On December 10, 2020 Kazia Therapeutics Limited (ASX: KZA;NASDAQ: KZIA), an Australian oncology-focused biotechnology company, reported that it has executed a Letter of Intent with the Pacific Pediatric Neuro-Oncology Consortium (PNOC) to launch a clinical trial of multiple therapies, including Kazia’s investigational new drug, paxalisib (formerly GDC-0084), in diffuse midline gliomas including diffuse intrinsic pontine glioma (DIPG) (Press release, Kazia Therapeutics, DEC 10, 2020, View Source [SID1234572773]).

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The new clinical trial, PNOC022, will employ an adaptive trial design to test several therapies in different combinations and in different subsets of patients. In addition to paxalisib, the other therapies involved will initially include ONC201, manufactured by Oncoceutics, Inc, and panobinostat, manufactured by SecuraBio, Inc. The study is expected to open initially in the United States and will then expand to other countries during CY2021.

Key Points

PNOC022 uses cutting-edge clinical trial design to efficiently and rapidly evaluate combination therapies in DIPG, under the leadership of world experts in the field
Lead investigator is Professor Sabine Mueller, a leading paediatric neuro-oncologist and co-founder of PNOC
Study is guided by Australian research at University of Newcastle, under leadership of Associate Professor Matt Dun, who serves as a scientific advisor
Combination approach builds on recent positive data from St Jude SJPI3K study (NCT03696355) with paxalisib as single agent in DIPG, and brings together several of the most promising candidates in the global pipeline for DIPG
Kazia will provide paxalisib investigational product; study is fully funded by PNOC
Kazia CEO, Dr James Garner, commented, "DIPG and diffuse midline gliomas have emerged as an exciting second front in the development of paxalisib as a brain cancer therapy. Work by Dr Chris Tinkle and colleagues at St Jude Children’s Research Hospital has taught us a great deal about how to use this drug in a paediatric population. In parallel, extensive laboratory research by Associate Professor Matt Dun and colleagues has generated a rich and comprehensive data set to inform combination use. We are delighted to now have the opportunity to work with the PNOC team to bring these insights together and to take paxalisib into the next chapter of its development as a potential therapy for DIPG."

Clinical Trial Design

PNOC022 will enrol children and young adults with diffuse midline gliomas, a category of brain tumours that includes DIPG. The study will include separate cohorts comprising patients with newly diagnosed disease, patients who have completed initial radiotherapy, and patients who have experienced disease progression after treatment.

At the outset, all patients will be treated with ONC201, combined with either paxalisib or panobinostat. The study employs an adaptive design, in which different arms will opened and closed based on emerging preclinical and clinical data. The primary endpoint will be the proportion of patients progression-free at six months (PFS6) for newly diagnosed patients, and overall survival (OS) for recurrent patients.

The lead investigator will be Professor Sabine Mueller, a board-certified neurologist and paediatric neuro-oncologist whose research focuses on novel therapies in childhood brain cancer. Professor Mueller holds an academic appointment in the Department of Neurology, Neurosurgery and Pediatrics at the University of California, San Francisco (UCSF) and serves as head of the clinical programme at the DMG Centre at the Children’s Hospital of the University of Zurich. She obtained her medical degree from the University of Hamburg, and also holds a PhD in molecular biology.

Professor Mueller commented, "DIPG remains one of the most challenging of childhood cancers. No drug treatment has ever demonstrated meaningful efficacy. The PNOC022 study brings a different approach, uniting the best of preclinical research with novel clinical trial techniques. We look forward to commencing enrolment to the study shortly, and very much hope that we are able to generate new hope for patients and their families."

Commencement of the study remains subject to execution of a definitive contract and is dependent on approval by the US FDA and Institutional Review Boards. It is expected that PNOC022 will initially open in the United States in 1H CY2021, with expansion to other countries taking place in CY2021. Discussions are ongoing regarding the potential inclusion of Australian sites in the study.

Australian Scientific Research

The design of the PNOC022 study has been extensively informed by laboratory research in DIPG, and in particular by research undertaken at the University of Newcastle, Hunter Medical Research Institute (HMRI) by Associate Professor Matt Dun and colleagues. The HMRI team has conducted laboratory research with paxalisib for several years and has generated a powerful body of data combining paxalisib with other investigational drugs. This research has been partly funded by RUN DIPG, a not-for-profit organisation led by Associate Professor Dun, the DIPG Collaborative, Defeat DIPG Michael Moiser Foundation and the McDonald Jones Foundation. The robust mechanistic data is expected to be published in high impact scientific journals in coming months.

