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Plus Therapeutics Presents Positive Phase 1 Data from ReSPECT-GBM Clinical Trial at the European Society for Medical Oncology Congress 2022

On September 12, 2022 Plus Therapeutics, Inc. (Nasdaq: PSTV) (the "Company"), a clinical-stage pharmaceutical company developing innovative, targeted radiotherapeutics for rare and difficult-to-treat cancers, reported Phase 1 data from the ReSPECT-GBM Phase 1/2a dose escalation clinical trial evaluating the Company’s lead investigational targeted radiotherapeutic, Rhenium-186 NanoLiposome (186RNL), in recurrent glioblastoma (GBM) in an oral presentation at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress 2022, being held September 9-13, 2022 in Paris, France (Press release, PLUS THERAPEUTICS, SEP 12, 2022, View Source;_hsmi=225740869&_hsenc=p2ANqtz–6YFoZ8ZUpThJHOJugmdD8dgg2haHyg6iYf86gY_0MCeKN2rY0_GGFEXgLIEtD4CesBA5r_5RUW2PTlyFZ_lP6B5F-qQ&utm_content=225740869&utm_source=hs_email [SID1234619446]).

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"Radiation is lethal to cancer cells and rhenium-186 is an ideal radioisotope for the treatment of glioblastoma. Furthermore, the unique drug formulation allows the radiation to stay in the brain for days, if not weeks," said Andrew J. Brenner, M.D., Ph.D., Professor of Medicine, Neurology, and Neurosurgery at The University of Texas Health Science Center at San Antonio and principal investigator of the ReSPECT-GBM clinical trial. "In the ReSPECT-GBM Phase 1 trial, we achieved up to 20 times the amount of radiation compared to external beam radiation therapy, and we observed a statistically significant improvement in survival in those patients receiving a therapeutic dose of radiation compared to those that did not."

The oral presentation titled, The ReSPECT-GBM Phase 1/2a Dose Escalation Trial of Rhenium-186 NanoLiposome (186RNL) in Recurrent Glioma via Convection Enhanced Delivery (CED) & Planned Phase 2b Trial [2770], reviews data from the Phase 1 ReSPECT-GBM trial which evaluated 23 adult patients with recurrent GBM across 8 cohorts of increasing dose and treated over a seven-year period.

Key findings include:

No dose-limiting toxicities (DLT) have been observed and the procedure is very well tolerated with a strong safety profile. Minimal systemic radiation has been observed and the majority of adverse events have been mild or moderate and considered causally unrelated to the procedure.
Improved median overall survival (OS) rates correlated with the absorbed tumor radiation dose. When patients were stratified based on receipt of either a therapeutic or a subtherapeutic absorbed dose of radiation to the tumor, a statistically significant improvement in survival was observed. Specifically, patients receiving a therapeutic absorbed radiation dose (>100 Gray) had a median OS of 22.9 (95% CI of 8.8-42.3) months compared to those receiving a subtherapeutic absorbed radiation dose (<100 Gray) whose median OS was 5.6 months (95% CI of 1.6-9.4). Currently, three patients remain alive, all in the therapeutic group.
Feasibility to deliver up to at least 20 times more radiation to the tumor than the standard of care, external beam radiation therapy (EBRT). A maximum of 32.2 mCi in 12.3 mL of volume has been delivered in and near the tumors, and a maximum average absorbed dose of radiation of 740 Gray has been successfully administered in a single procedure.
Average absorbed radiation dose to the tumor increased in latter dosing cohorts with greater administered doses of Re-186 β-particle radiation, larger drug convection enhanced delivery (CED) infusate volumes, more catheters used (up to 4 versus 1), and higher convection flow rates. In cohorts 5 and later, 82% of patients received a therapeutic radiation dose of >100Gray.
Single-photon emission computerized tomography and (SPECT)/CT scanning were used during treatment to compute tumor coverage and dosimetry. Post treatment imaging analyses, including MRI, relative cerebral blood volume (rCBV) analysis and treatment response assessment maps (TRAMs) correlated with a positive tumor response and confirmed the presence of pseudoprogression in patients with positive tumor responses.
ReSPECT-GBM will proceed to an NIH and U.S. Food and Drug Administration (FDA) approved Phase 2 trial in the U.S. at the current non-DLT 186RNL dose and will expand exploring higher radiation doses in larger volumes to treat larger tumors. Additionally, two or more 186RNL administrations, if indicated, will be evaluated and reviewed with the FDA, as well as expanded safety, imaging and efficacy data to support a planned future registrational trial.
"The Phase 1 data offer important and objective insight and data into 186RNL’s potential to safely prolong patient survival and suggests that there is an overall survival benefit when a 186RNL dose of more than 100 Gray is achieved," said Norman LaFrance, M.D., Chief Medical Officer and Senior Vice President at Plus Therapeutics. "The planned Phase 2 study using cGMP 186RNL will leverage a higher dose and volume that could potentially show a greater survival rate in patients with recurrent GBM."

