A Trial to Investigate TransCon TLR7/8 Agonist in Combination with Pembrolizumab, TransCon TLR7/8 Agonist in Combination with TransCon IL-2 β/γ, or Pembrolizumab Monotherapy as Neoadjuvant Therapy in Participants with Stage III-IVA Resectable Locoregionally Advanced Head and Neck Squamous Cell Carcinoma (LA-HNSCC)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Ascendis Pharma Oncology Division A/S

Participant type

Patients

Age range

18-64 years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

11 Mar 2024 → 29 Mar 2025

Decision date (initial)

2024-02-09

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

Ascendis Pharma Oncology Division A/S

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Therapy, Efficacy, Others

To evaluate MPR of TransCon TLR7/8 Agonist in combination with pembrolizumab and TransCon TLR7/8 Agonist in combination with TransCon IL-2 β/γ as compared with pembrolizumab monotherapy

Secondary objectives 2

1. To evaluate the anti-tumor activity of TransCon TLR7/8 Agonist in combination with pembrolizumab and TransCon TLR7/8 Agonist in combination with TransCon IL-2 β/γ as compared with pembrolizumab monotherapy
2. To evaluate the safety and tolerability of TransCon TLR7/8 Agonist in combination with pembrolizumab and TransCon TLR7/8 Agonist in combination with TransCon IL-2 β/γ

Conditions and MedDRA coding

Stage III-IVA Resectable Locoregionall Advanced Head and Neck Squamous Cell Carcinoma (LA-HNSCC)

Study design 1 period

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 12

1. Participants must be at least 18 years of age at the time of signing the informed consent
2. 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
3. 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
4. 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
5. Is eligible and plans for primary LA-HNSCC surgery based on investigator decision and per local practice
6. 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
7. 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
8. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
9. 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
10. Has at least one lesion that is deemed by the investigator to be easily and safely accessible for IT injection
11. 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
12. 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 12

1. 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.
2. 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
3. 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)
4. Positive for HIV
5. 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
6. 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
7. A known bleeding disorder that is deemed to place the participant at unacceptable risk for bleeding complications from IT injections or biopsies
8. 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
9. Has received prior radiotherapy or systemic anticancer therapy for HNSCC
10. 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
11. Vaccination with live, attenuated vaccines within 4 weeks of C1D1
12. Women who are breastfeeding or have a positive serum pregnancy test

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. MPR as assessed by external independent pathology review (IPR) is defined as ≤10% invasive squamous cell carcinoma (SCC) within the resected primary tumor specimen and all sampled regional lymph nodes

Secondary endpoints 6

1. Pathological complete response (pCR) as assessed by external IPR at the time of definitive surgery is defined as no residual invasive SCC within the resected primary tumor specimen and all sampled regional lymph nodes
2. pCR per local assessment for pathological review
3. MPR per local assessment for pathological review
4. EFS is defined as the time from the date of randomization to the date of first record of any of the following events: disease progression; local or distant recurrence as assessed with imaging or biopsy as indicated, or death due to any cause
5. OS is defined as the time from randomization to death due to any cause
6. Incidence and severity of adverse events (AEs) and serious adverse events (SAEs)

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 3

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Ascendis Pharma Oncology Division A/S

Sponsor organisation

Ascendis Pharma Oncology Division A/S

Address

Tuborg Boulevard 12

City

Hellerup

Postcode

2900

Country

Denmark

Scientific contact point

Organisation

Ascendis Pharma Oncology Division A/S

Contact name

Joan Morris

Public contact point

Organisation

Ascendis Pharma Oncology Division A/S

Contact name

Joan Morris

Third parties 8

Locations

5 EU/EEA countries · 44 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Summary of results Art. 37(4) CTR

Layperson summary Annex V

Documents 47 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

8 submissions — initial application plus substantial / non-substantial modifications