On October 1, 2021 Cancer Research Institute (CRI) reported that Next week on October 7-8, 2021, the Cancer Research Institute (CRI)—a nonprofit organization dedicated to harnessing the immune system’s power to control and potentially cure all types of cancer—will offer its 2021 CRI Immunotherapy Patient Summit as a free, virtual event (Press release, Cancer Research Institute, OCT 1, 2021, View Source [SID1234590683]). Tamron Hall—Emmy Award-winning host of the Tamron Hall television show, executive producer, author, and philanthropist—will moderate the Summit for the second year.

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"This event that brings medical experts together with thousands of patients to discuss the growing promise of cancer immunotherapy happens nowhere else," Hall said. "For those of us who have lost someone to cancer or are going through treatment right now, the CRI Summit offers a vital lifeline of helpful information, connecting patients and their caregivers to clinical trials and emerging treatments, and I am proud to be a part of it."

Over the course of two days, the Summit will highlight the growing implications of immunotherapy for more than 10 cancer types, provide education on the basics of immunotherapy and how clinical trials work, and address cancer care disparities for the first time as part of this program.

"This is our fifth CRI Immunotherapy Patient Summit and our second in an online format open and available to anyone, again free of charge as with all our Summits," said Jill O’Donnell-Tormey, Ph.D., chief executive officer and director of scientific affairs at Cancer Research Institute. "Immunotherapy is no longer just a research frontier. Clinical breakthroughs are multiplying, and this Summit is where patients, caregivers, health care professionals, and advocates alike can gain insight on the full range of advances, learn about clinical trial options, and ask their questions."

The expanded Summit program begins on Thursday, October 7, at 1:00 PM ET and runs from 1:00 PM to 5:30 PM ET on Thursday and on Friday, October 8. Highlights include:

Breakout sessions led by top academic experts on the progress of immunotherapy against a wide range of cancer types—encouraging questions from the patients present
A panel of diverse patient advocates to discuss racial disparities in cancer care—addressing financial and social barriers—and ways to respond through self-advocacy and support networks
Nuts-and-bolts sessions on the science behind immunotherapy and how clinical trials work.
Patients and caregivers registered for the Summit also can request a free, confidential one-on-one consultation in English or Spanish with one of CRI’s Clinical Trial Navigators, who can help locate immunotherapy clinical trials appropriate to an individual’s diagnosis, treatment history, and circumstances.

Summit registration is available at: View Source

Day 1 topics and speakers will include:

Immunotherapy 101: The Basics and Beyond
Ellen Puré, Ph.D., University of Pennsylvania
Live Q&A moderated by Tamron Hall

Immunotherapy Clinical Trials
Kunle Odunsi, M.D., Ph.D., University of Chicago

Immunotherapy Patient Perspectives
Moderated by Stephen Estrada, Colorectal Cancer Veteran

Blood Cancer and Immunotherapy
Hearn Jay Cho, M.D., Ph.D., Mount Sinai Tisch Cancer Institute

Colorectal Cancer and Immunotherapy
Van Morris, M.D., The University of Texas MD Anderson Cancer Center

Brain Cancer and Immunotherapy
David A. Reardon, M.D., Harvard Medical School and Dana-Farber Cancer Institute

Head and Neck Cancer and Immunotherapy
Nabil F. Saba, M.D., FACP, Winship Cancer Institute at Emory University

Day 2 topics and speakers will include:

Conversation About Cancer Care Disparities
Moderated by Karen Peterson, Breast Cancer Veteran

Breast Cancer and Immunotherapy
Leisha Emens, M.D., Ph.D., University of Pittsburgh Medical Center

Lung Cancer and Immunotherapy
Patrick Forde, M.D., Johns Hopkins Medicine

Prostate Cancer and Immunotherapy
Ana Aparicio, M.D., The University of Texas MD Anderson Cancer Center

Ovarian Cancer and Immunotherapy
Dmitriy Zamarin, M.D., Ph.D., Memorial Sloan Kettering Cancer Center

Melanoma and Immunotherapy
Margaret Callahan, M.D., Ph.D., Memorial Sloan Kettering Cancer Center

Bladder Cancer and Immunotherapy
Arjun Balar, M.D., Perlmutter Cancer Center at New York University Langone Health

