On January 22, 2024 AIM ImmunoTech Inc. (NYSE American: AIM) ("AIM" or the "Company") reported that the first subject has been enrolled at Erasmus Medical Center ("Erasmus MC") in a Phase 1b/2 clinical trial combining AIM’s Ampligen (rintatolimod) with AstraZeneca’s anti-PD-L1 immune checkpoint inhibitor Imfinzi (durvalumab) for the treatment of late-stage pancreatic cancer (the "DURIPANC Study") (Press release, AIM ImmunoTech, JAN 22, 2024, View Source [SID1234639404]).

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Data strongly suggests Ampligen has therapeutic synergy when combined with checkpoint inhibitors – potentially increasing cancer treatment efficacy and subject survival rates. A successful DURIPANC Study could make AIM an especially attractive partnership or buyout target for Big Pharma. Data already strongly suggests that Ampligen synergistically enhances anti-PD-1 therapy. Strong positive clinical data from the DURIPANC study would also support our belief that Ampligen could synergistically enhance anti-PD-L1 therapies. Such broad-spectrum success could create value. AIM recently took an important step to secure potential stockholder value when it received a U.S. patent for the use of Ampligen as part of a combination therapy with an anti-PD-L1 antibody, which is an immune checkpoint inhibitor that helps the body attack tumor cells.

The DURIPANC Study is an investigator-initiated, exploratory, open-label, single-center study with the full name "Combining anti-PD-L1 immune checkpoint inhibitor durvalumab with TLR-3 agonist rintatolimod in patients with metastatic pancreatic ductal adenocarcinoma for therapy effect." The primary objective of the Phase 1b portion is to determine the safety of combination therapy with Imfinzi and Ampligen. The primary objective of the Phase 2 portion is to determine the clinical benefit rate of the combination therapy.

"We expect to complete the Phase 1b portion of the study within six months," states Prof. Casper H.J. van Eijck, MD, PhD, the DURIPANC Study’s Coordinating Investigator.

See ClinicalTrials.gov: NCT05927142 for more information.

AIM CEO Thomas K. Equels stated: "Ampligen’s potential as part of a combination therapy is a relatively simple equation. One, elevated PD-L1 expression – which is known to occur in pancreatic cancer – has been associated with increased exhaustion of peripheral and intra-tumoral cytotoxic T cells, commonly called ‘killer’ T cells. Two, data indicate that Ampligen has the potential to mitigate T cell exhaustion. Three, Ampligen can increase the number and activity of immune cells in the blood and tumor. And four, Imfinzi inhibits PD-L1 activity, thereby making those activated immune cells in the tumor microenvironment more effective at fighting the cancerous tumor. Data from our Dutch Early Access Program strongly supports Ampligen’s potential to increase progression-free survival and overall survival. Our hope for the DURIPANC trial is that at a minimum we see an even longer period of stable disease, also called progression-free survival. However, we also believe this combination of drugs has the potential to decrease tumor size or even to cure the cancer, which is defined as being tumor free for at least five years. That would be a dramatic breakthrough in the treatment of a highly lethal and treatment-resistant human cancer."

The study is expected to enroll up to 18 subjects in its Phase 1b portion and up to 25 subjects in its Phase 2 portion. Subjects will start with Ampligen 200 mg via IV infusion twice per week for a total of 6 weeks (12 doses). Ampligen dose will be escalated to 400 mg according to a 3+3 DLT design. The first dose of Ampligen will be administered preferably 4-6 weeks after the last chemotherapy FOLFIRINOX dose. After two doses of Ampligen, the first dose of durvalumab 1500 mg via IV infusion will be introduced in week 2. Patients will continue to receive 1500 mg durvalumab via IV infusion every 4 weeks for up to a maximum of 48 weeks (up to 12 doses/cycles) with the last administration on week 48 or until confirmed disease progression according to Response Evaluation Criteria in solid Tumors (RECIST 1.1), unless there is unacceptable toxicity, withdrawal of consent, or another discontinuation criterion is met.

On January 20, 2024 Radiopharm Theranostics Limited (ASX:RAD) (Radiopharm or the Company), a developer of diagnostic and therapeutic radiopharmaceutical products, reported it has entered into strategic agreements with Lantheus Holdings, Inc. (LNTH.NASDAQ), a leading radiopharmaceutical-focused company, and its affiliates (Lantheus). Lantheus has agreed to make an initial equity investment of A$7.5 million (US$4.99 million) and will have an option to invest a further A$7.5 million (US$5 million) within 6 months on the same terms. Additionally, Radiopharm has agreed to transfer two of its early preclinical assets to Lantheus for A$3.0 million (US$2.0 million) pursuant to a separate transfer and development agreement.

