Description:
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.
Title
- Brief Title: 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
Clinical Trial IDs
- ORG STUDY ID:
TCTLR-101
- SECONDARY ID:
transcendIT-101
- NCT ID:
NCT04799054
Conditions
- Advanced Solid Tumor
- Locally Advanced Solid Tumor
- Metastatic Solid Tumor
Interventions
Drug | Synonyms | Arms |
---|
TransCon TLR7/8 Agonist | | Part 1 Dose Escalation: TransCon TLR7/8 Agonist |
Pembrolizumab | | Part 2 Dose Escalation: TransCon TLR7/8 Agonist with Pembrolizumab |
Purpose
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.
Trial Arms
Name | Type | Description | Interventions |
---|
Part 1 Dose Escalation: TransCon TLR7/8 Agonist | Experimental | TransCon TLR7/8 Agonist in escalating doses to evaluate safety/tolerability and to determine the MTD and RP2D. | |
Part 2 Dose Escalation: TransCon TLR7/8 Agonist with Pembrolizumab | Experimental | TransCon TLR7/8 Agonist with Pembrolizumab in escalating doses to evaluate safety/tolerability and determine the MTD and RP2D. | - TransCon TLR7/8 Agonist
- Pembrolizumab
|
Part 3 Dose Expansion: TransCon TLR7/8 Agonist with Pembrolizumab | Experimental | TransCon TLR7/8 Agonist with Pembrolizumab using RP2D from Part 2 to evaluate safety/tolerability and anti-tumor activity of the combination. | - TransCon TLR7/8 Agonist
- 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.
- At least 2 lesions of measurable disease.
- Willingness to undergo biopsies.
- Demonstrated adequate organ function within 14 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 anti-CTLA-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.
- Participants who have received systemic interferon alpha within the previous 24 weeks
prior to enrollment 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 48 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 interval (e.g., repeated demonstration of a
QTc interval >480 milliseconds (ms) (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.
Maximum Eligible Age: | N/A |
Minimum Eligible Age: | 18 Years |
Eligible Gender: | All |
Healthy Volunteers: | No |
Primary Outcome Measures
Measure: | Safety and Tolerability |
Time Frame: | Through study completion, expected average of 2 years |
Safety Issue: | |
Description: | Treatment emergent and treatment related adverse events (assessed by CTCAE v5.0), serious adverse events (SAEs), adverse events leading to treatment discontinuation, deaths |
Secondary Outcome Measures
Measure: | Overall Response Rate |
Time Frame: | Average of two years |
Safety Issue: | |
Description: | Response assessed by RECIST v1.1 and itRECIST (response assessment for intratumoral immunotherapy for injected and noninjected lesions) |
Measure: | Duration of Response |
Time Frame: | Average of two years |
Safety Issue: | |
Description: | 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 |
Measure: | Time to Response |
Time Frame: | Expected up to 1 year from first dose |
Safety Issue: | |
Description: | Time from date of first dose of study treatment to first occurrence of response (CR or PR) |
Measure: | Progression Free Survival (PFS) |
Time Frame: | Average of two years |
Safety Issue: | |
Description: | Time from date of first dose of study treatment to first documentation of disease progression or death due to any cause |
Measure: | Overall Survival (OS) |
Time Frame: | Average of two years |
Safety Issue: | |
Description: | Time from date of first dose of study treatment to date of death due to any cause |
Measure: | PK characterization - Cmax |
Time Frame: | Average of two years |
Safety Issue: | |
Description: | 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 |
Measure: | PK characterization - tmax |
Time Frame: | Average of two years |
Safety Issue: | |
Description: | 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 |
Measure: | PK characterization - AUC0-t for first dose only |
Time Frame: | Average of two years |
Safety Issue: | |
Description: | 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 |
Measure: | PK characterization - t1/2 |
Time Frame: | Average of two years |
Safety Issue: | |
Description: | 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 |
Measure: | PK characterization - Ctrough |
Time Frame: | Average of two years |
Safety Issue: | |
Description: | 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 |
Details
Phase: | Phase 1/Phase 2 |
Primary Purpose: | Interventional |
Overall Status: | Recruiting |
Lead Sponsor: | Ascendis Pharma Oncology Division A/S |
Trial Keywords
- Ascendis Pharma
- TransCon TLR7/8 Agonist
- Locally Advanced Solid Tumor
- Metastatic Solid Tumor
- Advanced Solid Tumor
Last Updated
August 26, 2021