On October 8, 2024 Adcendo, a biotech company focused on the development of first-in-class ADCs for the treatment of cancers with a high unmet medical need, reported that the US Food & Drug Administration (FDA) has provided clearance of the IND application for the Phase I/II study of ADCE-D01 in patients with metastatic and/or unresectable STS (the ADCElerate-01 Trial) (Press release, ADCendo, OCT 8, 2024, View Source [SID1234647094]).

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ADCElerate-01 is a first-in-human Phase I/II multicenter, open-label, dose escalation and expansion study of ADCE-D01 as a monotherapy in patients with metastatic and/or unresectable STS. The primary objective of the study is to evaluate the safety and tolerability of ADCE-D01, to determine the maximum tolerated dose, as well as the recommended Phase II dose and schedule of ADCE-D01 monotherapy. The secondary objectives are to characterize the pharmacokinetics and to evaluate the preliminary efficacy of ADCE-D01. The study will recruit in the US and Europe, with a CTIS submission planned in the EU during the coming months.

Dr. Lone Ottesen, Chief Medical Officer of Adcendo, said: "uPARAP is a highly attractive target for the development of an ADC in mesenchymal cancers including soft tissue sarcoma, as it is highly overexpressed in multiple STS subtypes, has unique internalization properties and shows only very low expression in healthy tissues. The IND clearance of ADCE-D01 is an important milestone for our program and our company, and we look forward to initiating patient enrolment for this study and working with our investigators to evaluate the therapeutic utility of this drug in STS patients as soon as possible."

Prof. Patrick Schöffski, Head of the Department of General Medical Oncology at the University Hospitals and the Laboratory of Experimental Oncology at the Catholic University in Leuven (KU Leuven), and Principal investigator of the ADCElerate-01 trial, commented: "Patients with metastatic soft tissue sarcoma have very limited treatment options and an extremely poor prognosis. We are intrigued by the biology and expression profile of uPARAP, as well as the extensive pre-clinical data package generated for ADCE-D01. ADCs have already significantly altered the therapeutic landscape for many solid tumor indications, and we are excited to be working with Adcendo to develop a potential pan-sarcoma ADC for our STS patients."

About ADCE-D01:

ADCE-D01 is an antibody-drug conjugate targeting the uPARAP receptor. uPARAP is a recycling endocytic receptor involved in collagen homeostasis and turnover. uPARAP exhibits a limited expression profile in healthy tissues but is highly upregulated in multiple mesenchymal cancers, including soft tissue sarcoma, bone sarcoma, GIST as well as mesothelioma and glioblastoma, making it a highly attractive target for ADC development.

On October 8, 2024 Blue Earth Therapeutics Ltd, an emerging leader in the development of therapeutic radiopharmaceuticals, reported further positive developments for its novel investigational radioligand therapies (Press release, Blue Earth Therapeutics, OCT 8, 2024, View Source [SID1234647093]). Enrolment of patients in the Phase 1 trial of Lutetium (177Lu) rhPSMA-10.1 Injection was completed in July. Early data from the trial suggests an encouraging safety profile. Radiation dosimetry performed for up to three cycles showed delivery of high tumour absorbed radiation doses relative to the dose delivered to the key normal organs, such as kidney and salivary glands. While final analysis is ongoing, the ratio between radiation dose to tumours vs. dose to the kidneys and salivary glands was compelling vs. published data1 for first generation radioligand therapies.

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This data opens the way for the Phase 2 portion of the Phase 1/2 trial to start later this year. The company has shared the intended Phase 2 study design with regulators and, subject to trial safety committee agreement, will test innovative dosing regimens in the Phase 2 study. Based on the advantageous results for absolute tumour and normal organ uptake seen in Phase 1, the Phase 2 study will explore the following concepts:

Administration of a significantly higher overall injected radioactivity in comparison to recent Phase 3 clinical trials of other agents.
Front loading of administered radioactivity.
Extending duration of administration of radioactivity to provide longer time on treatment.
In combination with the positive radiation dosimetry results seen in Phase 1 for Lutetium (177Lu) rhPSMA-10.1 Injection, these factors should further support the ultimate goal of delivering better outcomes for patients.

