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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04799054
Recruitment Status : Recruiting
First Posted : March 16, 2021
Last Update Posted : September 23, 2022
Sponsor:
Information provided by (Responsible Party):
Ascendis Pharma A/S ( Ascendis Pharma Oncology Division A/S )

Tracking Information
First Submitted Date  ICMJE February 26, 2021
First Posted Date  ICMJE March 16, 2021
Last Update Posted Date September 23, 2022
Actual Study Start Date  ICMJE March 18, 2021
Estimated Primary Completion Date May 2025   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: September 21, 2022)
  • Safety and Tolerability [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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 [ Time Frame: 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
Original Primary Outcome Measures  ICMJE
 (submitted: March 11, 2021)
  • Safety and Tolerability [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: September 21, 2022)
  • Overall Response Rate [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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) [ Time Frame: 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 [ Time Frame: Average of two years ]
  • Overall Survival (OS) [ Time Frame: Average of two years ]
    Time from date of first dose of study treatment to date of death due to any cause
  • PK characterization - Cmax [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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
Original Secondary Outcome Measures  ICMJE
 (submitted: March 11, 2021)
  • Overall Response Rate [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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) [ Time Frame: 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
  • Overall Survival (OS) [ Time Frame: Average of two years ]
    Time from date of first dose of study treatment to date of death due to any cause
  • PK characterization - Cmax [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE A Study of TransCon TLR7/8 Agonist With or Without Pembrolizumab in Patients With Advanced or Metastatic Solid Tumors
Official Title  ICMJE 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
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.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • 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  ICMJE
  • Drug: TransCon TLR7/8 Agonist
    TransCon TLR7/8 Agonist will be administered as an IT injection
  • Drug: Pembrolizumab
    Pembrolizumab will be administered IV
Study Arms  ICMJE
  • Experimental: Part 1 Monotherapy Dose Escalation and Optimization: TransCon TLR7/8 Agonist
    TransCon TLR7/8 Agonist in escalating doses to evaluate safety/tolerability and to determine the MTD and RP2D.
    Intervention: Drug: TransCon TLR7/8 Agonist
  • Experimental: Part 2 Combination Dose Escalation and Optimization: TransCon TLR7/8 Agonist with Pembrolizumab
    TransCon TLR7/8 Agonist with Pembrolizumab in escalating doses to evaluate safety/tolerability and determine the MTD and RP2D.
    Interventions:
    • Drug: TransCon TLR7/8 Agonist
    • Drug: Pembrolizumab
  • Experimental: Part 3 Phase 2 Combination Dose Expansion: TransCon TLR7/8 Agonist with Pembrolizumab
    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.
    Interventions:
    • Drug: TransCon TLR7/8 Agonist
    • Drug: Pembrolizumab
Publications * Zúñiga 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, Müller R, Voigt T, Bigott K, Tabrizifard M, Breinholt VM, Mirza AM, Rosen DB, Sprogøe 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.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: September 21, 2022)
220
Original Estimated Enrollment  ICMJE
 (submitted: March 11, 2021)
140
Estimated Study Completion Date  ICMJE March 2026
Estimated Primary Completion Date May 2025   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Mona Vimal +1-650-512-6411 mov@ascendispharma.com
Listed Location Countries  ICMJE Australia,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04799054
Other Study ID Numbers  ICMJE TCTLR-101
transcendIT-101 ( Other Identifier: Ascendis Pharma )
Has Data Monitoring Committee Not Provided
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Current Responsible Party Ascendis Pharma A/S ( Ascendis Pharma Oncology Division A/S )
Original Responsible Party Same as current
Current Study Sponsor  ICMJE Ascendis Pharma Oncology Division A/S
Original Study Sponsor  ICMJE Same as current
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Joan Morris Medical Monitor
PRS Account Ascendis Pharma A/S
Verification Date September 2022

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP