DFMO + Pembrolizumab for Lung Cancer

Overseen By Jhanelle E. Gray, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: H. Lee Moffitt Cancer Center and Research Institute

Must not be taking: Steroids, Immunosuppressants

Disqualifiers: Immunodeficiency, Active infection, Autoimmune, others

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

Compensation: Varies

Number of Visits: 6

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores the safety and effectiveness of combining DFMO (Difluoromethylornithine) and pembrolizumab for individuals with advanced non-small cell lung cancer (NSCLC). Researchers aim to determine if this combination benefits those who have not succeeded with other treatments. The trial consists of two parts: one to identify the optimal DFMO dose and another to test the treatment in individuals who have not previously received immunotherapy. Ideal candidates include those with advanced NSCLC, particularly those with the STK11 mutation who have exhausted standard treatment options. As a Phase 1 and Phase 2 trial, this research seeks to understand the treatment's effects and measure its initial effectiveness in a smaller group.

Will I have to stop taking my current medications?

The trial information does not specify if you need to stop taking your current medications. However, if you are on systemic steroid therapy at doses of 10 mg prednisone or more, you may need to stop or adjust it before starting the trial.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research shows that using Difluoromethylornithine (DFMO) with pembrolizumab might be safe and manageable for treating advanced or metastatic lung cancer. Studies have examined patient reactions to these drugs together, and results so far indicate that many patients can undergo the treatment without serious side effects.

Pembrolizumab is already used for other cancers, and doctors know it is generally safe and well-tolerated. DFMO, when combined with other drugs, has also demonstrated a good safety record in past trials. Patients experienced manageable side effects, meaning the treatment didn't cause severe problems for most people.

Since this trial is in the early stages, the main focus is on ensuring the combination is safe. Researchers are closely monitoring for any signs of toxicity or side effects. Overall, early findings suggest that this combination could be a promising option for patients with advanced lung cancer, with an emphasis on safety and tolerability. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of Difluoromethylornithine (DFMO) and Pembrolizumab for lung cancer because it brings a fresh approach to fighting this disease. Unlike traditional chemotherapy or targeted therapies, this duo combines an immune checkpoint inhibitor, Pembrolizumab, which boosts the body's immune response against cancer cells, with DFMO, which targets polyamine synthesis, a process crucial for cancer cell growth. By attacking the cancer from two angles, this treatment has the potential to be more effective for patients with advanced or metastatic non-small cell lung cancer (NSCLC), especially those who are new to immunotherapy.

What evidence suggests that DFMO + Pembrolizumab might be an effective treatment for advanced/metastatic NSCLC?

This trial will test the combination of two drugs, DFMO and pembrolizumab, to treat advanced or metastatic Non-Small Cell Lung Cancer (NSCLC). Research has shown that this combination might help treat NSCLC, and studies suggest it is safe and manageable for patients. Pembrolizumab alone has already helped some NSCLC patients live longer. Early evidence indicates that adding DFMO could enhance pembrolizumab's effectiveness by stopping tumor growth more effectively. This trial aims to determine if this treatment can improve outcomes for patients with specific genetic changes, such as those with STK11-mutant NSCLC. ^{1 2 3 4 6}

Who Is on the Research Team?

Jhanelle E. Gray, M.D.

Principal Investigator

Moffitt Cancer Center

Are You a Good Fit for This Trial?

This trial is for adults with advanced or metastatic Non-Small Cell Lung Cancer (NSCLC). Participants should not have had prior treatment with DFMO or pembrolizumab. They must be able to perform daily activities with minimal assistance and have acceptable organ function.

Inclusion Criteria

I have or can provide a sample of my cancer tissue if needed.

My cancer has an STK11 mutation.

I am willing to provide a new tissue sample from my tumor for the study.

Exclusion Criteria

Patients that have a known psychiatric or substance abuse disorder that would interfere with cooperation with the requirements of the trial.

I am currently being treated for an infection.

I have not had chest radiation of more than 30Gy in the last 6 months.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Phase I: Dose Escalation

Participants receive escalating doses of DFMO with a fixed dose of Pembrolizumab to determine the maximum tolerated dose

Up to 12 months

Pembrolizumab IV every 3 weeks

Phase II: Treatment

Participants receive DFMO at the maximum tolerated dose in combination with Pembrolizumab

Up to 5 years

Pembrolizumab IV every 3 weeks

Follow-up

Participants are monitored for overall survival, objective response rate, and progression-free survival

Up to 5 years

What Are the Treatments Tested in This Trial?

Interventions

• Difluoromethylornithine (DFMO)
• Pembrolizumab

Trial Overview The study tests the safety and effectiveness of combining Difluoromethylornithine (DFMO), a drug that targets cancer cell growth, with pembrolizumab, an immunotherapy drug. The goal is to see if this combination works better for treating NSCLC than current options.

How Is the Trial Designed?