"We are excited by the new data which support our best-in-class thesis and to have a clear path to move from Phase 1 to Phase 2 in the development of our lead therapy," said David Gauden, CEO. "We remain on track for the opening of Phase 2 in the next few months. We also expect to see the full Phase 1 results presented at a scientific meeting in 2025."

"The available science increasingly highlights that fixed dosing at fixed intervals is unlikely to be optimal. Front loading radioactivity and extending the time on therapy may lengthen time to disease progression. We will explore these concepts in Phase 2. Our intention is to optimize dosing now, with the aim of achieving the best possible outcomes for patients in a future pivotal trial," commented Dr Daniel Stevens, Head of Clinical Development and Medical at Blue Earth Therapeutics. "We think that adapting dosing based on data from the individual patient will be important for improved results."

The Phase 2 clinical trial of Lutetium (177Lu) rhPSMA-10.1 Injection is planned to open at approximately 15 sites across the US and Europe and enroll approximately 70 patients.

1 Ells, Zachary, et al. "Dosimetry of [177Lu] Lu-PSMA-Targeted Radiopharmaceutical Therapies in Patients with Prostate Cancer: A Comprehensive Systematic Review and Meta analysis." Journal of Nuclear Medicine (2024).

About Radiohybrid Prostate‐Specific Membrane Antigen (rhPSMA)
rhPSMA compounds are referred to as radiohybrid ("rh"), as each molecule possesses four distinct domains. The first consists of a Prostate‐Specific Membrane Antigen‐targeted receptor ligand. It is attached to two labelling moieties which may be radiolabeled with diagnostic isotopes such as 18F or 68Ga for PET imaging, or with therapeutic isotopes such as 177Lu or 225Ac for radioligand therapy, all of which are joined together by a modifiable linker which can be used to modulate important pharmacokinetic characteristics. Radiohybrid PSMA offers the potential for targeted treatment for men with prostate cancer and originated at the Technical University of Munich, Germany. Blue Earth Diagnostics acquired exclusive worldwide rights to rhPSMA diagnostic imaging technology from Scintomics GmbH in 2018, and therapeutic rights in 2020, and has sublicensed the therapeutic application to its sister company Blue Earth Therapeutics.

On October 8, 2024 Verismo Therapeutics, a clinical-stage CAR-T company developing novel KIR-CAR platform technology, reported that it has activated its CELESTIAL-301 Phase 1 clinical trial at Sarah Cannon Research Institute (SCRI) at Colorado Blood Cancer Institute (CBCI) (Press release, Verismo Therapeutics, OCT 8, 2024, https://www.prnewswire.com/news-releases/verismo-therapeutics-announces-the-activation-of-its-celestial-301-clinical-trial-at-colorado-blood-cancer-institute-302269554.html [SID1234647092]). CBCI offers clinical trials through SCRI, one of the world’s leading oncology research organizations conducting community-based clinical trials. CBCI is the largest and most experienced full-service blood and marrow transplant program in Colorado and among the top programs in the country, making it an ideal location for this clinical trial.

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CELESTIAL-301 will assess safety, tolerability, and preliminary efficacy of SynKIR-310 in patients with relapsed/refractory (r/r) B-cell Non-Hodgkin Lymphomas (B-cell NHL), including Diffuse Large B Cell lymphoma (DLBCL), Follicular Lymphoma (FL), Mantle Cell Lymphoma (MCL), and Marginal Zone Lymphoma (MZL). The Phase 1 multicenter clinical trial will enroll patients who previously received CAR T therapy but who have since relapsed or become refractory to it as well as patients who never received CAR T therapy.

CELESTIAL-301 trial seeks to address several areas of high unmet medical need. Commercially approved CAR T cell therapies have shown impressive high initial response rates in blood cancers. Over time, however, these therapies result in relapse in an estimated 40-50% of patients1. Such relapses are in part due to lack of long-term T cell effector function and persistence. There are currently very limited treatment options for patients with r/r DLBCL who relapse following treatment with commercial CAR T cell therapies. Ongoing clinical investigations into new and/or salvage therapies for these patients have not yet addressed the unmet medical need.

