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

(IL Believe Trial)

Recruiting at42 trial locations

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1 & 2

Recruiting

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

Breakthrough Therapy

Trial Summary

What is the purpose of this trial?

This trial is testing a new drug called TransCon IL-2 β/γ for adults with advanced or spreading solid tumors. The drug aims to boost the immune system to better fight cancer by slowly releasing a molecule that helps immune cells attack cancer cells. TransCon IL-2 β/γ is a new long-acting drug currently being evaluated.

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.

What data supports the effectiveness of the drug pembrolizumab in treating solid tumor cancers?

Pembrolizumab has been shown to improve survival in patients with metastatic non-small cell lung cancer, as it helps the immune system attack cancer cells more effectively. This suggests it could be beneficial in treating other solid tumors as well. ^{1 2 3 4 5}

What safety data exists for the treatment TransCon IL-2 β/γ + Pembrolizumab/Chemotherapy for Solid Tumor Cancers?

Pembrolizumab, a part of this treatment, has been associated with some side effects like pneumonitis (lung inflammation) in 1%-5% of patients and rare cases of type 1 diabetes. However, in nonhuman primate studies, pembrolizumab showed no significant toxic effects, and its safety has been demonstrated in human clinical trials. ^{2 3 4 6 7}

What makes the drug TransCon IL-2 β/γ + Pembrolizumab/Chemotherapy unique for treating solid tumor cancers?

This treatment is unique because it combines pembrolizumab, an immune checkpoint inhibitor that helps the immune system attack cancer cells, with TransCon IL-2 β/γ, which is designed to enhance the immune response, and chemotherapy, which directly kills cancer cells. This combination aims to provide a more comprehensive approach to treating solid tumors by leveraging different mechanisms to target cancer. ^{2 3 4 6 8}

Research Team

Davis Torrejon-Castro

Principal Investigator

Medical Monitor

Eligibility Criteria

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.

Trial Timeline

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

Treatment Details

Interventions

• Chemotherapy drug (Chemotherapy)
• Pembrolizumab (Checkpoint Inhibitor)
• Surgery (Procedure)
• TransCon IL-2 β/γ (Cytokine Therapy)
• TransCon TLR7/8 Agonist (TLR 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.

Participant Groups

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+

Findings from Research

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 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]

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]

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, 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]

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]

References

1. England pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Pembrolizumab for Treatment of Metastatic Non-Small Cell Lung Cancer: First-Line Therapy and Beyond. [2022]

2. Ireland pubmed.ncbi.nlm.nih.gov

Neoadjuvant anti-programmed death-1 immunotherapy by pembrolizumab in resectable non-small cell lung cancer: First clinical experience. [2022]

3. England pubmed.ncbi.nlm.nih.gov

Recurrent and atypical immune checkpoint inhibitor-induced pneumonitis. [2023]

4. United States 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. [2021]

5. United States pubmed.ncbi.nlm.nih.gov

Pembrolizumab for Treatment-Refractory Metastatic Castration-Resistant Prostate Cancer: Multicohort, Open-Label Phase II KEYNOTE-199 Study. [2021]

6. United States pubmed.ncbi.nlm.nih.gov

FDA Approves Pembrolizumab for BCG-Unresponsive NMIBC. [2021]

7. United States pubmed.ncbi.nlm.nih.gov

Programmed Cell Death-1 Inhibitor-Induced Type 1 Diabetes Mellitus. [2022]

8. China 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). [2023]