On April 5, 2021 Advaxis, Inc. (Nasdaq: ADXS), a clinical-stage biotechnology company focused on the development and commercialization of immunotherapy products, reported an agreement with Columbia University Irving Medical Center to fund a Phase 1 clinical study evaluating ADXS-504 in patients with biochemically recurrent prostate cancer (Press release, Advaxis, APR 5, 2021, https://ir.advaxis.com/news-releases/news-release-details/advaxis-announces-agreement-columbia-university-irving-medical [SID1234577583]). The study, expected to begin in Q2 2021, will be the first clinical evaluation of ADXS-504, Advaxis’ off-the-shelf neoantigen immunotherapy drug candidate for early prostate cancer. Mark Stein, M.D., associate professor of medicine in the Division of Hematology/Oncology at Columbia University Vagelos College of Physicians and Surgeons, will be the study’s principal investigator.

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The Phase 1 open-label study will evaluate the safety and tolerability of ADXS-504 monotherapy, administered via infusion, in 9-18 patients with biochemically recurrent prostate cancer, i.e., those with elevation of prostate-specific antigen (PSA) in the blood after radical prostatectomy or radical radiotherapy (external beam or brachytherapy) and who are not currently receiving androgen ablation therapy. The study will also evaluate preliminary clinical and immune responses following treatment with ADXS-504 monotherapy.

Nearly 248,530 men in the United States will be diagnosed with prostate cancer in 2021, and approximately 34,130 will die from this disease. Many more men with prostate cancer will experience rising prostate-specific antigen (PSA) levels following local therapy with radical radiotherapy or prostatectomy, a condition known as biochemical recurrence (BCR). BCR is not typically associated with imminent death, and biochemical progression may occur over a prolonged period. Clinicians treating men with BCR thus face a difficult set of decisions in attempting to delay the onset of metastatic disease and death while avoiding over-treating patients whose disease may never affect their overall survival or quality of life.

"Currently, men with biochemically recurrent prostate cancer are either monitored for a period of time without intervention or may be started on medicine to decrease the level of testosterone in the body, which can have significant side effects," said Dr. Stein. "Therefore, we need new approaches to stimulate the body’s immune system to control the prostate cancer. Given the encouraging results from a Phase 2 study of ADXS-PSA, which targets a single-antigen, in combination with KEYTRUDA, in men with advanced prostate cancer, and emerging signals of potential clinical activity of the Company’s multi-antigen technology in non-small cell lung cancer, we are excited to have the opportunity to explore the potential of ADXS-504 immunotherapy as a novel treatment modality for biochemically recurrent prostate cancer."

ADXS-504 is a novel Lm-based immunotherapy, bioengineered to elicit T cell responses against 24 tumor antigens that include 14 peptide antigens derived from frequently occurring and commonly shared hotspot mutations in patients with prostate cancer and 10 peptide antigens derived from sequence-optimized tumor-associated antigens (TAAs) that are differentially expressed or overexpressed in prostate cancer. ADXS-504 is designed to express multiple tumor antigen targets to which patients may generate a broad set of effector T cells for tumor control. Similar to Advaxis’ other Lm-based immunotherapies, ADXS-504 is expected to induce an innate immune response followed by the adaptive response and modification of the immunosuppressive tumor microenvironment (TME) by reducing regulatory T cells (Tregs) and myeloid-derived suppressor cell (MDSC) frequencies in the TME.

Kenneth A. Berlin, President and Chief Executive Officer of Advaxis said, "We are pleased to be working with Columbia University Irving Medical Center to conduct the first clinical evaluation of ADXS-504 in earlier stages of prostate cancer where drug constructs of this type could potentially control micrometastasis efficiently. The strategic decision to transition the ADXS-504 to an investigator-sponsored study at Columbia will provide access to world-class expertise and has the potential to accelerate patient recruitment in order to expedite our clinical progress. We are encouraged by our momentum and look forward to continued progress across our ADXS-HOT program, which also includes ongoing studies in NSCLC in the first line setting and in patients who have progressed on pembrolizumab."