SynKIR-310 relies on Verismo’s unique KIR-CAR platform and proprietary CD19 binder (DS191). SynKIR-310 is directed by DS191 to target a similar epitope of CD19 as the commercially approved CAR T therapies, with the added potential to prolong the anti-tumor T cell function and persistence. This could potentially improve KIR-CAR T Cell persistence and prevent early disease relapse in patients with aggressive lymphomas.

"This trial embodies Verismo’s continued commitment to combatting advanced cancers and addressing high areas of unmet medical need," said Dr. Laura Johnson, CSO of Verismo Therapeutics. "SynKIR-310 has significant potential to help patients with B-cell Non-Hodgkin Lymphomas and be especially beneficial for patients that relapsed after previous infusions of CAR T cell therapies."

Verismo achieved IND clearance from the FDA in May 2024 to proceed with this multicenter clinical trial investigating SynKIR-310. SynKIR-310 is Verismo’s second clinical pipeline following SynKIR-110, which targets aggressive mesothelin-expressing solid tumors. For more information about the CELESTIAL-101 clinical trial, please visit ClinicalTrials.gov: NCT06544265.

About the KIR-CAR Platform
The KIR-CAR platform is a multi-chain CAR T cell therapy and has been shown in preclinical animal models to be capable of maintaining antitumor T cell activity even in challenging tumor microenvironments. Using NK cell derived KIR and DAP12 split signaling provides a novel combined activation and co-stimulation separate from the usual T cell stimulation pathways. It also enables sustained chimeric receptor expression and improves KIR-CAR T cell long term function. This results in prolonged T cell functional persistence and leads to regression of solid tumors and blood cancers in preclinical models that are resistant to traditional CAR T cell therapies. The KIR-CAR platform is being investigated in combination with many additional emerging technologies to potentially provide the next-generation multimodal targeted immunotherapy for patients in need.

On October 8, 2024 Rgenta Therapeutics, a biotechnology company pioneering the development of a new class of oral small molecules targeting RNA and RNA regulation for oncology and neurological disorders, reported that the first patients have been dosed in the Phase 1a/b clinical trial of RGT-61159 (Press release, Rgenta Therapeutics, OCT 8, 2024, View Source [SID1234647091]). This novel drug candidate is being developed for the potential treatment of adenoid cystic carcinoma (ACC), colorectal cancer (CRC) and other solid tumors as well as acute myeloid leukemia (AML).

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"Currently, there are no effective systemic treatment options for ACC. Patients with this rare and aggressive cancer, which carries a high risk of recurrence and metastasis, face an urgent need for innovative treatment approaches," said Lillian Siu, M.D., director of the Phase I Program and co-director of the Bras and Family Drug Development Program at the Princess Margaret Cancer Centre, Toronto, Canada. Enrique Sanz-Garcia, M.D., staff medical oncologist and the principal investigator on the trial at the Princess Margaret Cancer Centre added, "The MYB inhibitor, RGT-61159, represents one such innovative approach designed to address the root cause of ACC and we are excited to evaluate this novel drug candidate in this first-in-human Phase 1 clinical trial."

"Patients with colorectal cancer whose disease has failed initial therapy also have poor outcomes," observed Alexander Spira, M.D., Ph.D., chief executive officer and clinical director of NEXT Oncology-Virginia. "RGT-61159 has a novel mechanism of action and targets a known oncogenic driver. We are pleased to collaborate with Rgenta in exploring the potential of this new agent."

"We are excited to move our first asset into the clinic which is a significant milestone for Rgenta, and to work with a group of world-class clinicians on this trial," said Simon Xi, Ph.D., co-founder and chief executive officer of Rgenta. "At Rgenta we have established a platform to discover and develop small molecule RNA targeting medicines with the goal of unlocking the therapeutic potential of historically undruggable targets in human diseases and we look forward to establishing a robust pipeline of clinical assets."

Rgenta’s Phase 1a/b clinical trial of RGT-61159 is a multi-center, open-label study dose escalation and expansion study in patients with advanced relapsed or refractory ACC or CRC. The Phase 1a/b study will evaluate safety, tolerability, pharmacokinetics and target engagement and clinical efficacy of RGT-61159 in patients with ACC or CRC. Additional information about the Phase 1a/b clinical trial can be accessed at ClinicalTrials.gov (NCT06462183).

