Evaluation of TransCon TLR7/8 Agonist and Pembrolizumab, Alone or Combined with TransCon IL-2 β/γ, in Stage III-IVA Resectable LA-HNSCC
- Trial ID
- 2023-506092-10-00
- Protocol
- ASND0038
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the **major pathological response (MPR)** of the **TransCon TLR7/8 Agonist** in combination with **pembrolizumab** and the TransCon TLR7/8 Agonist in combination with **TransCon IL-2 β/γ**, compared to pembrolizumab monotherapy. This is clinically relevant as it aims to determine the efficacy of these combination therapies as neoadjuvant treatments in patients with Stage III-IVA resectable locoregionally advanced head and neck squamous cell carcinoma (LA-HNSCC), potentially improving surgical outcomes and long-term prognosis.
Secondary objectives include: - Evaluating the anti-tumor activity of the TransCon TLR7/8 Agonist in combination with pembrolizumab and the TransCon TLR7/8 Agonist in combination with TransCon IL-2 β/γ, compared to pembrolizumab monotherapy. - Assessing the safety and tolerability of the TransCon TLR7/8 Agonist in combination with pembrolizumab and the TransCon TLR7/8 Agonist in combination with TransCon IL-2 β/γ. These objectives are crucial for understanding the potential benefits and risks associated with these novel therapeutic combinations.
Participants
The clinical trial involves a total of **49 participants** diagnosed with **Stage III-IVA Resectable Locoregionally Advanced Head and Neck Squamous Cell Carcinoma (LA-HNSCC)**. The study population includes both male and female subjects, all of whom are at least 18 years of age. Participants were selected based on their ability to provide informed consent and their eligibility for primary LA-HNSCC surgery, as determined by the investigator. The trial does not include a vulnerable population. Participants are required to have adequate organ function and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Lifestyle considerations such as diet, physical activity, or habits are not specified in the available data. The selection criteria ensure that participants have a local histologically confirmed new diagnosis of resectable, non-metastatic squamous cell carcinoma, with specific staging and HPV status requirements. The trial does not specify any particular lifestyle modifications or restrictions beyond the use of effective contraceptive methods for participants of childbearing potential.
Plans and Procedures
The clinical trial is designed to evaluate the **major pathological response (MPR)** of TransCon TLR7/8 Agonist in combination with **pembrolizumab**, TransCon TLR7/8 Agonist in combination with TransCon IL-2β/γ, and pembrolizumab monotherapy in participants with Stage III-IVA resectable locoregionally advanced head and neck squamous cell carcinoma (LA-HNSCC). This is a randomized, open-label, Phase II trial. The trial is expected to commence recruitment on February 20, 2024, and conclude by July 30, 2027. The study involves a series of visits, starting with a screening visit to confirm eligibility based on inclusion criteria such as age, tumor accessibility, and organ function. Participants will be randomly assigned to one of the treatment arms and will receive the investigational products via intravenous infusion or intratumoral use, depending on the assigned group.
Participants will undergo regular follow-up visits to monitor treatment response and safety, with assessments including imaging and laboratory tests. The primary endpoint is the MPR, defined as ≤10% invasive squamous cell carcinoma within the resected primary tumor specimen and all sampled regional lymph nodes. Secondary endpoints include pathological complete response (pCR), event-free survival (EFS), overall survival (OS), and the incidence and severity of adverse events. The trial will also assess the pathological response at the time of definitive surgery.
The expected duration of participant involvement is up to 42 days of treatment, with additional time for follow-up assessments. Conditions that may lead to early termination from the study include disease progression, unacceptable toxicity, or withdrawal of consent. Participants are required to adhere to the treatment schedule and assessments to avoid delays in definitive surgery. The trial aims to provide valuable insights into the efficacy of the investigational combinations as neoadjuvant therapy for LA-HNSCC.
Treatment
The clinical trial involves the administration of **TransCon IL-2 β/γ**, a biotechnological product formulated as a **solution for infusion**. This experimental medication is administered via **intravenous infusion**. The dosing regimen includes a maximum daily dose of 0.12 mg/kg and a total maximum dose of 0.24 mg/kg over a treatment period of 42 days. The active substance, **TransCon IL-2 β/γ**, is a protein-based compound developed by Ascendis Pharma Oncology Division A/S. Participant compliance with the dosing schedule will be monitored throughout the trial.