Support for the 2021 CRI Immunotherapy Patient Summit is generously provided by the following:

Sponsors
Gold: Bristol Myers Squibb
Silver: Merck
Bronze: Genentech, GSK, Lilly Oncology, Novartis, Pfizer, Regeneron, Sanofi Genzyme

Friend
Foundation Medicine

Host Institutions
The University of Texas MD Anderson Cancer Center, NYU Langone Health

On September 30, 2021 Aileron Therapeutics (Nasdaq: ALRN), a chemoprotection oncology company focused on fundamentally transforming the experience of chemotherapy for cancer patients, reported it will present new preclinical data at the upcoming AACR (Free AACR Whitepaper)-NCI-EORTC AACR-NCI-EORTC (Free AACR-NCI-EORTC Whitepaper) International Conference on Molecular Targets and Cancer Therapeutics (EORTC-NCI-AACR) (Free ASGCT Whitepaper) (Free EORTC-NCI-AACR Whitepaper) demonstrating a potential secondary application of its novel, selective chemoprotective agent ALRN-6924 to also protect against radiation-induced toxicities (Press release, Aileron Therapeutics, SEP 30, 2021, View Source [SID1234590571]).

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Aileron is currently developing ALRN-6924, a first-in-class MDM2/MDMX dual inhibitor, to selectively protect healthy cells in patients with cancers that harbor p53 mutations to reduce or eliminate chemotherapy-induced side effects while preserving chemotherapy’s attack on cancer cells. ALRN-6924 is designed to activate p53 in normal cells, which in turn upregulates p21, which pauses cell cycle in normal cells but not in p53-mutated cancer cells. A Phase 1b randomized, double-blind, placebo-controlled study is currently underway in the United States and Europe evaluating ALRN-6924 in patients with advanced p53-mutated non-small cell lung cancer undergoing treatment with first-line carboplatin plus pemetrexed with or without immunotherapy. Aileron is pursuing a clinical development strategy designed to advance its vision to bring selective chemoprotection to all patients with
p53-mutated cancer regardless of type of cancer or chemotherapy.

In the AACR (Free AACR Whitepaper)-NCI-EORTC poster presentation, Aileron will share data showing ALRN-6924’s activity as a radioprotective agent in preclinical models of acute radiation toxicity, leveraging the same mechanism of action that enables ALRN-6924 to protect against chemotherapy-induced toxicities. The poster details are as follows:

Poster Title: The Investigational Chemoprotection Drug ALRN-6924, a Dual Inhibitor of MDMX and MDM2, Shows Potential for Radioprotection

Poster #: P211

Date/Time: All poster presentations will be made available by the conference at the opening of the meeting on October 7, 2021 at 9:00 a.m. ET.

On September 30, 2021 OncoNano Medicine, Inc. reported a poster presentation at The American Association for Cancer Research (AACR) (Free AACR Whitepaper) Virtual Conference on Tumor Immunology and Immunotherapy to be held on October 5-6, 2021 (Press release, OncoNano Medicine, SEP 30, 2021, View Source [SID1234590589]).

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Full details of the presentation are listed below:

TITLE: ONM-501 ― A Synthetic Polyvalent STING Agonist for Cancer Immunotherapy

PRESENTER: Qintai Su, Ph.D.
DATE: October 5-6, 2021
LOCATION: Virtual

The development of ONM-501 represents a new concept in STING activation that could overcome the challenges observed with earlier STING agonists. ONM-501 encapsulates the endogenous STING agonist cGAMP with a proprietary micelle that induces polyvalent STING condensation and prolongs innate immune activation to offer dual ‘burst’ and ‘sustained’ STING activation for a potential highly effective immunotherapy against cancer.

On September 30, 2021 CNS Pharmaceuticals, Inc. (NASDAQ: CNSP) ("CNS" or the "Company"), a biopharmaceutical company specializing in the development of novel treatments for primary and metastatic cancers in the brain and central nervous system, reported the dosing of the first patients in its Berubicin clinical development program for the treatment of recurrent glioblastoma multiforme (GBM), one of the most aggressive types of brain cancer (Press release, CNS Pharmaceuticals, SEP 30, 2021, View Source [SID1234590605]). Further patient enrollment, randomization and dosing is currently underway as well as a robust lineup of clinical sites located globally which are advancing toward activation and enrollment.

