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Kazia Presents Further Paxalisib and Cantrixil Data at AACR, Reinforcing Positive Efficacy Signals for both Drugs

On June 22, 2020 Kazia Therapeutics Limited (ASX: KZA;NASDAQ: KZIA), an Australian oncology-focused biotechnology company, reported to share poster presentations of interim data from the ongoing phase II study of paxalisib (formerly GDC-0084) in glioblastoma, the most common and most aggressive form of primary brain cancer, and from the phase I study of Cantrixil in ovarian cancer (Press release, Kazia Therapeutics, JUN 22, 2020, View Source [SID1234561360]).

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Key Points

Previous paxalisib data presented at ASCO (Free ASCO Whitepaper) was based on Stage 1 (n=9) of the ongoing phase II study in glioblastoma. This interim analysis at AACR (Free AACR Whitepaper) includes all patients in the study (n=30), and therefore provides a more robust and substantial data set
Progression-free survival (PFS) for paxalisib is 8.5 months, versus 8.4 months in the previous analysis
Paxalisib overall survival (OS) remains at 17.7 months, in line with ASCO (Free ASCO Whitepaper) data
A separate poster on the investigator-initiated study of paxalisib in combination with radiotherapy is presented by clinicians at Memorial Sloan Kettering Cancer Center in New York. It noted a ‘robust response’ in the first treated patient
Cantrixil data shows one complete response (CR) to treatment, meaning no measurable disease, and two partial responses (PR), for an overall response rate of 19% (3 / 16 evaluable patients)
Summary of Paxalisib Data in Comparison to Temozolomide (existing standard of care)

Temozolomide[1]
(FDA-approved treatment)

Paxalisib

(interim phase II data)

Progression-Free Survival (PFS)

5.3 months

8.5 months

Overall Survival (OS)

12.7 months

17.7 months

Kazia CEO, Dr James Garner, commented, "The data summarized in these posters help to strengthen our confidence in both our clinical programs. As paxalisib moves towards commencement of the GBM AGILE pivotal study in the second half of calendar 2020, these findings will be used to support set-up activities. In the meantime, the fact that the PFS has remained robust as the analysis is extended out to the full data set gives us a great deal of additional confidence in the efficacy signal it provides. For Cantrixil, the emergence of one complete responder (CR) to treatment is very positive, and these new results will help us to explore partnering opportunities over the second half of the year."

AACR Annual Meeting

The American Association of Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting is one of the leading global academic conferences for oncology research. It is typically attended by more than 20,000 clinicians, researchers, industry executives, and investors, representing over 140 countries. The conference is being conducted through a virtual format this year and has been broken into two sections. AACR (Free AACR Whitepaper) Virtual Meeting I took place 27-28 April 2020, and AACR (Free AACR Whitepaper) Virtual Meeting II is being held 22-24 June 2020.

The paxalisib poster is found under number CT205 (NCT03522298), and the Cantrixil poster under CT166 (NCT02903771). Registration to the virtual meeting is free and interested parties may register via the AACR (Free AACR Whitepaper) website. The posters can be viewed on our website:

View Source

Initial Data from Memorial Sloan-Kettering Study of Paxalisib with Radiotherapy

Dr Jonathan Yang and team at Memorial Sloan Kettering Cancer Center in New York, NY, also presented a poster (number CT252) on their ongoing phase I study of paxalisib in combination with radiotherapy (NCT04192981). The poster principally reported the design of their study, but also noted a ‘robust response’ in the first patient treated. Further data is expected as the study progresses

Next Steps

The paxalisb phase II study remains ongoing with a number of patients in follow-up and approximately half of the total enrolled patient population still receiving drug at the time of analysis. Kazia expects to complete the study in 1H CY2021.

Set-up work is well underway for paxalisib’s planned entry into the GBM AGILE pivotal study, and it is expected that the first patient will be enrolled in the second half of calendar 2020.

The Cantrixil phase I study is now complete and analysis is underway, with final data expected in the second half of calendar 2020.

