ZL-1218 + Pembrolizumab for Advanced Cancer

Recruiting at 14 trial locations

Overseen By Zai Lab 1218-001 Study Team

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Zai Lab (Hong Kong), Ltd.

Must not be taking: Corticosteroids, Antibiotics, Vaccines, others

Disqualifiers: Brain metastasis, Cardiac disease, Pneumonitis, others

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

Compensation: Varies

Number of Visits: Unknown

60 Participants Needed

Trial Summary

What is the purpose of this trial?

The purpose of this study is to characterize the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary antitumor activity of ZL-1218 as a single agent and as combination therapy in subjects with advanced solid tumor malignancies.

Will I have to stop taking my current medications?

The trial protocol does not specify if you need to stop taking your current medications, but you cannot have had any systemic anti-cancer treatment within 4 weeks before starting the study drug.

What data supports the effectiveness of the drug Pembrolizumab in treating advanced cancer?

Pembrolizumab has shown strong effectiveness in treating various cancers, including melanoma and non-small-cell lung cancer, by helping the immune system attack cancer cells. It has demonstrated high response rates and improved survival in these conditions, suggesting potential benefits for other advanced cancers as well. ^{1 2 3 4 5}

Is the combination of ZL-1218 and Pembrolizumab safe for humans?

Pembrolizumab, also known as KEYTRUDA or MK-3475, has been shown to be generally safe in humans, with common side effects including tiredness, skin rash, itching, and diarrhea. Less common side effects can include thyroid issues, inflammation of the colon, liver, or lungs. However, specific safety data for the combination with ZL-1218 is not provided in the available research. ^{1 6 7 8 9}

What makes the drug ZL-1218 + Pembrolizumab unique for advanced cancer?

The combination of ZL-1218 with pembrolizumab is unique because it pairs a novel treatment (ZL-1218) with pembrolizumab, a drug that enhances the immune system's ability to fight cancer by blocking the PD-1 pathway, which is known to help T cells attack cancer cells more effectively. This combination may offer a new approach for treating advanced cancers by potentially increasing the effectiveness of the immune response against tumors. ^{1 10 11 12 13}

Eligibility Criteria

Adults with advanced solid tumors that can't be surgically removed or have spread, and who haven't responded to standard treatments or can't tolerate them. Participants need to be in fairly good health (ECOG 0-1), have a measurable tumor not previously treated with radiation, and agree to biopsies. They shouldn't have had recent vaccines, heart issues, cancer treatments within the last month, major surgery within four weeks, active lung inflammation not caused by infection, uncontrolled brain metastasis or infections needing antibiotics.

Inclusion Criteria

At least one target lesion as defined by RECIST v1.1 on CT, PET/CT, or MRI scan

My advanced cancer is not responding to standard treatments, or I can't tolerate them.

I am fully active or can carry out light work.

Exclusion Criteria

I have not received a live vaccine in the last 30 days.

I haven't had any cancer treatments in the last 4 weeks.

I have a history of lung inflammation not caused by an infection.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose Escalation

Participants receive ZL-1218 as a single agent and in combination with Pembrolizumab to determine the recommended dose

Approximately 24 months

Cohort Expansion

Participants receive the recommended dose of ZL-1218, with or without Pembrolizumab, to further evaluate safety and efficacy

Approximately 24 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

4-8 weeks

Treatment Details

Interventions

• Pembrolizumab
• ZL-1218

Trial Overview The trial is testing ZL-1218 alone and combined with Pembrolizumab on patients with various types of advanced cancers. It aims to understand how safe these drugs are when used together or separately, how they affect the body (pharmacokinetics/dynamics), and their initial effectiveness against tumors.

Participant Groups

Group I: Part 2: Cohort Expansion; Prior CPI Therapy Experimental Treatment 2 Interventions

Drug: ZL-1218 ZL-1218 recommended dose Drug: Pembrolizumab (KEYTRUDA®) Combination treatment with ZL-1218

Group II: Part 2: Cohort Expansion; CPI therapy Naive Experimental Treatment 2 Interventions

Drug: ZL-1218 ZL-1218 recommended dose Drug: Pembrolizumab (KEYTRUDA®) Combination treatment with ZL-1218

Group III: Part 1: Dose Escalation; ZL-1218 in combination with Pembrolizumab Experimental Treatment 2 Interventions

Drug: ZL-1218 ZL-1218 dose escalation Drug: Pembrolizumab (KEYTRUDA®) Combination treatment with ZL-1218

Group IV: Part 1: Dose Escalation; ZL-1218 Experimental Treatment 1 Intervention

Drug: ZL-1218 ZL-1218 dose escalation

Who Is Running the Clinical Trial?

