darleukin (L19IL2) / Philogen - LARVOL DELTA

IMMUNOSABR2: IMMUNOtherapy and Stereotactic ABlative Radiotherapy (IMMUNOSABR) a Phase II Study (clinicaltrials.gov) - P2 | N=88 | Terminated | Sponsor: Maastricht University Medical Center | Active, not recruiting ➔ Terminated; This trial is not transitioning to the Clinical Trial Regulation (CTR) EU No 536/2014.

Trial termination • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • IL2

Theratri: A Study to Evaluate the Safety and Preliminary Signs of Efficacy of [177Lu]Lu-OncoFAP-23 Alone or in Combination with L19-IL2 As a Treatment of Metastatic FAP-positive Solid Tumors (clinicaltrials.gov) - P1 | N=56 | Not yet recruiting | Sponsor: Philogen S.p.A. | Initiation date: Dec 2024 ➔ May 2025

Trial initiation date • Oncology • Solid Tumor

Theratri: A Study to Evaluate the Safety and Preliminary Signs of Efficacy of [177Lu]Lu-OncoFAP-23 Alone or in Combination with L19-IL2 As a Treatment of Metastatic FAP-positive Solid Tumors (clinicaltrials.gov) - P1 | N=56 | Not yet recruiting | Sponsor: Philogen S.p.A.

Combination therapy • Metastases • New P1 trial • Oncology • Solid Tumor

Antibodies to watch in 2024. (PubMed, MAbs) - "In this installment, we discuss key details for 16 antibody therapeutics granted a first approval in 2023, as of November 17 (lecanemab (Leqembi), rozanolixizumab (RYSTIGGO), pozelimab (VEOPOZ), mirikizumab (Omvoh), talquetamab (Talvey), elranatamab (Elrexfio), epcoritamab (EPKINLY), glofitamab (COLUMVI), retifanlimab (Zynyz), concizumab (Alhemo), lebrikizumab (EBGLYSS), tafolecimab (SINTBILO), narlumosbart (Jinlitai), zuberitamab (Enrexib), adebrelimab (Arelili), and divozilimab (Ivlizi))...These nearly 50 product candidates include numerous innovative bispecific antibodies, such as odronextamab, ivonescimab, linvoseltamab, zenocutuzumab, and erfonrilimab, and antibody-drug conjugates, such as trastuzumab botidotin, patritumab deruxtecan, datopotamab deruxtecan, and MRG002, as well as a mixture of two immunocytokines (bifikafusp alfa and onfekafusp alfa)...Our analyses indicate that these molecules have approval success rates in the range of 14-32%, with higher rates..."

Journal • Infectious Disease • Novel Coronavirus Disease • Oncology • Respiratory Diseases

Intralesional administration of L19IL2/L19TNF in high-risk locally advanced basal cell carcinoma or cutaneous squamous cell carcinoma. (ASCO 2024) - P2 | "Here, we investigate a combination of two immunocytokines (Bifikafusp alfa (L19IL2) and Onfekafusp alfa (L19TNF)) targeting the extradomain B of fibronectin (EDB) for the treatment of high-risk locally advanced BCC and cSCC. The first part of the trial has been completed with 28 laBCC pts and 12 lacSCC pts evaluable for safety and efficacy. The pre-specified activity goal for the first stage of accrual was met, and the second stage of accrual began in September 2023, with a total of 39 BCC and 18 cSCC pts enrolled so far."

