zalifrelimab (UGN-301) / Recepta, Agenus, Betta Pharma - LARVOL DELTA

DOXORUBICIN PLUS BOTENSILIMAB, A NEXT GENERATION CTLA4 INHIBITOR, WITH OR WITHOUT BALSTILIMAB, A PD1 INHIBITOR, IN PATIENTS WITH ADVANCED SOFT TISSUE SARCOMAS (CTOS 2025) - P2 | "We hypothesized that concurrent doxorubicin (DOX) would improve STS immunogenicity and boost efficacy of ICIs, including BOT with or without BAL. We expanded a previously reported Phase 2 trial of DOX plus first-generation CTLA4 inhibitor zalifrelimab (ZAL) plus BAL (NCT04028063). DOX with BOT +/- BAL exhibits safety and efficacy consistent with prior experience of DOX/ZAL/BAL. Further investigation is needed to determine biomarkers of response/resistance and the optimal timing/sequence of DOX/ICIs to further improve outcomes."

Clinical • IO biomarker • Metastases • Oncology • Sarcoma • Soft Tissue Sarcoma • Solid Tumor

UGN-301 (zalifrelimab), an anti-CTLA4 antibody for use in high-grade non-muscle invasive bladder cancer (GlobeNewswire) - P1 | N=51 | NCT05375903 | Sponsor: UroGen Pharma Ltd. | "Enrollment is complete in the dose escalation phase of UGN-301, alone and in combination with fixed dose UGN-201 or gemcitabine. The treatments demonstrated an acceptable safety profile and were generally well tolerated across dose levels. Responses were observed in both monotherapy and combination therapy arms, and patient follow-up is ongoing to further assess the durability of these responses."

Enrollment closed • P1 data • Bladder Cancer

A single arm phase 2 trial of doxorubicin plus zalifrelimab (anti-CTLA-4 antibody) and balstilimab (anti-PD-1 antibody) in advanced/metastatic soft tissue sarcomas. (PubMed, Clin Cancer Res) - P2 | "Although the study did not meet the predefined endpoint for PFS improvement, promising signals of efficacy warrant future investigation including response/resistance biomarkers to inform patient selection."

IO biomarker • Journal • P2 data • Oncology • Sarcoma • Soft Tissue Sarcoma • Solid Tumor

Doxorubicin Plus Dual Checkpoint Blockade for Soft Tissue Sarcomas (clinicaltrials.gov) - P2 | N=65 | Recruiting | Sponsor: University of Colorado, Denver | N=28 ➔ 65

Checkpoint inhibition • Enrollment change • Oncology • Sarcoma • Soft Tissue Sarcoma • Solid Tumor

UroGen Pharma Announces Encouraging Results from a Phase 1 Dose-Escalation Study Evaluating UGN-301 in Non-Muscle Invasive Bladder Cancer (Businesswire) - P1 | N=51 | NCT05375903 | Sponsor: UroGen Pharma Ltd. | "Data presented at the 2025 American Urological Association Annual Meeting...With respect to clinical activity observed in the trial, among evaluable patients who received UGN-301, 46% (6 of 13) of those with Ta/T1 disease and 33% (2 of 6) of those with carcinoma in situ (CIS) ± Ta/T1 disease were recurrence-free or had achieved a complete response at week 12. Notably, 60% (3 of 5) of patients with Ta/T1 disease treated with 300 mg continued to remain recurrence-free at the 15-month disease assessment, including one patient with high-grade T1 disease. In the 500 mg cohort, 25% (1 of 4) of patients with CIS disease and 33% (1 of 3) of patients with Ta/T1 disease remained disease-free at six months, both of whom are still active participants in the study."

P1 data • Bladder Cancer

UroGen Announces Data Presentations at the American Urological Association 2025 Annual Meeting Highlighting Emerging Evidence Supporting Our Portfolio for Urothelial Cancers (Businesswire) - "UroGen Pharma Ltd...announced that data on investigational drug UGN-102 (mitomycin) for intravesical solution, JELMYTO (mitomycin) for pyelocalyceal solution and UGN-301 (zalifrelimab) will be presented at the American Urological Association (AUA) 2025 Annual Meeting being held in Las Vegas, Nevada from April 26-29."

