TILT-123 + Pembrolizumab for Ovarian Cancer

(PROTA Trial)

Recruiting at 4 trial locations

Overseen By TILT Trials

Age: 18+

Sex: Female

Trial Phase: Phase 1 & 2

Sponsor: TILT Biotherapeutics Ltd.

Must not be taking: Immunosuppressants, Steroids, Anthracyclines, others

Disqualifiers: Autoimmune, Immunodeficiency, Cardiac, Hepatic, 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

76 Participants Needed

Trial Summary

Do I have to stop taking my current medications for the trial?

The trial protocol does not specify if you need to stop taking your current medications. However, you cannot have had any anti-cancer therapy within 30 days before the first virus injection, and certain therapies like hormonal therapy must have been started at least 3 months before. It's best to discuss your specific medications with the trial team.

What data supports the effectiveness of the drug TILT-123 + Pembrolizumab for ovarian cancer?

Research shows that pembrolizumab, a part of this treatment, has shown some effectiveness in treating advanced ovarian cancer, especially in patients whose tumors express PD-L1, a protein that helps cancer cells hide from the immune system. Additionally, combining pembrolizumab with other drugs like carboplatin has shown activity in treating recurrent ovarian cancer, suggesting potential benefits when used in combination therapies. ^{1 2 3 4 5}

Is the combination of TILT-123 and Pembrolizumab safe for humans?

Pembrolizumab, also known as KEYTRUDA, has been studied in various clinical trials and is generally considered safe, though it can cause immune-related side effects like fatigue, nausea, and rare cases of type 1 diabetes. In nonhuman primate studies, pembrolizumab showed no significant toxic effects, supporting its safety profile in humans. ^{1 4 6 7 8}

What makes the TILT-123 + Pembrolizumab treatment unique for ovarian cancer?

The TILT-123 + Pembrolizumab treatment is unique because it combines an oncolytic virus (TILT-123) that helps stimulate the immune system with an immune checkpoint inhibitor (Pembrolizumab) to enhance the body's ability to fight ovarian cancer. This combination aims to improve the effectiveness of immune therapies, which have shown limited success when used alone for this type of cancer. ^{1 2 9 10 11}

What is the purpose of this trial?

This is an open-label, phase 1/2, dose-escalation, multicenter and multinational trial evaluating the safety of oncolytic adenovirus TILT-123 in combination with Pembrolizumab, or Pembrolizumab and Pegylated Liposomal Doxorubicin in patients with platinum resistant or refractory ovarian cancer.

Eligibility Criteria

This trial is for women over 18 with ovarian cancer that's resistant to platinum treatment and can't be cured with existing therapies. Participants must have a tumor or carcinomatosis suitable for direct virus injection, good organ function, agree to contraception use, an ECOG/WHO score of 0-1, and a life expectancy over 3 months.

Inclusion Criteria

My cancer can be measured or observed but doesn't need to meet specific criteria.

Patients must be willing to use adequate forms of contraception from screening, during the trial, and for a minimum of 120 days after end of treatment.

Signed and dated informed consent(s) by the participant or legal representative before any trial-related activities.

Exclusion Criteria

Has a known psychiatric or substance abuse disorder that would interfere with the participant's ability to cooperate with the requirements of the study.

I haven't had cancer treatment in the last 30 days.

I have an immune system disorder or have been on steroids recently.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose-escalation Treatment

Participants receive multiple administrations of TILT-123 and pembrolizumab, with dose escalation based on safety data

8-12 weeks

Combination Treatment

Participants receive TILT-123, pembrolizumab, and pegylated liposomal doxorubicin at the maximum tolerated dose

8-12 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4-8 weeks

Treatment Details

Interventions

• Pembrolizumab
• TILT-123

Trial Overview The trial tests the safety of TILT-123 (an oncolytic adenovirus) combined with Pembrolizumab in patients with advanced ovarian cancer. It's an early-phase study where doses increase gradually to find safe levels. Patients receive both treatments directly into tumors or the abdominal cavity.

Participant Groups

Group I: Phase 2 part - TILT-123 and pembrolizumab Experimental Treatment 2 Interventions

Patients will receive multiple administrations of TILT-123 and pembrolizumab at the dose level defined in the Phase 1 part of the trial.

Group II: Phase 1b part - TILT-123 and pembrolizumab and pegylated liposomal doxorubicin Experimental Treatment 3 Interventions

Patients will receive multiple administrations of TILT-123 and pembrolizumab and pegylated liposomal doxorubicin. TILT-123 will be administered at the maximum tolerated dose or maximum feasible dose.

Group III: Phase 1 part - TILT-123 and pembrolizumab Experimental Treatment 2 Interventions

Patients will receive multiple administrations of TILT-123 and pembrolizumab. Escalation to the next dose of TILT-123 level will occur when the safety data has been evaluated for all patients in the preceding dose level.

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?

TILT Biotherapeutics Ltd.

Lead Sponsor

Trials

5

Recruited

100+

Merck Sharp & Dohme LLC

Industry Sponsor

Trials

4,096

Recruited

5,232,000+

Chirfi Guindo

Merck Sharp & Dohme LLC

Chief Marketing Officer since 2022

Degree in Engineering from Ecole Centrale de Paris, MBA from New York University Stern School of Business

Robert M. Davis

Merck Sharp & Dohme LLC

Chief Executive Officer since 2021

JD from Northwestern University Pritzker School of Law, MBA from Northwestern University Kellogg Graduate School of Management, Bachelor's in Finance from Miami University

Findings from Research

In a phase Ib trial involving 26 patients with advanced PD-L1-positive ovarian cancer, pembrolizumab demonstrated a confirmed objective response rate of 11.5%, indicating some level of antitumor activity, with 1 complete response and 2 partial responses observed.

