CC-486 + Pembrolizumab for Lung Cancer

No longer recruiting at 64 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Celgene

Must not be taking: Hypomethylating agents, Anti-PD-1

Disqualifiers: EGFR/ALK mutation, Active infection, Autoimmune, others

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

Prior Safety Data This treatment has passed at least one previous human trial

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

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 29

Duration: 60-61 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests whether adding CC-486, an oral chemotherapy drug, to pembrolizumab improves outcomes for individuals with advanced or metastatic non-small cell lung cancer. The trial compares two groups: one receives the combination of CC-486 and pembrolizumab, while the other receives pembrolizumab with a placebo. Individuals previously treated with platinum-based chemotherapy for stage IIIB or IV non-small cell lung cancer and who have measurable disease might be suitable candidates. As a Phase 2 trial, the research focuses on assessing the treatment's effectiveness in an initial, smaller group of participants.

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 certain treatments like monoclonal antibodies or have had recent radiation therapy, you may need to wait a specific period before starting the trial. It's best to discuss your current medications with the trial team to get a clear answer.

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

Research has shown that using CC-486 (a pill form of azacitidine) with pembrolizumab has been studied for safety in cancer treatment. The study found that some patients experienced side effects when these two drugs were used together, leading to shorter treatment durations.

Pembrolizumab alone has FDA approval for other uses, indicating general safety. However, like all treatments, it can also cause side effects.

In summary, both treatments have been researched before. Pembrolizumab is generally considered safe, but combining it with CC-486 has shown some side effects. Prospective trial participants should discuss these findings with their doctor. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about CC-486 combined with pembrolizumab for lung cancer treatment because it introduces a unique approach compared to standard therapies like chemotherapy and targeted drugs. CC-486 is an investigational form of azacitidine that could modify the immune environment to enhance pembrolizumab, an immune checkpoint inhibitor known for unleashing the immune system to attack cancer cells. This combination may offer a new mechanism to boost the body's natural defenses against lung cancer, potentially leading to better outcomes than current treatments. In the other trial arm, pembrolizumab is paired with a placebo to maintain study blinding, but researchers hope this comparison will highlight the added benefit of CC-486 in enhancing pembrolizumab’s effectiveness.

What evidence suggests that the combination of CC-486 and pembrolizumab could be effective for non-small cell lung cancer?

This trial will compare two treatment arms: one where participants receive a combination of CC-486 and pembrolizumab, and another where participants receive pembrolizumab with a placebo. Research shows that combining CC-486 with pembrolizumab might not extend the time patients live without their lung cancer worsening compared to using pembrolizumab alone. However, one study found that patients who received the combination lived for an average of 11.9 months after starting treatment. While this combination shows some potential, it also caused more side effects, leading to reduced treatment. Pembrolizumab alone has been proven to help lung cancer patients live longer, especially when combined with chemotherapy. The five-year survival rate for patients using pembrolizumab with chemotherapy was about 19%, highlighting its effectiveness. ^{1 2 4 6 7}

Who Is on the Research Team?

Bristol-Myers Squibb

Principal Investigator

Bristol-Myers Squibb

Are You a Good Fit for This Trial?

This trial is for adults with stage IIIB or IV non-small cell lung cancer (NSCLC) who have had only one prior platinum-based chemotherapy. They must not be pregnant, agree to contraception, and have good organ function. Excluded are those with certain medical conditions, previous treatments like azacitidine, or severe allergies to trial drugs.

Inclusion Criteria

You have visible signs of disease in medical imaging tests according to specific guidelines.

I can carry out all my usual activities without help.

I have stage IIIB or IV lung cancer and had one platinum-based treatment.

Exclusion Criteria

I have been diagnosed with HIV.

My non-squamous lung cancer may have EGFR or ALK mutations.

You are allergic to azacitidine or mannitol, or any other ingredients used to make CC-486.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive CC-486 plus pembrolizumab or placebo plus pembrolizumab in 21-day cycles

60-61 weeks

Every 21 days

Follow-up

Participants are monitored for safety and effectiveness after treatment, with anticancer treatment and survival followed every 8 weeks

Until death, withdrawal of consent, or lost-to follow-up

Every 8 weeks

What Are the Treatments Tested in This Trial?

