On April 9, 2021 Kazia Therapeutics Limited (ASX: KZA; NASDAQ: KZIA), an Australian oncology-focused drug development company, reported to share new data from its ongoing phase II study of paxalisib in glioblastoma, the most common and most aggressive form of primary brain cancer (Press release, Kazia Therapeutics, APR 9, 2021, View Source [SID1234577773]).

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The data is the subject of a poster presentation at the American Association of Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting, which is being held virtually from 10-15 April 2021, and from 17-21 May 2021.

Key Points

Pharmacokinetic (PK) data, which shows how long paxalisib remains in the human body, strongly supports 60mg once daily dosing, confirming planned administration schedule for commercial launch.

Analysis of food effect shows no significant difference between taking paxalisib with food versus on an empty stomach, allowing for a less restrictive administration schedule in commercial use.

Study remains ongoing, with a number of patients still in follow-up. Final data is now expected in 2H CY2021.

Kazia CEO, Dr James Garner, commented, "this is extremely useful and encouraging data, as we begin to compile regulatory documentation for paxalisib and give shape to its potential commercial approval. These results give us great confidence that we are administering the drug at the right dose, at the right frequency, and under the correct conditions. Moreover, the data helps to confirm the approach that we have taken in the GBM AGILE pivotal study."

He added, "a lot of our efforts at present are focused on assembling the complex package of scientific information that is required to secure FDA approval for any new drug. Today’s data provides one more piece in that jigsaw. More broadly, the phase II study is drawing to a conclusion, and we expect to be able to share final data in the second half of this year."

The poster can be viewed on the Company’s website at View Source

Background

The phase II study of paxalisib (NCT03522298) opened to recruitment in May 2018. It was designed to establish the most appropriate dose for use in newly-diagnosed patients, and to seek initial indications of potential clinical efficacy.

The study had previously determined a maximum tolerated dose (MTD) of 60mg, administered once daily. This determination was based primarily on safety findings, which suggested increased toxicity at a higher dose. Today’s PK data corroborates this finding, and shows that increased doses provide limited additional benefit in terms of drug exposure. In effect, these two independent variables both point to a dose of 60mg, giving a high degree of confidence that this is appropriate for future studies and for commercialisation.

Interim analyses of efficacy data from this study have previously shown encouraging signals of clinical efficacy, with a median overall survival (OS) of 17.5 months and a median progression-free survival (PFS) of 8.4 months reported at the most recent data cut. These figures compare very favourably to historical controls for temozolomide, which provide an OS of 12.7 months and a PFS of 5.3 months.

The phase II study remains ongoing, with a number of patients in follow-up, and is expected to deliver final data in 2H CY2021.

In January 2021, paxalisib opened to recruitment in the GBM AGILE pivotal study, which is expected to provide the basis for registration in the US and other territories.

On April 9, 2021 Iovance Biotherapeutics, Inc. (NASDAQ: IOVA), a late-stage biotechnology company developing novel T cell-based cancer immunotherapies, reported data from Cohort 2 in the C-144-01 study of lifileucel in advanced melanoma (Press release, Iovance Biotherapeutics, APR 9, 2021, View Source [SID1234577772]). These data will be part of an oral presentation in a Clinical Trials Plenary Session at the upcoming American Association for Cancer Research (AACR) (Free AACR Whitepaper) 2021 Annual Meeting.

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"We are very excited to report our latest Cohort 2 melanoma data in an oral presentation at AACR (Free AACR Whitepaper)," said Maria Fardis, Ph.D., President and Chief Executive Officer of Iovance Biotherapeutics. "The long term follow up data show that median duration of response was not reached at 28.1 months of median study follow up. Furthermore, overall response rate remained at 36.4 percent and we saw a continued deepening of response in 17 percent of the patients. The data continue to demonstrate durability and depth of our lifileucel TIL therapy response after a one-time treatment, in a difficult to treat patient population with advanced melanoma. We are honored that AACR (Free AACR Whitepaper) has chosen our melanoma Cohort 2 data to be featured in a clinical trials plenary session."