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The net proceeds of Lantheus’ investment will be used by the Company for drug manufacturing, clinical trials and general working capital.

Subject to shareholder approval for the purposes of ASX Listing Rule 7.1, under a subscription agreement entered into with Radiopharm (Subscription Agreement), Lantheus has subscribed for up to:

a) A$7.5 million (US$4.99 million) at A$0.05 (US$0.033) per share;
b) unlisted options with a six-month term after the date the subscription shares are issued to invest up to an additional A$7.5 million (US$5 million) at A$0.05 (US$0.033) per share; and
c) one option for every four shares subscribed for (inclusive of any shares further subscribed for in the next six months), exercisable at A$0.06 per option expiring in August 2026.

Under a separate transfer and development agreement, Radiopharm has assigned and sub-licensed two of its preclinical assets to Lantheus for A$3.0 million (US$2.0 million). Assets covered under the agreement are a TROP2 targeting nanobody and a LRRC15 targeting mAb.

B. Riley Securities is acting as financial advisor to the Company on the Lantheus transactions.

Further terms of Lantheus investment

Under the Subscription Agreement, and subject to shareholder approval at an upcoming extraordinary general meeting, Lantheus will be issued up to:

149,625,180 shares under the Placement amounting to a subscription amount of US$4.99 million (A$7.5 million) (Lantheus Shares), subject to 12 months escrow;
149,925,040 unlisted options with an exercise price of A$0.05 (5 cents) and an expiry date six months from the date of issue of the Lantheus Shares (Lantheus Options), with 12 months escrow applying to any shares issued on exercise of the options; and
37,406,295 options (i.e. one (1) new option for every four (4) new Lantheus Shares issued) with an exercise price of A$0.06 and an expiry date approximately 2 years from the date the Lantheus Shares are issued (Lantheus Placement Options),
subject to and upon exercise of the Lantheus Options, up to 37,481,260 additional options (on the basis of one (1) new option for every four (4) new Lantheus Shares issued upon exercise of the Lantheus Options) with an exercise price of A$0.06 and an expiry date approximately 2 years from the date the Lantheus Shares are issued (Second Tranche Lantheus Options),
(together, the Lantheus Interests).

Other key terms of the Subscription Agreement (noting undefined terms have the meanings ascribed to them in the Subscription Agreement) include:

Other key terms of the Lantheus Options, Lantheus Placement Options and Second Tranche Lantheus Options are:
Subject to compliance with the Australian Corporations Act, the options may be exercised during the exercise period and, within five Business Days of exercise, the Company will:
allot and issue the number of Shares as specified in the Exercise Notice and for which the Exercise Price has been received by the Company in cleared funds; and
apply for official quotation on the ASX of Shares issued pursuant to the exercise of the Subscription Option; and
Shares issued as a result of the exercise of an option will be fully paid and rank pari passu in all respects with all other Shares then on issue.
The Company provides standard warranties regarding its standing and the issue of the Lantheus Interests and the Company indemnifies Lantheus against any loss to Lantheus’ investment in the Company which Lantheus suffers or is liable for arising directly or indirectly from a warranty being untrue or inaccurate. Lantheus provides standard warranties regarding its standing.
Lantheus may terminate the agreement before completion if:
the Company is prevented from issuing or allotting the Lantheus Shares by the order of a court of competent jurisdiction or by a government agency;
The Australian Securities and Investment Commission or the Takeovers Panel commences, or threatens to commence, any inquiry, hearing investigation or regulatory action or issues any order or interim order or other proceedings in relation to the Company, the Lantheus Shares or the Lantheus Options;
the Company commits a material breach of the Subscription Agreement; or
any of the Company warranties cease to be true and accurate.
Lantheus may terminate the Subscription Agreement if Shareholder approval (in the form contemplated above) is not obtained within a three-month period.
As is customary with these types of arrangements, the agreement contains typical investor protections such as negative covenants and representations and warranties by the Company.
Other key terms of the transfer and development agreement include:

The Company and its subsidiary, Radiopharm Theranostics (USA), Inc., a Nevada corporation, together have agreed to transfer and assign to Lantheus each of their title, and interest in the TROP2 targeting nanobody and a LRRC15 targeting mAb assets, including all data and information regarding the compounds and technologies; and
As is customary with these types of arrangements, the agreement contains typical assignee protections such as risk allocation clauses and representations and warranties made by the Company and Radiopharm Theranostics (USA), Inc. in respect of each entity’s standing and its ownership of and rights in the assets being assigned and sold.

