Table 3

List of potential drug candidates in cervical cancer

Drug characteristics			Relevant data on cervical cancer					Potential setting in cervical cancer
Drug	Main approved indications	Off-patent	Mechanism of action(s) in cervical cancer	Candidate biomarker(s)	Registered cervical cancer trials and main results of human data	Role(s)*		First line, with chemoradiotherapy First line, adjuvant First line, maintenance Recurrent/metastatic
Drug	Main approved indications	Off-patent	Mechanism of action(s) in cervical cancer	Candidate biomarker(s)		Radio-sensitizer	Immune-modulator
Arsenic trioxide	Acute promyelocytic leukemia	Yes	Prevention of migration through CXCR4 inhibition, direct cytotoxicity, radiosensitization	No prominent biomarker identified	NCT00005999: completed trial with single agent in recurrent setting. No results available. ChiCTR1900023822: ongoing trial as neoadjuvant treatment with carboplatin. No results available	Yes	No	First line, with chemoradiotherapy Recurrent/metastatic
Artesunate	Malaria	Yes	Direct cytotoxicity, radiosensitization, enhancement of TRAIL-induced cell death, inhibition of HOTAIR expression	No prominent biomarker identified	None	Yes	No	First line, with chemoradiotherapy
Atovaquone	Toxoplasmosis, Pneumocystis carinii pneumonia	Yes	Inhibition of mitochondrial respiratory chain complex III	Hypoxia biomarker(s)	None	No	No	Recurrent/metastatic
Bortezomib	Multiple myeloma, mantle cell lymphoma	Yes	Inhibition of NF-κB, proteasomal activity and hypoxia-related HIF-1α expression, enhancement of the apoptosis-inducing TRAIL receptor antibody efficacy and induction of apoptosis	No prominent biomarker identified	NCT00106262: terminated trial because of lack of accrual. NCT00329589: completed trial in combination with chemoradiotherapy. No results available	Yes	Yes	First line, with chemoradiotherapy Recurrent/metastatic
Cetuximab	Squamous cell head and neck cancer, colorectal cancer	Yes	Inhibition of EGFR, radiosensitization	EGFR protein expression	NCT00957411, NCT00101192, NCT00499031, NCT00104910, NCT00518193, NCT00997009: 6 completed or terminated trials with results available, although always showing limited or no benefit. 2006-003759-19 and NCT00292955: trials with unknown status or prematurely terminated without any results available	Yes	No	First line, with chemoradiotherapy Recurrent/metastatic
Chlorpromazine	Psychotic disorders, nausea and vomiting, anxiety, hiccups	Yes	Radiosensitization	No prominent biomarker identified	No registered trial, but publication of human data showing a 53% complete response in combination with radiotherapy compared with 39% complete response with radiotherapy alone29	Yes	No	First line, with chemoradiotherapy
Cidofovir	CMV-retinitis in AIDS	Yes	Decrease E6 and E7 expression, DNA damage by incorporation into DNA, radiosensitization	No prominent biomarker identified	NCT02515877 and NCT00811408: Prematurely discontinued trials showing a complete response in 8 out of 9 patients with 2 year and 4 year overall survival rates estimated at 93% and 84%, respectively, and 2 year progression-free survival is 76%	Yes	No	First line, with chemoradiotherapy
Decitabine	Acute myeloid leukemia	Yes	Inhibition of the nucleic acid synthesis	No prominent biomarker identified	No registered trial, but publication of phase II study in recurrent and/or metastatic patients showing an 8/21 partial response and 5/21 stable disease in combination with cisplatin. Median progression-free interval is 16 weeks and median survival is 19 weeks30	No	No	Recurrent/metastatic
Deferoxamine	Acute iron intoxication, chronic iron overload	Yes	Increase hCtr1 and TfR1 expression through upregulation of Sp1 and induce TfR1 expression through the Sp1–NF-κB p65-dependent pathway, platinum sensitization	No prominent biomarker identified	None	No	No	First line, with chemoradiotherapy Recurrent/metastatic
Doxycycline	Respiratory, urinary tract and ophthalmic infection	Yes	Direct cytotoxic, inhibition of MMP2 and MMP9 expression, induction of apoptosis and inhibition of EMT and migration	No prominent biomarker identified	NCT02874430: ongoing phase II trial. No results available	No	No	First line, with chemoradiotherapy Recurrent/metastatic
Erlotinib	Non-small cell lung cancer, pancreatic cancer	Yes	Inhibition of EGFR	EGFR protein expression	NCT00031993: completed trial showing a 94% complete response in combination with chemoradiotherapy. The 2 year and 3 year cumulative overall- and progression-free survival rates were 92% and 81%, and 80% and 74%, respectively. As single agent erlotinib seems to be inactive. NCT00428194: withdrawn trial because of lack of accrual	No	No	First line, with chemoradiotherapy Recurrent/metastatic