Jason Chesney, M.D., Ph.D., Director, James Graham Brown Cancer Center, University of Louisville and C-144-01 study investigator stated, "Melanoma patients who have progressed on immune checkpoint and BRAF/MEK inhibitors are among the most challenging patients for oncologists to treat. The updated results of the C-144-01 study continue to demonstrate that autologous tumor infiltrating lymphocytes (TILs; lifileucel) induce durable clinical responses in 36 percent of patients in the study. This study also creates opportunities for additional trials of TILs in many other cancer types and in combination with immunomodulatory agents."

The Cohort 2 data are available in the abstract titled, "Lifileucel (LN-144), a cryopreserved autologous tumor infiltrating lymphocyte (TIL) therapy in patients with advanced (unresectable or metastatic) melanoma: durable duration of response at 28-month follow up." Data highlights as of the December 14, 2020 data cut extract used for the abstract submitted to AACR (Free AACR Whitepaper) were as follows:

Lifileucel showed a 36.4% overall response rate (4.5% complete responses and 31.8% partial responses) and median duration of response (DOR) was not reached at 28.1 months of median study follow up as assessed by investigators (n=66).
The Cohort 2 patients had heavily pretreated metastatic melanoma with high baseline disease burden. They have progressed on multiple prior therapies (3.3 mean prior therapies), including anti-PD1 and BRAF/MEK inhibitors if BRAFV600 mutation positive.
The adverse event profile was consistent with the underlying advanced disease, lymphodepletion and IL-2 regimens, with no additional adverse events emerging over time.
The abstract is available in the AACR (Free AACR Whitepaper) Online Meeting Planner at www.aacr.org and on the Iovance website at www.iovance.com/our-science/publications. The data from the abstract will be highlighted in additional detail at the AACR (Free AACR Whitepaper) 2021 Annual Meeting. Details of the oral presentation are as follows:

Abstract Title: Lifileucel (LN-144), a cryopreserved autologous tumor infiltrating lymphocyte (TIL) therapy in patients with advanced (unresectable or metastatic) melanoma: durable duration of response at 28-month follow up
Authors: Jason Alan Chesney, MD, PhD, et al.
Abstract Number: 5329
Presentation Number: CT008
Session Title: Immunooncology and Cell Therapy Trials
Session Date and Time: Saturday, April 10, 2021, 4:45 PM – 5:00 PM ET
Location: AACR (Free AACR Whitepaper) Virtual Annual Meeting 2021 at www.aacr.org
In addition to the oral presentation, three Iovance poster presentations at AACR (Free AACR Whitepaper) will highlight the design of clinical trials in progress in solid tumors and chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL). These posters are intended to educate physicians about study design and will not include clinical data. Posters will be available from 8:30 a.m. ET on Saturday, April 10 through Monday, June 21, 2021 in the Virtual ePoster Hall at www.aacr.org and on the Iovance website at www.iovance.com/our-science/publications.

Abstract Title: A Phase 2, multicenter study of autologous tumor infiltrating lymphocytes (TIL) (LN-144/LN-145/LN-145-S1) in patients with solid tumors (IOV-COM-202)
Authors: Scott Gettinger, MD, et al.
Abstract Number: CT235
Abstract Title: A Phase 1/2 study evaluating the safety and efficacy of IOV-2001 in patients with relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) (IOV-CLL-01)
Authors: Meixiao Long, MD, PhD, et al.
Abstract Number: CT244
Abstract Title: A phase 2 multicenter study of autologous tumor infiltrating lymphocytes (TIL; LN-145) cell therapy in patients with metastatic non-small cell lung cancer (IOV-LUN-202)
Authors: Erminia Massarelli, MD, PhD, et al.
Abstract Number: CT246

On April 9, 2021 Interim data from a first-in-human trial evaluating the safety, therapeutic activity and maximum tolerable dose of THOR-707 (SAR444245), a highly differentiated not-alpha interleukin-2 (IL-2) candidate, as a monotherapy and in combination with anti-PD-1, reported that it will be presented Saturday, April 10 as a late-breaking poster presentation at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting (Press release, Sanofi, APR 9, 2021, View Source [SID1234577771]). The Saturday late-breaking poster session will include additional updated data.