(Press release, Radiopharm Theranostics, JAN 20, 2024, View Source [SID1234661591])

On January 20, 2024 Bristol Myers Squibb (NYSE: BMY) reported results from the Phase 3 CheckMate -8HW trial evaluating Opdivo (nivolumab) plus Yervoy (ipilimumab) compared to investigator’s choice of chemotherapy (mFOLFOX-6 or FOLFIRI with or without bevacizumab or cetuximab) as a first-line treatment for patients with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer (mCRC) (Press release, Bristol-Myers Squibb, JAN 20, 2024, View Source;8HW-Trial/default.aspx [SID1234639399]). The dual immunotherapy combination of Opdivo and Yervoy demonstrated a statistically significant and clinically meaningful improvement in the primary endpoint of progression-free survival (PFS) as assessed by Blinded Independent Central Review (BICR), with a reduction in the risk of disease progression or death by 79% (Hazard Ratio [HR]: 0.21; 95% Confidence Interval [CI]: 0.14-0.32; p<0.0001) compared to chemotherapy in patients with centrally confirmed MSI-H/dMMR mCRC.

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These late-breaking data (Abstract #LBA768) will be featured in an oral presentation at the 2024 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Gastrointestinal Cancers Symposium on Saturday, January 20 at 9:15 a.m. Pacific Time and will be highlighted as part of the Congress’ official press program.

Improvement in PFS was noted beginning at approximately three months and was sustained throughout. Median PFS was not yet reached in the Opdivo plus Yervoy arm (95% CI: 38.4-NE) vs. 5.9 months in the chemotherapy arm (95% CI: 4.4-7.8). Consistent PFS benefit was observed across all pre-specified subgroups, including patients with KRAS or NRAS mutations, and those with baseline liver, lung, or peritoneal metastases.

The safety profile for the combination of Opdivo plus Yervoy remained consistent with previously reported data and was manageable with established protocols, with no new safety signals identified. Grade 3/4 treatment-related adverse events (TRAEs) occurred in 23% of patients in the Opdivo plus Yervoy arm and 48% of patients in the chemotherapy arm. Any grade TRAE-related discontinuation was 17% in the Opdivo plus Yervoy arm and 32% in the chemotherapy arm.

"Patients with MSI-H/dMMR metastatic colorectal cancer are less likely to benefit from chemotherapy," said Thierry Andre, M.D., Head of the Medical Oncology Department, Sorbonne University and Hospital Saint-Antoine, Paris, France. "An impressive improvement in PFS and sustained benefit beginning at three months was observed with nivolumab plus ipilimumab versus chemotherapy in this trial. These results demonstrate the meaningful efficacy of this combination with practice-changing potential for this patient population."

Opdivo plus Yervoy is the first dual immunotherapy regimen to demonstrate significant efficacy benefit compared to chemotherapy as first line treatment in MSI-H/dMMR mCRC.

"With research from the full CheckMate clinical development program, BMS has revolutionized the oncology landscape and helped change survival expectations for people with cancer. Today, with these data from CheckMate -8HW, we showed that Opdivo plus Yervoy reduced the risk of disease progression or death by an unprecedented 79%," said Dana Walker, M.D., M.S.C.E., vice president, global program lead, gastrointestinal and genitourinary cancers, Bristol Myers Squibb. "These results build on the benefit of Opdivo and Yervoy in MSI-H/dMMR metastatic colorectal cancer as previously demonstrated in CheckMate -142 and reinforce our commitment to exploring the potential of these therapies to help more patients in need."

CheckMate -8HW is ongoing to assess the second dual primary endpoint of PFS in patients receiving Opdivo plus Yervoy compared to Opdivo alone across all lines of therapy, as well as secondary endpoints, including overall survival (OS).

Bristol Myers Squibb thanks the patients and investigators involved in the CheckMate -8HW clinical trial.

About CheckMate -8HW

CheckMate -8HW (NCT04008030) is a Phase 3 randomized, open-label trial evaluating Opdivo plus Yervoy compared to Opdivo alone or investigator’s choice chemotherapy (mFOLFOX-6 or FOLFIRI with or without bevacizumab or cetuximab) in patients with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer (mCRC).

Approximately 830 patients were randomized to receive either Opdivo monotherapy (Opdivo 240 mg Q2W for six doses, followed by Opdivo 480 mg Q4W), Opdivo plus Yervoy (Opdivo 240 mg plus Yervoy 1 mg/kg Q3W for four doses, followed by Opdivo 480 mg Q4W), or investigator’s choice of chemotherapy. The dual primary endpoints of the trial are progression-free survival (PFS) per blinded independent central review (BICR) for Opdivo plus Yervoy compared to investigator’s choice of chemotherapy in the first line setting and PFS per BICR for Opdivo plus Yervoy compared to Opdivo alone across all lines of therapy. The trial also includes several secondary safety and efficacy endpoints, including overall survival (OS).

