citoplurikin (IRX-2) / Ernexa Therapeutics - LARVOL DELTA

Pre-operative IRX-2 in Early Stage Breast Cancer (ESBC) (clinicaltrials.gov) - P1 | N=16 | Completed | Sponsor: Providence Health & Services | Active, not recruiting ➔ Completed

Trial completion • Breast Cancer • Male Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • HER-2

NeoIRX: Pembrolizumab, IRX-2, and Chemotherapy in Triple Negative Breast Cancer (clinicaltrials.gov) - P2 | N=12 | Active, not recruiting | Sponsor: Providence Health & Services | Trial completion date: Jun 2025 ➔ Dec 2025

Trial completion date • Breast Cancer • Inflammatory Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer

IRX-2, Cyclophosphamide, and Nivolumab in Treating Patients With Recurrent or Metastatic and Refractory Liver Cancer (clinicaltrials.gov) - P1 | N=8 | Active, not recruiting | Sponsor: City of Hope Medical Center | Trial completion date: May 2025 ➔ Mar 2026 | Trial primary completion date: May 2025 ➔ Mar 2026

Trial completion date • Trial primary completion date • Hepatocellular Cancer • Liver Cancer • Oncology • Solid Tumor

IRX-2 Regimen and Durvalumab, for Incurable H&N Squamous Cell Carcinoma (clinicaltrials.gov) - P1 | N=19 | Completed | Sponsor: H. Lee Moffitt Cancer Center and Research Institute | Active, not recruiting ➔ Completed

Trial completion • Head and Neck Cancer • Hypopharyngeal Cancer • Laryngeal Cancer • Oncology • Oral Cancer • Oropharyngeal Cancer • Otorhinolaryngology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck

IRX-2 Regimen in Treating Women With Cervical Squamous Intraepithelial Neoplasia 3 or Squamous Vulvar Intraepithelial Neoplasia 3 (clinicaltrials.gov) - P2 | N=10 | Terminated | Sponsor: University of Southern California | Active, not recruiting ➔ Terminated; Lack of efficacy

Trial termination • Bowens Disease • Cervical Cancer • Cervical Squamous Cell Carcinoma • Gynecology • Oncology • Solid Tumor • Squamous Cell Carcinoma • Vulvar Cancer

Pre-operative IRX-2 in Early Stage Breast Cancer (ESBC) (clinicaltrials.gov) - P1 | N=16 | Active, not recruiting | Sponsor: Providence Health & Services | Trial completion date: Dec 2024 ➔ Dec 2025

Trial completion date • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Breast Cancer • Male Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • HER-2

IRX-2, Cyclophosphamide, and Nivolumab in Treating Patients With Recurrent or Metastatic and Refractory Liver Cancer (clinicaltrials.gov) - P1 | N=8 | Active, not recruiting | Sponsor: City of Hope Medical Center | Trial completion date: Dec 2024 ➔ May 2025 | Trial primary completion date: Dec 2024 ➔ May 2025

Trial completion date • Trial primary completion date • Hepatocellular Cancer • Hepatology • Liver Cancer • Oncology • Solid Tumor

IRX-2 Regimen in Treating Women with Cervical Squamous Intraepithelial Neoplasia 3 or Squamous Vulvar Intraepithelial Neoplasia 3 (clinicaltrials.gov) - P2 | N=11 | Active, not recruiting | Sponsor: University of Southern California | Trial completion date: Nov 2024 ➔ Aug 2025 | Trial primary completion date: Nov 2024 ➔ Aug 2025

Trial completion date • Trial primary completion date • Bowens Disease • Cervical Cancer • Cervical Squamous Cell Carcinoma • Gynecology • Oncology • Solid Tumor • Squamous Cell Carcinoma • Vulvar Cancer

IRX-2 Regimen and Durvalumab, for Incurable H&N Squamous Cell Carcinoma (clinicaltrials.gov) - P1 | N=19 | Active, not recruiting | Sponsor: H. Lee Moffitt Cancer Center and Research Institute | Trial completion date: Dec 2024 ➔ Sep 2025

Trial completion date • Head and Neck Cancer • Hypopharyngeal Cancer • Laryngeal Cancer • Oncology • Oral Cancer • Oropharyngeal Cancer • Otorhinolaryngology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck

Pre-operative IRX-2 in Early Stage Breast Cancer (ESBC) (clinicaltrials.gov) - P1 | N=16 | Active, not recruiting | Sponsor: Providence Health & Services | Trial completion date: May 2024 ➔ Dec 2024

Trial completion date • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Breast Cancer • Male Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • HER-2

NeoIRX: Pembrolizumab, IRX-2, and Chemotherapy in Triple Negative Breast Cancer (clinicaltrials.gov) - P2 | N=12 | Active, not recruiting | Sponsor: Providence Health & Services | Trial primary completion date: Jun 2024 ➔ Jul 2023

