On January 12, 2023 ViewRay, Inc. (NASDAQ: VRAY) reported that findings from the phase III randomized controlled MIRAGE trial (NCT04384770) were published on January 12 in JAMA Oncology. The MIRAGE trial compared MRI-guided and CT-guided stereotactic body radiation therapy (SBRT) for localized prostate cancer and found MRI-guided radiation therapy – delivered with MRIdian – to be superior in substantially reducing acute genitourinary (GU) and gastrointestinal (GI) toxicity. MRI-guided radiation was also associated with significantly better patient-reported quality of life metrics.

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The MIRAGE trial was led by Amar Kishan, M.D. (first author) and Michael L. Steinberg, M.D. (senior author) at the University of California, Los Angeles (UCLA). The study was independently designed, conducted, and analyzed exclusively by UCLA. In this trial, the investigator team randomized 156 patients to receive either MRI-guided SBRT or CT-guided SBRT. Acute grade ≥2 GU toxicity rates were significantly lower with MRI guidance vs. CT guidance (24.4% in the MRI group vs. 43.4% in the CT group). Acute grade ≥2 GI toxicity rates were also significantly lower with MRI guidance (0.0% in the MRI group vs. 10.5% in the CT group). On multivariate analysis, which controls for differences in the use of a rectal spacer, prostate size, and baseline urinary symptoms, the MRI-guided arm was associated with a 60% reduction in odds of grade ≥2 GU toxicity.

More notably, there were improvements in multiple patient-reported outcomes. Significantly more patients receiving CT-guided SBRT experienced large increases in urinary symptoms, as measured by a >15 points increase in International Prostate Symptom Score (IPSS) (6.8% in the MRI group vs. 19.4% in the CT group). Similarly, a significantly greater percentage of patients experienced a clinically notable decrease in bowel-related quality of life with CT-guided, as measured by the Expanded Prostate Cancer Index Composite-26 (EPIC-26) survey (25.0% in the MRI group vs. 50.0% in the CT group). Finally, though it is too early to conclude, as more than 2/3rds of men on the trial received hormonal therapy, exploratory analysis in men who did not receive hormonal therapy showed that patient-reported sexual-function scores (by EPIC-26) decreased more in men receiving CT-guided SBRT.

"To our knowledge, this trial is the first phase III randomized controlled trial comparing MRI guidance to CT guidance in any disease site," said Dr. Steinberg, Professor and the Chair of the Department of Radiation Oncology at UCLA. "MRI-guided radiation has apparent theoretical benefits in this treatment scenario, and it was important to conduct a rigorous comparison. Given the significance of the outcomes realized, we’ve evolved our prostate cancer treatment approach at UCLA to preferentially utilize MRI-guided SBRT."

"Radiation is accepted as an effective and safe standard-of-care option for many men with prostate cancer, but there is always the opportunity for improvement of reducing toxicity. The prostate is a highly mobile target, and the motion of the prostate needs to be accounted for to maximize treatment effectiveness. Accounting for this motion typically requires creating a margin around the prostate (rather than just the prostate itself)," said Dr. Kishan, Associate Professor and Chief of the Genitourinary Oncology Service at UCLA. "We felt that MRI-guided radiotherapy allows a much tighter margin around the prostate to be targeted due to both the enhanced imaging capabilities of MRI and the ability to track the prostate and control the beam in real time during treatment. The significant reduction in urinary and bowel toxicity seen in our trial reflects the importance and relevance of this tighter margin made possible by MRI-guided radiation therapy."

To date, more than 27,000 patients have been treated with MRIdian. Currently, 56 MRIdian systems are installed at hospitals around the world where they are used to treat a wide variety of solid tumors and are the focus of numerous ongoing research efforts. MRIdian has been the subject of hundreds of peer-reviewed publications, scientific meeting abstracts, and presentations. For a list of treatment centers, please visit: View Source

Conflicts of Interest: Amar Kishan, M.D. discloses research funding from the Department of Defense, the National Institutes of Health, the Jonsson Comprehensive Cancer Foundation, the Prostate Cancer Foundation, and the American Society for Radiation Oncology. He also discloses research support, not related to this study, from ViewRay, Inc. He discloses consulting fees from ViewRay, Inc. and Varian Medical Systems, Inc. Dr. Kishan also discloses low-value stock held in ViewRay, Inc.