Metastases • Basal Cell Carcinoma • Non-melanoma Skin Cancer • Oncology • Squamous Cell Carcinoma • Squamous Cell Skin Cancer • EDB-FN

IMMUNOSABR2: IMMUNOtherapy and Stereotactic ABlative Radiotherapy (IMMUNOSABR) a Phase II Study (clinicaltrials.gov) - P2 | N=88 | Active, not recruiting | Sponsor: Maastricht University Medical Center | Recruiting ➔ Active, not recruiting | N=126 ➔ 88

Enrollment change • Enrollment closed • Metastases • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • IL2

IMMUNOSABR2: IMMUNOtherapy and Stereotactic ABlative Radiotherapy (IMMUNOSABR) a Phase II Study (clinicaltrials.gov) - P2 | N=126 | Recruiting | Sponsor: Maastricht University Medical Center | Trial completion date: Dec 2023 ➔ Dec 2024 | Trial primary completion date: Dec 2022 ➔ Dec 2024

Metastases • Trial completion date • Trial primary completion date • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • IL2

Neoadjuvant L19IL2/L19TNF- Pivotal Study (clinicaltrials.gov) - P3 | N=214 | Recruiting | Sponsor: Philogen S.p.A. | Trial primary completion date: Dec 2023 ➔ Oct 2024

Surgery • Trial primary completion date • Melanoma • Oncology • Solid Tumor • BRAF

Intralesional administration of L19IL2/L19TNF in difficult-to-treat non-melanoma skin cancer shows a favorable safety profile and preliminary clinical activity (ESMO 2023) - P2 | "Here we investigate a combination of 2 immune cytokines (Bifikafusp alfa (L19IL2) and Onfekafusp alfa (L19TNF) targeting the extra domain B of fibronectin (EDB) for selective delivery of immunostimulatory payloads to the tumor site. In the 3 SCC pts, ORR was 33.3 % with 1 pCR. Conclusions The tolerable safety profile of L19IL2/L19TNF and the results obtained in pts with NMSC justify further exploring the potential of intralesional administration of immunostimulatory drugs in this setting."

Clinical • Basal Cell Carcinoma • Non-melanoma Skin Cancer • Oncology • Skin Cancer • Solid Tumor • Squamous Cell Carcinoma • EDB-FN

A Phase I/II Study of the Tumor-targeting Human L19-IL2 Monoclonal Antibody-cytokine Fusion Protein in Combination With Rituximab in Relapsed or Refractory Diffuse Large B-cell Lymphoma (DLBCL) (clinicaltrials.gov) - P1/2 | N=6 | Terminated | Sponsor: Philogen S.p.A. | Trial completion date: Dec 2022 ➔ Sep 2023 | Active, not recruiting ➔ Terminated | Trial primary completion date: Dec 2022 ➔ Sep 2023; Slow progression due to difficulties in finding eligible patients. Competitive clinical trials with innovative agents and new approved products leaddefinitive stop.

Combination therapy • Trial completion date • Trial primary completion date • Trial termination • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • CD20 • IL2

Intralesional administration of L19IL2/L19TNF in difficult-to-treat BCC patients shows favorable safety profile and leads to complete remission of tumor lesions (EADO 2023) - "Here, we investigated a combination of two antibody-cytokine fusion proteins Bifikafusp alfa and Onfekafusp alfa further referred as L19IL2 and L19TNF targeting the extradomain B of fibronectin (EDB) for the selective delivery of immunostimulatory payloads to the tumor site. Intralesional L19IL2/L19TNF administration demonstrates good safety profile and clinical efficacy in difficult to-treat BCC. Further investigation of intralesional L19IL2/L19TNF in BCC as well as in other NMSC indications is needed."

Clinical • Basal Cell Carcinoma • Non-melanoma Skin Cancer • Oncology • Skin Cancer • Solid Tumor • Squamous Cell Carcinoma

Philogen Announces Clinical Trial Collaboration with MSD (GlobeNewswire) - "Philogen...announces that it has entered into a Clinical Trial Collaboration and Supply Agreement with MSD (Merck & Co., Inc., Rahway, NJ, USA). Under the terms of the supply agreement, MSD provides their anti-PD-1 therapy, KEYTRUDA® (pembrolizumab), to be evaluated in combination with Philogen's immunocytokines L19IL2, L19TNF, and Nidlegy™ in a randomized Phase II clinical trial. The study provides an opportunity to explore the combination of immunocytokines and PD-1 blockade in stage III and IV unresectable melanoma patients who failed prior checkpoint inhibitor therapies."

