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

Official Title

3CI Study: Childhood Cancer Combination Immunotherapy. Phase Ib and Expansion Study of Nivolumab Combination Immunotherapy in Children, Adolescent and Young Adult (CAYA) Patients With Relapsed/Refractory Hypermutant Cancers

Summary:

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 tumour cells to grow and spread. Tumour mutational burden (TMB) is the total amount of genetic changes or "mutations" found in tumour 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.

Trial Description

Primary Outcome:

• Incidence of adverse events

Secondary Outcome:

• Objective overall response rate (ORR)
• Clinical benefit rate (CBR)
• Progression-free survival
• Overall survival

PRIMARY OBJECTIVE:

• To confirm the safety and tolerability of nivolumab-based combination therapy in children, adolescent and young adult (CAYA) patients with relapsed/refractory hypermutant cancers (including solid tumours, central nervous system [CNS] tumours, neuroblastoma, and lymphoma).
• To determine the tolerability, define and describe the toxicities, and determine the recommended phase 2 dose (RP2D) of nivolumab and ipilimumab combination therapy in CAYA patients with relapsed/refractory hypermutant cancers.

SECONDARY OBJECTIVE:

• To assess objective overall response rate (ORR) to the nivolumab-based combination therapy in CAYA patients with relapsed/refractory hypermutant cancers within the confines of a Phase 1b study.

EXPLORATORY OBJECTIVES:

• To assess clinical benefit rate (CBR) (objective response and stable disease for at least two [2] protocol reassessments), progression-free survival (PFS), and overall survival (OS) following nivolumab-based combination therapy in CAYA patients with relapsed/refractory hypermutant cancers.
• To explore correlations between tumour genotype (including tumour mutation burden [TMB], specific gene mutations, etc.) and response to nivolumab-based combination therapy in CAYA patients with relapsed/refractory hypermutant cancers.
• To discover biomarkers predicting response of hypermutant CAYA cancers undergoing PD-1 blockade including tumour neoantigen formation, specific T-cell receptor rearrangements (TCRR) of tumour infiltrating lymphocytes (TILs), and detailed characterization and activation of the immune infiltrations including the TILs.
• To explore the use of minimally invasive methods to monitor and predict response to immune checkpoint inhibition in hypermutant cancers including assessment of circulating tumour deoxyribonucleic acid (DNA) and circulating T-cells immunophenotypic profiling (differentiation markers, cytokines, etc.).

OUTLINE:
PART I: Patients undergo collection of tissue samples for TMB level. Patients with elevated TMB may be eligible for Part II.

PART II: Patients are assigned to 1 of 2 dose levels.

DOSE LEVEL 1: Patients receive nivolumab intravenously (IV) over 30-90 minutes and ipilimumab IV over 30 minutes on day 1. Treatment repeats every 21 days for 4 cycles in the absence of disease progression or unacceptable toxicity. Patients then receive nivolumab IV over 30-90 minutes on days 1 and 15. Treatment repeats every 28 days for up to 23 cycles in the absence of disease progression or unacceptable toxicity.

DOSE LEVEL -1: Patients receive nivolumab IV over 30-90 minutes on days 1 and 15. Treatment repeats every 28 days for up to 26 cycles in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up at 30 days and then every 12 weeks for 1 year.

View this trial on ClinicalTrials.gov