What side effects are associated with this type of intervention?

Common side effects of melanoma treatments involving nivolumab (anti-PD-1) and ipilimumab (anti-CTLA-4) include immune-related adverse events such as skin reactions, endocrine disorders, gastrointestinal issues, and liver toxicity. These can manifest as rash, colitis, hepatitis, and thyroid dysfunction. Cryoablation therapy, which destroys cancer cells by freezing, can cause localized pain, swelling, and potential damage to nearby tissues. When combined, these treatments may lead to a higher incidence of immune-related side effects and localized complications from the cryoablation procedure.

What prior FDA approvals exist?

Nivolumab (anti-PD-1) and Ipilimumab (anti-CTLA-4) have both received FDA approval for the treatment of advanced melanoma. Nivolumab was approved for use in patients with unresectable or metastatic melanoma, either as a monotherapy or in combination with Ipilimumab. The combination of Nivolumab and Ipilimumab has shown improved progression-free survival and overall survival compared to monotherapy with either agent alone. This combination leverages the complementary mechanisms of action of the two drugs to enhance the immune response against cancer cells. Additionally, Pembrolizumab (another anti-PD-1 drug) has also been approved for similar indications in melanoma treatment.

What other types of research exist?

Promising novel alternatives for melanoma treatment in 2024 include: 1) Pembrolizumab (anti-PD-1) as adjuvant therapy, which has shown improved distant metastasis-free survival in high-risk stage II melanoma. 2) Combination therapies involving Dabrafenib and Trametinib for patients with BRAF-mutated melanoma, which have demonstrated significant benefits in adjuvant settings. 3) Experimental approaches such as CAR-T cell therapies, which are being tested in clinical trials and may offer new avenues for treatment.

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Immunotherapy + Cryoablation for Pediatric Solid Cancers

Phase 2

Waitlist Available

Led By Marie Nelson, MD

Research Sponsored by Children's National Research Institute

Eligibility Criteria Checklist

Specific guidelines that determine who can or cannot participate in a clinical trial

Must have

Therapeutic options: The patient's cancer must have relapsed after or failed to respond to frontline curative therapy

Therapeutic options: The patient's cancer must have relapsed after or failed to respond to frontline curative therapy and there must not be other potentially curative treatment options available. Curative therapy may include surgery, radiation therapy in past, chemotherapy, or combination of these modalities.

Must not have

Active or prior documented autoimmune or inflammatory disorders

Uncontrolled intercurrent illness

Timeline

Screening 3 weeks

Treatment Varies

Follow Up 12 months

Awards & highlights

All Individual Drugs Already Approved

No Placebo-Only Group

Summary

This trial tests a combination of freezing tumors and using two immune-boosting drugs in young patients with hard-to-treat tumors. The freezing method kills some cancer cells directly, while the drugs help the immune system attack others.

Who is the study for?

This trial is for pediatric and young adult patients aged between 1 and less than 40 years with relapsed or refractory solid tumors, including osteosarcoma and Ewing sarcoma. Participants must have measurable disease, be candidates for cryoablation therapy, and have no other curative treatment options available. They should not be part of another clinical study or have unresolved severe side effects from previous treatments.

What is being tested?

The trial investigates the effectiveness of combining cryoablation therapy (freezing cancer cells) with two immune checkpoint inhibitors: nivolumab (anti-PD-1) and ipilimumab (anti-CTLA-4). It's a phase II study where all participants receive this combination to see how well it works against various solid tumors in children and young adults.

What are the potential side effects?

Potential side effects include immune-related reactions such as inflammation in different organs, skin issues like rash or itching, hormonal gland problems which could affect energy levels, digestion etc., flu-like symptoms, muscle pain, infusion reactions during treatment administration, possible liver inflammation leading to jaundice or fatigue.

Eligibility Criteria

Inclusion Criteria

You may be eligible if you check “Yes” for the criteria below

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My cancer came back or didn't respond after initial treatment meant to cure it.

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My cancer returned or didn't respond to initial treatment, and no other cure is available.

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I am between 1 and 40 years old.

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My cancer is a confirmed solid tumor like osteosarcoma, Ewing sarcoma, or rhabdomyosarcoma.

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I am mostly active and can do things for myself.

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I have at least one tumor that can be treated with freezing therapy.

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I have at least two tumors that can be measured.

Exclusion Criteria

You may be eligible for the trial if you check “No” for criteria below:

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I have or had an autoimmune or inflammatory disorder.

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I do not have any unmanaged ongoing illnesses.

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I have had another type of cancer.

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I have cancer that has spread to my brain or spinal cord.

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I am not currently on any cancer treatments like chemotherapy or hormone therapy.

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I do not have active infections like TB, hepatitis B or C, or HIV.

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I am not pregnant, breastfeeding, and willing to use birth control if of childbearing potential.

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I have not had major surgery in the last 28 days.

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I have never stopped an immunotherapy treatment because of severe side effects.

Timeline

Screening ~ 3 weeks3 visits

Treatment ~ Varies

Follow Up ~ 12 months

Screening ~ 3 weeks

Treatment ~ Varies

Follow Up ~12 months

This trial's timeline: 3 weeks for screening, Varies for treatment, and 12 months for reporting.

Treatment Details

Study Objectives

Study objectives can provide a clearer picture of what you can expect from a treatment.