Another investigational product in the trial is the **TransCon TLR7/8 Agonist**, which is a chemical compound provided as a **suspension for injection**. This medication is administered through **intratumoral use**. The dosing schedule allows for a maximum daily dose of 0.5 mg/mL and a total maximum dose of 1 unit over a 42-day treatment period. The active substance, **ACP-017**, is a polymer-based compound developed by Ascendis Pharma Bone Diseases A/S. Compliance with the administration protocol will be closely monitored.
The trial also includes the use of **KEYTRUDA 25 mg/mL concentrate for solution for infusion**, a non-experimental treatment serving as a comparator. This medication is administered via **intravenous infusion**. The dosing regimen specifies a maximum daily dose of 200 mg and a total maximum dose of 400 mg over a 42-day treatment period. The active substance, **pembrolizumab**, is a protein-based compound manufactured by Merck Sharp & Dohme B.V. The product will be relabeled for the purpose of this clinical trial, and participant adherence to the dosing schedule will be monitored.
Efficacy
Efficacy in the clinical trial will be assessed using several primary and secondary endpoints. The primary endpoint is the **Major Pathological Response (MPR)**, which is defined as having 10% or less invasive squamous cell carcinoma (SCC) within the resected primary tumor specimen and all sampled regional lymph nodes. This will be evaluated by an external independent pathology review (IPR).
Secondary endpoints include the **Pathological Complete Response (pCR)**, assessed by external IPR at the time of definitive surgery, defined as no residual invasive SCC within the resected primary tumor specimen and all sampled regional lymph nodes. Additional secondary endpoints are pCR and MPR per local assessment for pathological review, Event-Free Survival (EFS), Overall Survival (OS), and the incidence and severity of adverse events (AEs) and serious adverse events (SAEs). EFS is defined as the time from the date of randomization to the date of first record of disease progression, local or distant recurrence, or death due to any cause. OS is defined as the time from randomization to death due to any cause.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Participants must be at least 18 years of age at the time of signing the informed consent
- Capable of giving signed informed consent as described in Appendix 3 of the protocol, which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol
- Has local histologically confirmed new diagnosis of resectable, non-metastatic SCC that is either: Stage III tumor HPV-positive oropharyngeal primary that is tumor size (T) 4, lymph node involvement (N) 0-2, no distant metastases (M0); Stage III or IVA oropharyngeal tumor HPV-negative; or Stage III or IVA larynx/hypopharynx/oral cavity primaries regardless of HPV status (as per American Joint Committee on Cancer [AJCC] Staging, 8th edition, see Appendix 13 of the protocol
- Has available archived or fresh core or excisional biopsy of a tumor lesion. Note: Fine needle aspirations may be allowed after discussion with Medical Monitor
- Is eligible and plans for primary LA-HNSCC surgery based on investigator decision and per local practice
- Has results from testing tumor HPV status by p16 IHC for oropharyngeal tumors. (HPV DNA analysis for HPV tumor status is acceptable if that is the local standard of care analysis
- Has adequate organ function at screening: 7.1 Total bilirubin ≤1.5 × upper limit of normal (ULN) (<3 × ULN if participant has history of Gilbert’s Syndrome). 7.2 Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≤3 × ULN. 7.3 Creatinine clearance (CrCl) ≥45 mL/min (calculated by the Cockcroft-Gault Equation, see Appendix 9 of the protocol). 7.4 Absolute neutrophil count (ANC) ≥1.0 × 10^9/L (1000/mm^3). 7.5 Hemoglobin ≥9 g/dL. 7.6 Platelet count ≥75 × 10^9/L (75,000/mm^3). 7.7 International normalized ratio (INR) and activated partial thromboplastin time (aPTT) ≤1.5 × ULN, unless participant is receiving anticoagulant therapy. 7.8 Thyroid-stimulating hormone (TSH) within normal limits. If TSH is not within normal limits, participant will be considered eligible if total T3 or free T4 are within normal limits
- Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
- In the opinion of the investigator, participant is able to adhere to the treatment schedule and required assessments so as not to incur a delay of the definitive surgery
- Has at least one lesion that is deemed by the investigator to be easily and safely accessible for IT injection
- For women of childbearing potential (WOCBP): agreement to remain abstinent (refrain from heterosexual intercourse) or use highly effective contraceptive methods (those with a failure rate of <1% per year), and agreement to refrain from donating eggs, from the time of a negative pregnancy test at screening, during the treatment period, and for 160 days after the last dose of study drug, or per local guidelines, whichever is longer
- For men with a female partner of childbearing potential or pregnant female partner: agreement to remain abstinent (refrain from heterosexual intercourse) or use a double barrier method of contraception (i.e., condom plus spermicide), and agreement to refrain from donating sperm during the treatment period (C1D1) and for 160 days following the last dose of study drug or per local guidelines, whichever is longer: For male participants with a female partner, see the paragraph in inclusion criterion 11 regarding the reliability of sexual abstinence
Exclusion Criteria
- Active autoimmune conditions, regardless of need for immunosuppressive treatment at the time of screening, with the exception of participants well controlled on physiologic endocrine replacement.
- Cardiopatía significativa definida por: 2.1 Insuficiencia cardíaca congestiva de clase III o IV según la Asociación Neoyorquina de Cardiología o la Sociedad Europea de Cardiología. 2.2 Angina inestable. 2.3 Infarto de miocardio en las últimas 24 semanas. 2.4 Hipertensión no controlada. 2.5 Arritmias cardíacas inestables
- Prolongación marcada inicial del intervalo QT/QTc (p. ej., demostración repetida de un intervalo QTc >480 ms) (Criterios Terminológicos Frecuentes para la Clasificación de Acontecimientos Adversos [grado 1 de los CTCAE]) utilizando el intervalo QT corregido según la fórmula de Fridericia (QTcF)
- Positive for HIV
- Has known active hepatitis B or C infection. 5.1 Active hepatitis B is defined as a known positive hepatitis B surface antigen (HbsAg) result. 5.2 Active hepatitis C is defined by a known positive hepatitis C antibody result and known quantitative HCV RNA results greater than the lower limits of detection of the local assay
- Has a history of other malignancy within the past 3 years, except for locally curable cancers that have been apparently cured or successfully resected, such as (but not limited to): basal or squamous cell skin cancer, superficial bladder cancer, gastric cancer, or carcinoma in situ of the prostate, cervix, or breast
- A known bleeding disorder that is deemed to place the participant at unacceptable risk for bleeding complications from IT injections or biopsies
- Prior treatment with or known hypersensitivity or allergy(ies) to any systemic anticancer treatment (approved or investigational) to include IL-2, IL-2 variants, TLR agonists, anti-PD-1, anti-PD-L1, and variants
- Has received prior radiotherapy or systemic anticancer therapy for HNSCC
- Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone or equivalent) or any other form of immunosuppressive therapy within 7 days prior to randomization
- Vaccination with live, attenuated vaccines within 4 weeks of C1D1
- Women who are breastfeeding or have a positive serum pregnancy test
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Germany | Not Recruiting | 20 Feb 2024 | 9 |
 Hungary | Not Recruiting | 20 Feb 2024 | 4 |
 Italy | Not Recruiting | 20 Feb 2024 | 8 |
 Poland | Not Recruiting | 20 Feb 2024 | 4 |
 Spain | Not Recruiting | 20 Feb 2024 | 18 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
TransCon IL-2 ß/ү | Test | SOLUTION FOR INFUSION | INTRAVENIOUS INFUSION | 0.12 | 42 | PRD10820825 |
TransCon TLR7/8 Agonist | Test | SUSPENSION FOR INJECTION | INTRATUMORAL USE | 0.5 | 42 | PRD9278735 |
KEYTRUDA 25 mg/mL concentrate for solution for infusion | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENIOUS INFUSION | 200 | 42 | PRD4323105 |