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OsteosarcomaPhase 2NCT05302921

Neoadjuvant Dual Checkpoint Inhibition and Cryoablation in Relapsed/Refractory Pediatric Solid Tumors

A Phase 2 study testing Cryoablation Therapy, Nivolumab and Ipilimumab in people with Osteosarcoma and Ewing Sarcoma, run by Children's National Research Institute at 1 site in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial summary

The is a phase II, single arm, open-label, multi-site trial studying the combination of cryoablation therapy and dual checkpoint inhibition with nivolumab (anti-PD-1) and ipilimumab (anti-CTLA-4) given at the recommended phase 2 dose (RP2D) in pediatric and young adult patients with relapsed or refractory solid tumors. Read more about this study

Who is it for?
Ages 1 year to 39 years
Conditions the study is for
Osteosarcoma, Ewing Sarcoma, Rhabdomyosarcoma
What is being tested?
Cryoablation Therapy, Nivolumab and Ipilimumab
Type of treatment
Surgery or procedure
Could I receive a placebo?
No, everyone receives an active treatment
How many people
5 participants
Where
1 siteUnited States
Study dates
18 Feb 2022to 12 Mar 2024
Phase
Phase 2
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 1 year to 39 years
  • All sexes
  • No healthy volunteers
  • Child, Adult

Who may be able to join

  • Informed Consent: Guardian/parent or patient capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol. Written informed consent obtained from the patient/legal representative prior to performing any protocol-related procedures, including screening evaluations.
  • Age: >1 year and <40 years at time of enrollment on study.
  • Diagnosis: histologically confirmed solid tumors (at time of original diagnosis or relapse), including osteosarcoma, Ewing sarcoma family of tumors, and rhabdomyosarcoma for disease-specific arms. For non-statistical cohort, other types of tumors are eligible, including but not limited to melanoma, hepatic tumors, Wilms tumor, neuroblastoma, and non-rhabdomyosarcoma soft tissue sarcomas.
  • Measurable/Evaluable Disease: Patients must have at least TWO measurable/evaluable solid target lesions.
  • Candidate for Cryoablation Therapy: Patients must have at least one tumor available for cryoablation 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.
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  • Performance Status: Karnofsky ≥50% for patients >16 years of age and Lansky ≥60% for patients ≤16 years of age. Patients who are unable to walk because of paralysis but are up in a wheelchair, will be considered ambulatory for purpose of assessing performance score.
  • Prior Therapy:
  • Patients must have fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy prior to enrolling on this study.
  • No limitation on the number of prior chemotherapy regimens that the patient may have • received prior to study entry.
  • Myelosuppressive chemotherapy: At least 21 days after last dose of cytotoxic or myelosuppressive chemotherapy and at least 6 weeks after last dose of nitrosurea.
  • Immunotherapy: At least 21 days must have elapsed from infusion of last dose of antibody, interleukins, interferons, and cytokines. Toxicity related to prior antibody therapy must be recovered to Grade ≤1.
  • Biologic (anti-cancer agent): The last dose must be at least 7 days prior to study entry.
  • Radiation/Cryoablation therapy: Patient must still be a candidate for additional radiation therapy or cryoablation therapy as deemed by study team's radiation oncologist/interventional radiologist.
  • Stem Cell Transplantation:
  • Allogeneic (non-autologous) bone marrow or stem cell transplant or any stem cell infusion including DLI or boost infusion: ≥100 days after infusion, no evidence of GVHD and no requirement for immunosuppression.
  • Autologous stem cell infusion including boost infusion or cellular therapy (eg. Modified T cells, NK cells, dendritic cells): ≥42 days must have elapsed since infusion prior to study entry.
  • Growth Factors: At least 14 days after last dose of a long-acting growth factor (such as pegfilgrastim) or 7 days for short acting growth factor.
  • Concurrent Therapies: No chemotherapy or biologic therapy is permitted.
  • Adequate normal organ and marrow function as defined below:
  • Absolute neutrophil count (ANC) ≥ 750 per mm3.
  • Platelet count ≥75,000 per mm3(transfusion independent).
  • Serum bilirubin ≤1.5 x institutional upper limit of normal (ULN). This will not apply to patients with confirmed Gilbert's syndrome (persistent or recurrent hyperbilirubinemia that is predominantly unconjugated in the absence of hemolysis or hepatic pathology.
  • AST (SGOT)/ALT (SGPT) ≤3x institutional upper limit of normal unless liver metastases are present, in which case it must be ≤5x ULN.
  • Age adjusted normal serum creatinine (see table below) OR a measured creatinine clearance (CL) >70 mL/min or Calculated creatinine clearance >70 mL/min by the Schwartz equation, by radioisotope GFR, or 24-hour urine collection.
  • Evidence of negative urinary or serum pregnancy test for post-menarchal females.
  • Patient is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow up.