Zai Lab (Hong Kong), Ltd.

Lead Sponsor

Trials

4

Recruited

430+

Zai Biopharmaceutical (Shanghai) Co., Ltd.

Collaborator

Trials

1

Recruited

60+

Zai Biopharmaceutical (Suzhou) Co., Ltd.

Industry Sponsor

Trials

2

Recruited

90+

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

Pembrolizumab is a monoclonal antibody that effectively blocks the PD-1 receptor on T cells, enhancing their ability to attack cancer cells, particularly in melanoma patients.

In a Phase I study involving 411 patients, pembrolizumab demonstrated high durable response rates with minimal toxicity, indicating its potential as a safe and effective treatment option for melanoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab joins the anti-PD-1 armamentarium in the treatment of melanoma. Hersey, P., Gowrishankar, K.[2017]

In a study involving 1034 patients with previously treated, PD-L1-positive advanced non-small-cell lung cancer, pembrolizumab significantly improved overall survival compared to docetaxel, with median survival times of 12.7 months for pembrolizumab 10 mg/kg versus 8.5 months for docetaxel.

Pembrolizumab also demonstrated a favorable safety profile, with fewer grade 3-5 treatment-related adverse events (13% for 2 mg/kg and 16% for 10 mg/kg) compared to docetaxel (35%), making it a promising treatment option for this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Herbst, RS., Baas, P., Kim, DW., et al.[2022]

In a phase 2 study involving 86 patients with advanced soft-tissue or bone sarcoma, pembrolizumab demonstrated some efficacy, particularly in undifferentiated pleomorphic sarcoma (40% response rate) and dedifferentiated liposarcoma (20% response rate), although the overall response rate did not meet the primary endpoint.

The treatment was associated with some serious adverse events, including immune-related conditions like adrenal insufficiency and pneumonitis, highlighting the need for careful monitoring during therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab in advanced soft-tissue sarcoma and bone sarcoma (SARC028): a multicentre, two-cohort, single-arm, open-label, phase 2 trial. Tawbi, HA., Burgess, M., Bolejack, V., et al.[2022]

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 the KEYNOTE-024 study involving 305 patients with untreated advanced non-small-cell lung cancer, pembrolizumab significantly improved overall survival (OS) compared to platinum-based chemotherapy, with a median OS of 30.0 months versus 14.2 months for chemotherapy.

Pembrolizumab also had a better safety profile, with fewer treatment-related severe adverse events (31.2% for pembrolizumab vs. 53.3% for chemotherapy), indicating it is a safer option for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Updated Analysis of KEYNOTE-024: Pembrolizumab Versus Platinum-Based Chemotherapy for Advanced Non-Small-Cell Lung Cancer With PD-L1 Tumor Proportion Score of 50% or Greater. Reck, M., Rodríguez-Abreu, D., Robinson, AG., et al.[2022]

Pembrolizumab, an anti-PD-1 antibody, has shown significant efficacy in treating advanced melanoma, demonstrating superior progression-free survival compared to chemotherapy in Phase II trials and improved overall survival in Phase III trials.

The treatment is generally well tolerated with a favorable safety profile, though common side effects include fatigue and rash, while less frequent but serious immune-related adverse events can occur.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab in the management of metastatic melanoma. Spain, L., Younger, E., Hatipoglu, E., et al.[2020]

In a study involving 173 patients with advanced melanoma who had not responded to previous treatments, pembrolizumab showed an overall response rate of 26% at both 2 mg/kg and 10 mg/kg doses, indicating its potential effectiveness in this challenging patient population.

The treatment was well tolerated with no drug-related deaths, and the safety profiles were similar across both doses, with fatigue, pruritus, and rash being the most common side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Anti-programmed-death-receptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced melanoma: a randomised dose-comparison cohort of a phase 1 trial. Robert, C., Ribas, A., Wolchok, JD., et al.[2022]

In a study of 67 advanced melanoma patients treated with pembrolizumab, the drug demonstrated a 27% overall response rate, with 6.5% achieving complete responses, indicating its efficacy even in heavily pretreated patients.

