A Study of TransCon TLR7/8 Agonist With or Without Pembrolizumab in Patients With Advanced or Metastatic Solid Tumors

Study Overview
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Brief Summary
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TransCon TLR7/8 Agonist is an investigational drug being developed for treatment of locally advanced or metastatic solid tumors. This Phase 1/2 study will evaluate TransCon TLR7/8 Agonist as monotherapy or in combination with pembrolizumab in dose escalation and dose expansion. Participants will receive intratumoral (IT) injection of TransCon TLR7/8 Agonist every cycle. The primary objectives are to evaluate safety and tolerability, and define the Maximum Tolerated Dose (MTD) and Recommended Phase 2 Dose (RP2D) of TransCon TLR7/8 Agonist alone or in combination with pembrolizumab.

Detailed Description
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Toll-like receptors (TLRs) are a class of proteins that play a key role in innate immune cell recognition of foreign pathogens, stimulating innate and adaptive immune responses. TransCon TLR7/8 Agonist is designed as a long-acting localized delivery prodrug of resiquimod, a potent toll-like receptor (TLR) 7/8 agonist, with the potential to prolong high local concentrations of resiquimod and promote potent anti-tumoral responses while reducing systemic drug exposure and related adverse events. TransCon TLR7/8 Agonist is expected to stimulate innate and adaptive immune response in the tumor microenvironment and enhance the activity of checkpoint inhibitors like pembrolizumab.

Official Title
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Phase 1/2, Open-label, Dose Escalation and Dose Expansion Study of TransCon TLR7/8 Agonist Alone or in Combination With Pembrolizumab in Participants With Locally Advanced or Metastatic Solid Tumor Malignancies

Conditions
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Advanced Solid Tumor, Locally Advanced Solid Tumor, Metastatic Solid Tumor, Head and Neck Squamous Cell Carcinoma HNSCC, HPV-associated Cancers, Neoadjuvant Melanoma, Neoadjuvant Cutaneous Squamous Cell Carcinoma (cSCC)

Intervention / Treatment
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* Drug: TransCon TLR7/8 Agonist
* Drug: Pembrolizumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: At least 18 years of age. Participants must have histologically confirmed locally advanced, recurrent or metastatic solid tumor malignancies that cannot be treated with curative intent (surgery or radiotherapy). Participants must have progressed on or be intolerant of available standard of care treatment options or have disease for which there is no standard of care treatment available, with the exception of participants enrolling to the neoadjuvant cohorts. At least 2 lesions of measurable disease, unless specified otherwise in the selection criteria. Willingness to undergo biopsies. Demonstrated adequate organ function within 28 days of Cycle 1 Day 1 (C1D1). Life expectancy >12 weeks as determined by the Investigator. Eastern Cooperative Oncology Group (ECOG) performance status 0, 1, or 2. Participants who have undergone treatment with anti-PD-1, anti-PD-L1, or antiCTLA 4 antibody must have at least 4 weeks from the last dose of antibody and evidence of disease progression per investigator assessment before enrollment. Participants who have previously received an immune checkpoint inhibitor prior to enrollment must have any immune related toxicities resolved to ≤Grade 1 or baseline (prior to the checkpoint inhibitor) to be eligible. Female and male participants of childbearing potential who are sexually active must agree to use highly effective methods of contraception. Exclusion Criteria: Participants who have been previously treated with a TLR agonist (excluding topical agents for unrelated disease) are not eligible. Other active malignancies within the last 2 years are excluded. Active autoimmune diseases, regardless of need for immunosuppressive treatment at the time of screening, with the exception of patients well controlled on physiologic endocrine replacement. Systemic immunosuppressive treatment with the exception for patients on corticosteroid taper (for example, for chronic obstructive pulmonary disease exacerbation). Participants cannot start dosing on study until steroid dose is at or lower than 10 mg per day prednisone or equivalent. Women who are breastfeeding or have a positive serum pregnancy test during screening or within 72 hours prior to C1D1 are not eligible. Vaccination with live, attenuated vaccines within 4 weeks of enrollment. Symptomatic central nervous system metastases. Known bleeding disorder that is deemed to place the patient at unacceptable risk for bleeding complications from intratumoral injections or biopsies. Known hypersensitivity to any component of TransCon TLR7/8 Agonist or pembrolizumab. Any uncontrolled bacterial, fungal, viral, or other infection. Treatment with any other anti-cancer systemic treatment (approved or investigational) or radiation therapy within 4 weeks of first dosing on study is not allowed. Significant cardiac disease A marked baseline prolongation of QT/QTc (corrected QT) interval (e.g., repeated demonstration of a QTc interval >480 ms (National Cancer Institute NCI) Common Terminology Criteria for Adverse Events [CTCAE] grade 1) using Fredericia's QT correction formula. A history of additional risk factors for Torsades de Pointes (TdP) (e.g., heart failure, clinically significant hypokalemia, family history of Long QT Syndrome). The use of concomitant medications that prolong the QT/QTc interval within 14 days of enrollment. Positive for HIV or with active hepatitis B or C infection.

