Cryoablation + Ipilimumab + Nivolumab for Melanoma

Overseen By Meghan J Mooradian, MD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Massachusetts General Hospital

Must be taking: Ipilimumab, Nivolumab

Must not be taking: Investigational agents, Systemic anticoagulants

Disqualifiers: Symptomatic brain metastasis, Pregnancy, 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

Compensation: Varies

Number of Visits: 1

Duration: 8-12 weeks

37 Participants Needed

Trial Summary

Do I have to stop taking my current medications for the trial?

The trial protocol does not specify if you need to stop taking your current medications. However, you cannot be on more than 10mg of oral prednisone or its equivalent, and you must be able to hold systemic anticoagulation if required by the operator for cryoablation.

What data supports the effectiveness of the treatment Cryoablation + Ipilimumab + Nivolumab for Melanoma?

Research shows that the combination of nivolumab and ipilimumab, both immune system-boosting drugs, improves survival and response rates in advanced melanoma compared to using ipilimumab alone. This suggests that combining these drugs with cryoablation (a technique that freezes and destroys cancer cells) could potentially enhance treatment effectiveness. ^{1 2 3 4 5}

Is the combination of cryoablation, ipilimumab, and nivolumab safe for treating melanoma?

The combination of ipilimumab and nivolumab can cause various immune-related side effects, which can be severe in some cases. Common side effects include colitis (inflammation of the colon), pneumonitis (lung inflammation), and diarrhea. While most side effects are mild to moderate, some can be serious and require careful monitoring and management. ^{6 7 8 9 10}

What makes the treatment of cryoablation combined with ipilimumab and nivolumab unique for melanoma?

This treatment is unique because it combines cryoablation (a technique that freezes and destroys cancer cells) with two immune checkpoint inhibitors, ipilimumab and nivolumab, which work together to enhance the body's immune response against melanoma. This combination aims to improve the effectiveness of the immune system in targeting and eliminating cancer cells compared to using the drugs alone. ^{1 2 5 11 12}

What is the purpose of this trial?

The aim of this study is to find out whether the combination of two approved drugs, ipilimumab and nivolumab, in combination with cryoablation are safe and effective for participants who have an unresectable melanoma that is resistant, or is growing, after receiving immunotherapy with a PD-1 inhibitor. The names of the study interventions involved in this study are: * Cryoablation (an interventional radiology procedure that freezes part of a tumor) * Ipilimumab (an immunotherapy) * Nivolumab (an immunotherapy)

Research Team

Meghan J Mooradian, MD

Principal Investigator

Massachusetts General Hospital

Eligibility Criteria

Adults over 18 with unresectable melanoma that's grown despite prior immunotherapy can join. They must be fit for dual checkpoint inhibition, have a tumor suitable for cryoablation, good organ/marrow function, and no untreated serious medical issues or need for high-dose steroids. Those with treated hepatitis C or controlled HIV are eligible. Pregnant women and those on certain cancer therapies or with symptomatic brain metastases cannot participate.

Inclusion Criteria

I am an adult with melanoma that can't be removed surgically and it got worse after treatment with specific immune therapies.

I have a tumor that can be measured with scans or physical exams.

I am HIV positive, on treatment, and my viral load is undetectable.

Exclusion Criteria

I have recovered from side effects of previous cancer treatments.

I do not have any uncontrolled illnesses.

My cancer is getting worse despite being on ipilimumab/nivolumab.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants receive ipilimumab and nivolumab with cryoablation. Core Needle Biopsy followed by cryoablation between Cycle 1 - 2.

8-12 weeks

Multiple visits for drug administration and procedures

Follow-up

Participants are monitored for safety and effectiveness after cryoablation. Surveillance CT scans and follow-up for 6 months to assess safety.

6 months

Regular visits for CT scans and assessments

Long-term follow-up

Participants followed for duration of response and overall survival.

Up to 3 years

Treatment Details

Interventions

• Cryoablation
• Ipilimumab
• Nivolumab

Trial Overview The trial tests if combining two immunotherapies (ipilimumab and nivolumab) with cryoablation is safe/effective in patients whose melanoma has worsened after PD-1 inhibitor therapy. Cryoablation freezes part of the tumor while the drugs help the immune system fight cancer.

Participant Groups

Group I: Ipilimumab + Nivolumab + Cryoablation Experimental Treatment 3 Interventions

Study will be conducted in two stages: Stage 1: Will enroll 15 participants, and if 6 or more have clinical benefit, the study will proceed to Stage 2. * Baseline CT scan. * Cycle 1-4: Pre-determined doses of ipilimumab and nivolumab. Medications administered under direction of treating oncologist. * Day 2 - 14: Core Needle Biopsy followed by cryoablation between Cycle 1 - 2 * Surveillance CT scan at weeks 8 - 12, weeks 16 - 24. * Follow up for 6 months to assess safety after cryoablation. Participants followed for duration of response. Stage 2: Will enroll 22 participants * Baseline CT scan. * Cycle 1-4: Pre-determined doses of ipilimumab and nivolumab. Medications administered under direction of treating oncologist. * Day 2- 14: Core Needle Biopsy followed by cryoablation between Cycle 1 - 2. * Surveillance CT scan at weeks 8 - 12, weeks 16 - 24 * Follow up period to assess safety 6 months after cryoablation. Patients followed for duration of response.

