On September 15, 2020 Cullinan Oncology, LLC, the German Cancer Research Center and the Eberhard Karls University of Tübingen, Faculty of Medicine (University of Tübingen), Germany, reported the formation of Cullinan Florentine, a company focused on developing a novel FLT3 x CD3 bispecific antibody for the treatment of patients with acute myeloid leukemia (AML) (Press release, Cullinan Oncology, SEP 15, 2020, View Source [SID1234565193]). This antibody has been developed in Tübingen within the German Cancer Consortium (DKTK), whose core center is the German Cancer Research Center (DKFZ) in Heidelberg. Cullinan Florentine has acquired an exclusive license to develop CLN-049 from the University of Tübingen and the DKFZ.

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"We believe the receptor tyrosine kinase FLT3 is among the most attractive targets in AML but is largely untapped as a target for T cell engaging antibodies," stated Jennifer Michaelson, Ph.D., Chief Development Officer, Biologics at Cullinan Oncology. "Given CLN-049’s robust preclinical package and ease of manufacturability, we believe this bispecific antibody has the potential to be a superior treatment option for AML patients. We are looking forward to filing an IND for CLN-049 by year end."

AML is a rapidly progressing cancer that forms in the bone marrow and results in an increased number of abnormal white blood cells in the bloodstream and bone marrow. AML remains one of the most challenging blood cancers, with high unmet medical need due to low median survival rates in patients. FLT3 is expressed on leukemic cells from the majority of AML patients, including prominent expression on leukemic progenitor cells.

FLT3 is a commercially validated target in AML, yet unlike small molecule inhibitors targeting FLT3, a T cell engaging antibody like CLN-049, which binds to the extracellular domain of FLT3, is agnostic to mutations in the intracellular signaling domain, opening up a broader patient population and avoiding resistance mechanisms. FLT3 has potential advantages over the more commonly selected target antigens for T cell engagers, such as CD33 and CD123, given the low-level expression of FLT3 on normal myeloid cells and hematopoietic stem cells. CLN-049 is therefore predicted to have an improved safety profile.

"We’ve long held the belief that FLT3 is among the most attractive targets in AML," stated Helmut Salih, DKFZ/DKTK Professor and physician at Tübingen University Hospital, and Gundram Jung, Professor at Tübingen University, the originators of the molecule. "And we look forward to advancing CLN-049 into clinical testing with the help of the Cullinan team given their deep domain expertise in the bispecific field."

On September 15, 2020 AVEO Oncology (Nasdaq: AVEO) reported that final overall survival (OS) results from its Phase 3 TIVO-3 study were published in the journal European Urology (Press release, AVEO, SEP 15, 2020, View Source [SID1234565192]). TIVO-3 is the Company’s pivotal Phase 3 trial comparing tivozanib, AVEO’s next-generation vascular endothelial growth factor (VEGF) receptor tyrosine kinase inhibitor (TKI) drug candidate, to sorafenib in third and fourth line renal cell carcinoma (RCC) . The article, titled "Final Overall Survival Results from a Phase 3 Study to Compare Tivozanib to Sorafenib as Third- or Fourth-line Therapy in Subjects with Metastatic Renal Cell Carcinoma," is available online first via this link.

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"TIVO-3 represents the first positive superiority study in the growing population of patients who have relapsed or become refractory to multiple lines of therapy, including checkpoint inhibitors," said 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, and lead author. "TIVO-3 data suggest a favorable safety and efficacy profile relative to sorafenib as demonstrated by superior anti-tumor progression free survival and overall response activity vs. another VEGFR TKI, coupled with fewer dose reductions, interruptions and discontinuations. The OS hazard ratio (HR) is consistent with previous Phase 3 studies comparing two VEGF-directed agents. I believe that tivozanib has the potential to offer patients a meaningful new treatment option in a setting currently lacking an evidence-based standard of care."

"For RCC patients who have relapsed or are refractory to multiple lines of therapy, the lack of well controlled clinical data to guide treatment decisions in this advanced relapsed/refractory population poses challenges for patients and treating physicians," said Michael Bailey, president and chief executive officer of AVEO. "We expect that Tivozanib’s TIVO-3 data has the potential to guide important treatment decisions in this setting and ultimately improve outcomes and patient experience. We look forward to working with the U.S. Food and Drug Administration (FDA) as they continue to review our New Drug Application (NDA) submission."