Pacific Pediatric Neuro-Oncology Consortium (PNOC)

The Pacific Pediatric Neuro-Oncology Consortium (PNOC) is an international consortium, with study sites in the United States, Canada, Swizterland, Europe, India, Israel, and Australia. PNOC is dedicated to bringing new therapies to children and young adults with brain tumours, using the latest scientific understanding to inform a personalised medicine approach.

PNOC comprises 225 leading specialists in childhood brain cancer and is currently driving sixteen international clinical trials. In Australia, the organisation collaborates closely with the Australia and New Zealand Children’s Hematology / Oncology Group (ANZCHOG). PNOC’s research is substantially supported by the PNOC Foundation, the Pediatric Brain Tumor Foundation, and other not-for-profit entities.

Paxalisib Clinical Program

The initiation of this trial will bring the number of ongoing clinical studies of paxalisib in brain cancer to eight.

Indication

Phase

Sponsor

Registration

Glioblastoma

II

Kazia Therapeutics

NCT03522298

Glioblastoma

II / III

Global Coalition for Adaptive Research

NCT03970447

DIPG & DMGs

I

St Jude Children’s Research Hospital

NCT03696355

DIPG & DMGs

N/A*

Pacific Pediatric Neuro-Oncology Consortium

(TBD)

Breast Cancer Brain Metastases

II

Dana-Farber Cancer Institute

NCT03765983

Brain Metastases

II

Alliance for Clinical Trials in Oncology

NCT03994796

Brain Metastases

I

Memorial Sloan-Kettering Cancer Center

NCT04192981

Primary CNS Lymphoma

II

Dana-Farber Cancer Institute

(TBD)

*Note – the PNOC022 has not adopted a ‘phase’ designation and is described as an ‘adaptive platform study’

Next Steps

Recruitment to this study is expected to commence in 1H CY2021.

On December 10, 2020 Ultimovacs ASA ("Ultimovacs", ticker ULTI), reported positive five-year Overall Survival (OS) data from the Phase I trial evaluating the company’s universal cancer vaccine, UV1, in combination with the checkpoint inhibitor, ipilimumab, in patients with metastatic malignant melanoma (Press release, Ultimovacs, DEC 10, 2020, View Source [SID1234572618]). After 5-years of follow-up, 50% of the patients in the open-label trial were still alive, providing encouraging signals of long-term survival benefit for UV1 in this late-stage patient population and as compared to historical data of ipilimumab monotherapy. As previously reported at ASCO (Free ASCO Whitepaper)-SITC in 2020, the trial achieved its primary endpoints of safety and tolerability. These results represent the third clinical trial with UV1 to provide positive data for 5-years of patient follow-up, further strengthening UV1’s profile as a safe and potentially effective addition to immuno-oncology treatment regimens.

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"When we look at the trial results of ipilimumab monotherapy conducted in nearly identical clinical settings and patient population, we see in the literature a 5-year survival rate around 20%, median overall survival of around 16 months and median progression free survival of about 3.5 to 4 months," stated Jens Bjørheim, Chief Medical Officer at Ultimovacs. "Combining ipilimumab, which was the standard-of-care treatment at the time of the study initiation, with UV1, resulted in promising signs of improved survival with a safe and well-tolerated profile. At 5 years of follow-up, the median overall survival had not been reached and 50% of the patients were still alive, which are encouraging results in patients with metastatic melanoma."

A total of 12 malignant melanoma patients with metastatic disease were treated in the Phase I trial. Eight patients of the 12 received UV1 combined with ipilimumab as first line treatment, and the remaining four patients received the combination after progression on previous systemic treatment. Immune responses toward the UV1 peptides occurred very early post administration, with 91% of the evaluable patients showing an immune response. In the efficacy-evaluable patient population, one patient achieved a complete tumor response and three patients achieved a partial response, resulting in an objective response rate of 44%. Primary endpoints for the study included the safety and tolerability of UV1 as well as initial signs of clinical response. As per the data cut-off at the end of November 2020, every patient in the trial reached at least 60 months of follow-up post treatment with UV1 and ipilimumab. At the five-year mark, the OS rate was 50%, median OS had not yet been reached and median Progression Free Survival (mPFS) was 6.7 months. Over the course of the follow-up period, none of the patients experienced any unexpected safety issues related to UV1.