Who cannot join

  • Concurrent enrollment in another clinical study, unless it is an observational (non-interventional) clinical study or during the follow-up period of an interventional study.
  • Any unresolved toxicity NCI CTCAE Grade ≥2 from previous anticancer therapy with the exception of alopecia, vitiligo, and the laboratory values defined in the inclusion criteria.
  • Any concurrent chemotherapy, IP, biologic, or hormonal therapy for cancer treatment. Concurrent use of hormonal therapy for non-cancer-related conditions (e.g., hormone replacement therapy) is acceptable.
  • Major surgical procedure within 28 days prior to the first dose of IP. Note: Local surgery of isolated lesions for palliative intent and central line placement are acceptable.
  • History of allogenic organ transplantation.
  • Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease [e.g., colitis or Crohn's disease], diverticulitis [with the exception of diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome [granulomatosis with polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, etc]). The following are exceptions to this criterion:
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  • Patients with vitiligo or alopecia
  • Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable on hormone replacement
  • Any chronic skin condition that does not require systemic therapy
  • Patients without active disease in the last 5 years may be included but only after consultation with the study physician
  • Patients with celiac disease controlled by diet alone
  • Uncontrolled intercurrent illness, including but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, interstitial lung disease, serious chronic gastrointestinal conditions associated with diarrhea, or psychiatric illness/social situations that would limit compliance with study requirement, substantially increase risk of incurring AEs or compromise the ability of the patient to give written informed consent.
  • History of another primary malignancy except for
  • Malignancy treated with curative intent and with no known active disease ≥5 years before the first dose of IP and of low potential risk for recurrence
  • Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease
  • Adequately treated carcinoma in situ without evidence of disease
  • History of leptomeningeal carcinomatosis.
  • Known brain metastases or spinal cord compression. Patients with suspected brain metastases at screening should have an MRI (preferred) or CT each preferably with IV contrast of the brain prior to study entry (skull/bone metastases allowed if does not invade dura and no evidence of CNS edema associated).
  • History of active primary immunodeficiency.
  • Active infection including tuberculosis (clinical evaluation that includes clinical history, physical examination and if needed radiographic testing, and TB testing in line with local practice), hepatitis B (known positive HBV surface antigen (HBsAg) result), hepatitis C, or human immunodeficiency virus (positive HIV 1/2 antibodies). Patients with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody [anti-HBc] and absence of HBsAg) are eligible. Patients positive for hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA.
  • Current or prior use of immunosuppressive medication within 14 days before the first dose of nivolumab or ipilimumab. The following are exceptions to this criterion:
  • Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra articular injection)
  • Systemic corticosteroids at physiologic doses
  • Steroids as premedication for hypersensitivity reactions (e.g., as premedication for blood products or CT scan premedication)
  • Receipt of live attenuated vaccine within 30 days prior to the first dose of IP. Note: Patients, if enrolled, should not receive live vaccine whilst receiving IP and up to 30 days after the last dose of IP.
  • Female patients who are pregnant or breastfeeding or male or female patients of reproductive potential who are not willing to employ effective birth control from screening to 180 days after the last dose of nivolumab and ipilimumab combination therapy.
  • Known allergy or hypersensitivity to any of the study drugs or any of the study drug excipients.
  • Must not have experienced a toxicity that led to permanent discontinuation of prior immunotherapy.
  • All AEs while receiving prior immunotherapy must have completely resolved or resolved to baseline prior to screening for this study.
  • Must not have experienced a ≥Grade 3 immune related AE or an immune related neurologic or ocular AE of any grade while receiving prior immunotherapy. NOTE: Patients with endocrine AE of ≤Grade 2 are permitted to enroll if they are stably maintained on appropriate replacement therapy and are asymptomatic.
  • Must not have required the use of additional immunosuppression other than corticosteroids for the management of an AE, not have experienced recurrence of an AE if re-challenged, and not currently require maintenance doses of > physiologic dosing of prednisone or equivalent per day.
  • Judgment by the investigator that the patient is unsuitable to participate in the study and the patient is unlikely to comply with study procedures, restrictions and requirements.
  • Known allergy or hypersensitivity to IP therapies.

Trial locations and contacts

1 site in 1 country.

United States1 site

  • Children's National Hospital

    Washington D.C., District of Columbia, 20010

Other trials in United States

About this study

Official title: Phase II Study Investigating the Efficacy of Neoadjuvant Dual Checkpoint Inhibition and Cryoablation Therapy in Children, Adolescents, and Young Adults With Relapsed/Refractory Solid Tumors

The is a phase II, single arm, open-label, multi-site trial studying the combination of cryoablation therapy and dual checkpoint inhibition with nivolumab (anti-PD-1) and ipilimumab (anti-CTLA-4) given at the recommended phase 2 dose (RP2D) in pediatric and young adult patients with relapsed or refractory solid tumors.