In June 2020, AVEO announced that the FDA accepted for filing its NDA seeking approval for tivozanib as a treatment for relapsed or refractory RCC. The FDA has assigned the application standard review and a Prescription Drug User Fee Act target action date of March 31, 2021. The FDA also indicated that they do not currently plan on convening an Oncologic Drug Advisory Committee (ODAC) to discuss the application. The NDA submission is based on the TIVO-3 study and is also supported by three additional trials in RCC and includes safety data from over 1,000 clinical trial subjects and several years of commercial availability in Europe.

Results in Detail

Patients enrolled in the TIVO-3 trial (n=350) were randomized and stratified by prior regimen and IMDC prognostic score. Prior treatment regimens included prior checkpoint inhibitor and VEGF TKI therapies (n=91), two prior VEGF TKI therapies (n=159) and prior VEGF TKI and other therapies (n=100). As previously announced, the TIVO-3 trial met the primary endpoint of progression free survival (PFS), with a median PFS of 5.6 months in the tivozanib arm vs. 3.9 months in the sorafenib arm (HR=0.73; p=0.02), and the secondary endpoint of overall response rate (ORR) (18% vs. 8%; p=0.02).

For the secondary endpoint of OS, the OS HR, which assesses the overall relative risk of death, was 0.97 (95% CI: 0.75-1.24; p=0.82), favoring tivozanib and improving from the previously reported interim HR of 0.99. 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), and treatment related AEs leading to permanent discontinuation were 8% for tivozanib vs. 15% for sorafenib.

About Tivozanib (FOTIVDA)

Tivozanib is an oral, once-daily, next-generation vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor (TKI) discovered by Kyowa Kirin and approved as FOTIVDA for the treatment of adult patients with advanced renal cell carcinoma (RCC) in the European Union and other countries in the EUSA territory. 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 RCC.8 Tivozanib has been investigated in several tumor types, including renal cell, hepatocellular, colorectal, ovarian and breast cancers. Tivozanib is also being studied by partner Kyowa Kirin in non-oncology indications.

On September 15, 2020 BostonGene Corporation, a biomedical software company committed to defining optimal precision medicine-based therapies for cancer patients, reported a scientific collaboration with Brigham and Women’s Hospital, a world-class academic medical center and a major teaching hospital of Harvard Medical School based in Boston, Massachusetts (Press release, BostonGene, SEP 15, 2020, View Source [SID1234565190]).

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In this collaboration, BostonGene provides the analysis of whole transcriptome sequencing (RNA seq) data sets generated from tumor and blood samples from patients with recurrent glioblastoma (GBM) treated with an oncolytic virus as part of a Phase I clinical trial. As part of the effort, BostonGene correlation analysis aims to identify novel biomarkers of response to therapy. The collaboration will further demonstrate the powerful advantages of transcriptomic data analysis for prediction of the response to novel therapies for malignant brain tumors.

"We are very excited to enter into this collaboration with BostonGene in our efforts to fully understand the molecular underpinnings of responses to novel engineered viruses-based therapies," said Ennio Antonio Chiocca, MD, PhD, Neurosurgeon-in-Chief and Chairman, Department of Neurosurgery at Brigham and Women’s Hospital. "This collaboration is another step in allowing us to make better individual treatment decisions for patients with GBM."

"We’re honored to collaborate with Brigham and Women’s Hospital to demonstrate the clinical utility of BostonGene’s analytical tools that have been designed to improve diagnosis and treatment decisions for cancer patients," said Andrew Feinberg, President & CEO at BostonGene. "We firmly believe that advanced computational analytics will better equip physicians as they identify personalized treatment plans."

On September 15, 2020 Tyme Technologies, Inc. (NASDAQ: TYME), an emerging biotechnology company developing cancer metabolism-based therapies (CMBTsTM), reported that the final results of its SM-88 Phase II Prostate Cancer study designed to evaluate the safety, tolerability and efficacy of SM-88 in patients with non-metastatic biochemical recurrent prostate cancer, was published on September 13th, 2020 in the peer-reviewed journal Investigational New Drugs (Press release, TYME, SEP 15, 2020, View Source [SID1234565184]). The article, titled "Phase II Trial of SM-88, a Cancer Metabolism Based Therapy, in Non-Metastatic Biochemical Recurrent Prostate Cancer," is available online at View Source

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The study demonstrated that SM-88 had promising efficacy and safety outcomes for prostate cancer patients while sparing testosterone. The study also demonstrated a reduction of CTCs, an important prognostic indicator, that may prove to be a better surrogate for patient outcomes than PSA, particularly for SM-88.