Group I: Phase 1: Dose Escalation for Pembrolizumab and Difluoromethylornithine (DFMO) Experimental Treatment 2 Interventions

Difluoromethylornithine (DFMO) + Pembrolizumab Pre-treated or treatment naive advanced or metastatic NSCLC. The phase I dose escalation will include a fixed dose of Pembrolizumab IV every 3 weeks and escalating doses of DFMO (three dose levels) to determine the maximum tolerated dose (MTD) to be used in the phase II portion of the trial. DFMO level -1: Dose Level -1: 4500 mg/m2 by mouth (PO) once a day (QD). DFMO Level 1: (start): 6750 mg/m2 PO QD Dose Level 2: 9000 mg/m2 PO QD

Group II: Phase II: Pembrolizumab and Difluoromethylornithine (DFMO) Active Control 2 Interventions

Difluoromethylornithine (DFMO) + Pembrolizumab Advanced/metastatic NSCLC who are immunotherapy naïve. Pembrolizumab IV flat dose every 3 weeks DFMO dose to be determined (TBD) based on maximum tolerated dose (MTD) and dose limiting toxicities (DLT) in Phase I dose escalation.

Difluoromethylornithine (DFMO) is already approved in United States for the following indications:

Approved in United States as IWILFIN for:

• High-risk neuroblastoma

Who Is Running the Clinical Trial?

H. Lee Moffitt Cancer Center and Research Institute

Lead Sponsor

Trials

576

Recruited

145,000+

Published Research Related to This Trial

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 real-life study of 108 patients with advanced non-small cell lung cancer (NSCLC) and a PD-L1 tumor proportion score of ≥50%, pembrolizumab showed a median progression-free survival of 10.1 months, similar to results from the KEYNOTE-024 trial.

The treatment was generally well-tolerated, with only 8% of patients experiencing grade 3 adverse events, and no severe (grade 4 or 5) adverse events reported, indicating a favorable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

First-line pembrolizumab for non-small cell lung cancer patients with PD-L1 ≥50% in a multicenter real-life cohort: The PEMBREIZH study. Amrane, K., Geier, M., Corre, R., et al.[2021]

In the KEYNOTE-189 study, first-line treatment with pembrolizumab combined with pemetrexed-platinum significantly improved overall survival (OS) to a median of 22.0 months compared to 10.7 months for the placebo group, indicating a strong efficacy in treating metastatic nonsquamous non-small-cell lung cancer (NSCLC).

The combination therapy also resulted in a median progression-free survival (PFS) of 9.0 months versus 4.9 months for placebo, with benefits observed regardless of tumor PD-L1 expression or the presence of liver/brain metastases, while maintaining a similar incidence of serious adverse events between the two groups.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Updated Analysis From KEYNOTE-189: Pembrolizumab or Placebo Plus Pemetrexed and Platinum for Previously Untreated Metastatic Nonsquamous Non-Small-Cell Lung Cancer. Gadgeel, S., Rodríguez-Abreu, D., Speranza, G., et al.[2021]

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]

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]

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]

Nivolumab and pembrolizumab are FDA-approved monoclonal antibodies that target PD-1, helping to enhance T cell activity against cancer by blocking the PD-1/PD-L1 interaction, which allows cancer cells to escape immune detection.

Both drugs have shown efficacy across multiple cancer types, including melanoma and non-small cell lung cancer, and are considered interchangeable options for treating these conditions, which may help manage the rising costs of cancer therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab and pembrolizumab: Monoclonal antibodies against programmed cell death-1 (PD-1) that are interchangeable. Prasad, V., Kaestner, V.[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]

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]

Citations

1. cancer.gov cancer.gov/clinicaltrials/NCI-2024-00864

Difluoromethylornithine in Combination with ... Giving DFMO in combination with pembrolizumab may be safe, tolerable and/or effective in treating patients with advanced or metastatic STK11-mutant NSCLC.

2. clinicaltrials.gov clinicaltrials.gov/study/NCT06219174

Study Details | NCT06219174 | Targeting ODC as an ... The purpose of this study is to establish the safety, toxicity, and tolerability of Difluoromethylornithine (DFMO) in combination with pembrolizumab in ...

3. esmoopen.com esmoopen.com/article/S2059-7029(25)01445-0/fulltext

Phase I dose-escalation trial of AMXT 1501 dicaprate plus ... AMXT 1501 plus DFMO produced an almost complete blockade of tumor growth, with a durable effect after treatment ceased. Evidence from this model ...

4. clinicaltrials.gov clinicaltrials.gov/study/NCT06219174?term=DFMO&rank=4

Targeting ODC as an Immunotherapeutic Target in STK11 ... The purpose of this study is to establish the safety, toxicity, and tolerability of Difluoromethylornithine ( DFMO ) in combination with pembrolizumab in ...

5. merck.com merck.com/news/keytruda-pembrolizumab-demonstrates-long-term-survival-benefit-in-certain-patients-with-earlier-or-advanced-stages-of-non-small-cell-lung-cancer-nsclc/

KEYTRUDA® (pembrolizumab) Demonstrates Long-Term ... Five-year exploratory follow-up analysis of KEYNOTE-671 continued to show clinically meaningful improvements in overall survival and ...

6. cdek.pharmacy.purdue.edu cdek.pharmacy.purdue.edu/trial/NCT06219174/

Trial | NCT06219174 The purpose of this study is to establish the safety, toxicity, and tolerability of Difluoromethylornithine (DFMO) in combination with pembrolizumab in ...