Activity and Safety of Danvatirsen and Pembrolizumab in HNSCC
- Registration Number
- NCT05814666
- Lead Sponsor
- Flamingo Therapeutics NV
- Brief Summary
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.
- 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.
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 81
- Must have given written informed consent (signed and dated).
- Aged ≥18 years at the time of informed consent.
- 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.
- Presence of measurable tumor per RECIST v1.1 criteria.
- 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.
- Baseline fresh tumor biopsy or archival specimen.
- ECOG performance status of 0 or 1.
- Adequate organ function within 10 days of study treatment,
- Oxygen saturation on room air ≥92% by pulse oximetry.
- Females must be non-pregnant and non-lactating and either be postmenopausal or agree to adequate birth control.
- Males must be surgically sterile or agree to adequate birth control.
- Has an estimated life expectancy of at least 3 months.
- Has recovered from all complications or surgery and all toxicities of prior therapy
- Prior therapy for metastatic HNSCC.
- Has disease suitable for local therapy with curative intent.
- Primary tumor of the nasopharynx.
- Has received prior therapy with an anti-programmed death 1 (PD-1), anti PD L1, or anti-programmed death-ligand-2 (PD-L2).
- Radiation therapy (or other non-systemic therapy) within 2 weeks of Day 1 of study treatment.
- Known autoimmune disease that has required systemic treatment
- Known immunodeficiency or receiving systemic steroid therapy that would be the equivalent of >10 mg prednisone daily
- Prior allogeneic tissue/solid organ transplant.
- Has significant cardiovascular disease
- Has received a live vaccine within 30 days
- Active infection requiring systemic antiviral or antimicrobial therapy
- History of (non-infectious) pneumonitis that required steroids or current pneumonitis.
- History of other malignancies
- Active HIV infection except patients who are currently stable on antiretroviral therapy for at least 4 weeks
- Active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection.
- Treated or untreated parenchymal brain metastases or leptomeningeal disease.
- 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.
- Hypersensitivity to any component of danvatirsen or pembrolizumab.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Danvatirsen plus pembrolizumab Danvatirsen 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. Danvatirsen plus pembrolizumab 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. Pembrolizumab Pembrolizumab Pembrolizumab IV every 3 weeks after the Danvatirsen dose.
- Primary Outcome Measures
Name Time Method Confirmed ORR Up to 18 months 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
- Secondary Outcome Measures
Name Time Method DOR in tumors with CPS ≥50 Up to 18months Duration of response by RECIST v1.1 in tumors with CPS ≥50
Area under the plasma concentration-time curve Up to 18 months Area under the plasma concentration-time curve over the dosing interval \[AUCtau\] of danvatirsen at defined timepoints in the combination regimen
Time to maximum plasma concentration Up to 18 months Time to maximum plasma concentration \[Tmax\]) after single and multiple doses at defined timepoints in the combination regimen
Immunogenicity of danvatirsen Up to 18 months Anti-danvatirsen antibody titers at defined timepoints in the combination regimen
Number of participants with treatment-related adverse events as assessed by CTCAE v5.0 Up to 18 months Drug induced toxicities are assessed and graded according to Common Toxicity Criteria for Adverse Events (CTCAE) Version 5.0.
DCR & CR Rate Up to 18months Disease control rate and complete response rate by RECIST v1.1
OS Up to 30months Overall survival, defined as time from randomization to death from any cause
Trough concentration Up to 18 months Trough concentration \[Ctrough\] of danvatirsen at defined timepoints in the combination regimen
DOR Up to 18months Duration of Response by RECIST v1.1
ORR in tumors with CPS ≥50 Up to 18months Overall response rate per RECIST v1.1 in tumors with CPS ≥ 20 and ≥ 50
Maximum plasma concentration Up to 18 months Maximum concentration recorded \[Cmax\]of danvatirsen at defined timepoints in the combination regimen
PFS Up to 18months 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
Trial Locations
- Locations (31)
Emory University Hospital Midtown
🇺🇸Atlanta, Georgia, United States
University of Maryland Baltimore, Greenebaum Comprehensive Cancer Center
🇺🇸Baltimore, Maryland, United States
UT Southwestern Medical Center/Simmons Comprehensive Cancer Center
🇺🇸Dallas, Texas, United States
The Catholic University of Korea - Eunpyeong St. Mary's Hospital
🇰🇷Seoul, Korea, Republic of
Saint James's University Hospital (SJUH) - St James's Institute of Oncology
🇬🇧Leeds, United Kingdom
The Clatterbridge Cancer Centre NHS Foundation Trust
🇬🇧Liverpool, United Kingdom
The University of Arizona Cancer Center
🇺🇸Tucson, Arizona, United States
University of California Irvine (UCI)
🇺🇸Irvine, California, United States
TMPN Hunt Cancer Care
🇺🇸Torrance, California, United States
University of California Los Angeles
🇺🇸Westwood, California, United States
University of Colorado Hospital (UCH) Anschutz Cancer Pavilion
🇺🇸Aurora, Colorado, United States
Miami Cancer Institute
🇺🇸Miami, Florida, United States
University of Illinois Cancer Center
🇺🇸Chicago, Illinois, United States
AMR Kansas City Oncology
🇺🇸Merriam, Kansas, United States
University of Kansas Medical Center
🇺🇸Westwood, Kansas, United States
Mary Bird Perkins Cancer Center
🇺🇸Baton Rouge, Louisiana, United States
Comprehensive Cancer Centers of Nevada
🇺🇸Las Vegas, Nevada, United States
Morristown Medical Center
🇺🇸Morristown, New Jersey, United States
Mount Sinai
🇺🇸New York, New York, United States
Stony Brook Cancer Center
🇺🇸Stony Brook, New York, United States
The Christ Hospital Cancer Center
🇺🇸Cincinnati, Ohio, United States
University of Cincinnati Medical Center
🇺🇸Cincinnati, Ohio, United States
University Hospitals Cleveland
🇺🇸Cleveland, Ohio, United States
Prisma Health Cancer Institute
🇺🇸Greenville, South Carolina, United States
Dong-A University Hospital
🇰🇷Busan, Korea, Republic of
Kosin University College of Medicine - Kosin University Gospel Hospital (KUGH)
🇰🇷Busan, Korea, Republic of
Gyeongsang National University Hospital
🇰🇷Jinju, Korea, Republic of
Korea University Medical Center (KUMC)
🇰🇷Seoul, Korea, Republic of
Barts Health MHS Trust (Barts and The London NHS Trust) - St Bartholomew's (Barts) Hospital
🇬🇧London, United Kingdom
The Royal Marsden NHS Foundation Trust
🇬🇧Surry, United Kingdom
East and North Hertfordshire NHS Trust, Lister Hospital
🇬🇧Northwood, Middlesex, United Kingdom