DEC-C + Nivolumab for Melanoma

Overseen By Tessa McSpadden

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: University of Colorado, Denver

Must not be taking: Immunosuppressants, Cytotoxic chemotherapy

Disqualifiers: Leptomeningeal disease, Active hepatitis, 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: Unknown

8 Participants Needed

Trial Summary

What is the purpose of this trial?

Activation of the RIG-I innate immune pathway and increased expression of tumor antigens and pro-immune genes by DEC-C during Nivolumab treatment may enhance the frequency and activity of anti-tumor immune cells (CD4+ and CD8+ T-cells, NK cells) and reduce the frequency and activity of immunosuppressive cells. This may increase the overall effectiveness and success of Nivolumab treatment. This pilot clinical trial will demonstrate whether combinatorial immunotherapeutic approaches that target epigenetic immune repression and RIG-I activity can favorably alter the tumor immune cell microenvironment and benefit patients with mucosal melanoma.

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 be on drugs metabolized by CDA or on immunosuppressive therapy with more than 10mg/day of prednisone within 14 days of enrollment.

What data supports the effectiveness of the drug combination DEC-C and Nivolumab for treating melanoma?

Nivolumab has shown a long-term survival benefit for patients with advanced melanoma, and decitabine has been studied for its potential to make melanoma cells more sensitive to immune responses. This suggests that combining these drugs might help in treating melanoma by enhancing the immune system's ability to fight the cancer. ^{1 2 3 4 5}

Is the combination of DEC-C and Nivolumab safe for humans?

Nivolumab, also known as Opdivo, is generally considered safe for humans, but it can cause side effects like fatigue, diarrhea, and skin rash. It may also lead to more serious immune-related side effects, such as inflammation of the liver or lungs. While DEC-C (Oral Decitabine/Cedazuridine) is not specifically mentioned, the safety of Nivolumab has been evaluated in various conditions, including melanoma. ^{6 7 8 9 10}

What makes the drug DEC-C + Nivolumab unique for treating melanoma?

DEC-C + Nivolumab is unique because it combines an oral form of decitabine with cedazuridine, which helps increase the effectiveness of decitabine, with Nivolumab, an intravenous drug that blocks a protein called PD-1, allowing the immune system to better attack melanoma cells. This combination offers a novel approach by integrating an oral component with an established immune checkpoint inhibitor. ^{2 11 12 13 14}

Research Team

Martin McCarter

Principal Investigator

Colorado Research Center

Eligibility Criteria

This trial is for adults aged 18-100 with advanced mucosal melanoma, who may have had prior immune therapy. They must be able to undergo biopsies, have good organ function, and not be pregnant or breastfeeding. Participants need a negative pregnancy test and agree to use contraception if applicable. HIV-positive individuals can join if they meet certain conditions.

Inclusion Criteria

Women of childbearing potential must have a negative pregnancy test and agree to use effective contraceptive method

Patients must be willing to have archived tumor specimens utilized for correlative studies

My kidney function is normal.

Exclusion Criteria

I have cancer that has spread to the lining of my brain and spinal cord.

I do not have an active Hepatitis B or C infection.

I don't have any health issues that could affect the trial's results.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Phase Ib Treatment

Participants receive DEC-C and Nivolumab to assess the RP2D using a TITE-BOIN design

Estimated 6-12 weeks

Phase II Treatment

Evaluate efficacy and safety of DEC-C and Nivolumab at the RP2D

24 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

24 months

Treatment Details

Interventions

• Nivolumab
• Oral Decitabine/Cedazuridine (DEC-C)

Trial Overview The study tests Oral Decitabine/Cedazuridine (DEC-C) combined with Nivolumab in patients with mucosal melanoma. It aims to see if DEC-C can boost the body's immune response against cancer by activating specific pathways and increasing tumor-fighting cells while on Nivolumab treatment.

