On June 23, 2020 Oncotarget reported that to examine the role of RSK in AML, the authors analyzed apoptosis and the cell cycle profile following treatment with BI-D1870, a potent inhibitor of RSK (Press release, EurekAlert!, JUN 23, 2020, View Source [SID1234561423]). BI-D1870 treatment increased the G2/M population and induced apoptosis in Acute Myeloid Leukemia cell lines and patient Acute Myeloid Leukemia cells .

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Therefore, the authors investigated whether BI-D1870 potentiates the anti-leukemic activity of vincristine by targeting mitotic exit.

Combination treatment of BI-D1870 and vincristine synergistically increased mitotic arrest and apoptosis in acute leukemia cells.

These data show that BI-D1870 induces apoptosis of AML cells alone and in combination with vincristine through blocking mitotic exit, providing a novel approach to overcoming vincristine resistance in AML cells.

"Data show that BI-D1870 induces apoptosis of AML cells alone and in combination with vincristine through blocking mitotic exit"
Dr. Kathleen M. Sakamoto from Stanford University School of Medicine said, "Acute myeloid leukemia (AML) is a genetically and phenotypically heterogeneous hematologic malignancy characterized by the accumulation of immature myeloid blasts with resultant peripheral blood cytopenia."

Treatment of cells with microtubule targeting agents, including paclitaxel and the vinca alkaloid vincristine, blocks the proper formation of the mitotic spindle through inhibition of microtubule dynamics, resulting in the prolonged mitotic arrest of cancer cells.

MTAs-treated mitotic arrested cells may undergo apoptosis in mitosis, however, the rapid degradation of Cyclin B due to an insufficient SAC leads to the mitotic slippage into tetraploid G1 stage in resistant cells.

Though vinca alkaloid microtubule-destabilizing compounds have shown clinical efficacy against various hematological malignancies and were included in combination chemotherapy of the VAPA study, they are not currently used in induction chemotherapy for AML due to their high toxicity against lymphoid cells and rapid degradation by myeloperoxidase in AML cells.

In this study, they demonstrate that BI-D1870, a potent inhibitor of RSK, induces mitotic arrest, and apoptosis in AML cells without inhibiting CDC2 and CDC25C. Furthermore, BI-D1870 synergizes with vinca alkaloid vincristine in AML cells, suggesting that inhibition of mitotic exit with BI-D1870 could be a promising novel approach for AML therapy in combination with MTAs.

The Sakamoto Research Team concluded in their Oncotarget Research Paper that BI-D1870 is a reversible pan-RSK inhibitor, showing > 500-fold higher activity for RSK than other AGC kinases.

BI-D1870 also inhibits the activity of PLK1, Aurora-B, MELK, PIM3, MST2, and GSK3β at higher concentrations than for RSK. BI-D1870 and BRD7389 have been reported to inhibit proliferation and significantly increase the G2/M population in melanoma cells.

BI-D1870 does not have proper physicochemical properties for clinical application.

Future structure-activity relationships study for BI-D1870 is required to improve solubility and pharmacokinetic profiles for in vivo preclinical and clinical studies.

On June 23, 2020 Amphivena Therapeutics, a clinical-stage immuno-oncology company focused on developing immuno-therapeutics that restore anti-cancer immunity, reported translational data for the lead clinical candidate from its ReSTORE (Relieve Suppression of T cells in Oncology and Reinvigorate Effectors) platform of bivalent T-cell engagers, AMV564, at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) 2020 Virtual Annual Meeting II (Press release, Amphivena Therapeutics, JUN 23, 2020, View Source [SID1234561422]).

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Findings presented include:

AMV564 administration by subcutaneous route in solid tumor patients was well tolerated; no cytokine release syndrome or dose-limiting toxicities have been observed
Reduction in both MDSC and regulatory T cells was apparent, consistent with relief of immune suppression
AMV564 promoted favorable effector CD8 and CD4 Th1 polarization in patients, along with a cytokine and chemokine milieu conducive to T cell activation and trafficking, and antigen presentation
The clinical benefit was highlighted by a confirmed complete response (RECIST 1.1) with AMV564 monotherapy treatment in a patient following several prior lines of therapy (including prior checkpoint inhibitor)
"The translational data we are presenting at AACR (Free AACR Whitepaper) provides further validation and informs our clinical observations with AMV564 and its dual actions to relieve immune suppression via MDSC depletion and concomitant activation and polarization of effector CD8 and Th1 CD4 T cells, representing a new treatment paradigm for cancer," said Curtis Ruegg, Ph.D., Chief Executive Officer of Amphivena Therapeutics. "We look forward to expanding this study to additional selected patient cohorts who could benefit from this mechanism of action".

