TransCon (TC) TLR7/8 Agonist, TC IL-2 β/γ, Pembrolizumab Prior to Surgery for Advanced Head and Neck Squamous Cell Carcinoma

Study Overview
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Brief Summary
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The purpose of this trial is to evaluate the safety and efficacy of TransCon TLR7/8 Agonist, TransCon IL-2 β/γ, and pembrolizumab given prior to curative intent surgery in treatment of participants with newly diagnosed Stage III/IVA resectable locoregionally advanced head and neck squamous cell carcinoma (LA-HNSCC). After surgery, participants will receive local standard-of-care treatment and will be followed for safety, efficacy, and survival for up to 2 years. This trial contains a safety run-in to evaluate the safety and tolerability of the two treatment arms: Arm A (TransCon TLR7/8 Agonist plus pembrolizumab) and Arm B (TransCon TLR7/8 Agonist plus TransCon IL-2 β/γ). The safety run-in will be followed by the randomized Phase 2, open-label part of the trial comparing the safety, efficacy and survival of treatment Arm A or Arm B compared to treatment Arm C (pembrolizumab monotherapy).

Detailed Description
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This is a randomized, Phase 2, open-label, multicenter trial of 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 LA-HNSCC. This trial starts with a safety run-in of 12 participants, 6 participants each in Arms A (TransCon TLR7/8 Agonist plus pembrolizumab) and B (TransCon TLR7/8 Agonist plus TransCon IL-2 β/γ) randomized 1:1. After completing the safety run-in, 80 participants will be randomized in a 2:2:1 ratio in 3 treatment Arms A, B or C (pembrolizumab monotherapy). Once randomized, participants should begin treatment within 5 calendar days. Participants enrolled after the safety run-in, into the 2:2:1 randomization part of the trial, will be stratified as follows: oropharyngeal HPV p16 positive versus oropharyngeal HPV p16 negative or larynx/hypopharyngeal/oral cavity regardless of HPV p16 status. All participants should receive study drug(s) every 21 days (Q21D) for 2 cycles followed by curative-intent surgery. After surgery, participants may receive standard-of-care treatment in the adjuvant setting, as per investigator's decision and local guidelines.

Official Title
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BelieveIT-201: Phase 2, Randomized Open-labeled Trial of TransCon (TC) TLR7/8 Agonist in Combination With Pembrolizumab or With TC IL-2 β/γ, or Pembrolizumab Alone as Neoadjuvant Therapy for Stage III-IVA Resectable Locoregionally Advanced Head and Neck Squamous Cell Carcinoma

Conditions
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Head and Neck Neoplasms

Intervention / Treatment
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* Drug: TransCon TLR7/8 Agonist
* Drug: Pembrolizumab
* Drug: TransCon IL-2 β/γ


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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 (M) 0; Stage III or IVA oropharyngeal tumor HPV-negative; or Stage III or IVA larynx/hypopharynx/oral cavity primaries regardless of HPV status (per American Joint Committee on Cancer [AJCC] Staging, 8th edition). 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 tumor HPV status by p16 immunohistochemistry (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. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1. Has at least one lesion that is deemed by the investigator to be easily and safely accessible for IT injection. Exclusion Criteria: Active autoimmune conditions. Has significant cardiac disease. Has a known bleeding disorder that is deemed to place the participant at unacceptable risk for bleeding complications from IT injections or biopsies. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy (in doses exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to randomization.

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: TransCon TLR7/8 Agonist in combination with pembrolizumab<br>Participants receive 2 cycles, once every 3 weeks of TransCon TLR7/8 Agonist intratumoral (IT) injection in combination with pembrolizumab as a 30-minute intravenous (IV) infusion | Drug: TransCon TLR7/8 Agonist<br>* TLR7/8 agonist prodrug<br>Drug: Pembrolizumab<br>* A type of immunotherapy that works by blocking the PD-1 pathway to help prevent cancer cells from hiding<br>* Other names: Keytruda™;|
| Experimental: TransCon TLR7/8 Agonist in combination with TransCon IL-2 β/γ<br>Participants receive 2 cycles, once every 3 weeks of TransCon TLR7/8 Agonist (IT injection) in combination with TransCon IL-2 β/γ as a 30-minute IV infusion | Drug: TransCon TLR7/8 Agonist<br>* TLR7/8 agonist prodrug<br>Drug: TransCon IL-2 β/γ<br>* Sustained systemic release of IL-2 β/γ with selective receptor binding that may stimulate the immune system to kill cancer cells<br>|
| Active Comparator: Pembrolizumab<br>Participants receive 2 cycles, once every 3 weeks of pembrolizumab alone as a 30-minute IV infusion | Drug: Pembrolizumab<br>* A type of immunotherapy that works by blocking the PD-1 pathway to help prevent cancer cells from hiding<br>* Other names: Keytruda™;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Major Pathological Response | The proportion of participants with a major pathological response (mPR) as assessed by the Central Pathologist at the time of definitive surgery. mPR is defined as ≤10% invasive squamous cell carcinoma within the resected primary tumor specimen and all the sampled regional lymph nodes. | Up to 6 weeks after Cycle 2 (each cycle is 21 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pathological Complete Response | A central pathology laboratory and local hospital pathologist will evaluate if all the tumor is completely gone from the primary tumor and all the lymph nodes that were removed at surgery. | Up to 6 weeks after Cycle 2 (each cycle is 21 days) | 
| Event Free Survival | 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 determined by radiology scans or tumor biopsy as needed, or death due to any cause. | Up to 5 years | 
| Overall Survival | The time from randomization to death due to any cause. | Up to 5 years | 
| Safety and Tolerability | Incidence and severity of adverse events (AEs) and serious adverse events (SAEs). | From time of signing of the ICF up to 100 (±7) days following the last dose of study drug | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Neoadjuvant Head and Neck, HNSCC, Head and Neck Cancer, TransCon TLR7/8 Agonist, TC TLR7/8, TransCon IL-2 β/γ, TC IL-2 β/γ, Neoadjuvant, LA-HNSCC, Locoregionally Advanced HNSCC