Testing the Combination of Two Immunotherapy Drugs (Nivolumab and Ipilimumab) in Children, Adolescent, and Young Adult Patients With Relapsed/Refractory Cancers That Have an Increased Number of Genetic Changes, The 3CI Study

Withdrawn before enrolling · Phase 1

Conditions studied: Constitutional Mismatch Repair Deficiency Syndrome, Hematopoietic and Lymphoid Cell Neoplasm, Lynch Syndrome, Recurrent Lymphoma, Recurrent Malignant Solid Neoplasm, Recurrent Neuroblastoma, Recurrent Primary Central Nervous System Neoplasm, Refractory Lymphoma, Refractory Malignant Solid Neoplasm, Refractory Neuroblastoma, Refractory Primary Central Nervous System Neoplasm, Xeroderma Pigmentosum

In brief

This phase Ib trial investigates the side effects of the combination of nivolumab and ipilimumab, and to see how well they work in treating patients with cancers that have come back (relapsed) or does not respond to treatment (refractory) and have an increased number of genetic changes. Immunotherapy with monoclonal antibodies, such as nivolumab and ipilimumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Tumor mutational burden (TMB) is the total amount of genetic changes or "mutations" found in tumor cells. Some studies in adults with cancer have shown that patients with a higher TMB (an increased number of genetic changes) are more likely to respond to immunotherapy drugs. There is also evidence that nivolumab and ipilimumab can shrink or stabilize cancer in adult patients with cancer. This study is being done to help doctors learn if the combination of nivolumab and ipilimumab can help children, adolescents, and young adults patients live longer.

Key facts

Study ID

NCT04500548

Run by

National Cancer Institute (NCI)

People needed

0

Starts

2021-05-11

Expected to finish

2022-06-21

Last updated by the study team

2026-06-10

Who can join

Age: 1 and older, up to 25. Sex: any. Healthy volunteers: not accepted.

You may qualify if…

• PART 1: Patients must have histologically or cytologically confirmed malignancy at the time of initial diagnosis, relapse, or recurrence. Patients must have recurrent or refractory cancer for which standard curative or palliative measures do not exist or are no longer effective
• Patients with multiple concurrent and/or sequential neoplasms are eligible
• Patients with central nervous system (CNS) tumors are eligible, except those with diffuse intrinsic pontine glioma
• Patients with lymphoma are eligible; patients with leukemia are excluded
• Chemotherapy-naive patients are eligible in cases where first-line therapy does not include chemotherapy (e.g., surgery only for ependymoma management)
• PART 1: Patients must have evidence of one or more of the following criteria in current or previous tumor:
• Microsatellite instability (MSI-H)
• Mutation causing functional loss of mismatch repair gene expression (MLH1, MSH2, MSH6, PMS2, EPCAM, MSH3)
• Hypermutation in any tumor (including primary malignancy for patients with relapse or previous cancer diagnoses)
• Functional mutation of POLE or POLD1 genes
• A syndrome linked to hypermutant cancer predisposition such as congenital mismatch repair deficiency (CMMRD), Lynch syndrome, or xeroderma pigmentosum (XP) is also permitted
• Other factors or sequencing evidence not listed above but which may be predictive of hypermutant cancer may be permitted after discussion with the protocol principal investigator
• PART 1: A tumor tissue specimen must be provided for molecular profiling, including TMB analysis. The specimen may be archival or prospective, from a medically necessary surgery, biopsy, or excision. Tissue will not be obtained solely for this trial. A specimen from the time of most recent relapse/progression is preferred, but not mandatory
• Tissue is preferred. However, if necessary, previously extracted DNA may be used with the approval of the protocol principal investigator if extracted in a clinically certified laboratory and prepared in an Foundation Medicine Inc. (FMI), TMB assay-compatible manner
• PART 1: All patients and/or their parents or legally authorized representatives must have the ability to understand and the willingness to sign a written informed consent. Assent, where appropriate, will be obtained according to local policy. Patients with impaired decision-making capacity will not be excluded
• PART 2: Patients must have histologically or cytologically confirmed malignancy at the time of initial diagnosis, relapse, or recurrence. Patients must have recurrent or refractory cancer for which standard curative or palliative measures do not exist or are no longer effective
• Patients with multiple concurrent and/or sequential neoplasms are eligible
• Patients with CNS tumors are eligible, except those with diffuse intrinsic pontine glioma or bulky tumors
• Patients with lymphoma are eligible (provided other criteria, such as bone marrow function, are met); patients with leukemia are excluded
• Chemotherapy-naive patients are eligible in cases where first-line therapy does not include chemotherapy (e.g., surgery only for ependymoma management)
• PART 2: Patients must have measurable disease
• Patients with neuroblastoma without measurable soft tissue but with iobenguane (MIBG) avid disease are eligible
• Patients with bone marrow only disease are excluded
• PART 2: Patients must have confirmation of cancer with a TMB of >= 10 mutations (mut)/megabase (Mb) as determined by an next generation sequencing (NGS) targeted cancer gene panel performed by Foundation Medicine Inc. (FMI). Proof of TMB eligibility can be from Part 1 participation or a previously acquired FMI report
• PART 2: Patients must have recovered from the acute toxic effects of all prior anti-cancer therapies (with the exception of alopecia and lymphopenia)

