TROP2 ADC + Anti-PD-1 for Solid Cancer

Recruiting at 6 trial locations

Overseen By Monica Mita, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: LigaChem Biosciences, Inc.

Must not be taking: Systemic steroids

Disqualifiers: Active CNS metastases, Leptomeningeal disease, others

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

Compensation: Varies

Number of Visits: 6

300 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial tests a new cancer treatment that targets and kills cancer cells directly and boosts the immune system. It is for patients with advanced cancers that don't respond to usual treatments. The study aims to find the best dose and safety of this new treatment.

Will I have to stop taking my current medications?

The trial requires that you stop taking systemic antineoplastic therapy (cancer treatment) within 5 half-lives or 4 weeks before starting the study drug. If you're on systemic steroids, you must be on a dose of 10 mg of prednisone or less per day, unless it's for stable brain metastases.

What data supports the effectiveness of the drug TROP2 ADC + Anti-PD-1 for solid cancer?

Research shows that drugs blocking PD-1, like pembrolizumab, have been effective in treating various cancers, including lung cancer and melanoma, by helping the immune system fight cancer cells. ^{1 2 3 4 5}

What is known about the safety of PD-1 inhibitors in humans?

PD-1 inhibitors, used in cancer treatments, can cause unique side effects due to their action on the immune system. These side effects, known as immune-related adverse events, can include issues like inflammation in various organs, and early recognition and management are important for safety. ^{6 7 8 9 10}

What makes the drug TROP2 ADC + Anti-PD-1 unique for treating solid cancer?

The drug TROP2 ADC + Anti-PD-1 is unique because it combines a PD-1 inhibitor, which helps the immune system attack cancer cells, with a TROP2-targeting antibody-drug conjugate (ADC) that delivers chemotherapy directly to cancer cells, potentially overcoming resistance seen in some cancers. ^{1 11 12 13 14}

Research Team

Jennifer Wheler, MD

Principal Investigator

AntibodyChem Biosciences

Eligibility Criteria

This trial is for adults with advanced solid tumors that haven't responded to standard treatments or have no such options. Participants must be in good physical condition (ECOG 0 or 1), have certain blood cell counts within a healthy range, and their organs must function well. They should not have unresolved side effects from previous cancer treatments except hair loss and skin changes.

Inclusion Criteria

I am willing to undergo biopsies before and during treatment if it's safe.

Measurable disease as defined by RECIST v1.1 or RANO-BM

My advanced cancer does not respond to standard treatments.

Exclusion Criteria

I am taking more than 10 mg of steroids daily, not for brain metastases.

My cancer has spread to my brain or spinal cord.

I have lasting side effects from cancer treatment, but they are mild except for hair loss or skin color loss.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose Escalation (Phase 1)

Evaluation of LCB84 as a single agent and in combination with an anti-PD-1 Ab to determine MTD and/or RP2D

Up to 24 months

IV infusion Q3W

Dose Expansion (Phase 2)

Continuation of treatment in select tumor types to assess efficacy and safety

Up to 24 months

IV infusion Q3W

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 48 months

Treatment Details

Interventions

• Anti-PD-1 monoclonal antibody
• LCB84

Trial Overview The study tests LCB84, a new drug targeting TROP2 on tumor cells, alone and combined with an anti-PD-1 antibody that helps the immune system fight cancer. Phase 1 finds the safest dose; Phase 2 expands testing to more patients with specific types of tumors.

Participant Groups

Group I: LCB84 monotherapy Experimental Treatment 1 Intervention

IV infusion Q3W

Group II: LCB84 + anti-PD-1 Experimental Treatment 2 Interventions

IV infusion Q3W

Anti-PD-1 monoclonal antibody is already approved in United States, European Union for the following indications:

Approved in United States as Nivolumab (Opdivo) for:

• Melanoma
• Non-small cell lung cancer
• Renal cell carcinoma
• Hodgkin lymphoma
• Head and neck squamous cell carcinoma
• Urothelial carcinoma
• Colorectal cancer
• Hepatocellular carcinoma
• Small cell lung cancer
• Esophageal squamous cell carcinoma
• Gastric cancer
• Gastroesophageal junction cancer