On April 5, 2021 Molecular Templates, Inc. (Nasdaq: MTEM, "Molecular Templates," or "MTEM"), a clinical-stage biopharmaceutical company focused on the discovery and development of proprietary targeted biologic therapeutics, engineered toxin bodies (ETBs), reported that, following discussion with its co-development partner Takeda, MTEM will assume full rights to TAK-169 including taking control of clinical development from Takeda (Press release, Molecular Templates, APR 5, 2021, View Source [SID1234577584]). In addition, MTEM announced the decision to discontinue development of MT-3724, MTEM’s only first-generation ETB. MTEM will focus on the clinical development of next-generation ETBs MT-5111, TAK-169, and MT-6402, as well as advancing next-generation preclinical ETB candidates against targets including CTLA-4, CD20, SLAMF-7 and CD45.

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Takeda has communicated that its decision to turn over full rights of TAK-169, a second-generation ETB targeting CD38, was the result of Takeda’s ongoing portfolio prioritization. MTEM believes that TAK-169 is a potent molecule with a novel mechanism of action in multiple myeloma. It has demonstrated a favorable safety and efficacy profile in in vivo models and potency against daratumumab refractory patient samples. TAK-169 is in an ongoing Phase 1 study with dose escalation planned through six dose cohorts, in which the first patient was dosed in February 2020. To date, Takeda has enrolled and treated four subjects in the Phase 1 study. There have been no life-threatening toxicities, and no signs of capillary leak syndrome (CLS). The maximum tolerated dose (MTD) has not been reached, patient screening continues, and dose escalation is ongoing. One dose limiting toxicity (grade 2 myocarditis) was assessed in one subject. A mild elevation in Troponin I was noted in this subject after the third dose of TAK-169. No EKG or echocardiographic abnormalities and no clinical symptoms were noted. A stable elevation in high-sensitivity troponin was seen although no comparison to baseline was available as baseline levels were not required per protocol at the time. An independent radiologist and cardiologist reviewed the imaging in the case and concluded that there was weak to intermediate evidence of myocarditis. The subject had multiple pre-existing cardiac risk factors. No other cardiac adverse events were observed in any other subject. Pharmacokinetic and pharmacodynamic data of this first cohort have been in-line with predicted outcomes. MTEM looks forward to accelerating the full enrollment and completion of this safety and dose-finding study. MTEM’s manufacturing of TAK-169 has been qualified by Takeda and MTEM has sufficient TAK-169 drug supply to continue the Phase 1 study as planned. MTEM’s assumption of the full rights to TAK-169 is expected to result in cost savings in 2021 and MTEM’s guidance of cash runway into 2H23 is unchanged. Upon transfer of the full TAK-169 rights to MTEM, per the terms of the collaboration agreement, MTEM will owe Takeda low-single digit royalties on future net sales of TAK-169. MTEM anticipates that the transition of TAK-169 development from Takeda to MTEM will be conducted over the next 90 days.

In conjunction with taking on full development of TAK-169, MTEM has decided to discontinue development of MT-3724 to focus its resources on the development of next-generation ETBs. As previously disclosed, MT-3724 was placed on partial clinical hold by the U.S. Food and Drug Administration (FDA) following a treatment-related fatality in one subject who experienced Grade 5 CLS in the Phase 2 MT-3724 monotherapy study. Markedly high pharmacokinetic assay readings were observed in this and other subjects treated with a specific lot of MT-3724 material. Apart from this one subject, no life-threatening CLS events have been observed in any subject treated with MT-3724 at any dose tested and no instances of CLS of Grade 2 or higher have been observed with monotherapy treatment at doses of 50 mcg/kg or lower from any other lot of MT-3724 material. The FDA placed MT-3724 on a full clinical hold in late March and requested additional information and the development of a new quantitative assay specific to MT-3724, which would take significant time and investment away from MTEM’s priorities. At such time, MTEM had already discontinued dosing in all MT-3724 studies, as previously disclosed. Based on the foregoing, MTEM has now decided to discontinue development of MT-3724 to focus its resources on the development of next-generation ETBs.

