danvatirsen (AZD9150) / AstraZeneca, Ionis, Flamingo Therapeutics - LARVOL DELTA

NCI-2018-01296: Danvatirsen and Durvalumab in Treating Patients With Advanced and Refractory Pancreatic, Non-Small Cell Lung Cancer, and Mismatch Repair Deficient Colorectal Cancer (clinicaltrials.gov) - P2 | N=39 | Active, not recruiting | Sponsor: M.D. Anderson Cancer Center | Trial completion date: Apr 2025 ➔ Aug 2025 | Trial primary completion date: Apr 2025 ➔ Aug 2025

dMMR • IO biomarker • Mismatch repair • Trial completion date • Trial primary completion date • Colorectal Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Pancreatic Cancer • Solid Tumor • CTCs

HUDSON: Phase II Umbrella Study of Novel Anti-cancer Agents in Patients With NSCLC Who Progressed on an Anti-PD-1/PD-L1 Containing Therapy (clinicaltrials.gov) - P2 | N=527 | Active, not recruiting | Sponsor: AstraZeneca | Trial primary completion date: Sep 2026 ➔ Sep 2024

Biomarker • IO biomarker • Trial primary completion date • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

Oligonucleotide-Based Modulation of Macrophage Polarization: Emerging Strategies in Immunotherapy. (PubMed, Immun Inflamm Dis) - "Optimizing delivery platforms, enhancing molecular stability, and rigorous safety profiling are critical. Integration with emerging modalities-such as engineered CAR‑macrophages-will enable precise, disease‑specific interventions, and advance oligonucleotide‑guided macrophage modulation toward clinical translation."

Journal • Review • Infectious Disease • Oncology

ASO-mediated STAT3 knockdown relieves immunosuppression sensitizing tumors to immunotherapies (AACR 2025) - P2 | "Our study aims to dissect the immune-modulatory effects of danvatirsen, an antisense oligonucleotide (ASO) targeting the transcription factor Signal Transducer and Activator of Transcription 3 (STAT3) currently being studied in combination with pembrolizumab in the PEMDA-HN trial, a randomized Phase 2 trial in recurrent/metastatic head and neck squamous cell carcinoma (NCT05814666). Similar results were obtained in the EMT6 model. In conclusion, these data showed that ASO-mediated STAT3 KD relieves immunosuppression thereby sensitizing tumors to immunotherapies."

Breast Cancer • Head and Neck Cancer • Lung Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • STAT3

Study to Assess MEDI4736 With Either AZD9150 or AZD5069 in Advanced Solid Tumors & Relapsed Metastatic Squamous Cell Carcinoma of Head & Neck (clinicaltrials.gov) - P1/2 | N=340 | Active, not recruiting | Sponsor: AstraZeneca | Trial completion date: Mar 2025 ➔ Aug 2025

IO biomarker • Monotherapy • Trial completion date • Head and Neck Cancer • Oncology • Prostate Cancer • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck

Flamingo Therapeutics Announces Poster Presentation on the Immune-Modulatory Effects of Danvatirsen at the American Association for Cancer Research (AACR) Annual Meeting (PRNewswire) - "Flamingo Therapeutics...today announced that an abstract has been accepted for presentation at the American Association for Cancer Research (AACR) annual meeting being held in Chicago, IL from April 25-30, 2025."

Clinical data • Oncology

BISCAY: Open-Label, Randomised, Multi-Drug, Biomarker-Directed, Phase 1b Study in Pts w/ Muscle Invasive Bladder Cancer (clinicaltrials.gov) - P1 | N=117 | Active, not recruiting | Sponsor: AstraZeneca | Trial completion date: Mar 2025 ➔ Jan 2026

Biomarker • Trial completion date • Bladder Cancer • Genito-urinary Cancer • Oncology • Solid Tumor • CCNE1 • CDKN2A • HRD • MYCL • MYCN • RB1

STAT3 Signaling Pathway in Health and Disease. (PubMed, MedComm (2020)) - "We systematically discuss therapeutic strategies, including JAK inhibitors (tofacitinib, ruxolitinib), Src Homology 2 domain inhibitors (S3I-201, STATTIC), antisense oligonucleotides (AZD9150), and nanomedicine-based drug delivery systems, which enhance specificity and bioavailability while reducing toxicity. By integrating molecular mechanisms, disease pathology, and emerging therapeutic interventions, this review fills a critical knowledge gap in STAT3-targeted therapy. Our insights into STAT3 signaling crosstalk, epigenetic regulation, and resistance mechanisms offer a foundation for developing next-generation STAT3 inhibitors with greater clinical efficacy and translational potential."

