DCR-PDL1 for Cancer

Overseen By Novo Nordisk

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Dicerna Pharmaceuticals, Inc., a Novo Nordisk company

Disqualifiers: CNS metastases, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: 8 weeks

32 Participants Needed

Trial Summary

What is the purpose of this trial?

The study will evaluate the safety, tolerability, and pharmacokinetics of intravenous DCR-PDL1 in adults with solid tumors. Participants will be enrolled in one of 4 ascending-dose cohorts. Each treatment cycle will consist of multiple intravenous (IV) doses. Dose escalation decisions will be based on data collected during the dose-limiting toxicity (DLT) period.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

What data supports the effectiveness of the treatment DCR-PDL1 for cancer?

Research shows that blocking PD-L1, a protein that helps cancer cells hide from the immune system, can be a promising way to treat cancer. Studies have found that targeting PD-L1 can improve survival in some cancer patients by enhancing the body's immune response against tumors. ^{1 2 3 4 5}

What safety data exists for DCR-PDL1 treatment in humans?

PD-1 and PD-L1 inhibitors, which include treatments like DCR-PDL1, have been associated with various side effects, including immune-related issues like anemia (low red blood cell count), neutropenia (low white blood cell count), and thrombocytopenia (low platelet count). These treatments have shown some adverse effects in cancer patients, but understanding and managing these side effects is crucial for safe use. ^{6 7 8 9 10}

What makes the drug DCR-PDL1 unique for cancer treatment?

DCR-PDL1 is unique because it targets the PD1/PDL1 pathway, which is a mechanism that tumors use to escape the immune system. By blocking this pathway, DCR-PDL1 helps the immune system recognize and attack cancer cells, offering a novel approach compared to traditional treatments that may not specifically target immune evasion. ^{3 5 11 12 13}

Research Team

Clinical Transparency (dept. 2834)

Principal Investigator

Novo Nordisk A/S

Eligibility Criteria

This trial is for adults with solid tumors. Participants will be placed into one of four groups to receive increasing doses of DCR-PDL1, given through the veins. Specific eligibility details are not provided, but typically include factors like type and stage of tumor, previous treatments, and overall health.

Inclusion Criteria

My cancer is advanced, not responding to standard treatments, or there are no treatments available.

I am 18 years old or older.

Measurable disease according to RECIST version 1.1

Exclusion Criteria

I have brain or spinal cord metastases not managed by surgery or radiation.

Other protocol defined exclusion criteria could apply

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive multiple IV doses of DCR-PDL1 during each treatment cycle in one of 4 ascending-dose cohorts

8 weeks

Multiple visits for IV dosing

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• DCR-PDL1

Trial Overview The study tests the safety and how well the body handles DCR-PDL1 when administered intravenously in adults with solid tumors. It involves multiple IV doses within treatment cycles, with close monitoring to decide if higher doses can be safely given.

Participant Groups

Group I: DCR-PDL1 Experimental Treatment 1 Intervention

Participants will receive multiple IV doses of DCR-PDL1 during each treatment cycle.

Who Is Running the Clinical Trial?

Dicerna Pharmaceuticals, Inc., a Novo Nordisk company

Lead Sponsor

Trials

19

Recruited

580+

Findings from Research

In a study of 128 cancer patients undergoing immune checkpoint inhibitor therapy, high levels of circulating soluble programmed death-1 ligand (sPD-L1) were linked to a higher likelihood of disease progression (41.8% vs. 20.7% for low levels), indicating its potential as a prognostic marker.

Patients with elevated sPD-L1 levels had significantly shorter progression-free survival (PFS) and overall survival (OS), with median PFS of 2.9 months compared to 6.3 months and median OS of 7.4 months compared to 13.3 months for those with low levels, suggesting that sPD-L1 could help predict treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Soluble PD-L1 is a predictive and prognostic biomarker in advanced cancer patients who receive immune checkpoint blockade treatment. Oh, SY., Kim, S., Keam, B., et al.[2021]

In a study of 158 patients with metastatic non-small cell lung cancer (mNSCLC) receiving chemotherapy, those with low levels of programmed cell death protein-1 ligand (PDL-1) experienced longer progression-free survival (PFS) compared to those with high PDL-1 levels, indicating that PDL-1 levels may influence treatment outcomes.