Approved in United States as Pembrolizumab (Keytruda) for:

• Melanoma
• Non-small cell lung cancer
• Head and neck squamous cell carcinoma
• Urothelial carcinoma
• Colorectal cancer
• Hepatocellular carcinoma
• Small cell lung cancer
• Esophageal squamous cell carcinoma
• Gastric cancer
• Gastroesophageal junction cancer
• Cervical cancer
• Endometrial cancer

Approved in European Union as Nivolumab (Opdivo) for:

• Melanoma
• Non-small cell lung cancer
• Renal cell carcinoma
• Hodgkin lymphoma
• Squamous cell carcinoma of the head and neck
• Urothelial carcinoma
• Colorectal cancer
• Hepatocellular carcinoma
• Small cell lung cancer
• Esophageal squamous cell carcinoma
• Gastric cancer
• Gastroesophageal junction cancer

Approved in European Union as Pembrolizumab (Keytruda) for:

• Melanoma
• Non-small cell lung cancer
• Head and neck squamous cell carcinoma
• Urothelial carcinoma
• Colorectal cancer
• Hepatocellular carcinoma
• Small cell lung cancer
• Esophageal squamous cell carcinoma
• Gastric cancer
• Gastroesophageal junction cancer
• Cervical cancer
• Endometrial cancer

Who Is Running the Clinical Trial?

LigaChem Biosciences, Inc.

Lead Sponsor

Trials

14

Recruited

890+

LegoChem Biosciences, Inc

Lead Sponsor

Trials

13

Recruited

740+

AntibodyChem Biosciences, Inc.

Collaborator

Trials

1

Recruited

300+

Findings from Research

The PD-1/PD-L1 pathway is a key target for cancer immunotherapy, with the FDA having approved several monoclonal antibodies that block this interaction to enhance the immune response against tumors.

Current research is expanding the development of additional PD-1 and PD-L1 monoclonal antibodies, indicating a promising future for this class of drugs in cancer treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Mini-Review for Cancer Immunotherapy: Molecular Understanding of PD-1/PD-L1 Pathway & Translational Blockade of Immune Checkpoints. Li, Y., Li, F., Jiang, F., et al.[2023]

In a study of 38 patients with non-small cell lung cancer (NSCLC) treated with pembrolizumab, the median overall survival was 11.08 months, indicating that the drug is a viable treatment option for this patient group.

The study found that while pembrolizumab's effectiveness in real-life settings appears lower than in clinical trials, it still provides significant benefits, particularly for patients with high PD-L1 expression, and highlights the importance of monitoring for immune-related adverse events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Real-world efficacy and safety of pembrolizumab in patients with non-small cell lung cancer: a retrospective observational study. Cavaille, F., Peretti, M., Garcia, ME., et al.[2022]

In a study of 61 patients with advanced cancer, those receiving more than 5 doses of anti-PD1 therapy had significantly better overall survival (12.6 months) compared to those receiving fewer doses (4.4 months), highlighting the importance of treatment duration.

Baseline blood markers, particularly the neutrophil-to-lymphocyte ratio (NLR) and lymphocyte-to-monocyte ratio (LMR), were found to be significant predictors of response to anti-PD1 therapy, suggesting they could serve as useful biomarkers for immunotherapy outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Translational relevance of baseline peripheral blood biomarkers to assess the efficacy of anti-programmed cell death 1 use in solid malignancies. Varayathu, H., Sarathy, V., Thomas, BE., et al.[2022]

In a study of 185 advanced melanoma patients who discontinued anti-PD-1 therapy after a median of 12 months without disease progression, 78% remained free of progression after a median follow-up of 18 months, indicating that many patients can safely stop treatment without immediate relapse.

Patients who achieved a complete response (CR) had a lower risk of progression (14%) compared to those with partial response (PR) (32%) or stable disease (SD) (50%), suggesting that treatment duration may need to be tailored based on the patient's response to therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Discontinuation of anti-PD-1 antibody therapy in the absence of disease progression or treatment limiting toxicity: clinical outcomes in advanced melanoma. Jansen, YJL., Rozeman, EA., Mason, R., et al.[2023]

Zimberelimab (GLS-010) is a highly effective human monoclonal antibody that binds strongly to the PD-1 receptor, blocking its interaction with PD-L1/2, which is crucial for T cell activation.