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"As one of the most aggressive, deadly and treatment-resistant cancers that forms in the brain where current standard of care remains ineffective in ~60% of patients, the treatment landscape for GBM is in desperate need of a better treatment option. We continue to be encouraged by the data seen from Berubicin to date and are excited to now have patient dosing underway in this potentially pivotal trial. Our team is committed to expeditiously advancing the study and look forward to further understanding the full potential of Berubicin to offer improvement and overall survival in this devastating disease," stated Erin Dunbar, M.D., founding physician of the Brain Tumor Center and Director of Neuro-Oncology at Piedmont Atlanta Hospital, and Principal Investigator for the study.

Berubicin is a novel anthracycline and the first anthracycline to appear to cross the blood-brain barrier currently being evaluated in a global potentially pivotal study evaluating its efficacy and safety. The potentially pivotal trial is an adaptive, multicenter, open-label, randomized and controlled study in adult patients with recurrent glioblastoma multiforme (WHO Grade IV) after failure of standard first-line therapy. Approximately 243 patients with GBM after failure of standard first line therapy will be randomized in a 2:1 ratio to receive Berubicin or lomustine for the evaluation of Overall Survival, the primary endpoint of the study. Overall Survival is a rigorous endpoint that the U.S. Food and Drug Administration (FDA) has recognized as a basis for approval of oncology drugs when a statistically significant improvement can be shown relative to a randomized control arm.

In the Phase 1 clinical trial previously conducted evaluating Berubicin in patients with previously treated disease, 44% of the patients showed clinical benefit (49% of the Avastin-naïve patient population), with the demonstration that it was effective based on this patient population with a dismal median survival rate of only 14.6 months from diagnosis. One patient in the Phase 1 study had a durable Complete Response (CR, a demonstrated lack of detectable cancer cells) that has continued for 14 years, and another patient had a durable partial response, with others showing substantial stabilization of disease. Additionally, the novel anthracycline agent Berubicin appears to have a toxicity profile consistent with that of other anthracyclines and demonstrates activity as monotherapy for recurrent glioblastoma multiforme. Berubicin has side effects that are able to be effectively treated and managed.

"I am extremely pleased with the progress made to-date in this potentially pivotal trial. Our team has been working intensely to open sites in the U.S. and in Europe, understanding where we can best advance this important study. With hundreds of potentially competing GBM trials currently enrolling patients, the fact that we’ve been able to bring these initial sites on-line and get patients enrolled and dosed not only supports our strategic evaluation and selection, but also allows our data demonstrating Berubicin’s potential effectiveness to continue to convince the medical community that we have a new drug with impressive potential. With the de-risked profile of Berubicin, its mechanism of action, history of development, encouraging Phase 1 data, and safety in study design, I am personally more optimistic about our work than at any time since joining the Company," commented John Climaco, CEO of CNS Pharmaceuticals.

"The investigator dedication to advance the science and development of Berubicin we’re seeing here is meaningful to these patients that are out of options. Berubicin provides an innovative option for treatment in GBM as a safe and potentially effective therapy. We look forward to providing data at the interim analysis of the study," added Sandra L. Silberman, M.D., Ph.D. Chief Medical Officer of CNS Pharmaceuticals.

A pre-planned, non-binding futility analysis will be performed after approximately 30 to 50% of all planned patients have completed the primary endpoint at 6 months. This review will include additional evaluation of safety as well as secondary efficacy endpoints. Enrollment will not be paused during this interim analysis.

The FDA recently granted CNS Pharmaceuticals Fast Track Designation for Berubicin which enables more frequent interactions with the FDA to expedite the development and review process. As previously announced, the Company also received Orphan Drug Designation from the FDA which may provide seven years of marketing exclusivity upon approval of an NDA. Taken together the Company believes these important designations can be seen as a recognition of the significance of not only the unmet clinical need in GBM, but of our Berubicin program.

For more information about the potentially pivotal Berubicin trial, visit clinicaltrials.gov and reference identifier NCT04762069.