Clinical data • Bladder Cancer • Urothelial Cancer

Treatment of recurrent non-muscle invasive bladder cancer with UGN-301 (zalifrelimab): results of a phase 1 dose-escalation study (AUA 2025) - P1 | "Local delivery of UGN-301 formulated in RTgel allowed sustained exposure of zalifrelimab in the bladder while limiting systemic exposure, thus mitigating the risk of toxicities associated with CTLA-4 inhibition. UGN-301 was well tolerated at all dose levels with a favorable safety profile. Evaluation of UGN-301 in combination with UGN-201 (Arm B) and gemcitabine (Arm C) is ongoing in the USA, Italy, and Spain."

P1 data • Bladder Cancer • Genito-urinary Cancer • Oncology • Solid Tumor

ImmunoGenesis Doses First Patient in Phase 1/2 Clinical Trial of IMGS-101 in Combination With Balstilimab (anti-PD-1) and Zalifrelimab (anti-CTLA-4) in Relapsed or Refractory Advanced Prostate, Pancreatic, and HPV(-) Head & Neck Tumors (PRNewswire) - "ImmunoGenesis...announced the first patient has been dosed in the company's Phase 1/2 clinical trial of its hypoxia reversal agent IMGS-101 (evofosfamide) in combination with Balstilimab (anti-PD-1) and Zalifrelimab (anti-CTLA-4) at The University of Texas MD Anderson Cancer Center in Houston, Texas....The Phase 1/2, open-label, multicenter study (NCT06782555) consists of a dose escalation and expansion portion to evaluate the safety, pharmacokinetics, and anti-tumor activity of IMGS-101 in combination with Balstilimab and Zalifrelimab in adult patients with locally advanced or metastatic castration-resistant prostate cancer (CRPC), pancreatic cancer, and human papillomavirus-(HPV) negative squamous cell carcinoma of the head and neck (SCCHN)."

Trial status • Castration-Resistant Prostate Cancer • Pancreatic Cancer • Squamous Cell Carcinoma of Head and Neck

RaPiDS- A Phase 2 Study of Anti-PD-1 Independently or in Combination With Anti-CTLA-4 in Second-Line Cervical Cancer (clinicaltrials.gov) - P2 | N=212 | Active, not recruiting | Sponsor: Agenus Inc. | Trial primary completion date: Jan 2025 ➔ Aug 2025

Trial primary completion date • Cervical Cancer • Oncology • Solid Tumor

A Phase 1 Dose-escalation Study of UGN-301 in Patients With Recurrent Non-muscle Invasive Bladder Cancer (NMIBC) (clinicaltrials.gov) - P1 | N=51 | Active, not recruiting | Sponsor: UroGen Pharma Ltd. | Recruiting ➔ Active, not recruiting

Enrollment closed • Bladder Cancer • Genito-urinary Cancer • Oncology • Solid Tumor • Urothelial Cancer

A Study of Evofosfamide in Combination with Zalifrelimab and Balstilimab (clinicaltrials.gov) - P1/2 | N=71 | Recruiting | Sponsor: ImmunoGenesis

New P1/2 trial • Genito-urinary Cancer • Head and Neck Cancer • Hepatology • Oncology • Pancreatic Cancer • Prostate Cancer • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck

NUMANTIA: Study to Evaluate the Safety and Efficacy of Treatment With NLM-001 and Standard Chemotherapy Plus Zalifrelimab in Patients With Advanced Pancreatic Cancer (clinicaltrials.gov) - P1/2 | N=28 | Active, not recruiting | Sponsor: Nelum Corp | Trial completion date: Oct 2024 ➔ Apr 2025 | Trial primary completion date: Oct 2024 ➔ Apr 2025

Trial completion date • Trial primary completion date • Hepatology • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor

Balstilimab (bal) alone or with zalifrelimab (zal) treatment for cervical cancer: An open-label, non-comparative, randomised, phase II trial (ESMO Asia 2024) - P2 | "16/74 (21.6%) pts in the bal arm and 7/41 (17.1%) pts in the bal + zal arm received prior bevacizumab. The pharmacokinetic (PK) profile of bal + zal was consistent with the data from bal monotherapy, indicating no impact of zal on the PK of bal. Conclusions Bal monotherapy and bal plus zal showed promising clinical efficacy and manageable safety profile in PD-L1 positive, recurrent or metastatic cervical cancer."