The treatment was generally well-tolerated, with 73.1% of patients experiencing treatment-related adverse events, but no deaths or treatment discontinuations due to these events, suggesting that pembrolizumab has a manageable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab in patients with programmed death ligand 1-positive advanced ovarian cancer: Analysis of KEYNOTE-028. Varga, A., Piha-Paul, S., Ott, PA., et al.[2019]

The combination of pembrolizumab and carboplatin was found to be well-tolerated and showed activity in patients with recurrent platinum-resistant ovarian cancer, with a median overall survival of 11.3 months.

Patients with a higher ratio of peripheral CD8+PD1+Ki67+ T cells to tumor burden had significantly longer overall survival, suggesting this ratio could help identify those who may benefit more from this treatment approach.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab with low-dose carboplatin for recurrent platinum-resistant ovarian, fallopian tube, and primary peritoneal cancer: survival and immune correlates. Liao, JB., Gwin, WR., Urban, RR., et al.[2022]

In a study involving patients with recurrent platinum-resistant ovarian cancer, the combination of pembrolizumab, cisplatin, and gemcitabine resulted in an overall response rate of 60%, but the duration of response was relatively short at 4.9 months.

The addition of pembrolizumab did not show a significant benefit over chemotherapy alone, leading to the decision to close the trial for further accrual after an interim analysis indicated modest outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II trial of cisplatin, gemcitabine and pembrolizumab for platinum-resistant ovarian cancer. Walsh, CS., Kamrava, M., Rogatko, A., 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]

In a study of 317 patients with advanced recurrent ovarian cancer treated with pembrolizumab, no significant associations were found between gene expression signatures and clinical outcomes, indicating that these markers may not be reliable predictors of treatment response.

However, higher densities of specific myeloid cell phenotypes (CD11c+ and CD11c+/MHCII-/CD163-/CD68-) in the tumor microenvironment were positively associated with better outcomes, suggesting that these immune cell populations could play a role in enhancing the efficacy of pembrolizumab.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Molecular determinants of clinical outcomes of pembrolizumab in recurrent ovarian cancer: Exploratory analysis of KEYNOTE-100. Ledermann, JA., Shapira-Frommer, R., Santin, AD., et al.[2023]

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, 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 (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]

Oncolytic adenoviral therapy with TILT-123 shows promise as a single-agent treatment for ovarian cancer and enhances the effectiveness of immune checkpoint inhibitors (ICIs) like anti-PD-1 and anti-PD-L1, leading to reduced tumor viability and improved T cell activation.

In mouse models, combining TILT-123 with ICIs significantly hindered tumor growth, suggesting that this combination therapy could be a viable approach for treating ovarian cancer in clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effective Combination Immunotherapy with Oncolytic Adenovirus and Anti-PD-1 for Treatment of Human and Murine Ovarian Cancers. Heiniö, C., Clubb, J., Kudling, T., et al.[2022]

Pembrolizumab (Keytruda) is approved for treating advanced endometrial carcinoma that is microsatellite instability-high or mismatch repair deficient, specifically for patients whose disease has progressed after previous treatments.

This approval is significant for patients who are not candidates for curative surgery or radiation, providing a new therapeutic option for a challenging stage of cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New Approved Use for Keytruda. Aschenbrenner, DS.[2022]

TILT-123, an oncolytic adenovirus designed to enhance T-cell therapies and immune checkpoint inhibitors, has been shown to be safe in animal studies, both as a standalone treatment and in combination with the anti-PD-1 immune checkpoint inhibitor.

The treatment effectively stimulates the immune response by expressing cytokines like tumor necrosis factor alpha and interleukin-2, and it is rapidly cleared from healthy tissues without causing damage to vital organs, supporting its progression to a phase 1 clinical trial in melanoma patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cytokine-Coding Oncolytic Adenovirus TILT-123 Is Safe, Selective, and Effective as a Single Agent and in Combination with Immune Checkpoint Inhibitor Anti-PD-1. Havunen, R., Kalliokoski, R., Siurala, M., et al.[2021]

References

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

Pembrolizumab in patients with programmed death ligand 1-positive advanced ovarian cancer: Analysis of KEYNOTE-028. [2019]

2. England pubmed.ncbi.nlm.nih.gov

Pembrolizumab with low-dose carboplatin for recurrent platinum-resistant ovarian, fallopian tube, and primary peritoneal cancer: survival and immune correlates. [2022]

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

Phase II trial of cisplatin, gemcitabine and pembrolizumab for platinum-resistant ovarian cancer. [2022]

4. 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]

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

Molecular determinants of clinical outcomes of pembrolizumab in recurrent ovarian cancer: Exploratory analysis of KEYNOTE-100. [2023]

6. 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]

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

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

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

FDA Approval Summary: Accelerated Approval of Pembrolizumab for Second-Line Treatment of Metastatic Melanoma. [2021]

9. Switzerland pubmed.ncbi.nlm.nih.gov

Effective Combination Immunotherapy with Oncolytic Adenovirus and Anti-PD-1 for Treatment of Human and Murine Ovarian Cancers. [2022]

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

New Approved Use for Keytruda. [2022]

11. Switzerland pubmed.ncbi.nlm.nih.gov

Cytokine-Coding Oncolytic Adenovirus TILT-123 Is Safe, Selective, and Effective as a Single Agent and in Combination with Immune Checkpoint Inhibitor Anti-PD-1. [2021]