Journal • Review • Cardiovascular • CNS Disorders • Immunology • Oncology • IL6

Preclinical study and parallel phase II trial evaluating antisense STAT3 oligonucleotide and checkpoint blockade for advanced pancreatic, non-small cell lung cancer and mismatch repair-deficient colorectal cancer. (PubMed, BMJ Oncol) - P2 | "In vitro experiments evaluated STAT3 inhibition in pancreatic stellate cells (PSCs) and myeloid-derived suppressor cells (MDSCs).A phase II trial employing a Simon II stage design tested the clinical efficacy of danvatirsen and durvalumab in non-small cell lung cancer (NSCLC), PDAC and mismatch repair-deficient colorectal cancer (MRD CRC). A rationale for the lack of objective responses is danvatirsen-induced myeloid immune suppression. NCT02983578."

Checkpoint inhibition • Journal • Mismatch repair • P2 data • Preclinical • Colorectal Cancer • Hepatology • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • Solid Tumor • CD4 • CD8 • PD-1 • STAT3

A Systematic Literature Review (SLR) of the Clinical Efficacy and Safety Evidence Associated With Treatments for Patients With Metastatic Non-Small Cell Lung Cancer (NSCLC) Who Progressed on Prior Therapies (ISPOR-EU 2024) - "Median overall survival (OS) (n=37) ranged from 3.4 (any third-line [3L] treatment following docetaxel+ramucirumab) to 22.8 months (durvalumab+ceralasertib); it was not estimable in 5 studies...Only 3 studies reported significant differences (p<0.05) in OS between treatments; including pembrolizumab+ramucirumab versus standard of care. Median progression-free survival (n=35) ranged from 1.4 (durvalumab+olaparib; durvalumab+oleclumab) to 12.3 months (docetaxel+ramucirumab); it was not estimable in 1 study (platinum/non-platinum-based chemotherapy). Overall objective response (n=31) ranged from 0% (multiple treatments including durvalumab+danvatirsen) to 100% (3L single-agent chemotherapy). Discontinuations due to adverse events (AEs; n=14) ranged from 0% (atezolizumab) to 40% of patients (nintedanib+docetaxel)... Outcomes with current treatments after progression on platinum-based chemotherapy and anti-PD-1/PD-L1 inhibitors remain poor, highlighting an unmet medical..."

Clinical • Metastases • Review • Anemia • Fatigue • Hematological Disorders • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

HUDSON: Phase II Umbrella Study of Novel Anti-cancer Agents in Patients With NSCLC Who Progressed on an Anti-PD-1/PD-L1 Containing Therapy (clinicaltrials.gov) - P2 | N=531 | Active, not recruiting | Sponsor: AstraZeneca | Trial completion date: Sep 2024 ➔ Sep 2026 | Trial primary completion date: Sep 2024 ➔ Sep 2026

Biomarker • IO biomarker • Trial completion date • Trial primary completion date • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

BISCAY: Open-Label, Randomised, Multi-Drug, Biomarker-Directed, Phase 1b Study in Pts w/ Muscle Invasive Bladder Cancer (clinicaltrials.gov) - P1 | N=117 | Active, not recruiting | Sponsor: AstraZeneca | Trial completion date: Jun 2024 ➔ Mar 2025

Biomarker • Trial completion date • Bladder Cancer • Genito-urinary Cancer • Oncology • Solid Tumor • CCNE1 • CD8 • CDKN2A • FGFR • HRD • IFNG • IL10 • IL2 • IL6 • MYCL • MYCN • RB1

Antisense oligonucleotides-based approaches for the treatment of multiple myeloma. (PubMed, Int J Biol Macromol) - "So far, pre-clinical and clinical studies showed promising results when Bcl-2 (Genasense), Mcl-1 (ISIS2048), STAT3 (ISIS345794) and IRF4 (ION251) were targeted using ASOs-based formulations. The relevant genetic targets in ASOs-based MM therapies were described, and the research results obtained in the studies conducted so far were analyzed, with a focus on the ASOs formulations that were already included in clinical trials. In the end, current challenges, and future perspectives of antisense therapy for MM were also discussed."