ABM Therapeutics Announces First Patient Dosed in Phase 1 Clinical Trial of ABM-1310 in the USA

On June 22, 2020 ABM Therapeutics, a clinical-stage biopharmaceutical company developing a new generation of BRAF inhibitor, reported that the first cancer patient has been successfully enrolled and dosed with ABM-1310 in the Phase 1 clinical trial in the USA (Press release, ABM Therapeutics, JUN 22, 2020, View Source [SID1234561359]). ABM-1310, the company’s lead candidate, demonstrated superior properties in pre-clinical animal models, is a highly selective, highly water-soluble, orally active, and brain-penetrant small molecule BRAF inhibitor.

Dosing the first patient in the USA represents another important milestone, both for ABM-1310 program and for patients. "We are so grateful to patients and their families, investigators and clinical study sites for their support on the study," Dr. Chen Chen, founder and CEO of ABM Therapeutics said. "Many cancer patients are affected by brain metastases, but current treatment options are limited. ABM-1310 significantly prolonged median survival time of brain metastases in preclinical models and is expected to be a new generation of BRAF inhibitors for the treatment of various malignant tumors and brain metastases. We have been at full speed conducting clinical development of ABM-1310 in the USA and hope to bring the potential therapeutic benefits to patients as soon as possible."

ABM-1310 phase 1 trial is a multi-center, open-label study to test the safety, tolerability, pharmacokinetics, and preliminary anti-tumor activity of ABM-1310 in patients with BRAF mutant advanced solid tumor and BRAF mutant patients with brain metastases. The goal of the study is to determine the optimal dose for phase 1b/2 studies.

"We have designed our Phase 1 trial to move efficiently through dose escalation and to increase the chance of seeing early signs of clinical activity by focusing on the BRAF mutant patient population. We look forward to producing important early clinical data to guide our future clinical development," said Dr. Charles Zhao, Chief Medical Officer of ABM Therapeutics. "Based on the preclinical potency of ABM-1310, we believe it could provide a profound benefit for patients in urgent need of new therapies as both a single agent and in combination with other therapies."

As a clinical-stage biotechnology company, ABM Therapeutics has broad and robust proprietary pipeline to construct a brain medicine R&D platform. It will continue to focus on the small molecule research and development of novel drugs for the treatment of cancer, with an emphasis on blood–brain barrier (BBB) penetration and brain metastasis. We look forward to working with international pharmaceutical companies and biotech companies from multiple perspectives to make our drug to benefit more patients in the world.

Castle Biosciences Announces Proposed Underwritten Public Offering of Common Stock

On June 22, 2020 Castle Biosciences, Inc. (Nasdaq: CSTL), reported that it has commenced a proposed underwritten public offering of 1,500,000 shares of its common stock (Press release, Castle Biosciences, JUN 22, 2020, View Source [SID1234561358]). Castle Biosciences also intends to grant the underwriters a 30-day option to purchase up to an additional 225,000 shares of common stock at the public offering price, less the underwriting discounts and commissions. The public offering price has not yet been determined. The offering is subject to market and other conditions, and there can be no assurance as to whether or when the offering may be completed, or as to the actual size or terms of the offering.

SVB Leerink and Baird are acting as joint book-running managers for the proposed offering and as representatives of the underwriters. Canaccord Genuity is acting as passive book-runner, and BTIG is acting as co-manager for the offering.

A registration statement on Form S-1 relating to these securities has been filed with the Securities and Exchange Commission (SEC) but has not yet become effective. These securities may not be sold, nor may offers to buy be accepted, prior to the time the registration statement becomes effective. The proposed offering will be made only by means of a prospectus.

Copies of the preliminary prospectus relating to the proposed offering may be obtained, when available, from: SVB Leerink LLC, Attention: Syndicate Department, One Federal Street, 37th Floor, Boston, MA 02110, by telephone: (800) 808‐7525, ext. 6218, or by e-mail: [email protected]; or from Robert W. Baird & Co. Incorporated, Attention: Syndicate Department, 777 East Wisconsin Ave., Milwaukee, WI 53202, by telephone: (800) 792-2473, or by email: [email protected].