The research also found a significant correlation between PDL-1 levels and the neutrophil-to-lymphocyte ratio (NLR), suggesting that patients with low PDL-1 and low NLR may benefit from immunogenic chemotherapies like gemcitabine and taxane as alternative treatment options.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

PDL-1 Expression and Survival in Metastatic Non-small Cell Lung Cancer Patients Who Received Chemotherapy as First-Line Treatment. Gursoy, P., Çakar, B., Gunenc, D., et al.[2022]

Genetically modifying T cells to express a PD1-CD28-4-1BB receptor (PD1-ACR) enhances their ability to overcome PDL1-mediated immunosuppression, leading to improved T cell activation and function.

In a mouse model of glioblastoma, PD1-ACR T cells effectively localized to tumors, suppressed tumor growth, and improved survival rates, suggesting a promising new approach for cancer therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The advantages of PD1 activating chimeric receptor (PD1-ACR) engineered lymphocytes for PDL1(+) cancer therapy. Tang, X., Li, Q., Zhu, Y., et al.[2020]

In a study of 158 advanced biliary tract cancer patients, higher levels of soluble PD-L1 (sPDL1) in serum were associated with significantly worse overall survival, indicating its potential as a prognostic biomarker.

Patients with sPDL1 levels of 0.94 ng/mL or higher had a median overall survival of 7.93 months compared to 14.10 months for those with lower levels, highlighting sPDL1 as an independent poor prognostic factor alongside the neutrophil-to-lymphocyte ratio.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Soluble programmed death-ligand 1 (sPDL1) and neutrophil-to-lymphocyte ratio (NLR) predicts survival in advanced biliary tract cancer patients treated with palliative chemotherapy. Ha, H., Nam, AR., Bang, JH., et al.[2022]

In a study of 62 lung cancer specimens, 71% showed positive expression of PDL-1, with significantly higher levels in non-small cell lung cancer (NSCLC) compared to small cell lung cancer (SCLC), suggesting PDL-1's role in tumor immune evasion.

The study indicates that while PDL-1 is overexpressed in lung cancer and correlates with EGFR overexpression, patients with positive PDL-1 expression had lower overall and progression-free survival, highlighting the need for alternative treatment strategies for PDL-1-negative tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

PDL-1 expression in lung carcinoma and its correlation with clinicopathological and prognostic characteristics. Farrag, M., Ibrahim, E., Abdelwahab, H., et al.[2022]

In a study of 191 patients with non-small cell lung cancer (NSCLC) treated with PD-1/PD-L1 inhibitors, those who experienced immune-related adverse events (irAEs) had significantly better treatment outcomes, with an objective response rate of 42.0% compared to 25.8% in those without irAEs.

The presence of irAEs was associated with improved progression-free survival, suggesting that these adverse events may indicate a more effective immune response to the treatment, although they did not correlate with overall survival.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immune-Related Adverse Events and Their Association With the Effectiveness of PD-1/PD-L1 Inhibitors in Non-Small Cell Lung Cancer: A Real-World Study From China. Chen, X., Nie, J., Dai, L., et al.[2022]

This study aims to create a comprehensive toxicity profile for anti-PD-1 and anti-PD-L1 drugs by analyzing systematic reviews and meta-analyses, focusing on treatment-related adverse events in cancer patients.

The research will utilize a network meta-analysis approach to synthesize data from various studies, ensuring a thorough understanding of the safety and adverse effects associated with these immunotherapy treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Anti-PD-1 and anti-PD-L1 drugs treatment-related adverse events for patients with cancer: Protocol for an overview of systematic reviews with meta-analyses. Li, J., Liu, M., Wang, J., et al.[2023]

Immune checkpoint antibodies targeting the PD-1/PD-L1 pathway have shown significant antitumor activity and have been approved for use as single-agent therapies in metastatic malignant melanoma and nonsmall-cell lung cancer.

Understanding the toxicities associated with PD-1/PD-L1 blockade and having effective management strategies is crucial for maximizing both the safety and efficacy of these treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Toxicities of the anti-PD-1 and anti-PD-L1 immune checkpoint antibodies. Naidoo, J., Page, DB., Li, BT., et al.[2023]

In a systematic review of 125 clinical trials involving over 20,000 patients, 66% experienced at least one treatment-related adverse event from PD-1 and PD-L1 inhibitors, with fatigue, pruritus, and diarrhea being the most common.

Nivolumab was found to have a higher incidence of adverse events compared to pembrolizumab, and PD-1 inhibitors generally led to more severe adverse events than PD-L1 inhibitors, highlighting the importance of understanding these differences for clinical decision-making.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment-Related Adverse Events of PD-1 and PD-L1 Inhibitors in Clinical Trials: A Systematic Review and Meta-analysis. Wang, Y., Zhou, S., Yang, F., et al.[2022]

The overall incidence of anaemia in patients receiving PD-(L)1 inhibitors was found to be 9.8%, with a higher occurrence in certain cancer types and phase II studies, indicating a notable risk that clinicians should monitor.