The median overall survival for cutaneous melanoma patients was 14 months, with an 18-month survival rate of 47.1%, and importantly, there were no serious adverse events reported, highlighting the safety of pembrolizumab in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab for advanced melanoma: experience from the Spanish Expanded Access Program. González-Cao, M., Arance, A., Piulats, JM., et al.[2018]

In a study of 88 advanced melanoma patients treated with pembrolizumab, 81.8% experienced any-grade toxicities, with skin and gastrointestinal issues being the most common side effects.

Despite the high incidence of side effects, pembrolizumab was found to be well tolerated in real-world settings, and severe toxicities were manageable with systemic steroids.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Real-world experience with pembrolizumab toxicities in advanced melanoma patients: a single-center experience in the UK. So, AC., Board, RE.[2022]

Pembrolizumab, a monoclonal antibody targeting PD-1, has shown significant efficacy in treating advanced non-small-cell lung cancer (NSCLC) across multiple clinical trials, particularly in patients with PD-L1 expression levels of 1% or higher.

The KEYNOTE studies identified specific patient populations that benefit most from pembrolizumab, highlighting the importance of PD-L1 as a companion diagnostic, while future research will explore its role in earlier stages of cancer treatment and in combination therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab in lung cancer: current evidence and future perspectives. Palumbo, G., Carillio, G., Manzo, A., et al.[2020]

In a review of 567 reports of immune-mediated necrotizing myopathy (IMNM), 14 cases were associated with pembrolizumab, indicating a significant link between this treatment and the adverse event, with a reporting odds ratio of 17.59.

The study emphasizes the importance of updated diagnostic criteria for IMNM and suggests that better collaboration between oncologists and neurologists is needed to address these neurological complications related to pembrolizumab treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immune-mediated necrotizing myopathy with pembrolizumab: a specific neuromuscular entity. Trenque, T., Lepoix, E., Trenque, A., et al.[2022]

In a phase 3 trial involving 305 patients with advanced non-small-cell lung cancer (NSCLC) expressing PD-L1, pembrolizumab significantly improved median progression-free survival to 10.3 months compared to 6.0 months with chemotherapy, indicating its efficacy as a treatment option.

Patients receiving pembrolizumab also experienced fewer treatment-related adverse events (73.4% vs. 90.0% for chemotherapy), highlighting its safety profile alongside its effectiveness in prolonging survival.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab versus Chemotherapy for PD-L1-Positive Non-Small-Cell Lung Cancer. Reck, M., Rodríguez-Abreu, D., Robinson, AG., et al.[2022]

Pembrolizumab is a monoclonal antibody that blocks the PD-1/PD-L1 interaction, which is crucial for preventing the immune system from attacking tumors, making it a key player in cancer immunotherapy.

It has been approved by the FDA for treating patients with advanced melanoma who have not responded to previous treatments, highlighting its efficacy in managing difficult cases of this aggressive cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New developments in the management of advanced melanoma - role of pembrolizumab. Improta, G., Leone, I., Donia, M., et al.[2020]

References

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

Pembrolizumab joins the anti-PD-1 armamentarium in the treatment of melanoma. [2017]

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

Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. [2022]

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

Pembrolizumab in advanced soft-tissue sarcoma and bone sarcoma (SARC028): a multicentre, two-cohort, single-arm, open-label, phase 2 trial. [2022]

4. 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]

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

Updated Analysis of KEYNOTE-024: Pembrolizumab Versus Platinum-Based Chemotherapy for Advanced Non-Small-Cell Lung Cancer With PD-L1 Tumor Proportion Score of 50% or Greater. [2022]

6. England pubmed.ncbi.nlm.nih.gov

Pembrolizumab in the management of metastatic melanoma. [2020]

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

Anti-programmed-death-receptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced melanoma: a randomised dose-comparison cohort of a phase 1 trial. [2022]

8. Italy pubmed.ncbi.nlm.nih.gov

Pembrolizumab for advanced melanoma: experience from the Spanish Expanded Access Program. [2018]

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

Real-world experience with pembrolizumab toxicities in advanced melanoma patients: a single-center experience in the UK. [2022]

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

Pembrolizumab in lung cancer: current evidence and future perspectives. [2020]

11. Germany pubmed.ncbi.nlm.nih.gov

Immune-mediated necrotizing myopathy with pembrolizumab: a specific neuromuscular entity. [2022]

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

Pembrolizumab versus Chemotherapy for PD-L1-Positive Non-Small-Cell Lung Cancer. [2022]

13. New Zealand pubmed.ncbi.nlm.nih.gov

New developments in the management of advanced melanoma - role of pembrolizumab. [2020]