This press release shall not constitute an offer to sell or a solicitation of an offer to buy, nor shall there be any offer or sale of these securities in any state or jurisdiction in which such offer, solicitation or sale would be unlawful prior to registration or qualification under the securities laws of such state or jurisdiction.

Verastem Oncology Announces Presentation of Preclinical Data Supporting the Combination of VS-6766 and Defactinib in Metastatic Uveal Melanoma

On June 222, 2020 Verastem, Inc. (Nasdaq:VSTM) (also known as Verastem Oncology), a biopharmaceutical company committed to developing and commercializing new medicines for patients battling cancer, reported results from a study that provides preclinical proof-of-concept for combining VS-6766, its RAF/MEK inhibitor, with defactinib, its focal adhesion kinase (FAK) inhibitor, for the treatment of metastatic uveal melanoma (UM), the most prevalent eye cancer among adults (Press release, Verastem, JUN 22, 2020, View Source [SID1234561357]). The data comprise one of four virtual posters with Verastem authors being presented today at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) 2020 Virtual Annual Meeting II, which is taking place June 22-24, 2020.

Uveal melanoma arises from the melanin-producing cells in the eye, similar to how it arises in cutaneous melanoma. While it’s considered rare, primary UM metastasizes in 50% of patients with only 8% of patients surviving 2 years after development of metastatic disease.1 Previously, MEK inhibitors, including selumetinib and trametinib, have failed to show substantial clinical benefit for patients with metastatic uveal melanoma.2,3 Indeed, no current therapies improve overall survival for metastatic UM and there is a high unmet need for novel therapies.4

In the current preclinical study, FAK inhibition (FAKi; e.g., defactinib) demonstrated synergistic growth-inhibitory effects in UM cells when combined with a MEK inhibitor (MEKi) or the investigational RAF/MEK inhibitor VS-6766. Additionally, MEKi increased phosphorylation of FAK, suggesting the need for FAK blockade in combination with MEKi for more complete antitumor effect. Accordingly, FAKi combination with MEKi induced apoptotic cell death leading to rapid tumor regression in UM xenografts, whereas the MEKi or FAKi as single agents showed tumor growth inhibition but failed to showed tumor shrinkage. Furthermore, the FAKi/MEKi combination was successful at reducing tumor burden in liver metastasis UM models.

"The study identified and reinforced FAK as a viable pathway to inhibit downstream from the GNAQ pathway, which is constitutively active in UM," said J. Silvio Gutkind, PhD, Distinguished Professor of Pharmacology and Associate Director for Basic Science at UC San Diego Moores Cancer Center, and senior investigator of the study. "We observed that co-targeting of FAK and RAF/MEK signaling led to tumor collapse in UM xenograft and liver metastasis models in vivo. Based on the encouraging results of this study, we are excited to work toward clinical testing of defactinib with VS-6766 for patients with metastatic uveal melanoma."

"These data build on a growing body of evidence that underscore the potential of the VS-6766/defactinib combination for treatment of a variety of solid tumors with significant medical need," said Brian Stuglik, Chief Executive Officer of Verastem Oncology. "We will continue to evaluate the combination in metastatic uveal melanoma along with rapidly advancing our broader clinical development program in solid tumors."

The combination of VS-6766 and defactinib is being evaluated in patients with Low Grade Serous Ovarian Cancer (LGSOC), and KRAS mutant non-small cell lung cancer (NSCLC) and colorectal cancer (CRC) in the ongoing investigator-initiated Phase I trial. The company also plans to support a Phase II investigator-initiated study of the combination of VS-6766 and defactinib in uveal melanoma anticipated to begin in late 2020.

