Azacitidine + Pembrolizumab for Melanoma

Overseen By Hussein Tawbi, MD, PHD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: M.D. Anderson Cancer Center

Must not be taking: Steroids, Immunosuppressants

Disqualifiers: Immunodeficiency, Active TB, 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

Compensation: Varies

Number of Visits: 13

Duration: Up to 24 months or 35 doses

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine if combining azacitidine, typically used for certain blood disorders, and pembrolizumab, an immunotherapy drug for melanoma, can help control advanced melanoma, a serious type of skin cancer. While azacitidine is usually used for blood disorders and pembrolizumab for melanoma, their combined use for this condition is new. The trial will also assess the safety of this combination for patients. Individuals with metastatic melanoma who haven't received PD-1 therapy or whose melanoma has progressed after such treatment might be suitable for this study. As a Phase 2 trial, this research focuses on evaluating the treatment's effectiveness in an initial, smaller group, offering participants a chance to contribute to potentially groundbreaking advancements in melanoma treatment.

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 or any form of immunosuppressive therapy, you must stop these at least 7 days before starting the trial treatment.

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

Research has shown that the combination of azacitidine and pembrolizumab is generally well-tolerated by patients. In one study, the most common side effects were mild nausea and tiredness. Another study found no unexpected safety issues with this drug combination.

Azacitidine has FDA approval for treating other blood disorders, and pembrolizumab is approved for skin cancer (melanoma). This approval indicates both drugs have undergone safety testing in humans. Although using them together for melanoma is new, early research suggests the combination does not introduce new risks.

Participants in the studies have managed the treatments well, with manageable side effects. This suggests the treatment is safe enough for further research in humans. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about Azacitidine combined with Pembrolizumab for treating metastatic melanoma because this combination might offer a new way to enhance the immune system’s ability to fight cancer. While most treatments for melanoma, like targeted therapies and existing PD-1 inhibitors, work by directly attacking cancer cells or blocking pathways that help them grow, Azacitidine may modify the tumor environment to make Pembrolizumab more effective. This could be particularly beneficial for patients who have not yet received PD-1 therapy and those whose cancer has progressed despite it. This approach may help more patients respond to treatment and potentially slow down disease progression.

What evidence suggests that this trial's treatments could be effective for melanoma?

Research has shown that pembrolizumab effectively treats advanced melanoma by slowing disease progression. In this trial, participants will receive a combination of pembrolizumab and azacitidine. Although azacitidine is approved for other uses, it is being studied here to determine if it can enhance the effects of pembrolizumab. Early studies on their combined use have shown promise, but more information is needed. This trial aims to determine how well this combination works specifically for melanoma. ^{2 3 4 5 6}

Who Is on the Research Team?

Hussein A. Tawbi

Principal Investigator

M.D. Anderson Cancer Center

Are You a Good Fit for This Trial?

This study is for adults with advanced melanoma who haven't had PD-1 therapy (Arm A) or have worsened despite it (Arm B). Participants need functioning organs, measurable disease, and must not be pregnant or breastfeeding. They should agree to use birth control and provide a tissue sample from the tumor. Those with active infections, recent other cancer treatments, certain heart diseases, CNS metastases, or immunodeficiency can't join.

Inclusion Criteria

Willing and able to provide written informed consent/assent for the trial

You have a disease that can be measured or evaluated using specific guidelines.

My blood, kidney, liver, and clotting tests are within normal ranges.

Exclusion Criteria

Known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial

You have had to take medicine for an autoimmune disease in the last 2 years.

You are allergic to certain medications or their ingredients.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive oral azacitidine daily for 15 days and pembrolizumab every 3 weeks in 3-week cycles

Up to 24 months or 35 doses

Visits on Day 1 of each cycle, with additional visits for scans and biopsies

Follow-up

Participants are monitored for safety and effectiveness after treatment

Every 12 weeks

MRI or CT scan every 12 weeks

Re-Treatment

Eligible participants may receive an additional year of pembrolizumab if disease worsens during follow-up

1 year

Same schedule as initial treatment

Long-Term Follow-Up

Participants receive a phone call every 12 weeks to check on their status

Ongoing

What Are the Treatments Tested in This Trial?

Interventions

• Azacitidine
• Pembrolizumab

Trial Overview The trial investigates if combining oral azacitidine (CC-486) with pembrolizumab (MK-3475) can control advanced melanoma and studies the safety of this mix. Both drugs are FDA approved separately; their combination for treating melanoma is experimental. Up to 71 participants at MD Anderson will receive these drugs to see how well they work together.

How Is the Trial Designed?

Group I: Arm B: Metastatic Melanoma - Post PD-1 Progression Experimental Treatment 2 Interventions

Thirty-five participants with metastatic melanoma that have progressed on PD-1 directed therapy enrolled in treatment Arm B. Treatment consists of 3-week cycles and continues until disease progression. Oral Azacitidine administered by mouth daily for 15 days (Days 1-15) of every cycle. Pembrolizumab administered by vein every 3 weeks and after the oral dose of Azacitidine on concurrent treatment days.

Group II: Arm A: Metastatic Melanoma - PD-1 Naive Experimental Treatment 2 Interventions

Thirty-six participants with metastatic melanoma that are PD-1 naïve enrolled in treatment Arm A. Treatment consists of 3-week cycles and continues until disease progression. Oral Azacitidine administered by mouth daily for 15 days (Days 1-15) of every cycle. Pembrolizumab administered by vein every 3 weeks and after the oral dose of Azacitidine on concurrent treatment days.