In preclinical studies, GLS-010 demonstrated significant anti-tumor effects in mice, indicating its potential as a promising treatment for cancer, warranting further investigation in clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Preclinical Characterization of GLS-010 (Zimberelimab), a Novel Fully Human Anti-PD-1 Therapeutic Monoclonal Antibody for Cancer. Lou, B., Wei, H., Yang, F., et al.[2022]

In a study involving 1738 patients with advanced solid tumors treated with avelumab, a PD-L1 antibody, only 10.2% experienced grade ≥3 treatment-related adverse events (TRAEs), indicating a generally well-tolerated safety profile.

Infusion-related reactions (IRRs) were common, occurring in 25.3% of patients, primarily at the first infusion, but serious IRRs (grade ≥3) were rare, suggesting that while some patients may experience reactions, they are typically manageable.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety profile of avelumab in patients with advanced solid tumors: A pooled analysis of data from the phase 1 JAVELIN solid tumor and phase 2 JAVELIN Merkel 200 clinical trials. Kelly, K., Infante, JR., Taylor, MH., et al.[2020]

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]

Monoclonal antibodies like nivolumab and pembrolizumab, which target PD-1, have shown a survival benefit and better tolerability compared to standard second-line chemotherapy in non-small cell lung cancer, as demonstrated in three phase III trials.

Patients receiving PD-1 inhibitors may experience unique immune-related adverse events that require early recognition and a multidisciplinary management approach, highlighting the need for ongoing education among healthcare providers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Monitoring and Management of Immune-Related Adverse Events Associated With Programmed Cell Death Protein-1 Axis Inhibitors in Lung Cancer. O'Kane, GM., Labbé, C., Doherty, MK., et al.[2018]

A patient treated with the anti-PD-1 monoclonal antibody pembrolizumab developed severe immune-related adverse events, including cardiac tamponade and secondary adrenal insufficiency, highlighting the potential serious side effects of this treatment.

Prompt initiation of corticosteroid therapy was crucial for the patient's recovery, emphasizing the importance of quick intervention in managing life-threatening immune-related adverse events associated with anti-PD-1 therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cardiac tamponade and adrenal insufficiency due to pembrolizumab: a case report. Oristrell, G., Bañeras, J., Ros, J., et al.[2022]

A systematic review of 5744 patients with non-small cell lung cancer (NSCLC) found that PD-1 inhibitors (nivolumab and pembrolizumab) and PD-L1 inhibitors (atezolizumab, durvalumab, and avelumab) have similar efficacy, with response rates of 19% and 18.6% respectively.

While the overall incidence of adverse events was comparable between the two groups, PD-1 inhibitors were associated with a slightly higher rate of immune-related adverse events (16% vs 11%) and pneumonitis (4% vs 2%), indicating a potential difference in safety profiles.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of the toxicity profile of PD-1 versus PD-L1 inhibitors in non-small cell lung cancer: A systematic analysis of the literature. Pillai, RN., Behera, M., Owonikoko, TK., et al.[2022]

In a study of 891 non-small cell lung cancer (NSCLC) patients treated with the PD-L1 inhibitor atezolizumab, overexpression of TROP2 was linked to poorer survival outcomes, indicating it may play a role in resistance to PD-L1 blockade.

TROP2 overexpression was associated with reduced T-cell infiltration in tumors, suggesting that measuring TROP2 levels could help identify NSCLC patients who might benefit from combining immunotherapy with anti-TROP2 treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

TROP2 is associated with primary resistance to immune checkpoint inhibition in patients with advanced non-small cell lung cancer. Bessede, A., Peyraud, F., Besse, B., et al.[2023]

Molecular dynamics simulations revealed that the BC-loop of the PD-1 receptor can adopt three different conformations, which play a crucial role in how PD-1 interacts with PD-L1 and the blocking antibody nivolumab.

