Activity and Safety of Danvatirsen and Pembrolizumab in HNSCC

Study Overview
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Brief Summary
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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
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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.

Official Title
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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)

Conditions
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HNSCC

Intervention / Treatment
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* Drug: Danvatirsen
* Drug: Pembrolizumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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 ≥20 determined by a Food and Drug Administration-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 Exclusion Criteria: 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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Danvatirsen plus pembrolizumab<br>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<br>* Danvatirsen is a STAT3 targeting drug.<br>* Other names: AZD9150;Drug: Pembrolizumab<br>* Pembrolizumab is a monoclonal antibody that binds to the PD-1 receptor and blocks its interaction with PD-L1 and PD-L2<br>* Other names: Keytruda;|
| Active Comparator: Pembrolizumab<br>Pembrolizumab IV every 3 weeks after the Danvatirsen dose. | Drug: Pembrolizumab<br>* Pembrolizumab is a monoclonal antibody that binds to the PD-1 receptor and blocks its interaction with PD-L1 and PD-L2<br>* Other names: Keytruda;|

What is the study measuring?
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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 |
| --- | --- | --- |
| Number of participants with treatment-related adverse events as assessed by CTCAE v5.0 | Drug induced toxicities are assessed and graded according to Common Toxicity Criteria for Adverse Events (CTCAE) Version 5.0. | Up to 18 months | 
| 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 | 
| ORR in tumors with CPS ≥50 | Overall response rate per RECIST v1.1 in tumors with CPS ≥50 | Up to 18months | 
| DOR in tumors with CPS ≥50 | Duration of response by RECIST v1.1 in tumors with CPS ≥50 | 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 | 
| 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 |