Azacitidine is already approved in European Union, United States, Canada, Japan for the following indications:

Approved in European Union as Vidaza for:

• Acute myeloid leukemia
• Chronic myelomonocytic leukemia
• Myelodysplastic syndromes

Approved in United States as Vidaza for:

• Myelodysplastic syndromes
• Chronic myelomonocytic leukemia

Approved in Canada as Vidaza for:

• Myelodysplastic syndromes
• Acute myeloid leukemia

Approved in Japan as Vidaza for:

• Myelodysplastic syndromes
• Acute myeloid leukemia

Who Is Running the Clinical Trial?

M.D. Anderson Cancer Center

Lead Sponsor

Trials

3,107

Recruited

1,813,000+

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

Celgene

Industry Sponsor

Trials

649

Recruited

130,000+

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Jay Backstrom

Celgene

Chief Medical Officer since 2016

MD

Mark Alles

Celgene

Chief Executive Officer since 2016

Bachelor's degree from Lock Haven University of Pennsylvania

Published Research Related to This Trial

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]

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 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]

Pembrolizumab (Keytruda) is the first anti-PD-1 therapy approved in the US for treating advanced malignant melanoma, specifically for patients who have progressed after prior treatments.

It is designed to target the PD-1 protein, enhancing the immune system's ability to fight cancer, and is currently under review for approval in the EU.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab: first global approval. Poole, RM.[2021]

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 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 phase III trial involving 1,019 patients with resected high-risk stage III melanoma, pembrolizumab significantly prolonged recurrence-free survival (RFS) compared to placebo, with a 3-year RFS rate of 63.7% versus 44.1%.

The benefits of pembrolizumab were consistent across various patient subgroups, including those with different tumor stages and BRAF mutation statuses, indicating its broad efficacy in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Longer Follow-Up Confirms Recurrence-Free Survival Benefit of Adjuvant Pembrolizumab in High-Risk Stage III Melanoma: Updated Results From the EORTC 1325-MG/KEYNOTE-054 Trial. Eggermont, AMM., Blank, CU., Mandala, M., et al.[2023]

In a real-world study of 532 patients with advanced melanoma treated with pembrolizumab, the median overall survival was 21.8 months, indicating its effectiveness outside of clinical trials.

Patients with better performance status (ECOG 0-1), normal LDH levels, and no recent corticosteroid use had significantly improved overall survival, highlighting the importance of these factors in treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Real-world experience with pembrolizumab in patients with advanced melanoma: A large retrospective observational study. Liu, FX., Ou, W., Diede, SJ., et al.[2022]

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 randomized trial comparing FDA-approved immune checkpoint inhibitors for advanced melanoma, pembrolizumab showed significantly better treatment outcomes than ipilimumab.

This study is notable as it is the first to directly compare these two therapies as first-line treatments, highlighting pembrolizumab's potential as a more effective option for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab superior to ipilimumab in melanoma. [2017]

In a real-life study of 125 patients with advanced melanoma treated with pembrolizumab, the median overall survival was 16.9 months, which indicates a significant benefit, but lower than the efficacy seen in clinical trials.

While 82% of patients experienced adverse events, the safety profile was comparable to that observed in the KEYNOTE-006 clinical trial, suggesting that pembrolizumab is generally safe for use in this population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Monitoring real-life utilization of pembrolizumab in advanced melanoma using the Portuguese National Cancer Registry. Borges, FC., Ramos, C., Ramos, A., et al.[2021]

Pembrolizumab (Keytruda) is an effective treatment for advanced melanoma, showing significant improvements in progression-free survival and overall response rates compared to ipilimumab and chemotherapy in clinical trials involving patients with varying treatment histories.

The drug has a manageable safety profile, with immune-related side effects that are generally reversible, making it a valuable option for patients who have not responded to other therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab: A Review in Advanced Melanoma. Deeks, ED.[2022]

Citations

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Study of Oral Azacitidine (CC-486) in Combination With ... The goal of this clinical research study is to learn if oral azacitidine (CC-486) and pembrolizumab (MK-3475) can help to control melanoma. The safety of this ...

2. ascopubs.org ascopubs.org/doi/10.1200/JCO.2019.37.15_suppl.9560

A phase II study of oral azacitidine (CC-486) in ... Tumor biopsies at baseline and post treatment were mandated. Results: 22pts, 11 in each arm, have been treated. The most common AEs were nausea, ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8740438/

Pembrolizumab plus azacitidine in patients with ... Metastatic CRC (mCRC) is usually associated with poor prognosis, with 5-year survival rates in the 5–8% range. Chemotherapy remains the backbone ...

4. withpower.com withpower.com/trial/azacitidine-pembrolizumab-for-melanoma-c03f5

Azacitidine + Pembrolizumab for Melanoma Pembrolizumab, an anti-PD-1 antibody, has shown significant efficacy in treating advanced melanoma, demonstrating superior progression-free survival compared to ...

5. ashpublications.org ashpublications.org/blood/article/144/Supplement%201/736/531082/Efficacy-and-Safety-of-Pembrolizumab-Added-to

Efficacy and Safety of Pembrolizumab Added to Azacitidine ... AZA + VEN is a standard of care treatment for pts with AML who are unfit for intensive chemotherapy. However, long-term survival remains limited ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT02816021

NCT02816021 | Study of Oral Azacitidine (CC-486) in ... The goal of this clinical research study is to learn if oral azacitidine (CC-486) and pembrolizumab (MK-3475) can help to control melanoma. The safety of this ...