About Berubicin

Berubicin is an anthracycline, a class of anticancer agents that are among the most powerful chemotherapy drugs and effective against more types of cancer than any other class of chemotherapeutic agents. Anthracyclines are designed to utilize natural processes to induce deoxyribonucleic acid (DNA) damage in targeted cancer cells by interfering with the action of topoisomerase II, a critical enzyme enabling cell proliferation. Berubicin treatment of brain cancer patients appeared to demonstrate positive responses that include one durable complete response in a Phase 1 human clinical trial conducted by Reata Pharmaceuticals, Inc. Berubicin, was developed by Dr. Waldemar Priebe, Professor of Medicinal Chemistry at The University of Texas MD Anderson Cancer Center.

On September 30, 2021 Race Oncology Limited ("Race") reported to share interim results from our collaborative preclinical melanoma research program with the University of Newcastle (ASX Announcement: 19 Mar 2021) (Press release, Race Oncology, SEP 30, 2021, View Source [SID1234591003]). Eminent melanoma researchers, Professor Xu Dong Zhang and Associate Professor Lei Jin, are leading the project.

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This program is exploring the use of Zantrene (bisantrene dihydrochloride) as a novel potential treatment for melanoma using cellular and mouse models. The aim is to identify drug combinations and melanoma subtypes that show improved treatment responses, with a focus on treatment-resistant melanomas.

These interim results showed Zantrene to be highly effective at killing a diverse range of high FTO producing melanoma cell subtypes. Data from the expression of the Fat Mass and Obesity-associated protein (FTO) showed an association between FTO expression level and sensitivity to Zantrene.

Zantrene has been identified as a potent targeted inhibitor of the Fat Mass and Obesity associated protein (FTO)1. Previous studies have observed that FTO is over-produced in approximately 50% of metastatic melanomas2 and that inhibition of FTO can overcome PD-1 immune checkpoint resistance in mouse melanoma models2,3. PD-1 immune checkpoint inhibitors have emerged as a front-line treatment for many types of cancer, including melanoma. While there have been major advances in melanoma treatments in recent decades, the five-year survival rate for advanced melanoma remains low4.

"These interim results are highly encouraging and support our clinical plans for Zantrene, with the correlation between FTO overexpression and sensitivity to Zantrene suggesting a strong anti-FTO therapeutic opportunity. The high sensitivity of many of the melanoma cell lines to Zantrene as a single agent at concentrations well below chemotherapeutic doses is unexpected and may offer new treatment options for melanoma patients."

Race CSO Dr Daniel Tillett
"While challenged by COVID 19 related shutdowns we appreciate the encouraging and continued work from the team at the University of Newcastle. Zantrene continues to positively surprise us – we are very pleased with these early results. Melanoma remains a difficult cancer to treat, and one that’s of particular relevance to the Australian community, so as we continue with this work, we look forward to learning more about our potential to offer new treatment options to patients."

Race CEO & MD Phillip Lynch
Study Background
Melanoma is unresponsive to existing anthracyclines, yet Zantrene showed significant historical in vitro activity against fresh human melanoma samples taken from patients in human tumor cloning assays5,6. In a subsequent Phase I trial of Zantrene administered weekly, a patient with metastatic melanoma achieved a complete response lasting 6 months7. This weekly dosing schedule would likely have resulted in sustained inhibition of FTO due to the long time Zantrene remains in the human body.

Despite these early successes, four subsequent Phase 2 studies of Zantrene in 100 melanoma patients used much longer dosing intervals of once every three or 4 weeks and did not achieve the same levels of clinical response, possibly due to limited, transient inhibition of FTO8-11. Seventeen patients (1/16, 2/16, 0/17, 14/51) achieved disease stabilization, but no further complete responses were observed.

In light of the recent discovery that Zantrene is a potent inhibitor of the m6A RNA demethylase FTO1 and that FTO is frequently overexpressed in metastatic melanoma2, Race sought to explore the use of Zantrene for treating melanoma, both as a single agent and in combination with other standard of care drugs. This research will also help inform the dose regimen to be explored in future clinical trials.

Study Highlights
1. Zantrene is highly effective in killing melanoma cells at sub-chemotherapeutic levels
Zantrene proved to be highly effective at killing melanoma cell lines, with 60% (15 of 25) displaying IC50 values below 100 nM concentrations (Table 1). This was seen with cell lines derived from both primary and metastatic melanoma patients. Interestingly, six of the 25 cell lines showed extreme sensitivity to Zantrene (IC50 values under 40 nM), suggesting that Zantrene may provide an effective single agent treatment for some patients.