"Oral SM-88 has demonstrated potential efficacy and a well-tolerated safety profile that may represent a new treatment option for more than 450,000 prostate cancer patients in the U.S. alone seeking a non-cytotoxic, non-hormonal therapy," said Giuseppe Del Priore, M.D., M.P.H., Chief Medical Officer at TYME. "We are encouraged by the clinical results of our unique proprietary approach using cancer metabolism-based therapies that we believe attack the cancer cells from within, interrupting the cancer metabolic processes."

From September 2016 to April 2019, twenty-three evaluable patients with non-metastatic pancreatic cancer with rising PSA levels, detectable circulating tumor cells and no radiographically detectable metastases were assessed in a Phase II trial. All patients received 230 mgs twice per day of SM-88 orally. Patients also received oral doses of methoxsalen (10 mg), phenytoin (50 mg), and sirolimus (0.5 mg) once per day. Most patients had previously received androgen-deprivation therapy (ADT) after radiation therapy or surgery, but ADT treatment changes were not permitted during the trial.

From the initial diagnoses of PSA rise, 100% of patients (23/23) remained free of metastatic progression (MFS) and 87% of patients (20/23) have maintained radiographic progression-free survival (rPFS) with a median duration of therapy of 6.5 months since starting SM-88 treatment. All patients who have maintained meaningful reductions in circulating tumor cells (CTCs) on SM-88 were 100% free of any radiographic progression.

At baseline, the median PSA for patients with radiographic progression was 13.4 compared to 5.6 for patients with no radiographic progression (p=0.02). Among evaluable patients, PSA stabilized in 83% of patients (19/23). Importantly, 52% of evaluable patients (12/23) experienced an improvement in median PSA doubling time (DT), a positive prognostic indicator. In all patients who completed three cycles of therapy, the median DT improved nearly 34.4% from 6.1 to 8.2 months (n=20). After 12 weeks, or three cycles of therapy, 78.2% of patients (18/23) demonstrated a decrease in CTC from baseline, with a median decrease of 65.3%.

Patients without local progression (20/23) had slightly higher testosterone levels at baseline and throughout treatment on SM-88 as compared to those who experienced local radiographic progression (3/23). According to the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire, patients generally reported stable cognitive and sexual function domain measures, with no detectable worsening in any domain. Patient weight, EKG QTc, glucose and hematocrit and other measures, which are often side effects of ADT, did not appear affected while receiving SM-88.

The SM-88 therapy was well tolerated in all patients. There were no treatment-related serious adverse events. No adverse events resulted in dose delay, discontinuation, or reduction. The majority of Grade 1 AEs possibly or probably related to the SM-88 investigational therapy were gastrointestinal in nature.

The Phase II prostate cancer trial results are from an investigational study. SM-88 is not approved for the treatment of patients with any disease condition.

About Advanced Prostate Cancer

Prostate cancer is the most common malignancy in men, accounting for approximately 31,620 deaths in the United States in 2019.1 Approximately 15% of men with prostate cancer present with metastatic disease, and 20% to 30% of men with localized disease treated with definitive local therapy subsequently develop metastatic disease. While the vast majority of patients with metastatic disease demonstrate a transient response to androgen deprivation, eventually all patients develop hormone refractory prostate cancer (HRPC) and virtually all prostate cancer deaths are due to the development of metastatic HRPC.2 While chemotherapy regimens have shown a modest survival advantage in HRPC patients, median survival remains approximately 19 months,3,4 and not all patients are candidates for chemotherapy. Novel agents and new approaches such as oral cancer metabolic-based therapies are needed.

About SM-88

SM-88 is an oral investigational modified proprietary tyrosine derivative that is believed to interrupt the metabolic processes of cancer cells by breaking down the cells’ key defenses and leading to cell death through oxidative stress and exposure to the body’s natural immune system. Clinical trial data have shown that SM-88 has demonstrated encouraging tumor responses across 15 different cancers, including pancreatic, lung, breast, prostate and sarcoma cancers with minimal serious grade 3 or higher adverse events. SM-88 is an investigational therapy that is not approved for any indication in any disease. Learn more.

