Pembrolizumab + Vorinostat for Lung Cancer

Overseen By Scott Antonia, M.D., Ph.D.

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: H. Lee Moffitt Cancer Center and Research Institute

Must not be taking: Systemic steroids, HDACi

Disqualifiers: Immunodeficiency, Active infection, Autoimmune, others

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

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: 3

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a combination of two drugs, pembrolizumab (an immunotherapy drug) and vorinostat (a type of histone deacetylase inhibitor), to determine their effectiveness for people with advanced lung cancer. Researchers aim to assess whether this drug duo is both safe and effective compared to pembrolizumab alone. People with advanced non-small cell lung cancer, who have tried other unsuccessful treatments, might be suitable for this study. As a Phase 1, Phase 2 trial, the study focuses on understanding how the treatment works in people and measuring its effectiveness in an initial, smaller group, offering participants a chance to contribute to groundbreaking research.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, you cannot participate if you are on certain immunosuppressive therapies or have recently received other cancer treatments. It's best to discuss your specific medications with the trial team.

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

Research has shown that pembrolizumab is usually well-tolerated. In studies with lung cancer patients, it has demonstrated a good safety record and offers long-term benefits. Some patients experienced side effects, but these were generally manageable.

Vorinostat, used for certain blood and lymph node cancers, is also generally well-tolerated according to studies. However, patients might experience side effects like tiredness or nausea.

When used together, early research suggests that the combination of these two drugs is mostly safe. In one study, only one out of nine patients experienced a severe side effect. This indicates the combination could be promising in terms of safety, but more research is needed to confirm this. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about Pembrolizumab combined with Vorinostat as a treatment for lung cancer because it offers a novel approach by harnessing the immune system and affecting gene expression. Pembrolizumab is an immune checkpoint inhibitor, which helps the immune system recognize and attack cancer cells. Vorinostat, on the other hand, is a histone deacetylase inhibitor that can alter the expression of certain genes, potentially making cancer cells more susceptible to immune attack. This combination targets cancer cells in a way that is different from standard treatments like chemotherapy, providing hope for more effective outcomes and potentially fewer side effects.

What evidence suggests that the combination of pembrolizumab and vorinostat could be an effective treatment for lung cancer?

Research has shown that pembrolizumab, one of the treatments in this trial, effectively treats lung cancer and helps patients live longer. In earlier studies, about 19-22% of patients treated with pembrolizumab survived for five years, highlighting its potential benefits.

This trial will also examine the combination of pembrolizumab with vorinostat. Early research suggests that this combination might improve results, especially for patients with certain immune system traits. However, adjustments in dosage have been necessary due to side effects like tiredness and nausea. While pembrolizumab alone has a strong track record, the benefits of adding vorinostat remain under investigation in this trial. ^{1 3 6 7 8}

Who Is on the Research Team?

Jhanelle E. Gray, M.D.

Principal Investigator

H. Lee Moffitt Cancer Center and Research Institute

Are You a Good Fit for This Trial?

Adults over 18 with Stage IV non-small cell lung cancer (NSCLC) can join this trial. Participants must have measurable disease, adequate organ function, and no prior treatments with certain immune therapies if in Phase II. They should not be on other HDAC inhibitors besides vorinostat or have had recent chemotherapy. Safe sex practices are required to avoid conception during the trial.

Inclusion Criteria

Your tumor has a PD-L1 score of at least 1%.

My diagnosis is Stage IV non-small cell lung cancer.

I am fully active or restricted in physically strenuous activity but can do light work.

Exclusion Criteria

I have a history of tuberculosis.

I have previously received treatments targeting the immune system for cancer.

I have an immune system disorder or have been on high-dose steroids or other immune-weakening medicines recently.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Phase I Dose Escalation

Dose escalation to determine the maximum tolerated dose (MTD) of pembrolizumab and vorinostat

Up to 12 months

Every 3 weeks

Phase I Expansion

Expansion at the maximum tolerated dose in NSCLC patients previously treated with anti-PD-1 or anti-PD-L1 therapy

Up to 12 months

Phase II Randomization

Randomization of patients to pembrolizumab alone or pembrolizumab plus vorinostat groups

Up to 2 years

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 2 years

What Are the Treatments Tested in This Trial?

Interventions

• Pembrolizumab
• Vorinostat

Trial Overview The study tests pembrolizumab alone versus its combination with vorinostat for advanced NSCLC patients. Pembrolizumab is FDA-approved for melanoma and lung cancer; vorinostat is approved for some blood cancers. The goal is to assess the safety and effectiveness of this drug combo.

How Is the Trial Designed?

Group I: Phase Ib Expansion Experimental Treatment 2 Interventions

Pembrolizumab plus Vorinostat. Level 1: Maximum Tolerated Dose (MTD)

Group II: Phase I Dose Escalation Experimental Treatment 2 Interventions

Level 1: Vorinostat 200mg by mouth (PO) Daily; Pembrolizumab 200 mg intravenously (IV) every (Q) 3 weeks. Level 2: Vorinostat 400 mg PO Daily; Pembrolizumab 200 mg IV Q3 weeks

Group III: Arm B: Pembrolizumab plus Vorinostat Active Control 2 Interventions

Pembrolizumab plus Vorinostat treatment. Level 1: MTD

Group IV: Arm A: Pembrolizumab Active Control 1 Intervention

Pembrolizumab treatment only. Level 1: Pembrolizumab 200 mg Q3 wks

Pembrolizumab is already approved in United States, European Union, United Kingdom for the following indications:

Approved in United States as KEYTRUDA for:

• Head and neck squamous cell carcinoma (HNSCC) with PD-L1 CPS ≥1
• Melanoma
• Non-small cell lung cancer (NSCLC)
• Urothelial carcinoma
• Colorectal cancer
• Gastric cancer
• Hepatocellular carcinoma
• Renal cell carcinoma
• Cervical cancer
• Endometrial carcinoma

Approved in European Union as KEYTRUDA for:

• Head and neck squamous cell carcinoma (HNSCC) with PD-L1 CPS ≥1
• Melanoma
• Non-small cell lung cancer (NSCLC)
• Urothelial carcinoma
• Colorectal cancer
• Gastric cancer
• Hepatocellular carcinoma
• Renal cell carcinoma
• Cervical cancer
• Endometrial carcinoma

Approved in United Kingdom as KEYTRUDA for:

• Untreated metastatic or unresectable recurrent head and neck squamous cell carcinoma (HNSCC) with PD-L1 CPS ≥1

Who Is Running the Clinical Trial?

H. Lee Moffitt Cancer Center and Research Institute

Lead Sponsor

Trials

576

Recruited

145,000+

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

Published Research Related to This Trial

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, a monoclonal antibody targeting PD-1, showed significant efficacy in treating a 79-year-old patient with advanced squamous cell lung cancer, leading to a complete response after just 3 cycles of treatment.

However, the patient developed acute myelomonocytic leukemia after starting pembrolizumab, highlighting a potential safety concern that warrants further investigation into the drug's effects on blood cell production.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Acute myelomonocytic leukemia during pembrolizumab treatment for non-small cell lung cancer: A case report. Kim, HB., Park, SG., Hong, R., et al.[2020]

Pembrolizumab, an immune checkpoint inhibitor targeting the PD-1 pathway, has shown significant durability of responses in previously treated patients with extensive-stage small-cell lung cancer (ES-SCLC), leading to its accelerated approval by the FDA for second- or third-line treatment.

In a recent clinical trial, pembrolizumab combined with platinum/etoposide improved progression-free survival in previously untreated ES-SCLC patients, although it did not demonstrate a significant improvement in overall survival compared to standard treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evidence to Date: Evaluating Pembrolizumab in the Treatment of Extensive-Stage Small-Cell Lung Cancer. Riano, I., Patel, SR., Liu, SV., et al.[2021]

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]

Pembrolizumab is a safe and effective immune checkpoint inhibitor that targets the PD-1 receptor, currently approved for treating advanced melanoma and metastatic non-small cell lung cancer (NSCLC).

Ongoing studies are exploring the potential of pembrolizumab in combination with other treatments for lung cancer and other cancer types, while also investigating biomarkers that may predict patient response to this therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab for the treatment of PD-L1 positive advanced or metastatic non-small cell lung cancer. Dang, TO., Ogunniyi, A., Barbee, MS., et al.[2020]

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 unresectable or metastatic melanoma based on two clinical trials involving 1,374 patients, showing significant improvements in overall survival compared to ipilimumab, with hazard ratios indicating a reduced risk of death.

Patients receiving pembrolizumab also experienced significant improvements in progression-free survival, although some immune-mediated adverse reactions like hypothyroidism and pneumonitis were noted, highlighting the importance of monitoring for side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Pembrolizumab for the Treatment of Patients with Unresectable or Metastatic Melanoma. Barone, A., Hazarika, M., Theoret, MR., et al.[2022]

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]

Citations

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Five-Year Outcomes With Pembrolizumab Versus ... With 5-year OS rates of up to 22%, these data support the continued use of pembrolizumab monotherapy as a standard-of-care treatment for previously untreated PD ...

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Five-Year Data for Merck's KEYTRUDA® (pembrolizumab ... Five-year overall survival rate of 19.4% and 18.4% for KEYTRUDA plus chemotherapy in KEYNOTE-189 and KEYNOTE-407, respectively.

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5-Year Real-World Outcomes With Frontline ... With 5-year follow-up in a real-world population, frontline pembrolizumab monotherapy continues to demonstrate long-term effectiveness.

4. nature.com nature.com/articles/s41416-024-02895-1

Real-world evidence for pembrolizumab in non-small cell ... Median OS of patients treated with 1 L pembrolizumab after 2017 was better (mono-/combination therapy: 13.8/12.8 months) than for patients ...

5. sciencedirect.com sciencedirect.com/science/article/pii/S0169500225000431

Five-year efficacy and safety of pembrolizumab as first-line ... The real-world 5-year survival rate of NSCLC cases with PD-L1 ≥ 50 % treated with first-line pembrolizumab was comparable to that in a clinical trial.

6. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/39952082/

Five-year efficacy and safety of pembrolizumab as first-line ... The real-world 5-year survival rate of NSCLC cases with PD-L1 ≥ 50 % treated with first-line pembrolizumab was comparable to that in a clinical trial.

7. ascopubs.org ascopubs.org/doi/10.1200/JCO.21.02885

Five-Year Outcomes With Pembrolizumab Versus ... The estimated 5-year OS rates were 11.9% and 7.4% in the pembrolizumab and chemotherapy groups, respectively (Data Supplement). Safety. In the ...

8. clinicaltrials.gov clinicaltrials.gov/study/NCT02142738

NCT02142738 | Study of Pembrolizumab (MK-3475) ... This is a study to assess the efficacy and safety of pembrolizumab (MK-3475/SCH 900475) compared to standard of care (SOC) platinum-based chemotherapies.