Licensing / partnership • Basal Cell Carcinoma • Cutaneous T-cell Lymphoma • Kaposi Sarcoma • Melanoma • Merkel Cell Carcinoma • Oncology • Skin Cancer • Solid Tumor • Squamous Cell Skin Cancer

IntriNSiC: L19IL2/L19TNF in Skin Cancer Patients (clinicaltrials.gov) - P2 | N=70 | Recruiting | Sponsor: Philogen S.p.A. | Not yet recruiting ➔ Recruiting | Initiation date: Jul 2022 ➔ Mar 2023

Enrollment open • Pan tumor • Trial initiation date • Basal Cell Carcinoma • Cutaneous T-cell Lymphoma • Genetic Disorders • Hematological Malignancies • Kaposi Sarcoma • Lymphoma • Merkel Cell Carcinoma • Neuroendocrine Tumor • Non-Hodgkin’s Lymphoma • Non-melanoma Skin Cancer • Oncology • Sarcoma • Skin Cancer • Solid Tumor • Squamous Cell Carcinoma • T Cell Non-Hodgkin Lymphoma

A Phase I/II Study of the Tumor-targeting Human L19-IL2 Monoclonal Antibody-cytokine Fusion Protein in Combination With Rituximab in Relapsed or Refractory Diffuse Large B-cell Lymphoma (DLBCL) (clinicaltrials.gov) - P1/2 | N=6 | Active, not recruiting | Sponsor: Philogen S.p.A. | Recruiting ➔ Active, not recruiting | N=38 ➔ 6 | Trial completion date: Dec 2019 ➔ Dec 2022 | Trial primary completion date: Dec 2019 ➔ Dec 2022

Enrollment change • Enrollment closed • Trial completion date • Trial primary completion date • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • CD20 • IL2

A Phase I/II Dose Escalation Study of the Tumor-targeting Human L19-IL2 Monoclonal Antibody-cytokine Fusion Protein in Combination With Dacarbazine for Patients With Metastatic Melanoma (clinicaltrials.gov) - P1/2 | N=96 | Active, not recruiting | Sponsor: Philogen S.p.A. | Trial completion date: Jun 2017 ➔ Jun 2022

Combination therapy • Trial completion date • Melanoma • Oncology • Solid Tumor • IL2

Efficacy of Neoadjuvant Intratumoral Darleukin/Fibromun (L19IL2 + L19TNF) in Patients with Clinical Stage IIIB/C Melanoma (Neo-DREAM). (PubMed, Ann Surg Oncol) - No abstract available

Journal • Melanoma • Oncology • Solid Tumor

[VIRTUAL] Targeting glioblastoma with novel immunocytokines. (ASCO 2020) - P1/2 | " Intravenous administration of L19-mIL12 or L19-mTNF prolonged survival and cured a proportion of tumor-bearing mice while no effect was seen with L19-IL2... The data obtained with the comprehensive preclinical characterization and subsequent clinical translation form the basis for future studies with immunocytokines as novel treatment option for patients with malignant brain tumors. Research Funding: Philogen, Swiss National Sience Foundation"

IO Biomarker • Brain Cancer • Glioblastoma • Oncology • Solid Tumor • CD8 • IL12A • IL2

Kinetically-controlled release of blocking molecules for the targeted enhancement of therapeutic activity in antibody-cytokine fusion proteins (AACR 2018) - "...In this poster we describe the experimental implementation of CORK Technology to improve the therapeutic index of the clinical stage L19-IL2 (L19 is an antibody fragment specific to the alternatively-spliced EDB domain of fibronectin, a marker of tumor angiogenesis)...The technology is applicable to other cytokine payloads and facilitates the development of targeted cytokine products with activity on demand (i.e., with increased activity at the tumor site, promoting an activation and proliferation of tumor-resident lymphocytes). Albeit still in its infancy, this elegant approach provides promising results and a strong rationale to further investigate this therapeutic power of the CORK Technology."