Everolimus	Neuroendocrine tumors, renal cell carcinoma, HR+ breast cancer	Yes	Radiosensitization, induction of apoptosis by targeting PI3K/AKT/mTOR pathways, inhibition of proliferation by inactivation of the HPV E7 oncoprotein	Alterations in the PI3k/AKT/mTOR pathway	NCT00428194: completed trial determining 5 mg/day as maximum tolerated dose of everolimus in combination with cisplatin and radiotherapy in locally advanced patients. NCT00967928: withdrawn trial because of lack of enrollment	Yes	No	First line, with chemoradiotherapy
Fulvestrant	HR+ breast cancer	Yes	Inhibition of aromatase	ER-α expression in stromal cells	NCT04579380: ongoing phase II trial. No results available	No	No	First line, with chemoradiotherapy Recurrent/metastatic
Gefitinib	Non-small cell lung cancer	Yes	Inhibition of EGFR	EGFR protein expression	No results available for the registered trials (CTRI/2017/12/010726 and NCT00049556), but publication of human data resulting in a median disease-free interval of 15 months in advanced or metastatic patients after recurrence. The median progression-free survival and median overall survival were 4 months and 5 months, respectively.31 Neoadjuvant chemotherapy, chemoradiation, followed by gefitinib maintenance in patients with locally advanced cervical cancer showed a 3 year overall survival of 70%, and 3 year progression-free survival of 51%32	No	No	First line, maintenance Recurrent/metastatic
Hydralazine and valproate	Hypertension (hydralazine), epilepsy and bipolar disorder (valproate)	Yes	Inhibition of HDAC and DNA methyltransferase, unmasking of chronic viral infection (valproate)	No prominent biomarker identified	NCT00532818 and NCT00404326: 2 completed trials on the combination showing improved progression-free survival in combination with topotecan/cisplatin over topotecan/cisplatin alone, also safety data with chemoradiotherapy	Yes	Yes	First line, with chemoradiotherapy First line, adjuvant Recurrent/metastatic
Interferon α-2b	Hairy cell leukemia, chronic hepatitis B and C	No	Immunomodulation	No prominent biomarker identified	NCT00138151: terminated trial showing that IFN α-2b in combination with paclitaxel and 13-cis retinoic acid is safe. Mixed results in other trials and limited role with radiotherapy, though results of one trial support testing IFN α-2b given before radiotherapy	Yes	Yes	First line, with chemoradiotherapy
Ipilimumab	Melanoma, renal cell carcinoma, non-small cell lung cancer	No	Inhibition of CTLA4 on T-cells	No prominent biomarker identified	NCT01711515: completed trial showing safety and preliminary efficacy as adjuvant therapy after chemoradiotherapy. NCT01693783 (phase II), NCT04256213, NCT03508570 (phase I), NCT03755739 (phase II-III), NCT03452332 (phase I): 5 trials ongoing. No results available	No	Yes	First line, adjuvant Recurrent/metastatic
Lovastatin	Hypercholesterolemia, coronary heart disease	Yes	Inhibition of the mevalonate pathway	HMG-CoA reductase expression	No registered trial, but publication of human data defining recommended phase II dose and showing disease stabilization in 3/12 recurrent or metastatic cervical cancer patients33	Yes	No	First line, with chemoradiotherapy Recurrent/metastatic
Lurbinectedin	Squamous cell lung cancer	No	DNA alkylation, elimination of cancer stem cells, inhibition of myeloid-derived suppressor cells	No prominent biomarker identified	None	No	Yes	First line, adjuvant Recurrent/metastatic
Melatonin	Primary insomnia	Yes	Production of reactive oxygen species in cancer cells (pro-oxidant)	No prominent biomarker identified	None	Yes	No	First line, with chemoradiotherapy Recurrent/metastatic
Metformin	Diabetes type 2	Yes	Inhibition of mitochondrial respiratory complex I leading to decreased tumor hypoxia and to radiosensitization	Hypoxia biomarker(s)	NCT02874430, NCT04275713 and NCT02394652: 3 phase II trials ongoing. No results available.	Yes	No	First line, with chemoradiotherapy Recurrent/metastatic
Mifepristone	Abortion, Cushing syndrome	Yes	Enhancement of chemoradiotherapy, prevention of cell migration	No prominent biomarker identified	None	Yes	No	First line, with chemoradiotherapy First line, adjuvant
Nelfinavir	HIV	Yes	Inhibition of PI3K-Akt and induction of endoplasmic reticulum stress	No prominent biomarker identified	NCT03256916: ongoing phase III trial. No results available. NCT01485731 and NCT02363829: completed trials showing safety and tolerability of 1250 mg twice daily added to cisplatin-based chemoradiotherapy in patients with locally advanced cervical cancer	Yes	No	First line, with chemoradiotherapy
Niclosamide	Tapeworm infections	Yes	Inhibition of mitochondrial respiratory complex I and mTOR	No prominent biomarker identified	None	Yes	No	First line, with chemoradiotherapy Recurrent/metastatic
Nicotinamide	Pellagra	Yes	Multiple, including radiosensitization (with carbogen in particular) through ROS generation and decreased hypoxia	Hypoxia biomarker(s)	No registered trial, but publication of human data showing safety with chemoradiotherapy and carbogen34	Yes	Yes	First line, with chemoradiotherapy Recurrent/metastatic
Niraparib	Ovarian cancer	No	Inhibition of PARP, radiosensitization and platinum sensitization	No prominent biomarker identified	NCT04395612, NCT04068753, NCT03644342 and EudraCT2019-001226-10: 4 ongoing phase II trials. No results available	Yes	No	First line, with chemoradiotherapy First line, adjuvant Maintenance
Olaparib	Ovarian cancer	No	Inhibition of PARP, radiosensitization and platinum sensitization	Poly-ADP-ribosylation level	NCT04641728, NCT04487587, NCT04483544, NCT03162627, jRCT2031210096 and NCT01237067: 4 ongoing phase II, 1 ongoing phase I, and 1 completed trials. No results available	Yes	No	First line, with chemoradiotherapy First line, adjuvant First line, maintenance
Pazopanib	Renal cell carcinoma, soft tissue sarcoma	No	Inhibition of VEGF and PDGF receptors (anti-angiogenesis)	No prominent biomarker identified	NCT00430781 and NCT00561795: 2 completed trials showing an overall response rate of 9% as single agent and increased progression-free survival and overall survival compared with lapatinib. NCT02348398: withdrawn trial. No results available	No	No	First line, adjuvant Recurrent/metastatic
Plerixafor	Mobilization of hematopoietic stem cells	No	Prevention of chemoradiotherapy-induced CXCL12/CXCR4 signaling resulting in intratumoral accumulation of myeloid cells	No prominent biomarker identified	None	Yes	Yes	First line, with chemoradiotherapy
Porfimer	Esophageal cancer	Yes	Radiosensitization by enhanced production of reactive oxygen species	No prominent biomarker identified	No registered trial, but case report showing a complete response35	Yes	No	Recurrent/metastatic
Ribavirin	Hepatitis C	Yes	Inhibition of eIF4E to overcome chemotherapy resistance	Eukaryotic translation initiation factor 4E expression	None	Yes	No	First line, with chemoradiotherapy Recurrent/metastatic
Ribociclib	Breast cancer	No	Inhibition of cyclin-dependent kinase 4 and 6	No prominent biomarker identified	None	No	No	Recurrent/metastatic
Rucaparib	Ovarian cancer	No	Inhibition of PARP, radiosensitization and platinum sensitization	No prominent biomarker identified	NCT03476798, NCT04171700 and NCT03795272: 2 ongoing phase II trials and one withdrawn trial. No results available	Yes	No	First line, with chemoradiotherapy First line, adjuvant First line, maintenance
Ruxolitinib	Myeloproliferative neoplasms	No	Restoration of CADM1, radiosensitization	Loss of CADM1 expression	None	Yes	No	First line, with chemoradiotherapy Recurrent/metastatic
Sacituzumab govitecan	Recurrent triple negative breast cancer	No	Inhibition of DNA topoisomerase I following cell internalization after binding to Trop-2, antibody-dependent cellular cytotoxicity	Trop-2 expression	None	No	No	Recurrent/metastatic
Sonidegib	Basal cell carcinoma	No	Inhibition of hedgehog pathway activation, radiosensitization	Hedgehog pathway activation	None	Yes	No	First line, with chemoradiotherapy First line, adjuvant
Zoledronic acid	Osteoporosis, skeletal related events	Yes	Direct cytotoxicity, inhibition of MMP-9 (indirect anti-angiogenesis)	No prominent biomarker identified	NCT00966992: terminated trial. No results available	Yes	No	First line, with chemoradiotherapy Recurrent/metastatic

*‘No’ means there is either no evidence it can play a role or there is evidence it does not play a role.
AKT, protein kinase B; CADM1, cell adhesion molecule 1; CMV, cytomegalovirus; CTL4, cytotoxic T-lymphocyte antigen-4; CXCL12, C-X-C chemokine ligand 12; CXCR4, C-X-C chemokine receptor type 4; EGFR, epidermal growth factor receptor; eIF4E, eukaryotic translation initiation factor 4E; EMT, epithelial-mesenchymal transition; ERα, estrogen receptor subtype alpha; hCtr1, human copper transporter 1; HDAC, histone deacetylase; HIF-1α, hypoxia-inducible factor-1 alpha; HMG-CoA, 3-hydroxy-3-methylglutaryl coenzyme A; HOTAIR, HOX transcript antisense RNA; HPV, human papillomavirus; HR, hormone receptor; IFN, interferon; MMP2, matrix metalloproteinase-2; MMP9, matrix metalloproteinase-9; mTOR, mammalian target of rapamycin; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; PARP, poly adenosine diphosphate-ribose polymerase; PDGF, platelet-derived growth factor; PI3K, phosphatidylinositol 3-kinase; ROS, reactive oxygen species; TfR1, transferrin receptor protein 1; TRAIL, TNF-related apoptosis-inducing ligand; Trop-2, tumour-associated calcium signal transducer 2; VEGF, vascular endothelial growth factor.