Activity and Safety of Danvatirsen and Pembrolizumab in HNSCC (PEMDA-HN)

An Open-Label, Phase II, Randomized, Controlled Study of Danvatirsen Plus Pembrolizumab Compared to Pembrolizumab Alone in Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma (HNSCC)

Open-label, Phase II, randomized, controlled 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 (R/M) HNSCC. Two-thirds of patients will be randomized to receive danvatirsen and pembrolizumab and one-third will be randomized to receive pembrolizumab alone.

Study Overview

• Status: Terminated
• Conditions: HNSCC
• Intervention / Treatment: Drug: Danvatirsen; Drug: Pembrolizumab

Detailed Description

This is a multicenter, open-label, Phase II, randomized, controlled study to determine the efficacy, safety, and other indicators of clinical and biological activity of the combination of danvatirsen and pembrolizumab as first-line treatment for R/M HNSCC.

After providing informed consent, patients will be assessed for eligibility during the screening phase of the study. All patients must be willing and able to provide a formalin fixed paraffin-embedded (FFPE) archival or fresh tumor sample collected during the screening period; a fresh biopsy is preferred if safe and feasible to obtain and consented to by the patient. Following the screening period, eligible patients will be randomized in a 2:1 ratio to danvatirsen + pembrolizumab or pembrolizumab monotherapy, respectively. Patients will receive treatment in 21-day cycles. Patients assigned to the pembrolizumab monotherapy arm will receive treatment until a criterion for discontinuation is met or a maximum of 24 months of treatment. Patients assigned to combination therapy will receive both treatments until a criterion for discontinuation is met or the patient has received a maximum of 24 months of treatment, after which they may remain on danvatirsen monotherapy.

Patients in both treatment arms will have radiologic tumor assessments every 6 weeks (±1 week), regardless of treatment delays, until objective disease progression, initiation of new anticancer treatment, death, withdrawal of consent, or end of study, whichever occurs first.

All patients who discontinue study treatment for any reason will have a safety follow-up visit 30 days (+7 days) after the last dose of study treatment and a follow-up for AEs 90 days (+7 days) after the last dose of pembrolizumab. Patients will be followed for survival at 12 week (±7 days) intervals until death or withdrawal of consent, whichever occurs first. Survival follow-up will continue until at least 15 months after the last patient is randomized in the study.