"In all four Phase I trials where UV1 has been tested, we have observed a consistent set of positive signals of clinical effect and a good safety profile for UV1. This strengthens our commitment to developing UV1 as a potential universal cancer vaccine that can be applied across multiple indications, in different combinations with other cancer treatments and in different stages of cancer," stated Carlos de Sousa, Chief Executive Officer at Ultimovacs."Our ongoing INITIUM Phase II clinical trial combines UV1 with ipilimumab and nivolumab in this patient population and today’s results reinforce the confidence we have in our approach of directing the immune system towards telomerase expressing cancer cells to improve clinical outcomes for patients in need of new treatment options."

About UV1

UV1 is a peptide-based vaccine inducing a specific T cell response against the universal cancer antigen telomerase. UV1 is being developed as a therapeutic cancer vaccine which may serve as a platform for use in combination with other immunotherapy which requires an ongoing T cell response for their mode of action. To date, UV1 has been tested in four phase I clinical trials in a total of 82 patients and maintained a positive safety and tolerability profile as well as encouraging signals of efficacy.

About UV1 Clinical Programs

As a universal cancer vaccine, UV1’s unique mechanism of action has the potential to be applicable across most cancer types. The clinical development of the UV1 vaccine includes three randomized, multinational, Phase II combination trials recruiting more than 400 patients in total. The INITIUM trial is an Ultimovacs-sponsored clinical trial recruiting 154 patients with metastatic malignant melanoma to evaluate UV1 in combination with ipilimumab and nivolumab as first-line treatment. The NIPU study is testing UV1 in combination with checkpoint inhibitors ipilimumab and nivolumab as second-line treatment in 118 patients with advanced malignant pleural mesothelioma, a rare lung cancer. The study is sponsored by Oslo University Hospital and Bristol-Myers Squibb is providing the checkpoint inhibitors for this study. Ultimovacs anticipates announcing data on the primary endpoints for the NIPU and INITIUM studies in 2022. A third Phase II clinical trial will evaluate UV1 in a new cancer indication in combination with indication-specific standard of care cancer therapies different from those to be tested in INITIUM and NIPU. In this new collaboration, Ultimovacs will supply UV1 and a big pharma company will supply its proprietary cancer treatment to the clinical trial group which will sponsor the trial.

On December 10, 2020 Fusion Pharmaceuticals Inc. (Nasdaq: FUSN), a clinical-stage oncology company focused on developing next-generation radiopharmaceuticals as precision medicines, reported that the first patient has been dosed in the multi-dose portion of the Phase 1 study evaluating [225Ac]-FPI-1434 (FPI-1434) in patients with advanced solid tumors (Press release, Fusion Pharmaceuticals, DEC 10, 2020, View Source [SID1234572635]). FPI-1434 is a radioimmunoconjugate that utilizes Fusion’s proprietary Fast-Clear linker to connect a humanized monoclonal antibody targeting the insulin-like growth factor 1 receptor (IGF-1R), with the alpha-emitting isotope actinium-225, creating a targeted alpha therapy (TAT).

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The Phase 1, multi-center, open-label clinical trial is designed to investigate the safety, tolerability and pharmacokinetics of FPI-1434 in patients with solid tumors expressing IGF-1R. The trial is also designed to establish the maximum tolerated dose for FPI-1434 and the recommended Phase 2 dose. As part of the precision medicine approach, prior to receiving the therapeutic injection of FPI-1434, patients are administered an indium-111 imaging analogue, [111In]-FPI-1547 (FPI-1547). The images collected are used to confirm the presence of tumor uptake and to ensure that estimated radiation doses to organs and tissues are below protocol-specified safety limits.

The multi-dose study follows completion of the single-dose portion of the Phase 1 study, which showed that FPI-1434 was generally well tolerated with no dose limiting toxicities or treatment-related serious adverse events reported to date. The multi-dose portion of the study is expected to enroll patients at sites in Canada, the United States and Australia. The initial patient cohort is being dosed with FPI-1434 at 75kBq/kg with repeat cycles every six weeks up to allowable limits.

"We are pleased with the results of the single-dose portion of our Phase 1 study of FPI-1434 which, following the evaluation of the Safety Review Committee, support initiating the multi-dosing portion of the study," said Chief Executive Officer John Valliant, Ph.D. "This is a critical next step in the FPI-1434 development program as data from the multi-dose portion of the study may provide important insights on potential anti-tumor activity. The multi-dosing trial will also inform the design of the Phase 2 program and assist in the selection of tumor indications to be pursued in planned expansion cohorts. This is especially important given the broad expression of IGF-1R across multiple tumor types."