There are no changes to the trials or plans for any other ETB product candidates, including MT-5111, TAK-169, and MT-6402, all of which utilize a next-generation ETB scaffold that has been designed to reduce or eliminate the propensity for innate immunity, including CLS. Furthermore, all MTEM ETBs other than MT-3724 are designed and manufactured to create a more homogeneous product that avoids the production of multiple species including protein aggregate species.

"We thank Takeda for co-discovering TAK-169 and all their efforts on developing the molecule. Takeda’s decision to reprioritize its pipeline allows MTEM to assume full rights to this promising program and we plan to take immediate steps to accelerate new site activation and patient enrollment in the TAK-169 study to generate data this year. While we are disappointed to discontinue development of MT-3724 after demonstrating forced internalization and having seen promising single agent responses in heavily pretreated DLBCL patients, the program provided important clinical proof of concept for our ETB platform and sets the stage for success with our next-generation ETBs," said Eric Poma, Ph.D., Molecular Templates’ Chief Executive and Scientific Officer. "Our next-generation ETBs including MT-5111, TAK-169, and MT-6402, all benefit from improvements over the first-generation ETB technology, including increased potency, a de-immunized Shiga-like Toxin A (SLT-A) scaffold, and simpler design and manufacturing resulting in a more homogeneous drug product. We look forward to making continued progress in 2021 with the Phase 1 studies of MT-5111, TAK-169, and MT-6402 and to advancing our earlier stage pipeline of next-generation ETBs against a variety of other targets."

About TAK-169

TAK-169 is an ETB consisting of a single chain variable fragment (scFv) with affinity for CD38, fused to the enzymatically active de-immunized SLT-A. TAK-169 is designed to bind and kill CD38 expressing cells in a manner consistent with SLT-A mediated cellular cytotoxicity. TAK-169 has been specifically designed to avoid competition with and to overcome the primary mechanisms of tumor resistance to daratumumab, the first approved monoclonal antibody targeting CD38. In preclinical investigation TAK-169 has been shown to be active in the presence of daratumumab. As such, TAK-169 may have the potential to be combined with approved CD38 targeted therapies. TAK-169 mediated ribosomal inhibition and cell death take place intracellularly so changes in the tumor microenvironment, such as CD55/59 upregulation, which inhibit immune-mediated mechanisms such as antibody-dependent cell-mediated cytotoxicity (ADCC) or complement dependent cytotoxicity (CDC) are not expected to inhibit TAK-169 activity.

On April 5, 2021 Blueprint Medicines Corporation (NASDAQ: BPMC), reported that it will host a live conference call and webcast at 8:00 a.m. ET on Monday, April 12, 2021 to review new data for multiple research- and clinical-stage programs across its precision oncology and hematology portfolio (Press release, Blueprint Medicines, APR 5, 2021, View Source [SID1234577585]). The data will also be presented at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2021, April 9-14, 2021.

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Conference Call Information

To access the live call, please dial (855) 728-4793 (domestic) or (503) 343-6666 (international) and refer to conference ID 5548976. A webcast of the conference call will be available in the Investors & Media section of Blueprint Medicines’ website at View Source The archived webcast will be available on Blueprint Medicines’ website approximately two hours after the conference call and will be available for 30 days following the call.

On April 5, 2021 Rain Therapeutics reported that it filed for a $100 million IPO to advance its lead MDM2 inhibitor RAIN-32 into Phase III testing (Press release, Rain Therapeutics, APR 5, 2021, View Source [SID1234577712]). The news comes months after the company closed a $63 million Series B and inlicensed RAIN-32 from Daiichi Sankyo.

