TransCon TLR7/8 Agonist + Pembrolizumab for Solid Cancers

Not currently recruiting at 45 trial locations

Overseen By Joan Ascendis Oncology Clinical Trials

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Ascendis Pharma Oncology Division A/S

Must not be taking: TLR agonists, QT prolonging

Disqualifiers: Active malignancies, Autoimmune diseases, Infections, Cardiac disease, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: Unknown

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new drug, TransCon TLR7/8 Agonist, for individuals with advanced or metastatic solid tumors that cannot be cured with surgery or radiation. Researchers aim to determine the drug's safety and effectiveness, both alone and in combination with pembrolizumab (KEYTRUDA), a drug already used in cancer treatment. Participants will receive the drug directly into their tumors, and the trial seeks to identify the optimal dose. Individuals with solid tumors unresponsive to other treatments and willing to undergo biopsies may be suitable candidates for this trial. As a Phase 1 trial, this research focuses on understanding the treatment's effects in humans, offering participants the opportunity to be among the first to receive this new therapy.

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop taking your current medications. However, you cannot take any other anti-cancer treatments or medications that prolong the QT/QTc interval within 14 days of starting the trial.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that the TransCon TLR7/8 Agonist, when used alone, is beginning to show positive effects in patients. Studies suggest it is safe when applied directly to tumors. Patients who have received this treatment, either alone or with pembrolizumab, have generally tolerated it well. Pembrolizumab, also known as Keytruda, is a well-known cancer drug. It is usually safe but can cause side effects like tiredness, cough, and nausea. Overall, both treatments have shown potential for safety in people. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Unlike the standard cancer treatments like chemotherapy or radiation, which broadly attack cancer cells and healthy cells alike, TransCon TLR7/8 Agonist combined with Pembrolizumab offers a more targeted approach. Pembrolizumab is an immune checkpoint inhibitor that helps the immune system recognize and attack cancer cells, while the TransCon TLR7/8 Agonist is designed to enhance this effect by stimulating specific immune pathways, potentially leading to a more robust anti-tumor response. This combination aims to maximize the immune system's ability to fight cancer while minimizing damage to healthy cells, which is why researchers are excited about its potential.

What evidence suggests that this trial's treatments could be effective for solid cancers?

Research has shown that TransCon TLR7/8 Agonist, when injected directly into tumors, exhibits strong anti-tumor effects independently. Early studies found it safe and capable of triggering a long-lasting immune response, which is promising for cancer treatment. In this trial, some participants will receive TransCon TLR7/8 Agonist alone to evaluate its safety and effectiveness. Others will receive a combination of TransCon TLR7/8 Agonist with pembrolizumab, a drug known to extend life in certain cancers like non-small cell lung cancer. Early signs indicate that this combination works well and is generally well-tolerated, suggesting it could effectively treat solid tumors. ^{1 2 4 5 6}

Who Is on the Research Team?

Joan Morris

Principal Investigator

Medical Monitor

Are You a Good Fit for This Trial?

Adults with advanced or metastatic solid tumors who have progressed after standard treatments, or for whom no standard care exists. They must not be pregnant, breastfeeding, HIV positive, or have active hepatitis B/C. Participants need resolved immune-related toxicities from prior therapies to ≤Grade 1 and agree to use contraception.

Inclusion Criteria

I have at least 2 measurable cancer lesions.

Any side effects from previous immune therapy have mostly gone away.

My condition worsened after standard treatments or no standard treatments are available for me.

Exclusion Criteria

I have a bleeding disorder that makes certain cancer tests risky for me.

I have an autoimmune disease but it's under control with hormone replacement therapy.

I have not had any other cancers in the last 2 years.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose Escalation

Participants receive escalating doses of TransCon TLR7/8 Agonist alone or in combination with pembrolizumab to evaluate safety and determine the MTD and RP2D

Cycle 1 (21 days for monotherapy, 28 days for combination)

Dose Expansion

Participants receive the RP2D of TransCon TLR7/8 Agonist with pembrolizumab to evaluate safety and anti-tumor activity

9 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

Average of 2 years

What Are the Treatments Tested in This Trial?

Interventions

• Pembrolizumab
• TransCon TLR7/8 Agonist

Trial Overview The trial is testing TransCon TLR7/8 Agonist alone or combined with Pembrolizumab in patients with solid tumors. It involves injecting the drug directly into the tumor and aims to find the safest and most effective dose levels.

How Is the Trial Designed?