Oncology

Head-to-head comparison of ADC and SMDC products, alone and in combination with antibody-IL2 fusion proteins (AACR 2018) - "...Instead, when the SMDC was administered together with L19-IL2 (a clinical-stage fusion protein capable of delivering interleukin-2 to the tumor neo-vasculature), all treated mice in the combination group could be rendered tumor-free, in a process which favored the influx of natural killer cells into the tumor mass...These findings may be of clinical significance, since carbonic anhydrase IX is over-expressed in the majority of clear-cell renal cell carcinomas and in approximately 30% of colorectal cancers. The targeted delivery of interleukin-2 helps potentiate the action of targeted cytotoxics leading to cancer eradication in models that cannot be cured by conventional chemotherapy."

Combination therapy • Head-to-Head • Colorectal Cancer • Renal Cell Carcinoma

DUNCAN: Intratumoral Administration of Daromun in Non-melanoma Skin Cancer Patients (clinicaltrials.gov) - P2; N=40; Recruiting; Sponsor: Philogen S.p.A.; Not yet recruiting ➔ Recruiting

Clinical • Enrollment open • Basal Cell Carcinoma • Genetic Disorders • Oncology • Solid Tumor

Immunocytokines are a promising immunotherapeutic approach against glioblastoma. (PubMed, Sci Transl Med) - P1/2 | "Furthermore, intravenous administration of L19-mIL12 or L19-mTNF cured a proportion of tumor-bearing mice, whereas L19-IL2 did not. Systemic administration of the fully human L19-TNF fusion protein to patients with glioblastoma (NCT03779230) was safe, decreased regional blood perfusion within the tumor, and was associated with increasing tumor necrosis and an increase in tumor-infiltrating CD4 and CD8 T cells. The extensive preclinical characterization and subsequent clinical translation provide a robust basis for future studies with immunocytokines to treat malignant brain tumors."

Journal • Glioblastoma • Glioma • Solid Tumor • CD8 • FN1 • IL12A • IL2 • TNFA

Neo-DREAM: Efficacy of Daromun Neoadjuvant Intratumoral Treatment in Clinical Stage IIIB/C Melanoma Patients (clinicaltrials.gov) - P3; N=186; Recruiting; Sponsor: Philogen S.p.A.; Trial completion date: Dec 2022 ➔ Dec 2024; Trial primary completion date: Jun 2020 ➔ Jun 2023

Clinical • Trial completion date • Trial primary completion date • Melanoma • Oncology • Solid Tumor

Stereotactic ablative body radiotherapy (SABR) combined with immunotherapy (L19-IL2) versus standard of care in stage IV NSCLC patients, ImmunoSABR: a multicentre, randomised controlled open-label phase II trial. (PubMed, BMC Cancer) - P2 | "The combination of SABR with or without ICI and the immunocytokine L19-IL2 will be tested as 1st, 2nd or 3rd line treatment in stage IV NSCLC patients in 14 centres located in 6 countries. This bimodal and trimodal treatment approach is based on the direct cytotoxic effect of radiotherapy, the tumour selective immunocytokine L19-IL2, the abscopal effect observed distant from the irradiated metastatic site(s) and the memory effect. The first results are expected end 2023."

Clinical • IO Biomarker • Journal • P2 data • Immune Modulation • Inflammation • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Thoracic Cancer • IL2

Clinical study phase II of L19IL2 in combination with dacarbazine in patients with metastatic melanoma (clinicaltrials.gov) - P2, 102; Sponsor: Philogen; Active, not recruiting -> Terminated.

Trial termination • Melanoma

Combination of SABR and L19-IL2 in Patients With Stage IV Lung Cancer (ImmunoSABR) (clinicaltrials.gov) - P2; N=141; Recruiting; Sponsor: Maastricht Radiation Oncology; Not yet recruiting ➔ Recruiting; Initiation date: Jul 2016 ➔ Dec 2015

Enrollment open • Trial initiation date • Biosimilar • Immunology • Non Small Cell Lung Cancer • Oncology