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Rain licenses and develops precision cancer therapies. The new lead program, RAIN-32, previously completed Phase I testing in patients with solid tumors or lymphomas. The influx of cash will support a pivotal Phase III trial in liposarcoma, which Rain intends to launch this year, plus two more Phase II trials in solid tumors and intimal sarcoma, respectively.

Preclinical data published by independent French researchers last year suggested MDM2 inhibitors had therapeutic potential for treating liposarcomas, where MDM2 amplification is common.

MDM2 is an inhibitor of tumor-suppressive p53, a notoriously challenging drug target. Several companies are developing MDM2 inhibitors to act upstream of p53, with limited success, which Rain attributes to dose-limiting hematological toxicities.

Last year, Roche ended development of its MDM2 inhibitor, idasanutlin, then in Phase II testing for patients with acute myeloid leukemia (AML). The most advanced anti-MDM2 therapy is APG-115, which Ascentage Pharma has in multiple Phase Ib/II trials for solid tumors and hematologic malignancies, plus a Phase II combination trial with checkpoint inhibitor Keytruda (pembrolizumab) for anti-PD-1 refractory or relapsed cancers. At least two other companies–Novartis and Aileron–also have MDM2 inhibitors in early clinical testing for several cancers.

According to Rain, the safety and tolerability data from Daiichi Sankyo’s trial suggest RAIN-32 can be dosed longer than other MDM2-targeting programs in development.

Rain also has a preclinical RAD52 inhibitor program, licensed from Drexel University in August 2020. RAD52 plays a role in DNA damage response and the company is exploring therapies for breast and ovarian cancers characterized by BRCA1/2 mutations. The company is aiming to select a lead clinical RAD52 inhibitor candidate in 2022. There are no known RAD52 inhibitors in clinical trials.

As recently as last year, its previous lead candidate tarloxotinib, licensed from the University of Auckland, was in Phase II testing for patients with EGFR and ErbB Exon 20 insertion mutations in solid tumors.

The company has not announced an end to the trial but tarloxotinib is not named in Rain’s Securities and Exchange Commission (SEC) forms or listed on the company’s website. Rain did not respond to a request for clarification in time for publication.

On April 5, 2021 Oncolytics Biotech Inc. (NASDAQ: ONCY) (TSX: ONC) reported that it will host a Key Opinion Leader (KOL) webinar discussing AWARE-1 data, the immunotherapeutic effects of pelareorep in breast cancer, and its synergistic activity with CAR T cells in solid tumors (Press release, Oncolytics Biotech, APR 5, 2021, sec.gov/Archives/edgar/data/1129928/000112992821000017/oncy_kolxpr.htm [SID1234577569]). The webinar will take place on Monday, April 12, 2021 at 2:00 pm ET.

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The webinar will feature presentations by Key Opinion Leaders Aleix Prat, M.D., Ph.D. (Clínic Barcelona) and Richard Vile, Ph.D., (Mayo Clinic). Dr. Prat’s portion of the presentation will focus on data from the AWARE-1 window-of-opportunity clinical trial evaluating pelareorep with and without atezolizumab (Tecentriq) in early-stage breast cancer, which will be presented at this year’s American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting. Dr. Vile will then discuss the results of a preclinical study evaluating pelareorep and chimeric antigen receptor (CAR) T cell combination therapy in solid tumors (link to PR, link to poster).
During the event, Oncolytics’ management team will also give a corporate update and discuss the company’s upcoming milestones. Dr. Prat, Dr. Vile, and company management will be available to answer questions following the formal presentations.

To register for the event, please click here.

