Table 2. Latest immunotherapy trials utilizing immune checkpoint inhibitors in patients with recurrent, relapsed, refractory, or metastatic OS <18 years of age, as of July 21, 2021.
Note: all clinical trials included were designed as open-label studies and are taking place in the United States.
Abbreviations – ADA: anti-drug antibody; AE: adverse events; CBR: clinical benefit rate; cis: cisplatin; Cmax: maximum plasma concentration; CR: confirmed response; DC: disease control; DLT: dose-limiting toxicity; DoR: duration of response; dox: doxorubicin; DR: disease response; EFS: event-free survival; Exp.: expression; GM-CSF: granulocyte-macrophage colony-stimulating factor; GPNMB: transmembrane glycoprotein NMB; HR: histological response; ifos: ifosfamide; IGF-1R: insulin-like growth factor 1 receptor; ir-RC: immune related response criteria; LRD: localized resectable disease; MAP: high-dose methotrexate; MD: metastatic disease; mo(s): months; MTD: maximum tolerated dose; no.: number; NCI: National Cancer Institute; NR: not recruiting; OMS: overall median survival; ORR: objective response rate; OS: overall survival; PET: positron emission tomography; PD: progression of disease; PFS: progression-free survival; Ph: phase; PK: pharmacokinetics; PR: partial response; pt(s): patient(s); RECIST: response evaluation criteria in solid tumors; SD: stable disease; t1/2: half-life; TRR: tumor response rate; UTAI: up to and including; w/: with; w/i: within; wk(s): week(s); yrs: years.
| Author(s) (NCI trial No.) | Study design | Ph | Status | Drug(s) used | Primary outcome | Secondary outcome | No. of OS pts <18 years | Outcome(s) |
| Lussier et al. [30] and Merchant et al. [31] (NCT02500797) | Randomized, crossover | II | Active, NR | Nivolumab +/- ipilimumab | Pts w/ CR (UTAI 44 mo) | DoR, CBR, PFS and OS (6 mo) | N/A | CR: initial single therapy (IST) = 2/42 (4.8%) vs. initial dual therapy (IDT) = 6/42 (14.3%) DoR: IST: 7.4 mo (3.2 to 11.6), IDT: 6.2 mo (1.4 to 14.1) 6 mo CBR in IST: 10 pt (3 to 22), IDT: 12 pt (6 to 28) PFS: IST = 1.7 mo (1.4 to 4.3), IDT = 4.1 mo (2.6 to 4.7); OMS: IST = 10.7 mo, IDT = 14.3 mo |
| Tawbi et al. [32] and Keung et al. [33] (NCT02301039) | Non-randomized cohort | II | Active, NR | Pembrolizumab | ORR (8 wks UTAI 5 yrs) | AE, PFS, ir-RC, OS (UTAI 5 yrs) | 6 | Bone sarcoma arm: ORR: 5% (5.5-25.3) 9/42 with AE; PFS in 8 (7 to 9); ir-RC: PR = 2 and CR = 0; OS: 52 (40 to 72) |
| Juergens et al. [37] (NCT00560235) | Non-randomized cohort | I/II | Complete | Figitumumab | ORR | PFS, OS, ADA titer | 107 | ORR = 14.2% (8.1 to 22.3), 25 = SD PFS = 1.9 mo (1.8 to 2.1); OS = 8.9 mo (7.2 to 10.8) = modest activity as monotherapy. Strong association b/w pretreatment serum IGF-1 and survival benefit identified (median 10.4 mo = p <0.001) |
| Schwartz et al. [38] (NCT01016015) | Non-randomized cohort | II | Complete | Cixutumumab + temsirolimus | RECIST 1.1 PFS (12 wks) | — | 4 | PFS = PR = 4, SD = 98, PD = 56 |
| Asmane et al. [39] (NCT00668148) | Non-randomized cohort | II | Complete | Cixutumumab | RECIST 1.1 PFS (12 wks) | PFS (UTAI 105.4 wks), ORR, OS, CBR | N/A youngest pt: 17 y/o | PFS = 27.3% (8.5 to 50.4), total = 31.9% (23.0 to 41.0); PFS (105.4 wk) = 6.4% (5.1 to 12.1), total = 6.7% (6.0 to 11.0); ORR: 5.6% (0.1 to 27.3), total = 1.8% (0.2 to 6.4); OS: 24.1 wks (12.6 to 37.6), total = 38.4 wks (31.1 to 52.0); CBR: 33.3% (13.3 to 59.0), total = 41.4% (32.2 to 51.2) |
| Turner et al. [40] (NCT00667342) | Non-randomized, parallel | II | Complete | Bevacizumab + cis + dox + MAP/bevacizumab + MAP + ifos + etoposide | Pts w/ DLT 3-yr EFS | Stratum HR, 2-yr EFS, 2-yr OS | 43 | Bevacizumab dosage scaling using ideal body weight would provide an improved dosing approach in children by minimizing PK variability and reducing likelihood of major wound healing complications. (p <0.05) 3-year EFS in LR: 0.575 (0.402 to 0.747), HR at wk 10: 24/42 (LRD + MD) w/ 5-50% tumor (grade IIB) seen, 11/42 w/ <5% tumor (grade III) seen, 2-yr EFS = 0.617 (0.470 to 0.764), 2-yr OS = 0.880 (0.782 to 0.978) |
| Children’s Oncology Group (NCT02470091) | Non-randomized cohort | I/II | Active, NR | Denosumab | DC (4 and 12 mo) | PK | 42 | Cohort I: measurable disease (RECIST 1.1) vs. cohort II: complete resection of all sites of MD w/i 30 d before enrolment at 12 mo, outcome in cohort II > cohort I — 6 patients w/ response (0.667 (0.195 to 0.904) |
| NCI (NCT02484443) | Non-randomized cohort | II | Active, NR | Dinutuximab + sargramostim (GM-CSF) | DC (12 mo) | t1/2 | 33 | DC: 11/39 (28.2%) t1/2α = 0.8 (0.566 to 1.89), t1/2β = 7.5 (7.25 to 7.86), Cmax = 18.4 (7.58 to 26.3) |
| NCI (NCT00831844) | Non-randomized cohort | II | Complete | Cixutumumab (anti-IGF-1R) | DR | — | 8 | DR > 24 wks = 0/9 pts |
| Kopp et al. [41] (NCT02487979) | Non-randomized cohort | I | Active, NR | Glembatumumab (CDX-011 against GPNMB) | Pts w/ DLT, 3-yr EFS | HR | Median age: 20.09 | DC in 3/22 (13.6%), 1/22 = PR, 2/22 = SD (extent of DC was not met for stage II), glycoprotein NMB (GPNMB) exp.: 13/19 with 3+ staining (strong) = no relation to Exp./response |
| Merchant et al. [42] (NCT00428272) | Non-randomized, parallel | I | Terminated | Lexatumumab (HGS-ERT2) +/- ifn-γ | MTD/DLTs (6 mo), PK (2 yr) | TRR, Exp. of pro-apoptotic proteins, ADA titer | N/A | TRR (3-24 cycles): SD = 5, CR/PR = 0, evidence of anti-tumor activity: 1 pt with recurrent progressive OS experienced resolution of clinical symptoms, PET activity and SD > 1 yr |