Interventions

• CC-486
• Pembrolizumab

Trial Overview The study tests if combining CC-486 (oral azacitidine) with pembrolizumab improves outcomes in NSCLC compared to pembrolizumab alone. Participants previously treated for advanced NSCLC will either receive the combination therapy or just pembrolizumab.

How Is the Trial Designed?

Group I: Pembrolizumab plus Placebo Experimental Treatment 2 Interventions

In this control arm, participants will receive pembrolizumab as a 30 minute IV infusion on day 1 of each 21-day cycle and placebo will be administered by mouth daily on days 1 to 14 of each 21 day cycle. Placebo will also be administered in order to allow blinding of the study.

Group II: CC-486 plus Pembrolizumab Experimental Treatment 2 Interventions

In the experimental arm, participants will receive a combination of two investigational drugs, CC-486 and pembrolizumab every 21-days.

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?

Celgene

Lead Sponsor

Trials

649

Recruited

130,000+

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Jay Backstrom

Celgene

Chief Medical Officer since 2016

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Mark Alles

Celgene

Chief Executive Officer since 2016

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Published Research Related to This Trial

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 (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]

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]

In a study involving 1033 patients with advanced non-small-cell lung cancer (NSCLC), pembrolizumab significantly improved overall survival compared to docetaxel, with a hazard ratio of 0.66, indicating a 34% reduction in the risk of death.

The effectiveness of pembrolizumab was consistent across both archival and newly collected tumor samples, with better outcomes observed in patients with higher PD-L1 expression (TPS ≥50%), showing hazard ratios of 0.64 and 0.40 for overall survival, respectively.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Use of archival versus newly collected tumor samples for assessing PD-L1 expression and overall survival: an updated analysis of KEYNOTE-010 trial. Herbst, RS., Baas, P., Perez-Gracia, JL., et al.[2023]

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 study of 100 patients with non-small cell lung cancer (NSCLC) treated with pembrolizumab, further stratification of PD-L1 tumor proportion score (TPS) beyond 50% did not significantly affect progression-free survival (PFS).

Smoking status was associated with improved PFS, while prior radiotherapy was linked to decreased PFS, indicating that these factors, along with performance status, may serve as important biomarkers for predicting response to pembrolizumab treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab monotherapy for non-small cell lung cancer (NSCLC): can patient stratification be improved in the UK Tayside population? A retrospective cohort study. Mander, ES., Merrick, CB., Nicholson, HA., et al.[2023]

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]

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]

Citations

1. sciencedirect.com sciencedirect.com/science/article/pii/S0959804918315351

Randomised phase 2 study of pembrolizumab plus CC ... After median follow-up of 11.3 and 12.2 months, the median OS in patients treated with pembrolizumab + CC-486 versus pembrolizumab + placebo was 11.9 months ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT02546986

Safety and Efficacy Study of CC-486 With MK-3475 to Treat ... The purpose of this study is to determine whether the combination therapy of CC-486 (oral azacitidine) and pembrolizumab provides improved patient outcomes ...

3. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/30654297/

Randomised phase 2 study of pembrolizumab plus CC- ... No improvement in PFS was observed with pembrolizumab + CC-486 versus pembrolizumab + placebo. Decreased treatment exposure due to adverse events may have ...

4. clinical-lung-cancer.com clinical-lung-cancer.com/article/S1525-7304(23)00268-1/fulltext

Pembrolizumab Plus Chemotherapy Per PD-L1 Stratum In ... Both trials demonstrated that pembrolizumab plus chemotherapy improved survival outcomes compared to chemotherapy alone, regardless of PD-L1 ...

5. merck.com merck.com/news/five-year-data-for-mercks-keytruda-pembrolizumab-plus-chemotherapy-showed-sustained-survival-benefit-versus-chemotherapy-alone-in-two-studies-for-metastatic-non-small-cell-lung-cancer-nsclc/

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.

6. cancer.gov cancer.gov/research/participate/clinical-trials-search/v?id=NCT02546986

Safety and Efficacy Study of CC-486 With MK-3475 to Treat ... The purpose of this study is to determine whether the combination therapy of CC-486 (oral azacitidine) and pembrolizumab provides improved patient outcomes ...

7. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0959804918315351

Randomised phase 2 study of pembrolizumab plus CC ... Preclinical and early clinical studies suggest that combining epigenetic agents with checkpoint inhibitors can potentially improve outcomes in patients with ...