For additional detail about the study, please visit View Source

About FPI-1434

FPI-1434 is a radioimmunoconjugate designed to target and deliver alpha emitting medical isotopes to cancer cells expressing IGF-1R, a receptor that is overexpressed on many tumor types. FPI-1434 utilizes Fusion’s Fast-Clear linker to connect a human monoclonal antibody that targets IGF-1R with actinium-225, a powerful alpha-emitting isotope with desirable half-life and decay chain properties.

Acknowledgement of US DOE and Actiunium-225 Supply

The actinium-225 used in this research was supplied by the United States Department of Energy Office of Science by the Isotope Program in the Office of Nuclear Physics.

On December 10, 2020 Crescendo Biologics Ltd (Crescendo), the drug developer of novel, targeted T cell enhancing therapeutics, reported that it has expanded its global, multi-target discovery and development collaboration with Takeda Pharmaceutical Company Limited (Takeda) after Crescendo achieved its sixth technical milestone (Press release, Crescendo Biologics, DEC 10, 2020, View Source [SID1234572619]).

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Under its ongoing collaboration and license agreement, Crescendo’s proprietary transgenic platform and engineering expertise is being used to build Humabody-based therapeutics against certain targets selected by Takeda.

The collaboration expansion gives Takeda access to a range of Crescendo’s half-life extension Humabodies for use with its two Humabody programmes, previously licensed in November 2018 and July 2019, and Humabody programmes Takeda licenses in the future during the term of the collaboration expansion.

This is the sixth technical milestone achieved by Crescendo in its collaboration with Takeda. Crescendo has successfully delivered novel oncology-targeted Humabody lead molecules using its robust in-house discovery process.

Theodora Harold, CEO of Crescendo, commented:

"Crescendo has again demonstrated its ability to deliver differentiated Humabody molecules against specific targets selected by Takeda, on schedule. The expansion of our collaboration, together with the achievement of this sixth milestone, further validates the excellent work being done at Crescendo to progress the next generation of differentiated cancer therapies."

Loïc Vincent, Head, Oncology Drug Discovery Unit, Takeda, commented:

"Our fruitful collaboration with Crescendo continues to show great progress. We are delighted to expand our work together, drawing on Takeda’s vast oncology drug discovery experience and Crescendo’s expertise in developing optimally constructed Humabody molecules to quickly advance novel therapeutics with transformative treatment potential towards the clinic."

On December 10, 2020 Denovo Biopharma, a pioneer in applying precision medicine to develop innovative therapies, reported it has licensed its seventh late-stage drug asset: endostatin (now named DB108) from Jiangsu Wuzhong Pharmaceutical Group Corporation ("Wuzhong Pharmaceutical" (Press release, Denovo Biopharma, DEC 10, 2020, View Source [SID1234572636]). Denovo gains global rights (except China) to develop, manufacture and commercialize endostatin.

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DB108 is a recombinant protein drug that inhibits tumor growth and metastasis by inhibiting angiogenesis. DB108 is obtained by expression in E. coli, has a molecular weight of 20KDa, a total of 184 amino acids, and the same amino acid sequence as naturally-occuring human endostatin. Wuzhong Pharmaceutical studied DB108 as a first-line treatment for non-small cell lung cancer (NSCLC ) in a Phase 3 clinical trial. This trial demonstrated DB108 had a good safety and tolerability profile. Although DB108 showed no significant difference in median overall survival versus control, it had a significant efficacy benefit in median progression-free survival.

Denovo Biopharma expands into protein therapeutics with DB108 acquisition

Dr. Michael F. Haller, Denovo Biopharma’s Chief Business Officer, said, "Wuzhong Pharmaceutical’s pioneering work on DB108 has laid a good foundation for our follow-up research and development. We plan on developing a targeted product through our whole-genome scanning platform technology to predict the efficacy of DB108 in a specific patient population. This product enables our expansion into the field of protein therapeutics."

Mr. Yao Jianlin, Chairman of Wuzhong Pharmaceutical, said, "Denovo Biopharma is a leading precision medicine company with superb biomarker research and development capabilities. Recombinant human endostatin injection is a novel medicine developed by Wuzhong Pharmaceutical that may provide better treatment options for clinical patients worldwide."