NC318 + Pembrolizumab for Lung Cancer

Overseen by Scott N. Gettinger

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 2

Recruiting

Sponsor: Yale University

Must be taking: PD-1 inhibitors

Must not be taking: Immunosuppressants

Disqualifiers: CNS metastases, Leptomeningeal carcinomatosis, others

No Placebo Group

Prior Safety Data

Breakthrough Therapy

Trial Summary

What is the purpose of this trial?

This trial is testing a new drug, NC318, alone or with Pembrolizumab, in patients with advanced lung cancer. It aims to help those who haven't responded to other treatments or have specific tumor characteristics. The drugs work by enhancing the immune system's ability to attack cancer cells.

Will I have to stop taking my current medications?

The trial requires that you stop taking systemic immunosuppressive medications (like certain steroids and drugs that suppress the immune system) at least 2 weeks before starting the trial. However, inhaled or topical steroids and standard-dose NSAIDs are allowed.

What data supports the effectiveness of the drug pembrolizumab for lung cancer?

Research shows that pembrolizumab, a drug that helps the immune system fight cancer, improves survival and slows disease progression in patients with advanced non-small cell lung cancer. It is especially effective in patients whose tumors have high levels of a protein called PD-L1. ^{1 2 3 4 5}

Is the combination of NC318 and Pembrolizumab safe for humans?

Pembrolizumab (also known as Keytruda) has been used in various cancer treatments and is generally considered safe, but it can cause side effects like fatigue, cough, nausea, and more serious immune-related issues like lung inflammation (pneumonitis) and liver inflammation (hepatitis). While specific safety data for the combination with NC318 is not provided, pembrolizumab's safety profile is well-documented in other conditions. ^{1 2 4 6 7}

What makes the drug combination of NC318 and pembrolizumab unique for lung cancer treatment?

The combination of NC318 and pembrolizumab is unique because it involves using pembrolizumab, a drug that blocks a pathway (PD-1/PD-L1) to help the immune system attack cancer cells, alongside NC318, which may target different aspects of the tumor environment, potentially enhancing the overall treatment effect for lung cancer. ^{1 2 4 8 9}

Research Team

Scott N. Gettinger

Principal Investigator

Yale University

Eligibility Criteria

This trial is for adults with advanced non-small cell lung cancer who have tried PD-1 axis inhibitor therapy and it didn't work (except Arm 2a). They should be relatively healthy, able to undergo a biopsy, and not have used immunosuppressive drugs recently. Those with certain gene mutations after treatment failure or intolerance are also eligible.

Inclusion Criteria

My cancer progressed or I couldn't tolerate treatment after a specific gene mutation.

You have a disease that can be measured using specific criteria.

My blood and organs are functioning well.

Exclusion Criteria

I had a severe reaction to previous immunotherapy.

I haven't taken any immune-weakening drugs in the last 2 weeks.

I have never received PD-1 axis inhibitor therapy.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Safety Run-in

Initial safety assessment of NC318 alone or in combination with pembrolizumab

6 weeks

Treatment

Participants receive NC318 alone or in combination with pembrolizumab, with tumor assessments every 8 weeks for the first 24 weeks

24 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment, with assessments every 12 weeks until disease progression

Up to 4 years

Treatment Details

Interventions

• NC318 (Monoclonal Antibodies)
• Pembrolizumab (Monoclonal Antibodies)

Trial Overview The study is testing the effectiveness of NC318 at two different doses, either alone or combined with Pembrolizumab. It's designed to see how well these treatments can control lung cancer that has spread and isn't responding to previous therapies.

Participant Groups

Group I: Arm 2a (naïve to PD-1 axis inhibitor)- NC318 and Pembrolizumab Experimental Treatment 2 Interventions

Arm 2a will enroll patients with advanced NSCLC who are naïve to PD-1 axis inhibitor therapy to receive combination therapy with NC318 and pembrolizumab.

Group II: Arm 2 (naïve to PD-1 axis inhibitor)- NC318 and Pembrolizumab Experimental Treatment 2 Interventions

Arm 2 will enroll patients with advanced NSCLC who are naïve to PD-1 axis inhibitor therapy to receive therapy with NC318 in combination with pembrolizumab.

Group III: Arm 1c - NC318 and Pembrolizumab Experimental Treatment 1 Intervention

At the discretion of the treating physician, advanced NSCLC patients on arm 1b will receive combination therapy with NC318 and pembrolizumab.

Group IV: Arm 1b - NC318 and Pembrolizumab Experimental Treatment 2 Interventions

At the discretion of the treating physician, advanced NSCLC patients on arm 1b will receive combination therapy with NC318 and pembrolizumab.