About RGT-61159
RGT-61159 is an orally available small molecule designed to specifically modulate splicing of the transcription factor MYB resulting in the inhibition of oncogenic MYB protein production, which has the potential to inhibit proliferation or induce cell death of cancer cells that overexpress MYB protein. MYB acts as a master regulator of cell proliferation differentiation processes and its aberrant expression has been demonstrated in multiple forms of human cancer including adenoid cystic carcinoma (ACC), acute myeloid leukemias (AML), T-cell acute lymphoblastic leukemias (T-ALL), colorectal cancer (CRC), small cell lung cancer (SCLC) and breast cancer.

About Adenoid Cystic Carcinoma (ACC)
It is estimated that approximately 200,000 people are living with ACC throughout the world including 11,000 in the US. While it is a rare cancer, ACC is the second most common cancer type arising in the salivary gland and is an aggressive malignancy with a tendency to infiltrate surrounding nerves and metastasize to distant sites. Overactivation of the MYB oncogene has been described as a hallmark of ACC and is noted in over 90% of ACC. Treatment for ACC is extremely challenging and may include surgery and/or radiation, which often fails to control local tumor recurrence and distant metastases. There are no effective targeted therapies available for patients with recurrent and/or metastatic disease. There is thus an unmet medical need for new therapeutic targets and treatment strategies for patients with this fatal cancer.

About Colorectal Cancer (CRC)
CRC is the third most prevalent cancer and the second leading cause of cancer-related mortality worldwide. According to the World Health Organization, in 2022, more than 1.9 million cases of CRC were diagnosed. Despite the improved early detection of CRC and the recent success of targeted therapeutics, approximately 15%-30% of patients present with metastases and 20%-50% of patients with initially localized disease will develop metastases. Patients with relapsed or refractory CRC who have exhausted all the available standard of care therapy options, have a very poor prognosis. MYB is significantly overexpressed in 80-85% of CRC and has been frequently found to be a predictive biomarker of tumor aggressiveness and poor prognosis. Developing novel therapies to treat patients with metastatic CRC remains a major unmet medical need.

On October 8, 2024 Pierre Fabre Laboratories, a global player in oncology, and Scorpion Therapeutics, Inc. ("Scorpion"), a pioneering clinical-stage oncology company dedicated to transforming the lives of cancer patients by redefining the frontier of precision medicine, reported that the first patient has been dosed in a Phase I/II, first-in-human dose-escalation, dose-optimization and dose-expansion trial (Press release, Pierre Fabre, OCT 8, 2024, View Source [SID1234647090]). This clinical trial evaluates PFL-241/STX-241, a highly differentiated, orally bioavailable, highly selective tyrosine kinase inhibitor ("TKI") targeting epidermal growth factor receptor ("EGFR") Exon 19 or 21 mutations with the co-occurring C797S mutation, a known resistance mechanism to 3rd generation EGFR inhibitors.

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The PFL-241/STX-241 Phase I/II trial is an open label, multi-center study that aims to assess the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and preliminary clinical efficacy of PFL-241/STX-241 as a monotherapy in patients with locally advanced or metastatic non-small cell lung cancer ("NSCLC") harboring EGFR Exon 19 or 21 mutations with the co-occurring C797S mutation.

NSCLC is the most common form of lung cancer and EGFR mutations are one of its most common disease drivers, occurring in up to 38 percent of tumors, depending on geography1,2,3.

"We are eager to begin the clinical evaluation of PFL-241/STX-241, our mutant-selective 4th generation EGFR inhibitor, a molecule with differentiated properties that we believe has the potential to become a best-in-class therapeutic option for patients developing resistance to current targeted therapy," said Francesco Hofmann, Head of Research and Development for Medical Care at Pierre Fabre Laboratories. "The initiation of this clinical trial highlights our team’s engagement and execution in strong partnership with Scorpion Therapeutics, and we look forward to demonstrating how patients could potentially benefit from this targeted therapy."