P2, N=24, Not yet recruiting, Boehringer Ingelheim

P2, N=53, Completed, EpicentRx, Inc. | Phase classification: P2a --> P2

P3, N=292, Active, not recruiting, EpicentRx, Inc. | Recruiting --> Active, not recruiting

P1, N=206, Terminated, Celgene | Active, not recruiting --> Terminated; Business objectives have changed.

P1, N=56, Completed, Bristol-Myers Squibb | Active, not recruiting --> Completed | N=218 --> 56 | Trial completion date: Jun 2026 --> Jul 2024 | Trial primary completion date: Jun 2026 --> Jul 2024

P1, N=20, Not yet recruiting, Chia Tai Tianqing Pharmaceutical Group Nanjing Shunxin Pharmaceutical Co., Ltd.

P1, N=13, Recruiting, Boehringer Ingelheim | Trial completion date: May 2025 --> Aug 2025 | Trial primary completion date: Mar 2025 --> Jun 2025

P1, N=3, Terminated, Chia Tai Tianqing Pharmaceutical Group Co., Ltd. | N=114 --> 3 | Trial completion date: Mar 2028 --> Jul 2024 | Recruiting --> Terminated | Trial primary completion date: Jun 2026 --> Jul 2024; Based on the current status of the same target research and the company's overall layout in the field of tumors, the early termination was determined after full communication with the principal investigator of the group leader unit.

P1, N=2, Terminated, EpicentRx, Inc. | N=24 --> 2 | Trial completion date: Dec 2024 --> Jul 2024 | Active, not recruiting --> Terminated | Trial primary completion date: Dec 2024 --> Jul 2024; Low Enrollment

P1, N=36, Active, not recruiting, Boehringer Ingelheim | Recruiting --> Active, not recruiting

P1, N=48, Active, not recruiting, Boehringer Ingelheim | Trial primary completion date: Nov 2024 --> Jul 2024

To overcome these issues, in this study, we have developed a multifunctional Immunosome where αCD40 is conjugated on the surface and RRX-001, a small molecule immunomodulator was encapsulated inside it...In addition, Immunosomes treated long-term surviving mice showed tumor specific immune memory response which prevented tumor growth upon rechallenge. Our results suggested that this novel formulation can be further explored in clinics to improve in vivo anti-tumor efficacy of αCD40 with long-lasting tumor specific immunity while reducing the associated toxicities.

Our pre-basic found excellent anti-tumor effects of c-di-AMP and RRx-001, respectively, and we further explored whether they could be combined synergistically for anti-tumor immunotherapy...Moreover, the combination of the two presented more powerful pro-vascular normalization and reversed tumor immunosuppression than the drug alone. This study demonstrates a new design option for anti-tumor combination therapy and the potential of tumor environmentally responsive hydrogel scaffolds in combination with anti-tumor immunotherapy.

To this end, DS-1103a, a newly developed anti-human SIRPα antibody (Ab), was assessed for the potential combination benefit with datopotamab deruxtecan (Dato-DXd) and trastuzumab deruxtecan (T-DXd), DXd-ADCs targeting human trophoblast cell-surface antigen 2 and human epidermal growth factor receptor 2, respectively. Furthermore, in syngeneic mouse models, both Dato-DXd and T-DXd combination with anti-mSIRPα Ab showed stronger anti-tumor activity over the monotherapies. Taken together, this study provides a preclinical rationale of novel therapies for solid tumors combining SIRPα-CD47 blockers with DXd-ADCs.

P1, N=43, Recruiting, Chia Tai Tianqing Pharmaceutical Group Nanjing Shunxin Pharmaceutical Co., Ltd.

P1, N=13, Recruiting, Boehringer Ingelheim | Trial completion date: Oct 2024 --> Mar 2025 | Trial primary completion date: Jul 2024 --> Jan 2025

P1, N=114, Recruiting, Chia Tai Tianqing Pharmaceutical Group Co., Ltd. | Not yet recruiting --> Recruiting

P1, N=48, Active, not recruiting, Boehringer Ingelheim | Recruiting --> Active, not recruiting | Trial primary completion date: Apr 2025 --> Nov 2024

P1, N=42, Recruiting, Boehringer Ingelheim | Trial completion date: Nov 2025 --> Jan 2025 | Trial primary completion date: Mar 2025 --> Jul 2024

P1, N=45, Recruiting, Boehringer Ingelheim | Active, not recruiting --> Recruiting | Trial primary completion date: Aug 2024 --> Apr 2025

P2, N=216, Recruiting, EpicentRx, Inc. | Not yet recruiting --> Recruiting

P1, N=218, Active, not recruiting, Bristol-Myers Squibb | Recruiting --> Active, not recruiting