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

Approved in United States as Yervoy for:

• Advanced melanoma
• Stage III unresectable melanoma
• Stage IV metastatic melanoma

Approved in European Union as Yervoy for:

• Advanced melanoma
• Stage III unresectable melanoma
• Stage IV metastatic melanoma

Who Is Running the Clinical Trial?

Massachusetts General Hospital

Lead Sponsor

Trials

3,066

Recruited

13,430,000+

William M. Wood Foundation

Collaborator

Trials

2

Recruited

70+

Findings from Research

In a phase 3 trial involving 906 patients with resected advanced melanoma, nivolumab demonstrated a significantly higher 12-month recurrence-free survival rate of 70.5% compared to 60.8% for ipilimumab, indicating it is more effective as adjuvant therapy.

Nivolumab also had a much lower incidence of severe treatment-related adverse events (14.4%) compared to ipilimumab (45.9%), suggesting it is a safer option for patients undergoing treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adjuvant Nivolumab versus Ipilimumab in Resected Stage III or IV Melanoma. Weber, J., Mandala, M., Del Vecchio, M., et al.[2023]

The combination of nivolumab and ipilimumab, two immune checkpoint inhibitors, is a promising treatment for advanced melanoma, enhancing the body's immune response against the cancer.

Adding denosumab to this treatment may further improve anti-tumor effects by counteracting the immunosuppressive environment created by CD8+ T cells, as suggested by recent reports.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Successful Treatment of Multiple Metastatic Melanoma with Nivolumab, Ipilimumab plus Denosumab Combined Therapy. Yoshida, S., Fujimura, T., Kambayashi, Y., et al.[2020]

The combination of ipilimumab and nivolumab is more effective in treating advanced melanoma compared to ipilimumab alone, leading to better patient responses.

However, this two-drug combination significantly increases the likelihood of side effects compared to using ipilimumab as a single treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab + ipilimumab ups melanoma response. [2018]

In a study of 47 patients with advanced melanoma who experienced acquired resistance to initial combination immunotherapy, reinduction with ipilimumab (with or without anti-PD-1) resulted in a modest response rate of 26% and a disease control rate of 45%.

While reinduction therapy showed some clinical activity, it also carried a significant risk of immune-related adverse events (irAEs), with 58% of patients experiencing them, including severe cases, and many patients experiencing recurrence of previously observed irAEs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Re-induction ipilimumab following acquired resistance to combination ipilimumab and anti-PD-1 therapy. Hepner, A., Atkinson, VG., Larkin, J., et al.[2021]

In a phase 2 trial involving 142 patients with untreated advanced melanoma, the combination of nivolumab and ipilimumab resulted in a 2-year overall survival rate of 63.8%, compared to 53.6% for those receiving ipilimumab alone, suggesting improved survival outcomes with the combination therapy.

However, the combination treatment was associated with a higher incidence of severe side effects, with 54% of patients experiencing grade 3-4 adverse events compared to 20% in the ipilimumab-only group, indicating a trade-off between efficacy and safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combined nivolumab and ipilimumab versus ipilimumab alone in patients with advanced melanoma: 2-year overall survival outcomes in a multicentre, randomised, controlled, phase 2 trial. Hodi, FS., Chesney, J., Pavlick, AC., et al.[2022]

In a study of 35 patients with advanced renal cell carcinoma treated with nivolumab plus ipilimumab, 62.9% experienced immune-related adverse events, which were associated with significantly longer progression-free and overall survival rates.

The presence of immune-related adverse events, particularly skin reactions, was identified as an independent predictor of better clinical outcomes, suggesting that these events could serve as effective biomarkers for treatment response.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immune-related adverse events are clinical biomarkers to predict favorable outcomes in advanced renal cell carcinoma treated with nivolumab plus ipilimumab. Ueda, K., Suekane, S., Kurose, H., et al.[2022]

In a study of 56 patients with metastatic melanoma who had severe immune-related adverse events (AEs) from ipilimumab, 36% experienced at least one immune-related AE after receiving anti-PD-1 therapy, indicating a notable risk of recurrence but also a manageable safety profile.

Despite the risk of AEs, anti-PD-1 therapy showed a 43% overall response rate and a median overall survival of 21 months, suggesting it may offer improved outcomes for patients previously affected by severe toxic effects from ipilimumab.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Association of Anti-Programmed Cell Death 1 Antibody Treatment With Risk of Recurrence of Toxic Effects After Immune-Related Adverse Events of Ipilimumab in Patients With Metastatic Melanoma. Brunot, A., Grob, JJ., Jeudy, G., et al.[2021]

A systematic review of 14 randomized controlled trials found that combining nivolumab (NIVO) with ipilimumab (IPI) significantly increases the risk of treatment-related adverse events (TRAEs) compared to NIVO alone, with an overall risk ratio of 1.11 for any grade TRAEs and 1.95 for severe (grade 3 or 4) TRAEs.

