The Nitrogen Mustards

Martin S. Highley; Bart Landuyt; Hans Prenen; Peter G. Harper; Ernst A. De Bruijn

doi:10.1124/pharmrev.120.000121

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Fig. 1
The structures of the nitrogen mustards.
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Fig. 2
The clinical doses of cyclophosphamide and their predominant therapeutic cellular targets.
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Fig. 3
The metabolism of cyclophosphamide.

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TABLE 1

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., 2015^a
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., 2020^b
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., 2013^a
1	Colorectal	CY 50 mg oral daily; imatinib 400 mg daily; bevacizumab 5 mg/kg every other week	CBR 20%	Kelley et al., 2013^a
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., 2021^a
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., 2010^a
2	Sarcoma	IF i.v. 6 g/m²; sorafenib 400 mg 2× daily	PR 17%	García Del Muro et al., 2018^c
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., 2014^a
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., 2012^a
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., 2011^a

CY, cyclophosphamide; IF, ifosfamide; M, melphalan; RP2D, recommended phase 2 dose.
^aNitrogen mustard pharmacokinetic data available
^bPhase 1: Navid et al., 2013^a
^cPhase 1: Martín-Liberal et al., 2014^a