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: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part 1 Monotherapy Dose Escalation and Optimization: TransCon TLR7/8 Agonist<br>TransCon TLR7/8 Agonist in escalating doses to evaluate safety/tolerability and to determine the MTD and RP2D. | Drug: TransCon TLR7/8 Agonist<br>* TransCon TLR7/8 Agonist will be administered as an IT injection<br>|
| Experimental: Part 2 Combination Dose Escalation and Optimization: TransCon TLR7/8 Agonist with Pembrolizumab<br>TransCon TLR7/8 Agonist with Pembrolizumab in escalating doses to evaluate safety/tolerability and determine the MTD and RP2D. | Drug: TransCon TLR7/8 Agonist<br>* TransCon TLR7/8 Agonist will be administered as an IT injection<br>Drug: Pembrolizumab<br>* Pembrolizumab will be administered IV<br>|
| Experimental: Part 3 Phase 2 Combination Dose Expansion: TransCon TLR7/8 Agonist with Pembrolizumab<br>TransCon TLR7/8 Agonist with Pembrolizumab using RP2D from Part 2 to evaluate safety/tolerability and anti-tumor activity of the combination in indication-specific dose expansion cohorts. | Drug: TransCon TLR7/8 Agonist<br>* TransCon TLR7/8 Agonist will be administered as an IT injection<br>Drug: Pembrolizumab<br>* Pembrolizumab will be administered IV<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and Tolerability | Treatment emergent and treatment related adverse events (assessed by CTCAE v5.0), serious adverse events (SAEs), adverse events leading to treatment discontinuation, deaths | Through study completion, expected average of 2 years | 
| Maximum Tolerated Dose (MTD) | Determine the maximum tolerated dose by assessing the Incidence of Dose Limiting Toxicities (DLTs), treatment emergent and treatment related adverse events (assessed by CTCAE v5.0), serious adverse events (SAEs), adverse events leading to treatment discontinuation and deaths. | Cycle 1 (each cycle is 21 days) in Part 1 (monotherapy dose escalation) and Cycle 1 (the first cycle is 28 days and 21 days thereafter) in Part 2 (combination therapy dose escalation) | 
| Recommended Phase 2 Dose (RP2D) | To determine a recommended phase 2 dose of TransCon TLR7/8 Agonist and combination regimen for further development by evaluating number of patients with treatment-related adverse events as assessed by CTCAE. | 12 months | 
| Response | Evaluate the Pathologic complete response (pCR) per local assessment for pathology review anti-tumor activity of TransCon TLR7/8 Agonist in combination with pembrolizumab in the Neoadjuvant Cohorts | 9 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate | Response assessed by RECIST v1.1 and itRECIST (response assessment for intratumoral immunotherapy for injected and noninjected lesions) | Average of two years | 
| Duration of Response | Time from first documentation of objective tumor response (CR or PR that is subsequently confirmed) to first documentation of disease progression or death due to any cause, whichever occurs first | Average of two years | 
| Time to Response | Time from date of first dose of study treatment to first occurrence of response (CR or PR) | Expected up to 1 year from first dose | 
| Progression Free Survival (PFS) | Time from date of first dose of study treatment to first documentation of disease progression or death due to any cause | Average of two years | 
| Event free survival (EFS) by RECIST 1.1 per investigator assessment |  | Average of two years | 
| Overall Survival (OS) | Time from date of first dose of study treatment to date of death due to any cause | Average of two years | 
| PK characterization - Cmax | Maximum observed plasma concentration of resiquimod, O-desethyl resiquimod (metabolite) and total resiquimod (sum of bound and unbound resiquimod) after IT administration of TransCon TLR7/8 Agonist alone or in combination with pembrolizumab | Average of two years | 
| PK characterization - tmax | Time to reach maximum plasma concentration of resiquimod, O-desethyl resiquimod (metabolite) and total resiquimod (sum of bound and unbound resiquimod) after IT administration of TransCon TLR7/8 Agonist alone or in combination with pembrolizumab | Average of two years | 
| PK characterization - AUC0-t for first dose only | Area under the plasma concentration-time curve from time zero to last sampling time at which the concentration is at or above the lower limit of quantification for resiquimod, O-desethyl resiquimod (metabolite) and total resiquimod (sum of bound and unbound resiquimod) after IT administration of TransCon TLR7/8 Agonist alone or in combination with pembrolizumab | Average of two years | 
| PK characterization - t1/2 | Apparent terminal half-life of resiquimod, O-desethyl resiquimod (metabolite) and total resiquimod (sum of bound and unbound resiquimod) after IT administration of TransCon TLR7/8 Agonist alone or in combination with pembrolizumab | Average of two years | 
| PK characterization - Ctrough | Plasma concentration immediately before next dosing of resiquimod, O-desethyl resiquimod (metabolite) and total resiquimod (sum of bound and unbound resiquimod) after IT administration of TransCon TLR7/8 Agonist alone or in combination with pembrolizumab | Average of two years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Ascendis Pharma, TransCon TLR7/8 Agonist, Locally Advanced Solid Tumor, Metastatic Solid Tumor, Advanced Solid Tumor