Based upon feedback from a Type C meeting with the FDA, the Company plans to initiate the ReSPECT-GBM Phase 2 trial in the second half of 2022, funded principally by the NIH. The Company intends to begin the ReSPECT-GBM Phase 2 trial utilizing cGMP 186RNL drug, which will be available in the second half of 2022. In this study, researchers plan to administer the recommended non-DLT dose of 22.3 mCi (total 186RNL activity) at a concentration of 2.5 mCi/mL in 8.8 mL total volume to patients with a tumor size of less than or equal to 20 cm3 as a starting point. Furthermore, the Company plans to evaluate further doses, including both increased dosing and multiple doses, and collect additional safety and efficacy data for the planned future registrational trial.

A copy of the presentation will be available under the Presentations tab of the Investors section of the Company’s website at the time of presentation at View Source

Agenus Initiates Botensilimab Phase 2 ACTIVATE Trials in Advanced MSS Colorectal Cancer and Advanced Melanoma

On September 12, 2022 Agenus (NASDAQ: AGEN), an immuno-oncology company with an extensive pipeline of therapeutics designed to activate the immune response to cancers and infections, reported the initiation of a global Phase 2 program of botensilimab, an Fc-enhanced anti-CTLA-4 that activates innate and adaptive immune responses (Press release, Agenus, SEP 12, 2022, View Source [SID1234619445]). These trials include ACTIVATE-Colorectal, a Phase 2 study designed to evaluate botensilimab as monotherapy and in combination with balstilimab (anti-PD-1) for the treatment of microsatellite stable colorectal cancer (MSS CRC), and ACTIVATE-Melanoma, a Phase 2 study designed to evaluate botensilimab as a single agent for advanced melanoma, refractory to either prior anti-PD-1 or combined anti-PD-1/anti-CTLA-4 therapy. An additional Phase 2 study in pancreatic cancer is anticipated to begin later in 2022.

"The Phase 1 botensilimab program demonstrated remarkable activity in poorly immunogenic and difficult to treat tumor types," said Steven O’Day, MD, Chief Medical Officer at Agenus. "In light of our compelling clinical data, we have received clearance from the FDA to initiate our Phase 2 development program in two indications and intend to expand to multiple additional indications as rapidly as possible with the aim of delivering a transformative new treatment option to patients in need."

ACTIVATE-Colorectal is a global, randomized, open-label, dose-optimization study evaluating the safety and efficacy of botensilimab as monotherapy and in combination with balstilimab in advanced refractory MSS CRC patients. Key elements of ACTIVATE-Colorectal include:

Patients must have received at least one prior chemotherapy regimen
Patients cannot have received prior PD-1, CTLA-4 or other immune checkpoint inhibitor therapy
Primary endpoint is overall response rate (ORR); secondary endpoints include duration of response (DOR), progression-free survival (PFS) and overall survival (OS)
Recruitment will be global, including sites in the United States and Europe
ACTIVATE-Melanoma is a global, randomized, open-label, multi-cohort, dose-optimization study evaluating the safety and efficacy of botensilimab as a single agent in advanced refractory melanoma. Key elements of ACTIVATE-Melanoma include:

Study will enroll patients who have failed prior anti-PD-1 therapy (cohort A) or both anti-PD1 and anti-CTLA-4 therapy (cohort B)
Primary endpoint is overall response rate (ORR); secondary endpoints include duration of response (DOR), progression-free survival (PFS) and overall survival (OS)
Recruitment will be global, including sites in the United States and Europe
About Microsatellite Stable Colorectal Cancer

Colorectal cancer remains the third most common cancer diagnosis and second-leading cause of cancer death worldwide, affecting 1.93 million and 916,000 individuals each year1. MSS colorectal cancer is a form of colorectal cancer where the cells’ DNA repair mechanisms remain intact2. It accounts for over 95% of metastatic colorectal cancer cases3 and has historically been unresponsive to immune checkpoint therapy4. Standard of care in pretreated metastatic MSS colorectal cancer offers limited benefit, with an approximate 1-2% response rate and a median of 6-7 months of survival5,6.

