On February 20, 2024 Philogen S.p.A. (BIT:PHIL) reported that the Phase III FIBROSARC trial (NCT04650984) will continue as planned by the protocol (Press release, Philogen, FEB 20, 2024, View Source [SID1234640287]). The decision was made by an Independent Data and Safety Monitoring Board (DSMB) following the review of efficacy and safety data in the pre-planned interim analysis.

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FIBROSARC is a Phase III 1:1 randomized trial (NCT04650984) which studies L19TNF in combination with doxorubicin (Experimental Arm) versus doxorubicin alone (Control Arm) in 118 patients as first-line therapy for advanced or metastatic Soft Tissue Sarcoma (STS). The primary objective of the study is Progression Free Survival (PFS), with an estimated 45% reduction in the risk of progression in the Experimental Arm (Hazard Ratio 0.55). The pre-planned interim analysis was carried out at 50% of the expected events (i.e., one event corresponds to a disease progression or death) necessary for the primary outcome.

The 46 events required to trigger the interim analysis were reached on 9th November 2023, and at the time of this Press Release the study has enrolled 97 out of 118 patients across 24 clinical centers in Germany, Italy, France, Poland, and Spain. The enrolment of 118 patients is expected to be completed in 2024.

Prof. Dario Neri, co-founder, CEO and CSO of Philogen, commented: "We are very pleased with the recommendation of the DSMB to continue the study as planned by the protocol. The Phase III FIBROSARC trial was designed to demonstrate a significant clinical benefit of L19TNF plus doxorubicin compared to doxorubicin alone. If the final analysis is successful, the study is expected to provide an innovative treatment option for patients with advanced or metastatic STS, for whom no new paradigm-shifting therapies have been available in the last decades."

Alfredo Covelli, MD, Chief Medical Officer of Philogen, commented: "Advanced or metastatic STS are aggressive tumors still treated with chemotherapy-based regimens that were approved in the 1970s. Most innovative therapies, such as immune checkpoint inhibitors, failed to provide a significant benefit to this patient population. We are excited to record the outcome of the interim analysis of FIBROSARC and look forward to seeing the final analysis."

L19TNF is also being evaluated in (i) a Phase IIb randomized trial in first-line metastatic Leiomyosarcoma in the United States (NCT03420014), (ii) a Phase II randomized trial in pre-treated advanced or metastatic Soft Tissue Sarcoma in Europe (NCT04733183), (iii) a Phase II randomized trial in Glioblastoma at first progression in Europe (NCT04573192), and (iv) a Phase I/II/IIb trial in newly diagnosed Glioblastoma in Europe (NCT04443010). Philogen is currently launching a new Phase II study in Glioblastoma at first or later progression in the United States, based on the very encouraging preliminary data observed in the European study. These results have already been published in the journal Science Translational Medicine in 2023 (Look at al. Sci. Trans. Med. 2023, 15:eadf2281).

About Onfekafusp alfa (L19TNF, also known as Fibromun)

L19TNF is a biopharmaceutical product, proprietary to Philogen, studied for the treatment of advanced Soft Tissue Sarcoma and Glioblastoma. It consists of the L19 antibody genetically fused to Tumor Necrosis Factor (TNF). L19 binds selectively to the Extra Domain B of Fibronectin, a protein expressed in tumors (and other diseases) but absent in most healthy adult tissues. TNF is a pro-inflammatory cytokine with anti-tumor activity that is preferentially localized by the L19 antibody to neoplastic masses. L19TNF is administered via a two-hour intravenous infusion. Late-stage clinical trials with registration potential are on-going in Soft Tissue Sarcoma and Glioblastoma. The product has pan-tumoral potential and could be explored for the therapy of other cancer types (e.g., lung, breast, colon, prostate cancers).

About FIBROSARC Phase III study (NCT04650984)

FIBROSARC is a Phase III international, multi-center, randomized, comparator-controlled, parallel-group study in subjects with advanced or metastatic soft tissue sarcoma. In the study, 118 patients will be enrolled and parallel assigned in a 1:1 fashion to one of two different arms, as follows:

Experimental Arm: Patients will receive 13 μg/kg L19TNF on days 1, 3 and 5 every 3 weeks in combination with 60 mg/m2 doxorubicin (once every 3 weeks).

Control Arm: Patients will receive 75 mg/m2 doxorubicin once every 3 weeks. The sample size is calculated based on a 2-sided significance level of 5% and an 80% power, assuming a 15% rate for permanent early censoring. The statistical analysis is designed to discriminate 8 months median PFS (mPFS) in the Experimental Arm versus 4.4 months mPFS in the Control Arm. The primary analysis of PFS will occur after approximately 92 PFS events.

