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

Primary Purpose

Advanced Solid Tumor, Locally Advanced Solid Tumor, Metastatic Solid Tumor

Status
Recruiting
Phase
Phase 1
Locations
International
Study Type
Interventional
Intervention
TransCon TLR7/8 Agonist
Pembrolizumab
Sponsored by
Ascendis Pharma Oncology Division A/S
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Advanced Solid Tumor focused on measuring Ascendis Pharma, TransCon TLR7/8 Agonist, Locally Advanced Solid Tumor, Metastatic Solid Tumor, Advanced Solid Tumor

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

  • Ascendis Pharma Investigational SiteRecruiting
  • Ascendis Pharma Investigational SiteRecruiting
  • Ascendis Pharma Investigational SiteRecruiting
  • Ascendis Pharma Investigational SiteRecruiting
  • Ascendis Pharma Investigational SiteRecruiting
  • Ascendis Pharma Investigational SiteRecruiting
  • Ascendis Pharma Investigational SiteRecruiting
  • Ascendis Pharma Investigational SiteRecruiting
  • Ascendis Pharma Investigational SiteRecruiting
  • Ascendis Pharma Investigational SiteRecruiting
  • Ascendis Pharma Investigational SiteRecruiting
  • Ascendis Pharma Investigational SiteRecruiting
  • Ascendis Pharma Investigational SiteRecruiting
  • Ascendis Pharma Investigational Site
  • Ascendis Pharma Investigational SiteRecruiting

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Experimental

Experimental

Arm Label

Part 1 Monotherapy Dose Escalation and Optimization: TransCon TLR7/8 Agonist

Part 2 Combination Dose Escalation and Optimization: TransCon TLR7/8 Agonist with Pembrolizumab

Part 3 Phase 2 Combination Dose Expansion: TransCon TLR7/8 Agonist with Pembrolizumab

Arm Description

TransCon TLR7/8 Agonist in escalating doses to evaluate safety/tolerability and to determine the MTD and RP2D.

TransCon TLR7/8 Agonist with Pembrolizumab in escalating doses to evaluate safety/tolerability and determine the MTD and RP2D.

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.

Outcomes

Primary Outcome Measures

Safety and Tolerability
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)
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)
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
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 Outcome Measures

Overall Response Rate
Response assessed by RECIST v1.1 and itRECIST (response assessment for intratumoral immunotherapy for injected and noninjected lesions)
Duration of Response
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 from date of first dose of study treatment to first occurrence of response (CR or PR)
Progression Free Survival (PFS)
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
Overall Survival (OS)
Time from date of first dose of study treatment to date of death due to any cause
PK characterization - Cmax
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 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
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
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
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

Full Information

First Posted
February 26, 2021
Last Updated
August 2, 2023
Sponsor
Ascendis Pharma Oncology Division A/S
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1. Study Identification

Unique Protocol Identification Number
NCT04799054
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
Study Type
Interventional

2. Study Status

Record Verification Date
August 2023
Overall Recruitment Status
Recruiting
Study Start Date
March 18, 2021 (Actual)
Primary Completion Date
May 2025 (Anticipated)
Study Completion Date
March 2026 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Ascendis Pharma Oncology Division A/S

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
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

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Sequential Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
220 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Part 1 Monotherapy Dose Escalation and Optimization: TransCon TLR7/8 Agonist
Arm Type
Experimental
Arm Description
TransCon TLR7/8 Agonist in escalating doses to evaluate safety/tolerability and to determine the MTD and RP2D.
Arm Title
Part 2 Combination Dose Escalation and Optimization: TransCon TLR7/8 Agonist with Pembrolizumab
Arm Type
Experimental
Arm Description
TransCon TLR7/8 Agonist with Pembrolizumab in escalating doses to evaluate safety/tolerability and determine the MTD and RP2D.
Arm Title
Part 3 Phase 2 Combination Dose Expansion: TransCon TLR7/8 Agonist with Pembrolizumab
Arm Type
Experimental
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
TransCon TLR7/8 Agonist
Intervention Description
TransCon TLR7/8 Agonist will be administered as an IT injection
Intervention Type
Drug
Intervention Name(s)
Pembrolizumab
Intervention Description
Pembrolizumab will be administered IV
Primary Outcome Measure Information:
Title
Safety and Tolerability
Description
Treatment emergent and treatment related adverse events (assessed by CTCAE v5.0), serious adverse events (SAEs), adverse events leading to treatment discontinuation, deaths
Time Frame
Through study completion, expected average of 2 years
Title
Maximum Tolerated Dose (MTD)
Description
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.
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)
Title
Recommended Phase 2 Dose (RP2D)
Description
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.
Time Frame
12 months
Title
Response
Description
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
Time Frame
9 weeks
Secondary Outcome Measure Information:
Title
Overall Response Rate
Description
Response assessed by RECIST v1.1 and itRECIST (response assessment for intratumoral immunotherapy for injected and noninjected lesions)
Time Frame
Average of two years
Title
Duration of Response
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
Time Frame
Average of two years
Title
Time to Response
Description
Time from date of first dose of study treatment to first occurrence of response (CR or PR)
Time Frame
Expected up to 1 year from first dose
Title
Progression Free Survival (PFS)
Description
Time from date of first dose of study treatment to first documentation of disease progression or death due to any cause
Time Frame
Average of two years
Title
Event free survival (EFS) by RECIST 1.1 per investigator assessment
Time Frame
Average of two years
Title
Overall Survival (OS)
Description
Time from date of first dose of study treatment to date of death due to any cause
Time Frame
Average of two years
Title
PK characterization - Cmax
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
Time Frame
Average of two years
Title
PK characterization - tmax
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
Time Frame
Average of two years
Title
PK characterization - AUC0-t for first dose only
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
Time Frame
Average of two years
Title
PK characterization - t1/2
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
Time Frame
Average of two years
Title
PK characterization - Ctrough
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
Time Frame
Average of two years