Specific adverse events were notably higher with the combination therapy, including colitis (RR = 4.52), pneumonitis (RR = 3.06), and diarrhea (RR = 1.68), indicating that while the combination may be effective, it comes with increased safety concerns.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adverse Events Induced by Nivolumab Plus Ipilimumab vs. Nivolumab Monotherapy among Cancer Patients: A Systematic Review and Meta-Analysis. Kamat, S., Patel, J., Brown, BR., et al.[2022]

Nivolumab combined with ipilimumab significantly improves treatment outcomes in cancer, showing higher rates of complete response (CR), partial response (PR), and overall response rate (ORR) compared to either drug alone, based on a meta-analysis of 11 studies.

While the combination therapy N1I3 (1 mg/kg nivolumab and 3 mg/kg ipilimumab) was more effective than N3I1 (3 mg/kg nivolumab and 1 mg/kg ipilimumab), it also had a higher incidence of serious adverse events, though overall safety was still considered acceptable.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The efficacy and safety of combined immune checkpoint inhibitors (nivolumab plus ipilimumab): a systematic review and meta-analysis. Chen, J., Li, S., Yao, Q., et al.[2021]

Ipilimumab has shown a positive impact on overall survival in patients with stage IV melanoma, with long-term follow-up indicating its effectiveness compared to conventional treatments.

While 84.8% of patients experience drug-related adverse events, most are mild to moderate; however, severe reactions can occur, necessitating careful monitoring and management, especially when combined with other therapies like vemurafenib.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CTLA-4 blockade with ipilimumab: biology, safety, efficacy, and future considerations. Camacho, LH.[2022]

In a cohort of 64 adults with advanced melanoma treated with nivolumab and ipilimumab, 91% experienced clinically significant immune-related adverse events (AEs), highlighting the treatment's potential for serious side effects.

Despite the high incidence of AEs, most patients did not complete all 4 doses of the treatment, suggesting that fewer doses may still provide clinical benefits without the need for extensive immunosuppression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Measuring Toxic Effects and Time to Treatment Failure for Nivolumab Plus Ipilimumab in Melanoma. Shoushtari, AN., Friedman, CF., Navid-Azarbaijani, P., et al.[2023]

Ipilimumab, the first drug to improve survival in advanced melanoma, works by inhibiting CTLA-4 on T cells, but newer PD-1 inhibitors like nivolumab and pembrolizumab have shown better efficacy and safety.

The combination of ipilimumab and nivolumab enhances response rates and progression-free survival in advanced melanoma patients, but it also increases the risk of immune-related toxicities, leading to its FDA approval in 2015 for BRAF wild-type cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ipilimumab Combined with Nivolumab: A Standard of Care for the Treatment of Advanced Melanoma? Carlino, MS., Long, GV.[2018]

References

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

Adjuvant Nivolumab versus Ipilimumab in Resected Stage III or IV Melanoma. [2023]

2. Switzerland pubmed.ncbi.nlm.nih.gov

Successful Treatment of Multiple Metastatic Melanoma with Nivolumab, Ipilimumab plus Denosumab Combined Therapy. [2020]

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

Nivolumab + ipilimumab ups melanoma response. [2018]

4. England pubmed.ncbi.nlm.nih.gov

Re-induction ipilimumab following acquired resistance to combination ipilimumab and anti-PD-1 therapy. [2021]

5. England pubmed.ncbi.nlm.nih.gov

Combined nivolumab and ipilimumab versus ipilimumab alone in patients with advanced melanoma: 2-year overall survival outcomes in a multicentre, randomised, controlled, phase 2 trial. [2022]

6. England pubmed.ncbi.nlm.nih.gov

Immune-related adverse events are clinical biomarkers to predict favorable outcomes in advanced renal cell carcinoma treated with nivolumab plus ipilimumab. [2022]

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

Association of Anti-Programmed Cell Death 1 Antibody Treatment With Risk of Recurrence of Toxic Effects After Immune-Related Adverse Events of Ipilimumab in Patients With Metastatic Melanoma. [2021]

8. England pubmed.ncbi.nlm.nih.gov

Adverse Events Induced by Nivolumab Plus Ipilimumab vs. Nivolumab Monotherapy among Cancer Patients: A Systematic Review and Meta-Analysis. [2022]

9. England pubmed.ncbi.nlm.nih.gov

The efficacy and safety of combined immune checkpoint inhibitors (nivolumab plus ipilimumab): a systematic review and meta-analysis. [2021]

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

CTLA-4 blockade with ipilimumab: biology, safety, efficacy, and future considerations. [2022]

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

Measuring Toxic Effects and Time to Treatment Failure for Nivolumab Plus Ipilimumab in Melanoma. [2023]

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

Ipilimumab Combined with Nivolumab: A Standard of Care for the Treatment of Advanced Melanoma? [2018]