The study is ongoing to assess the second dual primary endpoint of PFS in patients receiving Opdivo plus Yervoy compared to Opdivo alone across all lines of therapy, as well as secondary endpoints.

About MSI-H or dMMR Colorectal Cancer

Colorectal cancer (CRC) is a cancer that develops in the colon or the rectum, which are part of the body’s digestive or gastrointestinal system. CRC is the third most commonly diagnosed cancer in the world. In 2020, it is estimated that there were approximately 1,931,000 new cases of the disease; it is the second leading cause of cancer-related deaths among men and women combined.

Mismatch repair deficiency (dMMR) occurs when the proteins that repair mismatch errors in DNA replication are missing or non-functional, leading to microsatellite instability-high (MSI-H) tumors. Approximately 5-7% of metastatic CRC patients have dMMR or MSI-H tumors; they are less likely to benefit from conventional chemotherapy and typically have a poor prognosis.

On January 19, 2024 Adaptam Therapeutics reported ERC Proof of Concept projects funded by the European Research Council (ERC) are designed for researchers who currently hold ERC projects and wish to explore the commercial potential of their research (Press release, Adaptam Therapeutics, JAN 19, 2024, View Source [SID1234657090]). These projects are focused on establishing proof of concept for an idea generated during ERC-funded projects. The €150,000 grant is primarily aimed at activities directed to exploring the commercial or societal potential of the research.

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Specifically, the "TAM-ADaCT" project presented by Adaptam Therapeutics and now supported by the ERC Proof of Concept program aims to study the efficacy of novel antibody-drug conjugates (ADCs) directed against suppressor cells in the tumor microenvironment. This recently awarded ERC Proof of Concept grant builds upon a previous ERC Starting grant secured by Prof. Asis Palazon while at CIC bioGUNE.

Various immunotherapy strategies have shown promise in clinical trials, especially the use of inhibitors targeting so-called immune "checkpoint" receptors. However, current immunotherapies are effective in only a small fraction of patients, presenting a medical need that must be addressed across multiple cancer types. Notably, the tumor microenvironment has specific characteristics that affect the immune response, including reduced oxygenation, aberrant vascularization, and altered nutrient availability. All these factors influence the success of immunotherapies.

Prof. Palazon commented: "We are thrilled to receive this ERC Proof of Concept grant, which represents a pivotal step in advancing our innovative approach to targeting tumor-associated macrophages. By focusing on the immunosuppressive myeloid environment within tumors, we aim to develop a novel antibody-drug conjugate that could significantly enhance the efficacy of cancer treatments. Our goal is to offer more effective therapeutic options for patients who currently do not benefit from existing immunotherapies."

On January 19, 2024 CARsgen Therapeutics Holdings Limited (Stock Code: 2171.HK), a company focused on innovative CAR T-cell therapies for the treatment of hematologic malignancies and solid tumors, reported that at the 2024 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Gastrointestinal Cancers Symposium ("ASCO GI"), the Company presented a poster with study results for satricabtagene autoleucel ("satri-cel", R&D code: CT041, an autologous CAR-T product candidate against Claudin18.2), which include the dose escalation results of the Phase 1b ELIMYN18.2 study (Cohort A) in gastric/gastroesophageal (GC/GEJ) or pancreatic cancer (PC) in the US (Press release, Carsgen Therapeutics, JAN 19, 2024, View Source [SID1234639373]).

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"The treatment options for advanced GC/GEJ or PC patients are limited. The data we presented at the 2024 ASCO (Free ASCO Whitepaper) GI of the Phase 1b ELIMYN18.2 study demonstrated encouraging safety and efficacy profile of satri-cel (CT041), a first-in-class CAR T-cell against Claudin18.2. We will continue to drive the global clinical development of satri-cel and look forward to sharing more data updates on satri-cel in the future." Raffaele Baffa, MD, PhD, Chief Medical Officer of CARsgen Therapeutics, remarked.