Read the detailed description

Patients less than 40 years old with relapsed/refractory solid tumors and at least two 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]).

Being tested
Cryoablation Therapy, Nivolumab, Ipilimumab
Keywords
Refractory Pediatric Solid Tumor, Relapsed Pediatric Solid Tumor
Medical subject headings
Osteosarcoma, Sarcoma, Ewing, Rhabdomyosarcoma, Melanoma, Hepatoblastoma, Carcinoma, Hepatocellular, Neuroblastoma, Wilms Tumor

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Cryoablation TherapyProcedure or surgery

    Also called Cryosurgery, Cryotherapy, Cryoablation

    Cryoablation therapy is an established method of cancer treatment in adults and pediatrics with certain types of tumors and is standard of care for certain tumors in the setting of progression/relapse.

    Percutaneous image-guided Cryoablation (cryosurgery, cryotherapy) is a technique that utilizes successive rapid freeze/thaw cycles to destroy tumor cells. This technique is performed by inserting specialized needles known as cryoprobes into target tumors under imaging guidance with Computed Tomography (CT) and Ultrasound (US), or Magnetic Resonance Imaging (MRI). After the cryoprobe needles are placed within the target tumor, rapid cooling of liquid gas inserted into these probes leads to temperatures reaching -20 to -40 degrees Celsius.

    Cryoablation therapy of one disease site will be done starting Day 3 and prior to Day 15 of Cycle 1 only.

  • NivolumabDrug

    Nivolumab (Bristol Myers Squibb) is a human monoclonal antibody (immunoglobulin G4) that targets the programmed death-1 cluster of differentiation 279 (CD279) cell surface membrane receptor.

    Nivolumab and ipilimumab will be given on day 1 of 21-day cycles for cycles 1-4, followed by nivolumab alone on days 1 and 15 of 28-day cycles for cycles 5+. Patients will receive up to 13 cycles of therapy unless unacceptable toxicity or progression of disease.

  • IpilimumabDrug

    Ipilimumab (Bristol Myers Squibb) is a fully human monoclonal immunoglobulin G1Κ specific for human cytotoxic T-lymphocyte antigen 4 (CTLA-4, cluster of differentiation [CD]152), which is expressed on a subset of activated T-cells.

    Nivolumab and ipilimumab will be given on day 1 of 21-day cycles for cycles 1-4, followed by nivolumab alone on days 1 and 15 of 28-day cycles for cycles 5+. Patients will receive up to 13 cycles of therapy unless unacceptable toxicity or progression of disease.

Study groups in NCT05302921
Study groupRoleWhat they receive
All patientsExperimentalPatients 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)
Receives: Procedure: Cryoablation Therapy; Drug: Nivolumab; Drug: Ipilimumab

What is being measured

The primary outcome is the main question the study is designed to answer.

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

    Patients will undergo consistent imaging prior to every odd cycle of therapy and utilize the Response Evaluation Criteria in Solid Tumors (RECIST) v 1.1.

    Measured: 12 months

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

    Toxicities will be defined using the Common Terminology Criteria for Adverse Events (CTCAE) v. 5.

    Measured: 12 months

Secondary outcomes (4)

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

    Patients in the non-statistical cohort will under consistent imaging prior to every odd cycle measured by Response Evaluation Criteria in Solid Tumors (RECIST) v. 1.1.

    Measured: 12 months

  2. 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

    Peripheral blood will be collected from patients at baseline, following neoadjuvant immunotherapy/prior to cryoablation, and prior to each cycle of immunotherapy.

    Measured: 12 months

  3. 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

    Each question will be rated from the following: Excellent (5) to Poor (1), Never (5) to Always (1), or Never (1) to Almost Always (5)

    Measured: 12 months

  4. Health outcomes as assessed by the Parent Proxy Scale v1.0 Global Health 7+2 at baseline, prior to start of each cycle, and last trial visit

    Each question will be rated from the following: Excellent (5) to Poor (1), Never (5) to Always (1), or Never (1) to Almost Always (5)

    Measured: 12 months

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted31 Mar 2022
  2. Study start18 Feb 2022
  3. Primary completion12 Mar 2024
  4. Study completion12 Mar 2024

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
5 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT05302921
Sponsor's protocol ID
CNH-0012021
Status last verified
Dec 2024
First submitted
3 Mar 2022
Last updated
1 Jan 2025
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Cryoablation Therapy, Nivolumab and Ipilimumab in people with Osteosarcoma and Ewing Sarcoma, run by Children's National Research Institute at 1 site in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 27 inclusion and 33 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 1 Jan 2025. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Disease response measured with consistent imaging utilizing the Response Evaluation Criteria in Solid Tumors (RECIST) v 1.1 (time frame: 12 months). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT05302921.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 1 Jan 2025.

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