On September 15, 2020 Codiak BioSciences, Inc., a clinical-stage company focused on pioneering the development of exosome-based therapeutics as a new class of medicines, reported the initiation of subject dosing in its Phase 1 clinical trial of its novel exosome therapeutic candidate, exoIL-12 (Press release, Codiak Biosciences, SEP 15, 2020, View Source [SID1234565183]). Engineered using Codiak’s proprietary engEx Platform and designed to display IL-12 on the exosome surface, exoIL-12 is designed to enhance dose control of IL-12 and limit systemic exposure and associated toxicity by localizing IL-12 in the tumor microenvironment (TME). The trial will evaluate single ascending doses (SAD) of exoIL-12 in healthy volunteers and then transition to patients with early stage cutaneous T cell lymphoma (CTCL) with repeat dosing of pharmacologically active doses identified in the healthy volunteer SAD study. The trial is Codiak’s first human clinical trial and the first of two clinical development programs Codiak expects to initiate in 2020.

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"To our knowledge, exoIL-12 is the first engineered exosome to enter clinical development, which makes the initiation of this trial a true milestone not only for Codiak but for the entire exosome therapeutics field," said Douglas E. Williams, Ph.D., CEO, Codiak. "Our engEx platform allows us to engineer exosomes to selectively deliver potent therapeutic payloads, such as IL-12, to potentially enhance the therapeutic index. We believe that exoIL-12 may unlock the well-documented therapeutic potential of this cytokine by retaining its activity within the tumor and reducing systemic exposure and the adverse events seen in the past with other formulations of IL-12."

Codiak is initially focusing development of exoIL-12 on tumors that have previously shown clinical responses to IL-12 used as a monotherapy, such as CTCL. While the biological rationale for IL-12 as a cancer treatment has been validated in previous human clinical studies, its utility has been severely limited due to serious adverse events caused by systemic exposure.

Codiak has engineered exoIL-12 to display fully active IL-12 on the surface of the exosome, which is designed to facilitate potent local pharmacology at the tumor injection site with precisely quantified doses. Exosomal delivery has demonstrated limited systemic exposure to IL-12 in preclinical models and resulted in significant and prolonged pharmacodynamic activity and both local and systemic anti-tumor immune responses.

The Phase 1 clinical trial, which is being conducted at the Phase 1 unit Richmond Pharmacology LTD, London, UK, is designed to evaluate safety, tolerability, pharmacokinetics and pharmacodynamics of exoIL-12 following single ascending subcutaneous doses in healthy volunteers, followed by repeat dose exoIL-12 into the lesions of stage IA-IIB CTCL patients. Patients with CTCL will be monitored for safety, pharmacokinetics, pharmacodynamic effects in blood and tumor biopsies, and local and systemic anti-tumor efficacy using validated CTCL assessment criteria. Preliminary results from healthy volunteers are anticipated by the end of 2020 and safety, biomarker and preliminary efficacy results from CTCL patients are anticipated in mid-2021.

About exoIL-12

exoIL-12 is Codiak’s exosome therapeutic candidate engineered to display fully active IL-12 on the surface of the exosome, using the exosomal protein, PTGFRN, as a scaffold protein, and designed to facilitate potent local pharmacology at the injection site with precisely quantified doses. By limiting systemic exposure of IL-12 and associated toxicity, Codiak hopes to enhance the therapeutic index with exoIL-12, delivering a more robust tumor response, dose control and an improved safety profile.

Codiak intends to focus development of exoIL-12 on tumors that have, in previous clinical testing, shown clinical responses to IL-12 used as a monotherapy. This includes cutaneous T cell lymphoma (CTCL), melanoma, Merkel cell carcinoma, Kaposi sarcoma, glioblastoma multiforme and triple negative breast cancer.

About the engEx Platform

Codiak’s proprietary engEx Platform is designed to enable the development of engineered exosome therapeutics for a wide spectrum of diseases and to manufacture them reproducibly and at scale to pharmaceutical standards. By leveraging the inherent biology, function and tolerability profile of exosomes, Codiak is developing engEx exosomes designed to carry and protect potent drug molecules, provide selective delivery and elicit the desired pharmacology at the desired tissue and cellular sites. Through its engEx Platform, Codiak seeks to direct tropism and distribution by engineering exosomes to carry on their surface specific targeting drug moieties, such as proteins, antibodies/fragments, and peptides, individually or in combination. Codiak scientists have identified two exosomal proteins that serve as surface and luminal scaffolds. By engineering the exosome surface or lumen and optimizing the route of administration, Codiak aims to deliver engEx exosomes to the desired cell and tissue to more selectively engage the drug target, potentially enhancing the therapeutic index by improving potency and reducing toxicity.