Details for all abstracts selected for presentation at the AACR (Free AACR Whitepaper) 2020 Virtual Meeting II are as follows:

Title: FAK and MEK co-targeting: A new multimodal precision therapy for GNAQ-driven uveal melanoma
Lead author: Justine S. Paradis
Poster #: 6406/30
Session: PO.ET06.05
Date and Time: Monday, June 22, 2020; 9:00 a.m. to 6:00 p.m. EDT
URL: View Source!/9045/presentation/5323

Title: The dual PI3K-δ/PI3K-γ inhibitor duvelisib inhibits signaling and proliferation of solid tumor cells expressing PI3K-δ and/or PI3K-γ
Lead author: Silvia Coma
Poster #: 663/10
Session: PO.ET06.06
Date and Time: Monday, June 22, 2020; 9:00 a.m. to 6:00 p.m. EDT
URL: View Source!/9045/presentation/1880

Title: Single cell expression analysis of PIK3 genes to direct solid tumor treatment with the dual PI3K-δ,γ inhibitor duvelisib
Lead author: Samantha Hidy
Poster #: 1552/3
Session: PO.TB06.02
Date and Time: Monday, June 22, 2020; 9:00 a.m. to 6:00 p.m. EDT
URL: View Source!/9045/presentation/7806

Title: PEGylated recombinant human hyaluronidase, PEGPH20, significantly enhances the anti-tumor activity of the combination of focal adhesion kinase Inhibitor and anti-PD-1 antibody by targeting CXCR4-expressing myeloid cells in a murine model of PDAC
Lead author: Arsen Osipov
Poster #: 1588/9
Session: PO.TB06.04
Date and Time: Monday, June 22, 2020; 9:00 a.m. to 6:00 p.m. EDT
URL: View Source!/9045/presentation/7864

About VS-6766

VS-6766 (formerly known as CH5126766, CKI27 and RO5126766) is a unique inhibitor of the RAF/MEK signaling pathway. In contrast to other MEK inhibitors in development, VS-6766 blocks both MEK kinase activity and the ability of RAF to phosphorylate MEK. This unique mechanism allows VS-6766 to block MEK signaling without the compensatory activation of MEK that appears to limit the efficacy of other inhibitors. The combination of VS-6766 and the focal adhesion kinase (FAK) inhibitor defactinib is currently being investigated in an investigator-initiated Phase 1 dose escalation and expansion study. The expansion cohorts are currently ongoing in patients with KRAS mutant advanced solid tumors, including low grade serous ovarian cancer (LGSOC), non-small cell lung cancer (NSCLC) and colorectal cancer (CRC).6 The ongoing clinical study of the VS-6766/defactinib combination is supported by single-agent Phase 2 studies which investigated defactinib in KRAS mutant NSCLC7 and VS-6766 in KRAS mutant NSCLC and LGSOC.5

About Defactinib

Defactinib (VS-6063) is an oral small molecule inhibitor of FAK and PYK2 that is currently being evaluated as a potential combination therapy for various solid tumors. The Company has received Orphan Drug designation for defactinib in ovarian cancer and mesothelioma in the US, EU and Australia. Preclinical research by Verastem Oncology scientists and collaborators at world-renowned research institutions has described the effect of FAK inhibition to enhance immune response by decreasing immuno-suppressive cells, increasing cytotoxic T cells, and reducing stromal density, which allows tumor-killing immune cells to enter the tumor.8,9 Additionally, in both preclinical and clinical studies, FAK activation has been shown to occur as a potential resistance mechanism in response to MEK inhibitor treatment, and synergy of a FAK inhibitor with a RAF/MEK inhibitor has been shown in several preclinical models. The combination of defactinib and VS-6766 is currently being investigated in an investigator-initiated Phase 1 dose escalation and expansion study. The expansion cohorts are currently ongoing in patients with KRAS mutant advanced solid tumors, including low grade serous ovarian cancer (LGSOC), non-small cell lung cancer (NSCLC) and colorectal cancer (CRC).6 The ongoing clinical study of the VS-6766/defactinib combination is supported by single-agent Phase 2 studies which investigated defactinib in KRAS mutant NSCLC7 and VS-6766 in KRAS mutant NSCLC and LGSOC.8 Defactinib is also in clinical testing in combination with pembrolizumab for treatment of patients with pancreatic cancer, NSCLC and mesothelioma.10