P3, N=292, Recruiting, EpicentRx, Inc. | Active, not recruiting --> Recruiting

P1, N=47, Active, not recruiting, Boehringer Ingelheim | Recruiting --> Active, not recruiting

P3, N=18, Terminated, EpicentRx, Inc. | Trial completion date: Aug 2022 --> Mar 2024

P1, N=24, Active, not recruiting, EpicentRx, Inc. | Trial completion date: Mar 2024 --> Dec 2024 | Trial primary completion date: Dec 2023 --> Dec 2024

The use of RRx-001 with the function of downregulating the expression of innate immune checkpoint molecule CD47 provides a powerful means for treating advanced HCC containing a substantial proportion of immunosuppressive macrophages...Combined with the ROS generation and an upregulated "eat me" signal level of DOX, BEA-D@R collectively increased RNS generation, enhanced T cell infiltration, and maximized macrophage phagocytosis, leading to an average of 40% tumor elimination in a mice model bearing an initial tumor of approximately 300 mm3 that mimics advanced HCC. Overall, this study uncovered the "all-in-one" immunotherapeutic functionalities of a clinical translatable nanoplatform for enhanced immunotherapy of advanced HCC.

P1, N=114, Not yet recruiting, Chia Tai Tianqing Pharmaceutical Group Co., Ltd.

P2, N=216, Not yet recruiting, EpicentRx, Inc. | Initiation date: Dec 2023 --> Apr 2024

In vitro, BMS-986351 increased phagocytic activity against cell lines from solid tumors and hematological malignancies, and this effect was markedly enhanced when BMS-986351 was combined with the opsonizing antibodies cetuximab and rituximab. A phase I dose escalation/ expansion study of BMS-986351 for the treatment of advanced solid and hematologic malignancies is underway (NCT03783403).

P1/2, N=145, Suspended, LaNova Medicines Limited

P1, N=2, Terminated, Boehringer Ingelheim | Completed --> Terminated; Company decision

P1, N=230, Active, not recruiting, Celgene | Trial completion date: Aug 2025 --> Aug 2024

P1, N=45, Recruiting, Boehringer Ingelheim | N=150 --> 45

P1, N=2, Completed, Boehringer Ingelheim | Active, not recruiting --> Completed

P1/2, N=145, Suspended, LaNova Medicines Limited | Recruiting --> Suspended

Simultaneously, RRX-001 reduces CD47 protein levels, aiding in preventing immune escape by calreticulin-rich cancer cells. In lung tumor models in male mice, this combined approach shows anti-tumor effects and immunity against tumor re-exposure, highlighting its potential for lung cancer immunotherapy.

P1, N=12, Recruiting, Boehringer Ingelheim | N=22 --> 12 | Trial completion date: Jul 2024 --> Dec 2024 | Trial primary completion date: Nov 2023 --> Apr 2024

PREVLAR was a Phase 2 study that randomized 53 head and neck cancer patients 1:1 to receive four doses of RRx-001 prior to the start of intensity modulated radiation therapy (IMRT) in 2.0-2.2 Gy fractions/weekday to a cumulative radiation dose of up to 72 Gy plus cisplatin administered either weekly (40 mg/m2) or tri-weekly (100 mg/m2) vs. cisplatin plus IMRT alone (control). The RRx-001 “four before and no more” pre-treatment dosing regimen is not only convenient for patients and their caregivers but also reduces several toxicities including, most likely, financial toxicity. This is likely to bolster its adoption once RRx-001 becomes part of the medical armamentarium for the treatment of SOM. We plan more rigorously to test the effect of RRx-001 on financial toxicity in an upcoming Phase 2b trial in head and neck cancer called KEVLARx, n = 216.

In this small proof of concept trial, RRx-001 infusion resulted in a reduction of multiple, biologically-related, side effects associated with a standard chemoradiation regimen used to the treatment of head and neck cancers. KEVLAR, a larger Phase 2b trial is planned to begin enrollment in Q4 of 2023 at about thirty sites in North America.

For added color and context, the review includes real-world examples with RRx-001, a new molecular entity (NME) in Phase 3 and with fast-track status in head and neck cancer, and AdAPT-001, an oncolytic adenovirus armed with a transforming growth factor-beta (TGF-β) trap in a Phase 1/2 clinical trial with which the authors, as employees of the biopharmaceutical company, EpicentRx, are closely involved. An alphabetized glossary of key terms and acronyms used throughout this manuscript is also included for easy reference (See Table 1).

Conclusions BI 770371 showed manageable toxicity alone and in combination with ezabenlimab. The trial is ongoing.