Conflicts of Interest: Michael L. Steinberg, M.D. discloses health policy consulting fees from ViewRay, Inc.

Disclaimer:
Nothing in this material is intended to provide specific medical advice or to take the place of written law or regulations.

The MRIdian Linac System is not appropriate for all patients, including those who are not candidates for magnetic resonance imaging. Radiation treatments may cause side effects that can vary depending on the part of the body being treated. The most frequent ones are typically temporary and may include, but are not limited to, irritation to the respiratory, digestive, urinary, or reproductive systems; fatigue; nausea; skin irritation; and hair loss. In some patients, side effects can be severe. Treatment sessions may vary in complexity and duration. Radiation treatment is not appropriate for all cancers. You should discuss the potential for side effects and their severity as well as the benefits of radiation and magnetic resonance imaging with your doctor to make sure radiation treatment is right for you.

On January 12, 2023 Actinium Pharmaceuticals, Inc. (NYSE AMERICAN: ATNM) (Actinium or the Company), a leader in the development of targeted radiotherapies, reported that data from its pivotal Phase 3 SIERRA trial of Iomab-B have been accepted as a late-breaker presentation at the Transplantation & Cellular Therapy (TCT) Tandem Meetings of the American Society for Transplantation and Cellular Therapy (ASTCT) and the Center for International Blood & Marrow Transplant Research (CIBMTR) (Press release, Actinium Pharmaceuticals, JAN 12, 2023, View Source;cellular-therapy-tandem-meetings-301720055.html [SID1234626225]). TCT, the largest bone marrow transplant (BMT) focused medical conference globally, is being held February 15 – 19, 2023 at the World Center Marriott in Orlando, Florida.

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TCT Late-Breaker Presentation Details:

Presentation Title: Efficacy and Safety Results of the SIERRA Trial: A Multicenter, Pivotal Phase 3 Study of Iomab-B Prior to Allogeneic Hematopoietic Cell Transplantation Versus Conventional Care in Older Patients with Active, Relapsed or Refractory Acute Myeloid Leukemia

Date: Saturday, February 18, 2022

Time: 5:00 PM EST

Presenter: Dr. Boglarka Gyurkocza, Memorial Sloan Kettering Cancer Center

Location: World Center Marriot, Cypress 3

Actinium will host a conference call and webcast on Saturday, February 18, 2023 at 6:00 PM EST following the SIERRA late-breaker presentation at TCT. Additionally, Actinium will host a webcasted KOL event at 8:00 AM EST on Tuesday, February 28, 2023. Additional details will be announced in advance of these events and when available, they can be found on Actinium’s investor relations page View Source

About Iomab-B and the Pivotal Phase 3 SIERRA Trial
Iomab-B is a first-in-class targeted radiotherapy intended to improve patient access to potentially curative BMT by simultaneously and rapidly depleting blood cancer, immune and bone marrow stem cells that uniquely express CD45. Multiple studies have demonstrated increased survival in patients receiving BMT, however, an overwhelming majority of patients with blood cancers do not receive BMT as current approaches do not produce a remission, which is needed to advance to BMT, or are too toxic. Studied in over 400 patients, prior studies with Iomab-B have demonstrated nearly universal access to BMT, increased survival and tolerability in multiple clinical trials including the recently completed pivotal Phase 3 SIERRA trial in patients with active (leukemic blasts >5%), relapsed or refractory acute myeloid leukemia (r/r AML) age 55 and above. The SIERRA trial produced positive topline results, meeting its primary endpoint of durable Complete Remission (dCR) of 6 months with statistical significance (p<0.0001). Actinium intends to submit a Biologics License Application (BLA) seeking approval for Iomab-B to address patients age 55+ with r/r AML who cannot access BMT with currently available therapies. Iomab-B has been granted Orphan Drug Designation from the U.S. Food and Drug Administration (FDA) and has patent protection into 2037.