Journal • Review • Bone Marrow Transplantation • Gene Therapies • Hematological Disorders • Hematological Malignancies • Multiple Myeloma • Oncology • Transplantation • BCL2 • IL6 • IRF4 • MCL1 • MYC • STAT3

A Phase 1 Study Investigating the Safety and Efficacy of Danvatirsen As Monotherapy Followed By Combination with Venetoclax in Patients with Relapsed/Refractory MDS and AML (ASH 2024) - P1 | "Samples for biomarker analysis are collected and being analyzed. Updated data will be reported at the ASH Annual Meeting."

Clinical • IO biomarker • Monotherapy • P1 data • Acute Myelogenous Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology • MCL1 • STAT3

Flamingo Therapeutics Announces Poster Presentation on AML Phase 1 IIT Study at ASH 2024 (PRNewswire) - "Flamingo Therapeutics...announced that an abstract has been selected for presentation at the 66th Annual ASH Annual Meeting and Exposition, being held in San Diego, CA from December 7-9, 2024. The abstract, selected for a poster presentation, is a Trials-in-Progress presentation of a Phase 1 investigator-initiated study of danvatirsen monotherapy followed by danvatirsen combination with venetoclax in relapsed/refractory AML and intermediate/high risk MDS (NCT05986240). The study is being conducted at Albert Einstein / Montefiore Medical Center in New York City and MD Anderson Cancer Center in Houston."

Trial status • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology

AZD9150 Plus Durvalumab Alone or in Combination With Chemotherapy in Patients With Advanced, Solid Tumours and in Patients With Non-Small-Cell Lung Cancer (clinicaltrials.gov) - P1 | N=76 | Completed | Sponsor: AstraZeneca | Active, not recruiting ➔ Completed

Combination therapy • Metastases • Trial completion • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

Flamingo Therapeutics Announces First Patients Dosed in the United Kingdom and Korea in Ongoing Phase II PEMDA-HN Study for Head and Neck Squamous Cell Carcinoma (HNSCC) (PRNewswire) - "Flamingo Therapeutics...announced that the PEMDA-HN trial has expanded beyond the United States into the UK and Korea. Patient enrollment in the USA started in February 2024 and now the first patients have been dosed in these new geographies. The PEMDA-HN trial is evaluating danvatirsen in combination with KEYTRUDA (pembrolizumab), Merck's anti-PD-1 therapy, in patients with recurrent/metastatic head and neck squamous cell carcinoma (HNSCC)....PEMDA-HN (NCT05814666) is a multicenter, open-label, randomized study evaluating the efficacy and safety of danvatirsen in combination with pembrolizumab compared with pembrolizumab alone as first-line treatment of patients with recurrent/metastatic HNSCC whose tumor expresses PD-L1."

Trial status • Squamous Cell Carcinoma of Head and Neck

PEMDA-HN, an open-label, phase II, randomized controlled study of danvatirsen plus pembrolizumab compared to pembrolizumab alone in first-line recurrent and/or metastatic head and neck squamous cell carcinoma (RM HNSCC). (ASCO 2024) - P2 | "The SCORES study in recurrent and/or metastatic (RM) HNSCC patients, naïve to programmed cell death (ligand)1 (PD-(L)1) therapy, demonstrated that DANVA in combination with the PD-L1 inhibitory antibody durvalumab administered in the second line setting appeared to result in a higher objective response rate (ORR) (22.6% [12.3-36.2]) compared with the ORRs seen with durvalumab alone in prior studies (Cohen E. et al. Exploratory endpoints include but are not limited to target engagement and biomarker evaluation. The study is being, or will be, conducted at US, South Korea and United-Kingdom study centers."