Severe cases of neutropenia and thrombocytopenia were rare, with incidences of 1.07% and 1.8% respectively, suggesting that while anaemia is a concern, other serious blood-related toxicities are less common with PD-(L)1 therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Haematological toxicities with immunotherapy in patients with cancer: a systematic review and meta-analysis. Petrelli, F., Ardito, R., Borgonovo, K., et al.[2019]

In a study of 899 lymphoma cases, PDL1 was found to be expressed in a significant portion of classical Hodgkin lymphoma (70%) and primary mediastinal B-cell lymphomas (35%), indicating its potential role in tumor immune evasion.

The expression of PDL1 in classical Hodgkin lymphoma correlated with increased immune cell activity, such as granzyme+ T cells and CD68+ macrophages, suggesting that PDL1 may serve as a marker for immune response and could help identify patients who might benefit from PD1/PDL1-targeted therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evaluation of the diagnostic and prognostic value of PDL1 expression in Hodgkin and B-cell lymphomas. Menter, T., Bodmer-Haecki, A., Dirnhofer, S., et al.[2022]

The study found that MACC1, c-Met, and PDL1 are all upregulated in gastric cancer tissues, indicating a positive correlation that may contribute to immune evasion in tumors.

Silencing MACC1 enhances antitumor immunity, while its overexpression reduces tumor immunity, suggesting that targeting MACC1 could be a promising strategy for improving immunotherapy in gastric cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

MACC1 regulates PDL1 expression and tumor immunity through the c-Met/AKT/mTOR pathway in gastric cancer cells. Tong, G., Cheng, B., Li, J., et al.[2021]

In a study of 150 renal cell carcinoma (RCC) patients, 44% showed positive expression of the PD-L1 protein, which is linked to the tumor's ability to evade the immune response.

There was a significant association between high tumor grades and positive PD-L1 expression, suggesting that targeting the PD-1/PD-L1 pathway could be a promising immunotherapy strategy for aggressive RCC cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Programmed Death Ligand 1; An Immunotarget for Renal Cell Carcinoma. Chandrasekaran, D., Sundaram, S., N, K., et al.[2020]

References

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

Soluble PD-L1 is a predictive and prognostic biomarker in advanced cancer patients who receive immune checkpoint blockade treatment. [2021]

2. Turkey pubmed.ncbi.nlm.nih.gov

PDL-1 Expression and Survival in Metastatic Non-small Cell Lung Cancer Patients Who Received Chemotherapy as First-Line Treatment. [2022]

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

The advantages of PD1 activating chimeric receptor (PD1-ACR) engineered lymphocytes for PDL1(+) cancer therapy. [2020]

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

Soluble programmed death-ligand 1 (sPDL1) and neutrophil-to-lymphocyte ratio (NLR) predicts survival in advanced biliary tract cancer patients treated with palliative chemotherapy. [2022]

5. England pubmed.ncbi.nlm.nih.gov

PDL-1 expression in lung carcinoma and its correlation with clinicopathological and prognostic characteristics. [2022]

6. Switzerland pubmed.ncbi.nlm.nih.gov

Immune-Related Adverse Events and Their Association With the Effectiveness of PD-1/PD-L1 Inhibitors in Non-Small Cell Lung Cancer: A Real-World Study From China. [2022]

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

Anti-PD-1 and anti-PD-L1 drugs treatment-related adverse events for patients with cancer: Protocol for an overview of systematic reviews with meta-analyses. [2023]

8. England pubmed.ncbi.nlm.nih.gov

Toxicities of the anti-PD-1 and anti-PD-L1 immune checkpoint antibodies. [2023]

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

Treatment-Related Adverse Events of PD-1 and PD-L1 Inhibitors in Clinical Trials: A Systematic Review and Meta-analysis. [2022]

10. England pubmed.ncbi.nlm.nih.gov

Haematological toxicities with immunotherapy in patients with cancer: a systematic review and meta-analysis. [2019]

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

Evaluation of the diagnostic and prognostic value of PDL1 expression in Hodgkin and B-cell lymphomas. [2022]

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

MACC1 regulates PDL1 expression and tumor immunity through the c-Met/AKT/mTOR pathway in gastric cancer cells. [2021]

13. Thailand pubmed.ncbi.nlm.nih.gov

Programmed Death Ligand 1; An Immunotarget for Renal Cell Carcinoma. [2020]