Participant Groups

Group I: Oral Decitabine/Cedazuridine (DEC-C) and Nivolumab in Mucosal Melanoma Experimental Treatment 1 Intervention

Nivolumab is already approved in United States, European Union, Canada, Switzerland for the following indications:

Approved in United States as Opdivo for:

• Advanced or metastatic gastric cancer
• Gastroesophageal junction cancer
• Esophageal adenocarcinoma
• Melanoma
• Non-small cell lung cancer
• Renal cell carcinoma
• Hodgkin lymphoma
• Head and neck squamous cell carcinoma
• Urothelial carcinoma
• Colorectal cancer
• Hepatocellular carcinoma
• Esophageal squamous cell carcinoma

Approved in European Union as Opdivo for:

• Melanoma
• Non-small cell lung cancer
• Renal cell carcinoma
• Hodgkin lymphoma
• Head and neck squamous cell carcinoma
• Urothelial carcinoma
• Colorectal cancer
• Gastric cancer
• Gastroesophageal junction cancer
• Esophageal adenocarcinoma

Approved in Canada as Opdivo for:

• Melanoma
• Non-small cell lung cancer
• Renal cell carcinoma
• Hodgkin lymphoma
• Head and neck squamous cell carcinoma
• Urothelial carcinoma
• Colorectal cancer
• Gastric cancer
• Gastroesophageal junction cancer
• Esophageal adenocarcinoma

Approved in Switzerland as Opdivo for:

• Melanoma
• Non-small cell lung cancer
• Renal cell carcinoma
• Hodgkin lymphoma
• Head and neck squamous cell carcinoma
• Urothelial carcinoma
• Colorectal cancer
• Gastric cancer
• Gastroesophageal junction cancer
• Esophageal adenocarcinoma

Who Is Running the Clinical Trial?

University of Colorado, Denver

Lead Sponsor

Trials

1,842

Recruited

3,028,000+

National Comprehensive Cancer Network

Collaborator

Trials

121

Recruited

7,400+

Taiho Oncology, Inc.

Industry Sponsor

Trials

79

Recruited

12,700+

Tim Whitten

Taiho Oncology, Inc.

Chief Executive Officer since 2018

MBA and Pharmacy degree

Harold Keer

Taiho Oncology, Inc.

Chief Medical Officer

MD, PhD

Findings from Research

Nivolumab is shown to be the most cost-effective treatment option for advanced melanoma patients in England, with incremental cost-effectiveness ratios of £24,483 for BRAF mutation-negative and £17,362 for mutation-positive patients.

The analysis utilized a Markov state-transition model based on patient-level data from clinical trials, indicating that nivolumab provides long-term survival benefits while being economically favorable compared to other treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The cost-effectiveness of nivolumab monotherapy for the treatment of advanced melanoma patients in England. Meng, Y., Hertel, N., Ellis, J., et al.[2020]

A retrospective analysis of adverse events related to PD-1/PD-L1 inhibitors revealed a significant association between Pembrolizumab and hepatitis B reactivation (HBVr), with a reporting odds ratio of 2.32, indicating a higher risk compared to other treatments.

No cases of HBVr were reported with Ipilimumab or Avelumab, suggesting that not all immune checkpoint inhibitors carry the same risk, highlighting the need for further prospective studies to confirm these findings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hepatitis B Virus Reactivation in Cancer Patients Treated With Immune Checkpoint Inhibitors. Burns, EA., Muhsen, IN., Anand, K., et al.[2023]

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]

Nivolumab significantly improved overall survival and progression-free survival in patients with unresectable or metastatic melanoma compared to dacarbazine, with hazard ratios of 0.42 and 0.43 respectively, based on a trial involving 418 patients.

