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

NCT05302921 | Completed Phase 2 DMC FDA Drug

• 1 other identifier: CNH-0012021
• Study Type: interventional
• Target: 5
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

Osteosarcoma; Ewing Sarcoma; Rhabdomyosarcoma; Relapsed Pediatric Solid Tumor; Refractory Pediatric Solid Tumor; Melanoma; Hepatoblastoma; Hepatocellular Carcinoma; Neuroblastoma; Wilms Tumor

Keywords

Refractory Pediatric Solid Tumor; Relapsed Pediatric Solid Tumor

Outcome Measures

Primary Outcomes (2)

• 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.

  12 months

• 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.

  12 months

Secondary Outcomes (4)

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

  12 months

• 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

  12 months

• 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

  12 months

• 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

  12 months

Study Arms (1)

All patients

EXPERIMENTAL

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)

Procedure: Cryoablation Therapy; Drug: Nivolumab; Drug: Ipilimumab

Interventions

Cryoablation Therapy PROCEDURE

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.

Also known as: Cryosurgery, Cryotherapy, Cryoablation

All patients

Nivolumab DRUG

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.

All patients

Ipilimumab DRUG

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.

All patients

Eligibility Criteria

• Age: 1 Year - 39 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• 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.
• 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:

You may not qualify if:

• 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 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:
• 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

Sponsors & Collaborators

• Children's National Research Institute: lead
• Bristol-Myers Squibb: collaborator

Study Sites (1)

Children's National Hospital

Washington D.C., District of Columbia, 20010, United States

Location

MeSH Terms

Conditions

Osteosarcoma; Sarcoma, Ewing; Rhabdomyosarcoma; Melanoma; Hepatoblastoma; Carcinoma, Hepatocellular; Neuroblastoma; Wilms Tumor

Interventions

Cryosurgery; Cryotherapy; Nivolumab; Ipilimumab

Condition Hierarchy (Ancestors)

Neoplasms, Bone Tissue; Neoplasms, Connective Tissue; Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Neoplasms; Sarcoma; Myosarcoma; Neoplasms, Muscle Tissue; Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Nevi and Melanomas; Skin Neoplasms; Neoplasms by Site; Skin Diseases; Skin and Connective Tissue Diseases; Neoplasms, Complex and Mixed; Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Liver Neoplasms; Digestive System Neoplasms; Digestive System Diseases; Liver Diseases; Neuroectodermal Tumors, Primitive, Peripheral; Neuroectodermal Tumors, Primitive; Neoplasms, Neuroepithelial; Kidney Neoplasms; Urologic Neoplasms; Urogenital Neoplasms; Neoplastic Syndromes, Hereditary; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Kidney Diseases; Urologic Diseases; Male Urogenital Diseases; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Intervention Hierarchy (Ancestors)

Ablation Techniques; Surgical Procedures, Operative; Therapeutics; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Study Officials

• AeRang Kim, MD, PhD

  Children's National Research Institute

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Oncologist

Study Record Dates

• First Submitted: March 3, 2022
• First Posted: March 31, 2022
• Study Start: February 18, 2022
• Primary Completion: March 12, 2024
• Study Completion: March 12, 2024
• Last Updated: January 1, 2025

Record last verified: 2024-12

Locations

US (1)