Trial primary completion date • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer

Neoadjuvant Cytokine (IRX-2) Immunotherapy for Resectable Oral Cavity Carcinoma: Final Results of the INSPIRE Trial (AHNS-COSM 2024) - "This regimen consisted of an initial dose of cyclophosphamide (300mg/m2) followed by 10 days of regional perilymphatic IRX-2 cytokine injections and daily oral indomethacin, zinc and omeprazole (IRX) compared to the identical regimen without IRX-2 cytokines (Con)... Although survival outcomes did not reach statistical significance, the trial demonstrated the safety and feasibility of neoadjuvant cytokine immunotherapy that was associated with significant increases in TILs and a strong trend for improved outcomes in patients with advanced (Stage III/ IV) disease. The lack of toxicity or serious adverse events support future combination therapy with other neoadjuvant 62 immunotherapy or chemotherapy regimens. Patient acceptance of adjuvant immunotherapy regimens is a challenge."

Clinical • IO biomarker • Oncology • Oral Cancer • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck

IRX-2, Cyclophosphamide, and Nivolumab in Treating Patients With Recurrent or Metastatic and Refractory Liver Cancer (clinicaltrials.gov) - P1 | N=8 | Active, not recruiting | Sponsor: City of Hope Medical Center | Phase classification: P1b ➔ P1 | Trial completion date: Dec 2023 ➔ Dec 2024 | Trial primary completion date: Dec 2023 ➔ Dec 2024

Metastases • Phase classification • Trial completion date • Trial primary completion date • Gastrointestinal Cancer • Hepatocellular Cancer • Hepatology • Liver Cancer • Oncology • Solid Tumor

Pre-operative IRX-2 in Early Stage Breast Cancer (ESBC) (clinicaltrials.gov) - P1 | N=16 | Active, not recruiting | Sponsor: Providence Health & Services | Trial completion date: Jan 2023 ➔ May 2024

Trial completion date • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Breast Cancer • Male Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • HER-2

IRX-2 Regimen and Durvalumab, for Incurable H&N Squamous Cell Carcinoma (clinicaltrials.gov) - P1 | N=19 | Active, not recruiting | Sponsor: H. Lee Moffitt Cancer Center and Research Institute | Trial completion date: Dec 2023 ➔ Dec 2024

Trial completion date • Head and Neck Cancer • Hypopharyngeal Cancer • Laryngeal Cancer • Oncology • Oral Cancer • Oropharyngeal Cancer • Otorhinolaryngology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck

Association of pathologic complete response with the 27-gene IO score and week 3 IOpath response following neoadjuvant pembrolizumab +/- intralymphatic cytokines in the neoIRX trial (SABCS 2023) - P2 | " Subjects with stage II-III TNBC were randomized 1:1 (n=12) to receive induction pembrolizumab (200mg IV) +/- peri-areolar IRX-2 (IRX-2 arm: 1 ml SQ x2 daily for 10 days + cyclophosphamide 300 mg/m2 IV x 1) preceding initiation of pembrolizumab + NAC... A subset of TNBCs experience brisk IO response following single-cycle IO (IOpath response), which is associated with 100% pCR in this preliminary dataset, highlighting IOpath as a potential surrogate biomarker to guide NAC de-escalation or omission in early-stage TNBC. Baseline 27-gene IO score predicts pCR and week 3 IOpath response. A future study is planned (neoINBRX) to evaluate the feasibility of combining baseline IO score with week 3 IOpath response to identify and treat IO-sensitive tumors with chemotherapy-sparing IO combination therapy."

Clinical • IO biomarker • Breast Cancer • Triple Negative Breast Cancer • IFNG

IRX-2 Regimen and Durvalumab, for Incurable H&N Squamous Cell Carcinoma (clinicaltrials.gov) - P1 | N=19 | Active, not recruiting | Sponsor: H. Lee Moffitt Cancer Center and Research Institute | Phase classification: P1b ➔ P1

Phase classification • Head and Neck Cancer • Hypopharyngeal Cancer • Laryngeal Cancer • Oncology • Oral Cancer • Oropharyngeal Cancer • Otorhinolaryngology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck

IRX-2 Regimen in Treating Women With Cervical Squamous Intraepithelial Neoplasia 3 or Squamous Vulvar Intraepithelial Neoplasia 3 (clinicaltrials.gov) - P2 | N=11 | Active, not recruiting | Sponsor: University of Southern California | Recruiting ➔ Active, not recruiting | N=60 ➔ 11 | Trial primary completion date: Nov 2023 ➔ Nov 2024

Enrollment change • Enrollment closed • Trial primary completion date • Bowens Disease • Cervical Cancer • Gynecology • Oncology • Solid Tumor • Squamous Cell Carcinoma • Vulvar Cancer