The untransformed melanocyte cell line (normal) was highly resistant to cell killing by Zantrene, as were some of the melanoma cell lines (Table 1). The molecular mechanisms underlying this resistance to Zantrene remain to be determined.

Cell Line IC50 (nM)
HEMm-MP 1403
MEL-BP 1003
SK-MEL-110 1002
SK-Mel-28 515
Mel-JD 335
MM426 312
Mel-RM 178
Mel-RMu 167
Mel-CV 115
Mel-FH 102
MM200 96
A375 87
MM170-5 85
MM283 79
ME1007 78
SK-MEL-37 75
IgR3 72
SK-MEL-13 67
ME4405 53
MEL-BE 39
MV3 39
MEL-EH 37
MEL-JR 30
MEL-KD 28
MM962 23

Table 1. IC50 values for Zantrene
2. Sensitivity to Zantrene is independent of BRAF and NRAS mutational status
Zantrene sensitivity did not show any correlation to either BRAF or NRAS mutational status, with individual mutant and wild type cell lines displaying a wide range of IC50 values. This result suggests that Zantrene may show utility in patients resistant to BRAF and NRAS inhibitors.

Cell Line IC50 (nM) BRAF NRAS
HEMn-MP 1403 Wild Wild
SK-Mel-28 515 Mutant Wild
Mel-JD 335 Wild Mutant
Mel-RM 178 Wild Mutant
Mel-Rmu 167 Mutant Wild
Mel-CV 115 Mutant Wild
Mel-FH 102 Wild Wild
ME1007 78 Wild Wild
MM200 96 Mutant Wild
IgR3 72 Mutant Wild
ME4405 53 Wild Mutant
Table 2. Effect of Zantrene on BRAF and NRAS mutant cell lines.
3. Sensitivity to Zantrene correlates with FTO expression levels
Zantrene sensitivity was correlated with FTO protein overexpression levels (Figure 1 and Table 3).

Figure 1. FTO protein expression determined by western blot.
The eight most Zantrene-resistant cell lines (i.e. those with an IC50 values greater than 100 nM) had a median FTO expression level 1.4 fold higher that of the untransformed (normal) melanocyte cell line, HEMn-MP.

In contrast, the 15 most sensitive melanoma cell lines had a median increase in FTO protein levels of 2.5 fold. The five most sensitive cell lines (i.e. those with IC50 values below 40 nM) had an average increase in FTO protein levels 3.8 fold higher (Table 3).

Cell Line FTO Level
HEMm-MP 1.0
Mel-BP 2.2
SK-MEL-110 5.0
SK-Mel-28 1.0
Mel-JD 1.3
MM426 2.8
Mel-RM 1.6
Mel-RMu 1.4
Mel-CV 1.4
Mel-FH 2.6
MM200 1.1
70W 1.9
MM170-5 3.5
MM283 2.4
ME1007 1.3
SK-MEL-37 2.4
IGR3 2.7
SK-MEL-13 4.4
ME4405 2.0
Mel-BE 1.7
MV3 5.8
Mel-EH 2.2
Mel-JR 3.6
Mel-KD 2.5
MM962 5.0
Table 3. FTO protein levels normalized to the FTO level of the normal human melanocyte cell line HEMn-MP.
The SK-MEL-10 was an exception to the trend of high FTO overexpression being associated with high sensitivity to Zantrene. This cell line had an IC50 value over 1000 nM while displaying an FTO expression level 5 fold that of HEMn-MP. The reason for this resistance is unknown, but may be linked to high expression of drug efflux pumps like MDR1 that are known to reduce the intracellular concentration of Zantrene.

Conclusions
Zantrene showed unexpectedly effective killing of melanoma cell lines at concentrations well below 100 nM (sub-chemotherapeutic), with a number of cell lines displaying very high sensitivity (less than 40 nM)
Zantrene proved effective at killing melanoma cell lines with BRAF or NRAS mutations
Sensitivity to Zantrene was correlated with overproduction of the FTO protein, supporting Race’s clinical plans for using Zantrene in combination with standard of care drugs for the treatment of melanoma patients.