Primary study objectives

Disease response measured with consistent imaging utilizing the Response Evaluation Criteria in Solid Tumors (RECIST) v 1.1

Incidence and severity of study treatment-related adverse events measured by the Common Terminology Criteria for Adverse Events (CTCAE) v. 5

Secondary study objectives

Biomarkers of response to checkpoint inhibition (number/activity of immune cells, cytokines, chemokines, C-reactive protein) will be measured in peripheral blood by flow cytometry at baseline and throughout study

Disease response in rare tumors (non-statistical cohort) measured with consistent imaging utilizing the Response Evaluation Criteria in Solid Tumors (RECIST v 1.1)

Health outcomes as assessed by the PROMIS® Pediatric Scale v1.0 Global Health 7+2 scores at baseline, prior to start of each cycle, and last trial visit

+1 more

Side effects data

From 2024 Phase 3 trial • 529 Patients • NCT02017717

80%

Fatigue

70%

Diarrhoea

70%

Headache

40%

Vomiting

40%

Aspartate aminotransferase increased

40%

Rash maculo-papular

40%

Alanine aminotransferase increased

40%

Lipase increased

30%

Partial seizures

30%

Hemiparesis

30%

Gait disturbance

30%

Fall

30%

Cough

30%

Dry skin

30%

Amylase increased

30%

Nausea

30%

Confusional state

20%

Malignant neoplasm progression

20%

Pyrexia

20%

Candida infection

20%

Mucosal infection

20%

Decreased appetite

20%

Back pain

20%

Dysphonia

20%

Hypotension

20%

Colitis

20%

Hyperthyroidism

20%

Oedema peripheral

20%

Muscular weakness

20%

Hypothyroidism

10%

Tinnitus

10%

Cushingoid

10%

Diabetic ketoacidosis

10%

Procedural haemorrhage

10%

Blood bilirubin increased

10%

Bradycardia

10%

Sinus tachycardia

10%

Hyperglycaemia

10%

Hypocalcaemia

10%

Neck pain

10%

Brain oedema

10%

Hydrocephalus

10%

Lethargy

10%

Seizure

10%

Hypertension

10%

Palpitations

10%

Cheilitis

10%

Presyncope

10%

Face oedema

10%

Oedema

10%

Conjunctivitis

10%

Enterocolitis infectious

10%

Oral candidiasis

10%

Pneumonia

10%

Sinusitis

10%

Staphylococcal infection

10%

Blood alkaline phosphatase increased

10%

Spinal pain

10%

Tremor

10%

Dizziness

10%

Dysarthria

10%

Urinary retention

10%

Dyspnoea exertional

10%

Nasal congestion

10%

Pneumonitis

10%

Dermatitis

10%

Erythema

10%

Rash

10%

Klebsiella infection

10%

Hypomagnesaemia

10%

Syncope

10%

Haemorrhage intracranial

10%

Pancreatitis

10%

Cholecystitis

10%

Upper respiratory tract infection

10%

Acute kidney injury

10%

Dermatitis bullous

10%

Lymphopenia

10%

Optic nerve disorder

10%

Visual impairment

10%

Dehydration

10%

Hypokalaemia

10%

Scoliosis

10%

Cognitive disorder

10%

Memory impairment

10%

Hallucination

10%

Insomnia

10%

Irritability

10%

Urinary incontinence

10%

Dyspnoea

10%

Dermatitis acneiform

10%

Pelvic venous thrombosis

10%

Sepsis

100%

80%

60%

40%

20%

Study treatment Arm

Cohort 1: Arm N1+I3

Cohort 2: Arm B

Part A Cohort 1c: Arm N3+RT+TMZ

Part A Cohort 1d: Arm N3+RT

Part B Cohort 1c: Arm N3+RT+TMZ

Part B Cohort 1d: Arm N3+RT

Cohort 1: Arm N3

Cohort 1b: Arm N3+I1

Cohort 2: Arm N3

Awards & Highlights

All Individual Drugs Already Approved

Therapies where all constituent drugs have already been approved are likely to have better-understood side effect profiles.

No Placebo-Only Group

All patients enrolled in this study will receive some form of active treatment.

Trial Design

1Treatment groups

Experimental Treatment

Group I: All patientsExperimental Treatment3 Interventions

Patients less than 40 years old with relapsed/refractory solid tumors and at least 2 sites of measurable disease will receive the current pediatric RP2D of nivolumab and ipilimumab for one cycle and undergo cryoablation therapy of one tumor site. Patients will continue to receive cycles of checkpoint inhibition as long as there is no disease progression of unacceptable toxicity (maximum of 13 cycles \[12 months\]). There are 4 patient cohorts: 1. Osteosarcoma 2. Ewing sarcoma 3. Rhabdomyosarcoma 4. All other solid tumors (non-statistical)

Treatment

First Studied

Drug Approval Stage

How many patients have taken this drug

Ipilimumab

FDA approved

Nivolumab

FDA approved

0 / 16Eligibility criteria met

Research Highlights

Information in this section is not a recommendation. We encourage patients to speak with their healthcare team when evaluating any treatment decision.

Mechanism Of Action

Side Effect Profile

Prior Approvals

Other Research

The most common treatments for melanoma include cryoablation, nivolumab, and ipilimumab. Cryoablation destroys cancer cells by freezing them, which can also trigger an immune response. Nivolumab, a PD-1 inhibitor, enhances the immune system's ability to attack cancer cells by blocking the PD-1 pathway, preventing cancer cells from evading immune detection. Ipilimumab, a CTLA-4 inhibitor, further boosts the immune response by blocking CTLA-4, a checkpoint that normally downregulates immune activity. These treatments are significant for melanoma patients as they provide a comprehensive approach to targeting and eliminating cancer cells, potentially leading to more effective and long-lasting treatment outcomes.

Rate of freeze alters the immunologic response after cryoablation of breast cancer.