About the KOLs

Aleix Prat, M.D., Ph.D. is the Head of the Medical Oncology Department of the Hospital Clínic Barcelona (Spain), Associate Professor at the University of Barcelona, Head of the Translational Genomics and Targeted Therapeutics in Solid Tumors Lab at IDIBAPS, and President of the governing board of the Spanish Breast Cancer Cooperative Research Group (SOLTI), which performs clinical trials of excellence in oncology. He was also named a member of the Executive Board of The Breast International Group (BIG) in 2018. BIG is an international non-profit organization that is linked to more than 3,000 hospitals and includes more than 10,000 experts and more than 56 cooperative groups from around the world.
Over his career, Dr. Prat obtained worldwide prestige as a research scientist in the field of breast cancer genomics and biomarker development. In 2008, he became a postdoctoral research associate (2008-2012) at the Lineberger Comprehensive Cancer Center (University of North Carolina at Chapel Hill, USA) in the Laboratory of Prof. Charles M. Perou, a world-renowned translational researcher in breast cancer. During this postdoctoral experience, he discovered and characterized a new molecular subtype of breast cancer, known as a Claudin-low (Prat et al. Breast Cancer Research 2010; Citations: 1,518). In addition, he contributed to the breast cancer portion of The Cancer Genome Atlas (Nature 2012; Citations: 4,661), which was a landmark molecular characterization study in the field of cancer research.

Richard Vile, Ph.D. is a world-renowned scientist and member of the Oncolytics Scientific Advisory Board with extensive experience studying pelareorep. As a recognized KOL, his research focuses on several areas of immuno-oncology, including oncolytic viruses, adoptive cell therapies (ACTs) such as chimeric antigen receptor (CAR) T cells, and potential synergistic interactions between oncolytic viruses and ACTs. In addition to his role as a professor at the Mayo Clinic ("Mayo"), Dr. Vile is the Director of Mayo’s Immuno-oncology and Gene and Virus Therapy programs and Co-Director of the Cancer Immunology and Immunotherapy program. He also serves on the editorial board of several prestigious scientific journals, including Molecular Therapy, Gene Therapy, The Journal of Gene Medicine, and OncoImmunology. Dr. Vile received his B.A. in Biochemistry from the University of Oxford and his Ph.D. in Viral Vectors from the University of London.

About AWARE-1
AWARE-1 is an open label window-of-opportunity study in early-stage breast cancer enrolling 38 patients into five cohorts:
•Cohort 1 (n=10), HR+ / HER2- (pelareorep + letrozole)

•Cohort 2 (n=10), HR+ / HER2- (pelareorep + letrozole + atezolizumab)

•Cohort 3 (n=6), TNBC (pelareorep + atezolizumab)

•Cohort 4 (n=6), HR+ / HER2+ (pelareorep + trastuzumab + atezolizumab)

•Cohort 5 (n=6), HR- / HER2+ (pelareorep + trastuzumab + atezolizumab)
The study combines pelareorep, without or with atezolizumab, and the standard of care therapy according to breast cancer subtype. Tumor tissue is collected from patients as part of their initial breast cancer diagnosis, again on day three following initial treatment, and finally at three weeks following treatment, on the day of their mastectomy. Data generated from this study are intended to confirm that pelareorep is acting as a novel immunotherapy, to evaluate potential synergy between pelareorep and checkpoint blockade, and to provide comprehensive biomarker data by breast cancer subtype. The primary endpoint of the study is overall CelTIL score (a measurement of cellularity and tumor-infiltrating lymphocytes). Secondary endpoints for the study include CelTIL by breast cancer subtype, safety, and tumor and blood-based biomarkers.
For more information about the AWARE-1 study, refer to View Source
About Pelareorep

Pelareorep is a non-pathogenic, proprietary isolate of the unmodified reovirus: a first-in-class intravenously delivered immuno-oncolytic virus for the treatment of solid tumors and hematological malignancies. The compound induces selective tumor lysis and promotes an inflamed tumor phenotype through innate and adaptive immune responses to treat a variety of cancers and has been demonstrated to be able to escape neutralizing antibodies found in patients.