About Advanced Refractory Melanoma

Melanoma is a serious skin cancer that affects approximately 132,000 individuals each year and has been growing in incidence7. Advanced refractory melanoma refers to cancer that has spread to other parts of the body and stopped responding to medical therapy. Recent advances in the use of targeted therapy and immunotherapy, including anti-PD-1 and anti-CTLA-4, have improved survival for patients diagnosed with advanced melanoma. However, while anti-PD-1 monotherapy can be effective as a first-line treatment for some patients with metastatic melanoma, roughly half fail to achieve an objective response and those who do often subsequently relapse.8,9,10 Those patients with non-BRAF mutated tumors who are refractory to or who relapse after having received anti-PD-1 and anti-CTLA-4 therapy have few effective treatment options.

About Botensilimab

Botensilimab is a novel innate and adaptive immune activator that binds CTLA-4. The antibody was designed to enhance FcγR effector functions while avoiding complement-related toxicities and has demonstrated activity in cancer patients for whom current immuno-oncology agents have historically been ineffective. As presented at SITC (Free SITC Whitepaper) 2021, botensilimab is the first CTLA-4 inhibitor to demonstrate clinical responses across nine cold and treatment-resistant cancers. At ESMO (Free ESMO Whitepaper) GI 2022, botensilimab demonstrated unprecedented activity in combination with balstilimab in MSS colorectal cancer, with a 24% response rate and 73% disease control rate in heavily pre-treated patients with a median of 4 prior lines of therapy.

Kiniksa Pharmaceuticals Announces Closing of Global License Agreement with Genentech for Vixarelimab

On September 12, 2022 Kiniksa Pharmaceuticals, Ltd. (Nasdaq: KNSA) (Kiniksa), a biopharmaceutical company with a portfolio of assets designed to modulate immunological pathways across a spectrum of diseases, reported the closing of the global license agreement with Roche and Genentech, a member of the Roche Group (Genentech), for the rights to develop and commercialize vixarelimab, a fully human monoclonal antibody targeting oncostatin M receptor beta (OSMRβ) (Press release, Kiniksa Pharmaceuticals, SEP 12, 2022, View Source [SID1234619444]). Closing of the transaction was subject to customary closing conditions and expiration of the waiting period under the Hart-Scott-Rodino (HSR) Antitrust Improvements Act of 1976.

Under the terms of the license agreement, Kiniksa will receive $100 million in upfront and near-term payments, which include $80 million within 30 days of the closing of the transaction and $20 million within 30 days after Kiniksa’s delivery of certain drug supplies to Genentech. In addition, Kiniksa is eligible to receive up to approximately $600 million in certain clinical, regulatory, and sales-based milestones, before fulfilling upstream financial obligations. Kiniksa is also eligible to receive royalties on annual net sales. Genentech obtains rights for the global development and commercialization of vixarelimab.

Kiniksa expects that its cash and cash equivalents, including the proceeds received from the vixarelimab global license agreement with Genentech, will fund its current operating plan into at least 2025.

Onconova Therapeutics Announces Updated Data From Investigator-Sponsored Phase 1/2a Trial Evaluating Rigosertib In Combination With Nivolumab In Advanced KRAS-Mutated Non-Small Cell Lung Cancer At The ESMO Congress 2022

On September 12, 2022 Onconova Therapeutics, Inc. (NASDAQ: ONTX), ("Onconova"), a clinical-stage biopharmaceutical company focused on discovering and developing novel products for patients with cancer, reported updated data from an investigator-sponsored Phase 1/2a trial of oral rigosertib plus the anti-PD-1 immune checkpoint inhibitor (ICI) nivolumab in advanced KRAS-mutated (KRAS+) non-small cell lung cancer (NSCLC) (Press release, Onconova, SEP 12, 2022, View Source [SID1234619443]). The data, which are featured in a poster at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress 2022, show an early and encouraging signal of efficacy in the trial’s extensively pre-treated population. The studied doublet has been well tolerated to-date.