The pivotal Phase 3 SIERRA (Study of Iomab-B in Elderly relapsed or refractory AML) is a 153-patient, randomized, multi-center clinical trial, studying Iomab-B compared to the control arm of physician’s choice of salvage therapy. Control arm options included chemotherapies like cytarabine and daunorubicin and targeted agents such as a Bcl-2 inhibitor (Venetoclax), FLT3 inhibitors and IDH 1/2 inhibitors. The SIERRA control arm reflects real-world treatment of r/r AML patients with over 20 single agents or combination of agents as no standard of care exists for this patient population. Data from full patient enrollment presented at the Transplantation & Cellular Therapy Tandem Meetings in April 2022 showed that 100% of patients receiving Iomab-B accessed BMT and engrafted without delay. Iomab-B was also shown to be well tolerated given its targeted nature, consistent with its previous clinical data. The SIERRA trial enrolled patients at 24 leading transplant centers in the United States and Canada that perform over 30% of AML BMTs.

Developed at the Fred Hutchinson Cancer Research Center, a pioneer in the field of BMT, Iomab-B is supported by data in six disease indications including leukemias, lymphomas and multiple myeloma, which afflict over 100,000 patients annually. Actinium intends to pursue additional indications for Iomab-B beyond AML. Actinium also intends to pursue international regulatory approvals independently and through partnerships. In April 2022, Actinium licensed the European, Middle East and North African commercial rights for Iomab-B to Immedica AB, a fully-fledged independent pharmaceutical company headquartered in Sweden. In exchange, Actinium received an upfront payment of $35 million USD with the potential for an additional $417 million USD in regulatory and sales milestones and mid-twenty percent royalties. Europe represents a commercial opportunity double the size of the United States by number of patients with AML receiving BMT. Iomab-B has been granted Orphan Drug Designation by the European Medicines Agency (EMA) and has received positive Scientific Advice from the Committee for Medicinal Products for Human Use (CHMP) of the EMA indicating that the Phase 3 SIERRA trial design, primary endpoint and planned statistical analysis are acceptable as the basis for a Marketing Authorization Application.

On January 12, 2023 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 an investigator-initiated Phase 1b/2 trial evaluating the Company’s novel anthracycline, Berubicin, which will be conducted at the Pomeranian Medical University (PUM) in Szczecin, Poland (Press release, CNS Pharmaceuticals, JAN 12, 2023, prnewswire.com/news-releases/cns-pharmaceuticals-announces-investigator-initiated-phase-1b2-trial-to-be-conducted-at-the-pomeranian-medical-university-in-poland-301719938.html [SID1234626224]).

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The study, titled "Evaluation of the safety and efficacy of Berubicin in the treatment of central nervous system lymphomas," will be a single center, single-arm, open-label Phase 1b/2 clinical trial assessing the efficacy, safety, and pharmacokinetics of Berubicin in a multidrug treatment regimen for adult patients with newly diagnosed or relapsed/refractory primary central nervous system lymphoma (PCNSL) and non-Hodgkin’s lymphoma with central nervous system involvement (NHL-CNSI). The primary efficacy endpoint for the study is to evaluate the safety and tolerability of Berubicin in combination with other cytostatic agents and to determine the recommended Phase 2 dose (RP2D) of Berubicin.

"Based on the data seen to date, Berubicin has continued to demonstrate an overall safety profile more favorable than other known anthracyclines and we remain encouraged by its potential. We are committed to Berubicin’s continued development as a much-needed oncology tool and are therefore providing the study drug to the PUM for their Phase 1b/2 clinical study. Given the unmet needs and current prognosis for CNS lymphomas, the optimal treatment strategy is to improve overall survival, to which we believe Berubicin can contribute. We look forward to further understanding the potential of Berubicin in this disease and the findings from this study," commented John Climaco, CEO of CNS Pharmaceuticals.

Patients enrolled in the investigator-initiated Phase 1b/2 study will receive Berubicin in escalated doses in an accelerated model assigning one patient per cohort, which will reduce the number of patients that may be treated with sub-therapeutic doses. The purpose of the dose escalation strategy is to evaluate dose limiting toxicities (DLT) and establish the appropriate dose to utilize into Phase 2 (recommended Phase 2 dose, RP2D). The initial escalation by 40% in the next cohorts will be based on safety assessments. After completing a treatment cycle, if a patient does not have any DLTs, they can proceed to the next dose level, and additional patients can be enrolled to explore higher doses. If any patient experiences DLT, that dosing cohort will be expanded to 3 patients. If 2 patients develop DLT, the given dose will be considered toxic and the next cohort will start treatment at a dose reduced by 20%.

