TransCon IL-2 β/γ + Pembrolizumab/Chemotherapy for Solid Tumor Cancers

(IL Believe Trial)

Recruiting at 55 trial locations

Overseen By Davis Ascendis Oncology Clinical Trials

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Ascendis Pharma Oncology Division A/S

Must not be taking: Immunosuppressants, IL-2 variants

Disqualifiers: CNS metastases, Autoimmune diseases, Cardiac disease, others

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

Compensation: Varies

Number of Visits: Unknown

345 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new drug, TransCon IL-2 β/γ, to determine its effectiveness in treating advanced solid tumors, including those that have metastasized. The study evaluates the drug's safety and efficacy when used alone or with other treatments like chemotherapy or pembrolizumab, which aids the immune system in fighting cancer. Individuals with advanced solid tumors that are not treatable by surgery or radiation may qualify for this trial. As a Phase 1/Phase 2 trial, the research aims to understand how the treatment works in people and measure its effectiveness in an initial, smaller group, offering participants a chance to contribute to groundbreaking cancer treatment advancements.

Will I have to stop taking my current medications?

The trial requires a washout period (time without taking certain medications) of at least 4 weeks for those who have been treated with specific immunotherapies like anti-PD-1, anti-PD-L1, or anti-CTLA-4 antibodies. If you are on systemic immunosuppressive treatment, you may need to stop, except for corticosteroid tapering. The protocol does not specify other medications, so it's best to discuss with the trial team.

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

Research has shown that TransCon IL-2 β/γ, a new treatment being tested for advanced cancers, is generally well-tolerated both alone and in combination with other drugs like pembrolizumab and chemotherapy. Earlier studies indicated that patients using TransCon IL-2 β/γ, either by itself or with other treatments, did not exhibit any new safety concerns, suggesting it might be safe for people with solid tumors.

When combined with pembrolizumab, studies have found that most patients did not experience significant side effects. Similarly, when used with chemotherapy, TransCon IL-2 β/γ was generally safe, and patients tolerated the treatment well.

Since this trial is in its early stages, it is important to note that these studies focus on determining the treatment's safety for people. While TransCon IL-2 β/γ is still under investigation, more data will help confirm its safety. However, current findings are promising for those considering joining the trial. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about TransCon IL-2 β/γ because it offers a novel approach to fighting solid tumor cancers. Unlike traditional chemotherapy, which targets rapidly dividing cells, TransCon IL-2 β/γ works by enhancing the body's immune response specifically through the activation of certain immune cells. This investigational treatment uses a sustained-release prodrug technology that allows for prolonged action, potentially leading to better targeting of cancer cells with reduced side effects. Additionally, when combined with pembrolizumab or other treatments, it may enhance the overall anti-tumor activity, offering new hope for patients with limited options.

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

Research has shown that TransCon IL-2 β/γ delivers promising results in early studies. In this trial, some participants will receive TransCon IL-2 β/γ alone, while others will receive it with treatments like pembrolizumab or chemotherapy. It is generally well-tolerated and has led to significant improvements in patients with advanced solid tumors. Early data suggests that, when combined with chemotherapy, it can be effective against difficult cancers, such as platinum-resistant ovarian cancer. TransCon IL-2 β/γ boosts the immune system's ability to fight cancer, thanks to its long-lasting design that targets specific parts of the immune system. While more research is needed, these early findings offer hope that it could be a helpful treatment option. ^{1 2 4 6 7}

Who Is on the Research Team?

Davis Torrejon-Castro

Principal Investigator

Medical Monitor

Are You a Good Fit for This Trial?

Adults with advanced solid tumors who are at least 18, have good organ function and a life expectancy over 12 weeks. They must not be pregnant or breastfeeding, agree to contraception if of childbearing potential, and have no severe allergies to study drugs or significant health issues like uncontrolled infections or heart disease.

Inclusion Criteria

My organs are functioning well according to recent tests.

My cancer is advanced and cannot be cured with surgery or radiation, except as part of initial treatment.

I had immunotherapy and any side effects are now mild or gone, except for those controlled by hormone replacement.