Details of the Presentation:

Session Title: Novel Immunotherapies and Mechanisms
Session Start Date/Time: Tuesday, June 23, 2020, 9:00 – 10:45 AM ET
Title: AMV564, a bivalent, bispecific T-cell engager, depletes myeloid-derived suppressor cells and activates T cells in cancer patients
Authors: Victoria Smith, et al.
Oral Presentation Number: 5699

The presentation is available on the AACR (Free AACR Whitepaper) Annual Meeting website and in addition, the presentation recording and slides are available on the Presentations & Publications page on the Amphivena website.

About AMV564

AMV564 relieves immune suppression via targeted depletion of MDSC and drives T cell activation and polarization to restore anti-cancer immunity. To date, over 80 patients have received AMV564 across three Phase 1 clinical trials for patients with solid tumors, acute myeloid leukemia (AML), and myelodysplastic syndromes (MDS).

On June 23, 2020 InxMed (Shanghai) Co., Ltd. ("InxMed" or "Company"), a clinical stage biotech company dedicated to developing innovative, individualized medicines with international impact, reported that the company has released the research data of "FAK inhibitor IN10018 overcomes drug resistance of KRAS G12C inhibition" at "Late Breaking Research" session of 2020 AACR (Free AACR Whitepaper) virtual meeting II (Press release, InxMed, JUN 23, 2020, View Source [SID1234561421]).

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KRAS G12C inhibitors are under clinical phase II development. Even though it has shown anti-tumor effect on KRAS G12C mutant tumor types, its drug resistance problem, similar to other target therapies, has caught increasing awareness by research community. InxMed’s IN10018 is a potent and selective ATP-competitive focal adhesion kinase (FAK) small molecule inhibitor under clinical development stage in United States, Australia, and China. Early clinical data of IN10018 has demonstrated a favorable safety profile and promising efficacy signals against different tumor types. Emerging science also showed that IN10018 potentially overcomes fibrotic barrier and immune tolerance, boosting multi-modalities including targeted therapy, chemotherapy, immune-therapy and radiation therapy.

The combination of KRAS G12C inhibitors and IN10018 was evaluated in both in vitro and in vivo. The data released showed that FAK signaling is significantly induced by KRAS G12C inhibition, serving as one predominant mechanism of drug resistance of KRAS G12C inhibition, and IN10018 can significantly decrease the FAK signaling induced by KRAS G12C inhibition, rendering synergistic anti-tumor effects on various types of cancer. Furthermore, our data has shown KRAS G12C inhibitors can induce significant generation of fibrosis in tumor tissues – one important adaptive drug resistance mechanism, and IN10018 can decreases the level of fibrosis induced by KRAS G12C inhibitors and therefore overcome drug resistance. Our pioneering research indicates the synergistic effect between IN10018 and KRAS G12C inhibitors, which can support the continuous clinical exploration of this combination treatment regimen.

On June 23, 2020 SkylineDx reported that it signed the 10th collaboration agreement with an academic partner for research under the extensive Falcon R&D Program to further validate both melanoma (skin cancer) tests (Press release, SkylineDx, JUN 23, 2020, View Source [SID1234561420]). The 10 clinical centers represent 6 countries on 3 continents with data on over 3,500 cutaneous melanoma patients. The data generated will be used in the validation of the Merlin and Peregrine assay. The Merlin assay has been developed to predict a patient’s risk of having metastasis in the sentinel lymph node. If a patient is identified as low-risk, the surgery that removes the sentinel lymph node can be safely avoided. The Merlin assay is developed on a US patient dataset[2] and validated in a European dataset[3]. The group of patients without metastasis in their sentinel lymph nodes, are currently considered low risk, although a significant number of patients will see their melanoma returning within 5 years. The Peregrine assay has been developed to identify patients at high risk of disease recurrence within this group of patients now considered low-risk, so treatment options can be discussed[4-5].

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"I am very pleased that we are continuing our research with global partners for retrospective validation studies. Even more clinical groups have expressed interest to collaborate and are likely to be added in the near future to this research initiative. Processing of the biobanked samples is in full swing and we expect to have all the results for analyses by the end of 2020. The peer reviewed publication will follow shortly in 2021," explains Dharminder Chahal, CEO SkylineDx.

About Merlin & Peregrine

Both assays are using the CP-GEP model, a powerful algorithm that calculates the risk of metastasis in a patient’s sentinel lymph nodes (predictive use) and the risk of the melanoma returning (prognostic use). The model is able to calculate risk on an individual basis through a combination analysis of 8 genes from the patient’s primary tumor, the tumor thickness and the patient’s age. The model has been previously published in JCO Precision Oncology[2]. The predictive use of the CP-GEP model is the main focus of the Merlin Study Initiative. The prognostic use of the CP-GEP model is the main focus of the Peregrine Study Initiative. Both are developed under the wings of the Falcon R&D Program. More information on www.falconprogram.com.