About advanced or metastatic Soft Tissue Sarcoma

STS is a rare group of mesenchymal cancers originating from connective tissues, which collectively account for 1% of all adult cancers. Surgery is the first line of treatment for early stage and localized disease. However, distant metastases occur in many patients, especially in those with high-grade tumors. For patients with unresectable STS, chemotherapy is the standard of treatment and doxorubicin is the recognized standard of care for first line advanced or metastatic STS.

On February 20, 2024 Monopar Therapeutics Inc. (Nasdaq: MNPR), a clinical-stage biopharmaceutical company focused on developing innovative treatments for cancer patients, reported it has received Human Research Ethics Committee (HREC) clearance in Australia to commence a Phase 1 dosimetry trial of its novel radiopharmaceutical MNPR-101-Zr (Press release, Monopar Therapeutics, FEB 20, 2024, View Source [SID1234640286]).

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The MNPR-101-Zr Phase 1 dosimetry clinical trial will enroll patients with advanced cancers and will utilize positron emission tomography (PET) imaging to assess tumor uptake, normal organ biodistribution, and safety.

MNPR-101-Zr is a zirconium-89 (imaging radioisotope) labeled version of MNPR-101, Monopar’s proprietary first-in-class humanized monoclonal antibody that is highly selective against the urokinase plasminogen activator receptor (uPAR). PET imaging studies in preclinical xenograft models of triple-negative breast, colorectal, and pancreatic cancers displayed high and selective uptake of MNPR-101-Zr in these uPAR-expressing tumors. The imaging results, along with corresponding in vivo efficacy studies with actinium-225 (Ac-225, a powerful alpha-emitting therapeutic radioisotope) bound to MNPR-101 in preclinical xenograft tumor models, support the development MNPR-101 as a targeted radiopharmaceutical for multiple advanced cancer indications.

"This is a significant milestone for Monopar," said Chandler Robinson, MD, Monopar’s Chief Executive Officer. "Following more than 18 months of extensive preclinical development, we believe we are well-positioned in this space. This is our first human clinical trial using our uPAR targeting agent. There has been quite impressive clinical data generated in the radiopharma sector of late, such as against PSMA and SSTR2 expressing cancers, and we believe this to be just the beginning."

If the tumor uptake, biodistribution, and safety look encouraging in this Phase 1 clinical trial, which is anticipated to enroll around 12 patients and to initiate in the near future, the plan is to evaluate the efficacy in humans of a therapeutically radio-labeled version of MNPR-101 bound to an isotope such as Ac-225.

On February 20, 2024 Merck (NYSE: MRK), known as MSD outside of the United States and Canada, reported the U.S. Food and Drug Administration (FDA) has accepted for priority review a new supplemental Biologics License Application (sBLA) seeking approval for KEYTRUDA, Merck’s anti-PD-1 therapy, in combination with standard of care chemotherapy (carboplatin and paclitaxel), followed by KEYTRUDA as a single agent for the treatment of patients with primary advanced or recurrent endometrial carcinoma (Press release, Merck & Co, FEB 20, 2024, View Source [SID1234640285]). The FDA has set a Prescription Drug User Fee Act (PDUFA), or target action, date of June 21, 2024.

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The sBLA is based on data from the Phase 3 NRG-GY018 trial. Results from the study, presented at the 2023 Society of Gynecologic Oncology (SGO) Annual Meeting on Women’s Cancer and simultaneously published in the New England Journal of Medicine, showed KEYTRUDA plus chemotherapy reduced the risk of disease progression or death by 46% (HR=0.54 [95% CI, 0.41-0.71]; p<0.00001) in patients whose cancer was mismatch repair proficient (pMMR) and by 70% (HR=0.30 [95% CI, 0.19-0.48]; p<0.00001) in patients whose cancer was mismatch repair deficient (dMMR), compared to chemotherapy alone.

"Endometrial cancer is the most common type of gynecological cancer, and frontline treatment options are limited for patients with advanced stage or recurrent disease," said Dr. Ramez Eskander, principal investigator and gynecologic oncologist, University of California San Diego, Moores Cancer Center. "The use of KEYTRUDA in this setting has the potential to address a significant unmet need for these patients."

"If approved, KEYTRUDA would be the first immunotherapy indicated for the frontline treatment of advanced endometrial cancer regardless of mismatch repair status," said Dr. Gursel Aktan, vice president, global clinical development, Merck Research Laboratories. "We are committed to working closely with the FDA to bring KEYTRUDA to these patients who are in need of additional treatment options, and we thank our collaborators for their partnership on this study."