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Interim safety, anti-tumor activity and biomarker data further validate the not-alpha IL-2 profile seen preclinically. In both the combination and monotherapy settings, initial activity was observed, with three confirmed partial responses, which includes patients who have received prior anti-PD-1 therapeutics.

"THOR-707 has a potentially best-in-class profile and reinforces the promise of our Synthorin technology platform to overcome difficult targets with precision biology," said John Reed, M.D. Ph.D., Global Head of Research & Development, Sanofi. "The activity observed both as single agent and with an anti-PD-1 further strengthens our belief that as a unique not-alpha IL-2, THOR-707 could become a backbone of future immuno-oncology therapies. We will continue to explore the molecule’s potential for best-in-disease combinations."

THOR-707 is a precisely PEGylated version of IL-2, where the PEG chain is attached to a novel amino acid inserted at a location on IL-2 that prevents it from engaging the alpha-receptor and binding to immune receptors that cause drug toxicities (IL-2R-alpha, CD25). The engineered IL-2 retains near-native binding to the beta-gamma receptors that selectively expand tumor-killing T effector cells and Natural Killer (NK) cells without the alpha-mediated immunosuppressive effects of regulatory T cells or eosinophil-mediated vascular leak syndrome.

Interim results indicate a similar pattern where CD8+ T cells and NK cells increased after the first dose of THOR-707 and sustained throughout the entire cycle , with a dose escalating effect; this effect was enhanced when combined with KEYTRUDA (pembrolizumab). No significant increases in CD4+ regulatory T cells or eosinophils were observed, indicative of not-alpha IL-2 receptor selectivity.

No dose-limiting toxicities were observed for THOR-707 at reported doses, up to 24 μg/kg as monotherapy and 16 μg/kg in combination. The most common treatment emergent adverse events (TEAEs) following the first dose included flu-like symptoms, fever, vomiting/nausea and chills. Symptoms were transient and resolved with standard supportive care. Among G3-4 related toxicities was a transient decrease in lymphocyte count, which preceded T cell expansion.

No eosinophilia or vascular leak syndrome was reported at any doses tested. IL-5 levels remained at or below the lowest level of detection, suggesting a rationale for the lack of IL-5 associated toxicity observed during treatment.

"Novel approaches, such as not-alpha IL-2, seek to activate this powerful immune pathway while mitigating current challenges with dosing and safety to potentially expand the patient population who could benefit from treatment," said Filip Janku, M.D. Ph.D., Associate Professor, Department of Investigational Cancer Therapeutics, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX. "Preclinically, THOR-707 appeared to activate an anti-tumor immune response without an increased risk of alpha-mediated toxicities, such as eosinophilia or vascular leak syndrome. While early, the interim clinical data at AACR (Free AACR Whitepaper) align very closely to what we saw in preclinical research and suggest further study of this not-alpha IL-2 molecule is warranted, both alone and in combination with a synergistic treatment such as anti-PD-1."

THOR-707 dose escalation has progressed beyond projected monotherapy RP2D of 24 μg/kg Q3W to 32 μg/kg Q3W to further characterize the upper bounds of the dose range.

In addition to testing THOR-707 in combination with KEYTRUDA, Sanofi is planning to evaluate the activity of this novel biologic in combination with other anti-PD-1 antibodies, including Libtayo1, (cemiplimab) anti-CD38 antibody Sarclisa (isatuximab) and anti-EGFR.