On June 23, 2020 Polynoma LLC, a U.S. immuno-oncology focused biopharmaceutical company and wholly-owned subsidiary of Hong Kong-listed CK Life Sciences Int’l., (Holdings) Inc., reported that the U.S. Food and Drug Administration (FDA) has granted its application for Fast Track designation of seviprotimut-L, its melanoma cancer vaccine for the adjuvant treatment of stage IIB/IIC melanoma patients post-resection to improve recurrence-free survival (Press release, Polynoma, JUN 23, 2020, View Source [SID1234561419]).

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"The Fast Track designation by the FDA provides further validation of seviprotimut-L as a potential new and important cancer vaccine for patients with localized melanoma," said Alan Yu, Chairman of Polynoma and Vice President & Chief Operating Officer at CK Life Sciences. "We look forward to advancing seviprotimut-L in a pivotal trial as an adjuvant treatment of melanoma."

Fast Track is designed to facilitate the development and expedite the review of drugs which treat serious or life-threatening conditions and fill an unmet medical need. The FDA defines filling an unmet medical need as "providing a therapy where none exists or providing a therapy which may be potentially better than available therapy,"1 based on criteria such as:

Showing superior effectiveness, or improved effect on serious outcomes;
Avoiding serious side effects of an available therapy;
Decreasing a clinically significant toxicity of an available therapy that is common and causes discontinuation of treatment;
Ability to address anticipated public health need.
Benefits of Fast Track designation include more frequent communication with the FDA, a rolling submission of the marketing application, and eligibility for Priority Review and Accelerated Approval, if relevant criteria are met.

The interval between progression from Stage II to Stage III/IV melanoma marks a critical therapeutic intervention point to improve survival. Treatment of Stage IIB/IIC melanoma is primarily limited to surgery, coupled with a "wait and see" approach. However, recurrence of the disease can occur following definitive resection of the melanoma. Many patients progress to more advanced stages following resection and five-year survival rates fall sharply after a patient passes from localized Stage II melanoma into regional Stage III disease (98.4% to 63.6%). Five-year survival rates are distinctly lower (22.5%) for metastatic Stage IV.2

Final analysis of clinical data from Part B1 of MAVIS (Melanoma Antigen Vaccine Immunotherapy Study), a Phase III study of seviprotimut-L was presented at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) ASCO (Free ASCO Whitepaper)20 Virtual Scientific Program, held online May 29-31, 2020.

Highlights of the presentation are as follows:

Improved outcomes in Stage IIB/C patients: Final analysis of subgroups confirmed the findings from the interim analysis, suggesting enhanced RFS for seviprotimut-L in patients with AJCC Stage IIB/IIC melanoma, particularly those under age 60, and those with ulceration, whose lesions are considered more serious because they have a greater risk of metastasis.3
Early evidence of survival benefit in Stage IIB/C patients: For Stage IIB/IIC melanoma patients under 60, there was a trend toward improved overall survival for those treated with seviprotimut-L.
Favorable adverse event profile: Seviprotimut-L was well-tolerated with treatment-emergent adverse events (AEs) similar to patients given placebo. There were no treatment-related serious adverse events.
About MAVIS
MAVIS (Melanoma Antigen Vaccine Immunotherapy Study) is a multicenter, double-blind, placebo-controlled adaptive Phase III trial to assess the safety and efficacy of seviprotimut-L, with primary endpoints of recurrence-free survival (RFS) and overall survival (OS) in patients with melanoma at high risk of recurrence after definitive surgical resection. MAVIS is being conducted under a Special Protocol Assessment (SPA) agreement with the FDA. For additional information about the trial, please visit View Source

About Seviprotimut-L
Seviprotimut-L is an allogeneic, polyvalent, partially purified shed melanoma antigen vaccine derived from three proprietary human melanoma cell lines. Seviprotimut-L stimulates humoral and cellular immune responses. Melanoma-associated antigens (MAAs) found in seviprotimut-L are taken up by antigen-presenting cells (e.g., dendritic cells) which then activate the production of antigen-specific cytotoxic T-lymphocytes (CTLs) as well as develop antibody responses against MAAs. These CTLs and antibodies then recognize and act on tumor cells expressing the MAAs on their surfaces, causing cell death. Seviprotimut-L is currently in development for the adjuvant treatment of patients with Stages IIB to IIIC melanoma, following definitive resection.