Nivolumab binds to the BC-loop through a conformational selection model, while PD-L1 binding induces an allosteric change in the BC-loop, suggesting that understanding these mechanisms can improve the design of immunotherapy drugs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Molecular dynamics of the immune checkpoint programmed cell death protein I, PD-1: conformational changes of the BC-loop upon binding of the ligand PD-L1 and the monoclonal antibody nivolumab. Roither, B., Oostenbrink, C., Schreiner, W.[2021]

The PD-1/PD-L1 signaling pathway is a crucial target for cancer therapy, as it plays a significant role in regulating T-cell activation and immune response against tumors.

Recent advancements in small-molecule inhibitors targeting the PD-1/PD-L1 pathway are emerging as promising alternatives to monoclonal antibodies, addressing some limitations of antibody-based therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Advance investigation on synthetic small-molecule inhibitors targeting PD-1/PD-L1 signaling pathway. Awadasseid, A., Wu, Y., Zhang, W.[2021]

In a study of 107 patients with advanced melanoma treated with nivolumab, the median overall survival was 16.8 months, with 1- and 2-year survival rates of 62% and 43%, indicating significant efficacy in this difficult-to-treat population.

Among patients who achieved tumor regression, 31% maintained their responses for a median duration of 2 years, and 71% of those who stopped treatment for reasons other than disease progression continued to show responses for at least 16 weeks, suggesting that the effects of nivolumab can be long-lasting even after treatment ends.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Survival, Durable Tumor Remission, and Long-Term Safety in Patients With Advanced Melanoma Receiving Nivolumab. Topalian, SL., Sznol, M., McDermott, DF., et al.[2023]

References

1. Switzerland pubmed.ncbi.nlm.nih.gov

A Mini-Review for Cancer Immunotherapy: Molecular Understanding of PD-1/PD-L1 Pathway & Translational Blockade of Immune Checkpoints. [2023]

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

Real-world efficacy and safety of pembrolizumab in patients with non-small cell lung cancer: a retrospective observational study. [2022]

3. India pubmed.ncbi.nlm.nih.gov

Translational relevance of baseline peripheral blood biomarkers to assess the efficacy of anti-programmed cell death 1 use in solid malignancies. [2022]

4. England pubmed.ncbi.nlm.nih.gov

Discontinuation of anti-PD-1 antibody therapy in the absence of disease progression or treatment limiting toxicity: clinical outcomes in advanced melanoma. [2023]

5. Switzerland pubmed.ncbi.nlm.nih.gov

Preclinical Characterization of GLS-010 (Zimberelimab), a Novel Fully Human Anti-PD-1 Therapeutic Monoclonal Antibody for Cancer. [2022]

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

Safety profile of avelumab in patients with advanced solid tumors: A pooled analysis of data from the phase 1 JAVELIN solid tumor and phase 2 JAVELIN Merkel 200 clinical trials. [2020]

7. England pubmed.ncbi.nlm.nih.gov

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

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

Monitoring and Management of Immune-Related Adverse Events Associated With Programmed Cell Death Protein-1 Axis Inhibitors in Lung Cancer. [2018]

9. England pubmed.ncbi.nlm.nih.gov

Cardiac tamponade and adrenal insufficiency due to pembrolizumab: a case report. [2022]

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

Comparison of the toxicity profile of PD-1 versus PD-L1 inhibitors in non-small cell lung cancer: A systematic analysis of the literature. [2022]

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

TROP2 is associated with primary resistance to immune checkpoint inhibition in patients with advanced non-small cell lung cancer. [2023]

12. England pubmed.ncbi.nlm.nih.gov

Molecular dynamics of the immune checkpoint programmed cell death protein I, PD-1: conformational changes of the BC-loop upon binding of the ligand PD-L1 and the monoclonal antibody nivolumab. [2021]

13. Netherlands pubmed.ncbi.nlm.nih.gov

Advance investigation on synthetic small-molecule inhibitors targeting PD-1/PD-L1 signaling pathway. [2021]

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

Survival, Durable Tumor Remission, and Long-Term Safety in Patients With Advanced Melanoma Receiving Nivolumab. [2023]