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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores whether a combination of two immunotherapy drugs, ipilimumab and nivolumab, along with cryoablation (a procedure that freezes part of a tumor), can safely and effectively treat melanoma that cannot be surgically removed and has stopped responding to other treatments. It targets individuals with melanoma that continues to grow despite treatment with drugs targeting the PD-1 pathway, such as pembrolizumab or nivolumab. This trial may suit those with melanoma resistant to these therapies and a tumor that can be safely frozen with cryoablation. As a Phase 2 trial, the research measures the treatment's effectiveness in an initial, smaller group, offering a chance to explore new treatment options.

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.

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

Studies have shown that combining ipilimumab and nivolumab with cryoablation is generally well-tolerated. Research involving 16 patients who underwent cryoablation while taking these drugs reported manageable side effects. Most side effects were mild, such as tiredness or a skin rash. More serious side effects were less common but included inflammation of the liver and lungs. Importantly, another study confirmed that this treatment combination is feasible and aids the immune system in fighting cancer. These findings suggest the treatment is relatively safe, but awareness of possible side effects remains important. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of cryoablation with ipilimumab and nivolumab for treating melanoma because it offers a novel approach by combining immunotherapy with a physical tumor-targeting technique. Unlike standard treatments like surgery, chemotherapy, or radiation, which directly remove or kill cancer cells, this treatment aims to boost the body's immune response against the cancer. Ipilimumab and nivolumab are immunotherapy drugs that activate the immune system to recognize and attack melanoma cells, while cryoablation uses extreme cold to destroy tumor tissue and potentially enhance the immune response. This combined approach not only targets the tumor directly but also helps the immune system to better identify and fight off melanoma cells throughout the body, which could lead to improved outcomes for patients.

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

In this trial, participants will receive a combination of two immunotherapy drugs, ipilimumab and nivolumab, along with cryoablation. Research has shown that using ipilimumab and nivolumab together can help treat advanced melanoma. Specifically, studies found that this combination helped 59% of patients with advanced melanoma live longer, reducing the risk of disease progression or death by 45% compared to other treatments. Cryoablation, a technique that freezes part of the tumor, is believed to enhance the immune response by altering the tumor's environment. Early evidence suggests that combining cryoablation with these drugs might improve their effectiveness by further boosting the body's ability to fight cancer cells. Overall, promising data supports this combination for people with difficult-to-treat melanoma. ^{1 2 6 7 8}

Who Is on the Research Team?

Meghan J Mooradian, MD

Principal Investigator

Massachusetts General Hospital

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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]

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]

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 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]

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]

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]

Citations

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Cryoablation and post-progression immune checkpoint ... We hypothesized that cryoablation may modify the immune microenvironment through direct modulation of the tumor, thereby generating an anti-tumor response.

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Advanced Melanoma Skin Cancer | Clinical Trial Results 59% of those given OPDIVO® + YERVOY® for advanced melanoma survived, versus. In the clinical trial, people given OPDIVO + YERVOY had a 45% lower risk of ...

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OPDIVO® (nivolumab) + YERVOY® (ipilimumab) Efficacy in ... Final, 10-year outcomes with nivolumab plus ipilimumab in advanced melanoma (Suppl.). N Engl J Med. Published online September 15, 2024. YERVOY [package insert] ...

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Leveraging cryoablation and checkpoint inhibitors for high- ... Moreover, an off-label low-dose ICIs protocol of ipilimumab (0.3 mg/kg) plus nivolumab (0.5 mg/kg) has already proven safe and effective in 131 unselected stage ...

6. jvir.org jvir.org/article/S1051-0443(21)01322-1/abstract

Safety and Feasibility of Cryoablation during ... Sixteen patients were treated with 27 cryoablation procedures while receiving ipilimumab and nivolumab from April 2017 to July 2020. ... outcomes. J Vasc ...

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Preoperative immune checkpoint inhibition and ... We provide preliminary evidence that preoperative cryoablation plus ipilimumab and nivolumab is feasible, inducing systemic adaptive immune activation.

8. centerwatch.com centerwatch.com/clinical-trials/listings/NCT05779423/cryoablationipilimumabnivolumab-in-melanoma

Cryoablation+Ipilimumab+Nivolumab in Melanoma The aim of this study is to find out whether the combination of two approved drugs, ipilimumab and nivolumab, in combination with ...