(P 417) VITAS: ATEZOLIZUMAB IN COMBINATION WITH CHEMOTHERAPY FOR PEDIATRIC RELAPSED/REFRACTORY SOLID TUMORS: AN OPEN-LABEL, PHASE I/II, SINGLE-ARM, MULTI-CENTER TRIAL IN PROGRESS

Objective: Children with relapsed or refractory solid tumors have poor outcomes and limited treatment options. Immune checkpoint immunotherapy (ICI) has revolutionized the care of multiple adult cancers but to date has shown limited effectiveness as monotherapy in pediatric solid tumors. A multitude of reasons have been proposed to explain this disparity, including lower mutational burden in pediatric tumors, immature immune systems in pediatric populations, and distinct gut microbiomes. However, there remains scant evidence to provide mechanistic insight into and strategies for overcoming this resistance.
Combining ICI with chemotherapy may improve these outcomes. Cytotoxic chemotherapy can expose tumor antigens and create an immunogenic tumor microenvironment. Commonly used chemotherapies can also induce immune-mediated anti-tumor responses that in turn may be amplified by ICI. Indeed, chemotherapy + ICI is now standard of care for multiple adult cancers. Yet it remains unknown whether that success can be extended to a pediatric population.
The combination of vincristine, irinotecan, and temozolomide (VIT) is well-tolerated and has clinical activity in multiple tumor types. Further, VIT may promote anti-tumor immune responses through selectively depleting inhibitory regulatory T cells, increasing tumor mutational burden, and increasing tumor antigen presentation. VIT has also demonstrated efficacy against relapsed/refractory (R/R) rhabdomyosarcoma (RMS), with objective response rates (ORR) up to 40% reported in prior studies. Additionally, there is evidence that the PD-1/PD-L1 signaling axis is biologically relevant in RMS, as PD-L1 expression increases after treatment with chemotherapy.

Methods: VITAS (NCT04796012) is a phase I/II open-label single arm, multi-center study of VIT plus the anti-PD-L1 mAb Atezolizumab in children and young adults with R/R Solid tumors. The study will be conducted in two sequential phases: a phase I feasibility cohort, enrolling patients with any R/R solid tumor, and a phase II R/R RMS efficacy cohort (Figure 1). Eligible patients must be ≥ 6 months and ≤ 18 years old. Patients will receive atezolizumab 15 mg/kg (max 1,200 mg) on Day 1 of each 21-day cycle; with vincristine (1.5 mg/m2 on Day 1), irinotecan (50 mg/m2 IV on Days 1-5) and temozolomide (100 mg/m2 PO or IV on Days 1-5). The primary phase I feasibility endpoint will be the number of patients with dose-limiting toxicities (DLT) in the first two cycles of therapy. Six patients will be accrued at a dose level, and the treatment regimen will be deemed feasible if no more than 2 patients develop DLTs. Adverse events (AEs) are graded per CTCAE v5.
If the primary feasibility endpoint is met, the study will proceed into the phase II RMS efficacy cohort. The primary endpoint of this cohort is ORR per RECIST v1.1. The null hypothesis is that the true ORR is 0.2. and the alternative hypothesis is that the true ORR is 0.5. Simon’s minimax two-stage design will be used with 9 patients in stage I and a total accrual of 17. If there are 2 or fewer responses in stage I the study will be stopped early. If there are 7 or more responses among 17 patients, we reject the null hypothesis and deem that the treatment is promising. The design controls the type I error rate at 0.05 and yields the power of 0.8. Tumor, blood and stool are collected at predetermined time points for interrogation of biological correlates of response to treatment (Figure 2).
At the time of this report, six patients have consented, four have initiated therapy (Table 1), and three have completed the DLT window without DLT. For these three patients, the most common AEs (all grades) have been nausea (n=3,100%), vomiting (n=3, 100%), diarrhea (n=3, 100%), fatigue (n=3, 100%), anorexia (n=2, 67%), and weight loss (n=2, 67%). One patient experienced Grade 2 immune-related colitis. Two patients experienced Grade ≥ 3 AEs (Neutrophil count decreased, weight loss, anorexia, hypoglycemia, Table 2). One patient with RMS had a sustained partial response through 15 cycles of therapy. Enrollment is ongoing in the phase I feasibility cohort.

Results: Not applicable.

Conclusion: Not applicable.