Clinical • P2 data • Cervical Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • CTLA4

RaPiDS- A Phase 2 Study of Anti-PD-1 Independently or in Combination With Anti-CTLA-4 in Second-Line Cervical Cancer (clinicaltrials.gov) - P2 | N=212 | Active, not recruiting | Sponsor: Agenus Inc. | Trial primary completion date: Aug 2024 ➔ Jan 2025

Combination therapy • Monotherapy • Trial primary completion date • Cervical Cancer • Oncology • Solid Tumor

SUO 2024: UR001: A Phase 1 Dose-Escalation Study of UGN-301 (Zalifrelimab) in Patients with Recurrent Non Muscle Invasive Bladder Cancer (UroToday) - P1 | N=60 | NCT05375903 | Sponsor: UroGen Pharma Ltd. | "A phase 1 study (UR001) was initiated to evaluate the safety and determine the recommended phase 2 dose of UGN-301 as monotherapy and in combination with other agents in patients with recurrent NMIBC....One patient at 700 mg had 50-fold lower concentration than achieved with systemic administration and 2550-fold lower than the urine concentration. Among the evaluable patients with Ta/T1 and CIS +/- Ta/T1 disease, 46% (6 of 13) and 33% (2 of 6), respectively, were recurrence free or had a complete response at week 12. One patient with HG Ta treated with 100 mg remained recurrence free through 9 months, and 3 of 5 patients with Ta/T1 disease treated with 300 mg remained recurrence free at 15 month disease assessment (including 1 patient with HG T1 disease)."

P1 data • Bladder Cancer

Doxorubicin Plus Dual Checkpoint Blockade for Soft Tissue Sarcomas (clinicaltrials.gov) - P2 | N=28 | Recruiting | Sponsor: University of Colorado, Denver | Trial completion date: Nov 2025 ➔ Nov 2026 | Trial primary completion date: Nov 2024 ➔ Nov 2025

Checkpoint block • Checkpoint inhibition • Combination therapy • Metastases • Trial completion date • Trial primary completion date • Oncology • Sarcoma • Soft Tissue Sarcoma • Solid Tumor

A PHASE 1 DOSE-ESCALATION STUDY OF UGN-301 (ZALIFRELIMAB) IN PATIENTS WITH RECURRENT NON-MUSCLE INVASIVE BLADDER CANCER (NMIBC) (SUO 2024) - P1 | "The combination arms are investigating UGN-301 with intravesical UGN-201 [imiquimod, a toll-like receptor 7 agonist] (Arm B) or gemcitabine (Arm C). Local delivery of UGN-301 formulated in reverse thermal gel allowed sustained exposure of zalifrelimab in the bladder while limiting systemic exposure and thus mitigating the risk of systemic immune related toxicities associated with CTLA-4 inhibition. At all dose levels, including the MFD, UGN-301 was well tolerated and had a favorable safety profile. Together with the observed efficacy, continued evaluation of UGN-301 for the treatment of NMIBC is warranted."

Clinical • P1 data • Bladder Cancer • Genito-urinary Cancer • Infectious Disease • Nephrology • Oncology • Solid Tumor

A PHASE 1 DOSE-ESCALATION STUDY OF UGN-301 (ZALIFRELIMAB) AS MONOTHERAPY AND IN COMBINATION WITH OTHER AGENTS IN PATIENTS WITH RECURRENT NON-MUSCLE INVASIVE BLADDER CANCER (NMIBC) (SUO 2024) - P1 | "Arm A will investigate UGN-301 monotherapy dose‑escalation, Arm B will investigate UGN-301 dose-escalation + UGN-201 (imiquimod), a toll-like receptor 7 agonist with immune-stimulating anti-tumor effects and Arm C will investigate UGN-301 dose escalation + gemcitabine. Both combinations arms have been initiated and the study is recruiting in the United States, Italy and Spain (NCT05375903). "

