and efficacy data.

In October, more mature interim efficacy data evaluated by local investigators and radiologists in 18 of 21 patients with at least 12 weeks of follow-up were presented. These data demonstrate further improved clinical benefit compared to previous presentations. This includes median time to progression ~5 months, with >50% of patients still on study. In addition to showing improved clinical efficacy with the combination of fostrox and Lenvima, compared to published monotherapy Lenvima study data in second-line HCC, the safety and tolerability profile remains good. No new, unexpected side effects have been reported with the combination and a continued low need for dose reduction of Lenvima is seen.

In August 2023 a Scientific Advisory Council with world-leading liver cancer experts was formed to support the company in moving the clinical development of fostrox forward.

The Scientific Advisory Council members are;

Dr. Jeff Evans is a Professor of Translational Cancer Research in the School of Cancer Sciences, University of Glasgow, and Honorary Consultant in Medical Oncology at the Beatson West of Scotland Cancer Centre, Glasgow, UK. He is the Lead of the Glasgow Experimental Cancer Medicine Centre (ECMC) and National Clinical Lead of the NHS Scotland Cancer Research Network. He is an investigator in the fostrox clinical development program.

Dr. Richard Finn is a Professor of Medicine at the Geffen School of Medicine at UCLA Department of Medicine, Division of Hematology/Oncology. Dr. Finn splits his time between patient care and directing the Translational Research Laboratory in the Division of Hematology/Oncology. His research interests are focused on the development of targeted therapeutics for solid tumors across histologies. Dr Finn has been the primary investigator of several, ground-breaking studies in HCC, including the ground-breaking ImBrave 150 study.

Dr. Jeong Heo is a Professor of Internal Medicine at Pusan National University School of Medicine and Director of Gastroenterology and Hepatology at Pusan National University Hospital. During his career, Professor Heo has held a number of academic positions, university and hospital appointments and has been principal investigator in many clinical trials for phase I-IV of hepatitis B, C and hepatocellular carcinoma. He is an investigator in the fostrox clinical program.

Dr. Maria Reig is the Head of the BCLC and Liver Oncology Unit at Hospital Clinic of Barcelona in Spain. Her expertise and area of interest is the development of prognostic models for patients with liver cancer and evaluation of treatment options with special emphasis in systemic therapy as well as new research about immune modulation and cancer emergence after antiviral treatment. She is an investigator in the fostrox clinical program.

Dr. Arndt Vogel is managing senior consultant and Professor in the Department of Gastroenterology, Hepatology and Endocrinology at Hannover Medical School. He is also head of the GI-Cancer Center and of the Center for Personalized Medicine at Medical School Hannover. His scientific focus is the translational and clinical research in gastrointestinal cancer. Professor Vogel is member and chairman of Hepatobiliary Cancer Study Group of the AIO, a collaborative group in clinical oncology in Germany. Within ESMO, he is member of the ESMO Guidelines Steering Committee. Furthermore, Professor Vogel has responsibilities in the establishment of the national guideline and is the coordinator of the ESMO clinical practice guideline on the management of hepatocellular carcinoma and biliary tract cancer.