Exclusion Criteria

I have a serious heart condition.

My heart's electrical cycle is longer than usual.

I am not on immunosuppressive treatment, except for a corticosteroid taper.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose Escalation

TransCon IL-2 β/γ is administered in escalating doses to evaluate safety/tolerability and determine the MTD and RP2D

12 months

Dose Expansion

TransCon IL-2 β/γ is administered as monotherapy or in combination with other therapies to evaluate safety/tolerability and anti-tumor activity

15 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

2 years

What Are the Treatments Tested in This Trial?

Interventions

• Chemotherapy drug
• Pembrolizumab
• Surgery
• TransCon IL-2 β/γ
• TransCon TLR7/8 Agonist

Trial Overview The trial is testing TransCon IL-2 β/γ alone or combined with Pembrolizumab and/or chemotherapy in adults with advanced solid tumors. It's an early-phase study assessing different doses to find the safest and most effective levels for treatment.

How Is the Trial Designed?

Group I: Part 4 Combination Dose Optimization Experimental Treatment 2 Interventions

TransCon IL-2 β/γ + Pembrolizumab TransCon IL-2 β/γ using the RP2D in titrating doses and/or different dose frequencies with Pembrolizumab

Group II: Part 3 Monotherapy Dose Expansion: TransCon IL-2 β/γ followed by surgery Experimental Treatment 2 Interventions

(Optional Arm): TransCon IL-2 β/γ using the RP2D followed by surgery to evaluate safety/tolerability and anti-tumor activity of the combination

Group III: Part 3 Combination Dose Expansion:TransCon IL-2 β/γ with TransCon TLR7/8 Agonist followed by surgery Experimental Treatment 3 Interventions

TransCon IL-2 β/γ with TransCon TLR7/8 Agonist using the RP2D followed by surgery to evaluate safety/tolerability and anti-tumor activity of the combination

Group IV: Part 3 Combination Dose Expansion:TransCon IL-2 β/γ + Pembrolizumab + SOC Chemo followed by surgery Experimental Treatment 4 Interventions

TransCon IL-2 β/γ using the RP2D with Pembrolizumab and SOC Chemotherapy followed by surgery to evaluate safety/tolerability and anti-tumor activity of the combination

Group V: Part 3 Combination Dose Expansion: TransCon IL-2 β/γ with TransCon TLR7/8 Agonist Experimental Treatment 2 Interventions

TransCon IL-2 β/γ with TransCon TLR7/8 Agonist using the RP2D to evaluate safety/tolerability and anti-tumor activity of the combination

Group VI: Part 3 Combination Dose Expansion: TransCon IL-2 β/γ with SOC Chemo Experimental Treatment 2 Interventions

TransCon IL-2 β/γ using the RP2D with SOC Chemotherapy to evaluate safety/tolerability and anti-tumor activity of the combination

Group VII: Part 3 Combination Dose Expansion: TransCon IL-2 β/γ with Pembrolizumab followed by surgery Experimental Treatment 3 Interventions

TransCon IL-2 β/γ using the RP2D with Pembrolizumab followed by surgery to evaluate safety/tolerability and anti-tumor activity of the combination

Group VIII: Part 3 Combination Dose Expansion: TransCon IL-2 β/γ monotherapy Experimental Treatment 1 Intervention

TransCon IL-2 β/γ monotherapy

Group IX: Part 3 Combination Dose Expansion: TransCon IL-2 β/γ + trastuzumab emtansine (T-DM1) Experimental Treatment 2 Interventions

TransCon IL-2 β/γ + trastuzumab emtansine (T-DM1)

Group X: Part 3 Combination Dose Expansion: TransCon IL-2 β/γ + trastuzumab Experimental Treatment 2 Interventions

TransCon IL-2 β/γ + trastuzumab

Group XI: Part 3 Combination Dose Expansion Experimental Treatment 2 Interventions

TransCon IL-2 β/γ + Pembrolizumab TransCon IL-2 β/γ using the RP2D with Pembrolizumab

Group XII: Part 2 Combination Dose Escalation: TransCon IL-2 β/γ with Pembrolizumab Experimental Treatment 2 Interventions

TransCon IL-2 β/γ with Pembrolizumab in escalating doses to evaluate safety/tolerability and determine the MTD and RP2D

Group XIII: Part 1 Monotherapy Dose Escalation: TransCon IL-2 β/γ Experimental Treatment 1 Intervention

TransCon IL-2 β/γ in escalating doses to evaluate safety/tolerability and to determine the MTD and RP2D

Who Is Running the Clinical Trial?