After considering the data from the Phase 1 clinical trial in patients with CNS gliomas, treatment of patients with CNS lymphomas is planned to start with a higher initial dose of Berubicin (4.8 mg/m2).

A total of up to approximately 60 patients are planned to be enrolled. The minimum participation in the study for an individual patient is approximately 21 weeks. After the end-of-treatment follow-up visit, patients will enter a post-study follow-up period of up to 3 years.

Berubicin is currently being evaluated for efficacy and safety in the treatment of glioblastoma multiforme (GBM), an aggressive and incurable form of brain cancer, by CNS Pharmaceuticals in an ongoing, potentially pivotal global study. 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 January 12, 2023 MediciNova, Inc., a biopharmaceutical company traded on the NASDAQ Global Market (NASDAQ: MNOV) and the JASDAQ Market of the Tokyo Stock Exchange (Code Number: 4875), reported that the Phase 2 clinical trial evaluating MN-166 (ibudilast) in recurrent and newly diagnosed glioblastoma conducted at Dana-Farber Cancer Institute has completed enrollment (Press release, MediciNova, JAN 12, 2023, View Source [SID1234626223]). This Phase 1/2 clinical trial was divided into a dose-escalation phase (Part 1) followed by a fixed-dose phase (Part 2). Part 1 evaluated the safety and tolerability of an escalating dose of MN-166 (ibudilast) when given in combination with temozolomide (TMZ) and determined a safe and tolerable dose of MN-166 (ibudilast) to be used in Part 2 of the study. Part 2 will evaluate the efficacy of MN-166 (ibudilast) and TMZ combination treatment. Tumor tissues were obtained from the initial surgery or biopsy. We evaluated the correlation of MN-166 and TMZ combination therapy to clinical outcomes and tumor tissue analysis findings.

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Preliminary tumor tissue analysis and clinical outcome findings from Part 1 participants will be presented at the 20th Annual World Congress of SBMT (Society for Brain Mapping and Therapeutics) to be held February 16 – 19, 2023.

Kazuko Matsuda, MD, PhD, MPH, Chief Medical Officer of MediciNova, Inc., commented, "We have completed enrollment and are actively treating the remaining patients in Part 2 of the trial. We look forward to reporting the interesting findings from tumor tissue analysis and clinical outcomes at the 20th Annual World Congress of SBMT, including potential predictors of treatment response to MN-166 plus TMZ combination therapy in glioblastoma. We will release more information after SBMT meeting."

About Glioblastoma

According to the American Association of Neurological Surgeons, glioblastoma is an aggressive brain cancer that often results in death during the first 15 months after diagnosis. Glioblastoma develops from glial cells (astrocytes and oligodendrocytes), grows rapidly, and commonly spreads into nearby brain tissue. Glioblastoma is classified as Grade IV, the highest grade, in the World Health Organization (WHO) brain tumor grading system. The American Brain Tumor Association reports that glioblastoma represents about 15% of all primary brain tumors and approximately 10,000 cases of glioblastoma are diagnosed each year in the U.S. Despite decades of advancements in neuroimaging, neurosurgery, chemotherapy and radiation therapy, only modest improvements have been achieved and the prognosis has not improved for individuals diagnosed with glioblastoma. Median survival is about 11-15 months for adults with more aggressive glioblastoma (IDH-wildtype) who receive standard treatment of surgery, temozolomide, and radiation therapy.

About MN-166 (ibudilast)

MN-166 (ibudilast) is a small molecule compound that inhibits phosphodiesterase type-4 (PDE4) and inflammatory cytokines, including macrophage migration inhibitory factor (MIF). It is in late-stage clinical development for the treatment of neurodegenerative diseases such as ALS (amyotrophic lateral sclerosis), progressive MS (multiple sclerosis), and DCM (degenerative cervical myelopathy); and is also in development for glioblastoma, CIPN (chemotherapy-induced peripheral neuropathy), and substance use disorder. In addition, MN-166 (ibudilast) was evaluated in patients that are at risk for developing acute respiratory distress syndrome (ARDS).