Group V: Arm 1a - NC318 only Experimental Treatment 1 Intervention

At the discretion of the treating physician, advanced NSCLC patients on arm 1a will receive NC318 alone.

Who Is Running the Clinical Trial?

Yale University

Lead Sponsor

Trials

1,963

Recruited

3,046,000+

Nancy J. Brown

Yale University

Chief Medical Officer since 2020

MD from Yale School of Medicine

Peter Salovey

Yale University

Chief Executive Officer since 2013

PhD in Psychology from Yale University

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Dr. Douglas R. Lowy

National Cancer Institute (NCI)

Chief Executive Officer since 2023

MD from New York University School of Medicine

Dr. Monica Bertagnolli

National Cancer Institute (NCI)

Chief Medical Officer since 2022

MD from Harvard Medical School

NextCure, Inc.

Industry Sponsor

Trials

8

Recruited

660+

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 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, a PD-1 inhibitor, has demonstrated clinical effectiveness in treating various solid tumors, particularly in patients with PD-L1-positive non-small-cell lung cancer and unresectable/metastatic melanoma.

Early-phase trials and ongoing studies are focused on further confirming the clinical benefits of pembrolizumab in thoracic malignancies, highlighting its potential as a significant treatment option in cancer therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab for the treatment of thoracic malignancies: current landscape and future directions. Karim, S., Leighl, N.[2017]

In a phase 3 trial involving 1177 participants with completely resected stage IB-IIIA non-small-cell lung cancer (NSCLC), pembrolizumab significantly improved median disease-free survival to 53.6 months compared to 42.0 months for placebo, indicating its efficacy as an adjuvant therapy.

The safety profile of pembrolizumab was consistent with previous studies, showing no new safety signals, although serious adverse events were more common in the pembrolizumab group (24%) compared to placebo (15%), highlighting the need for careful monitoring.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab versus placebo as adjuvant therapy for completely resected stage IB-IIIA non-small-cell lung cancer (PEARLS/KEYNOTE-091): an interim analysis of a randomised, triple-blind, phase 3 trial. O'Brien, M., Paz-Ares, L., Marreaud, S., et al.[2022]

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]

The KEYNOTE-001 trial demonstrated that pembrolizumab significantly improves clinical outcomes for patients with advanced non-small cell lung cancer, indicating its efficacy as a treatment option.

Patients whose tumors express PD-L1 in at least 50% of cells showed better responses to pembrolizumab, suggesting that PD-L1 expression is a key factor in predicting treatment effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab Shows Promise for NSCLC. [2015]

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]

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]

In a Phase 2 study involving 35 patients with non-small cell lung cancer, neoadjuvant pembrolizumab was found to be safe and well tolerated, with only one surgery delay due to thyroiditis and no mortality within 90 days post-surgery.

The study showed a high rate of R0 resection (88%) and a major pathologic response in 28% of patients, indicating that pembrolizumab may be more effective than standard neoadjuvant chemotherapy in this setting.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Perioperative outcomes of pulmonary resection after neoadjuvant pembrolizumab in patients with non-small cell lung cancer. Tong, BC., Gu, L., Wang, X., et al.[2022]

A 68-year-old patient with stage IV lung adenocarcinoma showed an unexpected positive response to paclitaxel after failing treatment with pembrolizumab, an anti-PD-1 immunotherapy.

The patient experienced a response duration of over fourteen months with paclitaxel, suggesting that combining or sequencing chemotherapy with immunotherapy may enhance treatment effectiveness in certain cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Prolonged response with paclitaxel after immunotherapy by pembrolizumab in lung cancer]. Zapata, E., Mennecier, B., Leduc, C., et al.[2017]

References

1. 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]

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

Pembrolizumab for the treatment of thoracic malignancies: current landscape and future directions. [2017]

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

Pembrolizumab versus placebo as adjuvant therapy for completely resected stage IB-IIIA non-small-cell lung cancer (PEARLS/KEYNOTE-091): an interim analysis of a randomised, triple-blind, phase 3 trial. [2022]

4. 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]

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

Pembrolizumab Shows Promise for NSCLC. [2015]

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

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

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

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

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

Perioperative outcomes of pulmonary resection after neoadjuvant pembrolizumab in patients with non-small cell lung cancer. [2022]

9. France pubmed.ncbi.nlm.nih.gov

[Prolonged response with paclitaxel after immunotherapy by pembrolizumab in lung cancer]. [2017]