About COPIKTRA (duvelisib)

COPIKTRA is an oral inhibitor of phosphoinositide 3-kinase (PI3K), and the first approved dual inhibitor of PI3K-delta and PI3K-gamma, two enzymes known to help support the growth and survival of malignant B-cells. PI3K signaling may lead to the proliferation of malignant B-cells and is thought to play a role in the formation and maintenance of the supportive tumor microenvironment.11,12,13 COPIKTRA is indicated for the treatment of adult patients with relapsed or refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) after at least two prior therapies and relapsed or refractory follicular lymphoma (FL) after at least two prior systemic therapies. COPIKTRA is also being developed by Verastem Oncology for the treatment of peripheral T-cell lymphoma (PTCL), for which it has received Fast Track status and Orphan Drug Designation, and is being investigated in combination with other agents through investigator-sponsored studies.14 For more information on COPIKTRA, please visit www.COPIKTRA.com. Information about duvelisib clinical trials can be found on www.clinicaltrials.gov.

F-star Therapeutics Presents Data on FS222 at 2020 AACR Annual Meeting

On June 22, 2020 F-star Therapeutics Ltd., a clinical-stage biopharmaceutical company focused on transforming the lives of patients with cancer through the development of innovative tetravalent bispecific (mAb2) antibodies, reported that preclinical data on FS222, a potentially best-in-class conditional agonist, targeting both CD137 and PD-L1, will be presented in a poster session at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Virtual Annual Meeting II being held from June 22 to June 24, 2020 (Press release, F-star, JUN 22, 2020, View Source [SID1234561356]).

FS222 targets PD-L1 (programmed death-ligand 1), the immune checkpoint protein which regulates the balance of activated T cells in the immune system and is over-expressed on many solid tumors, and CD137, a co-stimulatory molecule from the tumor necrosis factor receptor superfamily (TNFRSF), which is widely known to be upregulated on CD8+ T cells or "killer T cells". Currently, only a fraction of patients respond to monotherapies that block the PD-1/PD-L1 pathway, and monotherapy CD137-targeting molecules have yet to demonstrate significant responses in patients without toxicity.

The preclinical data presented in the poster session show that FS222 simultaneously binds PD-L1 and multimeric CD137 with sub-nanomolar affinity resulting in potent T cell activation, superior to a combination of monoclonal antibodies. These data also show that the bispecific antibody’s tetravalency enhances its activity by providing optimal PD-L1 blockade, as well as potent CD137 agonism, resulting in significant T cell activation.

CD137 agonism and the magnitude of downstream T cell activation was shown to be dependent on the prevalence of PD-L1 expressing cells, demonstrating the conditional nature of FS222’s mechanism of action. Furthermore, data from a non-human primate dose-range finding study, also included in the poster, show little evident toxicity upon repeated dosing with FS222.

A regulatory application to commence clinical development of FS222 is in preparation.

A link to the poster can be found here.

Neil Brewis, CSO of F-star, said: "We see a compelling rationale for the clinical testing of FS222, which we believe has the potential to provide meaningful and long-lasting benefit to patients with solid tumors, beyond current checkpoint inhibitors. With FS222, we have the potential to leverage a focused, potent and safe immune response, outperforming CD137 and PD-L1 monospecific antibodies and providing greater benefit to patients than a combination approach."

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Kazia Presents Further Paxalisib and Cantrixil Data at AACR, Reinforcing Positive Efficacy Signals for both Drugs

ABM Therapeutics Announces First Patient Dosed in Phase 1 Clinical Trial of ABM-1310 in the USA

Castle Biosciences Announces Proposed Underwritten Public Offering of Common Stock

Verastem Oncology Announces Presentation of Preclinical Data Supporting the Combination of VS-6766 and Defactinib in Metastatic Uveal Melanoma

F-star Therapeutics Presents Data on FS222 at 2020 AACR Annual Meeting