Group I: Part 3 Phase 2 Combination Dose Expansion: TransCon TLR7/8 Agonist with Pembrolizumab Experimental Treatment 2 Interventions

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.

Group II: Part 2 Combination Dose Escalation and Optimization: TransCon TLR7/8 Agonist with Pembrolizumab Experimental Treatment 2 Interventions

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

Group III: Part 1 Monotherapy Dose Escalation and Optimization: TransCon TLR7/8 Agonist Experimental Treatment 1 Intervention

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

Pembrolizumab is already approved in United States, European Union, United Kingdom for the following indications:

Approved in United States as KEYTRUDA for:

• Head and neck squamous cell carcinoma (HNSCC) with PD-L1 CPS ≥1
• Melanoma
• Non-small cell lung cancer (NSCLC)
• Urothelial carcinoma
• Colorectal cancer
• Gastric cancer
• Hepatocellular carcinoma
• Renal cell carcinoma
• Cervical cancer
• Endometrial carcinoma

Approved in European Union as KEYTRUDA for:

• Head and neck squamous cell carcinoma (HNSCC) with PD-L1 CPS ≥1
• Melanoma
• Non-small cell lung cancer (NSCLC)
• Urothelial carcinoma
• Colorectal cancer
• Gastric cancer
• Hepatocellular carcinoma
• Renal cell carcinoma
• Cervical cancer
• Endometrial carcinoma

Approved in United Kingdom as KEYTRUDA for:

• Untreated metastatic or unresectable recurrent head and neck squamous cell carcinoma (HNSCC) with PD-L1 CPS ≥1

Who Is Running the Clinical Trial?

Ascendis Pharma Oncology Division A/S

Lead Sponsor

Trials

3

Recruited

560+

Published Research Related to This Trial

Pembrolizumab, a PD-1 inhibitor, has demonstrated clinical effectiveness in treating various solid tumors, particularly in patients with PD-L1-positive non-small-cell lung cancer and unresectable/metastatic melanoma.

Early-phase trials and ongoing studies are focused on further confirming the clinical benefits of pembrolizumab in thoracic malignancies, highlighting its potential as a significant treatment option in cancer therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab for the treatment of thoracic malignancies: current landscape and future directions. Karim, S., Leighl, N.[2017]

Pembrolizumab (KEYTRUDA) was approved by the FDA for treating unresectable or metastatic melanoma based on two clinical trials involving 1,374 patients, showing significant improvements in overall survival compared to ipilimumab, with hazard ratios indicating a reduced risk of death.

Patients receiving pembrolizumab also experienced significant improvements in progression-free survival, although some immune-mediated adverse reactions like hypothyroidism and pneumonitis were noted, highlighting the importance of monitoring for side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Pembrolizumab for the Treatment of Patients with Unresectable or Metastatic Melanoma. Barone, A., Hazarika, M., Theoret, MR., et al.[2022]

Pembrolizumab (Keytruda) was approved by the FDA for treating metastatic non-small cell lung cancer (mNSCLC) in patients with tumors expressing PD-L1, showing significant improvements in overall survival (OS) and progression-free survival (PFS) in two major clinical trials with thousands of participants.

In the KEYNOTE-024 trial, pembrolizumab demonstrated a 40% reduction in the risk of death compared to chemotherapy, while in the KEYNOTE-010 trial, it also showed a significant survival advantage over chemotherapy in patients who had previously progressed on treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Pembrolizumab for Treatment of Metastatic Non-Small Cell Lung Cancer: First-Line Therapy and Beyond. Pai-Scherf, L., Blumenthal, GM., Li, H., et al.[2022]

In a study of 123 patients with advanced nonsquamous NSCLC, the combination of pembrolizumab and pemetrexed-carboplatin (PC) significantly improved the objective response rate (56.7% vs. 30.2% with PC alone) and progression-free survival (PFS) compared to PC alone, with a hazard ratio (HR) of 0.53.

The updated analysis showed a favorable overall survival (OS) hazard ratio of 0.56 for the pembrolizumab plus PC group, indicating a significant survival benefit, although 41% of patients experienced grade 3 to 5 treatment-related adverse events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

24-Month Overall Survival from KEYNOTE-021 Cohort G: Pemetrexed and Carboplatin with or without Pembrolizumab as First-Line Therapy for Advanced Nonsquamous Non-Small Cell Lung Cancer. Borghaei, H., Langer, CJ., Gadgeel, S., et al.[2022]

In the phase II KEYNOTE-199 study involving 258 patients with metastatic castration-resistant prostate cancer (mCRPC), pembrolizumab demonstrated modest antitumor activity, with objective response rates of 5% in PD-L1-positive patients and 3% in PD-L1-negative patients, indicating some effectiveness in this challenging population.

