HNSCC
Conditions
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.
Interventions
DRUGDanvatirsen
Danvatirsen is a STAT3 targeting drug.
DRUGPembrolizumab
Pembrolizumab is a monoclonal antibody that binds to the PD-1 receptor and blocks its interaction with PD-L1 and PD-L2
Sponsors
Flamingo Therapeutics NV
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| Immunogenicity of Danvatirsen | Up to 18 months | Anti-danvatirsen antibody titers at defined timepoints in the combination regimen |
| Number of Participants With Adverse Events as Assessed by CTCAE v5.0 | Up to 18 months | Adverse Events are assessed and graded according to Common Toxicity Criteria for Adverse Events (CTCAE) Version 5.0. |
| DOR | Up to 18months | Duration of Response by RECIST v1.1 |
| DCR & CR Rate | Up to 18months | Disease control rate and complete response rate by RECIST v1.1 |
| ORR in Tumors With CPS ≥20 and ≥ 50 | Up to 18months | Overall response rate per RECIST v1.1 in tumors with CPS\< 20, CPS ≥ 20 and CPS ≥ 50 |
| DOR in Tumors With CPS ≥20 and ≥50 | Up to 18months | Duration of response by RECIST v1.1 in tumors with CPS ≥ 20 and ≥50 |
| 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 |
| OS | Up to 30months | Overall survival, defined as time from randomization to death from any cause |
| Maximum Plasma Concentration | Up to 18 months | Maximum concentration recorded \[Cmax\]of danvatirsen at defined timepoints in the combination regimen |
| Trough Concentration | Up to 18 months | Trough concentration \[Ctrough\] 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 |
| 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 |
Countries
South Korea, United Kingdom, United States
Contacts
STUDY_CHAIRNabil Saba, MD
Emory University
Participant flow
Recruitment details
Enrollment was open from May 2023 through May 2025. Patients were recruited from community based practices, research institutions and universities located in the United States, United Kingdom and South Korea. An early assessment of response in patients with CPS ≥1 and \<20 was performed and the response rate in this subgroup did not pass the minimum prespecified efficacy level, subsequently eligibility was restricted to patients with CPS ≥20.
Pre-assignment details
From May 2023 through May 2025, 94 patients were screened, 69 met the eligibility criteria and were randomized. Of the 69 patients that started the treatment period (45 danvatirsen combination arm/24 pembrolizumab arm), 3 patients in the pembrolizumab arm discontinued the study before receiving treatment. 66 patients in total received treatment (45 danvatirsen combination/21 pembrolizumab)
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 26 Participants |
| Age, Categorical Between 18 and 65 years | 27 Participants |
| Age, Continuous | 64.7 years STANDARD_DEVIATION 10.94 |
| Eastern Cooperative Group Performance Status (ECOG ECOG = 0 | 7 Participants |
| Eastern Cooperative Group Performance Status (ECOG ECOG = 1 | 14 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 60 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Human Papillomavirus (HPV) Negative | 6 Participants |
| Human Papillomavirus (HPV) Positive | 5 Participants |
| Human Papillomavirus (HPV) Unknown | 10 Participants |
| PD-L1 Combined Positive Score (CPS) 1-19 | 7 Participants |
| PD-L1 Combined Positive Score (CPS) >=20 | 14 Participants |
| PD-L1 Combined Positive Score (CPS) 20-49 | 6 Participants |
| PD-L1 Combined Positive Score (CPS) >=50 | 21 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 6 Participants |
| Race (NIH/OMB) White | 42 Participants |
| Region of Enrollment South Korea | 11 Participants |
| Region of Enrollment United Kingdom | 3 Participants |
| Region of Enrollment United States | 18 Participants |
| Sex: Female, Male Female | 11 Participants |
| Sex: Female, Male Male | 17 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 8 / 45 | 4 / 21 |
| other Total, other adverse events | 44 / 45 | 18 / 21 |
| serious Total, serious adverse events | 25 / 45 | 6 / 21 |
Outcome results
None listed