IRX-2, Cyclophosphamide, and Nivolumab in Treating Patients With Recurrent or Metastatic and Refractory Liver Cancer (clinicaltrials.gov) - P1b | N=8 | Active, not recruiting | Sponsor: City of Hope Medical Center | Trial completion date: Jun 2023 ➔ Dec 2023 | Trial primary completion date: Jun 2023 ➔ Dec 2023

Metastases • Trial completion date • Trial primary completion date • Gastrointestinal Cancer • Hepatocellular Cancer • Hepatology • Liver Cancer • Oncology • Solid Tumor

NeoIRX trial: Immunologic induction with peri-lymphatic cytokines to enhance pembrolizumab (pembro) response in stage II/III triple-negative breast cancer (TNBC). (ASCO 2023) - P2 | " Subjects with stage II/III TNBC were randomized to receive induction pembrolizumab (all subjects: 200mg IV) +/- peri-areolar IRX-2 (IRX-2 arm: 1 ml SQ x2 daily for 10 days + cyclophosphamide 300 mg/m2 IV x 1) preceding initiation of NACT + pembro... Induction IRX-2 + pembro is well tolerated and is associated with encouraging outcomes, supporting further study of peri-lymphatic induction cytokine therapy in stage II/III TBNC. Post-induction radiographic and histologic outcomes may identify patients with immune-responsive tumors, for whom NACT de-escalation may be a promising therapeutic approach to mitigate toxicity. Clinical trial information: NCT04373031."

IO biomarker • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • IFNG • PD-L1

INSPIRE: IRX-2 Regimen in Patients With Newly Diagnosed Stage II, III, or IVA Squamous Cell Carcinoma of the Oral Cavity (clinicaltrials.gov) - P2 | N=105 | Completed | Sponsor: Brooklyn ImmunoTherapeutics, LLC | Unknown status ➔ Completed

Trial completion • Head and Neck Cancer • Oncology • Oral Cancer • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck

IRX-2, Cyclophosphamide, and Pembrolizumab in Treating Participants With Recurrent or Metastatic Gastric or Gastroesophageal Junction Cancer (clinicaltrials.gov) - P1b/2 | N=9 | Completed | Sponsor: City of Hope Medical Center | Active, not recruiting ➔ Completed | N=20 ➔ 9

Enrollment change • Metastases • Trial completion • Esophageal Cancer • Gastric Cancer • Gastroesophageal Junction Adenocarcinoma • Gastrointestinal Cancer • Oncology • Solid Tumor • PD-L1

Pembrolizumab, IRX-2, and Chemotherapy in Triple Negative Breast Cancer (clinicaltrials.gov) - P2 | N=12 | Active, not recruiting | Sponsor: Providence Health & Services | Recruiting ➔ Active, not recruiting | N=30 ➔ 12

Enrollment change • Enrollment closed • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer

[VIRTUAL] Concordance of multispectral immunofluorescence (mIF) with programmed death ligand 1 (PD-L1) and stromal tumor infiltrating lymphocyte (sTILs) clinical assays in early-stage breast cancer (BC). (ASCO 2020) - P1 | "mIF is concordant with SP142 and sTIL prognostic assays, but with increased precision to quantify treatment related changes. Regression modeling can dramatically improve the utility of mIF as a surrogate immune-based biomarker. Our approach is being utilized in ongoing phase II studies to compare the activity of pembrolizumab +/- locoregional cytokines (IRX-2) in triple negative BC, and paclitaxel/trastuzumab +/- pembrolizumab +/- pertuzumab in HER2-positive BC."

Clinical • IO biomarker • Breast Cancer • Oncology • Solid Tumor • CD163 • CD8 • Cytokeratin • FOXP3 • HER-2 • PD-L1

Tumor infiltrating lymphocyte recruitment in patients with early stage breast cancer after intramammary IRX-2 cytokine immunotherapy. (ASCO-SITC 2018) - P1; "Beginning 21 days prior to surgical resection, enrolled operable patients with stage I-III ESBC received the pre-operative IRX-2 regimen consisting of a single low dose of cyclophosphamide (300 mg/m2 to facilitate T-regulatory cell depletion), followed by 10 days of subcutaneous peri-areolar injections of IRX-2 into the affected breast (1 mL × 2 at tumor axis and at 90°). Peri-lymphatic IRX-2 was well tolerated with preliminary evidence of sTIL recruitment, PDL1 upregulation, and peripheral lymphocyte activation. Study enrollment is ongoing, including patients for a pre-neoadjuvant-chemotherapy triple-negative ESBC cohort."

Clinical • Tumor-Infiltrating Lymphocyte • Breast Cancer • Oncology • Solid Tumor