The treatment was generally well-tolerated, with 60% of patients experiencing treatment-related adverse events, but only 5% discontinuing due to these events, suggesting that pembrolizumab has an acceptable safety profile while providing encouraging overall survival estimates, particularly in patients with bone-predominant disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab for Treatment-Refractory Metastatic Castration-Resistant Prostate Cancer: Multicohort, Open-Label Phase II KEYNOTE-199 Study. Antonarakis, ES., Piulats, JM., Gross-Goupil, M., et al.[2021]

In a phase II trial involving 15 patients with resectable non-small cell lung cancer (NSCLC), neoadjuvant treatment with pembrolizumab showed a major pathologic response in 27% of patients, indicating promising antitumor activity before surgery.

The treatment was found to be feasible and safe, with only 33% of patients experiencing moderate adverse events, and no postoperative mortality, suggesting that pembrolizumab does not compromise surgical outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neoadjuvant anti-programmed death-1 immunotherapy by pembrolizumab in resectable non-small cell lung cancer: First clinical experience. Eichhorn, F., Klotz, LV., Kriegsmann, M., et al.[2022]

Pembrolizumab, an immune checkpoint inhibitor, can cause pneumonitis in 1%-5% of patients, and this case report highlights an atypical presentation of this side effect in a patient with metastatic squamous cell carcinoma.

The patient was successfully treated with steroid therapy after ruling out other potential causes, leading to complete resolution of the pneumonitis, emphasizing the importance of recognizing and managing atypical cases of checkpoint inhibitor-pneumonitis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Recurrent and atypical immune checkpoint inhibitor-induced pneumonitis. Jeon, WJ., Nguyen, J., Castillo, DR., et al.[2023]

Pembrolizumab (KEYTRUDA) was approved by the FDA for treating advanced melanoma, showing an overall response rate of 24% in a trial of 89 patients, with 86% of responses lasting at least 6 months.

While there are potential immune-mediated side effects, the benefits of prolonged tumor response durations were deemed to outweigh these risks, marking an improvement over existing treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Accelerated Approval of Pembrolizumab for Second-Line Treatment of Metastatic Melanoma. Chuk, MK., Chang, JT., Theoret, MR., et al.[2021]

Pembrolizumab (Keytruda) effectively blocks the PD-1 pathway, enhancing T-cell activity against tumors, which supports its role in promoting tumor regression and immune rejection.

Preclinical studies in cynomolgus monkeys showed that pembrolizumab has a favorable safety profile with no significant toxicological findings, aligning with its demonstrated safety and efficacy in human clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Biophysical and Immunological Characterization and In Vivo Pharmacokinetics and Toxicology in Nonhuman Primates of the Anti-PD-1 Antibody Pembrolizumab. Hutchins, B., Starling, GC., McCoy, MA., et al.[2021]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT04799054

NCT04799054 | A Study of TransCon TLR7/8 Agonist With ... 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 ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9484246/

Intratumoral delivery of TransCon™ TLR7/8 Agonist ... Significant single agent anti-tumor activity was observed, and cytokine and immune cell profiling provided evidence of prolonged activation of ...

3. ascopubs.org ascopubs.org/doi/10.1200/JCO.2024.42.16_suppl.2601

TransCon IL-2 β/γ alone or in combination with ... Conclusions: TC-IL2 β/γ alone and in combination with P or TransCon TLR7/8 Agonist is generally well-tolerated with meaningful clinical ...

4. jitc.bmj.com jitc.bmj.com/content/10/Suppl_2/A795

initial results from dose escalation Conclusions The transcendIT-101 trial indicates TransCon TLR7/8 Agonist has a well-tolerated safety profile as monotherapy and in combination with pembrolizumab ...

5. investors.ascendispharma.com investors.ascendispharma.com/news-releases/news-release-details/dose-escalation-data-transcendit-101-ascendis-pharmas-phase-12

Dose Escalation Data from transcendIT-101, ... Early signs of clinical activity were observed in patients receiving TransCon TLR7/8 Agonist as monotherapy or in combination with ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT05081609

NCT05081609 | A Study to Investigate Safety and ... TransCon IL-2 β/γ is an investigational drug being developed for treatment of locally advanced or metastatic solid tumors. This is a first-in-human, open-label, ...