You may not qualify if…

• PART 1: Patients with history of autoimmune disease
• PART 1: Patients with history of interstitial lung disease or pneumonitis are not eligible
• PART 1: Patients who have received solid organ transplant or allogenic stem cell transplant are not eligible
• PART 1: Patients who have been previously treated with a combination of anti-PD-1/PD-L1 and anti-CTLA-4 inhibitors are not eligible
• PART 2: Patients requiring systemic corticosteroids or other forms of immunosuppressive therapy within 7 days prior to treatment initiation are not eligible
• Following treatment initiation, systemic corticosteroids or other forms of immunosuppressive therapy are permitted if administered for the treatment of toxicity, tumor flare, or pseudo-progression and can be tapered. In most cases study treatment must be held until the dose is tapered to 10 mg/day prednisone or equivalent. The protocol principal investigator must be consulted prior to resuming treatment
• Physiologic corticosteroids up to 5 mg/day prednisone or equivalent are permitted
• Topical, ocular, intra-articular, intra-nasal, inhaled corticosteroids are permitted
• Patients with CNS tumors receiving steroids for intracranial mass effect must be able to discontinue these at least 7 days prior to treatment initiation
• PART 2: Patients who are receiving other anticancer agent(s) are not eligible
• PART 2: Patients who are receiving or have received any other investigational agent(s) within 14 days prior to treatment initiation are not eligible
• PART 2: Patients with CNS tumors with any of the following characteristics on imaging are not eligible:
• Tumor with any evidence of uncal herniation or mass effect leading to severe midline shift
• Tumor > 6 cm in single maximal dimension
• Tumor that in the opinion of the investigator shows significant mass effect
• PART 2: Patients with uncontrolled intercurrent illness/condition that would limit compliance with the study requirements are not eligible. This includes, but is not limited to, ongoing active infection, symptomatic congestive heart failure (New York Heart Association class III or IV), unstable angina pectoris, cardiac arrhythmia, psychiatric illness/social situations
• PART 2: The study agents have the potential for teratogenic or abortifacient effects. Females of reproductive potential must have a negative serum pregnancy test within 72 hours prior to treatment initiation. Additional pregnancy tests (serum or urine) should be obtained during study participation in accordance with local standards and guidelines
• Females of reproductive potential may not participate unless they have agreed to use an effective method of contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of treatment, and as follows:
• A period of 5 months after the last dose of nivolumab
• A period of 3 months after the last dose of ipilimumab
• Should a female patient become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform the investigator immediately
• Due to the unknown but potential risk for adverse events (AEs) in nursing infants secondary to treatment of the mother with the study agents, breastfeeding must be discontinued if the mother is treated on study
• Males will not be required to use contraceptive measures
• Note: Females of reproductive potential are defined as those who are past the onset of menarche and are not surgically sterile (i.e., bilateral salpingectomy, bilateral oophorectomy, complete hysterectomy)
• PART 2: Patients with history of autoimmune disease (such as autoimmune thyroid disease or inflammatory bowel disease) that has required systemic treatment within 2 years prior to treatment initiation are not eligible

Where it is running

• Lucile Packard Children's Hospital Stanford University — Palo Alto, California, United States
• Children's Hospital Colorado — Aurora, Colorado, United States
• Washington University School of Medicine — St Louis, Missouri, United States
• Children's Hospital of Philadelphia — Philadelphia, Pennsylvania, United States
• Baylor College of Medicine/Dan L Duncan Comprehensive Cancer Center — Houston, Texas, United States
• Seattle Children's Hospital — Seattle, Washington, United States
• University of Wisconsin Carbone Cancer Center - University Hospital — Madison, Wisconsin, United States
• British Columbia Children's Hospital — Vancouver, British Columbia, Canada
• Hospital for Sick Children — Toronto, Ontario, Canada

Full record on ClinicalTrials.gov

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