The most common side effects of nivolumab included fatigue, diarrhea, and rash, but it was still considered to have a favorable benefit-risk profile compared to dacarbazine.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approval of Nivolumab for the First-Line Treatment of Patients with BRAFV600 Wild-Type Unresectable or Metastatic Melanoma. Beaver, JA., Theoret, MR., Mushti, S., et al.[2018]

In a real-world study of 709 patients with advanced melanoma treated with ipilimumab plus nivolumab, 50.7% experienced severe treatment-related adverse events, highlighting the need for careful monitoring during therapy.

Despite the high rate of adverse events, the combination therapy showed promising long-term survival outcomes, with a median overall survival of 28.7 months and a 4-year overall survival rate of 50% for patients similar to those in the CheckMate-067 trial.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Real-world Outcomes of Ipilimumab Plus Nivolumab Combination Therapy in a Nation-wide Cohort of Advanced Melanoma Patients in the Netherlands. van Zeijl, MCT., van Breeschoten, J., de Wreede, LC., et al.[2023]

Nivolumab, a PD-1 inhibitor, has demonstrated significant safety and efficacy in treating various advanced solid tumors, including melanoma and lung cancer, based on multiple high-level studies.

Future research should aim to identify predictive biomarkers for treatment response and explore the potential of combining nivolumab with other therapies, as well as determining the best treatment strategies and duration.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An update on the pharmacodynamics, pharmacokinetics, safety and clinical efficacy of nivolumab in the treatment of solid cancers. Wong, AC., Ma, B.[2018]

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]

Nivolumab, a monoclonal antibody targeting the programmed death receptor-1, has shown promising efficacy in treating advanced malignant melanoma, with nearly 25% of patients achieving a partial tumor response in a phase II trial involving previously treated stage III/IV patients.

The treatment demonstrated a durable clinical benefit, with a median progression-free survival of 172 days and an acceptable safety profile, as less than 18% of patients experienced severe adverse events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab: a review of its use in patients with malignant melanoma. Deeks, ED.[2021]

References

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

For Whom the Bell Tolls? A Toll-Like Receptor 9 Agonist's Journey from Vaccine Adjuvant to Promising Agent in Anti-PD-1-Resistant Melanoma. [2022]

2. Germany pubmed.ncbi.nlm.nih.gov

The cost-effectiveness of nivolumab monotherapy for the treatment of advanced melanoma patients in England. [2020]

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

Pilot early phase II study of decitabine and carboplatin in patients with advanced melanoma. [2022]

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

Pharmaceutical approval update. [2020]

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

Decitabine up-regulates S100A2 expression and synergizes with IFN-gamma to kill uveal melanoma cells. [2018]

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

Hepatitis B Virus Reactivation in Cancer Patients Treated With Immune Checkpoint Inhibitors. [2023]

7. England pubmed.ncbi.nlm.nih.gov

Pembrolizumab in the management of metastatic melanoma. [2020]

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

FDA Approval of Nivolumab for the First-Line Treatment of Patients with BRAFV600 Wild-Type Unresectable or Metastatic Melanoma. [2018]

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

Real-world Outcomes of Ipilimumab Plus Nivolumab Combination Therapy in a Nation-wide Cohort of Advanced Melanoma Patients in the Netherlands. [2023]

10. China pubmed.ncbi.nlm.nih.gov

Immune checkpoint inhibitors in clinical practice: update on management of immune-related toxicities. [2022]

11. England pubmed.ncbi.nlm.nih.gov

An update on the pharmacodynamics, pharmacokinetics, safety and clinical efficacy of nivolumab in the treatment of solid cancers. [2018]

12. England pubmed.ncbi.nlm.nih.gov

Pembrolizumab joins the anti-PD-1 armamentarium in the treatment of melanoma. [2017]

13. New Zealand pubmed.ncbi.nlm.nih.gov

Nivolumab: a review of its use in patients with malignant melanoma. [2021]

14. Brazil pubmed.ncbi.nlm.nih.gov

Effects of nivolumab in peritoneal carcinamatosis of malign melanoma in mouse model. [2018]