Poster #356: CLDN18.2 Chimeric Antigen Receptor T Cell Therapy for Patients with Advanced Gastric and Pancreatic Adenocarcinoma: Results of ELIMYN18.2 Phase 1b Clinical Trial

The single-arm, open-label, Phase 1b/2 study (NCT04404595) evaluated the safety and efficacy of satri-cel in patients with Claudin18.2-positive histologically confirmed advanced GC/GEJ or PC who had progressed or were intolerant of at least 2 prior lines (GC/GEJ) or 1 prior line (PC) of systemic therapy. The Phase 1b study consisted of a modified 3+3 dose escalation/de-escalation with 5 dose levels (DLs) to be tested. Patients received a preconditioning regimen of fludarabine, cyclophosphamide, and nab-paclitaxel, followed by 1-3 cycles of satri-cel.

Herein, the Company presented the updated results of safety and determination of the Recommended Phase 2 Dose (RP2D). DL3 (600×106 cells) was selected as RP2D and enrollment in Phase 2 is currently ongoing. Adverse Events (AEs) were graded per CTCAE Version 5.0 and CRS and ICANS were graded by ASTCT 2019 consensus criteria. Objective Response Rate (ORR) and Clinical Benefit Rate (CBR) were assessed per RECIST 1.1, and tumor response (CR or PR) was confirmed by an imaging scan after the initial response assessment. CBR is defined as the incidence of a best overall response of CR, PR, or SD≥180 days.

As of September 15, 2023, the median follow-up duration was 8.9 months (range:1.5-18.7 months). 19 patients were treated (7 GC/GEJ, 12 PC) across 3 DLs ranging from 250-600×106 cells: DL1: 250-300×106 (n=6), DL2: 375-400×106 (n=6), DL3: 600×106 (n=7). All patients received prior systemic therapy, among which 6 GC/GEJ (85.7%) and 7 PC (58.3%) patients received ≥ 3 lines of prior systemic treatment. Median number of prior systemic treatment lines of patients with GC/GEJ or PC were 4 (2,10) and 3 (1,5) respectively. Median number of metastatic organs of all patients was 2.0. All patients received at least one infusion and median number of infusions for all patients was 2.0 (1,3).

Safety

Overall, the safety profile of satri-cel was encouraging. No hemophagocytic lymphohistiocytosis (HLH), dose-limiting toxicities (DLTs), or treatment-related deaths were reported. The vast majority of CRS was Grade 1 with three Grade 2 events and two Grade 3 events. Apart from 1 patient who experienced Grade 1 immune effector cell-associated neurotoxicity syndrome (ICANS), no other ICANS events of any grade were observed. All events resolved.

Efficacy

As of September 15, 2023, the median follow-up duration was 8.9 months (range:1.5 to 18.7 months). 1 patient with GC/GEJ in DL3 achieved a CR. The confirmed ORR in patients with GC/GEJ in all DLs was 42.9% (3/7). CBR in patients with GC/GEJ or PC in DL3 was 71.4% (5/7) and in patients with GC/GEJ in all DLs was 57.1% (4/7). The median progression-free survival (mPFS) and median duration of response (mDOR) was 5.7 months and 6.9 months respectively in patients with GC/GEJ in all DLs. In DL3, median overall survival (mOS) in patients with GC/GEJ or PC was 12.9 months. The mOS in patients with GC/GEJ or PC in all DLs was 8.9 months.

Conclusion

The safety profile of satri-cel, the first autologous Claudin18.2 CAR T cell therapy, was encouraging. Initial efficacy was promising in heavily pre-treated Claudin18.2-positive advanced GC/GEJ and PC population and consistent with earlier reports.

About Satri-cel

Satri-cel (CT041) is an autologous CAR T-cell product candidate against the protein Claudin18.2 that has the potential to be the first-in-class globally. Satri-cel targets the treatment of Claudin18.2 positive solid tumors with a primary focus on gastric cancer/gastroesophageal junction cancer (GC/GEJ) and pancreatic cancer (PC). Trials in CARsgen include investigator-initiated trials (NCT03874897), a Phase Ib clinical trial for advanced GC/GEJ and PC and a confirmatory Phase II clinical trial for advanced GC/GEJ in China (CT041-ST-01, NCT04581473), a Phase I clinical trial for PC adjuvant therapy in China (CT041-ST-05, NCT05911217), and a Phase 1b/2 clinical trial for advanced gastric or pancreatic adenocarcinoma in North America (CT041-ST-02, NCT04404595). Satri-cel was granted Regenerative Medicine Advanced Therapy (RMAT) Designation by U.S. FDA for the treatment of advanced GC/GEJ with Claudin18.2-positive tumors in January 2022 and was granted PRIME eligibility by the EMA for the treatment of advanced gastric cancer in November 2021. Satri-cel received Orphan Drug designation from the U.S. FDA in 2020 for the treatment of GC/GEJ and Orphan Medicinal Product designation from the EMA in 2021 for the treatment of advanced gastric cancer.