Clinical • Combination therapy • Monotherapy • P1 data • Bladder Cancer • Genito-urinary Cancer • Oncology • Solid Tumor

rHSC-DIPGVax Plus Checkpoint Blockade for the Treatment of Newly Diagnosed DIPG and DMG (clinicaltrials.gov) - P1 | N=36 | Recruiting | Sponsor: Ann & Robert H Lurie Children's Hospital of Chicago | Trial completion date: Mar 2025 ➔ Dec 2025 | Trial primary completion date: Dec 2024 ➔ Jun 2025

Checkpoint block • Checkpoint inhibition • Combination therapy • Trial completion date • Trial primary completion date • Brain Cancer • CNS Tumor • Diffuse Intrinsic Pontine Glioma • Diffuse Midline Glioma • Glioma • Oncology • Solid Tumor

Phase Ib/IIa study to evaluate safety and efficacy of priming treatment with the hedgehog inhibitor NLM-001 prior to gemcitabine and nab-paclitaxel plus zalifrelimab as first-line treatment in patients with advanced pancreatic cancer: NUMANTIA study (ESMO-GI 2024) - P1/2 | "Background: FOLFIRINOX and gemcitabine (G) in combination with nab-paclitaxel (nP) are the standard first-line treatment for patients (Pt) with advanced pancreatic cancer (aPC) but the impact on outcomes is limited... Safety profile of study treatment is as expected for G+nP standard regimen. No new safety signals were observed for the NLM-001 + G+nP+Z treatment. Preliminary efficacy results are promising."

Clinical • Metastases • P1/2 data • Gastrointestinal Cancer • Hematological Disorders • Hepatology • Neutropenia • Oncology • Pancreatic Cancer • Solid Tumor • CA 19-9

Ligand Reports First Quarter 2024 Financial Results (Businesswire) - "On May 7, Ligand announced a $100 million royalty financing agreement with Agenus, Inc. Under the terms of the agreement, in exchange for an initial $75 million payment, Ligand will receive 18.75% of the royalties and 31.875% of the future milestones on six Agenus-partnered oncology programs including BMS-986442 (Bristol Myers Squibb), AGEN2373 (Gilead Sciences), INCAGN2385 and INCAGN2390 (Incyte), MK-4830 (Merck), and UGN-301 (UroGen Pharma)."

Financing • Licensing / partnership • Oncology

A Phase 1 Dose-escalation Study of UGN-301 in Patients With Recurrent Non-muscle Invasive Bladder Cancer (NMIBC) (clinicaltrials.gov) - P1 | N=60 | Recruiting | Sponsor: UroGen Pharma Ltd. | Trial completion date: Dec 2024 ➔ Dec 2025 | Trial primary completion date: Dec 2024 ➔ Dec 2025

Combination therapy • Monotherapy • Trial completion date • Trial primary completion date • Bladder Cancer • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • Urothelial Cancer

AGEN1884 Plus AGEN2034 Combined With Cisplatin-Gemcitabine for Muscle-Invasive Bladder Cancer (clinicaltrials.gov) - P2 | N=4 | Terminated | Sponsor: The University of Texas Health Science Center at San Antonio | Active, not recruiting ➔ Terminated; PI left the institution

Combination therapy • Trial termination • Bladder Cancer • Genito-urinary Cancer • Oncology • Solid Tumor

A Phase II Study of Balstilimab Independently or in Combination With Zalifrelimab in Advanced Cervical Cancer (clinicaltrials.gov) - P2 | N=0 | Withdrawn | Sponsor: Agenus Inc. | N=177 ➔ 0 | Recruiting ➔ Withdrawn

Combination therapy • Enrollment change • Metastases • Trial withdrawal • Cervical Cancer • Gastric Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor

NUMANTIA: Study to Evaluate the Safety and Efficacy of Treatment With NLM-001 and Standard Chemotherapy Plus Zalifrelimab in Patients With Advanced Pancreatic Cancer (clinicaltrials.gov) - P1/2 | N=28 | Active, not recruiting | Sponsor: Nelum Corp | Recruiting ➔ Active, not recruiting

Enrollment closed • Metastases • Gastrointestinal Cancer • Hepatology • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • Solid Tumor