• Study Type: Interventional
• Enrollment (Actual): 69
• Phase: Phase 2

Contacts and Locations

Study Locations

• South Korea
  • Busan, South Korea, 49201
    • Dong-A University Hospital
  • Busan, South Korea, 602-702
    • Kosin University College of Medicine - Kosin University Gospel Hospital (KUGH)
  • Jinju, South Korea, 52727
    • Gyeongsang National University Hospital
  • Seoul, South Korea, 02841
    • Korea University Medical Center (KUMC)
  • Seoul, South Korea
    • The Catholic University of Korea - Eunpyeong St. Mary's Hospital
• United Kingdom
  • Leeds, United Kingdom
    • Saint James's University Hospital (SJUH) - St James's Institute of Oncology
  • Liverpool, United Kingdom
    • The Clatterbridge Cancer Centre NHS Foundation Trust
  • London, United Kingdom, SW3 6JJ
    • The Royal Marsden NHS Foundation Trust
  • London, United Kingdom, EC1A 7BE
    • Barts Health MHS Trust (Barts and The London NHS Trust) - St Bartholomew's (Barts) Hospital
  • Northwood, United Kingdom, HA6 2RN
    • East and North Hertfordshire NHS Trust, Lister Hospital
  • Sutton, United Kingdom, SM2 5PT
    • The Royal Marsden NHS Foundation Trust
• United States
  • Arizona
    • Tucson, Arizona, United States, 85719
      • The University of Arizona Cancer Center
  • California
    • Irvine, California, United States, 92617
      • University of California Irvine (UCI)
    • Torrance, California, United States, 90505
      • TMPN Hunt Cancer Care
    • Westwood, Los Angeles, California, United States, 90024
      • University of California Los Angeles
  • Colorado
    • Aurora, Colorado, United States, 80045
      • University of Colorado Hospital (UCH) Anschutz Cancer Pavilion
  • Florida
    • Miami, Florida, United States, 33176
      • Miami Cancer Institute
  • Georgia
    • Atlanta, Georgia, United States, 30308
      • Emory University Hospital Midtown
  • Illinois
    • Chicago, Illinois, United States, 60612
      • University of Illinois Cancer Center
  • Kansas
    • Merriam, Kansas, United States, 66204
      • AMR Kansas City Oncology
    • Westwood, Kansas, United States, 66205
      • University of Kansas Medical Center
  • Louisiana
    • Baton Rouge, Louisiana, United States, 70809
      • Mary Bird Perkins Cancer Center
  • Maryland
    • Baltimore, Maryland, United States, 21201
      • University of Maryland Baltimore, Greenebaum Comprehensive Cancer Center
  • Nevada
    • Las Vegas, Nevada, United States, 89169
      • Comprehensive Cancer Centers of Nevada
  • New Jersey
    • Morristown, New Jersey, United States, 07960
      • Morristown Medical Center
  • New York
    • New York, New York, United States, 10029
      • Mount Sinai
    • Stony Brook, New York, United States, 11794
      • Stony Brook Cancer Center
  • Ohio
    • Cincinnati, Ohio, United States, 45229
      • University of Cincinnati Medical Center
    • Cincinnati, Ohio, United States, 45219
      • The Christ Hospital Cancer Center
    • Cleveland, Ohio, United States, 44106
      • University Hospitals Cleveland
  • South Carolina
    • Greenville, South Carolina, United States, 29605
      • Prisma Health Cancer Institute
  • Texas
    • Dallas, Texas, United States, 75390
      • UT Southwestern Medical Center/Simmons Comprehensive Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Must have given written informed consent (signed and dated).
2. Aged ≥18 years at the time of informed consent.
3. Recurrent/metastatic histologically or cytologically proven squamous cell carcinoma of the head and neck that is considered incurable by local therapy. Eligible primary tumor locations are oropharynx, oral cavity, hypopharynx, and larynx.
4. Presence of measurable tumor per RECIST v1.1 criteria.
5. Detectable PD-L1 expression in tumor, defined as CPS ≥1 determined by a FDA or national regulatory agency of the country in which the patient resides.-approved test.
6. Baseline fresh tumor biopsy or archival specimen.
7. ECOG performance status of 0 or 1.
8. Adequate organ function within 10 days of study treatment,
9. Oxygen saturation on room air ≥92% by pulse oximetry.
10. Females must be non-pregnant and non-lactating and either be postmenopausal or agree to adequate birth control.
11. Males must be surgically sterile or agree to adequate birth control.
12. Has an estimated life expectancy of at least 3 months.
13. Has recovered from all complications or surgery and all toxicities of prior therapy

Exclusion Criteria:

1. Prior therapy for metastatic HNSCC.
2. Has disease suitable for local therapy with curative intent.
3. Primary tumor of the nasopharynx.
4. Has received prior therapy with an anti-programmed death 1 (PD-1), anti PD L1, or anti-programmed death-ligand-2 (PD-L2).
5. Radiation therapy (or other non-systemic therapy) within 2 weeks of Day 1 of study treatment.
6. Known autoimmune disease that has required systemic treatment
7. Known immunodeficiency or receiving systemic steroid therapy that would be the equivalent of >10 mg prednisone daily
8. Prior allogeneic tissue/solid organ transplant.
9. Has significant cardiovascular disease
10. Has received a live vaccine within 30 days
11. Active infection requiring systemic antiviral or antimicrobial therapy
12. History of (non-infectious) pneumonitis that required steroids or current pneumonitis.
13. History of other malignancies
14. Active HIV infection except patients who are currently stable on antiretroviral therapy for at least 4 weeks
15. Active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection.
16. Treated or untreated parenchymal brain metastases or leptomeningeal disease.
17. Treatment with another investigational drug, biological agent, or device within 1 month of screening, or 5 half-lives of investigational agent (if known), whichever is longer.
18. Hypersensitivity to any component of danvatirsen or pembrolizumab.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Danvatirsen plus pembrolizumab; Danvatirsen dosing: Week 1: Danvatirsen intravenously (IV) on Days 1, 3, and 5 Week 2 and subsequent weeks: Danvatirsen IV weekly Pembrolizumab dosing: Pembrolizumab every 3 weeks after the Danvatirsen dose.	Drug: Danvatirsen; Danvatirsen is a STAT3 targeting drug.; Other Names: ISIS 481464; AZD9150; Drug: Pembrolizumab; Pembrolizumab is a monoclonal antibody that binds to the PD-1 receptor and blocks its interaction with PD-L1 and PD-L2; Other Names: Keytruda
Active Comparator: Pembrolizumab; Pembrolizumab IV every 3 weeks	Drug: Pembrolizumab; Pembrolizumab is a monoclonal antibody that binds to the PD-1 receptor and blocks its interaction with PD-L1 and PD-L2; Other Names: Keytruda