Ascendis Pharma Oncology Division A/S

Lead Sponsor

Trials

3

Recruited

560+

Ascendis Pharma A/S

Lead Sponsor

Trials

15

Recruited

1,600+

Published Research Related to This Trial

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 real-life study of 121 patients with advanced non-squamous non-small cell lung cancer, the combination of pembrolizumab and chemotherapy resulted in a median progression-free survival of 9 months and overall survival of 20.6 months, demonstrating its efficacy as a first-line treatment.

The treatment was generally well-tolerated, with manageable side effects; however, 17.5% of patients experienced grade 3-4 adverse events, and there were two treatment-related deaths, indicating the need for careful monitoring during therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab plus pemetrexed-carboplatin combination in first-line treatment of advanced non-squamous non-small cell lung cancer: a multicenter real-life study (CAP29). Renaud, E., Ricordel, C., Corre, R., et al.[2023]

Pembrolizumab, a PD-1 inhibitor used in cancer treatment, can lead to rare but serious immune-related adverse events, including type 1 diabetes mellitus, occurring in about 0.2% of cases.

A review of 42 cases revealed that patients may develop diabetic ketoacidosis during treatment, highlighting the need for blood glucose monitoring and awareness of this potential side effect among clinicians.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Programmed Cell Death-1 Inhibitor-Induced Type 1 Diabetes Mellitus. Clotman, K., Janssens, K., Specenier, P., 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]

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 (Keytruda) has been approved by the FDA for treating high-risk, non-muscle invasive bladder cancer (NMIBC) in patients who are unresponsive to BCG therapy and are either ineligible for or have opted not to undergo cystectomy.

This approval specifically targets patients with carcinoma in situ (CIS) with or without papillary tumors, highlighting its role as a treatment option for those with limited surgical options.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approves Pembrolizumab for BCG-Unresponsive NMIBC. Wright, KM.[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]

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]

Citations

1. clinicaltrials.eu clinicaltrials.eu/inn/transcon-il-2%CE%B2-%CE%B3/

Transcon Il-2Β/Γ – Application in Therapy and Current ... TransCon IL-2β/γ is an innovative drug being studied in clinical trials for the treatment of various advanced and metastatic solid tumors.

2. 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, ...

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

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

4. investors.ascendispharma.com investors.ascendispharma.com/news-releases/news-release-details/ascendis-pharma-presents-new-data-and-updated-results-phase-12

News Release In this trial, TransCon IL-2 β⁄γ alone or in combination with pembrolizumab or TransCon TLR7/8 Agonist was generally well tolerated with no new ...

5. asco.org asco.org/abstracts-presentations/ABSTRACT381576

IL believe: A phase 1/2, open-label, dose escalation and ... IL believe: A phase 1/2, open-label, dose escalation and dose expansion study of TransCon IL-2 β/γ alone or in combination with pembrolizumab or standard-of- ...

6. jitc.bmj.com jitc.bmj.com/content/10/7/e004991

TransCon IL-2 β/γ: a novel long-acting prodrug with ... Aldesleukin is rapidly cleared requiring frequent dosing, resulting in high Cmax likely potentiating toxicity. Thus, IL-2 cancer immunotherapy ...

7. investors.ascendispharma.com investors.ascendispharma.com/news-releases/news-release-details/ascendis-presents-updated-and-new-transcontm-il-2-bg-monotherapy

Ascendis Presents Updated and New TransCon™ IL-2 β⁄γ ... TransCon IL-2 β⁄γ administered every three weeks was generally well tolerated as a monotherapy or in combination with pembrolizumab, with no meaningful effect ...