Clinical • IO biomarker • Metastases • P2 data • Head and Neck Cancer • Hematological Disorders • Hematological Malignancies • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • STAT3

Flamingo Therapeutics Presents Poster at ASCO 2024 on Phase II PEMDA-HN Trial for Head and Neck Squamous Cell Carcinoma (HNSCC) (PRNewswire) - "Flamingo Therapeutics...today announced the presentation of a Trial-in-Progress poster at the 2024 Annual Meeting of the American Society of Clinical Oncology (ASCO 2024) taking place in Chicago, Illinois....PEMDA-HN (NCT05814666) is a multicenter, open-label, randomized study evaluating the efficacy and safety of danvatirsen in combination with pembrolizumab compared with pembrolizumab alone as first-line treatment of patients with recurrent/metastatic HNSCC whose tumor expresses PD-L1."

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

Flamingo Therapeutics Announces First Patient Dosed in Investigator-Initiated Trial (IIT) Evaluating Danvatirsen in Phase 1 for AML/MDS Cancers (PRNewswire) - "Flamingo Therapeutics...announced that the first patient has been dosed in an Investigator-initiated Trial (IIT) evaluating the safety and efficacy of danvatirsen in patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) who have relapsed or are refractory to frontline therapy. The IIT is being conducted by leading researchers at Montifore Einstein Comprehensive Cancer Center (MECCC; New York, USA) and MD Anderson Cancer Center (MDACC; Houston, USA). In the Phase 1 trial, the STAT3 inhibiting oligonucleotide danvatirsen, discovered by Ionis, will be evaluated as a monotherapy and also in combination with venetoclax, an approved frontline treatment in relapsed/refractory MDS and AML....The IIT is a Phase I study (NCT05986240) investigating danvatirsen as both a monotherapy and in combination with venetoclax in patients with AML or intermediate/high/very high risk MDS who have relapsed or are refractory to frontline therapy."

Trial status • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology

PEMDA-HN: Activity and Safety of Danvatirsen and Pembrolizumab in HNSCC (clinicaltrials.gov) - P2 | N=81 | Recruiting | Sponsor: Flamingo Therapeutics NV | Trial completion date: Aug 2025 ➔ May 2026 | Trial primary completion date: Sep 2024 ➔ May 2025

Metastases • Trial completion date • Trial primary completion date • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • PD-L1

Use of Combination Immunotherapy Before Lung Cancer Surgery (THE ASCO POST) - "'This study builds on the growing evidence that combination immunotherapy has a role in the neoadjuvant setting for this patient population,' said Tina Cascone, MD, PhD...'Ultimately, we want to give patients a chance to live longer without their cancer returning.'"

Media quote

AZD9150 Plus Durvalumab Alone or in Combination With Chemotherapy in Patients With Advanced, Solid Tumours and in Patients With Non-Small-Cell Lung Cancer (clinicaltrials.gov) - P1 | N=76 | Active, not recruiting | Sponsor: AstraZeneca | Trial completion date: Dec 2025 ➔ Jun 2024

Combination therapy • Metastases • Trial completion date • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

Biomarker-directed combination effective in immunotherapy-resistant lung cancer - "'Patients with advanced non-small cell lung cancer face significant challenges when standard-of-care treatments fail,' said corresponding author John Heymach...'For these individuals, options become limited, emphasising the urgent need for innovative approaches. Our study represents a promising advancement in addressing this unmet need and holds the potential to offer more effective therapeutic strategies to improve outcomes for this population.'"

Biomarker • Media quote

NCI-2018-01296: Danvatirsen and Durvalumab in Treating Patients With Advanced and Refractory Pancreatic, Non-Small Cell Lung Cancer, and Mismatch Repair Deficient Colorectal Cancer (clinicaltrials.gov) - P2 | N=39 | Active, not recruiting | Sponsor: M.D. Anderson Cancer Center | Trial completion date: Apr 2024 ➔ Apr 2025 | Trial primary completion date: Apr 2024 ➔ Apr 2025

IO biomarker • Metastases • Mismatch repair • Trial completion date • Trial primary completion date • Colorectal Cancer • Gastrointestinal Cancer • Hepatology • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Pancreatic Cancer • Solid Tumor • CD8 • CTCs • STAT3