"The emerging data being presented at ESMO (Free ESMO Whitepaper) are encouraging, as treatment with rigosertib plus nivolumab led to both complete and partial responses in patients with KRAS-mutated lung cancers who failed prior ICI therapy," said Dr Rajwanth Veluswamy, the principal investigator of the study. "Objective responses showcased rigosertib’s KRAS mutation-agnostic mechanism of action, as each responding patient had a tumor with a different underlying variant. This differentiates rigosertib from agents targeting a single KRAS mutation variant, and positions it to potentially address the unmet needs of a much broader patient population. In addition, the ESMO (Free ESMO Whitepaper) data demonstrated activity in multiple patients with both low PD-L1 expression at diagnosis and STK11/LKB1 co-mutations, both poor predictive features for current lung cancer treatments."

Key data from the presentation include:

Demographics:

All enrolled patients failed at least one line of prior therapy with a PD-1 checkpoint inhibitor (includes evaluable and non-evaluable patients)
80% of enrolled patients failed at least two lines of prior therapy
Response results (as of August 15th, 2022-data cutoff date):

3 of 14 evaluable patients achieved an objective response
1 patient achieved a complete response (CR) as per RECIST Criteria, with complete resolution of the primary lung tumor as well as sites of metastatic disease.
2 patients achieved a partial response (PR)
Responses were achieved in patients with 3 distinct KRAS mutations (CR: KRAS G12V; PRs: KRAS G12C/STK11 and Q61H/STK11)
The mean duration of response is 6.75 months
4 of 14 evaluable patients achieved disease control (CR, PR, or stable disease)
Safety results:

The studied doublet has been generally well tolerated. Treatment-related adverse events (TRAE) have been mostly mild and manageable.
One dose limiting toxicity of grade 3 hyponatremia has been observed (previously documented with rigosertib)
Urinary toxicities well documented with rigosertib are the most common TRAE
No unexpected safety events or synergistic toxicities have been observed
Steven M. Fruchtman, M.D., President and Chief Executive Officer of Onconova, commented, "The evidence of efficacy observed in the trial’s highly challenging population suggests rigosertib may synergize with ICI and potentially provide clinical benefit to patients with limited therapeutic options. This hypothesis is supported both by these latest clinical data and the results of preclinical studies in multiple indications. Looking forward, we expect the maturation of the trial’s current results, as well as the new data we expect to collect by enrolling additional patients, to provide key insights that will inform the next steps for rigosertib’s current investigator-sponsored study program."

The ESMO (Free ESMO Whitepaper) poster (#1018P) is titled "Phase 1/2 Trial of Rigosertib and Nivolumab for KRAS Mutated Non-Small Cell Lung Cancer (NSCLC) Patients." It is currently available for viewing on the congress’s virtual platform and is being presented by the trial’s principal investigator, Rajwanth Veluswamy, M.D., Assistant Professor, Medicine, Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, today during Poster Session 14. The poster is available on the "Scientific Presentations" section of the Onconova website.

About the Investigator-sponsored Phase 1/2a Trial

This Phase 1/2a trial is designed to evaluate the combination of rigosertib and nivolumab in advanced KRAS+ metastatic NSCLC patients who have progressed on standard-of-care with anti-PD-1 monotherapy or anti-PD-1 in combination with chemotherapy. It includes a dose-escalating Phase 1 portion followed by a Phase 2a dose-expansion portion. Patients in the trial receive oral rigosertib twice daily on days 1-21, and intravenous nivolumab on days 1 and 15 of 28-day cycles. The primary endpoints of the trial are safety assessments to determine maximum tolerated dose, and overall response rate. Secondary endpoints include progression-free survival and overall survival. For more information on the trial, see ClinicalTrials.gov Identifier: NCT04263090.

Transgene Confirms the Potential of the Intravenous Route of its Invir.IO™ Oncolytic Viruses against Solid Tumors with TG6002 Phase I Data Presented at ESMO Congress 2022

On September 12, 2022 Transgene (Euronext Paris: TNG) (Paris:TNG), a biotech company that designs and develops virus-based immunotherapeutics against cancer, reported that positive confirmatory data from the Phase I trial evaluating TG6002 administered intravenously (IV) in combination with oral 5-FC in patients with advanced gastrointestinal carcinomas (Press release, Transgene, SEP 12, 2022, View Source [SID1234619442]).

