Clinical Trials /

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

NCT04799054

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.

Related Conditions:
  • Malignant Solid Tumor
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

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

DrugSynonymsArms
TransCon TLR7/8 AgonistPart 1 Dose Escalation: TransCon TLR7/8 Agonist
PembrolizumabPart 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

NameTypeDescriptionInterventions
Part 1 Dose Escalation: TransCon TLR7/8 AgonistExperimentalTransCon TLR7/8 Agonist in escalating doses to evaluate safety/tolerability and to determine the MTD and RP2D.
  • TransCon TLR7/8 Agonist
Part 2 Dose Escalation: TransCon TLR7/8 Agonist with PembrolizumabExperimentalTransCon 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 PembrolizumabExperimentalTransCon 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