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. 2022 Sep 22;32(11):1377–1386. doi: 10.1136/ijgc-2022-003585

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

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.