Editor’s Note: Sanofi previously entered into an agreement with Merck & Co. Inc., Kenilworth, NJ, USA (known as MSD outside the U.S. and Canada) to conduct a Phase 2 trial evaluating THOR-707 combined with or in sequenced administration with KEYTRUDA.

About THOR-707 (SAR444245)

THOR-707 is a precisely PEGylated engineered version of IL-2 with an increased half-life being investigated for the treatment of many types of malignancies. Additionally, pharmacology is being assessed to determine if THOR-707 may allow for less frequent dosing. In pre-clinical experiments, THOR-707 exhibited the ability to induce the expansion of CD8+T-cells suggesting potential for anti-tumor effects both as single agent as well as in combination with an anti-PD-1 monoclonal antibody. THOR-707 is not approved by any regulatory authority.

THOR-707 is the first molecule from the Synthorin technology platform. Synthorins are novel proteins built on Sanofi’s unique Expanded Genetic Alphabet platform, which allows scientists to fill important gaps in protein therapeutics by vastly expanding the variety of building blocks available to bioengineers. Used on its own or in combination with other Sanofi technologies, the Expanded Genetic Alphabet platform is enabling the company’s scientists and bioengineers to develop novel biologics for cancer and other diseases.

On April 9, 2021 Sanofi reported the successful completion of its acquisition of Kymab Group Ltd., adding KY1005 to its pipeline, a fully human monoclonal antibody targeting key immune system regulator OX40L (Press release, Sanofi, APR 9, 2021, View Source [SID1234577770]). The acquisition continues to build on Sanofi’s leading presence in immunology aligned with the company’s strategy to pursue best-in-class treatments in defined areas.

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Kymab’s pipeline also includes the oncology asset KY1044, an ICOS agonist monoclonal antibody, currently in early Phase1/2 development as monotherapy and in combination with an anti-PD-L1.

On April 9, 2021 Evotec SE (Frankfurt Stock Exchange: EVT, MDAX/TecDAX, ISIN: DE0005664809) reported the most advanced asset arising from their joint venture with Exscientia has entered human clinical trials (Press release, Evotec, APR 9, 2021, View Source;announcements/press-releases/p/evotec-and-exscientia-announce-start-of-human-clinical-trials-of-novel-immuno-oncology-drug-6045 [SID1234577769]). The A2a receptor antagonist, which is in development for adult patients with advanced solid tumours, was co-invented and developed between Exscientia and Evotec, including application of Exscientia’s next generation 3-D evolutionary AI-design platform, Centaur Chemist. The drug candidate has potential for best-in-class characteristics, with high selectivity for the target receptor, bringing together potential benefits of reduced systemic side effects as well as minimal brain exposure to avoid potential undesired centrally-mediated side effects.

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Tumour cells produce high levels of adenosine, a molecule that helps them escape immune system detection by binding to the A2a receptor on cancer-fighting T-cells, reducing T-cell ability to eliminate disease. Therefore, this highly selective A2a receptor antagonist is being investigated for its ability to prevent adenosine from binding to the T-cell receptor and potentially promote anti-tumour T-cell activity.

Dr Craig Johnstone, Chief Operating Officer of Evotec, commented: "We highly value our ongoing partnership with Exscientia, which has been highly collaborative and productive in every respect. We are therefore delighted to announce the start of clinical development of our co-owned A2a antagonist with Exscientia in the hope that the fruits of our collaboration can bring potential benefits to patients in the future."

Prof. Andrew Hopkins, CEO and founder of Exscientia, said: "We set ambitious therapeutic objectives for this project, especially high selectivity for the A2a receptor and central nervous system (CNS) sparing properties, in order to reduce the likelihood of potential side effects. Even with these challenging objectives, we were able to discover our candidate molecule within 8 months of project initiation."

Exscientia will lead further clinical development of the molecule and Evotec will retain co-ownership rights throughout clinical development.