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)
Conditions
Keywords
Ascendis Pharma, TransCon TLR7/8 Agonist, Locally Advanced Solid Tumor, Metastatic Solid Tumor, Advanced Solid Tumor
Brief summary
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
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.
Interventions
TransCon TLR7/8 Agonist will be administered as an IT injection
DRUGPembrolizumab
Pembrolizumab will be administered IV
Sponsors
Ascendis Pharma Oncology Division A/S
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Safety and Tolerability | Through study completion, expected average of 2 years | Treatment emergent and treatment related adverse events (assessed by CTCAE v5.0), serious adverse events (SAEs), adverse events leading to treatment discontinuation, deaths |
| Maximum Tolerated Dose (MTD) | 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) | 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. |
| Recommended Phase 2 Dose (RP2D) | 12 months | 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. |
| Response | 9 weeks | 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 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Response Rate | Average of two years | Response assessed by RECIST v1.1 and itRECIST (response assessment for intratumoral immunotherapy for injected and noninjected lesions) |
| Duration of Response | Average of two years | 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 |
| Time to Response | Expected up to 1 year from first dose | Time from date of first dose of study treatment to first occurrence of response (CR or PR) |
| Progression Free Survival (PFS) | Average of two years | Time from date of first dose of study treatment to first documentation of disease progression or death due to any cause |
| Event free survival (EFS) by RECIST 1.1 per investigator assessment | Average of two years | — |
| Overall Survival (OS) | Average of two years | Time from date of first dose of study treatment to date of death due to any cause |
| PK characterization - Cmax | Average of two years | 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 |
| PK characterization - tmax | Average of two years | 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 |
| PK characterization - AUC0-t for first dose only | Average of two years | 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 |
| PK characterization - t1/2 | Average of two years | 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 |
| PK characterization - Ctrough | Average of two years | 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 |
Countries
Australia, Netherlands, South Korea, Spain, Taiwan, United States
Contacts
STUDY_DIRECTORJoan Morris
Medical Monitor
Outcome results
None listed