Studies of nitrogen mustards combined with small-molecule targeted agents and monoclonal antibodies
| Phase | Malignancy | Combination | Activity | Reference |
|---|---|---|---|---|
| 1b/2 | Breast | CY 600 mg/m2 i.v.; doxorubicin 60 mg/m2 i.v. every 3 weeks; sunitinib 12.5 mg daily for 1 week prior to each cycle (neoadjuvant) | OR 91% | Wong et al., 2016 |
| 2 | Breast | CY 50 mg oral daily; letrozole 2.5 mg daily; sorafenib 400 mg 2× daily every fifth day (neoadjuvant) | OR 100% | Bazzola et al., 2015a |
| 2 | Solid tumors | CY 50 mg/m2 oral daily; sorafenib 90 mg/m2 2× daily; bevacizumab 15 mg/kg every 3 weeks (children and young adults) | PR 14% | Federico et al., 2020b |
| 2 | Neuroendocrine | CY fixed dose 50 mg oral daily; sorafenib commencing at 200 mg 2× daily and increased | OR 5.3% | Quintela-Fandino et al., 2013 |
| 1 | Ovary | CY 50 mg oral daily; pazopanib; MTD pazopanib 600 mg daily | OR 50% | Dinkic et al., 2017 |
| 1 | Solid tumors | CY oral; imatinib; RP2D CY 50 mg 2× daily, imatinib 800 mg daily | OR 0% | Adenis et al., 2013a |
| 1 | Colorectal | CY 50 mg oral daily; imatinib 400 mg daily; bevacizumab 5 mg/kg every other week | CBR 20% | Kelley et al., 2013a |
| 1 | Breast | CY 50 mg oral daily; methotrexate 2.5 mg oral 2× daily on days 1 and 2 of each week; vandetanib; MTD of vandetanib 200 mg daily | CBR 25% | Mayer et al., 2012 |
| 1 | Breast | CY oral; veliparib; RP2D CY 125 mg daily, veliparib 200 mg 2× daily every 3 weeks | CBR 19% | Anampa et al., 2018 |
| 1 | Breast (B) Ovary (O) | CY 50 mg oral daily days 1 to 5 weekly; olaparib; RP2D of olaparib 300 mg 2× daily | OR 0% B; OR 48% O | Lee et al., 2019 |
| 1 | Renal cell | CY oral; fixed dose of everolimus 10 mg daily; optimum Treg-depleting CY dose 50 mg daily continuously | PR 5% | Huijts et al., 2019 |
| 2 | Melanoma | CY 300 mg/m2 oral on day 1 and ipilimumab 10 mg/kg on day 3 for 4 cycles every 3 weeks, followed by ipilimumab 3 cycles every 12 weeks | OR 0% | Pavlick et al., 2014 |
| 2 | STS | CY 50 mg oral 2× daily, 1 week on, 1 week off; pembrolizumab 200 mg every 3 weeks | OR 2% | Toulmonde et al., 2018 |
| 2 | Osteosarcoma | CY 50 mg oral 2× daily, 1 week on, 1 week off; pembrolizumab 200 mg on day 8 every 3 weeks | PR 6.7% | Le Cesne et al., 2019 |
| 1 | Solid tumors | CY 200 mg/m2 i.v. prior to cemiplimab 3 mg/kg every 2 weeks | SD 50% | Papadopoulos et al., 2020 |
| 1 | Solid tumors | Evofosfamide i.v. on days 1 and 8 of cycles 1 and 2; ipilimumab 3 mg/kg on day 8 of cycles 1 to 4; cycles every 3 weeks for 4 cycles; RP2D of evofosfamide 560 mg/m2 | PR 16.7%; SD 66.7% | Hegde et al., 2021a |
| 1 | Solid tumors | IF i.v. 9 g/m2 for 3 days or 6 g/m2 for 5 days every 3 weeks; sunitinib; MTD of sunitinib 12.5 mg daily | PR 9.4% | Hamberg et al., 2010a |
| 2 | Sarcoma | IF i.v. 6 g/m2; sorafenib 400 mg 2× daily | PR 17% | García Del Muro et al., 2018c |
| 1 | Solid tumors | IF i.v. continuous infusion over 3 days every 3 weeks; pazopanib; RP2D of IF 9 g/m2; RP2D of pazopanib 800 mg daily | PR 22% | Hamberg et al., 2014a |
| 1 | CLL | Chlorambucil 8 mg/m2 oral daily days 3 to 7; imatinib daily for 10 days; cycles every 28 days; RP2D of imatinib 400 mg | OR 45% | Hebb et al., 2011 |
| 1 | Melanoma | ILI-M 7.5 or 10 mg/l; sorafenib daily for 7 days before and after ILI-M; MTD of sorafenib 400 mg daily | OR 35% | Beasley et al., 2012a |
| 2 | Melanoma | ILI-M 7.5 to 10 mg/l and ILI actinomycin D 500 μg; ipilimumab 10 mg/kg | OR 85% | Ariyan et al., 2018 |
| 2 | Melanoma | ILI-M 7.5 or 10 mg/l on day 1; ADH-1 4000 mg i.v. on days 1 and 8 | OR 60% | Beasley et al., 2011a |
CY, cyclophosphamide; IF, ifosfamide; M, melphalan; RP2D, recommended phase 2 dose.
aNitrogen mustard pharmacokinetic data available
bPhase 1: Navid et al., 2013a
cPhase 1: Martín-Liberal et al., 2014a