darleukin (L19IL2) / Philogen - LARVOL DELTA

PH-ICKPD1-02/21: A phase 2 study of the efficacy of intratumorally administered L19IL2 or L19TNF or L19IL2/L19TNF, all in combination with systemic anti-PD1 Pembrolizumab, in stage III/IV unresectable melanoma patients with resistance to anti-PD1 checkpoint inhibitors (INTACT / MeRCI) (clinicaltrialsregister.eu) - P1/2 | N=65 | Not yet recruiting | Sponsor: Philogen S.p.A.

Checkpoint inhibition • New P1/2 trial • Melanoma • Oncology • Solid Tumor • BRAF

PH-L19IL2CORK-01/25: A Phase I study to evaluate the safety and efficacy of L19IL2 in combination with ruxolitinib in patients with advanced solid tumors. (clinicaltrialsregister.eu) - P1 | N=96 | Not yet recruiting | Sponsor: Philogen S.p.A.

New P1 trial • Colorectal Cancer • Kidney Cancer • Oncology • Pancreatic Cancer • Renal Cell Carcinoma • Solid Tumor

L19IL2/TNF in patients with basal cell carcinoma (clinicaltrialsregister.eu) - P1/2 | N=53 | Not yet recruiting | Sponsor: Philogen S.p.A.

New P1/2 trial • Basal Cell Carcinoma • Non-melanoma Skin Cancer • Oncology

PHL19IL2TNFCOMB04/24: L19IL2 or L19TNF or L19IL2/TNF in patients with basal cell carcinoma (BCC) (clinicaltrialsregister.eu) - P1/2 | N=85 | Not yet recruiting | Sponsor: Philogen S.p.A.

New P1/2 trial • Basal Cell Carcinoma • Non-melanoma Skin Cancer • Oncology

L19IL2/L19TNF in patients with cutaneous squamous cell carcinoma (clinicaltrialsregister.eu) - P1/2 | N=54 | Not yet recruiting | Sponsor: Philogen S.p.A.

New P1/2 trial • Non-melanoma Skin Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Skin Cancer

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 | Recruiting | Sponsor: Philogen S.p.A. | Not yet recruiting ➔ Recruiting

Enrollment open • Solid Tumor • FAP

L19IL2/L19TNF in Patients With Cutaneous Squamous Cell Carcinoma (clinicaltrials.gov) - P2 | N=92 | Not yet recruiting | Sponsor: Philogen S.p.A.

New P2 trial • Non-melanoma Skin Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Skin Cancer

L19IL2 or L19TNF or L19IL2/TNF in Patients With Basal Cell Carcinoma (BCC) (clinicaltrials.gov) - P2 | N=180 | Not yet recruiting | Sponsor: Philogen S.p.A.

New P2 trial • Basal Cell Carcinoma • Non-melanoma Skin Cancer • Oncology

L19IL2/TNF in Patients With Basal Cell Carcinoma (clinicaltrials.gov) - P2 | N=92 | Not yet recruiting | Sponsor: Philogen S.p.A.

New P2 trial • Basal Cell Carcinoma • Non-melanoma Skin Cancer • Oncology

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