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Confirmed ORR	Determine the ORR (Partial response [PR] + CR defined according to RECIST v1.1) as determined by the Investigator for the combination of danvatirsen and pembrolizumab compared with pembrolizumab alone	Up to 18 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
DOR	Duration of Response by RECIST v1.1	Up to 18months
DCR & CR Rate	Disease control rate and complete response rate by RECIST v1.1	Up to 18months
PFS	Progression-free survival by RECIST v1.1, defined as the time from randomization to the first documentation of progressive disease (PD) or death from any cause, whichever comes first	Up to 18months
OS	Overall survival, defined as time from randomization to death from any cause	Up to 30months
Number of Participants With Adverse Events as Assessed by CTCAE v5.0	Adverse Events are assessed and graded according to Common Toxicity Criteria for Adverse Events (CTCAE) Version 5.0.	Up to 18 months
ORR in Tumors With CPS ≥20 and ≥ 50	Overall response rate per RECIST v1.1 in tumors with CPS< 20, CPS ≥ 20 and CPS ≥ 50	Up to 18months
DOR in Tumors With CPS ≥20 and ≥50	Duration of response by RECIST v1.1 in tumors with CPS ≥ 20 and ≥50	Up to 18months
Maximum Plasma Concentration	Maximum concentration recorded [Cmax]of danvatirsen at defined timepoints in the combination regimen	Up to 18 months
Trough Concentration	Trough concentration [Ctrough] of danvatirsen at defined timepoints in the combination regimen	Up to 18 months
Area Under the Plasma Concentration-time Curve	Area under the plasma concentration-time curve over the dosing interval [AUCtau] of danvatirsen at defined timepoints in the combination regimen	Up to 18 months
Time to Maximum Plasma Concentration	Time to maximum plasma concentration [Tmax]) after single and multiple doses at defined timepoints in the combination regimen	Up to 18 months
Immunogenicity of Danvatirsen	Anti-danvatirsen antibody titers at defined timepoints in the combination regimen	Up to 18 months

Collaborators and Investigators

• Sponsor: Flamingo Therapeutics NV
• Investigators: Study Chair: Nabil Saba, MD, Emory University

Study record dates

Study Major Dates

• Study Start (Actual): May 30, 2023
• Primary Completion (Actual): August 14, 2025
• Study Completion (Actual): August 14, 2025

Study Registration Dates

• First Submitted: March 10, 2023
• First Submitted That Met QC Criteria: April 3, 2023
• First Posted (Actual): April 18, 2023

Study Record Updates

• Last Update Posted (Actual): January 30, 2026
• Last Update Submitted That Met QC Criteria: January 14, 2026
• Last Verified: December 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Neoplasms by Histologic Type; Head and Neck Neoplasms; Neoplasms, Glandular and Epithelial; Carcinoma; Carcinoma, Squamous Cell; Squamous Cell Carcinoma of Head and Neck; Antineoplastic Agents, Immunological; Immune Checkpoint Inhibitors; Antineoplastic Agents; Molecular Mechanisms of Pharmacological Action; pembrolizumab; danvatirsen
• Other Study ID Numbers: FLM-6774-201

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No