As previously reported on Current Reports on Forms 8-K filed July 6, 2022, August 2, 2022 and August 9, 2022, on June 30, 2022, Ensysce Biosciences, Inc. ("Ensysce" or the "Company") entered into a Securities Purchase Agreement (the "SPA") for an aggregate financing of $8.0 million with institutional investors (Filling, Ensysce Biosciences, JAN 12, 2023, View Source [SID1234626219]). At two closings under the SPA, which occurred on June 30, 2022 and August 8, 2022, the Company issued to the investors (i) senior secured convertible promissory notes in the aggregate principal amount of $8.48 million for an aggregate purchase price of $8.0 million (the "Notes") and (ii) warrants (the "Warrants") to purchase 9,335,780 shares of the Company’s common stock, par value $0.0001 per share (the "Common Stock") in the aggregate. Under the SPA, the conversion price for converting Notes into the Common Stock, after several downward resets, is $2.006 per share (the "Conversion Price"), subject to adjustment under certain events. In addition, following a reverse stock split in October 2022, the number of Warrants is now 466,788.

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On January 12, 2023, the parties to the SPA agreed to a Letter Agreement amending the SPA ("Letter Agreement") to take certain actions. Among other matters, the parties to the Letter Agreement (i) reduced the Conversion Price for the remaining balance of the Company’s outstanding Notes from $2.006 to $0.7512 (the "New Conversion Price") for the period from January 12, 2023 until May 12, 2023 (the "Period"), and (ii) agreed to register any additional shares of Common Stock required to give the holders registered shares upon conversion of the Notes if exceeding those shares already registered on a Form S-3 that was declared effective on December 29, 2022. The remaining balance of the Notes was $3,339,931 as of the date of the Letter Agreement. Following the Period, the prior conversion price of $2.006 will apply. In addition, the parties have agreed that to the extent the investors receive shares as an interest payment or upon a redemption notice pursuant to Sections 2(a) and 6(b) of the Notes, any cash true-up payment based on the New Conversion Price will not be required to be paid for one hundred and twenty days. The parties have also agreed that accelerations of payment that are permitted under the Notes for any given month may be made over four conversion notices instead of two conversion notices during the period from January 12, 2023 until May 12, 2023.

The New Conversion Price meets a minimum price requirement established by The Nasdaq Stock Market in connection with a potential issuance of 20% or more of the Common Stock of a public company or 20% or more of the voting power outstanding before the potential issuance. The Letter Agreement may result in the need for the Company to issue more than 20% of its shares of Common Stock. If the New Conversion Price did not meet the minimum price requirement, then the Letter Agreement would have to be approved by Company stockholders. The New Conversion Price is the price that was the lower of: (i) the Nasdaq Official Closing Price (as reflected on Nasdaq.com) immediately preceding the signing of the Letter Agreement; or (ii) the average Nasdaq Official Closing Price of the Common Stock (as reflected on Nasdaq.com) for the five trading days immediately preceding the signing of the Letter Agreement. On the date of execution of the Letter Agreement, the (i) the Nasdaq Official Closing Price (as reflected on Nasdaq.com) immediately preceding the signing of the Letter Agreement was $0.7600; and (ii) the average Nasdaq Official Closing Price of the Common Stock (as reflected on Nasdaq.com) for the five trading days immediately preceding the signing of the Letter Agreement was $0.7512.

There is no change to the exercise price of the Warrants because of the execution of the Letter Agreement. The Letter Agreement also includes certain conditions that the Company must satisfy in connection with the transaction.

The Company has registered with the Securities and Exchange Commission (the "SEC") the resale of the shares of Common Stock issuable upon conversion of the Notes as well as the shares of Common Stock issuable upon the exercise of the Warrants pursuant to the Registration Rights Agreement, dated June 30, 2022, by and among the Company and the purchasers signatory to the SPA. The Company registered the resale of additional shares of Common Stock upon conversion of the Notes in December 2022 and may be required to register additional shares of Common Stock upon conversion of the Notes as a result of the Letter Agreement.