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
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.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Elizabeth Bradley
Phone
+1 650-520-8145
Email
ELBR@ascendispharma.com
First Name & Middle Initial & Last Name or Official Title & Degree
Joan Morris
Phone
+1 650-709-8737
Email
JMO@ascendispharma.com
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Joan Morris
Organizational Affiliation
Medical Monitor
Official's Role
Study Director
Facility Information:
Facility Name
Ascendis Pharma Investigational Site
City
Duarte
State/Province
California
ZIP/Postal Code
91010
Country
United States
Individual Site Status
Recruiting
Facility Name
Ascendis Pharma Investigational Site
City
San Francisco
State/Province
California
ZIP/Postal Code
94158
Country
United States
Individual Site Status
Recruiting
Facility Name
Ascendis Pharma Investigational Site
City
Stanford
State/Province
California
ZIP/Postal Code
94304
Country
United States
Individual Site Status
Recruiting
Facility Name
Ascendis Pharma Investigational Site
City
Chicago
State/Province
Illinois
ZIP/Postal Code
60637
Country
United States
Individual Site Status
Recruiting
Facility Name
Ascendis Pharma Investigational Site
City
Iowa City
State/Province
Iowa
ZIP/Postal Code
52242
Country
United States
Individual Site Status
Recruiting
Facility Name
Ascendis Pharma Investigational Site
City
Louisville
State/Province
Kentucky
ZIP/Postal Code
40202
Country
United States
Individual Site Status
Recruiting
Facility Name
Ascendis Pharma Investigational Site
City
Canton
State/Province
Ohio
ZIP/Postal Code
44718
Country
United States
Individual Site Status
Recruiting
Facility Name
Ascendis Pharma Investigational Site
City
Cincinnati
State/Province
Ohio
ZIP/Postal Code
45219
Country
United States
Individual Site Status
Recruiting
Facility Name
Ascendis Pharma Investigational Site
City
Cleveland
State/Province
Ohio
ZIP/Postal Code
44106
Country
United States
Individual Site Status
Recruiting
Facility Name
Ascendis Pharma Investigational Site
City
Pittsburgh
State/Province
Pennsylvania
ZIP/Postal Code
15232
Country
United States
Individual Site Status
Recruiting
Facility Name
Ascendis Pharma Investigational Site
City
Knoxville
State/Province
Tennessee
ZIP/Postal Code
37920
Country
United States
Individual Site Status
Recruiting
Facility Name
Ascendis Pharma Investigational Site
City
Fairfax
State/Province
Virginia
ZIP/Postal Code
22031
Country
United States
Individual Site Status
Recruiting
Facility Name
Ascendis Pharma Investigational Site
City
Wollongong
State/Province
New South Wales
ZIP/Postal Code
2500
Country
Australia
Individual Site Status
Recruiting
Facility Name
Ascendis Pharma Investigational Site
City
Clayton
State/Province
Victoria
ZIP/Postal Code
3168
Country
Australia
Individual Site Status
Withdrawn
Facility Name
Ascendis Pharma Investigational Site
City
Frankston
State/Province
Victoria
ZIP/Postal Code
3199
Country
Australia
Individual Site Status
Recruiting

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
36123697
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.
Results Reference
derived

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

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