This trial was sponsored by the U.S. National Cancer Institute (NCI), part of the National Institutes of Health. NRG Oncology designed and led the trial with funding from the NCI and participation from all the National Clinical Trials Network (NCTN) Groups. Merck provided funding and support through a Cooperative Research and Development Agreement (CRADA) between Merck and NCI.

This review is also being conducted under Project Orbis, an initiative of the FDA Oncology Center of Excellence that provides a framework for concurrent submission and review of oncology drugs among its international partners. Health authorities in Israel, Canada, Australia, Singapore and Brazil will review this application as part of Project Orbis.

In the U.S., KEYTRUDA has two approved indications in endometrial cancer. One indication, based on KEYNOTE-775/Study 309, is in combination with LENVIMA (lenvatinib), in collaboration with Eisai, for the treatment of patients with advanced endometrial carcinoma that is pMMR, as determined by an FDA-approved test, or not microsatellite instability-high (MSI-H), who have disease progression following prior systemic therapy in any setting and are not candidates for curative surgery or radiation. The second indication, based on KEYNOTE-158, is as a single agent, for the treatment of patients with advanced endometrial carcinoma that is MSI-H or dMMR, as determined by an FDA-approved test, who have disease progression following prior systemic therapy in any setting and are not candidates for curative surgery or radiation.

Merck has a comprehensive clinical development program in breast and gynecologic (ovarian, cervical, and endometrial) cancers, comprised of more than 20 Merck-sponsored Phase 3 studies evaluating KEYTRUDA as monotherapy and in combination with other medicines. In endometrial cancer, Merck is evaluating KEYTRUDA in the first-line setting for advanced or recurrent disease that is dMMR (KEYNOTE-C93/ENGOT-en15/GOG-3064) and in the adjuvant setting (KEYNOTE-B21/ENGOT-en11/GOG-3053).

About NRG-GY018

NRG-GY018, also known as Merck’s KEYNOTE-868, is a randomized, blinded, placebo-controlled Phase 3 trial (ClinicalTrials.gov, NCT03914612) evaluating KEYTRUDA in combination with standard of care chemotherapy (carboplatin and paclitaxel) versus placebo plus standard of care chemotherapy for the treatment of measurable stage III, IVA, IVB or recurrent endometrial cancer in pMMR and dMMR cohorts. The primary endpoint is progression-free survival (PFS), and secondary endpoints include overall survival, objective response rate, duration of response and safety. The trial enrolled 816 patients who were randomized to receive:

KEYTRUDA plus chemotherapy (carboplatin and paclitaxel) every three weeks for approximately six cycles followed by KEYTRUDA as a single agent every six weeks for up to 14 cycles, or
Placebo plus chemotherapy (carboplatin and paclitaxel) every three weeks for approximately six cycles.
Enrolled patients were required to have MMR IHC testing prior to randomization; 591 patients were determined to have pMMR tumors, and 225 were determined to have dMMR tumors.

About endometrial carcinoma

Endometrial carcinoma begins in the inner lining of the uterus, which is known as the endometrium, and is the most common type of cancer in the uterus. In the U.S., it is estimated there will be approximately 67,880 new cases of uterine body cancer and approximately 13,250 deaths from the disease in 2024. Globally, endometrial cancer is the sixth most common cancer in women and 15th most common cancer overall.

On February 20, 2024 ENPICOM, an innovative bioinformatics software solutions provider, reported a collaboration with Erasmus Medical Center, Rotterdam, a distinguished leader in cancer research (Press release, Erasmus Medical Center, FEB 20, 2024, View Source [SID1234640284]). The aim of this partnership is to identify and develop nanobodies against cancer by utilizing ENPICOM’s immune repertoire data analysis services and software solutions.

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"We selected ENPICOM to support our project because of their unique software that is specifically designed for antibody discovery workflows and their ability to operate as an extension of our team," said project lead Dr. Guido Jenster, professor of Experimental Urological Oncology at Erasmus MC. "By combining the strengths of our team and ENPICOM’s expertise, we are well-positioned to make significant progress in our pursuit of discovering novel cancer therapeutics." The collaboration is funded by the Ministry of Economic Affairs by means of the PPP Allowance made available by the Top Sector Life Sciences & Health to stimulate public-private partnerships.

"We are excited that Erasmus MC, a distinguished leader in cancer research, has chosen ENPICOM to advance the frontier of nanobody-based treatments." stated Paul van der Velde, CEO at ENPICOM. "Nanobodies hold immense potential as a transformative tool in cancer therapy."

Compared to traditional antibodies, nanobodies are much smaller, enhancing tissue penetration and tumor infiltration. Moreover, nanobodies tend to have longer CDR3 regions, enabling them to better recognize hidden epitopes. Their simple single-chain structure also grants nanobodies greater stability and ease of production and engineering.

ENPICOM’s IGX Platform is specifically designed to analyze antibody sequencing data and discover a diverse set of developable candidates. The software seamlessly integrates sequence and experimental assay data, allowing for efficient cluster, phylogenetic, and display enrichment analyses in a secure and scalable environment. Moreover, to ensure the best antibody candidates are selected for follow-up studies the platform enables high-throughput structural modeling of antibodies to accurately identify and annotate exposed liabilities. This makes it a powerful solution to streamline any antibody discovery workflow and easily identify the best antibody candidates for further development.

In addition to the IGX Platform, ENPICOM offers full-service immune repertoire sequencing and analysis in collaboration with Cerba Research. Furthermore, ENPICOM offers on-demand repertoire analysis and custom development to support non-standard R&D – a solid combination of immunology, bioinformatics and software engineering to take on anything touching adaptive immune repertoires.

On February 20, 2024 Iterion Therapeutics, an oncology-focused biopharmaceutical company developing small molecule inhibitors of Transducin beta-like protein 1 (TBL1), a downstream target in the Wnt/beta-catenin signaling pathway, reported that it is actively enrolling a Phase 1b/2a clinical trial of its lead molecule, tegavivint, in patients with advanced hepatocellular carcinoma (HCC) that have failed at least one line of systemic therapy (Press release, Iterion Therapeutics, FEB 20, 2024, View Source [SID1234640280]).

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Activation of the Wnt/beta-catenin pathway is a hallmark of several forms of cancer, including HCC, in which approximately half of patients have tumors with Wnt-activating mutations. Unfortunately, key members of this pathway (including beta-catenin) have either been resistant to conventional drug development or plagued with off-target toxicities. Extensive pre-clinical study results across multiple tumor types suggest that TBL1 is a downstream target that is necessary for Wnt/beta-catenin-activated oncogenesis. TBL1 binds nuclear beta-catenin thus stabilizing the transcription complex necessary to turn on cancer-causing genes. Tegavivint’s direct binding to TBL1 displaces beta-catenin and disrupts this complex, allowing the degradation of free nuclear beta-catenin and preventing downstream oncogenic gene transcription.

"By targeting TBL1, tegavivint promotes potent inhibition of nuclear beta-catenin oncogenic activity without inducing toxicities observed for other drugs that are upstream in the Wnt-pathway" stated Rahul Aras, Ph.D., President & CEO for Iterion Therapeutics. "HCC is a devastating cancer with a high prevalence of Wnt-activated tumors, and we are committed to developing tegavivint for this patient population that otherwise has very few therapeutic options".

HCC is the sixth most commonly diagnosed cancer and the third leading cause of cancer death globally. In 2023, the National Cancer Institute (NCI) estimated 41,210 new HCC cases diagnosed in the US, with 29,380 deaths. The overall prognosis is poor, with a 5-year survival rate of 21.6%. Wnt-activation plays multiple roles in the pathogenesis of HCC by initiating tumorigenesis, promoting metastasis, and enhancing an immunosuppressive tumor microenvironment. Patients with elevated nuclear beta-catenin and TBL1 demonstrate particularly poor outcomes. Despite this, there are no FDA-approved therapies targeting this pathway.

"There is a desperate need for novel targeted therapies to address the large unmet clinical need in HCC" expressed Casey Cunningham, M.D., Chief Medical Officer for Iterion Therapeutics. "Tegavivint has demonstrated excellent tolerability and has the potential to address a large portion of this population by directly inhibiting beta-catenin’s oncogenic activity".

The ongoing clinical trial will enroll approximately 35 patients in dose escalation and optimization cohorts of patients with unresectable locally advanced or metastatic HCC that have failed at least one line of systemic treatment. The study will evaluate safety and clinical efficacy in addition to pharmacokinetic and pharmacodynamic markers to determine a Recommended Phase 2 Dose (RP2D) in HCC. Tegavivint has demonstrated safety, clinical and pharmacodynamic activity in a Phase 1 clinical study of patients with desmoid tumors.

For more information about this Phase 1b/2a clinical trial of tegavivint in patients with advanced HCC, please visit www.ClinicalTrials.gov using the identifier NCT05797805.