Clinical trial NCT04799054: A Study of TransCon TLR7/8 Agonist With or Without Pembrolizumab in Patients With Advanced or Metastatic Solid Tumors
Official title: 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
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE1
PHASE2
Conditions: 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)
Keywords: Ascendis Pharma
TransCon TLR7/8 Agonist
Locally Advanced Solid Tumor
Metastatic Solid Tumor
Advanced Solid Tumor
Lead sponsor: Ascendis Pharma A/S
Sponsor class: INDUSTRY
First posted: 2021-03-16
Enrollment: 188
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Safety and Tolerability
timeFrame: Through study completion, expected average of 2 years
measure: Maximum Tolerated Dose (MTD)
timeFrame: 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)
measure: Recommended Phase 2 Dose (RP2D)
timeFrame: 12 months
measure: Response
timeFrame: 9 weeks
Secondary outcomes:
measure: Overall Response Rate
timeFrame: Average of two years
measure: Duration of Response
timeFrame: Average of two years
measure: Time to Response
timeFrame: Expected up to 1 year from first dose
measure: Progression Free Survival (PFS)
timeFrame: Average of two years
measure: Event free survival (EFS) by RECIST 1.1 per investigator assessment
timeFrame: Average of two years
measure: Overall Survival (OS)
timeFrame: Average of two years
measure: PK characterization - Cmax
timeFrame: Average of two years
measure: PK characterization - tmax
timeFrame: Average of two years
measure: PK characterization - AUC0-t for first dose only
timeFrame: Average of two years
measure: PK characterization - t1/2
timeFrame: Average of two years
measure: PK characterization - Ctrough
timeFrame: Average of two years
Other outcomes:
Locations:
city: Duarte
country: United States
facility: Ascendis Pharma Investigational Site
state: California
city: Los Angeles
country: United States
facility: Ascendis Investigational Site
state: California
city: Orange
country: United States
facility: Ascendis Investigational Site
state: California
city: San Francisco
country: United States
facility: Ascendis Pharma Investigational Site
state: California
city: Tampa
country: United States
facility: Ascendis Investigational Site
state: Florida
city: Chicago
country: United States
facility: Ascendis Pharma Investigational Site
state: Illinois
city: Iowa City
country: United States
facility: Ascendis Pharma Investigational Site
state: Iowa
city: Louisville
country: United States
facility: Ascendis Pharma Investigational Site
state: Kentucky
city: Canton
country: United States
facility: Ascendis Pharma Investigational Site
state: Ohio
city: Cincinnati
country: United States
facility: Ascendis Pharma Investigational Site
state: Ohio
city: Cleveland
country: United States
facility: Ascendis Pharma Investigational Site
state: Ohio
city: Pittsburgh
country: United States
facility: Ascendis Pharma Investigational Site
state: Pennsylvania
city: Knoxville
country: United States
facility: Ascendis Pharma Investigational Site
state: Tennessee
city: Dallas
country: United States
facility: Ascendis Investigational Site
state: Texas
city: Dallas
country: United States
facility: Ascendis Investigational Site
state: Texas
city: Houston
country: United States
facility: Ascendis Investigational Site
state: Texas
city: Fairfax
country: United States
facility: Ascendis Pharma Investigational Site
state: Virginia
city: Wollongong
country: Australia
facility: Ascendis Pharma Investigational Site
state: New South Wales
city: Frankston
country: Australia
facility: Ascendis Pharma Investigational Site
state: Victoria
city: Bedford Park
country: Australia
facility: Ascendis Investigational Site
city: Dalseo-gu
country: Korea, Republic of
facility: Ascendis Investigational Site
city: Seocho-gu
country: Korea, Republic of
facility: Ascendis Investigational Site
city: Seogu
country: Korea, Republic of
facility: Ascendis Investigational Site
city: Seogu
country: Korea, Republic of
facility: Ascendis Investigational Site
city: Seongnam
country: Korea, Republic of
facility: Ascendis Investigational Site
city: Seoul
country: Korea, Republic of
facility: Ascendis Investigational Site
city: Seoul
country: Korea, Republic of
facility: Ascendis Investigational Site
city: Seoul
country: Korea, Republic of
facility: Ascendis Investigational Site
city: Suwon-si
country: Korea, Republic of
facility: Ascendis Investigational Site
city: Suwon-si
country: Korea, Republic of
facility: Ascendis Investigational Site
city: Amsterdam
country: Netherlands
facility: Ascendis Investigational Site
city: Rotterdam
country: Netherlands
facility: Ascendis Investigational Site
city: Barcelona
country: Spain
facility: Ascendis Investigational Site
city: Barcelona
country: Spain
facility: Ascendis Investigational Site
city: Barcelona
country: Spain
facility: Ascendis Investigational Site
city: Barcelona
country: Spain
facility: Ascendis Investigational Site
city: Madrid
country: Spain
facility: Ascendis Investigational Site
city: Madrid
country: Spain
facility: Ascendis Investigational Site
city: Madrid
country: Spain
facility: Ascendis Investigational Site
city: Madrid
country: Spain
facility: Ascendis Investigational Site
city: Murcia
country: Spain
facility: Ascendis Investigational Site
city: Málaga
country: Spain
facility: Ascendis Investigational Site
city: Pamplona
country: Spain
facility: Ascendis Investigational Site
city: Sevilla
country: Spain
facility: Ascendis Investigational Site
city: Valencia
country: Spain
facility: Ascendis Investigational Site
city: Taichung
country: Taiwan
facility: Ascendis Investigational Site
city: Taichung
country: Taiwan
facility: Ascendis Investigational Site
city: Tainan
country: Taiwan
facility: Ascendis Investigational Site
city: Taipei City
country: Taiwan
facility: Ascendis Investigational Site
Study officials:
affiliation: Medical Monitor
name: Joan Morris
role: STUDY_DIRECTOR
References:
citation: Zuniga LA, Lessmann T, Uppal K, Bisek N, Hong E, Rasmussen CE, Karlsson JJ, Zettler J, Holten-Andersen L, Bang K, Thakar D, Lee YC, Martinez S, Sabharwal SS, Stark S, Faltinger F, Kracker O, Weisbrod S, Muller R, Voigt T, Bigott K, Tabrizifard M, Breinholt VM, Mirza AM, Rosen DB, Sprogoe K, Punnonen J. Intratumoral delivery of TransCon TLR7/8 Agonist promotes sustained anti-tumor activity and local immune cell activation while minimizing systemic cytokine induction. Cancer Cell Int. 2022 Sep 19;22(1):286. doi: 10.1186/s12935-022-02708-6.