TG6002 is based on Transgene’s double deleted VVcopTK-RR- patented virus backbone, which forms the basis of the company’s Invir.IO platform, and is generating a pipeline of multi-armed therapeutic OV drug candidates.

These updated data generated on 37 patients treated at the highest dose levels of the Phase I demonstrated that the therapy is well tolerated and confirmed the mechanism of action of TG6002 administered IV. They were presented on September 11, 2022, in a poster presentation at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) meeting taking place in Paris (France) from September 9-13, 2022.

The findings are as follows:

TG6002 demonstrated good tolerability when administered weekly or on days 1,3 and 5. No major toxicities limiting the dose escalation process or the intensification of the schedule of administration were observed. Transient fever is the most common adverse event.
TG6002 is able to reach the tumor, replicate, and express its payload after IV administration.
Onset of a neutralizing antibody response is not associated with a decreased biological activity of the product.
These data further confirm the mechanism of action of the Invir.IO-based oncolytic viruses in humans.
The two IV administration schedules display different characteristics, that can both be leveraged in upcoming clinical trials. Three doses given once a week resulted in higher levels of expression of the payload than the more intensive schedule (3 injections within 5 days). The intensive schedule allowed for a longer lasting expression of the payload.
These findings support the potential of IV administration of Invir.IO-based oncolytic viruses, extending the use of these therapies to a broad range of solid tumors.

The overall Phase I program with TG6002 was aimed at establishing the tolerability and the potential different doses and administration schedules for further development. Additional data will be produced from the Phase I program and will be presented at a scientific congress in H1 2023.

Title of the poster: "Updated data of biodistribution and activity of oncolytic virus TG6002 after intravenous administration in patients with advanced gastrointestinal carcinomas"
Authors: Victor Moreno, Philippe Cassier, Bernard Doger, Emiliano Calvo, Maria De Miguel, Rocio Garcia-Carbonero, Carlos Gomez-Roca, Christiane Jungels, Sophie Sainte-Croix, Philippe Erbs, Alain Sadoun and Kaïdre Bendjama
Abstract Number: #4886
Poster Number: 392P
The abstract and the e-poster are available on the ESMO (Free ESMO Whitepaper) congress website here and the e-poster can be downloaded on the Transgene website here as well.

About the trial (NCT03724071)
This trial is a single-arm open-label Phase I/II trial evaluating the safety and tolerability of multiple ascending doses of TG6002 administered intravenously in combination with oral 5-FC, a non-cytotoxic pro-drug that can be converted in 5-FU, its active metabolite. Based on the safety profile of TG6002, several dose levels and administration schedules have been added to the initial Phase I clinical protocol. The trial has safety as primary endpoint for the Phase I. The trial also evaluates pharmacokinetic properties and biodistribution of TG6002, along with immune modulation of the tumor micro-environment. This European study enrolled patients suffering from advanced gastrointestinal carcinomas who have failed and/or are intolerant to standard therapeutic options in the Phase I part.
Dr. Philippe Cassier, M.D., Ph.D., head of the early-phase trials unit at Centre Léon Bérard (Lyon, France), is the principal investigator of the trial.

About TG6002
TG6002 has been engineered to directly kill cancer cells (oncolysis), to enable the production of a chemotherapy agent (5-FU) within the tumor, and to elicit an immune response by the body against the tumor cells. Its satisfactory safety profile after intravenous administration and its mechanism of action has been shown in human in a Phase I trial.
In preclinical experiments, TG6002 has been shown to induce the shrinkage of the primary tumor as well as the regression of distant metastases (Foloppe, et al., Molecular Therapy Oncolytics, View Source).
The production of 5-FU directly in the tumor aims to achieve a better anti-tumoral effect with limited chemotherapy-induced side effects.
TG6002 induces the production of 5-FU in the cancer cells it has infected, by enabling the local conversion of the pro-drug 5-FC (administered orally) into 5-FU. 5-FU is a common chemotherapy agent for patients with gastrointestinal cancers. This mechanism of action is based on the in-tumor expression of the proprietary FCU1 gene that has been encoded in the genome of TG6002, taking advantage of the virus selective replication in the tumor cells.
When administered systemically, 5-FU is associated with side effects that can lead to treatment discontinuation. With TG6002, 5-FU is produced within the tumor where it is expected to be present at a high concentration level in contrast to the very low levels anticipated in the rest of the patient’s body.